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Tian Y, Zong Y, Pang Y, Zheng Z, Ma Y, Zhang C, Gao J. Platelets and diseases: signal transduction and advances in targeted therapy. Signal Transduct Target Ther 2025; 10:159. [PMID: 40374650 DOI: 10.1038/s41392-025-02198-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 12/18/2024] [Accepted: 02/24/2025] [Indexed: 05/17/2025] Open
Abstract
Platelets are essential anucleate blood cells that play pivotal roles in hemostasis, tissue repair, and immune modulation. Originating from megakaryocytes in the bone marrow, platelets are small in size but possess a highly specialized structure that enables them to execute a wide range of physiological functions. The platelet cytoplasm is enriched with functional proteins, organelles, and granules that facilitate their activation and participation in tissue repair processes. Platelet membranes are densely populated with a variety of receptors, which, upon activation, initiate complex intracellular signaling cascades. These signaling pathways govern platelet activation, aggregation, and the release of bioactive molecules, including growth factors, cytokines, and chemokines. Through these mechanisms, platelets are integral to critical physiological processes such as thrombosis, wound healing, and immune surveillance. However, dysregulated platelet function can contribute to pathological conditions, including cancer metastasis, atherosclerosis, and chronic inflammation. Due to their central involvement in both normal physiology and disease, platelets have become prominent targets for therapeutic intervention. Current treatments primarily aim to modulate platelet signaling to prevent thrombosis in cardiovascular diseases or to reduce excessive platelet aggregation in other pathological conditions. Antiplatelet therapies are widely employed in clinical practice to mitigate clot formation in high-risk patients. As platelet biology continues to evolve, emerging therapeutic strategies focus on refining platelet modulation to enhance clinical outcomes and prevent complications associated with platelet dysfunction. This review explores the structure, signaling pathways, biological functions, and therapeutic potential of platelets, highlighting their roles in both physiological and pathological contexts.
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Affiliation(s)
- Yuchen Tian
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yao Zong
- Centre for Orthopaedic Research, Medical School, The University of Western Australia, Nedlands, Western Australia, Australia
| | - Yidan Pang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhikai Zheng
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yiyang Ma
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Changqing Zhang
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Junjie Gao
- Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute of Microsurgery on Extremities, and Department of Orthopedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Lazar S, Wurtzel JGT, Askari S, Cooper M, Zhao X, Ma P, Goldfinger LE. Argonaute2 modulates megakaryocyte development and sex-specific control of platelet protein expression and reactivity. Sci Rep 2025; 15:3590. [PMID: 39875491 PMCID: PMC11775343 DOI: 10.1038/s41598-025-88106-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 01/24/2025] [Indexed: 01/30/2025] Open
Abstract
Platelets are enriched in miRNAs and harbor Ago2 as the principal RNA silencing Argonaute. However, roles in thrombopoiesis and platelet function remain poorly understood. We generated megakaryocyte/platelet-specific Ago2-deleted (Ago2 KO) mice and assessed proteomic and functional effects. We predicted platelet hyperreactivity with Ago2 deletion due to large-scale upregulated protein expression. Platelet counts were normal. Mean volumes were increased, associated with larger, though fewer megakaryocytes. Ago2-deleted platelets from male mice showed hyperreactivity to thromboxane but not to other agonists compared to controls, whereas Ago2-deleted platelets from female mice showed normal reactivity. Ago2 KO mice displayed normal hemostasis and clot dynamics. Proteomes of Ago2-deleted and wild type platelets were mostly similar. However, Ago1 - undetectable in wild type platelets - was upregulated in Ago2-deleted platelets in both males and females, confirmed by immunoblotting. Female Ago2-deleted platelets selectively showed downregulation of a protein cohort established in breast cancer cells to be transcriptionally regulated by estrogen receptor-beta coupled to Ago2, whereas male Ago2-deleted platelets did not. Thus, Ago2 is important for platelet development and function, putatively partially rescued by upregulation of Ago1. Platelet reactivity controlled by Ago2 reflects sex-specific regulation of gene expression potentially at both transcriptional and translational levels in megakaryocytes and platelets.
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Affiliation(s)
- Sophia Lazar
- Department of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Jeremy G T Wurtzel
- Department of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Shayan Askari
- Department of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Matthew Cooper
- Department of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Xuefei Zhao
- Department of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Peisong Ma
- Department of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA
| | - Lawrence E Goldfinger
- Department of Medicine, Division of Hematology, Cardeza Foundation for Hematologic Research, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA.
- Cardeza Foundation for Hematologic Research, Thomas Jefferson University, 1020 Locust Street, Philadelphia, PA, 19107, USA.
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Yang H, Gao J, Ruan Y, Chen Z, Fang R, Zhang L, Wang Z, Yi T, Zhang Q, Luo Y, Chen L, Wu X. Efficacy and safety of avatrombopag in the treatment of chemotherapy-induced thrombocytopenia in children with acute lymphoblastic leukemia: a single-center retrospective study. Ther Adv Hematol 2024; 15:20406207241304300. [PMID: 39649520 PMCID: PMC11622298 DOI: 10.1177/20406207241304300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 11/13/2024] [Indexed: 12/11/2024] Open
Abstract
Background Chemotherapy-induced thrombocytopenia (CIT) commonly exacerbates the difficulty of cancer treatment, increasing bleeding risks and potentially reducing chemotherapy dosage, ultimately impacting its efficacy. However, there are limited studies about avatrombopag application in acute lymphoblastic leukemia (ALL) CIT. Objectives We aimed to evaluate the efficacy and safety of avatrombopag in treating CIT patients diagnosed with ALL. Design This retrospective study, using propensity score matching, included 42 pairs of cases treated with and without avatrombopag (CAT: 54 cases, CAT+: 30 cases). Methods Data of CIT-ALL children were retrospectively collected. The primary endpoint was platelet count (PC) response rate on day 10 ± 2 (defined as an increase of PC to ⩾75 × 109/L with the exclusion of platelet transfusion). Secondary efficacy endpoints, safety endpoints, and factors that predict PC response were also analyzed. Results In the avatrombopag group, the PC response rate was prominently higher on day 10 ± 2 (89.1%) versus the control group (56.4%, p = 0.005). On day 10 ± 2, the difference in median PC change from baseline was predominantly distinct in the avatrombopag group compared to the control group (p = 0.001). In the avatrombopag group, platelet recovery to ⩾25 and ⩾50 × 109/L was faster (p = 0.001, p = 0.002), and quicker platelet reaching ⩾75 × 109/L and ⩾100 × 109/L was achieved (p = 0.023, p = 0.011). The avatrombopag group not only increased the nadir PC (p = 0.009) but also reduced the total platelet transfusion compared to the control group (p = 0.047). Only one case (2.4%) experienced bleeding events after medication. Nine cases of secondary thrombocythemia were noted without other adverse events. There was no difference in event-free survival between the two groups (p = 0.648). Drug administration was prediction factor for PC response. Conclusion Avatrombopag is a potentially safe and effective treatment option for CIT in pediatric ALL.
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Affiliation(s)
- Huiyan Yang
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jingyu Gao
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yongsheng Ruan
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhaokun Chen
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruihan Fang
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Zhang
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhibiao Wang
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Tiantian Yi
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qian Zhang
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Luo
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Libai Chen
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong 510515, China
| | - Xuedong Wu
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, Guangdong 510515, China
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Antkowiak A, Batut J, Gaits-Iacovoni F. Linear podosomes display low Cdc42 activity for proplatelet elongation by megakaryocytes. Biochem Biophys Res Commun 2024; 734:150654. [PMID: 39241623 DOI: 10.1016/j.bbrc.2024.150654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 08/26/2024] [Accepted: 09/02/2024] [Indexed: 09/09/2024]
Abstract
Blood platelets result from differentiation of megakaryocytes (MKs) into the bone marrow. It culminates with the extension of proplatelets (PPT) through medullar sinusoids and release of platelets in the blood stream. Those processes are regulated by contact with the microenvironment mediated by podosomes. We previously demonstrated that contact of megakaryocytes to Collagen I fibers initiated the formation of linear podosomes required for proplatelets extension and release of mature platelets. MKs linear podosomes have the particularity of displaying mechanical pulling activity but, unlike other linear podosomes, they lack the ability of digesting the extracellular matrix (ECM), as we recently demonstrated. The Cdc42 small GTPase is required for actomyosin-dependent maturation of the demarcation membrane system (DMS), a membrane reservoir for PPT and platelets components. Cdc42 is a known protein of the podosomes core, and is instrumental to accurate platelets release into the sinusoids. Indeed, FRET analysis showed that Cdc42 activity was very high and central to DMS formation. Unexpectedly, even though we found the protein in linear podosomes, almost undetectable Cdc42 activity was detected in those structures. This observation suggests that Cdc42 could also act as scaffold to assemble proteins required for PPT formation/elongation along Collagen I fibers in MKs. Eventually, we demonstrated that linear podosomes appear as points of contact between Collagen I fibers and DMS membranes, to mechanically extend PPT along Collagen bundles, independently of Cdc42 activity.
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Affiliation(s)
- Adrien Antkowiak
- Univ. Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, 38000, Grenoble, France
| | - Julie Batut
- Unité de Biologie Moléculaire, Cellulaire et du Développement (MCD, UMR 5077), Centre de Biologie Intégrative (CBI, FR 3743), Université de Toulouse, CNRS, UPS, 118 Route de Narbonne F-31062, Toulouse, France
| | - Frédérique Gaits-Iacovoni
- Unité de Biologie Moléculaire, Cellulaire et du Développement (MCD, UMR 5077), Centre de Biologie Intégrative (CBI, FR 3743), Université de Toulouse, CNRS, UPS, 118 Route de Narbonne F-31062, Toulouse, France.
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Walther K, Gröger S, Vogler JAH, Wöstmann B, Meyle J. Inflammation indices in association with periodontitis and cancer. Periodontol 2000 2024; 96:281-315. [PMID: 39317462 PMCID: PMC11579835 DOI: 10.1111/prd.12612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 08/18/2024] [Accepted: 08/20/2024] [Indexed: 09/26/2024]
Abstract
Inflammation is a complex physiological process that plays a pivotal role in many if not all pathological conditions, including infectious as well as inflammatory diseases, like periodontitis and autoimmune disorders. Inflammatory response to periodontal biofilms and tissue destruction in periodontitis is associated with the release of inflammatory mediators. Chronic inflammation can promote the development of cancer. Persistence of inflammatory mediators plays a crucial role in this process. Quantification and monitoring of the severity of inflammation in relation to cancer is essential. Periodontitis is mainly quantified based on the severity and extent of attachment loss and/or pocket probing depth, in addition with bleeding on probing. In recent years, studies started to investigate inflammation indices in association with periodontal diseases. To date, only few reviews have been published focusing on the relationship between blood cell count, inflammation indices, and periodontitis. This review presents a comprehensive overview of different systemic inflammation indices, their methods of measurement, and the clinical applications in relation to periodontitis and cancer. This review outlines the physiological basis of inflammation and the underlying cellular and molecular mechanisms of the parameters described. Key inflammation indices are commonly utilized in periodontology such as the neutrophil to lymphocyte ratio. Inflammation indices like the platelet to lymphocyte ratio, platelet distribution width, plateletcrit, red blood cell distribution width, lymphocyte to monocyte ratio, delta neutrophil index, and the systemic immune inflammation index are also used in hospital settings and will be discussed. The clinical roles and limitations, relationship to systemic diseases as well as their association to periodontitis and treatment response are described.
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Affiliation(s)
- Kay‐Arne Walther
- Department of Periodontology, Dental ClinicJustus Liebig University of GiessenGiessenGermany
- Department of Prosthodontics, Dental ClinicJustus Liebig University of GiessenGiessenGermany
| | - Sabine Gröger
- Department of Periodontology, Dental ClinicJustus Liebig University of GiessenGiessenGermany
- Department of Orthodontics, Dental ClinicJustus Liebig University of GiessenGiessenGermany
| | | | - Bernd Wöstmann
- Department of Periodontology, Dental ClinicJustus Liebig University of GiessenGiessenGermany
- Department of Prosthodontics, Dental ClinicJustus Liebig University of GiessenGiessenGermany
| | - Jörg Meyle
- Department of Periodontology, Dental ClinicJustus Liebig University of GiessenGiessenGermany
- Department of Periodontology, Dental ClinicUniversity of BernBernSwitzerland
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Li J, Wang W, Jiang K, Cui J, Wang C, Liang T, Wang Y, Liu S, Zhou W. Risk Factors of Chemotherapy-Induced Thrombocytopenia After Oxaliplatin-Containing Chemotherapy for Gastrointestinal Malignancies. J Gastrointest Cancer 2024; 55:1144-1153. [PMID: 38713434 PMCID: PMC11347477 DOI: 10.1007/s12029-024-01059-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/20/2024] [Indexed: 05/08/2024]
Abstract
PURPOSE Thrombocytopenia is among the most common chemotherapy-related hematologic toxicities. We aim to determine the predictors of oxaliplatin chemotherapy-induced thrombocytopenia in patients with gastrointestinal tumors to guide the clinic. METHODS Clinical data of 750 patients with a malignant gastrointestinal tumor were included as the primary cohort. Basic clinical data, serological indices, and anthropometric indices of these patients were collected. According to the presence or absence of CIT, univariate analysis was performed to identify significant factors for multivariate analysis. In R language software, nomogram was constructed based on the results of multi-factor analysis, and the calibration curve and ROC curve were drawn. RESULTS Univariate analysis identified 17 factors as closely related to CIT occurrence, namely age, lymph node metastasis (N) stage, metastasis (M) stage, lung metastasis, other site metastasis, chemotherapy regimen, course of treatment, total dose of oxaliplatin, AST, albumin, neutrophils, monocytes, baseline platelets, transferrin, natural killer (NK) cell, phase angle, and SMI (P < 0.10). The binary logistic multivariate regression analysis revealed five independent risk factors for developing CIT (P < 0.05), including the M stage, total dose of oxaliplatin, albumin, baseline thrombocyte count, and NK cell. Based on the results of multivariate logistic regression analysis, R software was used to establish a nomogram model. The calibration curve shows that the combined predictor has good consistency. The area under the ROC curve was 0.877 and the best cut-off value was 0.3579613 (sensitivity, 78.9%; specificity, 81.8%), which showed the better prediction efficiency. CONCLUSION The total dose of oxaliplatin, M stage, albumin, baseline platelet count, and NK cell was independent risk factors for CIT. The sequentially constructed histogram model had a good predictive effect on the risk of thrombocytopenia caused by oxaliplatin chemotherapy in patients with gastrointestinal malignancies.
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Affiliation(s)
- Ju Li
- The First Hospital of Jilin University, Changchun, Jilin, China
| | - Wanqing Wang
- The First Hospital of Jilin University, Changchun, Jilin, China
| | - Kaipeng Jiang
- The First Hospital of Jilin University, Changchun, Jilin, China
| | - Jiuwei Cui
- The First Hospital of Jilin University, Changchun, Jilin, China
| | - Chang Wang
- The First Hospital of Jilin University, Changchun, Jilin, China
| | - Tingting Liang
- The First Hospital of Jilin University, Changchun, Jilin, China.
| | - Yizhuo Wang
- The First Hospital of Jilin University, Changchun, Jilin, China
| | - Shuhan Liu
- The First Hospital of Jilin University, Changchun, Jilin, China
| | - Wenshuo Zhou
- The First Hospital of Jilin University, Changchun, Jilin, China
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Becker IC, Wilkie AR, Nikols E, Carminita E, Roweth HG, Tilburg J, Sciaudone AR, Noetzli LJ, Fatima F, Couldwell G, Ray A, Mogilner A, Machlus KR, Italiano JE. Cell cycle-dependent centrosome clustering precedes proplatelet formation. SCIENCE ADVANCES 2024; 10:eadl6153. [PMID: 38896608 PMCID: PMC11186502 DOI: 10.1126/sciadv.adl6153] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Accepted: 05/14/2024] [Indexed: 06/21/2024]
Abstract
Platelet-producing megakaryocytes (MKs) primarily reside in the bone marrow, where they duplicate their DNA content with each cell cycle resulting in polyploid cells with an intricate demarcation membrane system. While key elements of the cytoskeletal reorganizations during proplatelet formation have been identified, what initiates the release of platelets into vessel sinusoids remains largely elusive. Using a cell cycle indicator, we observed a unique phenomenon, during which amplified centrosomes in MKs underwent clustering following mitosis, closely followed by proplatelet formation, which exclusively occurred in G1 of interphase. Forced cell cycle arrest in G1 increased proplatelet formation not only in vitro but also in vivo following short-term starvation of mice. We identified that inhibition of the centrosomal protein kinesin family member C1 (KIFC1) impaired clustering and subsequent proplatelet formation, while KIFC1-deficient mice exhibited reduced platelet counts. In summary, we identified KIFC1- and cell cycle-mediated centrosome clustering as an important initiator of proplatelet formation from MKs.
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Affiliation(s)
- Isabelle C. Becker
- Vascular Biology Program, Boston Children’s Hospital, 1 Blackfan Circle, Boston, MA 02115, USA
- Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
| | - Adrian R. Wilkie
- Vascular Biology Program, Boston Children’s Hospital, 1 Blackfan Circle, Boston, MA 02115, USA
- Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
| | - Emma Nikols
- Vascular Biology Program, Boston Children’s Hospital, 1 Blackfan Circle, Boston, MA 02115, USA
| | - Estelle Carminita
- Vascular Biology Program, Boston Children’s Hospital, 1 Blackfan Circle, Boston, MA 02115, USA
- Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
| | - Harvey G. Roweth
- Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
- Brigham and Women’s Hospital, 4 Blackfan Circle, Boston, MA 02115, USA
| | - Julia Tilburg
- Vascular Biology Program, Boston Children’s Hospital, 1 Blackfan Circle, Boston, MA 02115, USA
- Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
| | | | - Leila J. Noetzli
- Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
- Brigham and Women’s Hospital, 4 Blackfan Circle, Boston, MA 02115, USA
| | - Farheen Fatima
- Vascular Biology Program, Boston Children’s Hospital, 1 Blackfan Circle, Boston, MA 02115, USA
| | | | - Anjana Ray
- Brigham and Women’s Hospital, 4 Blackfan Circle, Boston, MA 02115, USA
| | - Alex Mogilner
- Courant Institute of Mathematical Sciences, New York University, 251 Mercer Street, New York, NY 10012, USA
| | - Kellie R. Machlus
- Vascular Biology Program, Boston Children’s Hospital, 1 Blackfan Circle, Boston, MA 02115, USA
- Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
| | - Joseph E. Italiano
- Vascular Biology Program, Boston Children’s Hospital, 1 Blackfan Circle, Boston, MA 02115, USA
- Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA
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Chen M, Li L, Xia Q, Chen X, Liao Z, Wang C, Shen B, Zhou M, Zhang Q, Zhang Y, Qian L, Yuan X, Wang Z, Xue C, An X, Liu B, Gu K, Hou M, Wang X, Wang W, Li E, Zhong J, Cheng J, Shu Y, Yang N, Wang H, Yang R, Liu T, Deng T, Ma F, Liao W, Qiu W, Chen Y, Chen X, Zhang M, Xu R, Li X, Feng J, Ba Y, Shi Y. A real-world observation on thrombopoietic agents for patients with cancer treatment-induced thrombocytopenia in China: A multicenter, cross-sectional study. Cancer 2024; 130:1524-1538. [PMID: 38515388 DOI: 10.1002/cncr.35292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 12/12/2023] [Accepted: 01/08/2024] [Indexed: 03/23/2024]
Abstract
BACKGROUND Studies on various thrombopoietic agents for cancer treatment-induced thrombocytopenia (CTIT) in China are lacking. This study aimed to provide detailed clinical profiles to understand the outcomes and safety of different CTIT treatment regimens. METHODS In this retrospective, cross-sectional study, 1664 questionnaires were collected from 33 hospitals between March 1 and July 1, 2021. Patients aged >18 years were enrolled who were diagnosed with CTIT and treated with recombinant interleukin 11 (rhIL-11), recombinant thrombopoietin (rhTPO), or a thrombopoietin receptor agonist (TPO-RA). The outcomes, compliance, and safety of different treatments were analyzed. RESULTS Among the 1437 analyzable cases, most patients were treated with either rhTPO alone (49.3%) or rhIL-11 alone (27.0%). The most common combination regimen used was rhTPO and rhIL-11 (10.9%). Platelet transfusions were received by 117 cases (8.1%). In multivariate analysis, rhTPO was associated with a significantly lower proportion of platelet recovery, platelet transfusion, and hospitalization due to chemotherapy-induced thrombocytopenia (CIT) than rhIL-11 alone. No significant difference was observed in the time taken to achieve a platelet count of >100 × 109/L and chemotherapy dose reduction due to CIT among the different thrombopoietic agents. The outcomes of thrombocytopenia in 170 patients who received targeted therapy and/or immunotherapy are also summarized. The results show that the proportion of platelet recovery was similar among the different thrombopoietic agents. No new safety signals related to thrombopoietic agents were observed in this study. A higher proportion of physicians preferred to continue treatment with TPO-RA alone than with rhTPO and rhIL-11. CONCLUSIONS This survey provides an overview of CTIT and the application of various thrombopoietic agents throughout China. Comparison of monotherapy with rhIL-11, rhTPO, and TPO-RA requires further randomized clinical trials. The appropriate application for thrombopoietic agents should depend on the pretreatment of platelets, treatment variables, and risk of bleeding. PLAIN LANGUAGE SUMMARY To provide an overview of the outcome of cancer treatment-induced thrombocytopenia in China, our cross-sectional study analyzed 1437 cases treated with different thrombopoietic agents. Most of the patients were treated with recombinant interleukin 11 (rhIL-11) and recombinant thrombopoietin (rhTPO). rhTPO was associated with a significantly lower proportion of platelet recovery and platelet transfusion compared with rhIL-11.
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Affiliation(s)
- Meiting Chen
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Lu Li
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qing Xia
- Department of Oncology, Renji Hospital, Medical College of Shanghai Jiaotong University, Shanghai, China
| | - Xiaobing Chen
- Departement of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Zijun Liao
- Departement of Medical Oncology, Shaanxi Cancer Hospital, Xi'an, China
| | - Chang Wang
- Department of Cancer Center, First Hospital of Jilin University, Changchun, China
| | - Bo Shen
- Department of Oncology, Jiangsu Cancer Institute, Nanjing, China
| | - Min Zhou
- Internal Medicine, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | - Qingyuan Zhang
- Department of Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yanqiao Zhang
- Department of Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Liting Qian
- Division of Life Sciences and Medicine, Department of Radiation Oncology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
| | - Xianglin Yuan
- Department of Oncology, Cancer Center of Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Zhehai Wang
- Department of Respiratory Medicine, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Cong Xue
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xin An
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Bin Liu
- Internal Medicine, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Kangsheng Gu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Mei Hou
- Lung Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaojia Wang
- Department of Breast Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Wei Wang
- Internal Medicine, First People's Hospital of Foshan, Foshan, China
| | - Enxiao Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University Medical College, Xi'an, China
| | - Jincai Zhong
- The First Affiliated Hospital of Guangxi Medicine University, Nanning, China
| | - Jing Cheng
- Cancer Center of Union Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Yongqian Shu
- Department of Oncology, Jiangsu Province Hospital, Nanjing Medical University, Nanjing, China
| | - Nong Yang
- Department of Pharmacy, Hunan Cancer Hospital, Changsha, China
| | - Huaqing Wang
- Department of Medical Oncology, Tianjin People's Hospital, Tianjin, China
| | - Runxiang Yang
- Department of Oncology, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical College, Kunming, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ting Deng
- Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Clinical Research Center for Cancer, Tianjin, China
| | - Fei Ma
- Internal Medicine, Cancer Hospital of the Chinese Academy of Medical Sciences, Beijing, China
| | - Wangjun Liao
- Internal Medicine-Oncology, Southern Medical University Nanfang Hospital, Guangzhou, China
| | - Wensheng Qiu
- The Second Department of Oncology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yu Chen
- Department of Oncology, Fujian Provincial Cancer Hospital, Fuzhou, China
| | - Xi Chen
- Department of Medical Oncology, Fuzhou General Hospital of Nanjing Military Command, Fuzhou, China
| | - Mingzhi Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ruilian Xu
- Department of Medical Oncology, Shenzhen People's Hospital, Shenzhen, China
| | - Xiaoling Li
- Department of Thoracic Cancer 1, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Jifeng Feng
- Department of Oncology, Jiangsu Cancer Institute, Nanjing, China
| | - Yi Ba
- Department of Gastrointestinal Medical Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Clinical Research Center for Cancer, Tianjin, China
| | - Yanxia Shi
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China
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9
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Tang D, Huang Y, Che Y, Yang C, Pu B, Liu S, Li H. Identification of platelet-related subtypes and diagnostic markers in pediatric Crohn's disease based on WGCNA and machine learning. Front Immunol 2024; 15:1323418. [PMID: 38420127 PMCID: PMC10899512 DOI: 10.3389/fimmu.2024.1323418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 01/29/2024] [Indexed: 03/02/2024] Open
Abstract
Background The incidence of pediatric Crohn's disease (PCD) is increasing worldwide every year. The challenges in early diagnosis and treatment of PCD persist due to its inherent heterogeneity. This study's objective was to discover novel diagnostic markers and molecular subtypes aimed at enhancing the prognosis for patients suffering from PCD. Methods Candidate genes were obtained from the GSE117993 dataset and the GSE93624 dataset by weighted gene co-expression network analysis (WGCNA) and differential analysis, followed by intersection with platelet-related genes. Based on this, diagnostic markers were screened by five machine learning algorithms. We constructed predictive models and molecular subtypes based on key markers. The models were evaluated using the GSE101794 dataset as the validation set, combined with receiver operating characteristic curves, decision curve analysis, clinical impact curves, and calibration curves. In addition, we performed pathway enrichment analysis and immune infiltration analysis for different molecular subtypes to assess their differences. Results Through WGCNA and differential analysis, we successfully identified 44 candidate genes. Following this, employing five machine learning algorithms, we ultimately narrowed it down to five pivotal markers: GNA15, PIK3R3, PLEK, SERPINE1, and STAT1. Using these five key markers as a foundation, we developed a nomogram exhibiting exceptional performance. Furthermore, we distinguished two platelet-related subtypes of PCD through consensus clustering analysis. Subsequent analyses involving pathway enrichment and immune infiltration unveiled notable disparities in gene expression patterns, enrichment pathways, and immune infiltration landscapes between these subtypes. Conclusion In this study, we have successfully identified five promising diagnostic markers and developed a robust nomogram with high predictive efficacy. Furthermore, the recognition of distinct PCD subtypes enhances our comprehension of potential pathogenic mechanisms and paves the way for future prospects in early diagnosis and personalized treatment.
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Affiliation(s)
- Dadong Tang
- Clinical Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yingtao Huang
- First Clinical Medical College, Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - Yuhui Che
- Clinical Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chengjun Yang
- Department of Otorhinolaryngology, Zigong Hospital of Traditional Chinese Medicine, Zigong, China
| | - Baoping Pu
- Clinical Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Shiru Liu
- Anorectal Disease Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Hongyan Li
- Anorectal Disease Department, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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10
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Rozumenko V, Liubich L, Pedachenko E, Staino L, Egorova D, Kot L, Malysheva T. SYSTEMIC INFLAMMATORY INDICES IN PATIENTS WITH MALIGNANT GLIOMAS AND EFFECTS OF PLATELET SECRETOME IN VITRO. Exp Oncol 2024; 45:409-420. [PMID: 38328849 DOI: 10.15407/exp-oncology.2023.04.409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Indexed: 02/09/2024]
Abstract
BACKGROUND To date, no significant clinical progress has been achieved in the treatment of brain malignant gliomas (MG), and the active search for non-invasive circulating biomarkers continues. The prognostic significance of the ratio of the main peripheral blood cell populations of patients with MG is evaluated. Considerable attention is paid to the secretome of platelets (Pt) of peripheral blood. AIM To evaluate the indicators of the peripheral blood cell population ratios in patients with brain MG and to study the influence of the secretome of Pt (SPt) of the peripheral blood of patients with brain MG in cell cultures in vitro. MATERIALS AND METHODS We studied samples of peripheral blood from patients with glioma CNS WHO grade G2 (n = 5), G3 (n = 12), and G4 (n = 20). The peripheral blood cell counts were analyzed in the preoperative period on an automatic hematology analyzer. The in vitro study of SPt was performed on the U251 human glioblastoma cell line cultured with SPt from MG patients or SPt pre-incubated with anti-TGF-β1 antibody. Cell cultures were observed for 72 h, and mitotic index (MI) was calculated. RESULTS In MG patients, the count of peripheral blood leukocytes and neutrophils increased (p < 0.05). The neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) increased by 2-3 times compared to control. Nevertheless, correlation analysis did not reveal significant relationships between quantitative indicators of peripheral blood cells and the tumor malignancy degree in MG patients. The MI in U251 cells increased under the influence of SPt from patients with MG (p < 0.021), correlated with the tumor degree of malignancy (r = 0.246, p = 0.014). Pre-incubation of SPt with anti-TGF-β1 antibody tends to neutralize this promitotic effect. CONCLUSION In MG patients, the integral indicators of NLR and SII increased but no significant relationship with the degree of tumor malignancy was found. In U251 cells, promitotic effects of SPt of MG patients partially decreased by anti-TGF-β1 antibody.
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Affiliation(s)
- V Rozumenko
- State Institution "Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine", Kyiv, Ukraine
| | - L Liubich
- State Institution "Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine", Kyiv, Ukraine
| | - E Pedachenko
- State Institution "Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine", Kyiv, Ukraine
| | - L Staino
- State Institution "Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine", Kyiv, Ukraine
| | - D Egorova
- State Institution "Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine", Kyiv, Ukraine
| | - L Kot
- State Institution "Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine", Kyiv, Ukraine
| | - T Malysheva
- State Institution "Romodanov Neurosurgery Institute, National Academy of Medical Sciences of Ukraine", Kyiv, Ukraine
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11
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Ellis ML, Terreaux A, Alwis I, Smythe R, Perdomo J, Eckly A, Cranmer SL, Passam FH, Maclean J, Schoenwaelder SM, Ruggeri ZM, Lanza F, Taoudi S, Yuan Y, Jackson SP. GPIbα-filamin A interaction regulates megakaryocyte localization and budding during platelet biogenesis. Blood 2024; 143:342-356. [PMID: 37922495 DOI: 10.1182/blood.2023021292] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 09/27/2023] [Accepted: 10/24/2023] [Indexed: 11/05/2023] Open
Abstract
ABSTRACT Glycoprotein Ibα (GPIbα) is expressed on the surface of platelets and megakaryocytes (MKs) and anchored to the membrane skeleton by filamin A (flnA). Although GPIb and flnA have fundamental roles in platelet biogenesis, the nature of this interaction in megakaryocyte biology remains ill-defined. We generated a mouse model expressing either human wild-type (WT) GPIbα (hGPIbαWT) or a flnA-binding mutant (hGPIbαFW) and lacking endogenous mouse GPIbα. Mice expressing the mutant GPIbα transgene exhibited macrothrombocytopenia with preserved GPIb surface expression. Platelet clearance was normal and differentiation of MKs to proplatelets was unimpaired in hGPIbαFW mice. The most striking abnormalities in hGPIbαFW MKs were the defective formation of the demarcation membrane system (DMS) and the redistribution of flnA from the cytoplasm to the peripheral margin of MKs. These abnormalities led to disorganized internal MK membranes and the generation of enlarged megakaryocyte membrane buds. The defective flnA-GPIbα interaction also resulted in misdirected release of buds away from the vasculature into bone marrow interstitium. Restoring the linkage between flnA and GPIbα corrected the flnA redistribution within MKs and DMS ultrastructural defects as well as restored normal bud size and release into sinusoids. These studies define a new mechanism of macrothrombocytopenia resulting from dysregulated MK budding. The link between flnA and GPIbα is not essential for the MK budding process, however, it plays a major role in regulating the structure of the DMS, bud morphogenesis, and the localized release of buds into the circulation.
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Affiliation(s)
- Marc L Ellis
- Thrombosis Research Group, The Heart Institute, Newtown, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia
| | - Antoine Terreaux
- Blood Cell Formation Lab, Walter and Eliza Hall Institute, Parkville, VIC, Australia
| | - Imala Alwis
- Thrombosis Research Group, The Heart Institute, Newtown, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia
| | - Rhyll Smythe
- Thrombosis Research Group, The Heart Institute, Newtown, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia
| | - Jose Perdomo
- Haematology Research Unit, St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Anita Eckly
- Université de Strasbourg, INSERM, French Blood Establishment (EFS) Grand Est, BPPS UMR-S 1255, FMTS, Strasbourg, France
| | - Susan L Cranmer
- Eastern Health Clinical School, Monash University, Box Hill, VIC, Australia
| | - Freda H Passam
- Thrombosis Research Group, The Heart Institute, Newtown, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia
| | - Jessica Maclean
- Thrombosis Research Group, The Heart Institute, Newtown, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia
| | - Simone M Schoenwaelder
- Thrombosis Research Group, The Heart Institute, Newtown, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia
- School of Medical Sciences, University of Sydney, Camperdown, NSW, Australia
| | - Zaverio M Ruggeri
- Department of Molecular Medicine, MERU-Roon Research Center on Vascular Biology, The Scripps Research Institute, La Jolla, CA
| | - Francois Lanza
- Université de Strasbourg, INSERM, French Blood Establishment (EFS) Grand Est, BPPS UMR-S 1255, FMTS, Strasbourg, France
| | - Samir Taoudi
- Blood Cell Formation Lab, Walter and Eliza Hall Institute, Parkville, VIC, Australia
- The University of Melbourne, Parkville, VIC, Australia
| | - Yuping Yuan
- Thrombosis Research Group, The Heart Institute, Newtown, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia
| | - Shaun P Jackson
- Thrombosis Research Group, The Heart Institute, Newtown, NSW, Australia
- Charles Perkins Centre, The University of Sydney, Camperdown, NSW, Australia
- Department of Molecular Medicine, MERU-Roon Research Center on Vascular Biology, The Scripps Research Institute, La Jolla, CA
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12
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Severin S, Gratacap MP, Bouvet L, Borret M, Kpotor AO, Chicanne G, Xuereb JM, Viaud J, Payrastre B. Phosphoinositides take a central stage in regulating blood platelet production and function. Adv Biol Regul 2024; 91:100992. [PMID: 37793962 DOI: 10.1016/j.jbior.2023.100992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 09/25/2023] [Indexed: 10/06/2023]
Abstract
Blood platelets are produced by megakaryocytes through a complex program of differentiation and play a critical role in hemostasis and thrombosis. These anucleate cells are the target of antithrombotic drugs that prevent them from clumping in cardiovascular disease conditions. Platelets also significantly contribute to various aspects of physiopathology, including interorgan communications, healing, inflammation, and thromboinflammation. Their production and activation are strictly regulated by highly elaborated mechanisms. Among them, those involving inositol lipids have drawn the attention of researchers. Phosphoinositides represent the seven combinatorially phosphorylated forms of the inositol head group of inositol lipids. They play a crucial role in regulating intracellular mechanisms, such as signal transduction, actin cytoskeleton rearrangements, and membrane trafficking, either by generating second messengers or by directly binding to specific domains of effector proteins. In this review, we will explore how phosphoinositides are implicated in controlling platelet production by megakaryocytes and in platelet activation processes. We will also discuss the diversity of phosphoinositides in platelets, their role in granule biogenesis and maintenance, as well as in integrin signaling. Finally, we will address the discovery of a novel pool of phosphatidylinositol 3-monophosphate in the outerleaflet of the plasma membrane of human and mouse platelets.
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Affiliation(s)
- Sonia Severin
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Marie-Pierre Gratacap
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Laura Bouvet
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Maxime Borret
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Afi Oportune Kpotor
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Gaëtan Chicanne
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Jean-Marie Xuereb
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Julien Viaud
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France
| | - Bernard Payrastre
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), INSERM UMR-1297 and Université Paul Sabatier, F-31432, Toulouse, France; Laboratoire d'Hématologie, Centre de Référence des Pathologies Plaquettaires, Centre Hospitalier Universitaire de Toulouse Rangueil, F-31432, Toulouse, France.
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13
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Thanasegaran S, Daimon E, Shibukawa Y, Yamazaki N, Okamoto N. Modelling Takenouchi-Kosaki syndrome using disease-specific iPSCs. Stem Cell Res 2023; 73:103221. [PMID: 37918315 DOI: 10.1016/j.scr.2023.103221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 10/10/2023] [Indexed: 11/04/2023] Open
Abstract
Takenouchi-Kosaki Syndrome (TKS) is a congenital multi-organ disorder caused by the de novo missense mutation c.191A > G p. Tyr64Cys (Y64C) in the CDC42 gene. We previously elucidated the functional abnormalities and thrombopoietic effects of Y64C using HEK293 and MEG01 cells. In the present study, we used iPSCs derived from TKS patients to model the disease and successfully recapitulated macrothrombocytopenia, a prominent TKS phenotype. The megakaryopoietic differentiation potential of TKS-iPSCs and platelet production capacity were examined using an efficient platelet production method redesigned from existing protocols. The results obtained showed that TKS-iPSCs produced fewer hematopoietic progenitor cells, exhibited defective megakaryopoiesis, and released platelets with an abnormally low count and giant morphology. We herein report the first analysis of TKS-iPSC-derived megakaryocytes and platelets, and currently utilize this model to perform drug evaluations for TKS. Therefore, our simple yet effective differentiation method, which mimics the disease in a dish, is a feasible strategy for studying hematopoiesis and related diseases.
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Affiliation(s)
- Suganya Thanasegaran
- Department of Molecular Medicine, Research Institute, Osaka Women's and Children's Hospital, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan
| | - Etsuko Daimon
- Department of Molecular Medicine, Research Institute, Osaka Women's and Children's Hospital, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan
| | - Yukinao Shibukawa
- Department of Molecular Medicine, Research Institute, Osaka Women's and Children's Hospital, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan
| | - Natsuko Yamazaki
- Department of Molecular Medicine, Research Institute, Osaka Women's and Children's Hospital, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan
| | - Nobuhiko Okamoto
- Department of Molecular Medicine, Research Institute, Osaka Women's and Children's Hospital, 840 Murodo-cho, Izumi, Osaka 594-1101, Japan.
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14
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Schwertz H, Middleton EA. Autophagy and its consequences for platelet biology. Thromb Res 2023; 231:170-181. [PMID: 36058760 PMCID: PMC10286736 DOI: 10.1016/j.thromres.2022.08.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/26/2022] [Accepted: 08/19/2022] [Indexed: 01/18/2023]
Abstract
Autophagy, the continuous recycling of intracellular building blocks, molecules, and organelles is necessary to preserve cellular function and homeostasis. In this context, it was demonstrated that autophagy plays an important role in megakaryopoiesis, the development and differentiation of hematopoietic progenitor cells into megakaryocytes. Furthermore, in recent years, autophagic proteins were detected in platelets, anucleate cells generated by megakaryocytes, responsible for hemostasis, thrombosis, and a key cell in inflammation and host immune responses. In the last decade studies have indicated the occurrence of autophagy in platelets. Moreover, autophagy in platelets was subsequently demonstrated to be involved in platelet aggregation, adhesion, and thrombus formation. Here, we review the current knowledge about autophagy in platelets, its function, and clinical implications. However, at the advent of platelet autophagy research, additional discoveries derived from evolving work will be required to precisely define the contributions of autophagy in platelets, and to expand the ever increasing physiologic and pathologic roles these remarkable and versatile blood cells play.
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Affiliation(s)
- Hansjörg Schwertz
- Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA; Division of Occupational Medicine, University of Utah, Salt Lake City, UT 84112, USA; Department of Occupational Medicine, Billings Clinic Bozeman, Bozeman, MT 59718, USA.
| | - Elizabeth A Middleton
- Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA; Division of Pulmonary Medicine and Critical Care, University of Utah, Salt Lake City, UT 84112, USA
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15
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Ye D, Li S, Ding Y, Ma Z, He R. Clinical value of mean platelet volume in predicting and diagnosing pre-eclampsia: a systematic review and meta-analysis. Front Cardiovasc Med 2023; 10:1251304. [PMID: 37868773 PMCID: PMC10587588 DOI: 10.3389/fcvm.2023.1251304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Accepted: 09/20/2023] [Indexed: 10/24/2023] Open
Abstract
Background Pre-eclampsia (PE) is a severe pregnancy complication. Thrombocytopenia and platelet dysfunction are common hematology disorders in PE. Previous studies considered mean platelet volume (MPV), a functional marker of platelets, as a potentially useful predictor for the diagnosis of PE. Methods PubMed, China Biomedical Literature Database, Chinese National Knowledge Infrastructure, Embase, Wanfang, VIP, and Cochrane Library databases were searched to gather diagnostic trials evaluating the diagnosis of PE using MPV, from their inception to 13 March 2023. We also searched Google Scholar and Baidu. Results A total of 22 studies from 20 articles were found. The pooled diagnostic accuracy of the MPV for PE recognition was as follows: sensitivity (SEN) 0.676 [95% confidence interval (CI) (0.658-0.694)], specificity (SPE) 0.710 [95% CI (0.703-0.717)], and diagnostic odds ratio (DOR) 7.012 [95% CI (4.226-11.636)], and the SROC-AUC and Q* indices were 0.7889 and 0.7262, respectively. The pooled SEN, SPE, and DOR of the diagnostic accuracy of MPV for PE before 16 weeks of gestation were 0.707 [95% CI (0.670-0.743)], 0.639 [95% CI (0.611-0.667)], and 4.026 [95% CI (2.727-5.943)], and the SROC-AUC and Q* indices were 0.7278 and 0.6753, respectively. For the interval of truncation values between 9 and 10 fl, the SROC-AUC and Q* indices for MPV were 0.8856 and 0.8162, respectively. Conclusions Available evidence suggests that MPV has a moderate predictive and diagnostic value for PE, particularly in diagnosing after 20 weeks of gestation. The diagnostic accuracy is higher when the MPV cut-off falls between 9 and 10 fl. The sensitivity of MPV alone in diagnosing PE is not high, and the combination of other markers for predictive diagnosis may better differentiate PE. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023425154, identifier: CRD42023425154.
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Affiliation(s)
- Dan Ye
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Shuwen Li
- Department of Obstetrics, Lanzhou University Second Hospital, Lanzhou, China
| | - Yi Ding
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Zhenqin Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Rongxia He
- Department of Obstetrics, Lanzhou University Second Hospital, Lanzhou, China
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16
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de Jonckheere B, Kollotzek F, Münzer P, Göb V, Fischer M, Mott K, Coman C, Troppmair NN, Manke MC, Zdanyte M, Harm T, Sigle M, Kopczynski D, Bileck A, Gerner C, Hoffmann N, Heinzmann D, Assinger A, Gawaz M, Stegner D, Schulze H, Borst O, Ahrends R. Critical shifts in lipid metabolism promote megakaryocyte differentiation and proplatelet formation. NATURE CARDIOVASCULAR RESEARCH 2023; 2:835-852. [PMID: 38075556 PMCID: PMC7615361 DOI: 10.1038/s44161-023-00325-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 07/27/2023] [Indexed: 08/29/2024]
Abstract
During megakaryopoiesis, megakaryocytes (MK) undergo cellular morphological changes with strong modification of membrane composition and lipid signaling. Here we adopt a lipid-centric multiomics approach to create a quantitative map of the MK lipidome during maturation and proplatelet formation. Data reveal that MK differentiation is driven by an increased fatty acyl import and de novo lipid synthesis, resulting in an anionic membrane phenotype. Pharmacological perturbation of fatty acid import and phospholipid synthesis blocked membrane remodeling and directly reduced MK polyploidization and proplatelet formation resulting in thrombocytopenia. The anionic lipid shift during megakaryopoiesis was paralleled by lipid-dependent relocalization of the scaffold protein CKIP-1 and recruitment of the kinase CK2α to the plasma membrane, which seems to be essential for sufficient platelet biogenesis. Overall, this study provides a framework to understand how the MK lipidome is altered during maturation and the impact of MK membrane lipid remodeling on MK kinase signaling involved in thrombopoiesis.
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Affiliation(s)
- Bianca de Jonckheere
- Institute of Analytical Chemistry, University of Vienna, Austria
- Vienna Doctoral School in Chemistry, University of Vienna, Austria
| | - Ferdinand Kollotzek
- DFG Heisenberg Group Cardiovascular Thromboinflammation and Translational Thrombocardiology, University of Tübingen, Germany
- Department of Cardiology and Angiology, University of Tübingen, Germany
| | - Patrick Münzer
- DFG Heisenberg Group Cardiovascular Thromboinflammation and Translational Thrombocardiology, University of Tübingen, Germany
- Department of Cardiology and Angiology, University of Tübingen, Germany
| | - Vanessa Göb
- Institute for Experimental Biomedicine, University Hospital Würzburg, Germany
- Rudolf Virchow Center for Integrative and Translational Bioimaging, Würzburg, Germany
| | - Melina Fischer
- DFG Heisenberg Group Cardiovascular Thromboinflammation and Translational Thrombocardiology, University of Tübingen, Germany
- Department of Cardiology and Angiology, University of Tübingen, Germany
| | - Kristina Mott
- Institute for Experimental Biomedicine, University Hospital Würzburg, Germany
| | - Cristina Coman
- Institute of Analytical Chemistry, University of Vienna, Austria
| | - Nina Nicole Troppmair
- Institute of Analytical Chemistry, University of Vienna, Austria
- Vienna Doctoral School in Chemistry, University of Vienna, Austria
| | - Mailin-Christin Manke
- DFG Heisenberg Group Cardiovascular Thromboinflammation and Translational Thrombocardiology, University of Tübingen, Germany
- Department of Cardiology and Angiology, University of Tübingen, Germany
| | - Monika Zdanyte
- DFG Heisenberg Group Cardiovascular Thromboinflammation and Translational Thrombocardiology, University of Tübingen, Germany
- Department of Cardiology and Angiology, University of Tübingen, Germany
| | - Tobias Harm
- Department of Cardiology and Angiology, University of Tübingen, Germany
| | - Manuel Sigle
- Department of Cardiology and Angiology, University of Tübingen, Germany
| | | | - Andrea Bileck
- Institute of Analytical Chemistry, University of Vienna, Austria
- Joint Metabolome Facility, University of Vienna and Medical University of Vienna, Austria
| | - Christopher Gerner
- Institute of Analytical Chemistry, University of Vienna, Austria
- Joint Metabolome Facility, University of Vienna and Medical University of Vienna, Austria
| | - Nils Hoffmann
- Institute of Analytical Chemistry, University of Vienna, Austria
- Forschungszentrum Jülich GmbH, Institute for Bio- and Geosciences (IBG-5) Jülich, Germany
| | - David Heinzmann
- Department of Cardiology and Angiology, University of Tübingen, Germany
| | - Alice Assinger
- Institute of Physiology, Centre of Physiology and Pharmacology, Medical University of Vienna, Austria
| | - Meinrad Gawaz
- Department of Cardiology and Angiology, University of Tübingen, Germany
| | - David Stegner
- Institute for Experimental Biomedicine, University Hospital Würzburg, Germany
- Rudolf Virchow Center for Integrative and Translational Bioimaging, Würzburg, Germany
| | - Harald Schulze
- Institute for Experimental Biomedicine, University Hospital Würzburg, Germany
| | - Oliver Borst
- DFG Heisenberg Group Cardiovascular Thromboinflammation and Translational Thrombocardiology, University of Tübingen, Germany
- Department of Cardiology and Angiology, University of Tübingen, Germany
| | - Robert Ahrends
- Institute of Analytical Chemistry, University of Vienna, Austria
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17
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Lopardo V, Montella F, Esposito RM, Zannella C, Aliberti SM, Capunzo M, Franci G, Puca AA, Ciaglia E. SARS-CoV-2 Lysate Stimulation Impairs the Release of Platelet-like Particles and Megakaryopoiesis in the MEG-01 Cell Line. Int J Mol Sci 2023; 24:4723. [PMID: 36902151 PMCID: PMC10003077 DOI: 10.3390/ijms24054723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 02/20/2023] [Accepted: 02/21/2023] [Indexed: 03/05/2023] Open
Abstract
SARS-CoV-2 infection causes a considerable inflammatory response coupled with impaired platelet reactivity, which can lead to platelet disorders recognized as negative prognostic factors in COVID-19 patients. The virus may cause thrombocytopenia or thrombocytosis during the different disease stages by destroying or activating platelets and influencing platelet production. While it is known that several viruses can impair megakaryopoiesis by generating an improper production and activation of platelets, the potential involvement of SARS-CoV-2 in affecting megakaryopoiesis is poorly understood. To this purpose, we explored, in vitro, the impact of SARS-CoV-2 stimulation in the MEG-01 cell line, a human megakaryoblastic leukemia cell line, considering its spontaneous capacity of releasing platelet-like particles (PLPs). We interrogated the effect of heat-inactivated SARS-CoV-2 lysate in the release of PLPs and activation from MEG-01, the signaling pathway influenced by SARS-CoV-2, and the functional effect on macrophagic skewing. The results highlight the potential influence of SARS-CoV-2 in the early stages of megakaryopoiesis by enhancing the production and activation of platelets, very likely due to the impairment of STATs signaling and AMPK activity. Overall, these findings provide new insight into the role of SARS-CoV-2 in affecting megakaryocyte-platelet compartment, possibly unlocking another avenue by which SARS-CoV-2 moves.
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Affiliation(s)
- Valentina Lopardo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Italy
| | - Francesco Montella
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Italy
| | - Roberta Maria Esposito
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Italy
| | - Carla Zannella
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
| | - Silvana Mirella Aliberti
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Italy
| | - Mario Capunzo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Italy
| | - Gianluigi Franci
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Italy
- Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
| | - Annibale Alessandro Puca
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Italy
- Cardiovascular Research Unit, IRCCS MultiMedica, 20138 Milan, Italy
| | - Elena Ciaglia
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Via Salvatore Allende, 84081 Baronissi, Italy
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18
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Dahariya S, Raghuwanshi S, Thamodaran V, Velayudhan SR, Gutti RK. Role of Long Non-Coding RNAs in Human-Induced Pluripotent Stem Cells Derived Megakaryocytes: A p53, HOX Antisense Intergenic RNA Myeloid 1, and miR-125b Interaction Study. J Pharmacol Exp Ther 2023; 384:92-101. [PMID: 36243404 DOI: 10.1124/jpet.121.001095] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/21/2022] [Accepted: 09/22/2022] [Indexed: 12/27/2022] Open
Abstract
Megakaryocytes (MKs) are rare polyploid cells found in the bone marrow and produce platelets. Platelets are small cell fragments that are essential during wound healing and vascular hemostasis. In vitro differentiation of MKs from human-induced pluripotent stem cell-derived CD34+ hematopoietic stem cells (hiPSC-HSCs) could provide an alternative treatment option for thrombocytopenic patients as a platelet source. In this approach, we developed a method to produce functional MKs from hiPSC-HSCs using a xeno-free and feeder-free condition and minimize the variation and risk from animal-derived products in cell culture. We have also investigated the genome-wide expression as well as functional significance of long noncoding RNAs (lncRNAs) in hiPSC-HSC-derived MKs to get insight into MK biology. We have performed lncRNAs expression profiling by using the Human LncProfilers qPCR Array Kit and identified 26 differentially regulated lncRNAs in hiPSC-HSC-derived MKs as compared with those in hiPSC-HSCs. HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) was the most highly upregulated lncRNA in hiPSC-HSC-derived MKs and phorbol 12-myristate 13-acetate (PMA)-induced megakaryocytic-differentiating K562 cells. Furthermore, we have studied the potential mechanism of HOTAIRM1 based on the interactions between HOTAIRM1, p53, and miR-125b in PMA-induced K562 cells. Our results demonstrated that during MK maturation, HOTAIRM1 might be associated with the transcriptional regulation of p53 via acting as a decoy for miR-125b. Thus, the interaction between HOTAIRM1, p53, and miR-125b is likely involved in controlling cell cycling (cyclin D1), reactive oxygen species production, and apoptosis to support terminal maturation of MKs. SIGNIFICANCE STATEMENT: In vitro generation of megakaryocytes (MKs) from human-induced pluripotent stem cell-derived hematopoietic stem cells (hiPSC-HSCs) could provide an alternative source of platelets for treating thrombocytopenic patients. This study has investigated the functional significance of long non-coding RNAs in hiPSC-HSC-derived MKs, which remains unclear. This study's findings suggest that the regulatory role of HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) in p53-mediated regulation of cyclin D1 during megakaryocytopoiesis is to promote MK maturation by decoying miR-125b.
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Affiliation(s)
- Swati Dahariya
- Stem Cell Research Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India (S.D., S.R., R.K.G.) and Centre for Stem Cell Research, Christian Medical College, Vellore, India (V.T., S.R.V.)
| | - Sanjeev Raghuwanshi
- Stem Cell Research Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India (S.D., S.R., R.K.G.) and Centre for Stem Cell Research, Christian Medical College, Vellore, India (V.T., S.R.V.)
| | - Vasanth Thamodaran
- Stem Cell Research Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India (S.D., S.R., R.K.G.) and Centre for Stem Cell Research, Christian Medical College, Vellore, India (V.T., S.R.V.)
| | - Shaji R Velayudhan
- Stem Cell Research Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India (S.D., S.R., R.K.G.) and Centre for Stem Cell Research, Christian Medical College, Vellore, India (V.T., S.R.V.)
| | - Ravi Kumar Gutti
- Stem Cell Research Laboratory, Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, India (S.D., S.R., R.K.G.) and Centre for Stem Cell Research, Christian Medical College, Vellore, India (V.T., S.R.V.)
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19
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Liang C, Zhang R, Xing X, Chen J, Yang H. Predictive value of platelet-related hematological markers in indicating the outcomes after laparoscopic intraperitoneal onlay mesh repair (IPOM). Surg Endosc 2022; 37:3471-3477. [PMID: 36575222 DOI: 10.1007/s00464-022-09845-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND The predictive value of hematological markers in the outcomes after laparoscopic intraperitoneal onlay mesh repair (IPOM) remains to be investigated. We aim to evaluate the role of platelet-related parameters after laparoscopic IPOM in patients with incisional hernias. METHODS The data of 95 patients who underwent laparoscopic IPOM for appendicectomy-related incisional hernias were retrospectively analyzed. The complete blood count analyses were measured preoperatively, and the outcomes were obtained from hospital records and follow-up calls to patients. Platelet-multiple-lymphocyte index (PLM), neutrophil-leukocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) values were calculated. The patients were grouped based on the recurrence and the postoperative complications after surgery. RESULTS Using cutoff values acquired by the Youden Index, we found platelet levels < 212.0 × 1000/μl, NLR > 2.33, LMR < 3.17, and PLM < 365.5 were revealed to be statistically significant in the recurrence of hernias based on univariant or multivariant analysis (p = < 0.05). We further divided the patients into two groups based on the cutoff value of PLM and found that a PLM value < 365.5 was significantly associated with the recurrence of incisional hernia (p = 0.018), the occurrence of postoperative seroma (p = 0.044), and there is a tendency that patients with PLM < 365.5 may suffer from other postoperative complications such as cardiopathy, respiratory infection, and hypoproteinemia (p = 0.089). CONCLUSION The preoperative hematological values, especially PLM, may indicate the outcomes in incisional hernias after laparoscopic IPOM.
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Affiliation(s)
- Chen Liang
- Department of Hernia and Abdominal Wall Surgery, Beijing Chao-Yang Hospital, No. 5 JingYuan Road, Shijingshan District, Beijing, 100043, China
| | - Rongjie Zhang
- Department of Hernia and Abdominal Wall Surgery, Beijing Chao-Yang Hospital, No. 5 JingYuan Road, Shijingshan District, Beijing, 100043, China
| | - Xiaowei Xing
- Department of Hernia and Abdominal Wall Surgery, Beijing Chao-Yang Hospital, No. 5 JingYuan Road, Shijingshan District, Beijing, 100043, China
| | - Jie Chen
- Department of Hernia and Abdominal Wall Surgery, Beijing Chao-Yang Hospital, No. 5 JingYuan Road, Shijingshan District, Beijing, 100043, China.,Department of Hernia and Abdominal Wall Surgery, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Huiqi Yang
- Department of Hernia and Abdominal Wall Surgery, Beijing Chao-Yang Hospital, No. 5 JingYuan Road, Shijingshan District, Beijing, 100043, China.
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20
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Manne BK, Campbell RA, Bhatlekar S, Ajanel A, Denorme F, Portier I, Middleton EA, Tolley ND, Kosaka Y, Montenont E, Guo L, Rowley JW, Bray PF, Jacob S, Fukanaga R, Proud C, Weyrich AS, Rondina MT. MAPK-interacting kinase 1 regulates platelet production, activation, and thrombosis. Blood 2022; 140:2477-2489. [PMID: 35930749 PMCID: PMC9918849 DOI: 10.1182/blood.2022015568] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 07/06/2022] [Accepted: 07/20/2022] [Indexed: 12/13/2022] Open
Abstract
The MAPK-interacting kinase (Mnk) family includes Mnk1 and Mnk2, which are phosphorylated and activated in response to extracellular stimuli. Mnk1 contributes to cellular responses by regulating messenger RNA (mRNA) translation, and mRNA translation influences platelet production and function. However, the role of Mnk1 in megakaryocytes and platelets has not previously been studied. The present study investigated Mnk1 in megakaryocytes and platelets using both pharmacological and genetic approaches. We demonstrate that Mnk1, but not Mnk2, is expressed and active in human and murine megakaryocytes and platelets. Stimulating human and murine megakaryocytes and platelets induced Mnk1 activation and phosphorylation of eIF4E, a downstream target of activated Mnk1 that triggers mRNA translation. Mnk1 inhibition or deletion significantly diminished protein synthesis in megakaryocytes as measured by polysome profiling and [35S]-methionine incorporation assays. Depletion of Mnk1 also reduced megakaryocyte ploidy and proplatelet forming megakaryocytes in vitro and resulted in thrombocytopenia. However, Mnk1 deletion did not affect the half-life of circulating platelets. Platelets from Mnk1 knockout mice exhibited reduced platelet aggregation, α granule secretion, and integrin αIIbβ3 activation. Ribosomal footprint sequencing indicated that Mnk1 regulates the translation of Pla2g4a mRNA (which encodes cPLA2) in megakaryocytes. Consistent with this, Mnk1 ablation reduced cPLA2 activity and thromboxane generation in platelets and megakaryocytes. In vivo, Mnk1 ablation protected against platelet-dependent thromboembolism. These results provide previously unrecognized evidence that Mnk1 regulates mRNA translation and cellular activation in platelets and megakaryocytes, endomitosis and thrombopoiesis, and thrombosis.
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Affiliation(s)
| | - Robert A. Campbell
- University of Utah Molecular Medicine Program, Salt Lake City, UT
- Department of Internal Medicine, University of Utah Health, Salt Lake City, UT
- Department of Pathology, University of Utah Health, Salt Lake City, UT
| | - Seema Bhatlekar
- University of Utah Molecular Medicine Program, Salt Lake City, UT
| | - Abigail Ajanel
- University of Utah Molecular Medicine Program, Salt Lake City, UT
- Department of Pathology, University of Utah Health, Salt Lake City, UT
| | - Frederik Denorme
- University of Utah Molecular Medicine Program, Salt Lake City, UT
| | - Irina Portier
- University of Utah Molecular Medicine Program, Salt Lake City, UT
| | - Elizabeth A. Middleton
- University of Utah Molecular Medicine Program, Salt Lake City, UT
- Department of Internal Medicine, University of Utah Health, Salt Lake City, UT
| | - Neal D. Tolley
- University of Utah Molecular Medicine Program, Salt Lake City, UT
| | - Yasuhiro Kosaka
- University of Utah Molecular Medicine Program, Salt Lake City, UT
| | - Emilie Montenont
- University of Utah Molecular Medicine Program, Salt Lake City, UT
| | - Li Guo
- University of Utah Molecular Medicine Program, Salt Lake City, UT
| | - Jesse W. Rowley
- University of Utah Molecular Medicine Program, Salt Lake City, UT
- Department of Internal Medicine, University of Utah Health, Salt Lake City, UT
| | - Paul F. Bray
- University of Utah Molecular Medicine Program, Salt Lake City, UT
- Department of Internal Medicine, University of Utah Health, Salt Lake City, UT
| | - Shancy Jacob
- University of Utah Molecular Medicine Program, Salt Lake City, UT
| | - Rikiro Fukanaga
- Department of Biochemistry, Osaka University of Pharmaceutical Sciences, Osaka, Japan
| | - Christopher Proud
- Lifelong Health, South Australian Health & Medical Research Institute, Adelaide, Australia
- Department of Biological Sciences, University of Adelaide, Adelaide, Australia
| | - Andrew S. Weyrich
- University of Utah Molecular Medicine Program, Salt Lake City, UT
- Department of Internal Medicine, University of Utah Health, Salt Lake City, UT
| | - Matthew T. Rondina
- University of Utah Molecular Medicine Program, Salt Lake City, UT
- Department of Internal Medicine, University of Utah Health, Salt Lake City, UT
- Department of Pathology, University of Utah Health, Salt Lake City, UT
- Department of Internal Medicine and the Geriatric Research, Education, and Clinical Center (GRECC), George E. Wahlen Veterans Affairs Medical Center (VAMC), Salt Lake City, UT
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21
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Rodrigues CF, Fernandes N, de Melo‐Diogo D, Correia IJ, Moreira AF. Cell-Derived Vesicles for Nanoparticles' Coating: Biomimetic Approaches for Enhanced Blood Circulation and Cancer Therapy. Adv Healthc Mater 2022; 11:e2201214. [PMID: 36121767 PMCID: PMC11481079 DOI: 10.1002/adhm.202201214] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 09/11/2022] [Indexed: 01/28/2023]
Abstract
Cancer nanomedicines are designed to encapsulate different therapeutic agents, prevent their premature release, and deliver them specifically to cancer cells, due to their ability to preferentially accumulate in tumor tissue. However, after intravenous administration, nanoparticles immediately interact with biological components that facilitate their recognition by the immune system, being rapidly removed from circulation. Reports show that less than 1% of the administered nanoparticles effectively reach the tumor site. This suboptimal pharmacokinetic profile is pointed out as one of the main factors for the nanoparticles' suboptimal therapeutic effectiveness and poor translation to the clinic. Therefore, an extended blood circulation time may be crucial to increase the nanoparticles' chances of being accumulated in the tumor and promote a site-specific delivery of therapeutic agents. For that purpose, the understanding of the forces that govern the nanoparticles' interaction with biological components and the impact of the physicochemical properties on the in vivo fate will allow the development of novel and more effective nanomedicines. Therefore, in this review, the nano-bio interactions are summarized. Moreover, the application of cell-derived vesicles for extending the blood circulation time and tumor accumulation is reviewed, focusing on the advantages and shortcomings of each cell source.
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Affiliation(s)
- Carolina F. Rodrigues
- CICS‐UBI – Health Sciences Research CentreUniversidade da Beira InteriorAv. Infante D. HenriqueCovilhã6200‐506Portugal
| | - Natanael Fernandes
- CICS‐UBI – Health Sciences Research CentreUniversidade da Beira InteriorAv. Infante D. HenriqueCovilhã6200‐506Portugal
| | - Duarte de Melo‐Diogo
- CICS‐UBI – Health Sciences Research CentreUniversidade da Beira InteriorAv. Infante D. HenriqueCovilhã6200‐506Portugal
| | - Ilídio J. Correia
- CICS‐UBI – Health Sciences Research CentreUniversidade da Beira InteriorAv. Infante D. HenriqueCovilhã6200‐506Portugal
| | - André F. Moreira
- CICS‐UBI – Health Sciences Research CentreUniversidade da Beira InteriorAv. Infante D. HenriqueCovilhã6200‐506Portugal
- CPIRN‐UDI/IPG – Center of Potential and Innovation in Natural Resources, Research Unit for Inland DevelopmentInstituto Politécnico da GuardaAvenida Dr. Francisco de Sá CarneiroGuarda6300‐559Portugal
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22
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Freitag M, Schwertz H. A New Role of NAP1L1 in Megakaryocytes and Human Platelets. Int J Mol Sci 2022; 23:ijms232314694. [PMID: 36499021 PMCID: PMC9737020 DOI: 10.3390/ijms232314694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/18/2022] [Accepted: 11/21/2022] [Indexed: 11/26/2022] Open
Abstract
Platelets (PLTs) are anucleate and considered incapable of nuclear functions. Contrastingly, nuclear proteins were detected in human PLTs. For most of these proteins, it is unclear if nuclear or alternatively assigned functions are performed, a question we wanted to address for nuclear assembly protein 1like 1 (NAP1L1). Using a wide array of molecular methods, including RNAseq, co-IP, overexpression and functional assays, we explored expression pattern and functionality of NAP1L1 in PLTs, and CD34+-derived megakaryocytes (MKs). NAP1L1 is expressed in PLTs and MKs. Co-IP experiments revealed that dihydrolipolylysine-residue acetyltransferase (DLAT encoded protein PDC-E2, ODP2) dynamically interacts with NAP1L1. PDC-E2 is part of the mitochondrial pyruvate-dehydrogenase (PDH) multi-enzyme complex, playing a crucial role in maintaining cellular respiration, and promoting ATP-synthesis via the respiratory chain. Since altered mitochondrial function is a hallmark of infectious syndromes, we analyzed PDH activity in PLTs from septic patients demonstrating increased activity, paralleling NAP1L1 expression levels. MKs PDH activity decreased following an LPS-challenge. Furthermore, overexpression of NAP1L1 significantly altered the ability of MKs to form proplatelet extensions, diminishing thrombopoiesis. These results indicate that NAP1L1 performs in other than nucleosome-assembly functions in PTLs and MKs, binding a key mitochondrial protein as a potential chaperone, and gatekeeper, influencing PDH activity and thrombopoiesis.
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Affiliation(s)
- Martin Freitag
- Department of Cardiac Surgery, Heart Center Leipzig-University Hospital, 04289 Leipzig, Germany
| | - Hansjörg Schwertz
- Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA
- Division of Occupational Medicine, University of Utah, Salt Lake City, UT 84112, USA
- Occupational Medicine at Billings Clinic Bozeman, Bozeman, MT 59715, USA
- Correspondence: or
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23
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Macedo de Sousa B, López-Valverde A, Caramelo F, Rodrigues MJ, López-Valverde N. Medium-Term Effect of Treatment with Intra-Articular Injection of Sodium Hyaluronate, Betamethasone and Platelet-Rich Plasma in Patients with Temporomandibular Arthralgia: A Retrospective Cohort Study. Life (Basel) 2022; 12:1739. [PMID: 36362894 PMCID: PMC9692948 DOI: 10.3390/life12111739] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 10/27/2022] [Accepted: 10/28/2022] [Indexed: 07/30/2023] Open
Abstract
Temporomandibular joint disorders are associated with pain and reduced jaw mobility. The aim of this study was to compare the long-term effect on pain of intra-articular TMJ injections of betamethasone, sodium hyaluronate and platelet-rich plasma. The sample was made up of 114 patients, who were randomly distributed into three groups at least three years ago and who achieved a total remission of pain after treatment. We found that the median number of months without pain was, according to each group, as follows: platelet-rich plasma: 33; sodium hyaluronate: 28; betamethasone: 19. Both platelet-rich plasma and sodium hyaluronate lead to significant pain-free time after treatment; when we compare bethametasone with the two other substances, it proved to be very ineffective.
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Affiliation(s)
- Bruno Macedo de Sousa
- Institute for Occlusion and Orofacial Pain, Faculty of Medicine, University of Coimbra, Polo I-Edifício Central Rua Larga, 3004-504 Coimbra, Portugal
| | - Antonio López-Valverde
- Department of Surgery, University of Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), P.º de San Vicente, 58-182, 37007 Salamanca, Spain
| | - Francisco Caramelo
- Laboratory of Biostatistics and Medical Informatics, Institute for Clinical and Biomedical Research (iCBR), School of Medicine, University of Coimbra, Polo 3, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal
| | - María João Rodrigues
- Institute for Occlusion and Orofacial Pain, Faculty of Medicine, University of Coimbra, Polo I-Edifício Central Rua Larga, 3004-504 Coimbra, Portugal
| | - Nansi López-Valverde
- Department of Medicine and Medical Specialties, Faculty of Health Sciences, Universidad Alcalá de Henares, 28871 Madrid, Spain
- Instituto de Investigación Biomédica de Salamanca (IBSAL), Avda. Alfonso X El Sabio S/N., 37007 Salamanca, Spain
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24
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Dai Z, Zhao T, Song N, Pan K, Yang Y, Zhu X, Chen P, Zhang J, Xia C. Platelets and platelet extracellular vesicles in drug delivery therapy: A review of the current status and future prospects. Front Pharmacol 2022; 13:1026386. [PMID: 36330089 PMCID: PMC9623298 DOI: 10.3389/fphar.2022.1026386] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 10/03/2022] [Indexed: 11/24/2022] Open
Abstract
Platelets are blood cells that are primarily produced by the shedding of megakaryocytes in the bone marrow. Platelets participate in a variety of physiological and pathological processes in vivo, including hemostasis, thrombosis, immune-inflammation, tumor progression, and metastasis. Platelets have been widely used for targeted drug delivery therapies for treating various inflammatory and tumor-related diseases. Compared to other drug-loaded treatments, drug-loaded platelets have better targeting, superior biocompatibility, and lower immunogenicity. Drug-loaded platelet therapies include platelet membrane coating, platelet engineering, and biomimetic platelets. Recent studies have indicated that platelet extracellular vesicles (PEVs) may have more advantages compared with traditional drug-loaded platelets. PEVs are the most abundant vesicles in the blood and exhibit many of the functional characteristics of platelets. Notably, PEVs have excellent biological efficacy, which facilitates the therapeutic benefits of targeted drug delivery. This article provides a summary of platelet and PEVs biology and discusses their relationships with diseases. In addition, we describe the preparation, drug-loaded methods, and specific advantages of platelets and PEVs targeted drug delivery therapies for treating inflammation and tumors. We summarize the hot spots analysis of scientific articles on PEVs and provide a research trend, which aims to give a unique insight into the development of PEVs research focus.
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Affiliation(s)
- Zhanqiu Dai
- Department of Spine Surgery, Zhejiang Provincial People’s Hospital, Hangzhou Medical College People’s Hospital, Hangzhou, Zhejiang, China
- Department of Orthopaedics, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Tingxiao Zhao
- Department of Spine Surgery, Zhejiang Provincial People’s Hospital, Hangzhou Medical College People’s Hospital, Hangzhou, Zhejiang, China
| | - Nan Song
- Department of Pathology, Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Kaifeng Pan
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Yang Yang
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
| | - Xunbin Zhu
- Department of Orthopaedics, The Second Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Pengfei Chen
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
- *Correspondence: Pengfei Chen, ; Jun Zhang, ; Chen Xia,
| | - Jun Zhang
- Department of Spine Surgery, Zhejiang Provincial People’s Hospital, Hangzhou Medical College People’s Hospital, Hangzhou, Zhejiang, China
- *Correspondence: Pengfei Chen, ; Jun Zhang, ; Chen Xia,
| | - Chen Xia
- Department of Spine Surgery, Zhejiang Provincial People’s Hospital, Hangzhou Medical College People’s Hospital, Hangzhou, Zhejiang, China
- Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Hangzhou, China
- Key Laboratory of Musculoskeletal System Degeneration and Regeneration Translational Research of Zhejiang Province, Hangzhou, China
- *Correspondence: Pengfei Chen, ; Jun Zhang, ; Chen Xia,
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25
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Vauclard A, Bellio M, Valet C, Borret M, Payrastre B, Severin S. Obesity: Effects on bone marrow homeostasis and platelet activation. Thromb Res 2022. [DOI: 10.1016/j.thromres.2022.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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26
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Zheng Y, Luo Z, Cao Z. Mean platelet volume as a predictive biomarker for in-hospital mortality in patients receiving invasive mechanical ventilation. BMC Pulm Med 2022; 22:353. [PMID: 36115956 PMCID: PMC9482743 DOI: 10.1186/s12890-022-02155-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 09/13/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Although mean platelet volume (MPV) has been reported to be associated with poor prognosis of various critical illness, the relationship between MPV and in-hospital mortality among patients undergoing invasive mechanical ventilation (IMV) is unclear.
Methods
A retrospective observational study including patients receiving IMV was conducted from January, 2014 to January, 2019. The patients were divided into two groups by MPV cutoff value. The receiver operating characteristics curve was used to evaluate the predictive ability of MPV for in-hospital mortality. Univariate and multivariate Cox regression analysis were conducted to analyze the value of MPV for predicting in-hospital mortality. Kaplan–Meier cumulative incidence curve was employed to observe the incidence of in-hospital mortality.
Results
A total of 274 patients were enrolled in the study, and 42 patients (15.3%) died in hospital. MPV > 11.4 fl was a valuable predictor for in-hospital mortality (AUC0.848; 95%CI, 0.800–0.889) with sensitivity 66.7%, and specificity = 86.21%. MPV > 11.4 fl was an independent risk factor for in-hospital mortality (adjusted HR 2.640, 95%CI, 1.208–5.767, P = 0.015). Compared to the group of MPV ≤ 11.4 fl, patients with MPV > 11.4 fl had increased mortality (log-rank test = 40.35, HR = 8.723, P < 0.0001). The relationship between MPV and in-hospital mortality was stronger in female patients than in male patients.
Conclusion
MPV > 11.4 fl is a more useful marker for predicting in-hospital mortality among critically ill patients receiving IMV, especially in female patients. Attention to the MPV marker is simple and profitable with immediate applicability in daily clinical practice.
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Vong P, Ouled-Haddou H, Garçon L. Histone Deacetylases Function in the Control of Early Hematopoiesis and Erythropoiesis. Int J Mol Sci 2022; 23:9790. [PMID: 36077192 PMCID: PMC9456231 DOI: 10.3390/ijms23179790] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/17/2022] Open
Abstract
Numerous studies have highlighted the role of post-translational modifications in the regulation of cell proliferation, differentiation and death. Among these modifications, acetylation modifies the physicochemical properties of proteins and modulates their activity, stability, localization and affinity for partner proteins. Through the deacetylation of a wide variety of functional and structural, nuclear and cytoplasmic proteins, histone deacetylases (HDACs) modulate important cellular processes, including hematopoiesis, during which different HDACs, by controlling gene expression or by regulating non-histone protein functions, act sequentially to provide a fine regulation of the differentiation process both in early hematopoietic stem cells and in more mature progenitors. Considering that HDAC inhibitors represent promising targets in cancer treatment, it is necessary to decipher the role of HDACs during hematopoiesis which could be impacted by these therapies. This review will highlight the main mechanisms by which HDACs control the hematopoietic stem cell fate, particularly in the erythroid lineage.
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Affiliation(s)
- Pascal Vong
- Université Picardie Jules Verne, HEMATIM UR4666, 80000 Amiens, France
| | | | - Loïc Garçon
- Université Picardie Jules Verne, HEMATIM UR4666, 80000 Amiens, France
- Service d’Hématologie Biologique, Centre Hospitalier Universitaire, CEDEX 1, 80054 Amiens, France
- Laboratoire de Génétique Constitutionnelle, Centre Hospitalier Universitaire, CEDEX 1, 80054 Amiens, France
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28
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Giaretta A, Petrucci G, Rocca B, Toffolo GM. Physiologically based modelling of the antiplatelet effect of aspirin: A tool to characterize drug responsiveness and inform precision dosing. PLoS One 2022; 17:e0268905. [PMID: 35976924 PMCID: PMC9385056 DOI: 10.1371/journal.pone.0268905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 05/11/2022] [Indexed: 11/18/2022] Open
Abstract
A computational approach involving mathematical modeling and in silico experiments was used to characterize the determinants of extent and duration of platelet cyclooxygenase (COX)-1 inhibition by aspirin and design precision dosing in patients with accelerated platelet turnover or reduced drug bioavailability. To this purpose, a recently developed physiologically-based pharmacokinetics (PK) and pharmacodynamics (PD) model of low-dose aspirin in regenerating platelets and megakaryocytes, was used to predict the main features and determinants of platelet COX-1 inhibition. The response to different aspirin regimens in healthy subjects and in pathological conditions associated with alterations in aspirin PK (i.e., severely obese subjects) or PD (i.e., essential thrombocytemya patients), were simulated. A model sensitivity analysis was performed to identify the main processes influencing COX-1 dynamics. In silico experiments and sensitivity analyses indicated a major role for megakaryocytes and platelet turnover in determining the extent and duration of COX-1 inhibition by once-daily, low-dose aspirin. They also showed the superiority of reducing the dosing interval vs increasing the once-daily dose in conditions of increased platelet turnover, while suggested specific dose adjustments in conditions of possible reduction in drug bioavailability. In conclusion, the consistency of our model-based findings with experimental data from studies in healthy subjects and patients with essential thrombocythemia supports the potential of our approach for describing the determinants of platelet inhibition by aspirin and informing precision dosing which may guide personalized antithrombotic therapy in different patient populations, especially in those under-represented in clinical trials or in those associated with poor feasibility.
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Affiliation(s)
- Alberto Giaretta
- Department of Information Engineering, University of Padova, Padova, Italy
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
- * E-mail: ,
| | - Giovanna Petrucci
- Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
| | - Bianca Rocca
- Department of Pharmacology, Catholic University School of Medicine, Rome, Italy
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Sarkar S, Thapa R, Naushin F, Gupta S, Bhar B, De R, Bhattacharya J. Antibiotic-Loaded Smart Platelet: A Highly Effective Invisible Mode of Killing Both Antibiotic-Sensitive and -Resistant Bacteria. ACS OMEGA 2022; 7:24102-24110. [PMID: 35874209 PMCID: PMC9301723 DOI: 10.1021/acsomega.1c07249] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Microbial pathogenesis is considered one of the most critical health challenges worldwide. Although several antibiotics have been procured and used, the microbes often manage to escape and become resistant to antibiotics. Thus, the discovery of new antibiotics and designing smart approaches toward their delivery are of great importance. In many cases, the delivery agents using foreign chemicals like lipids or polymers induce immunogenic responses of varying degrees and are limited to a shorter circulatory time and burst release. In the current work, we have designed a novel antibiotic delivery system where the antibiotic is encapsulated into a blood component-platelet. Platelets have been previously reported as efficient drug delivery vehicles for targeting cancer cells. On the other hand, during platelet-bacterial interaction, platelets can act as covercytes. Keeping this in mind, smart antibiotic-loaded platelets have been used for killing bacterial cells. The loading of the antibiotic was done using its typical nature of engulfing surrounding small molecules. The water-soluble antibiotics were loaded directly into the platelet, whereas the hydrophobic antibiotics were preloaded in polycaprolactone (FDA-approved polymer)-based nanovesicles to make them solubilized prior to loading inside the platelets. The antibiotic-loaded platelets (containing hydrophilic antibiotics or hydrophobic antibiotic -encapsulated polymer nanoparticles) were found to be stable when studied through platelet aggregometry. The carrier showed bactericidal effects at a significantly lower concentration at which the free antibiotic has negligible efficacy. This could be attributed to the molecular confinement of the antibiotics inside the platelets, therefore causing localization of the drug and leading to efficient activity against bacteria. Interestingly, the smart antibiotic-loaded platelets were capable of killing the resistant strains too at the same lower concentration regime. Therefore, the antibiotic-loaded platelet could emerge as a potential strategy for efficient delivery of antibiotics with a significant reduction of the dose required to achieve the intended antibacterial efficacy. Moreover, this antibiotic delivery method can be very useful to minimize immunogenic responses due to antibiotic administration and to avoid the development of drug resistance due to the invisible mode of delivery.
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Affiliation(s)
- Sounik Sarkar
- School
of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
| | - Roshni Thapa
- School
of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
- Special
Centre for Molecular Medicine, Jawaharlal
Nehru University, New Delhi 110067, India
| | - Farzana Naushin
- School
of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
| | - Saurabh Gupta
- School
of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
| | - Biswajit Bhar
- Institute
of Hematology & Transfusion Medicine, Medical College and Hospital, Kolkata 700073, India
| | - Rajib De
- Haematology
Department, NRS Medical College, Kolkata 700014, India
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30
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Caux M, Mansour R, Xuereb JM, Chicanne G, Viaud J, Vauclard A, Boal F, Payrastre B, Tronchère H, Severin S. PIKfyve-Dependent Phosphoinositide Dynamics in Megakaryocyte/Platelet Granule Integrity and Platelet Functions. Arterioscler Thromb Vasc Biol 2022; 42:987-1004. [PMID: 35708031 DOI: 10.1161/atvbaha.122.317559] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Secretory granules are key elements for platelet functions. Their biogenesis and integrity are regulated by fine-tuned mechanisms that need to be fully characterized. Here, we investigated the role of the phosphoinositide 5-kinase PIKfyve and its lipid products, PtdIns5P (phosphatidylinositol 5 monophosphate) and PtdIns(3,5)P2 (phosphatidylinositol (3,5) bisphosphate) in granule homeostasis in megakaryocytes and platelets. METHODS For that, we invalidated PIKfyve by pharmacological inhibition or gene silencing in megakaryocytic cell models (human MEG-01 cell line, human imMKCLs, mouse primary megakaryocytes) and in human platelets. RESULTS We unveiled that PIKfyve expression and its lipid product levels increased with megakaryocytic maturation. In megakaryocytes, PtdIns5P and PtdIns(3,5)P2 were found in alpha and dense granule membranes with higher levels in dense granules. Pharmacological inhibition or knock-down of PIKfyve in megakaryocytes decreased PtdIns5P and PtdIns(3,5)P2 synthesis and induced a vacuolar phenotype with a loss of alpha and dense granule identity. Permeant PtdIns5P and PtdIns(3,5)P2 and the cation channel TRPML1 (transient receptor potential mucolipins) and TPC2 activation were able to accelerate alpha and dense granule integrity recovery following release of PIKfyve pharmacological inhibition. In platelets, PIKfyve inhibition specifically impaired the integrity of dense granules culminating in defects in their secretion, platelet aggregation, and thrombus formation. CONCLUSIONS These data demonstrated that PIKfyve and its lipid products PtdIns5P and PtdIns(3,5)P2 control granule integrity both in megakaryocytes and platelets.
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Affiliation(s)
- Manuella Caux
- INSERM U1297, I2MC and Université Paul Sabatier, Toulouse, France (M.C., R.M., J.-M.X., G.C., J.V., A.V., F.B., B.P., H.T., S.S.)
| | - Rana Mansour
- INSERM U1297, I2MC and Université Paul Sabatier, Toulouse, France (M.C., R.M., J.-M.X., G.C., J.V., A.V., F.B., B.P., H.T., S.S.)
| | - Jean-Marie Xuereb
- INSERM U1297, I2MC and Université Paul Sabatier, Toulouse, France (M.C., R.M., J.-M.X., G.C., J.V., A.V., F.B., B.P., H.T., S.S.)
| | - Gaëtan Chicanne
- INSERM U1297, I2MC and Université Paul Sabatier, Toulouse, France (M.C., R.M., J.-M.X., G.C., J.V., A.V., F.B., B.P., H.T., S.S.)
| | - Julien Viaud
- INSERM U1297, I2MC and Université Paul Sabatier, Toulouse, France (M.C., R.M., J.-M.X., G.C., J.V., A.V., F.B., B.P., H.T., S.S.)
| | - Alicia Vauclard
- INSERM U1297, I2MC and Université Paul Sabatier, Toulouse, France (M.C., R.M., J.-M.X., G.C., J.V., A.V., F.B., B.P., H.T., S.S.)
| | - Frédéric Boal
- INSERM U1297, I2MC and Université Paul Sabatier, Toulouse, France (M.C., R.M., J.-M.X., G.C., J.V., A.V., F.B., B.P., H.T., S.S.)
| | - Bernard Payrastre
- INSERM U1297, I2MC and Université Paul Sabatier, Toulouse, France (M.C., R.M., J.-M.X., G.C., J.V., A.V., F.B., B.P., H.T., S.S.).,CHU de Toulouse, Laboratoire d'Hématologie, Toulouse, France (B.P.)
| | - Hélène Tronchère
- INSERM U1297, I2MC and Université Paul Sabatier, Toulouse, France (M.C., R.M., J.-M.X., G.C., J.V., A.V., F.B., B.P., H.T., S.S.)
| | - Sonia Severin
- INSERM U1297, I2MC and Université Paul Sabatier, Toulouse, France (M.C., R.M., J.-M.X., G.C., J.V., A.V., F.B., B.P., H.T., S.S.)
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31
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Marini I, Uzun G, Jamal K, Bakchoul T. Treatment of drug-induced immune thrombocytopenias. Haematologica 2022; 107:1264-1277. [PMID: 35642486 PMCID: PMC9152960 DOI: 10.3324/haematol.2021.279484] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Indexed: 01/19/2023] Open
Abstract
Several therapeutic agents can cause thrombocytopenia by either immune-mediated or non-immune-mediated mechanisms. Non-immune-mediated thrombocytopenia is due to direct toxicity of drug molecules to platelets or megakaryocytes. Immune-mediated thrombocytopenia, on the other hand, involves the formation of antibodies that react to platelet-specific glycoprotein complexes, as in classic drug-induced immune thrombocytopenia (DITP), or to platelet factor 4, as in heparin-induced thrombocytopenia (HIT) and vaccine-induced immune thrombotic thrombocytopenia (VITT). Clinical signs include a rapid drop in platelet count, bleeding or thrombosis. Since the patient's condition can deteriorate rapidly, prompt diagnosis and management are critical. However, the necessary diagnostic tests are only available in specialized laboratories. Therefore, the most demanding step in treatment is to identify the agent responsible for thrombocytopenia, which often proves difficult because many patients are taking multiple medications and have comorbidities that can themselves also cause thrombocytopenia. While DITP is commonly associated with an increased risk of bleeding, HIT and VITT have a high mortality rate due to the high incidence of thromboembolic complications. A structured approach to drug-associated thrombocytopenia/thrombosis can lead to successful treatment and a lower mortality rate. In addition to describing the treatment of DITP, HIT, VITT, and vaccine-associated immune thrombocytopenia, this review also provides the pathophysiological and clinical information necessary for correct patient management.
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Affiliation(s)
- Irene Marini
- Centre for Clinical Transfusion Medicine, Medical Faculty of Tübingen, University of Tübingen
| | - Gunalp Uzun
- Centre for Clinical Transfusion Medicine, Medical Faculty of Tübingen, University of Tübingen
| | - Kinan Jamal
- Centre for Clinical Transfusion Medicine, Medical Faculty of Tübingen, University of Tübingen
| | - Tamam Bakchoul
- Centre for Clinical Transfusion Medicine, Medical Faculty of Tübingen, University of Tübingen.
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32
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Kuter DJ. Treatment of chemotherapy-induced thrombocytopenia in patients with non-hematologic malignancies. Haematologica 2022; 107:1243-1263. [PMID: 35642485 PMCID: PMC9152964 DOI: 10.3324/haematol.2021.279512] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Indexed: 01/19/2023] Open
Abstract
Chemotherapy-induced thrombocytopenia (CIT) is a common complication of the treatment of non-hematologic malignancies. Many patient-related variables (e.g., age, tumor type, number of prior chemotherapy cycles, amount of bone marrow tumor involvement) determine the extent of CIT. CIT is related to the type and dose of chemotherapy, with regimens containing gemcitabine, platinum, or temozolomide producing it most commonly. Bleeding and the need for platelet transfusions in CIT are rather uncommon except in patients with platelet counts below 25x109/L in whom bleeding rates increase significantly and platelet transfusions are the only treatment. Nonetheless, platelet counts below 70x109/L present a challenge. In patients with such counts, it is important to exclude other causes of thrombocytopenia (medications, infection, thrombotic microangiopathy, post-transfusion purpura, coagulopathy and immune thrombocytopenia). If these are not present, the common approach is to reduce chemotherapy dose intensity or switch to other agents. Unfortunately decreasing relative dose intensity is associated with reduced tumor response and remission rates. Thrombopoietic growth factors (recombinant human thrombopoietin, pegylated human megakaryocyte growth and development factor, romiplostim, eltrombopag, avatrombopag and hetrombopag) improve pretreatment and nadir platelet counts, reduce the need for platelet transfusions, and enable chemotherapy dose intensity to be maintained. National Comprehensive Cancer Network guidelines permit their use but their widespread adoption awaits adequate phase III randomized, placebo-controlled studies demonstrating maintenance of relative dose intensity, reduction of platelet transfusions and bleeding, and possibly improved survival. Their potential appropriate use also depends on consensus by the oncology community as to what constitutes an appropriate pretreatment platelet count as well as identification of patient-related and treatment variables that might predict bleeding.
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Affiliation(s)
- David J Kuter
- Massachusetts General Hospital, Harvard Medical School, Boston, MA.
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33
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Zheng Y, Luo Z, Cao Z. Mean platelet volume is useful for predicting weaning failure: a retrospective, observational study. BMC Anesthesiol 2022; 22:160. [PMID: 35614411 PMCID: PMC9131520 DOI: 10.1186/s12871-022-01701-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 05/18/2022] [Indexed: 11/24/2022] Open
Abstract
Background To evaluate the usefulness of mean platelet volume (MPV), a marker of inflammation and stress, for predicting weaning failure in patients undergoing invasive mechanical ventilation (IMV) compared to traditional inflammation markers. Methods The retrospective observational study including patients who received IMV and underwent spontaneous breathing trial (SBT) was conducted in ICU at Beijing Chao-Yang hospital in China from January, 2013 to December, 2019. According to the weaning outcome, MPV, leukocyte count and C-reaction protein(CRP) were compared between weaning failure and weaning success group. Receiver-operating characteristics (ROC) curves and multivariate logistical regression analysis were constructed to analyze the value of these inflammatory markers for predicting weaning failure. Results A total of 261 patients were enrolled in the study and 54 patients (20.7%) experienced weaning failure (45 SBT failure and 9 extubation failure after successful SBT). MPV was a better predictor for weaning failure (AUC 0.777;95%CI, 0.722–0.826) than leukocyte count (AUC 0.6;95%CI,0.538–0.66) and CRP (0.627;95%CI,0.565–0.685). The cutoff value of MPV for predicting weaning failure was 11.3 fl with sensitivity 55.56%, specificity 87.92%, and diagnostic accuracy 81.22%. According to multivariate logistic regression analyses, MPV > 11.3 fl was an independent risk factor for predicting weaning failure. Conclusions MPV could be a more valuable marker for predicting weaning failure. and the patients with MPV > 11.3 fl should be attentively evaluated before weaning since they are at high risk of weaning failure, and it would be auspicable for those patients to undergo a noninvasive ventilation or high-flow nasal cannula oxygen therapy after extubation or even an early tracheostomy.
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Affiliation(s)
- Yingying Zheng
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
| | - Zujin Luo
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Zhixin Cao
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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Oprescu A, Michel D, Antkowiak A, Vega E, Viaud J, Courtneidge SA, Eckly A, de la Salle H, Chicanne G, Léon C, Payrastre B, Gaits-Iacovoni F. Megakaryocytes form linear podosomes devoid of digestive properties to remodel medullar matrix. Sci Rep 2022; 12:6255. [PMID: 35428815 PMCID: PMC9012751 DOI: 10.1038/s41598-022-10215-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 04/01/2022] [Indexed: 12/20/2022] Open
Abstract
Bone marrow megakaryocytes (MKs) undergo a maturation involving contacts with the microenvironment before extending proplatelets through sinusoids to deliver platelets in the bloodstream. We demonstrated that MKs assemble linear F-actin-enriched podosomes on collagen I fibers. Microscopy analysis evidenced an inverse correlation between the number of dot-like versus linear podosomes over time. Confocal videomicroscopy confirmed that they derived from each-other. This dynamics was dependent on myosin IIA. Importantly, MKs progenitors expressed the Tks4/5 adaptors, displayed a strong gelatinolytic ability and did not form linear podosomes. While maturing, MKs lost Tks expression together with digestive ability. However, those MKs were still able to remodel the matrix by exerting traction on collagen I fibers through a collaboration between GPVI, ß1 integrin and linear podosomes. Our data demonstrated that a change in structure and composition of podosomes accounted for the shift of function during megakaryopoiesis. These data highlight the fact that members of the invadosome family could correspond to different maturation status of the same entity, to adapt to functional responses required by differentiation stages of the cell that bears them.
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Affiliation(s)
- Antoine Oprescu
- INSERM, UMR1297, Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France
| | - Déborah Michel
- INSERM, UMR1297, Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France
| | - Adrien Antkowiak
- INSERM, UMR1297, Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France
| | - Elodie Vega
- INSERM, UMR1297, Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France
| | - Julien Viaud
- INSERM, UMR1297, Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France
| | - Sara A Courtneidge
- Department of Cell, Development and Cancer Biology, Oregon Health & Science University, Oregon, USA
| | - Anita Eckly
- INSERM, UMR_S1255, Université de Strasbourg, Etablissement Français du Sang-GEST, Strasbourg, France
| | - Henri de la Salle
- INSERM, UMR_S1255, Université de Strasbourg, Etablissement Français du Sang-GEST, Strasbourg, France
| | - Gaëtan Chicanne
- INSERM, UMR1297, Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France
| | - Catherine Léon
- INSERM, UMR_S1255, Université de Strasbourg, Etablissement Français du Sang-GEST, Strasbourg, France
| | - Bernard Payrastre
- INSERM, UMR1297, Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France.,CHU de Toulouse, laboratoire d'Hématologie, Toulouse, France
| | - Frédérique Gaits-Iacovoni
- INSERM, UMR1297, Université Toulouse III, Institut des Maladies Métaboliques et Cardiovasculaires, Toulouse, France. .,Molecular, Cellular and Developmental Biology Department (MCD, UMR5077), Centre de Biologie Intégrative (CBI, FR3743), University of Toulouse, CNRS, UPS, 31062, Toulouse, France.
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35
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Wang Q, Wei J, Jia X, Feng X, Ji Z, Ji X, Shao X. Downregulation of ADAM17 in pediatric immune thrombocytopenia impairs proplatelet formation. BMC Pediatr 2022; 22:164. [PMID: 35354403 PMCID: PMC8966352 DOI: 10.1186/s12887-022-03237-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/23/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Immune thrombocytopenia (ITP) is the most common etiology of acquired thrombocytopenia diseases in children. ITP is characterized by the immune-mediated decreased formation and excessive destruction of platelets. The pathogenesis and management of pediatric ITP are distinct from adult ITP. A disintegrin and metalloproteinase 17 (ADAM17) mediates the shedding of platelet receptor glycoprotein Ib α (GPIb α) in extracellular domain, functioning in the platelet activation and clearance. Our study aims to probe the roles and mechanisms of ADAM17 in pediatric ITP. METHODS The differently expressed ADAM17 in megakaryocytes was obtained from children with ITP through the next-generation RNA-Sequence. Hematoxylin-eosin and Giemsa staining were performed for cell morphology identification. Flow cytometry was applied to assess autoantibodies against platelets, subtypes of lymphocytes, the surface expression level of ADAM17 and polyploidization of megakaryocytes, as well as the full-length GP Ib α. RESULTS ADAM17 was significantly downregulated in megakaryocytes and platelets in children with ITP. Higher values of PDW and positive autoantibodies presence were observed in children with ITP. Loss of ADAM17 in mice led to defects in proplatelet formation and significantly elevated expression of phosphorylated myosin light chain (p-MLC) in megakaryocytes. CONCLUSIONS Our study indicated that the downregulation of ADAM17 might be an innate cause of inefficient platelet production in pediatric ITP.
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Affiliation(s)
- Qi Wang
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China.
| | - Jia Wei
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China
| | - Xi Jia
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China
| | - Xiao Feng
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China
| | - Zhenghua Ji
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China
| | - Xueqiang Ji
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China
| | - Xuejun Shao
- Department of Clinical Laboratory, Children's Hospital of Soochow University, Suzhou, 215025, Jiangsu Province, China.
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Liang C, Takahashi K, Furuya K, Ohkohchi N, Oda T. Dualistic role of platelets in living donor liver transplantation: Are they harmful? World J Gastroenterol 2022; 28:897-908. [PMID: 35317052 PMCID: PMC8908284 DOI: 10.3748/wjg.v28.i9.897] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 07/04/2021] [Accepted: 01/27/2022] [Indexed: 02/06/2023] Open
Abstract
Platelets are anucleate fragments mainly involved in hemostasis and thrombosis, and there is emerging evidence that platelets have other nonhemostatic potentials in inflammation, angiogenesis, regeneration and ischemia/reperfusion injury (I/R injury), which are involved in the physiological and pathological processes during living donor liver transplantation (LDLT). LDLT is sometimes associated with impaired regeneration and severe I/R injury, leading to postoperative complications and decreased patient survival. Recent studies have suggested that perioperative thrombocytopenia is associated with poor graft regeneration and postoperative morbidity in the short and long term after LDLT. Although it is not fully understood whether thrombocytopenia is the cause or result, increasing platelet counts are frequently suggested to improve posttransplant outcomes in clinical studies. Based on rodent experiments, previous studies have identified that platelets stimulate liver regeneration after partial hepatectomy. However, the role of platelets in LDLT is controversial, as platelets are supposed to aggravate I/R injury in the liver. Recently, a rat model of partial liver transplantation (LT) was used to demonstrate that thrombopoietin-induced thrombocytosis prior to surgery accelerated graft regeneration and improved the survival rate after transplantation. It was clarified that platelet-derived liver regeneration outweighed the associated risk of I/R injury after partial LT. Clinical strategies to increase perioperative platelet counts, such as thrombopoietin, thrombopoietin receptor agonist and platelet transfusion, may improve graft regeneration and survival after LDLT.
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Affiliation(s)
- Chen Liang
- Gastrointestinal and Hepatobiliary-Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Kazuhiro Takahashi
- Gastrointestinal and Hepatobiliary-Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Kinji Furuya
- Gastrointestinal and Hepatobiliary-Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Nobuhiro Ohkohchi
- Gastrointestinal and Hepatobiliary-Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
| | - Tatsuya Oda
- Gastrointestinal and Hepatobiliary-Pancreatic Surgery, University of Tsukuba, Tsukuba 3058575, Ibaraki, Japan
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Walle M, Asrie F, Gelaw Y, Getaneh Z. The role of platelet parameters for the diagnosis of preeclampsia among pregnant women attending at the University of Gondar Comprehensive Specialized Hospital antenatal care unit, Gondar, Ethiopia. J Clin Lab Anal 2022; 36:e24305. [PMID: 35202493 PMCID: PMC8993625 DOI: 10.1002/jcla.24305] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 01/22/2022] [Accepted: 02/12/2022] [Indexed: 11/17/2022] Open
Abstract
Background Preeclampsia (PE) is a pregnancy‐related illness characterized by high blood pressure (BP) and proteinuria after the 20th gestational week (GW). Platelet (PLT) parameter changes are the common hematological abnormalities observed in PE patients. The main aim of this study was to assess the role of PLT parameters for PE diagnosis among pregnant women. Methods A comparative cross‐sectional study was conducted at the University of Gondar Specialized Hospital. A total of 126 pregnant women (63 normotensive [NT] and 63 PE) were recruited using a convenient sampling method. Three milliliter blood was collected from each participant, and PLT parameters were determined using Sysmex XS‐500i analyzer. An independent t‐test supplemented with receiver‐operating characteristics (ROC) were used for comparisons and diagnostic value of PLT parameters between the study groups. Results Platelet count (PC) was significantly lower in the PE group compared to that in the NT group, whereas mean platelet volume (MPV), platelet large cell ratio (P‐LCR), and platelet distribution width (PDW) were significantly higher in PE. MPV had the largest area under the curve (AUC) [0.91: 95% CI; 0.85–0.96] followed by PC [0.79: 95% CI; 0.72–0.87]. MPV can differentiate PE patients from NT pregnant women at cut‐off value ≥12.10 fl (84.1% sensitivity and 87.3% specificity) while PC can indicate PE at a cut‐off value ≤176.5 × 109/L (65.1% sensitivity and 87.3% specificity). Conclusion A decreased PC and an increased MPV, P‐LCR, and PDW can be used as a simple, cost‐effective, quick, and reliable method of PE screening. Of them, MPV is the best indicator of PE.
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Affiliation(s)
- Muluken Walle
- Department of Medical laboratory science, College of Medicine and Health Sciences, Jigjiga University, Jigjiga, Ethiopia
| | - Fikir Asrie
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Yemataw Gelaw
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Zegeye Getaneh
- Department of Hematology and Immunohematology, School of Biomedical and Laboratory Sciences, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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Vélez-Páez JL, Legua P, Vélez-Páez P, Irigoyen E, Andrade H, Jara A, López F, Pérez-Galarza J, Baldeón L. Mean platelet volume and mean platelet volume to platelet count ratio as predictors of severity and mortality in sepsis. PLoS One 2022; 17:e0262356. [PMID: 34990467 PMCID: PMC8735631 DOI: 10.1371/journal.pone.0262356] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 12/21/2021] [Indexed: 01/20/2023] Open
Abstract
INTRODUCTION Sepsis is a public health problem due to its high prevalence and mortality. Mean platelet volume (MPV), a biomarker reported in routine blood counts, has been investigated and shows promise for determining fatal outcomes in septic patients. OBJECTIVE Evaluate whether the mean platelet volume (MPV) and mean platelet volume-to-platelet count (MPV/P) ratio are predictors of clinical severity and mortality in patients with sepsis. METHODS A prospective population cohort of 163 patients aged 18-97 years was recruited at the Intensive Care Unit of Pablo Arturo Hospital, Quito, Ecuador from 2017-2019 and followed up for 28 days. Patients were diagnosed with sepsis based on SEPSIS-3 septic shock criteria; in which the MPV and the MPV/P ratio were measured on days 1, 2, and 3. Sequential organ failure assessment (SOFA) score and presence of septic shock assessed clinical severity. Mortality on day 28 was considered the fatal outcome. RESULTS The average age of the patients was 61,15 years (SD 20,94) and female sex was predominant. MPV cutoff points at days 1, 2 and 3 were >9,45fL, >8,95fL and >8, 85fL; and (MPV/P) ratio >8, 18, >4, 12 y >3, 95, respectively. MPV at days 2 (9,85fL) and 3 (8,55fL) and (MPV/P) ratio at days 1 (4,42), 2 (4,21), and 3 (8,55), were predictors of clinical severity assessed by septic shock, which reached significance in the ROC curves. MPV and (MPV/P) ratio were also predictors of clinical severity determined by SOFA at days 1, 2, and 3, where higher values were observed in non-survivors reaching significance in all categories. MPV and MPV/P ratio at days 1, 2 and 3 were independent predictor factors of mortality using Cox proportional hazards model (HR 2,31; 95% CI 1,36-3,94), (HR 2,11; 95% CI 1,17-3,82), (HR 2,13; 95% CI 1,07-4,21) and (HR 2,38; 95% CI 1,38-4,12), (HR 2,15; 95% CI 1,14-4,06), (HR 4,43; 95% CI, 1,72-11,37) respectively. CONCLUSIONS MPV and the MPV/P ratio are predictors of clinical severity and mortality in sepsis. The MPV and its coefficient are indicators of the biological behavior of platelets in sepsis. They should be considered as a cost-effective and rapidly available tool that guides the treatment.
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Affiliation(s)
- Jorge Luis Vélez-Páez
- Facultad de Ciencias Médicas, Universidad Central del Ecuador, Quito, Ecuador
- Centro de Investigación Clínica en Medicina Crítica, Hospital Pablo Arturo Suárez, Quito, Ecuador
| | - Pedro Legua
- Instituto de Medicina Tropical Alexander von Humboldt, Universidad Peruana Cayetano Heredia, Lima, Perú
| | - Pablo Vélez-Páez
- Centro de Investigación Clínica en Medicina Crítica, Quito, Ecuador
- Unidad de Terapia Intensiva, Hospital General IESS de Ibarra, Imbabura, Ecuador
| | - Estefanía Irigoyen
- Centro de Investigación Clínica en Medicina Crítica, Hospital Pablo Arturo Suárez, Quito, Ecuador
| | - Henry Andrade
- Unidad de Terapia Intensiva, Hospital General IESS de Ibarra, Imbabura, Ecuador
| | - Andrea Jara
- Unidad de Emergencia, Hospital Básico de Machachi, Pichincha, Ecuador
| | - Fernanda López
- Instituto de Posgrado Medicina Crítica y Terapia Intensiva, Universidad Central del Ecuador, Quito, Ecuador
| | - Jorge Pérez-Galarza
- Facultad de Ciencias Médicas, Universidad Central del Ecuador, Quito, Ecuador
- Instituto de Investigación en Biomedicina, Universidad Central del Ecuador, Quito, Ecuador
| | - Lucy Baldeón
- Facultad de Ciencias Médicas, Universidad Central del Ecuador, Quito, Ecuador
- Instituto de Investigación en Biomedicina, Universidad Central del Ecuador, Quito, Ecuador
- * E-mail:
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Inhibition of LDHA to Induce EEF2 Release Enhances Thrombocytopoiesis. Blood 2022; 139:2958-2971. [PMID: 35176139 DOI: 10.1182/blood.2022015620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 02/14/2022] [Indexed: 11/20/2022] Open
Abstract
Translation is essential for megakaryocyte (MK) maturation and platelet production. However, how the translational pathways are regulated in this process remains unknown. In this study, we found that megakaryocyte/platelet-specific lactate dehydrogenase A (LdhA)-knockout mice showed an increased number of platelets with remarkably accelerated MK maturation and proplatelet formation. Interestingly, the role of LDHA in MK maturation and platelet formation did not depend on lactate content, which was the major product of LDHA. Mechanism studies revealed that LDHA interacted with eukaryotic elongation factor 2 (eEF2) in the cytoplasm, controlling the participation of eEF2 in translation at the ribosome. Furthermore, the interaction of LDHA and eEF2 was dependent on NADH, a coenzyme of LDHA. NADH-competitive inhibitors of LDHA could release eEF2 from the LDHA pool, up-regulate translation and enhance MK maturation in vitro. Among LDHA inhibitors, stiripentol significantly promoted the production of platelets in vivo under physiological state and in the immune thrombocytopenia model. Moreover, stiripentol could promote platelet production from human cord blood mononuclear cells (CBMCs)-derived megakaryocytes, and also have a superposed effect with romiplostim. In short, this study reveals a novel non-classical function of LDHA in translation and may serve as a potential target for thrombocytopenia therapy.
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Ribba AS, Fraboulet S, Sadoul K, Lafanechère L. The Role of LIM Kinases during Development: A Lens to Get a Glimpse of Their Implication in Pathologies. Cells 2022; 11:cells11030403. [PMID: 35159213 PMCID: PMC8834001 DOI: 10.3390/cells11030403] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/18/2022] [Accepted: 01/22/2022] [Indexed: 12/24/2022] Open
Abstract
The organization of cell populations within animal tissues is essential for the morphogenesis of organs during development. Cells recognize three-dimensional positions with respect to the whole organism and regulate their cell shape, motility, migration, polarization, growth, differentiation, gene expression and cell death according to extracellular signals. Remodeling of the actin filaments is essential to achieve these cell morphological changes. Cofilin is an important binding protein for these filaments; it increases their elasticity in terms of flexion and torsion and also severs them. The activity of cofilin is spatiotemporally inhibited via phosphorylation by the LIM domain kinases 1 and 2 (LIMK1 and LIMK2). Phylogenetic analysis indicates that the phospho-regulation of cofilin has evolved as a mechanism controlling the reorganization of the actin cytoskeleton during complex multicellular processes, such as those that occur during embryogenesis. In this context, the main objective of this review is to provide an update of the respective role of each of the LIM kinases during embryonic development.
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Discovery of a novel megakaryopoiesis enhancer, ingenol, promoting thrombopoiesis through PI3K-Akt signaling independent of thrombopoietin. Pharmacol Res 2022; 177:106096. [PMID: 35077844 DOI: 10.1016/j.phrs.2022.106096] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 01/08/2022] [Accepted: 01/20/2022] [Indexed: 01/09/2023]
Abstract
Thrombocytopenia, a most common complication of radiotherapy and chemotherapy, is an important cause of morbidity and mortality in cancer patients. However, there are still no approved agents for the treatment of radiation- and chemotherapy-induced thrombocytopenia (RIT and CIT, respectively). In this study, a drug screening model for predicting compounds with activity in promoting megakaryocyte (MK) differentiation and platelet production was established based on machine learning (ML), and a natural product ingenol was predicted as a potential active compound. Then, in vitro experiments showed that ingenol significantly promoted MK differentiation in K562 and HEL cells. Furthermore, a RIT mice model and c-MPL knock-out (c-MPL-/-) mice constructed by CRISPR/Cas9 technology were used to assess the therapeutic action of ingenol on thrombocytopenia. The results showed that ingenol accelerated megakaryopoiesis and thrombopoiesis both in RIT mice and c-MPL-/- mice. Next, RNA-sequencing (RNA-seq) was carried out to analyze the gene expression profile induced by ingenol during MK differentiation. Finally, through experimental verifications, we demonstrated that the activation of PI3K/Akt signaling pathway was involved in ingenol-induced MK differentiation. Blocking PI3K/Akt signaling pathway abolished the promotion of ingenol on MK differentiation. Nevertheless, inhibition of TPO/c-MPL signaling pathway could not suppress ingenol-induced MK differentiation. In conclusion, our study builds a drug screening model to discover active compounds against thrombocytopenia, reveals the critical roles of ingenol in promoting MK differentiation and platelet production, and provides a promising avenue for the treatment of RIT.
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Schrottmaier WC, Mussbacher M, Salzmann M, Kral-Pointner JB, Assinger A. PI3K Isoform Signalling in Platelets. Curr Top Microbiol Immunol 2022; 436:255-285. [PMID: 36243848 DOI: 10.1007/978-3-031-06566-8_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Platelets are unique anucleated blood cells that constantly patrol the vasculature to seal and prevent injuries in a process termed haemostasis. Thereby they rapidly adhere to the subendothelial matrix and recruit further platelets, resulting in platelet aggregates. Apart from their central role in haemostasis, they also kept some of their features inherited by their evolutionary ancestor-the haemocyte, which was also involved in immune defences. Together with leukocytes, platelets fight pathogenic invaders and guide many immune processes. In addition, they rely on several signalling pathways which are also relevant to immune cells. Among these, one of the central signalling hubs is the PI3K pathway. Signalling processes in platelets are unique as they lack a nucleus and therefore transcriptional regulation is absent. As a result, PI3K subclasses fulfil distinct roles in platelets compared to other cells. In contrast to leukocytes, the central PI3K subclass in platelet signalling is PI3K class Iβ, which underlines the uniqueness of this cell type and opens new ways for potential platelet-specific pharmacologic inhibition. An overview of platelet function and signalling with emphasis on PI3K subclasses and their respective inhibitors is given in this chapter.
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Affiliation(s)
- Waltraud C Schrottmaier
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Marion Mussbacher
- Department of Pharmacology and Toxicology, University of Graz, Graz, Austria
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, USA
| | - Manuel Salzmann
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - Julia B Kral-Pointner
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria
| | - Alice Assinger
- Department of Vascular Biology and Thrombosis Research, Centre of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria.
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Moore RP, O'Shaughnessy EC, Shi Y, Nogueira AT, Heath KM, Hahn KM, Legant WR. A multi-functional microfluidic device compatible with widefield and light sheet microscopy. LAB ON A CHIP 2021; 22:136-147. [PMID: 34859808 PMCID: PMC9022779 DOI: 10.1039/d1lc00600b] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
We present a microfluidic device compatible with high resolution light sheet and super-resolution microscopy. The device is a 150 μm thick chamber with a transparent fluorinated ethylene propylene (FEP) cover that has a similar refractive index (1.34) to water (1.33), making it compatible with top-down imaging used in light sheet microscopy. We provide a detailed fabrication protocol and characterize the optical performance of the device. We demonstrate that the device supports long-term imaging of cell growth and differentiation as well as the rapid addition and removal of reagents while simultaneously maintaining sterile culture conditions by physically isolating the sample from the dipping lenses used for imaging. Finally, we demonstrate that the device can be used for super-resolution imaging using lattice light sheet structured illumination microscopy (LLS-SIM) and DNA PAINT. We anticipate that FEP-based microfluidics, as shown here, will be broadly useful to researchers using light sheet microscopy due to the ability to switch reagents, image weakly adherent cells, maintain sterility, and physically isolate the specimen from the optics of the instruments.
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Affiliation(s)
- Regan P Moore
- Joint Biomedical Engineering Department, University of North Carolina at Chapel Hill, North Carolina State University, Chapel Hill, NC, 27599, USA.
| | - Ellen C O'Shaughnessy
- Pharmacology Department, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Yu Shi
- Joint Biomedical Engineering Department, University of North Carolina at Chapel Hill, North Carolina State University, Chapel Hill, NC, 27599, USA.
| | - Ana T Nogueira
- Pharmacology Department, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Katelyn M Heath
- Joint Biomedical Engineering Department, University of North Carolina at Chapel Hill, North Carolina State University, Chapel Hill, NC, 27599, USA.
| | - Klaus M Hahn
- Pharmacology Department, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
| | - Wesley R Legant
- Joint Biomedical Engineering Department, University of North Carolina at Chapel Hill, North Carolina State University, Chapel Hill, NC, 27599, USA.
- Pharmacology Department, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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Bong JH, Park JH, Sung JS, Lee CK, Lee GY, Kang MJ, Kim HO, Pyun JC. Rapid Analysis of Bacterial Contamination in Platelets without Pre-Enrichment Using Pig Serum-Derived Antibodies. ACS APPLIED BIO MATERIALS 2021; 4:7779-7789. [DOI: 10.1021/acsabm.1c00538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Ji-Hong Bong
- Department of Materials Science and Engineering, Yonsei University, 50 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Korea
| | - Jun-Hee Park
- Department of Materials Science and Engineering, Yonsei University, 50 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Korea
| | - Jeong Soo Sung
- Department of Materials Science and Engineering, Yonsei University, 50 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Korea
| | - Chang Kyu Lee
- Department of Materials Science and Engineering, Yonsei University, 50 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Korea
| | - Ga-Yeon Lee
- Department of Materials Science and Engineering, Yonsei University, 50 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Korea
| | - Min-Jung Kang
- Korea Institute of Science and Technology (KIST), Seoul 02792, Korea
| | - Hyun Ok Kim
- Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul 03722, Korea
| | - Jae-Chul Pyun
- Department of Materials Science and Engineering, Yonsei University, 50 Yonsei-Ro, Seodaemun-Gu, Seoul 03722, Korea
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O’Sullivan LR, Cahill MR, Young PW. The Importance of Alpha-Actinin Proteins in Platelet Formation and Function, and Their Causative Role in Congenital Macrothrombocytopenia. Int J Mol Sci 2021; 22:9363. [PMID: 34502272 PMCID: PMC8431150 DOI: 10.3390/ijms22179363] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 08/25/2021] [Accepted: 08/26/2021] [Indexed: 12/04/2022] Open
Abstract
The actin cytoskeleton plays a central role in platelet formation and function. Alpha-actinins (actinins) are actin filament crosslinking proteins that are prominently expressed in platelets and have been studied in relation to their role in platelet activation since the 1970s. However, within the past decade, several groups have described mutations in ACTN1/actinin-1 that cause congenital macrothrombocytopenia (CMTP)-accounting for approximately 5% of all cases of this condition. These findings are suggestive of potentially novel functions for actinins in platelet formation from megakaryocytes in the bone marrow and/or platelet maturation in circulation. Here, we review some recent insights into the well-known functions of actinins in platelet activation before considering possible roles for actinins in platelet formation that could explain their association with CMTP. We describe what is known about the consequences of CMTP-linked mutations on actinin-1 function at a molecular and cellular level and speculate how these changes might lead to the alterations in platelet count and morphology observed in CMTP patients. Finally, we outline some unanswered questions in this area and how they might be addressed in future studies.
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Affiliation(s)
- Leanne R. O’Sullivan
- School of Biochemistry & Cell Biology, University College Cork, T12 XF62 Cork, Ireland;
| | - Mary R. Cahill
- Department of Haematology and CancerResearch@UCC, Cork University Hospital, University College Cork, T12 XF62 Cork, Ireland;
| | - Paul W. Young
- School of Biochemistry & Cell Biology, University College Cork, T12 XF62 Cork, Ireland;
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Scheller I, Beck S, Göb V, Gross C, Neagoe RAI, Aurbach K, Bender M, Stegner D, Nagy Z, Nieswandt B. Thymosin β4 is essential for thrombus formation by controlling the G-actin/F-actin equilibrium in platelets. Haematologica 2021; 107:2846-2858. [PMID: 34348450 PMCID: PMC9713564 DOI: 10.3324/haematol.2021.278537] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Indexed: 12/14/2022] Open
Abstract
Coordinated rearrangements of the actin cytoskeleton are pivotal for platelet biogenesis from megakaryocytes but also orchestrate key functions of peripheral platelets in hemostasis and thrombosis, such as granule release, the formation of filopodia and lamellipodia, or clot retraction. Along with profilin (Pfn) 1, thymosin β4 (encoded by Tmsb4x) is one of the two main G-actin-sequestering proteins within cells of higher eukaryotes, and its intracellular concentration is particularly high in cells that rapidly respond to external signals by increased motility, such as platelets. Here, we analyzed constitutive Tmsb4x knockout (KO) mice to investigate the functional role of the protein in platelet production and function. Thymosin β4 deficiency resulted in a macrothrombocytopenia with only mildly increased platelet volume and an unaltered platelet life span. Megakaryocyte numbers in the bone marrow and spleen were unaltered, however, Tmsb4x KO megakaryocytes showed defective proplatelet formation in vitro and in vivo. Thymosin β4-deficient platelets displayed markedly decreased G-actin levels and concomitantly increased F-actin levels resulting in accelerated spreading on fibrinogen and clot retraction. Moreover, Tmsb4x KO platelets showed activation defects and an impaired immunoreceptor tyrosine-based activation motif (ITAM) signaling downstream of the activating collagen receptor glycoprotein VI. These defects translated into impaired aggregate formation under flow, protection from occlusive arterial thrombus formation in vivo and increased tail bleeding times. In summary, these findings point to a critical role of thymosin β4 for actin dynamics during platelet biogenesis, platelet activation downstream of glycoprotein VI and thrombus stability.
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Affiliation(s)
- Inga Scheller
- Institute of Experimental Biomedicine I, University Hospital, University of Würzburg, and Rudolf Virchow Center for Integrative and Translational BioImaging, University of Würzburg, Würzburg, Germany,*IS and SB contributed equally as co-first authors
| | - Sarah Beck
- Institute of Experimental Biomedicine I, University Hospital, University of Würzburg, and Rudolf Virchow Center for Integrative and Translational BioImaging, University of Würzburg, Würzburg, Germany,*IS and SB contributed equally as co-first authors
| | - Vanessa Göb
- Institute of Experimental Biomedicine I, University Hospital, University of Würzburg, and Rudolf Virchow Center for Integrative and Translational BioImaging, University of Würzburg, Würzburg, Germany
| | - Carina Gross
- Institute of Experimental Biomedicine I, University Hospital, University of Würzburg, and Rudolf Virchow Center for Integrative and Translational BioImaging, University of Würzburg, Würzburg, Germany
| | - Raluca A. I. Neagoe
- Institute of Experimental Biomedicine I, University Hospital, University of Würzburg, and Rudolf Virchow Center for Integrative and Translational BioImaging, University of Würzburg, Würzburg, Germany,Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK
| | - Katja Aurbach
- Institute of Experimental Biomedicine I, University Hospital, University of Würzburg, and Rudolf Virchow Center for Integrative and Translational BioImaging, University of Würzburg, Würzburg, Germany
| | - Markus Bender
- Institute of Experimental Biomedicine I, University Hospital, University of Würzburg, and Rudolf Virchow Center for Integrative and Translational BioImaging, University of Würzburg, Würzburg, Germany
| | - David Stegner
- Institute of Experimental Biomedicine I, University Hospital, University of Würzburg, and Rudolf Virchow Center for Integrative and Translational BioImaging, University of Würzburg, Würzburg, Germany
| | - Zoltan Nagy
- Institute of Experimental Biomedicine I, University Hospital, University of Würzburg, and Rudolf Virchow Center for Integrative and Translational BioImaging, University of Würzburg, Würzburg, Germany
| | - Bernhard Nieswandt
- Institute of Experimental Biomedicine I, University Hospital, University of Würzburg, and Rudolf Virchow Center for Integrative and Translational BioImaging, University of Würzburg, Würzburg, Germany,B. Nieswandt
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Wu X, Li Y, Tong H. Research Advances in the Subtype of Sepsis-Associated Thrombocytopenia. Clin Appl Thromb Hemost 2021; 26:1076029620959467. [PMID: 33054353 PMCID: PMC7573720 DOI: 10.1177/1076029620959467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The incidence and mortality of sepsis in the intensive care unit (ICU) are extremely high. Thrombocytopenia, one of the most common laboratory abnormalities, is correlated with prognosis in sepsis. The pathophysiology of sepsis-associated thrombocytopenia (SAT) remains unclear and may be associated with several factors such as platelet activation due to vascular injury and pathogen, suppression of bone marrow, platelet-targeted antibodies and desialylation. This review summarized all these possible mechanisms in the 3 subtypes of SAT: increased platelet consumption, reduced platelet production and increased platelet destruction. Based on the clinically available platelet parameters, the evidence for identifying SAT subtypes and the recent progress in treatments according to these subtypes are proposed to provide new prospects for the management of SAT.
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Affiliation(s)
- Xinghui Wu
- The First School of Clinical Medicine, 70570Southern Medical University, Guangzhou, People's Republic of China
| | - Yue Li
- Department of Intensive Care Unit, 26470PLA General Hospital of Southern Theatre Command, Key Laboratory of Tropical Zone Trauma Care and Tissue Repair of PLA, Guangzhou, People's Republic of China
| | - Huasheng Tong
- Department of Intensive Care Unit, 26470PLA General Hospital of Southern Theatre Command, Key Laboratory of Tropical Zone Trauma Care and Tissue Repair of PLA, Guangzhou, People's Republic of China
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Vélez PA, Baldeón R L, Vélez-Paez JL. The behavior of Mean Platelet Volume in Sepsis in critical patients with and without sepsis. BIONATURA 2021. [DOI: 10.21931/rb/2021.06.02.22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
The mean platelet volume is an anatomical biomarker that has shown its usefulness in various cardiovascular and metabolic pathologies; in sepsis, it has been positioning itself as an indicator of mortality, easily accessible and immediately applicable when reported in the routine blood count. This study demonstrates the mean platelet volume's biological behavior in critical patients with sepsis compared with non-septic patients. An observational, longitudinal, prospective, monocentric cohort study was conducted in 250 patients treated at the intensive care unit of the Pablo Arturo Suárez Hospital, Quito- Ecuador, from January 2019 January 2020. A group of patients with sepsis (n = 125) and without infectious pathologies (n = 125) were studied. The inclusion criteria were patients over 18 years of age of both genders, diagnosed with sepsis or septic shock using SEPSIS 3 criteria, and patients without septic pathology. The mean platelet volume (MPV) of days 1, 2, and 3 were studied. Septic patients had a mean APACHE (18.74 SD 9.52) higher than the non-septic ones (11.93 SD 7.01) (p = < 0.000). The MPV was consistently higher in patients with sepsis than non-septic patients, but it reached statistical significance on day 3 (9.13 SD 1.55 vs. 8.66 SD 1.34, p=0.042). The MPV on day 3 presented a significant area under the curve (AUC =0.580) (CI. 0.500-0.661), where the cut-off point according to Youden's index was positive for sepsis if MPV≥ 9.85 femtoliter (fL) with OR=3.30 and p-value= 0.005. Likewise, lactate on admission showed an AUC of 0.625 (CI. 0.555-0.694), with a cut-off point ≥of 1.15 mmol / L, OR=2.51, and p=0.007. Age and hypertension did not show a multivariate relationship with the presence of sepsis. It was shown that MPV is higher in patients with sepsis compared to non-septic ones. This observation reaches significance on day 3. Additionally, elevated lactate at admission was also associated with a septic state. On the other hand, platelet count did not show the expected behavior.
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Affiliation(s)
| | - Lucy Baldeón R
- Facultad de Ciencias Médicas-Universidad Central del Ecuador Instituto de Investigación en Biomedicina Universidad Central del Ecuador
| | - Jorge Luis Vélez-Paez
- Servicio de Medicina Crítica-Hospital Pablo Arturo Suárez Facultad de Ciencias Médicas-Universidad Central del Ecuador
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Actin/microtubule crosstalk during platelet biogenesis in mice is critically regulated by Twinfilin1 and Cofilin1. Blood Adv 2021; 4:2124-2134. [PMID: 32407474 DOI: 10.1182/bloodadvances.2019001303] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 03/13/2020] [Indexed: 01/24/2023] Open
Abstract
Rearrangements of the microtubule (MT) and actin cytoskeleton are pivotal for platelet biogenesis. Hence, defects in actin- or MT-regulatory proteins are associated with platelet disorders in humans and mice. Previous studies in mice revealed that loss of the actin-depolymerizing factor homology (ADF-H) protein Cofilin1 (Cof1) in megakaryocytes (MKs) results in a moderate macrothrombocytopenia but normal MK numbers, whereas deficiency in another ADF-H protein, Twinfilin1 (Twf1), does not affect platelet production or function. However, recent studies in yeast have indicated a critical synergism between Twf1 and Cof1 in the regulation of actin dynamics. We therefore investigated platelet biogenesis and function in mice lacking both Twf1 and Cof1 in the MK lineage. In contrast to single deficiency in either protein, Twf1/Cof1 double deficiency (DKO) resulted in a severe macrothrombocytopenia and dramatically increased MK numbers in bone marrow and spleen. DKO MKs exhibited defective proplatelet formation in vitro and in vivo as well as impaired spreading and altered assembly of podosome-like structures on collagen and fibrinogen in vitro. These defects were associated with aberrant F-actin accumulation and, remarkably, the formation of hyperstable MT, which appears to be caused by dysregulation of the actin- and MT-binding proteins mDia1 and adenomatous polyposis coli. Surprisingly, the mild functional defects described for Cof1-deficient platelets were only slightly aggravated in DKO platelets suggesting that both proteins are largely dispensable for platelet function in the peripheral blood. In summary, these findings reveal critical redundant functions of Cof1 and Twf1 in ensuring balanced actin/microtubule crosstalk during thrombopoiesis in mice and possibly humans.
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Heib T, Hermanns HM, Manukjan G, Englert M, Kusch C, Becker IC, Gerber A, Wackerbarth LM, Burkard P, Dandekar T, Balkenhol J, Jahn D, Beck S, Meub M, Dütting S, Stigloher C, Sauer M, Cherpokova D, Schulze H, Brakebusch C, Nieswandt B, Nagy Z, Pleines I. RhoA/Cdc42 signaling drives cytoplasmic maturation but not endomitosis in megakaryocytes. Cell Rep 2021; 35:109102. [PMID: 33979620 DOI: 10.1016/j.celrep.2021.109102] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 02/20/2021] [Accepted: 04/18/2021] [Indexed: 12/15/2022] Open
Abstract
Megakaryocytes (MKs), the precursors of blood platelets, are large, polyploid cells residing mainly in the bone marrow. We have previously shown that balanced signaling of the Rho GTPases RhoA and Cdc42 is critical for correct MK localization at bone marrow sinusoids in vivo. Using conditional RhoA/Cdc42 double-knockout (DKO) mice, we reveal here that RhoA/Cdc42 signaling is dispensable for the process of polyploidization in MKs but essential for cytoplasmic MK maturation. Proplatelet formation is virtually abrogated in the absence of RhoA/Cdc42 and leads to severe macrothrombocytopenia in DKO animals. The MK maturation defect is associated with downregulation of myosin light chain 2 (MLC2) and β1-tubulin, as well as an upregulation of LIM kinase 1 and cofilin-1 at both the mRNA and protein level and can be linked to impaired MKL1/SRF signaling. Our findings demonstrate that MK endomitosis and cytoplasmic maturation are separately regulated processes, and the latter is critically controlled by RhoA/Cdc42.
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Affiliation(s)
- Tobias Heib
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany
| | - Heike M Hermanns
- Department of Internal Medicine II, Hepatology Research Laboratory, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Georgi Manukjan
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany
| | - Maximilian Englert
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany
| | - Charly Kusch
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany
| | - Isabelle Carlotta Becker
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany
| | - Annika Gerber
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany
| | - Lou Martha Wackerbarth
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany
| | - Philipp Burkard
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany
| | - Thomas Dandekar
- Department of Bioinformatics, Biocenter, University of Würzburg, 97074 Würzburg, Germany
| | - Johannes Balkenhol
- Department of Internal Medicine II, Hepatology Research Laboratory, University Hospital Würzburg, 97080 Würzburg, Germany; Department of Bioinformatics, Biocenter, University of Würzburg, 97074 Würzburg, Germany
| | - Daniel Jahn
- Department of Internal Medicine II, Hepatology Research Laboratory, University Hospital Würzburg, 97080 Würzburg, Germany
| | - Sarah Beck
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany
| | - Mara Meub
- Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, 97074 Würzburg, Germany
| | - Sebastian Dütting
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany
| | - Christian Stigloher
- Imaging Core Facility, Biocenter, University of Würzburg, 97074 Würzburg, Germany
| | - Markus Sauer
- Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, 97074 Würzburg, Germany
| | - Deya Cherpokova
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany
| | - Harald Schulze
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany
| | - Cord Brakebusch
- Biotech Research and Innovation Centre (BRIC), University of Copenhagen, 2200 Copenhagen, Denmark
| | - Bernhard Nieswandt
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany.
| | - Zoltan Nagy
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany
| | - Irina Pleines
- Institute of Experimental Biomedicine, University Hospital, University of Würzburg, 97080 Würzburg, Germany; Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany.
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