1
|
Kapteijn MY, Bakker N, Koekkoek JAF, Versteeg HH, Buijs JT. Venous Thromboembolism in Patients with Glioblastoma: Molecular Mechanisms and Clinical Implications. Thromb Haemost 2025; 125:421-434. [PMID: 39168144 PMCID: PMC12040436 DOI: 10.1055/s-0044-1789592] [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: 04/11/2024] [Accepted: 08/06/2024] [Indexed: 08/23/2024]
Abstract
Patients with glioblastoma are among the cancer patients with the highest risk of developing venous thromboembolism (VTE). Long-term thromboprophylaxis is not generally prescribed because of the increased susceptibility of glioblastoma patients to intracranial hemorrhage. This review provides an overview of the current clinical standard for glioblastoma patients, as well as the molecular and genetic background which underlies the high incidence of VTE. The two main procoagulant proteins involved in glioblastoma-related VTE, podoplanin and tissue factor, are described, in addition to the genetic aberrations that can be linked to a hypercoagulable state in glioblastoma. Furthermore, possible novel biomarkers and future treatment strategies are discussed, along with the potential of sequencing approaches toward personalized risk prediction for VTE. A glioblastoma-specific VTE risk stratification model may help identifying those patients in which the increased risk of bleeding due to extended anticoagulation is outweighed by the decreased risk of VTE.
Collapse
Affiliation(s)
- Maaike Y. Kapteijn
- Division of Thrombosis and Hemostasis, Department of Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Nina Bakker
- Division of Thrombosis and Hemostasis, Department of Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Johan A. F. Koekkoek
- Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands
| | - Henri H. Versteeg
- Division of Thrombosis and Hemostasis, Department of Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Jeroen T. Buijs
- Division of Thrombosis and Hemostasis, Department of Medicine, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
| |
Collapse
|
2
|
Aksoy RA, Koca T, Şengün Y, Atak E, Korcum AF. The Impact of Coagulation Biomarkers on Survival Outcomes in Adult Glioblastoma. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:756. [PMID: 40283046 PMCID: PMC12029277 DOI: 10.3390/medicina61040756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/09/2025] [Accepted: 04/17/2025] [Indexed: 04/29/2025]
Abstract
Background and Objectives: Glioblastoma presents a significant challenge in oncology due to its aggressive nature and poor prognosis, despite advancements in treatment. This study aims to comprehensively evaluate the prognostic significance of coagulation biomarkers, including the novel albumin/D-dimer ratio, in adult glioblastoma patients. Material and Methods: This retrospective study included 74 adult glioblastoma patients who underwent Stupp protocol treatment. Blood samples were collected before radiotherapy to measure biomarkers, including prothrombin time (PT), activated partial thromboplastin time (aPTT), albumin, D-dimer, and the albumin/D-dimer ratio. The prognostic significance of these biomarkers for progression-free survival (PFS) and overall survival (OS) was assessed using both univariate and multivariate Cox regression analyses. Results: The median follow-up time was 12.2 months (range, 1-77.4 months). Univariate analysis revealed that ECOG performance status (p = 0.001), D-dimer (p = 0.03), and albumin (p = 0.001) were significant prognostic factors for PFS. Multivariate analysis identified albumin (p = 0.02) as an independent prognostic biomarker for PFS. For OS, univariate analysis showed that age (p = 0.004), ECOG performance status (p = 0.001), tumor volume (p = 0.007), extent of resection (p = 0.01), radiotherapy dose (p = 0.001), D-dimer (p = 0.02), albumin (p = 0.001), albumin/D-dimer ratio (p = 0.02), and PT (p = 0.002) were significant prognostic factors. Multivariate analysis revealed age (p = 0.04), extent of resection (p = 0.02), and PT (p = 0.04) as independent prognostic factors for OS. Conclusions: Our findings highlight the prognostic significance of coagulation biomarkers, particularly PT, D-dimer, albumin, and the albumin/D-dimer ratio, in glioblastoma. These biomarkers may serve as valuable tools for prognostic assessment and personalized treatment strategies, warranting further exploration in larger prospective studies.
Collapse
Affiliation(s)
- Rahmi Atıl Aksoy
- Department of Radiation Oncology, Akdeniz University Faculty of Medicine, Antalya 07070, Turkey; (T.K.); (Y.Ş.); (E.A.); (A.F.K.)
- Department of Radiation Oncology, Izmir City Hospital, Izmir 35530, Turkey
| | - Timur Koca
- Department of Radiation Oncology, Akdeniz University Faculty of Medicine, Antalya 07070, Turkey; (T.K.); (Y.Ş.); (E.A.); (A.F.K.)
| | - Yasemin Şengün
- Department of Radiation Oncology, Akdeniz University Faculty of Medicine, Antalya 07070, Turkey; (T.K.); (Y.Ş.); (E.A.); (A.F.K.)
- Department of Radiation Oncology, Van Education and Research Hospital, Van 65300, Turkey
| | - Ece Atak
- Department of Radiation Oncology, Akdeniz University Faculty of Medicine, Antalya 07070, Turkey; (T.K.); (Y.Ş.); (E.A.); (A.F.K.)
| | - Aylin Fidan Korcum
- Department of Radiation Oncology, Akdeniz University Faculty of Medicine, Antalya 07070, Turkey; (T.K.); (Y.Ş.); (E.A.); (A.F.K.)
| |
Collapse
|
3
|
Pelegrín-Mateo FJ, Zambrano CB, Vázquez EB, Escobar IG, Martín AM. Cancer genetic profile and risk of thrombosis. Eur J Intern Med 2025:S0953-6205(25)00137-2. [PMID: 40221227 DOI: 10.1016/j.ejim.2025.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 04/02/2025] [Accepted: 04/07/2025] [Indexed: 04/14/2025]
Abstract
Cancer-associated thrombosis (CAT) remains a leading cause of morbidity and mortality among oncology patients, with an incidence influenced by tumor type, stage, treatment, and molecular characteristics. This review explores the molecular determinants of venous thromboembolism (VTE) in cancer, emphasizing its pathophysiology and association with specific oncogenic alterations. Certain molecular profiles exhibit heightened VTE risk. In lung cancer, due to hypercoagulability mechanisms linked to tissue factor overexpression, an increased incidence of VTE has been reported in populations with ALK (30-40 %) and ROS1 rearrangements (34.7-46.6 %). In gastrointestinal cancers, while pancreatic adenocarcinoma has the highest VTE rates (up to 22 %), KRAS mutations seem to be implicated but not conclusively validated. Similarly, colorectal cancer mutations (KRAS/BRAFV600E) and antiangiogenic therapies may elevate thrombotic risk, warranting further study. High-grade gliomas, particularly glioblastomas, present VTE rates up to 30 %, driven by podoplanin-induced platelet aggregation. IDH1 mutations inversely correlate with thrombosis, highlighting its protective role. Emerging evidence suggests that agnostic biomarkers such as STK11 mutations influence VTE risk across tumor types, while others like KRAS, MET and BRCA mutations show inconclusive results. Large-scale validation studies are imperative to integrate molecular profiles into clinical practice. Until then, management decisions should be individualized, balancing the thrombotic risks with oncologic considerations.
Collapse
Affiliation(s)
- Francisco J Pelegrín-Mateo
- Medical Oncology Department, Hospital General Universitario Dr. Balmis, Av. Pintor Baeza 12, 03010. Alicante, Spain.
| | - Carmen Beato Zambrano
- Medical Oncology Department, Hospital Universitario Virgen de la Macarena, Av. Dr. Fedriani 3, 41009. Sevilla, Spain
| | - Elena Brozos Vázquez
- Medical Oncology Department, Complejo Hospitalario de A Coruña. C. As rubias 84, 15006. A Coruña, Spain
| | - Ignacio García Escobar
- Medical Oncology Department, Hospital General Universitario de Toledo, Av. Río Guadiana, 45007. Toledo, Spain
| | - Andrés Muñoz Martín
- Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Universidad Complutense. C. Dr Esquerdo 46, 28007. Madrid, Spain
| |
Collapse
|
4
|
Avitsian R, Mohammadi AM, Beresian J, Nuti AM, Jolly S, Volovetz J, Avitsian T, Budiansky AS, Mi J, Liu X. Duplex Ultrasound Screening for Deep Venous Thrombosis in Patients Undergoing Craniotomy for Intracranial Tumors: A Single Institutional Series. J Neurosurg Anesthesiol 2025; 37:232-238. [PMID: 39297241 DOI: 10.1097/ana.0000000000001007] [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: 03/18/2024] [Accepted: 08/21/2024] [Indexed: 03/04/2025]
Abstract
OBJECTIVE The frequency of duplex ultrasound screening (DUS) for deep vein thrombosis (DVT) in patients with brain tumors undergoing craniotomy is center-specific. We evaluated clinical conditions that increase the tendency to perform DUS, focusing on tumor type. METHODS This is a single-center retrospective analysis to assess the association of intracranial tumor type with DVT as a major decision-making indicator for DUS. A primary analysis investigated the association between tumor pathology and preoperative DVT, and a secondary analysis investigated the development of DVT postoperatively. Confounding factors were defined and included in both analyses. RESULTS Among 1478 patients, 751 had preoperative DUS and 35 (5%) had DVT. No significant difference in the odds of preoperative DVT was observed between patients having malignant glioma versus benign tumors (odds ratio [OR; 95% CI]: 1.68 [0.65, 4.35], P = 0.29), or metastatic tumors versus benign tumors (OR: 2.10; 95% CI: 0.75-5.89; P = 0.16). Among patients with negative preoperative DUS, 93 underwent postoperative evaluation and 20 (22%) were diagnosed with postoperative DVT. Malignant glioma or (OR: 1.69; 95% CI: 0.36-7.84; P = 0.50) metastatic tumors (OR: 1.84; 95% CI: 0.29-11.5; P = 0.52) were not associated with postoperative DVT versus benign tumors. CONCLUSION Brain tumor pathology may not increase the risk for DVT and may not be a good indicator for the selection of patients for DVT screening with DUS. The incidence of DVT in selective preoperative DUS was similar to studies that performed DUS on all patients. Further studies across multiple institutions are needed to develop criteria for DUS in brain tumor surgery.
Collapse
Affiliation(s)
| | | | | | | | - Sagar Jolly
- Department of Anesthesiology, Perioperative Medicine and Pain Management, Miller School of Medicine, University of Miami, Miami, FL
| | | | - Taleen Avitsian
- Emergency Department, Cleveland Clinic Akron General Hospital, Akron, OH
| | - Adele S Budiansky
- Department of Anesthesiology and Pain Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Junhui Mi
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH
| | - Xiaodan Liu
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH
| |
Collapse
|
5
|
Desai S, Thorat P, Majumdar A. A promise of nose to brain delivery of bevacizumab intranasal sol-gel formulation substantiated in rat C6 glioma model. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4123-4148. [PMID: 39417842 DOI: 10.1007/s00210-024-03536-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/09/2024] [Indexed: 10/19/2024]
Abstract
Glioblastoma is one of the rapidly spreading cancers, with its potent malignancy often linked to pronounced angiogenesis within tumors. To mitigate this vascularization profile, bevacizumab (Avastin®), a monoclonal antibody, has been utilized for its antiangiogenic activity. However, its effectiveness is hindered by challenges in crossing the blood-brain barrier and the risk of off-target organ toxicity. Delivering drugs directly from the nose to the brain through the olfactory or trigeminal nerves bypassing the blood-brain barrier offers enhanced bioavailability and a more precise targeting strategy. To overcome these challenges, we aimed to develop bevacizumab in situ gel loaded mesoporous silica nanoparticles for intranasal delivery and further examine their pharmacokinetic and pharmacodynamic characteristics. The intranasal gel of mesoporous silica nanoparticles loaded with bevacizumab was optimized and formulated using a factorial and quality by design approach. In the case of bevacizumab mesoporous silica nanoparticles, lower particle size and most negative zeta potential were selected as quality target product profiles which is important for drug loading on the mesoporous silica nanoparticles and also transport of these nanoparticles across the nasal mucosa to the brain. A design space with a multidimensional combination of input variables and process parameters has been demonstrated to assure quality. To optimize the design space and achieve the desired quality standards, the base catalyst and surfactant concentration were chosen as the critical process parameters, while particle size and zeta potential were identified as the critical quality attributes. The novel formulation was assessed for physicochemical parameters such as particle size, zeta potential, entrapment efficiency, appearance, color, consistency, and pH. Additionally, studies on in vitro release, ex vivo permeation, stability, nasal toxicity, organ safety, and bioavailability were conducted. The efficacy study was conducted in an orthotopic murine glioblastoma rat model in which C6 Luc cells were instilled in the striatum of the rat's brain. In vivo, bioluminescence imaging of brain tumors was carried out to observe the tumor regression after treatment with the intranasal and intravenous bevacizumab formulation. Biochemical parameters and histopathology were performed for organ safety studies. The optimized intranasal formulation exhibited an average particle size of 318.8 nm and a zeta potential of - 14.7 mV for the mesoporous silica nanoparticles. The formulation also demonstrated an entrapment efficiency of 91.34% and a loading capacity of 45.67%. Further pharmacokinetic studies revealed that the optimized intranasal bevacizumab formulation achieved a significantly higher brain concentration Cmax = 147.9 ng/ml, indicating improved bioavailability compared to rats administered with intravenous bevacizumab formulation (BEVATAS®), which had a Cmax of 127.2 ng/ml. Moreover, this nanoparticle formulation entirely mitigated systemic exposure to bevacizumab. Organ safety evaluation of different biochemical parameters and histopathological analyses revealed that the intranasal bevacizumab-treated group was showing less off-target organ toxicity compared to the group treated with intravenous bevacizumab formulation. Subsequently, the efficacy of this nanosystem was evaluated in an orthotopic glioblastoma rat model, monitoring tumor growth over time through in vivo bioluminescence imaging and assessing anti-angiogenic effects. Twenty-one days post-induction, mesoporous silica nanoparticles loaded with bevacizumab in situ gel exhibited a marked reduction in average bioluminescence radiance (4.39 × 103) from day 7 (1.35 × 107) emphasizing an enhanced anti-angiogenic effect compared to the group treated with intravenous bevacizumab formulation which showed a gradual decrease in average bioluminescence radiance (4.82 × 104) from day 7 (1.42 × 107). These results suggest that the proposed novel formulation of mesoporous silica nanoparticles loaded bevacizumab in situ gel could serve as a promising avenue to enhance glioblastoma treatment efficacy, thereby potentially improving patient quality of life and survival rates significantly. Furthermore, the success of this delivery method could open new avenues for treating other neurological disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and stroke. By providing effective brain-targeted therapies, this approach has the potential to revolutionize treatment options and improve outcomes for a broad spectrum of neurological conditions.
Collapse
Affiliation(s)
- Siddhesh Desai
- Department of Pharmacology, Bombay College of Pharmacy, Santacruz East, Mumbai, 400098, India
| | - Prajakta Thorat
- Department of Pharmacology, Bombay College of Pharmacy, Santacruz East, Mumbai, 400098, India
| | - Anuradha Majumdar
- Department of Pharmacology, Bombay College of Pharmacy, Santacruz East, Mumbai, 400098, India.
| |
Collapse
|
6
|
Zuo M, Li T, Wang Z, Xiang Y, Chen S, Liu Y. Research progress on platelets in glioma. Chin Med J (Engl) 2025; 138:28-37. [PMID: 39252160 PMCID: PMC11717503 DOI: 10.1097/cm9.0000000000003282] [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: 01/10/2024] [Indexed: 09/11/2024] Open
Abstract
ABSTRACT Gliomas are the most common primary neuroepithelial tumors of the central nervous system in adults, of which glioblastoma is the deadliest subtype. Apart from the intrinsically indestructible characteristics of glioma (stem) cells, accumulating evidence suggests that the tumor microenvironment also plays a vital role in the refractoriness of glioblastoma. The primary functions of platelets are to stop bleeding and regulate thrombosis under physiological conditions. Furthermore, platelets are also active elements that participate in a variety of processes of tumor development, including tumor growth, invasion, and chemoresistance. Glioma cells recruit and activate resting platelets to become tumor-educated platelets (TEPs), which in turn can promote the proliferation, invasion, stemness, and chemoresistance of glioma cells. TEPs can be used to obtain genetic information about gliomas, which is helpful for early diagnosis and monitoring of therapeutic effects. Platelet membranes are intriguing biomimetic materials for developing efficacious drug carriers to enhance antiglioma activity. Herein, we review the recent research referring to the contribution of platelets to the malignant characteristics of gliomas and focusing on the molecular mechanisms mediating the interaction between TEPs and glioma (stem) cells, as well as present the challenges and opportunities in targeting platelets for glioma therapy.
Collapse
Affiliation(s)
- Mingrong Zuo
- Department of Pediatric Neurosurgery, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Tengfei Li
- Department of Pediatric Neurosurgery, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Zhihao Wang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yufan Xiang
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Siliang Chen
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yanhui Liu
- Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| |
Collapse
|
7
|
Scheer M, Schenk G, Taute B, Richter M, Hlavac M, Gempt J, Krammer M, Shiban E, Sabel M, Stein M, Wienke A, Höllig A, Strauss C, Rampp S, Prell J. Intraoperative Intermittent Pneumatic Compression Reduces Incidence of Venous Thromboembolism in Patients Undergoing Craniotomy: Study Protocol of a Randomized Multicenter, Single-Blind Trial. NEUROSURGERY PRACTICE 2024; 5:e00109. [PMID: 39959548 PMCID: PMC11809995 DOI: 10.1227/neuprac.0000000000000109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 07/04/2024] [Indexed: 02/18/2025]
Abstract
BACKGROUND AND OBJECTIVE Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication in craniotomy patients. The duration of surgery has been identified as a risk factor for the development of VTE. In a pilot study, the use of intermittent pneumatic venous compression (IPC) dramatically reduced the incidence of VTE. Despite randomization, a significant difference in the duration of surgery between the groups limited the validity of this result. The study was underpowered to compensate for this problem. We now present the protocol of a multicenter trial. METHODS All patients receive medical compression stockings and low-molecular-weight heparin from the first postoperative day. The therapy group receives IPC stockings intraoperatively. Postoperatively, all patients receive lower-extremity duplex sonography to detect/exclude DVT within the first 7 postoperative days. Contrast-enhanced chest CT is the gold standard for the detection of PE and is performed in cases of clinical suspicion of PE. EXPECTED OUTCOMES The incidence of VTE is the primary end point. The distinction between symptomatic and asymptomatic, etiologies, influence of lesion type, duration of surgery, and mortality will be evaluated as secondary end points. The pilot study showed a VTE incidence of 26% in the control group vs 7% in the treatment group. To avoid overly optimistic treatment effect assumptions, we assume VTE rates of 9% and 24% in the treatment and control groups, respectively, and thus calculated a number of 127 patients per treatment group. DISCUSSION If this trial shows that intraoperative IPC reduces the risk of VTE to the extent observed in our pilot study (number needed to treat: 5.24), the potential benefit to neurosurgical patients would be significant. The results would potentially influence treatment guidelines by providing the high-quality evidence needed to make robust recommendations.
Collapse
Affiliation(s)
- Maximilian Scheer
- Department of Neurosurgery, University Hospital Halle, Halle, Germany
| | - Grit Schenk
- Department of Neurosurgery, University Hospital Halle, Halle, Germany
| | - Bettina Taute
- Department of Internal Medicine, Angiology Division, University Hospital Halle, Halle, Germany
| | - Michael Richter
- Coordination Center for Clinical Trials, University of Halle, Halle, Germany
| | - Michael Hlavac
- Department of Neurosurgery, Bezirksklinikum Günzburg, University of Ulm, Ulm, Germany
| | - Jens Gempt
- Department of Neurosurgery, University Hopsital Hamburg-Eppendorf, Hamburg, Germany
| | - Matthias Krammer
- Department of Neurosurgery, Klinikum Bogenhausen, München, Germany
| | - Ehab Shiban
- Department of Neurosurgery, Carl-Thiem-Klinikum Cottbus, Cottbus, Germany
| | - Michael Sabel
- Department of Neurosurgery, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Marco Stein
- Department of Neurosurgery, University Hospital Gießen, Giessen, Germany
| | - Andreas Wienke
- Institute of Medical Epidemiology, Biostatistics, and Informatics, University of Halle-Wittenberg, Halle, Germany
| | - Anke Höllig
- Department of Neurosurgery, University Hospital Aachen, Aachen, Germany
| | - Christian Strauss
- Department of Neurosurgery, University Hospital Halle, Halle, Germany
| | - Stefan Rampp
- Department of Neurosurgery, University Hospital Halle, Halle, Germany
- Department of Neurosurgery, Department of Neuroradiology, University Hospital Erlangen, Erlangen, Germany
| | - Julian Prell
- Department of Neurosurgery, University Hospital Halle, Halle, Germany
| |
Collapse
|
8
|
Zimmer K, Scheer M, Scheller C, Leisz S, Strauss C, Taute BM, Mühlenweg M, Prell J, Simmermacher S, Rampp S. Influence of postoperative D-dimer evaluation and intraoperative use of intermittent pneumatic vein compression (IPC) on detection and development of perioperative venous thromboembolism in brain tumor surgery. Acta Neurochir (Wien) 2024; 166:480. [PMID: 39592521 PMCID: PMC11599535 DOI: 10.1007/s00701-024-06379-2] [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: 10/04/2024] [Accepted: 11/22/2024] [Indexed: 11/28/2024]
Abstract
BACKGROUND OBJECTIVE Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication in craniotomy patients and is associated with increased morbidity and mortality. The duration of surgery is a known risk factor. Other factors such as positioning and tumor entity have hardly been investigated or are controversial. In two pilot studies, the determination of plasma D-dimer concentration led to a high detection rate of DVT, while the use of intermittent pneumatic venous compression (IPC) drastically reduced the incidence of VTE. In the present study we investigated the efficacy of the two approaches, either alone or in combination, in a large patient cohort. METHODS 1759 patients who underwent elective craniotomy between 2009 and 2023 were retrospectively analyzed. The staggered use of D-dimer determination and intraoperative use of IPC resulted in 3 groups: Group 1: no procedure; Group 2: D-dimer evaluation; Group 3: IPC and D-dimer evaluation. If the D-dimer level was ≥ 2 mg/l (Fibrinogen equivalent units; FEU), venous ultrasound was performed. Age, gender, tumor entity, duration and extent of surgery, patient positioning, type of VTE were also recorded and analyzed. RESULTS The introduction of postoperative D-dimer evaluation increased the rate of detection of thrombosis from 1.7% in group 1 to 22.6% in group 2. The addition of IPC reduced the rate of thrombosis to 4.4%. Age, gender and patient positioning did not affect the rate of VTE. We were able to confirm the duration of surgery as an individual risk factor and showed that WHO grade 4 tumors and metastasis have an increased VTE risk. CONCLUSIONS If D-Dimer levels are not analyzed routinely about 20% of craniotomy patients suffer from a clinically silent thrombosis. Each with the risk of fate PE. Intraoperative use of IPC during craniotomy dramatically reduces the risk of VTE.
Collapse
Affiliation(s)
- Katharina Zimmer
- Department of Neurosurgery University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Maximilian Scheer
- Department of Neurosurgery University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany.
| | - Christian Scheller
- Department of Neurosurgery University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Sandra Leisz
- Department of Neurosurgery University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Christian Strauss
- Department of Neurosurgery University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Bettina-Maria Taute
- Department of Cardiology, Angiology and Intensive Care Medicine, University Hospital Halle (Saale), Halle, Germany
| | - Martin Mühlenweg
- Department of Cardiology, Angiology and Intensive Care Medicine, University Hospital Halle (Saale), Halle, Germany
| | - Julian Prell
- Department of Neurosurgery University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Sebastian Simmermacher
- Department of Neurosurgery University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany
| | - Stefan Rampp
- Department of Neurosurgery University Hospital Halle (Saale), Martin-Luther-University Halle-Wittenberg, Halle, Germany
- Department of Neurosurgery, University Hospital Erlangen, Erlangen, Germany
| |
Collapse
|
9
|
Hovman FR, Poulsen FR, Hansen S, Dahlrot RH. The risk of venous thromboembolism in adult patients with diffuse glioma: a nationwide population-based study. Acta Oncol 2024; 63:887-892. [PMID: 39543846 PMCID: PMC11579532 DOI: 10.2340/1651-226x.2024.40137] [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: 02/22/2024] [Accepted: 10/29/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND AND PURPOSE Venous thromboembolism (VTE) is a cause of increased morbidity and risk of death. Studies report VTE in up to 30% of glioma patients but the results vary. The VTE risk is relevant when evaluating prophylaxis to avoid unnecessary bleeding or overdiagnosis. This study examines the VTE incidence in patients with glioma WHO grade 2-4, and when VTE occurred, risk factors, and overall survival (OS) for patients with WHO grade 4. MATERIALS AND METHODS In total 3,630 patients with WHO grade 2 (n = 230), grade 3 (n = 317), and grade 4 (n = 3,083) gliomas from 2010 to 2018 were identified using the Danish Neuro-Oncology Registry. VTE diagnoses and time of death were obtained from Statistics Denmark. RESULTS AND INTERPRETATION The VTE incidence was 5.2, 6.3, and 6.8% in patients with WHO grade 2, 3, and 4 gliomas, respectively. The VTE incidence rate was highest during the first 3 months after the diagnosis with 53 events. Increasing age (HR 1.03, 95%CI 1.01-1.04), male sex (HR 1.47, 95%CI 1.09-1.99), poor performance status (HR 1.57, 95%CI 1.10-2.25), and post-operative long-course radiochemotherapy (HR 2.10, 95%CI 1.19-3.72) were predictors of VTE in patients with glioma WHO grade 4. There was no difference in OS comparing patients having VTE to those without (p = 0.068). In conclusion, patients with glioma WHO grade 2-4 were at high risk of VTE, especially the first 3 months after diagnosis. Increasing age, male sex, poor performance status, and long-course radiochemotherapy were associated with increased risk of VTE in patients with glioma WHO grade 4.
Collapse
Affiliation(s)
- Frederik R Hovman
- Department of Oncology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
| | - Frantz R Poulsen
- Department of Neurosurgery, Odense University Hospital, Odense, Denmark; Department of Clinical Research, and BRIDGE (Brain Research - Inter Disciplinary Guided Excellence), University of Southern Denmark, Odense, Denmark
| | - Steinbjørn Hansen
- Department of Oncology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Rikke H Dahlrot
- Department of Oncology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| |
Collapse
|
10
|
Tonchev N, Pinchuk A, Dumitru CA, Neyazi B, Swiatek VM, Stein KP, Sandalcioglu IE, Rashidi A. Postoperative Acute Intracranial Hemorrhage and Venous Thromboembolism in Patients with Brain Metastases Receiving Acetylsalicylic Acid Perioperatively. Curr Oncol 2024; 31:4599-4612. [PMID: 39195326 PMCID: PMC11352282 DOI: 10.3390/curroncol31080343] [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: 07/11/2024] [Revised: 07/31/2024] [Accepted: 08/09/2024] [Indexed: 08/29/2024] Open
Abstract
Cranial operations are associated with a high risk of postoperative intracranial hemorrhage (pICH) and venous thromboembolic events, along with increased mortality and morbidity. With the use of acetylsalicylic acid (ASA) for prophylaxis becoming more prevalent, the risk of bleeding when ASA is administered preoperatively is unknown, as are the effects of discontinuation upon the occurrence of thromboembolic events, especially in societies with aging demographics. To address these questions, a retrospective analysis was performed using medical records and radiological images of 1862 patients subjected to brain tumor surgery over a decade in our department. The risk of pICH was compared in patients with metastases receiving ASA treatment versus patients not receiving ASA treatment. The occurrence of venous thromboembolic events after surgery was also evaluated. The study group consisted of 365 patients with different types of brain metastases. In total, 20 patients suffered pICH and 7 of these were associated with clinical neurological deterioration postoperatively. Of the 58 patients who took ASA preoperatively, 2 patients experienced pICH, compared with 5 patients in the non-ASA impact group (p = 0.120). Patients who took ASA were not at significantly higher risk of pICH and therefore a worse outcome compared to the group without ASA. Therefore, these data suggest that in patients at high cardiovascular risk, ASA can be safely continued during elective brain tumor surgery.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Ali Rashidi
- Department of Neurosurgery, Otto-von-Guericke-University Magdeburg, Leipziger Straße 44, 39120 Magdeburg, Germany; (N.T.); (A.P.); (B.N.); (V.M.S.); (K.P.S.); (I.E.S.)
| |
Collapse
|
11
|
Nguyen AV, Soto JM, Digbeu BD, Nguyen CY, Wu E, Huang JH, Kuo YF. Factors associated with longer survival among older medicare patients after diagnosis of supratentorial primary brain malignancies: a retrospective cohort study. Neurol Res 2024; 46:379-390. [PMID: 38415699 DOI: 10.1080/01616412.2024.2323335] [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: 04/09/2023] [Accepted: 02/21/2024] [Indexed: 02/29/2024]
Abstract
OBJECTIVES Despite recent advances, the prognosis for primary malignant brain tumors (PMBTs) remains poor. Some commonly prescribed medications may exhibit anti-tumor properties in various cancers, and neurodegenerative diseases may activate pathways that counteract gliomagenesis. Our study is focused on determining if there is a correlation between the use of metformin, beta-blockers, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs), or the presence of Parkinson's disease (PD), and the survival rates following a diagnosis of a PMBT. METHODS This analysis of the 100% Texas Medicare Database identified patients aged 66+ years diagnosed with a supratentorial PMBT from 2014-2017. Cox proportional hazards regression was employed to analyze survival following diagnosis and associations of survival with surgical intervention, radiation, PD diagnosis, and prescription of metformin, beta-blockers, ACEIs, or ARBs. RESULTS There were 1,943 patients who met study criteria, and the median age was 74 years. When medication utilization was stratified by none, pre-diagnosis only, post-diagnosis only, or both pre- and post-diagnosis (continuous), continuous utilization of metformin, beta-blockers, ACEIs, or ARBs was associated with prolonged survival compared to no utilization (hazard ratio [HR]:0.45, 95% CI:0.33-0.62; HR:0.71. 95% CI:0.59-0.86; HR:0.59, 95% CI:0.48-0.72; and HR:0.45, 95% CI:0.35-0.58 respectively). PD was also associated with longer survival (HR:0.59-0.63 across the four models). DISCUSSION Our study suggests that metformin, beta-blockers, ACEIs, ARBs, and comorbid PD are associated with a survival benefit among geriatric Medicare patients with supratentorial PMBTs.
Collapse
Affiliation(s)
- Anthony V Nguyen
- Department of Neurosurgery, Baylor Scott & White Health, Temple, TX, USA
| | - Jose M Soto
- Department of Neurosurgery, Baylor Scott & White Health, Temple, TX, USA
| | - Biai D Digbeu
- Department of Biostatistics and Data Science, Office of Biostatistics, University of Texas Medical Branch, Galveston, TX, USA
| | - Christine Y Nguyen
- Department of Internal Medicine, Baylor Scott & White Health, Scott and White Medical Center, Temple, TX, USA
| | - Erxi Wu
- Department of Neurosurgery, Baylor Scott & White Health, Temple, TX, USA
- Department of Surgery, Texas A&M University School of Medicine, Temple, TX, USA
- Department of Neurosurgery, Baylor College of Medicine, Temple, TX, USA
- Department of Pharmaceutical Sciences, Texas A&M University School of Pharmacy, College Station, TX, USA
- LIVESTRONG Cancer Institutes and Department of Oncology, Dell Medical School, the University of Texas at Austin, Austin, TX, USA
| | - Jason H Huang
- Department of Neurosurgery, Baylor Scott & White Health, Temple, TX, USA
- Department of Surgery, Texas A&M University School of Medicine, Temple, TX, USA
- Department of Neurosurgery, Baylor College of Medicine, Temple, TX, USA
| | - Yong-Fang Kuo
- Department of Biostatistics and Data Science, Office of Biostatistics, University of Texas Medical Branch, Galveston, TX, USA
| |
Collapse
|
12
|
Ranjan S, Leung D, Ghiaseddin AP, Taylor JW, Lobbous M, Dhawan A, Budhu JA, Coffee E, Melnick K, Chowdhary SA, Lu-Emerson C, Kurz SC, Burke JE, Lam K, Patel MP, Dunbar EM, Mohile NA, Peters KB. Practical guidance for direct oral anticoagulant use in the treatment of venous thromboembolism in primary and metastatic brain tumor patients. Cancer 2024; 130:1577-1589. [PMID: 38288941 DOI: 10.1002/cncr.35220] [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: 09/16/2023] [Revised: 11/17/2023] [Accepted: 11/27/2023] [Indexed: 04/13/2024]
Abstract
Management of venous thromboembolism (VTE) in patients with primary and metastatic brain tumors (BT) is challenging because of the risk of intracranial hemorrhage (ICH). There are no prospective clinical trials evaluating safety and efficacy of direct oral anticoagulants (DOACs), specifically in patients with BT, but they are widely used for VTE in this population. A group of neuro-oncology experts convened to provide practical clinical guidance for the off-label use of DOACs in treating VTE in patients with BT. We searched PubMed for the following terms: BTs, glioma, glioblastoma (GBM), brain metastasis, VTE, heparin, low-molecular-weight heparin (LWMH), DOACs, and ICH. Although prospective clinical trials are needed, the recommendations presented aim to assist clinicians in making informed decisions regarding DOACs for VTE in patients with BT.
Collapse
Affiliation(s)
- Surabhi Ranjan
- Department of Neurology, Cleveland Clinic Florida, Weston, Florida, USA
| | - Denise Leung
- Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA
| | - Ashley P Ghiaseddin
- Department of Neurosurgery, University of Florida, Gainesville, Florida, USA
| | - Jennie W Taylor
- Department of Neurology, University of California, San Francisco, California, USA
| | - Mina Lobbous
- Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Andrew Dhawan
- Rose Ella Burkhardt Brain Tumor & Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Joshua A Budhu
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Elizabeth Coffee
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Kaitlyn Melnick
- Department of Neurosurgery, University of Florida, Gainesville, Florida, USA
| | - Sajeel A Chowdhary
- Tampa General Hospital Cancer Institute, Tampa General Hospital, Tampa, Florida, USA
| | - Christine Lu-Emerson
- Department of Neurology, Maine Medical Center and Maine Health Cancer Care, Portland, Maine, USA
| | - Sylvia C Kurz
- Department of Neurology & Interdisciplinary Neuro-Oncology, Hertie Institute for Clinical Brain Research, Eberhard Karls University Tübingen, Tübingen, Germany
| | - Joy E Burke
- Department of Neurology, Beth Israel Lahey Health, Lahey Hospital and Medical Center, Burlington, Massachusetts, USA
| | - Keng Lam
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Mallika P Patel
- Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, USA
| | | | - Nimish A Mohile
- Department of Neurology, University of Rochester, Rochester, New York, USA
| | - Katherine B Peters
- Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, USA
| |
Collapse
|
13
|
Mahé I, Frère C, Pernod G, Sanchez O, Baih AI. [Translation into French and republication of: "Management of venous thromboembolic disease in patients with malignant brain tumours"]. Rev Med Interne 2024; 45:300-311. [PMID: 38763817 DOI: 10.1016/j.revmed.2024.05.016] [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: 11/17/2023] [Accepted: 11/17/2023] [Indexed: 05/21/2024]
Abstract
This article addresses the management of venous thromboembolism in patients with malignant brain tumours, including both primary and secondary (metastatic) tumours. The available data on patients on venous thromboembolism recurrence and bleeding risks in patients with brain tumours is limited, since these patients have been excluded from most randomised, interventional, head-to-head, clinical trials comparing low molecular weight heparins to vitamin K antagonists or to direct oral factor Xa inhibitors. More information is available from retrospective observational studies, which however were generally small, and carried a high risk of confounding. Their findings suggest that direct factor Xa inhibitor use is associated with lower rates of intracranial haemorrhage compared with low molecular weight heparins. Overall, the safety profile of direct oral factor Xa inhibitors when used to prevent venous thromboembolism recurrence in patients with either primary or secondary brain tumours appears to be favourable. The available data are in favour of using an anticoagulant at a full therapeutic dose in patients with primary and secondary brain tumours experiencing a venous thromboembolism, although they are not yet sufficiently robust to permit recommending a direct factor Xa inhibitor over low-molecular weight heparin.
Collapse
Affiliation(s)
- I Mahé
- Service de médecine interne, hôpital Louis-Mourier, Assistance publique-Hôpitaux de Paris, 92700 Colombes, France; Université Paris Cité, Inserm UMR S1140, innovations thérapeutiques en hémostase, Paris, France; F-CRIN INNOVTE Network, Saint-Étienne, France.
| | - C Frère
- Hôpital de la Pitié-Salpêtrière, Assistance publique-Hôpitaux de Paris, Sorbonne université, Inserm UMRS 1166, GRC 27 Greco, DMU BioGeMH, Paris, France
| | - G Pernod
- F-CRIN INNOVTE Network, Saint-Étienne, France; Service de médecine vasculaire, université Grenoble-Alpes, Grenoble, France
| | - O Sanchez
- Université Paris Cité, Inserm UMR S1140, innovations thérapeutiques en hémostase, Paris, France; F-CRIN INNOVTE Network, Saint-Étienne, France; Service de pneumologie et soins intensifs, hôpital européen Georges-Pompidou, Assistance publique-Hôpitaux de Paris, Paris, France
| | - A Id Baih
- Service de neuro-oncologie, Institut du cerveau - Paris Brain Institute, ICM, hôpitaux universitaires La Pitié-Salpêtrière - Charles-Foix, DMU Neurosciences, Sorbonne université, Assistance publique-Hôpitaux de Paris, Inserm, CNRS, Paris, France
| |
Collapse
|
14
|
Rolling CC, Mohme M, Bokemeyer C, Westphal M, Riethdorf S, Lamszus K, Pantel K, Klingler F, Langer F. Circulating Tumor Cells and Thromboembolic Events in Patients with Glioblastoma. Hamostaseologie 2024. [PMID: 38636546 DOI: 10.1055/a-2251-6766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2024] Open
Abstract
Patients with glioblastoma (GBM) are at increased risk for arterial and venous thromboembolism (TE). Risk factors include surgery, the use of corticosteroids, radiation, and chemotherapy, but also prothrombotic characteristics of the tumor itself such as expression of tissue factor, vascular endothelial growth factor, or podoplanin. Although distant metastases are extremely rare in this tumor entity, circulating tumor cells (CTCs) have been detected in a significant proportion of GBM patients, potentially linking local tumor growth characteristics to systemic hypercoagulability. We performed post hoc analysis of a study, in which GBM patients had been investigated for CTCs. Information on TE was retrieved from electronic patient charts. In total, 133 patients (median age, 63 years; interquartile range, 53-70 years) were analyzed. During follow-up, TE was documented in 14 patients (11%), including 8 venous and 6 arterial events. CTCs were detected in 26 patients (20%). Four (15%) patients with CTCs had a TE compared with 10 (9%) patients without CTCs. There was no difference in the frequency of TE events between patients with and those without detectable CTCs (p = 0.58). In summary, although our study confirms a high risk of TE in GBM patients, it does not point to an obvious association between CTCs and vascular thrombosis.
Collapse
Affiliation(s)
- Christina C Rolling
- Department of Oncology, Hematology and BMT with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Malte Mohme
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Carsten Bokemeyer
- Department of Oncology, Hematology and BMT with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Manfred Westphal
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sabine Riethdorf
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Katrin Lamszus
- Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Klaus Pantel
- Department of Tumour Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Felix Klingler
- Department of Oncology, Hematology and BMT with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florian Langer
- Department of Oncology, Hematology and BMT with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| |
Collapse
|
15
|
Zeng Q, Lu G, Yuan J, Ding J, Chen J, Gao X, Huang Y, Shi T, Yu H, Ni H, Li Y. Prevalence, characteristics, and risk factors of venous thromboembolism in patients with brain tumor undergoing craniotomy: a meta-analysis. Neurol Sci 2024; 45:1565-1580. [PMID: 37947983 DOI: 10.1007/s10072-023-07160-6] [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: 08/24/2023] [Accepted: 10/22/2023] [Indexed: 11/12/2023]
Abstract
BACKGROUND Brain tumor patients undergoing craniotomy are significantly associated with the development of venous thromboembolism (VTE), while the contributing factors remains controversial. Our study aimed to investigate the prevalence and risk factors for VTE in postoperational brain tumor patients. METHODS We searched the PubMed, Embase, Web of Science, Medline, and Cochrane Library databases from their inception to July 2023. Article selection, data extraction, and study quality assessment were performed independently by two reviewers. Publication bias was assessed using Egger's and Begg's tests. Stata 15.0 software was used for data analysis. RESULTS A total of 25 studies were considered, with a total of 49,620 brain tumor individuals. The pooled prevalence of VTE during hospitalization in postoperational brain tumor patients was 9% [95% CI: (0.08, 0.10)]. Moreover, our results demonstrated that patients with VTE were older than those without VTE [mean difference [MD] = 8.14, 95% CI: (4.97, 11.30)]. The following variables were significantly associated with VTE: prior history of VTE [OR = 7.81, 95% CI: (3.62, 16.88)], congestive heart failure [OR = 2.33, 95% CI: (1.08-5.05)], diabetes [OR = 1.87, 95% CI: (1.12-3.10)], hypertension [OR = 1.27, 95% CI: (1.07-1.50)], steroid use [OR = 1.63, 95% CI: (1.41, 1.88)], high white blood cells counts [MD = 0.32, 95% CI: (0.01, 0.63)], and high fibrinogen levels [MD = 0.19, 95% CI: (0.08, 0.30)]. CONCLUSION This meta-analysis identified risk factors for postoperational VTE in patients with brain tumor, which can serve as a theoretical foundation for medical staff to manage and treat VTE. TRIAL REGISTRATION CRD42023357459.
Collapse
Affiliation(s)
- Qingping Zeng
- School of Nursing, Medical College of Yangzhou University, Yangzhou University, Yangzhou, China
- Department of Neuro Intensive Care Unit, Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Guangyu Lu
- School of Public Health, Medical College of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Jing Yuan
- Department of Echocardiography, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Jiali Ding
- School of Nursing, Medical College of Yangzhou University, Yangzhou University, Yangzhou, China
- Department of Neuro Intensive Care Unit, Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Juan Chen
- School of Nursing, Medical College of Yangzhou University, Yangzhou University, Yangzhou, China
- Department of Neuro Intensive Care Unit, Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Xianru Gao
- School of Nursing, Medical College of Yangzhou University, Yangzhou University, Yangzhou, China
- Department of Neuro Intensive Care Unit, Clinical Medical College of Yangzhou University, Yangzhou, China
| | - Yujia Huang
- Department of Neuro Intensive Care Unit, Clinical Medical College of Yangzhou University, Yangzhou, China
- Neuro-Intensive Care Unit, Department of Neurosurgery, Clinical Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China
| | - Tian Shi
- Department of Neuro Intensive Care Unit, Clinical Medical College of Yangzhou University, Yangzhou, China
- Neuro-Intensive Care Unit, Department of Neurosurgery, Clinical Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China
| | - Hailong Yu
- Department of Neuro Intensive Care Unit, Clinical Medical College of Yangzhou University, Yangzhou, China
- Department of Neurology, Northern Jiangsu People's Hospital, Yangzhou, China
| | - Hongbin Ni
- Department of Neurosurgery, Nanjing Drum Tower Hospital, School of Medicine, Clinical College of Nanjing Medical University, Nanjing, 210008, Jiangsu, China.
| | - Yuping Li
- Department of Neuro Intensive Care Unit, Clinical Medical College of Yangzhou University, Yangzhou, China.
- Neuro-Intensive Care Unit, Department of Neurosurgery, Clinical Medical College, Yangzhou University, Yangzhou, 225001, Jiangsu, China.
| |
Collapse
|
16
|
Mahé I, Frère C, Pernod G, Sanchez O, Id Baih A. Management of venous thromboembolic disease in patients with malignant brain tumours. Arch Cardiovasc Dis 2024; 117:60-71. [PMID: 38087664 DOI: 10.1016/j.acvd.2023.11.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 11/17/2023] [Indexed: 12/27/2023]
Abstract
This article addresses the management of venous thromboembolism in patients with malignant brain tumours, including both primary and secondary (metastatic) tumours. The available data on patients on venous thromboembolism recurrence and bleeding risks in patients with brain tumours is limited, since these patients have been excluded from most randomised, interventional, head-to-head, clinical trials comparing low molecular weight heparins to vitamin K antagonists or to direct oral Factor Xa inhibitors. More information is available from retrospective observational studies, which however were generally small, and carried a high risk of confounding. Their findings suggest that direct Factor Xa inhibitor use is associated with lower rates of intracranial haemorrhage compared with low molecular weight heparins. Overall, the safety profile of direct oral Factor Xa inhibitors when used to prevent venous thromboembolism recurrence in patients with either primary or secondary brain tumours appears to be favourable. The available data are in favour of using an anticoagulant at a full therapeutic dose in patients with primary and secondary brain tumours experiencing a venous thromboembolism, although they are not yet sufficiently robust to permit recommending a direct Factor Xa inhibitor over low-molecular weight heparin.
Collapse
Affiliation(s)
- Isabelle Mahé
- Service de médecine interne, Hôpital Louis-Mourier, AP-HP, 178, rue des Renouillers, 92700 Colombes, France; Université Paris Cité, Inserm UMR S1140, innovations thérapeutiques en hémostase, Paris, France; F-CRIN INNOVTE network, Saint-Etienne, France.
| | - Corinne Frère
- Hôpital de la Pitié-Salpêtrière, Assistance publique-Hôpitaux de Paris, Sorbonne université, Inserm UMRS 1166, GRC 27 GRECO, DMU BioGeMH, Paris, France
| | - Gilles Pernod
- Service de médecine vasculaire,Université Grenoble-Alpes, Grenoble, France; F-CRIN INNOVTE network, Saint-Etienne, France
| | - Olivier Sanchez
- Université Paris Cité, Inserm UMR S1140, innovations thérapeutiques en hémostase, Paris, France; Service de Pneumologie et soins intensifs, hôpital européen Georges Pompidou, APHP, Paris, France; F-CRIN INNOVTE network, Saint-Etienne, France
| | - Ahmed Id Baih
- Sorbonne Université, AP-HP, Institut du Cerveau - Paris Brain Institute, ·ICM, Inserm, CNRS, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, DMU Neurosciences, Service de Neuro-Oncologie, Paris, France
| |
Collapse
|
17
|
Welch MR. Management of Complications in Neuro-oncology Patients. Continuum (Minneap Minn) 2023; 29:1844-1871. [PMID: 38085901 DOI: 10.1212/con.0000000000001359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
OBJECTIVE The purpose of this article is to familiarize the reader with the spectrum of neurologic and medical complications relevant to the care of patients with neurologic cancer while highlighting best practices to prevent morbidity and mortality. Topics include tumor-related epilepsy, vasogenic edema, complications of corticosteroid use, disruption of the hypothalamic-pituitary axis, venous thromboembolism, and opportunistic infection. LATEST DEVELOPMENTS In 2021, a joint guideline from the Society for Neuro-Oncology and the European Association of Neuro-Oncology reaffirmed recommendations first established in 2000 that patients with newly diagnosed brain tumors should not be prescribed an antiseizure medication prophylactically. For those with tumor-related epilepsy, monotherapy with a non-enzyme-inducing anticonvulsant is the preferred initial treatment, and levetiracetam remains the preferred first choice. Surveys of physician practice continue to demonstrate excessive use of glucocorticoids in the management of patients with both primary and metastatic central nervous system malignancy. This is particularly concerning among patients who require checkpoint inhibitors as the efficacy of these agents is blunted by concomitant glucocorticoid use, resulting in a reduction in overall survival. Finally, direct oral anticoagulants have been shown to be safe in patients with brain tumors and are now favored as first-line treatment among those who require treatment for venous thromboembolism. ESSENTIAL POINTS Medical care for patients impacted by primary and secondary central nervous system malignancy is complex and requires a committed team-based approach that routinely calls upon the expertise of physicians across multiple fields. Neurologists have an important role to play and should be familiar with the spectrum of complications impacting these patients as well as the latest recommendations for management.
Collapse
|
18
|
Liu D, Song D, Ning W, Guo Y, Lei T, Qu Y, Zhang M, Gu C, Wang H, Ji J, Wang Y, Zhao Y, Qiao N, Zhang H. Development and Validation of a Clinical Prediction Model for Venous Thromboembolism Following Neurosurgery: A 6-Year, Multicenter, Retrospective and Prospective Diagnostic Cohort Study. Cancers (Basel) 2023; 15:5483. [PMID: 38001743 PMCID: PMC10670076 DOI: 10.3390/cancers15225483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 11/02/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
BACKGROUND Based on the literature and data on its clinical trials, the incidence of venous thromboembolism (VTE) in patients undergoing neurosurgery has been 3.0%~26%. We used advanced machine learning techniques and statistical methods to provide a clinical prediction model for VTE after neurosurgery. METHODS All patients (n = 5867) who underwent neurosurgery from the development and retrospective internal validation cohorts were obtained from May 2017 to April 2022 at the Department of Neurosurgery at the Sanbo Brain Hospital. The clinical and biomarker variables were divided into pre-, intra-, and postoperative. A univariate logistic regression (LR) was applied to explore the 67 candidate predictors with VTE. We used a multivariable logistic regression (MLR) to select all significant MLR variables of MLR to build the clinical risk prediction model. We used a random forest to calculate the importance of significant variables of MLR. In addition, we conducted prospective internal (n = 490) and external validation (n = 2301) for the model. RESULTS Eight variables were selected for inclusion in the final clinical prediction model: D-dimer before surgery, activated partial thromboplastin time before neurosurgery, age, craniopharyngioma, duration of operation, disturbance of consciousness on the second day after surgery and high dose of mannitol, and highest D-dimer within 72 h after surgery. The area under the curve (AUC) values for the development, retrospective internal validation, and prospective internal validation cohorts were 0.78, 0.77, and 0.79, respectively. The external validation set had the highest AUC value of 0.85. CONCLUSIONS This validated clinical prediction model, including eight clinical factors and biomarkers, predicted the risk of VTE following neurosurgery. Looking forward to further research exploring the standardization of clinical decision-making for primary VTE prevention based on this model.
Collapse
Affiliation(s)
- Deshan Liu
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China; (D.L.); (D.S.); (W.N.); (Y.G.); (T.L.); (Y.Q.); (M.Z.); (C.G.); (H.W.); (J.J.)
| | - Dixiang Song
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China; (D.L.); (D.S.); (W.N.); (Y.G.); (T.L.); (Y.Q.); (M.Z.); (C.G.); (H.W.); (J.J.)
| | - Weihai Ning
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China; (D.L.); (D.S.); (W.N.); (Y.G.); (T.L.); (Y.Q.); (M.Z.); (C.G.); (H.W.); (J.J.)
| | - Yuduo Guo
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China; (D.L.); (D.S.); (W.N.); (Y.G.); (T.L.); (Y.Q.); (M.Z.); (C.G.); (H.W.); (J.J.)
| | - Ting Lei
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China; (D.L.); (D.S.); (W.N.); (Y.G.); (T.L.); (Y.Q.); (M.Z.); (C.G.); (H.W.); (J.J.)
| | - Yanming Qu
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China; (D.L.); (D.S.); (W.N.); (Y.G.); (T.L.); (Y.Q.); (M.Z.); (C.G.); (H.W.); (J.J.)
| | - Mingshan Zhang
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China; (D.L.); (D.S.); (W.N.); (Y.G.); (T.L.); (Y.Q.); (M.Z.); (C.G.); (H.W.); (J.J.)
| | - Chunyu Gu
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China; (D.L.); (D.S.); (W.N.); (Y.G.); (T.L.); (Y.Q.); (M.Z.); (C.G.); (H.W.); (J.J.)
| | - Haoran Wang
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China; (D.L.); (D.S.); (W.N.); (Y.G.); (T.L.); (Y.Q.); (M.Z.); (C.G.); (H.W.); (J.J.)
| | - Junpeng Ji
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China; (D.L.); (D.S.); (W.N.); (Y.G.); (T.L.); (Y.Q.); (M.Z.); (C.G.); (H.W.); (J.J.)
| | - Yongfei Wang
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai 200030, China; (Y.W.); (Y.Z.)
| | - Yao Zhao
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai 200030, China; (Y.W.); (Y.Z.)
| | - Nidan Qiao
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai 200030, China; (Y.W.); (Y.Z.)
| | - Hongwei Zhang
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing 100093, China; (D.L.); (D.S.); (W.N.); (Y.G.); (T.L.); (Y.Q.); (M.Z.); (C.G.); (H.W.); (J.J.)
| |
Collapse
|
19
|
Tao YN, Han Q, Jiao W, Yang LK, Wang F, Xue S, Shen M, Wang YH. Effects of ulinastatin therapy in deep vein thrombosis prevention after brain tumor surgery: A single-center randomized controlled trial. World J Clin Cases 2023; 11:7583-7592. [DOI: 10.12998/wjcc.v11.i31.7583] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 10/11/2023] [Accepted: 10/23/2023] [Indexed: 11/06/2023] Open
Abstract
BACKGROUND Venous thromboembolism (VTE) is a common neurosurgical complication after brain tumor resection, and its prophylaxis has been widely studied. There are no effective drugs in the clinical management of venous thromboembolism, and there is an absence of evidence-based medicine concerning the treatment of severe multiple traumas.
AIM To explore whether ulinastatin (UTI) can prevent VTE after brain tumor resection.
METHODS The present research included patients who underwent brain tumor resection. Patients received UTIs (400,000 IU) or placebos utilizing computer-based random sequencing (in a 1:1 ratio). The primary outcome measures were the incidence of VTE, coagulation function, pulmonary emboli, liver function, renal function, and drug-related adverse effects.
RESULTS A total of 405 patients were evaluated between January 2019 and December 2021, and 361 of these were initially enrolled in the study to form intention-to-treat, which was given UTI (n = 180) or placebo (n = 181) treatment in a random manner. There were no statistically significant differences in baseline clinical data between the two groups. The incidence of VTE in the UTI group was remarkably improved compared with that in the placebo group. UTI can improve coagulation dysfunction, pulmonary emboli, liver function, and renal function. No significant difference was identified between the two groups in the side effects of UTI-induced diarrhea, vomiting, hospital stays, or hospitalization costs. The incidence of allergies was higher in the UTI group than in the placebo group.
CONCLUSION The findings from the present research indicated that UTI can decrease the incidence of VTE and clinical outcomes of patients after brain tumor resection and has fewer adverse reactions.
Collapse
Affiliation(s)
- Yun-Na Tao
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Qian Han
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Wei Jiao
- Nursing, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Li-Kun Yang
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Fang Wang
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Shan Xue
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Meng Shen
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| | - Yu-Hai Wang
- Department of Neurosurgery, The 904th Hospital of Joint Logistic Support Force, Wuxi 214044, Jiangsu Province, China
| |
Collapse
|
20
|
Zheng Y, Zhang Z, Zhao J, Teo K, Nga VDW, Yeo TT, Lim MJR. Effect of blood type on mortality among patients with brain metastases. Clin Neurol Neurosurg 2023; 233:107963. [PMID: 37703616 DOI: 10.1016/j.clineuro.2023.107963] [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: 07/24/2023] [Revised: 09/01/2023] [Accepted: 09/05/2023] [Indexed: 09/15/2023]
Abstract
OBJECTIVE ABO blood type has been associated with mortality among patients with cancer, but this association has thus far not been investigated among patients with brain metastases. Hence, we aimed to investigate the association between ABO blood type and mortality among patients who underwent surgical resection of brain metastases. METHODS A single-center retrospective study of patients who underwent surgical resection of brain metastases between 2011 and 2019 was conducted. Cox proportional hazards models were constructed, adjusting for potential confounders, to evaluate whether blood type was independently associated with overall mortality. RESULTS A total of 158 patients were included in the analysis. The mean (SD) age of the cohort was 59.3 (12.0) years, and 67.7% of patients were female. The median overall survival of patients with blood type AB was 11.2 months, while the median overall survival of patients with blood types O, B, and A were 11.7, 13.5, and 14.4 months respectively. On univariate analysis, patients with blood type AB had a higher risk of overall mortality (p = 0.017). On multivariate analysis adjusting for potential confounders, blood type AB was again associated with a higher risk of overall mortality (HR: 2.29, 95% CI: 1.11-4.72, p = 0.025). CONCLUSION Blood type AB was independently associated with a higher risk of overall mortality among patients who underwent surgical resection of brain metastases, indicating the potential prognostic value of ABO blood type in brain metastases.
Collapse
Affiliation(s)
- Yilong Zheng
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Zheting Zhang
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Jiashen Zhao
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Kejia Teo
- Division of Neurosurgery, National University Hospital, Singapore
| | | | - Tseng Tsai Yeo
- Division of Neurosurgery, National University Hospital, Singapore
| | | |
Collapse
|
21
|
Jo J, Diaz M, Horbinski C, Mackman N, Bagley S, Broekman M, Rak J, Perry J, Pabinger I, Key NS, Schiff D. Epidemiology, biology, and management of venous thromboembolism in gliomas: An interdisciplinary review. Neuro Oncol 2023; 25:1381-1394. [PMID: 37100086 PMCID: PMC10398809 DOI: 10.1093/neuonc/noad059] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/28/2023] Open
Abstract
Patients with diffuse glioma are at high risk of developing venous thromboembolism (VTE) over the course of the disease, with up to 30% incidence in patients with glioblastoma (GBM) and a lower but nonnegligible risk in lower-grade gliomas. Recent and ongoing efforts to identify clinical and laboratory biomarkers of patients at increased risk offer promise, but to date, there is no proven role for prophylaxis outside of the perioperative period. Emerging data suggest a higher risk of VTE in patients with isocitrate dehydrogenase (IDH) wild-type glioma and the potential mechanistic role of IDH mutation in the suppression of production of the procoagulants tissue factor and podoplanin. According to published guidelines, therapeutic anticoagulation with low molecular weight heparin (LMWH) or alternatively, direct oral anticoagulants (DOACs) in patients without increased risk of gastrointestinal or genitourinary bleeding is recommended for VTE treatment. Due to the elevated risk of intracranial hemorrhage (ICH) in GBM, anticoagulation treatment remains challenging and at times fraught. There are conflicting data on the risk of ICH with LMWH in patients with glioma; small retrospective studies suggest DOACs may convey lower ICH risk than LMWH. Investigational anticoagulants that prevent thrombosis without impairing hemostasis, such as factor XI inhibitors, may carry a better therapeutic index and are expected to enter clinical trials for cancer-associated thrombosis.
Collapse
Affiliation(s)
- Jasmin Jo
- Department of Internal Medicine, Division of Hematology and Oncology, East Carolina University, Greenville, NC, USA
| | - Maria Diaz
- Department of Neurology, Division of Neuro-Oncology, Columbia University, New York, NY, USA
| | - Craig Horbinski
- Department of Pathology, Northwestern University, Chicago, IL, USA
| | - Nigel Mackman
- Department of Medicine and UNC Blood Research Center, University of North Carolina, Chapel Hill, NC, USA
| | - Stephen Bagley
- Department of Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Marika Broekman
- Department of Neurosurgery, University Medical Center, Utrecht, The Netherlands
| | - Janusz Rak
- Department of Pediatrics, McGill University, Montreal, Canada
| | - James Perry
- Department of Neurology, Sunnybrook Health Sciences Center, Toronto, Canada
| | - Ingrid Pabinger
- Department of Medicine, Medical University of Vienna, Vienna, Austria
| | - Nigel S Key
- Department of Medicine and UNC Blood Research Center, University of North Carolina, Chapel Hill, NC, USA
| | - David Schiff
- Department of Neurology, Division of Neuro-Oncology, University of Virginia, Charlottesville, VA, USA
| |
Collapse
|
22
|
Huo H, Shen S, Yang Y, Zhang H, Wu S, Bi T, Li Y. The risk of intracranial hemorrhage in glioma patients receiving anticoagulant treatment for venous thromboembolism: a bayesian network meta-analysis. J Thromb Thrombolysis 2023; 56:333-341. [PMID: 37341895 DOI: 10.1007/s11239-023-02851-5] [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] [Accepted: 06/11/2023] [Indexed: 06/22/2023]
Abstract
PURPOSE We aimed to perform a Bayesian network meta-analysis to assess the risk of intracranial hemorrhage (ICH) in patients with glioma receiving anticoagulant treatment for venous thromboembolism. METHODS The PubMed, Embase and Web of Science databases were searched for relevant publications until September 2022. All studies evaluating the risk of ICH in patients with glioma receiving anticoagulant treatment were included. Bayesian network meta-analysis and pairwise meta-analysis were performed to compare the ICH risk between the anticoagulant treatments. The Cochrane's Risk of Bias Tool and the Newcastle-Ottawa Scale (NOS) were used to evaluate the quality of studies. RESULTS A total of 11 studies with 1301 patients were included. Pairwise comparisons showed no significant differences excepted with LMWH vs. DOACs (OR: 7.28, 95% CI: 2.11-25.17) and LMWH vs. Placebo (OR: 3.66, 95% CI: 2.15-6.24). For network meta-analysis, significant difference was found between patients treated with LMWH vs. Placebo (OR: 4.16, 95% CI: 2.00-10.14) and LMWH vs. DOACs (OR: 10.13, 95% CI: 2.70-70.19). CONCLUSIONS It seems that LMWH has the highest risk of ICH in glioma patients, while no evidence indicates that DOACs increase the risk of ICH. The use of DOACs may perhaps be a better choice. Further larger studies focusing on the benefit-to-risk ratio are warranted.
Collapse
Affiliation(s)
- Huasong Huo
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, China
| | - Shurui Shen
- Department of Plastic and Cosmetic Surgery, First Hospital of Jilin University, Changchun, China
| | - Yin Yang
- Department of Hepatobiliary and Pancreatic Surgery, First Hospital of Jilin University, Changchun, China
| | - Hongwei Zhang
- Department of Gastrointestinal Colorectal and Anal Surgery, First Hospital of Jilin University, Changchun, China
| | - Shouwang Wu
- Department of Urology, First Hospital of Jilin University, Changchun, China
| | - Taiyu Bi
- Department of Thoracic Surgery, First Hospital of Jilin University, Changchun, China
| | - Yunqian Li
- Department of Neurosurgery, First Hospital of Jilin University, Changchun, China.
| |
Collapse
|
23
|
Meyer AD, Hughes TB, Rishmawi AR, Heard P, Shah S, Aune GJ. A cohort study on blood coagulation in childhood cancer survivors. Thromb Res 2023; 226:100-106. [PMID: 37141794 DOI: 10.1016/j.thromres.2023.04.025] [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: 09/05/2022] [Revised: 03/22/2023] [Accepted: 04/28/2023] [Indexed: 05/06/2023]
Abstract
Cancer survivors are at an increased risk of thromboembolism compared to the general pediatric population. Anticoagulant therapy decreases the risk of thromboembolism in cancer patients. We hypothesized that pediatric cancer survivors are in a chronically hypercoagulable state compared to healthy controls. Children who survived for more than five years from cancer diagnosis at the UT Health Science Center at San Antonio Cancer Survivorship Clinic were compared to healthy controls. The exclusion criteria were recent NSAID use or a history of coagulopathy. Coagulation analysis included platelet count, thrombin-antithrombin complexes (TAT), plasminogen activator inhibitor (PAI), routine coagulation assays, and thrombin generation with and without thrombomodulin. We enrolled 47 pediatric cancer survivors and 37 healthy controls. Platelet count was significantly lower in cancer survivors at a mean of 254 × 109/L (95%CI: 234-273 × 109/L) compared at 307 × 109/L (283-331 × 109/L) in healthy controls (p < 0.001), although not outside the normal range. Routine coagulation assays showed no differences, except for a significantly lower prothrombin time (PT) in cancer survivors (p < 0.004). Cancer survivors has significantly elevated biomarkers of the procoagulant state, such as TAT and PAI, compared to healthy controls (p < 0.001). A multiple logistic regression model controlling for age, BMI, gender, and race/ethnicity documented that a low platelet count, short prothrombin clot time, and higher procoagulant biomarkers (TAT and PAI) were significantly associated with past cancer therapy. Survivors of childhood cancer have a persistent procoagulant imbalance for more than five years after diagnosis. Further studies are needed to establish whether procoagulant imbalance increases the risk of thromboembolism in childhood cancer survivors.
Collapse
Affiliation(s)
- Andrew D Meyer
- Division of Critical Care, Department of Pediatrics, Long School of Medicine at The University of Texas Health Science Center, San Antonio, TX, United States of America.
| | - Tyler B Hughes
- Division of Critical Care, Department of Pediatrics, Long School of Medicine at The University of Texas Health Science Center, San Antonio, TX, United States of America.
| | - Anjana R Rishmawi
- Division of Critical Care, Department of Pediatrics, Long School of Medicine at The University of Texas Health Science Center, San Antonio, TX, United States of America
| | - Patty Heard
- Division of Critical Care, Department of Pediatrics, Long School of Medicine at The University of Texas Health Science Center, San Antonio, TX, United States of America.
| | - Shafqat Shah
- Division of Hematology/Oncology, Department of Pediatrics, Long School of Medicine at The University of Texas Health Science Center, San Antonio, TX, United States of America.
| | - Gregory J Aune
- Division of Hematology/Oncology, Department of Pediatrics, Long School of Medicine at The University of Texas Health Science Center, San Antonio, TX, United States of America; Greehey Children's Cancer Research Institute, San Antonio, TX, United States of America.
| |
Collapse
|
24
|
Ambulkar R, Parab SY, Vignesh B, Nagargoje V, Janu A, Parikh P, Moiyadi A. A prospective study to evaluate the use of surveillance venous ultrasonography to detect incidence of deep venous thrombosis following neurosurgical excision of brain tumors. J Neurosci Rural Pract 2023; 14:252-257. [PMID: 37181162 PMCID: PMC10174156 DOI: 10.25259/jnrp_26_2022] [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: 09/26/2022] [Accepted: 01/12/2023] [Indexed: 02/25/2023] Open
Abstract
Objectives Patients with brain tumors are prone to develop deep venous thrombosis (DVT) following neurosurgical excision of tumor. However, there is a deficiency of knowledge about the screening method, optimum frequency, and duration of the surveillance to diagnose DVT in the post-operative period. The primary objective was to find the incidence of DVT and associated risk factors. The secondary objectives were to find the optimum duration and frequency of surveillance venous ultrasonography (V-USG) in patients undergoing neurosurgery. Materials and Methods Hundred consecutive adult patients undergoing neurosurgical excision of brain tumors were included after their consent, over a period of 2 years. The risk factors for DVT were assessed in all the patients preoperatively. All patients underwent surveillance duplex V-USG of the upper and lower limbs at pre-planned time intervals in the perioperative period, by experienced radiologists and anesthesiologists. The occurrence of DVT was noted using the objective criteria. The association between the perioperative variables and the incidence of DVT was assessed using univariate logistic regression analysis. Results The most common prevalent risk factors were - malignancy (97%), major surgery (100%), and age >40 years (30%). Asymptomatic DVT was detected in the right femoral vein in one patient who underwent suboccipital craniotomy for high-grade medulloblastoma, on the 4th and 9th postoperative day, making the incidence of DVT 1%. The study found no association with perioperative risk factors and could not suggest the optimum duration and frequency of surveillance V-USG. Conclusion A low incidence of DVT (1%) was detected in patients undergoing neurosurgeries for brain tumors. Prevalent thromboprophylaxis practices and a shorter period of post-operative surveillance could be the reasons for the low incidence of DVT.
Collapse
Affiliation(s)
- Reshma Ambulkar
- Department of Anesthesiology, Critical Care and Pain, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Swapnil Yeshwant Parab
- Department of Anesthesiology, Critical Care and Pain, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - B. Vignesh
- Department of Anesthesiology, Critical Care and Pain, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Vidyasagar Nagargoje
- Department of Anesthesiology, Critical Care and Pain, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Amit Janu
- Department of Radiodiagnosis, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Prafulla Parikh
- Department of Medicine, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Aliasgar Moiyadi
- Department of Neurosurgical Services, Tata Memorial Centre, Mumbai, Maharashtra, India
| |
Collapse
|
25
|
Liu D, Song D, Ning W, Zhang X, Chen S, Zhang H. Efficacy and safety of prophylaxis for venous thromboembolism in brain neoplasm patients undergoing neurosurgery: a systematic review and Bayesian network meta-analysis. J Thromb Thrombolysis 2023; 55:710-720. [PMID: 36763224 DOI: 10.1007/s11239-023-02780-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/24/2023] [Indexed: 02/11/2023]
Abstract
Neurosurgeons often face this dilemma. Brain neoplasm patients undergoing neurosurgery are at a high risk of venous thrombosis. However, antithrombotic drugs may induce bleeding complications. Therefore, we compared the efficacy and safety of prophylaxis for venous thromboembolism (VTE) in brain neoplasm patients undergoing neurosurgery. We searched Cochrane Central Register of Controlled Trials, Ovid MEDLINE(R), and Embase from inception to January 2022 for randomized controlled trials (RCTs) comparing the prophylactic measures efficacy and safety for VTE in brain neoplasm patients undergoing neurosurgery. The main efficacy outcome was symptomatic or asymptomatic VTE. The safety outcomes included major bleeding, minor bleeding, all occurrences of bleeding, and all-cause mortality. We used (Log) odds ratio (OR) of various chemoprophylaxis regimens to judge the safety and effectiveness of VTE. Additionally, all types of intervention were ranked by the Surface Under the Cumulative Ranking (SUCRA) value. We included 10 RCTs with 1128 brain neoplasm patients undergoing neurosurgery. For symptomatic or asymptomatic VTE and proximal DVT or PE, DOACs, compared with placebo, can significantly reduce the events. DOACs were superior to all other interventions in the rank plot of these events. For major bleeding reduction, unfractionated heparin (SUCRA value = 0.21) demonstrated better safety efficacy than others. For minor bleeding reduction, DOACs had a significantly higher risk of minor bleeding compared with placebo [Log OR 16.76, 95% CrI (1.53, 61.13)], LMWH [Log OR 15.68, 95% CrI (0.26, 60.10)] and UFH [Log OR 15.93, 95% CrI (0.22, 60.16)] respectively. Except for placebo (SUCRA values of 0.13), UFH (SUCRA values of 0.37) depicted better safety efficacy than others. For all-cause mortality, we found UFH always had significantly lower all-cause mortality compared with low-molecular-weight heparin (LMWH) [Log OR = 14.17, 95% CrI (0.05, 48.35)]. UFH plus intermittent pneumatic compression (IPC) (SUCRA value of 0.12) displayed the best safety for all-cause mortality. In our study, DOACs were more effective as prophylaxis for VTE in brain neoplasm patients undergoing neurosurgery. Regarding the safety of prophylaxis for VTE, UFH of chemoprophylaxis consistently demonstrated better safety efficacy, involving either major bleeding, minor bleeding, bleeding, or all-cause mortality.
Collapse
Affiliation(s)
- Deshan Liu
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Dixiang Song
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Weihai Ning
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Xiaoyu Zhang
- Department of Anesthesiology, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China.,Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, 100093, China
| | - Shengyun Chen
- Department of Cerebralvascular Center, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China
| | - Hongwei Zhang
- Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, China.
| |
Collapse
|
26
|
Antithrombin Activity and Association with Risk of Thrombosis and Mortality in Patients with Cancer. Int J Mol Sci 2022; 23:ijms232415770. [PMID: 36555414 PMCID: PMC9784494 DOI: 10.3390/ijms232415770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 11/24/2022] [Accepted: 12/08/2022] [Indexed: 12/15/2022] Open
Abstract
Venous and arterial thromboembolism (VTE/ATE) are common complications in cancer patients. Antithrombin deficiency is a risk factor for thrombosis in the general population, but its connection to risk of cancer-associated thrombosis is unclear. We investigated the association of antithrombin activity levels with risk of cancer-associated VTE/ATE and all-cause mortality in an observational cohort study including patients with cancer, the Vienna Cancer and Thrombosis Study. In total, 1127 patients were included (45% female, median age: 62 years). Amongst these subjects, 110 (9.7%) patients were diagnosed with VTE, 32 (2.8%) with ATE, and 563 (49.9%) died. Antithrombin was not associated with a risk of VTE (subdistribution hazard ratio (SHR): 1.00 per 1% increase in antithrombin level; 95% CI: 0.99-1.01) or ATE (SHR: 1.00; 95% CI: 0.98-1.03). However, antithrombin showed a u-shaped association with the risk of all-cause death, i.e., patients with very low but also very high levels had poorer overall survival. In the subgroup of patients with brain tumors, higher antithrombin levels were associated with ATE risk (SHR: 1.02 per 1% increase; 95% CI: 1.00-1.04) and mortality (HR: 1.01 per 1% increase; 95% CI: 1.00-1.02). Both high and low antithrombin activity was associated with the risk of death. However, no association with cancer-associated VTE and ATE across all cancer types was found, with the exception of in brain tumors.
Collapse
|
27
|
Lilly GL, Sweeny L, Santucci N, Cannady S, Frost A, Anagnos V, Curry J, Sagalow E, Freeman C, Puram SV, Pipkorn P, Slijepcevic A, Fuson A, Bonaventure C, Wax MK. Perioperative Hypercoagulability in Free Flap Reconstructions Performed for Intracranial Tumors. Laryngoscope 2022; 133:1103-1109. [PMID: 36196963 DOI: 10.1002/lary.30417] [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: 04/30/2022] [Revised: 08/14/2022] [Accepted: 09/02/2022] [Indexed: 11/10/2022]
Abstract
OBJECTIVE(S) Patients with intracranial tumors have a higher risk of thromboembolic events. This risk increases at the time of surgical intervention. We have noted an anecdotal increase in perioperative flap thrombosis in patients undergoing free tissue transfer for intracranial tumor resection. This study aims to formally evaluate this risk. METHODS A multi-institutional retrospective chart review was performed of patients who underwent free tissue transfer for scalp/cranial reconstruction. Perioperative thrombosis and free flap outcomes were evaluated. RESULTS The 209 patients who underwent 246 free tissue transfers were included in the study. The 28 free flap scalp reconstructions were associated with intracranial tumors, 19 were performed following composite cranial resections with associated dural resection/reconstruction, and 199 were performed in the absence of intracranial tumors (control group). There was a significantly higher incidence of perioperative flap thrombosis in the intracranial tumor group (11/28, 39%) when compared to controls (38/199, 19%) (p = 0.0287). This was not seen when scalp tumors extended to the dura alone (4/19, 21%, p = 0.83). Therapeutic anticoagulation used for perioperative thrombosis (defined as intraoperative or in the immediate postoperative phase up to 5 days) was associated with a lower risk of flap failure, although this was not statistically significant (p = 0.148). Flap survival rates were equivalent between flaps performed for intracranial pathology (93.3%) and controls (95%). CONCLUSION There is an increase in perioperative flap thrombosis in patients with intracranial tumors undergoing free tissue scalp reconstruction. Anticoagulation appears to mitigate this risk. LEVEL OF EVIDENCE This recommendation is based on level 3 evidence (retrospective case-control studies, systematic review of retrospective studies, and case reports) Laryngoscope, 2022.
Collapse
Affiliation(s)
- Gabriela L Lilly
- Department of Otolaryngology - Head and Neck Surgery, Oregon Health and Science University, Portland, Oregon, USA
| | - Larissa Sweeny
- Department of Otolaryngology - Head and Neck Surgery, The University of Miami Health System, Miami, Florida, USA
| | - Nicole Santucci
- Department of Otolaryngology - Head and Neck Surgery, Oregon Health and Science University, Portland, Oregon, USA
| | - Steven Cannady
- Department of Otolaryngology - Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Ariel Frost
- Department of Otolaryngology - Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Vincent Anagnos
- Department of Otolaryngology - Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Joseph Curry
- Department of Otolaryngology - Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Emily Sagalow
- Department of Otolaryngology - Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Cecilia Freeman
- Department of Otolaryngology - Head and Neck Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Sidharth V Puram
- Department of Otolaryngology - Head and Neck Surgery, Washington University in St. Louis, St Louis, Missouri, USA
| | - Patrik Pipkorn
- Department of Otolaryngology - Head and Neck Surgery, Washington University in St. Louis, St Louis, Missouri, USA
| | - Allison Slijepcevic
- Department of Otolaryngology - Head and Neck Surgery, Oregon Health and Science University, Portland, Oregon, USA
| | - Andrew Fuson
- Department of Otolaryngology - Head and Neck Surgery, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Caroline Bonaventure
- Department of Otolaryngology - Head and Neck Surgery, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Mark K Wax
- Department of Otolaryngology - Head and Neck Surgery, Oregon Health and Science University, Portland, Oregon, USA
| |
Collapse
|
28
|
Low SK, Anjum Z, Mahmoud A, Joshi U, Kouides P. Isocitrate dehydrogenase mutation and risk of venous thromboembolism in glioma: A systematic review and meta-analysis. Thromb Res 2022; 219:14-21. [PMID: 36088710 DOI: 10.1016/j.thromres.2022.08.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/29/2022] [Accepted: 08/30/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Patients with malignancies including malignant gliomas have a relatively high risk for venous thromboembolism (VTE). Recent evidence has linked isocitrate dehydrogenase (IDH) mutation with reduced VTE risk in malignant glioma. This meta-analysis aims to quantify the association of IDH mutation status with risks of VTE in patients with glioma. METHODS We searched PubMed, Google Scholar, Medline OVID, Cochrane library, Cumulative Index to Nursing and Allied Health Literature databases to identify relevant studies. The overall odd ratio (OR) was pooled using the random-effects model. We evaluated the statistical heterogeneity using Cochran's Q statistics and I2 tests. We performed subgroup analyses according to age, tumor, study design, and study quality. RESULTS A total of 2600 patients from 8 studies were included in the meta-analysis. Patients with IDH mutant-type gliomas had a significantly lower risk of VTE (OR: 0.21, 95 % confidence interval [CI]: 0.09-0.46, I2 = 34 %) compared to patients with IDH wild-type gliomas. Among high-grade (III and IV) glioma, VTE events in IDH-mutant gliomas occurred with an OR of 0.28 (95 % CI: 0.14-0.53). No statistically significant decrease in the VTE risk was observed in grade II gliomas with IDH mutation compared to IDH wild-type gliomas, as indicated by the OR of 0.60 (95 % CI: 0.17-2.11). CONCLUSION IDH mutation is significantly associated with 79 % lower risk of VTE among patients with high-grade glioma compared to IDH wild-type. Our findings suggest the potential utility of IDH mutation status regarding thromboprophylaxis, and the need for further studies to elucidate the mechanism of the association.
Collapse
Affiliation(s)
- Soon Khai Low
- Department of Internal Medicine, Rochester General Hospital, NY, United States of America.
| | - Zauraiz Anjum
- Department of Internal Medicine, Rochester General Hospital, NY, United States of America
| | - Amir Mahmoud
- Department of Internal Medicine, Rochester General Hospital, NY, United States of America
| | - Utsav Joshi
- Department of Internal Medicine, Rochester General Hospital, NY, United States of America
| | - Peter Kouides
- Department of Hematology, Lipson Cancer Institute, Rochester General Hospital, NY, United States of America
| |
Collapse
|
29
|
Wienkamp AK, Erpenbeck L, Rossaint J. Platelets in the NETworks interweaving inflammation and thrombosis. Front Immunol 2022; 13:953129. [PMID: 35979369 PMCID: PMC9376363 DOI: 10.3389/fimmu.2022.953129] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 07/07/2022] [Indexed: 12/18/2022] Open
Abstract
Platelets are well characterized for their indispensable role in primary hemostasis to control hemorrhage. Research over the past years has provided a substantial body of evidence demonstrating that platelets also participate in host innate immunity. The surface expression of pattern recognition receptors, such as TLR2 and TLR4, provides platelets with the ability to sense bacterial products in their environment. Platelet α-granules contain microbicidal proteins, chemokines and growth factors, which upon release may directly engage pathogens and/or contribute to inflammatory signaling. Additionally, platelet interactions with neutrophils enhance neutrophil activation and are often crucial to induce a sufficient immune response. In particular, platelets can activate neutrophils to form neutrophil extracellular traps (NETs). This specific neutrophil effector function is characterized by neutrophils expelling chromatin fibres decorated with histones and antimicrobial proteins into the extracellular space where they serve to trap and kill pathogens. Until now, the mechanisms and signaling pathways between platelets and neutrophils inducing NET formation are still not fully characterized. NETs were also detected in thrombotic lesions in several disease backgrounds, pointing towards a role as an interface between neutrophils, platelets and thrombosis, also known as immunothrombosis. The negatively charged DNA within NETs provides a procoagulant surface, and in particular NET-derived proteins may directly activate platelets. In light of the current COVID-19 pandemic, the topic of immunothrombosis has become more relevant than ever, as a majority of COVID-19 patients display thrombi in the lung capillaries and other vascular beds. Furthermore, NETs can be found in the lung and other tissues and are associated with an increased mortality. Here, virus infiltration may lead to a cytokine storm that potently activates neutrophils and leads to massive neutrophil infiltration into the lung and NET formation. The resulting NETs presumably activate platelets and coagulation factors, further contributing to the subsequent emergence of microthrombi in pulmonary capillaries. In this review, we will discuss the interplay between platelets and NETs and the potential of this alliance to influence the course of inflammatory diseases. A better understanding of the underlying molecular mechanisms and the identification of treatment targets is of utmost importance to increase patients’ survival and improve the clinical outcome.
Collapse
Affiliation(s)
- Ann-Katrin Wienkamp
- Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
| | - Luise Erpenbeck
- Department of Dermatology, University Hospital Münster, Münster, Germany
| | - Jan Rossaint
- Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Münster, Münster, Germany
- *Correspondence: Jan Rossaint,
| |
Collapse
|
30
|
Kaptein FHJ, Stals MAM, Kapteijn MY, Cannegieter SC, Dirven L, van Duinen SG, van Eijk R, Huisman MV, Klaase EE, Taphoorn MJB, Versteeg HH, Buijs JT, Koekkoek JAF, Klok FA. Incidence and determinants of thrombotic and bleeding complications in patients with glioblastoma. J Thromb Haemost 2022; 20:1665-1673. [PMID: 35460331 PMCID: PMC9320838 DOI: 10.1111/jth.15739] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 04/12/2022] [Accepted: 04/13/2022] [Indexed: 12/03/2022]
Abstract
BACKGROUND Glioblastoma patients are considered to be at high risk of venous thromboembolism (VTE) and major bleeding (MB), although reliable incidence estimates are lacking. Moreover, the risk of arterial thromboembolism (ATE) in these patients is largely unknown. Our aim was to assess the cumulative incidence, predictors, and prognostic impact of VTE, ATE, and MB on subsequent complications and mortality. METHODS Cohort study of 967 consecutive patients diagnosed with glioblastoma between 2004-2020 in two hospitals. Patients were followed from 6 months before date of histopathological glioblastoma diagnosis up to 2 years after, or until an outcome of interest (VTE, ATE, and MB) or death occurred, depending on the analysis. Cumulative incidences were estimated with death as competing risk. Cox regression was used to identify predictors and the prognostic impact. RESULTS A total of 101 patients were diagnosed with VTE, 50 with ATE, and 126 with MB during a median follow-up of 15 months (interquartile range 9.0-22). The adjusted 1-year cumulative incidence of VTE was 7.5% (95% confidence interval [CI] 5.9-9.3), of ATE 4.1% (95% CI 3.0-5.6), and of MB 12% (95% CI 9.6-14). Older age, type of surgery, and performance status were predictors of VTE. Incident VTE during follow-up was associated with MB (adjusted HR 4.7, 95% CI 2.5-9.0). MB and VTE were associated with mortality (adjusted HR 1.7, 95% CI 1.3-2.1 and 1.3, 95% CI 1.0-1.7, respectively). CONCLUSION We found considerable incidences of VTE and MB in glioblastoma patients, with both complications associated with poorer prognosis. Our observations emphasize the need for prospective studies to determine optimal thromboprophylaxis and VTE treatment strategy in these patients.
Collapse
Affiliation(s)
- Fleur H. J. Kaptein
- Department of Medicine ‐ Thrombosis & HemostasisLeiden University Medical CentreLeidenThe Netherlands
| | - Milou A. M. Stals
- Department of Medicine ‐ Thrombosis & HemostasisLeiden University Medical CentreLeidenThe Netherlands
| | - Maaike Y. Kapteijn
- Department of Medicine ‐ Thrombosis & HemostasisLeiden University Medical CentreLeidenThe Netherlands
| | - Suzanne C. Cannegieter
- Department of Medicine ‐ Thrombosis & HemostasisLeiden University Medical CentreLeidenThe Netherlands
- Department of Clinical EpidemiologyLeiden University Medical CentreLeidenThe Netherlands
| | - Linda Dirven
- Department of NeurologyLeiden University Medical CentreLeidenThe Netherlands
- Department of NeurologyHaaglanden Medical CentreThe HagueThe Netherlands
| | | | - Ronald van Eijk
- Department of PathologyLeiden University Medical CentreLeidenThe Netherlands
| | - Menno V. Huisman
- Department of Medicine ‐ Thrombosis & HemostasisLeiden University Medical CentreLeidenThe Netherlands
| | - Eva E. Klaase
- Department of Medicine ‐ Thrombosis & HemostasisLeiden University Medical CentreLeidenThe Netherlands
| | - Martin J. B. Taphoorn
- Department of NeurologyLeiden University Medical CentreLeidenThe Netherlands
- Department of NeurologyHaaglanden Medical CentreThe HagueThe Netherlands
| | - Henri H. Versteeg
- Department of Medicine ‐ Thrombosis & HemostasisLeiden University Medical CentreLeidenThe Netherlands
| | - Jeroen T. Buijs
- Department of Medicine ‐ Thrombosis & HemostasisLeiden University Medical CentreLeidenThe Netherlands
| | - Johan A. F. Koekkoek
- Department of NeurologyLeiden University Medical CentreLeidenThe Netherlands
- Department of NeurologyHaaglanden Medical CentreThe HagueThe Netherlands
| | - Frederikus A. Klok
- Department of Medicine ‐ Thrombosis & HemostasisLeiden University Medical CentreLeidenThe Netherlands
| |
Collapse
|
31
|
Melnichnikova O, Zhilenkova Y, Sirotkina O, Zolotova E, Pishchulov K, Tastanbekov M, Paltsev A, Simakova M. Circulating Small Extracellular Vesicles Profiling and Thrombin Generation as Potential Markers of Thrombotic Risk in Glioma Patients. Front Cardiovasc Med 2022; 9:789937. [PMID: 35811733 PMCID: PMC9259782 DOI: 10.3389/fcvm.2022.789937] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 05/18/2022] [Indexed: 11/20/2022] Open
Abstract
Introduction Patients with glioma (GM) are at a high risk of venous thromboembolism (VTE). The role of microvesiculation in the cancer-associated thrombosis mechanisms has been previously demonstrated. This study aimed to evaluate the relative abundance of extracellular vesicles (EVs) and thrombin generation (TG) in combination with standard laboratory tests in patients with newly diagnosed GM as potential prognostic markers in VTE. Materials and Methods In the present study, 11 patients with newly diagnosed GM and 10 healthy volunteers were analyzed. EVs were counted and their cellular origin was determined (CytoFlex B4-R2-V2, Beckman Coulter, United States), as well as thrombin generation test (TGT) (Diagnostica Stago SAS, France) was performed. Results In patients with GM, the relative abundance of the CD41 + EVs (platelet-derived)—and CD105 + EVs (endothelial-derived) was significantly higher than in the control group (44.3 [40.5; 52.4] vs. 27.2 [22.9; 31.0]%, p = 0.002, and 5.4 [4.8; 7.8] vs. 1.9 [1.5; 2.8]%, p = 0.0003, respectively). The D-dimer level was higher in patients with GM compared with the control group (0.46 [0.38; 1.85] vs. 0.36 [0.27; 0.40] μg/ml FEU, p = 0.03, respectively). There was a trend toward an increase in the peak thrombin and velocity index (VI) in the GM group (p = 0.06). During the follow-up period, two patients (18%) developed thrombosis, had tumor sizes of more than 5 cm, thrombocytopenia, increased VI, and D-dimer. Conclusion Analysis of platelet-derived EVs, platelet count, and TGT in combination with D-dimer assessment could improve the stratification of patients prone to VTE, which needs to be confirmed in a larger sample.
Collapse
Affiliation(s)
- Olga Melnichnikova
- Personalized Medicine Centre, Almazov National Medical Research Centre, Saint Petersburg, Russia
- *Correspondence: Olga Melnichnikova,
| | - Yulia Zhilenkova
- Department of Laboratory Medicine and Genetics, Almazov National Medical Research Centre, Saint Petersburg, Russia
| | - Olga Sirotkina
- Personalized Medicine Centre, Almazov National Medical Research Centre, Saint Petersburg, Russia
| | - Ekaterina Zolotova
- Personalized Medicine Centre, Almazov National Medical Research Centre, Saint Petersburg, Russia
| | - Konstantin Pishchulov
- Personalized Medicine Centre, Almazov National Medical Research Centre, Saint Petersburg, Russia
| | - Malik Tastanbekov
- Department of Neurosurgery, Almazov National Medical Research Centre, Saint Petersburg, Russia
| | - Artem Paltsev
- Department of Neurosurgery, Almazov National Medical Research Centre, Saint Petersburg, Russia
| | - Maria Simakova
- Personalized Medicine Centre, Almazov National Medical Research Centre, Saint Petersburg, Russia
| |
Collapse
|
32
|
Hallan DR, Sciscent B, Rizk E. A Retrospective Comparative Cohort Study of Craniotomy and Prophylactic Enoxaparin Timing. Cureus 2022; 14:e23867. [PMID: 35530828 PMCID: PMC9076058 DOI: 10.7759/cureus.23867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Accepted: 04/06/2022] [Indexed: 11/06/2022] Open
Abstract
INTRODUCTION Post-operative venous thromboembolism (VTE) prophylaxis is the standard of care after craniotomy, but there is debate over when to initiate VTE prophylaxis to decrease the morbidity and mortality experienced by these patients. This study aims to determine the effects of starting enoxaparin on day one vs. day three after craniotomy. METHODS We used a multi-institutional health research network (TriNetX) to gather data from the electronic medical records of patients who started enoxaparin one day after craniotomy (cohort 1) and patients who started it three days later (cohort 2). Our primary endpoint was mortality, with the secondary endpoints of deep venous thrombosis (DVT), additional craniotomy, pulmonary embolism (PE), myocardial infarction (MI), ischemic stroke (IS), intracerebral hemorrhage (ICH), ventilator and tracheostomy dependence, or percutaneous endoscopic gastrostomy (PEG) tube dependence. Patients were propensity score-matched for demographics, common comorbidities, and anticoagulant and antiplatelet use. RESULTS After propensity score matching, 1,554 patients were identified in each cohort. In cohort 1, 21.171% of patients were deceased after five years vs. 26.126% in cohort 2 (p= 0.0012; OR 0.759, 95% CI (0.643,0.897)). The 30-day survival was 94.521% vs. 93.049%, the 90-day survival was 90.200% vs. 87.335%, and the 365-day survival was 80.619 vs. 76.817%. Deep venous thrombosis occurred in 5.277% of cohort 1 and 7.851% of cohort 2 (p=0.0038, OR 0.654, 95% CI [0.49,0.873]). There was no increase in intracerebral hemorrhage in cohort 1. There were no statistically significant differences in subsequent craniotomy rates, PE, MI, IS, ventilator/tracheostomy, or PEG tube dependence. CONCLUSION Starting enoxaparin on day one after craniotomy was associated with decreased mortality and DVTs, with no difference in rates of PE, MI, IS, tracheostomy/PEG dependence, or further craniotomy.
Collapse
Affiliation(s)
- David R Hallan
- Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, USA
| | - Bao Sciscent
- Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, USA
| | - Elias Rizk
- Neurosurgery, Penn State Health Milton S. Hershey Medical Center, Hershey, USA
| |
Collapse
|
33
|
Diaz M, Jo J. Venous Thrombotic Events and Anticoagulation in Brain Tumor Patients. Curr Oncol Rep 2022; 24:493-500. [PMID: 35179708 DOI: 10.1007/s11912-021-01178-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/28/2021] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW Brain tumor patients have a 20-30% risk of venous thromboembolism (VTE), with management complicated by risk of intracranial hemorrhage (ICH). Here we review the epidemiology, pathogenesis, and recommended management of VTE in brain tumors. RECENT FINDINGS New risk factors and molecular mechanisms of VTE in brain tumor patients have emerged, including the protective effect of IDH mutation in gliomas and the potential role of podoplanin-mediated platelet aggregation in thrombogenesis in these tumors. Recent studies show that the risk of ICH is not significantly higher in brain tumor patients receiving anticoagulation. Based on systemic cancer trials, direct oral anticoagulants (DOACs) may be a suitable alternative to traditional heparin treatment, but the applicability of these findings to brain tumors is unclear. Anticoagulation is indicated in the treatment of VTE for brain tumor patients, and appears to be reasonably safe; based on retrospective evidence, DOACs may be a reasonable agent.
Collapse
Affiliation(s)
- Maria Diaz
- Department of Neurology, Neurology Department, Memorial Sloan Kettering Cancer Center, 1275 York Avenue7th floor, New York, NY, C-71610065, USA
| | - Jasmin Jo
- Department of Internal Medicine, Division of Hematology and Oncology, East Carolina University, Brody 3E137, 600 Moye Blvd, NC, 27834, Greenville, USA.
| |
Collapse
|
34
|
Wang ZY, Wan YD, Liu XZ, Wang H, Jiang GY, Yang B. A Single-Center, Randomized, Double-Blind Study of 94 Patients Undergoing Surgery for Cerebral Glioma to Compare Postoperative Thromboprophylaxis with and without Rivaroxaban. MEDICAL SCIENCE MONITOR : INTERNATIONAL MEDICAL JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2022; 28:e934341. [PMID: 35140195 PMCID: PMC8845378 DOI: 10.12659/msm.934341] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background Venous thrombosis (VTE) is a common adverse event among inpatients, which can cause pulmonary embolism, and greatly increases mortality. The effects of rivaroxaban in patients undergoing brain glioma surgery have still not been explored. This single-center study of 94 patients undergoing surgery for cerebral glioma aimed to compare postoperative thromboprophylaxis with and without rivaroxaban. Material/Methods We designed a randomized, controlled, double-blind study to evaluate the effect of rivaroxaban on 94 patients undergoing brain glioma surgery. These patients were divided into a rivaroxaban group (administered at 10 mg per day from admission to discharge) and a placebo group. The primary study endpoint was incidence of VTE at discharge. The secondary endpoints included safety outcomes of major bleeding, allergy, or VTE-related death. Results A total of 94 patients were enrolled in the study: 47 in the rivaroxaban group and 47 in the placebo group. Baseline characteristics of participants were well-matched in both groups. A significant reduction was found in the incidence of VTE in the rivaroxaban treatment group versus the placebo group (1/47 vs 10/47 patients, P=0.008). The rate of major bleeding events was quite low in both group (1/47 vs 1/47 patients). One patient in the placebo group died due to a pulmonary embolism and intractable concomitant underlying diseases. Conclusions Our results indicate that treatment with rivaroxaban is a safe and effective thromboprophylaxis treatment in patients undergoing surgery for malignant cerebral glioma.
Collapse
Affiliation(s)
- Zi-Yan Wang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (mainland)
| | - You-Dong Wan
- Department of Emergency Intensive Care Unit, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Xian-Zhi Liu
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (mainland)
| | - Hao Wang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (mainland)
| | - Guang-Yi Jiang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (mainland)
| | - Bo Yang
- Department of Neurosurgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China (mainland)
| |
Collapse
|
35
|
Shi S, Cheng J, Zhao Y, Chen W. Incidence, and preoperative and intraoperative prognostic factors of deep venous thrombosis in patients with glioma following craniotomy. Clin Neurol Neurosurg 2021; 210:106998. [PMID: 34739883 DOI: 10.1016/j.clineuro.2021.106998] [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: 07/11/2021] [Revised: 09/24/2021] [Accepted: 10/17/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVES The aim of this study was to investigate the incidence of deep vein thrombosis (DVT) and the preoperative and intraoperative risk factors associated with DVT in glioma patients METHODS: We conducted a retrospective analysis of data obtained from glioma patients at Sanbo Hospital (Beijing, China) between 2018 and 2021. Symptomatic DVT was confirmed by Doppler ultrasonography. Multivariable logistic regression analysis was used to identify preoperative and intraoperative characteristics associated with DVT. Basic clinical variables and laboratory results were analyzed. RESULTS A total of 492 glioma patients were included. Of these, 73 (14.84%) developed DVT, and three (0.61%) developed DVT and pulmonary embolism (PE). Multivariate analyses revealed that the following factors were highly predictive of post-operative DVT: older age ranges of 46--55 years (odds ratio [OR]: 2.94; 95% confidence interval [CI]: 1.41--6.13; p = 0.004), 56--65 years (OR: 7.86; 95% CI: 3.63--17.03; p < 0.001), and > 65 years (OR: 4.94; 95% CI: 1.83--13.33; p = 0.002); partial thromboplastin time (APTT; OR: 0.91; 95% CI: 0.84--1.00; p = 0.040); D-dimer (OR: 2.21; 95% CI: 1.28--3.82; p = 0.005); and surgery duration (OR: 2.87; 95% CI: 1.6 --5.07; p < 0.001) CONCLUSIONS: Older age, preoperative APTT, D-dimer, and surgery duration independently increased the risk of developing postoperative DVT. These findings may facilitate the development of a thrombosis risk score that will allow physicians to develop individualized strategies to prevent DVT as early as possible.
Collapse
Affiliation(s)
- Shuhai Shi
- Department of Critical Care Medicine, Capital Medical University Affiliated Beijing Shijitan Hospital, 100038, Beijing, China
| | - Jingli Cheng
- Department of General practice medicine, Beijing Shijingshan Hospital, 100040, Beijing, China
| | - Ying Zhao
- Department of Critical Care Medicine, Sanbo Brain Hospital, Capital Medical University, 100093, Beijing, China
| | - Wei Chen
- Department of Critical Care Medicine, Capital Medical University Affiliated Beijing Shijitan Hospital, 100038, Beijing, China.
| |
Collapse
|
36
|
Desai PV, Krepostman N, Collins M, De Sirkar S, Hinkleman A, Walsh K, Fareed J, Darki A. Neurological Complications of Pulmonary Embolism: a Literature Review. Curr Neurol Neurosci Rep 2021; 21:59. [PMID: 34669060 PMCID: PMC8526526 DOI: 10.1007/s11910-021-01145-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2021] [Indexed: 01/21/2023]
Abstract
PURPOSE OF REVIEW The present review discusses in-depth about neurological complications following acute venous thromboembolism (VTE). RECENT FINDINGS Intracranial hemorrhage, acute ischemic cerebrovascular events, and VTE in brain tumors are described as central nervous system (CNS) complications of PE, while peripheral neuropathy and neuropathic pain are reported as peripheral nervous system (PNS) sequelae of PE. Syncope and seizure are illustrated as atypical neurological presentations of PE. Mounting evidence suggests higher risk of venous thromboembolism (VTE) in patients with neurological diseases, but data on reverse, i.e., neurological sequelae following VTE, is underexplored. The present review is an attempt to explore some of the latter issues categorized into CNS, PNS, and atypical complications following VTE.
Collapse
Affiliation(s)
- Parth V Desai
- Department of Cardiovascular Medicine, Loyola University Medical Center, Maywood, IL, 60153, USA
| | - Nicolas Krepostman
- Departmet of Internal Medicine, Loyola University Medical Center, Maywood, IL, 60153, USA
| | - Matthew Collins
- Departmet of Internal Medicine, Loyola University Medical Center, Maywood, IL, 60153, USA
| | - Sovik De Sirkar
- Departmet of Internal Medicine, Loyola University Medical Center, Maywood, IL, 60153, USA
| | - Alexa Hinkleman
- Departmet of Internal Medicine, Loyola University Medical Center, Maywood, IL, 60153, USA
| | - Kevin Walsh
- Departmet of Internal Medicine, Loyola University Medical Center, Maywood, IL, 60153, USA
| | - Jawed Fareed
- Department of Pathology and Laboratory Medicine and Department of Pharmacology and Neuroscience, Health Science Division, Cardiovascular Research Institute, Hemostasis and Thrombosis Research Division, Loyola University, Maywood, IL, 60153, USA
| | - Amir Darki
- Department of Cardiovascular Medicine, Loyola University Medical Center, Maywood, IL, 60153, USA.
| |
Collapse
|
37
|
Yerrabothala S, Gourley BL, Ford JC, Ahmed SR, Guerin SJ, Porter M, Wishart HA, Ernstoff MS, Fadul CE, Ornstein DL. Systemic coagulation is activated in patients with meningioma and glioblastoma. J Neurooncol 2021; 155:173-180. [PMID: 34652553 DOI: 10.1007/s11060-021-03865-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 10/04/2021] [Indexed: 12/14/2022]
Abstract
PURPOSE Up to 30% of patients with glioblastoma (GBM) develop venous thromboembolism (VTE) over the course of the disease. Although not as high, the risk for VTE is also increased in patients with meningioma. Direct measurement of peak thrombin generation (TG) allows quantitative assessment of systemic coagulation activation in patients with GBM and meningioma. Our aim was to determine the extent of systemic coagulation activation induced by brain tumors, to measure the shift between pre- and post-operative peak TG in patients with GBM, and to assess the relationship between pre-surgical peak TG and pre-operative brain tumor volume on imaging. METHODS Pre- and post-surgical plasma samples were obtained from successive patients with GBM and once from patients with meningioma and healthy age- and sex-matched blood donor controls. TG was measured using the calibrated automated thrombogram (CAT) assay, and tumor volumes were measured in pre-surgical MRI scans. RESULTS Pre-surgical peak TG was higher in patients with GBM than in controls (288.6 ± 54.1 nM vs 187.1 ± 41.7 nM, respectively, P < 0.001), and, in the nine patients with GBM and paired data available, peak TG was significantly reduced after surgery (323 ± 38 nM vs 265 ± 52 nM, respectively, P = 0.007). Similarly, subjects with meningioma demonstrated higher peak TG compared to controls (242.2 ± 54.9 nM vs 177.7 ± 57.0 nM, respectively, P < 0.001). There was no association between peak TG and pre-operative tumor volume or overall survival. CONCLUSION Our results indicate that systemic coagulation activation occurs with both meningioma and GBM, but to a greater degree in the latter. Preoperative peak TG did not correlate with tumor volume, but removal of GBM caused a significant decrease in coagulation activation.
Collapse
Affiliation(s)
- Swaroopa Yerrabothala
- Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.,Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | | | - James C Ford
- Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.,Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Syed Rakin Ahmed
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA.,Harvard Graduate Program in Biophysics, Harvard Medical School, Harvard University, Cambridge, MA, USA.,Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Stephen J Guerin
- Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.,Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Marc Porter
- Geisel School of Medicine at Dartmouth, Hanover, NH, USA.,University of Rochester Medical Center, Rochester, NY, USA
| | - Heather A Wishart
- Dartmouth Hitchcock Medical Center, Lebanon, NH, USA.,Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | - Marc S Ernstoff
- Cancer Treatment and Diagnosis, Developmental Therapy Program, National Cancer Institute, Bethesda, MD, USA
| | - Camilo E Fadul
- University of Virginia School of Medicine, Charlottesville, VA, USA
| | - Deborah L Ornstein
- Dartmouth Hitchcock Medical Center, Lebanon, NH, USA. .,Geisel School of Medicine at Dartmouth, Hanover, NH, USA. .,Department of Pathology & Laboratory Medicine, Dartmouth Hitchcock Medical Center and Norris Cotton Cancer Center, 1 Medical Center Dr., Lebanon, NH, 03756, USA.
| |
Collapse
|
38
|
The Incidence of Cancer Associated Thrombosis is Increasing Over Time. Blood Adv 2021; 6:307-320. [PMID: 34649273 PMCID: PMC8753193 DOI: 10.1182/bloodadvances.2021005590] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 09/21/2021] [Indexed: 11/20/2022] Open
Abstract
Cancer associated thrombosis (CAT) is an important cause of morbidity and mortality for patients with malignancy and varies by primary cancer type, stage and therapy. We aimed to characterize the incidence, risk factors, temporal trends and the effect on mortality of CAT. The California Cancer Registry was linked to the statewide hospitalization database to identify individuals with the 13 most common malignancies diagnosed 2005 -2017 and determine the 6 and 12-month cumulative incidence of CAT by venous thromboembolism (VTE) location, tumor type and stage after adjusting for competing risk of death. Cox proportional hazard regression models were used to determine risk factors associated with CAT and the effect of CAT on all-cause mortality. 942,019 patients with cancer were identified; 62,003 (6.6%) had an incident diagnosis of CAT. Patients with pancreatic, brain, ovarian, and lung cancer had the highest and patients with breast and prostate cancer had the lowest 12-month cumulative incidence of CAT. For most malignancies, men, those with metastatic disease and more co-morbidities, and African-Americans (vs. non-Hispanic Whites) were at highest risk for CAT. Patients diagnosed with cancer 2014-2017 had higher risk of CAT compared to those diagnosed 2005-2007. CAT was associated with increased overall mortality for all malignancies (HR ranges 1.89 - 4.79). The incidence of CAT increased over time and was driven by an increase in PE±DVT. CAT incidence varies based on tumor type and stage, and on individual risk factors including gender, race/ethnicity, and co-morbidities. For all tumor types CAT is associated with an increased mortality.
Collapse
|
39
|
Winther-Larsen A, Sandfeld-Paulsen B, Hvas AM. New Insights in Coagulation and Fibrinolysis in Patients with Primary Brain Cancer: A Systematic Review. Semin Thromb Hemost 2021; 48:323-337. [PMID: 34624915 DOI: 10.1055/s-0041-1733961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Patients with primary brain tumors have a high incidence of thrombosis and hemorrhage. The underlying mechanism is believed to be derangement of their hemostatic system. To get nearer a clarification of this, we aimed to systematically review the existing literature regarding primary and secondary hemostasis as well as fibrinolysis in patients with primary brain tumor. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases PubMed, Embase, and Web of Science were searched on December 15, 2020, without time restrictions. Studies were included if they evaluated at least one blood coagulation and/or fibrinolysis parameter in patients with primary brain cancer. In total, 26 articles including 3,288 patients were included. Overall, increased activity of secondary hemostasis was observed as increased prothrombin fragment 1 + 2 and endogenous thrombin generation levels were found in glioma patients compared with controls. Furthermore, data showed a state of hypofibrinolysis with increased plasminogen activator inhibitor 1 and prolonged clot lysis time in glioma patients. In contrast, no consistent increase in the primary hemostasis was identified; however, data suggested that increased sP-selectin could be a biomarker of increased venous thromboembolism risk and that increased platelet count may be prognostic for survival. Lastly, data indicated that fibrinogen and D-dimer could hold prognostic value. In conclusion, this review indicates that an increased activity of secondary hemostasis and impaired fibrinolysis could be important players in the pathogeneses behind the high risk of thromboembolisms observed in brain cancer patients. Thus, long-term thromboprophylaxis may be beneficial and additional studies addressing this issue are wanted.
Collapse
Affiliation(s)
- Anne Winther-Larsen
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | | | - Anne-Mette Hvas
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| |
Collapse
|
40
|
Brea EJ, Tiu BC, Connors JM. A comprehensive review of DOACs for cancer associated VTE prophylaxis or treatment. Postgrad Med 2021; 133:71-79. [PMID: 34255597 DOI: 10.1080/00325481.2021.1955542] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Cancer is a leading cause of venous thromboembolism (VTE), which contributes to significant morbidity and mortality in these patients. Increased thrombotic risk in cancer patients is modified by tumor-specific biology, disease-directed interventions, and individual comorbidities. Risk stratification for prophylaxis and treatment requires regular reevaluation of these factors, which can be facilitated by validated prediction tools. This review also discusses large clinical trial data (SELECT-D, HOKUSAI-VTE, ADAM VTE, CARAVAGGIO) demonstrating that direct oral anticoagulants (DOACs) are effective in the treatment of cancer-associated VTE, with comparable efficacy to the traditional choice of low molecular weight heparin. In the prophylactic setting derived from patients with cancer with increased VTE risk, DOACs also reduced the incidence of VTE with only modest increases in bleeding risk. The ease of DOAC administration and acceptable risk profile in the carefully selected patient make them an appealing choice for anticoagulation. In instances where the risk of gastrointestinal bleeding is of concern, apixaban, in particular, may still be a suitable option in place of LMWH. These improvements in our anticoagulation approach to cancer-associated VTE are well-timed to accompany the recent advances in disease-directed therapies that are enabling patients to live longer with cancer and therefore at increased risk of complications such as VTE.
Collapse
Affiliation(s)
- Elliott J Brea
- Hematology, Dana-Farber Cancer Institute, Boston, MA, USA.,Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Jean M Connors
- Hematology, Dana-Farber Cancer Institute, Boston, MA, USA.,Hematology Division, Brigham and Women's Hospital, Boston, MA, USA
| |
Collapse
|
41
|
Jo J, Donahue J, Sarai G, Petroni G, Schiff D. Management of Venous Thromboembolism in High-Grade Glioma: Does Low Molecular Weight Heparin Increase Intracranial Bleeding Risk? Neuro Oncol 2021; 24:455-464. [PMID: 34383073 DOI: 10.1093/neuonc/noab198] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Venous thromboembolism (VTE) occurs in up to 30% of patients with high-grade glioma (HGG). Concern for increased risk of intracranial hemorrhage (ICH) with therapeutic anticoagulation complicates VTE treatment. Some retrospective studies have reported an increased risk of ICH associated with therapeutic anticoagulation; however, effective alternatives to anticoagulation are lacking. The aim of our study is to assess the risk of ICH in HGG patients with VTE on low molecular weight heparin (LMWH). METHODS We performed a retrospective matched cohort study of HGG patients from 1/2005-8/2016. Blinded review of neuroimaging for ICH was performed. For analysis of the primary endpoint, estimates of cumulative incidence (CI) of ICH were calculated using competing risk analysis with death as competing risk; significance testing was performed using the Gray's test. Median survival was estimated using Kaplan-Meier method. RESULTS 220 patients were included, 88 (40%) with VTE treated with LMWH, 22 (10%) with VTE, not on anticoagulation (AC), and 110 (50%) without VTE. A total of 43 measurable ICH was recorded: 19 (26%) in LMWH, 3 (14%) in VTE not on AC, and 21 (19%) in non-VTE cohort. No significant difference was observed in the 1-year CI of ICH in the LMWH cohort and non-AC with VTE group (17% versus 9%; Gray's test, p=0.36). Among patients without VTE, the 1-year CI of ICH was 13%. Median survival was similar among all three cohorts. CONCLUSIONS Our data suggest that therapeutic LMWH is not associated with substantially increased risk of ICH in HGG patients.
Collapse
Affiliation(s)
- Jasmin Jo
- Department of Internal Medicine, Division of Hematology and Oncology, East Carolina University/Vidant Medical Center, Greenville, NC
| | - Joseph Donahue
- Department of Radiology, University of Virginia, Charlottesville, VA
| | - Guneet Sarai
- Department of Primary Care and Population Health, Virginia Commonwealth University, Richmond, VA
| | - Gina Petroni
- Department of Public Health Sciences, Division of Biostatistics, University of Virginia, Charlottesville, VA
| | - David Schiff
- Department of Neurology, Division of Neuro-Oncology, University of Virginia, Charlottesville, VA
| |
Collapse
|
42
|
Zhang S, Guo M, Liu Q, Liu J, Cui Y. Neutrophil extracellular traps induce a hypercoagulable state in glioma. IMMUNITY INFLAMMATION AND DISEASE 2021; 9:1383-1393. [PMID: 34288521 PMCID: PMC8589396 DOI: 10.1002/iid3.488] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/29/2021] [Accepted: 07/02/2021] [Indexed: 01/21/2023]
Abstract
Background Venous thromboembolism (VTE) is one of the leading complications in glioma patients. Neutrophil extracellular traps (NETs) have been reported to play a critical role in the physiopathology of cancer. We aimed to investigate the presence and potential role of NETs in the hypercoagulable state in glioma patients. Moreover, we evaluated the interaction between NETs and endothelial cells (ECs) in glioma patients. Methods The plasma levels of NETs were detected by enzyme‐linked immunosorbent assay. The NET procoagulant activity was performed based on fibrin formation assays. The NET generation and NET‐treated ECs in vitro were observed by confocal microscopy. Activated platelets (PLTs) and PLT‐neutrophil aggregates were detected by flow cytometry. Results Plasma NET markers were significantly higher in stage III/IV glioma patients than in stage I/II glioma patients and healthy subjects. PLTs from glioma patients tended to induce NET formation than those from healthy subjects. NETs contributed to the hypercoagulable state in glioma patients. After ECs were incubated with NETs isolated from stage III/IV glioma patients, they lost their intercellular connections and were converted into procoagulant phenotypes. Combining DNase I and activated protein C markedly decreased endothelial dysfunction. Conclusions Our results showed the interaction between NETs and hypercoagulability in glioma patients. Targeting NETs may be a potential therapeutic and prevention direction for thrombotic complications in glioma patients.
The plasma levels of NETs are increased in samples from high‐grade glioma. PLT induce the generation of NETs in glioma patients. NETs contribute to procoagulant in glioma patients and platelet activation and convert endothelial cells (ECs) to thrombogenicity.
Collapse
Affiliation(s)
- Shihua Zhang
- Department of Neurosurgery of the First Affiliated Hospital, Jiamusi University, Jiamusi, China
| | - Mengfan Guo
- Department of Pathology of the First Affiliated Hospital, Jiamusi University, Jiamusi, China
| | - Qianzi Liu
- Department of Pharmacy of Jiamusi University, Jiamusi, China
| | - Jingfeng Liu
- Department of Outpatient of the First Affiliated Hospital, Jiamusi University, Jiamusi, China
| | - Yankun Cui
- Department of Neurosurgery of the First Affiliated Hospital, Jiamusi University, Jiamusi, China
| |
Collapse
|
43
|
Mir Seyed Nazari P, Berghoff AS, Preusser M, Moik F, Posch F, Ricken G, Riedl J, Hell L, Marosi C, Hainfellner JA, Pabinger I, Ay C. Association of programmed cell death ligand 1 and circulating lymphocytes with risk of venous thromboembolism in patients with glioma. ESMO Open 2021; 5:e000647. [PMID: 32424065 PMCID: PMC7239522 DOI: 10.1136/esmoopen-2019-000647] [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: 11/26/2019] [Revised: 02/12/2020] [Accepted: 03/09/2020] [Indexed: 12/22/2022] Open
Abstract
Introduction The role of the adaptive immune system in the pathophysiology of cancer-associated venous thromboembolism (VTE) has not been investigated in detail. Programmed cell death ligand 1 (PD-L1) is an immune checkpoint molecule responsible for immune evasion in several cancer entities, as expression on tumour cells silences the T cell-mediated immune response. Given the interrelation between inflammation, haemostasis and cancer, we aimed to investigate the association of players of the adaptive immunity (eg, lymphocytes, tumour PD-L1) with risk of VTE in patients with glioma, one of the most prothrombotic cancer types. Methods In this prospective observational single-centre cohort study, patients with newly diagnosed glioma or regrowth after resection were included. Primary endpoint was objectively confirmed VTE. At study inclusion, a blood draw was performed. Tumour PD-L1 expression was assessed via immunohistochemistry. Results In total, 193 patients were included. PD-L1 expression in ≥1% of tumour cells was observed in 20/193 (10.4%) glioma. In multivariable cox-regression analysis, on adjustment for age, sex and WHO grade IV, systemic lymphocyte counts were significantly associated with risk of VTE (HR per 1 G/L increase (95% CI): 1.15 (1.03 to 1.29), p=0.013). In contrast, no significant difference in risk of VTE was found regarding the PD-L1 status: the cumulative 24 months probability of VTE was 17.0% in patients with no PD-L1 and 11.8% in those with PD-L1 expressing tumours (p=0.663). Conclusion In summary, PD-L1 expression was not associated with risk of VTE. Interestingly, peripheral lymphocytes, which are key players in adaptive immunity, were linked to an increased risk of glioma-associated VTE.
Collapse
Affiliation(s)
- Pegah Mir Seyed Nazari
- Division of Haematology and Haemostaseology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Anna S Berghoff
- Division of Oncology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Matthias Preusser
- Division of Oncology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Florian Moik
- Division of Haematology and Haemostaseology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Florian Posch
- Division of Oncology, Medical University of Graz, Graz, Austria
| | - Gerda Ricken
- Institute of Neurology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Julia Riedl
- Division of Haematology and Haemostaseology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Lena Hell
- Division of Haematology and Haemostaseology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Christine Marosi
- Division of Oncology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Johannes A Hainfellner
- Institute of Neurology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Ingrid Pabinger
- Division of Haematology and Haemostaseology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Cihan Ay
- Division of Haematology and Haemostaseology, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria; I M Sechenov First Moscow State Medical University, Moscow, Russian Federation.
| |
Collapse
|
44
|
Osada Y, Saito R, Miyata S, Shoji T, Shibahara I, Kanamori M, Sonoda Y, Kumabe T, Watanabe M, Tominaga T. Association between IDH mutational status and tumor-associated epilepsy or venous thromboembolism in patients with grade II and III astrocytoma. Brain Tumor Pathol 2021; 38:218-227. [PMID: 34269949 DOI: 10.1007/s10014-021-00406-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 06/29/2021] [Indexed: 12/30/2022]
Abstract
In previous studies, isocitrate dehydrogenase (IDH) mutations were associated with tumor-associated epilepsy (TAE) and venous thromboembolism (VTE). We examined the relationship between IDH mutations in grade II/III astrocytomas and TAE/VTE according to the 2016 World Health Organization classification. The clinical data of patients with newly diagnosed grade II/III gliomas who were treated at Tohoku University Hospital from January 2010 to December 2018 were reviewed. Associations between TAE or VTE and the clinical/biological characteristics, histology, and IDH1/2 mutational status in patients with grade II/III gliomas were evaluated. Of the initial 137 patients (290 hospitalizations), 117 patients (203 hospitalizations) were included in the TAE group and 124 patients (213 hospitalizations) were included in the VTE group. Seventy-eight patients (66.7%) in the TAE group were diagnosed with astrocytoma and 38/78 (48.3%) presented with TAE. According to the multivariable analysis, the IDH mutational status and male sex were associated independently with an increased risk of TAE (p < 0.05). Eighty-five patients (68.5%) in the VTE group were diagnosed with astrocytoma. VTE was observed in 16/161 (9.9%) hospitalizations. According to the multivariable analysis, age, diffuse astrocytoma histology, and resection were associated independently with an increased risk of VTE. The decision tree analysis showed that TAE was more frequent in younger patients while VTE was more frequent in older patients. This study demonstrated that the IDH mutational status was associated with TAE but not with VTE. Therefore, a future large-scale study is needed to provide sufficient evidence. TAE was more common in young patients, while VTE was more common in the elderly.
Collapse
Affiliation(s)
- Yoshinari Osada
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Ryuta Saito
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
| | - Satoshi Miyata
- Teikyo University Graduate School of Public Health, Tokyo, Japan
| | - Takuhiro Shoji
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Ichiyo Shibahara
- Department of Neurosurgery, Kitasato University Graduate School of Medicine, Kanagawa, Japan
| | - Masayuki Kanamori
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Yukihiko Sonoda
- Department of Neurosurgery, Yamagata University Graduate School of Medicine, Yamagata, Japan
| | - Toshihiro Kumabe
- Department of Neurosurgery, Kitasato University Graduate School of Medicine, Kanagawa, Japan
| | - Mika Watanabe
- Department of Pathology, Tohoku University Hospital, Sendai, Japan
| | - Teiji Tominaga
- Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| |
Collapse
|
45
|
Carlson JC, Cantu Gutierrez M, Lozzi B, Huang-Hobbs E, Turner WD, Tepe B, Zhang Y, Herman AM, Rao G, Creighton CJ, Wythe JD, Deneen B. Identification of diverse tumor endothelial cell populations in malignant glioma. Neuro Oncol 2021; 23:932-944. [PMID: 33367832 DOI: 10.1093/neuonc/noaa297] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Glioblastoma is the most common and aggressive type of primary brain tumor, as most patients succumb to the disease less than two years after diagnosis. Critically, studies demonstrate that glioma recruits surrounding blood vessels, while some work suggests that tumor stem cells themselves directly differentiate into endothelial cells, yet the molecular and cellular dynamics of the endothelium in glioma are poorly characterized. The goal of this study was to establish molecular and morphological benchmarks for tumor associated vessels (TAVs) and tumor derived endothelial cells (TDECs) during glioblastoma progression. METHODS Using In-Utero Electroporation and CRISPR/Cas9 genome engineering to generate a native, immunocompetent mouse model of glioma, we characterized vascular-tumor dynamics in three dimensions during tumor progression. We employed bulk and single-cell RNA-Sequencing to elucidate the relationship between TAVs and TDECs. We confirmed our findings in a patient derived orthotopic xenograft (PDOX) model. RESULTS Using a mouse model of glioma, we identified progressive alteration of vessel function and morphogenesis over time. We also showed in our mouse model that TDECs are a rare subpopulation that contributes to vessels within the tumor, albeit to a limited degree. Furthermore, transcriptional profiling demonstrates that both TAVs and TDECs are molecularly distinct, and both populations feature extensive molecular heterogeneity. Finally, the distinct molecular signatures of these heterogeneous populations are also present in human glioma. CONCLUSIONS Our findings show extensive endothelial heterogeneity within the tumor and tumor microenvironment and provide insights into the diverse cellular and molecular mechanisms that drive glioma vascularization and angiogenesis during tumorigenesis.
Collapse
Affiliation(s)
- Jeff C Carlson
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas.,Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas
| | - Manuel Cantu Gutierrez
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas.,Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas.,Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas
| | - Brittney Lozzi
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas
| | - Emmet Huang-Hobbs
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.,The Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, Texas
| | - Williamson D Turner
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas.,Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas.,Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas
| | - Burak Tepe
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
| | - Yiqun Zhang
- Dan L Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, Texas
| | - Alexander M Herman
- Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas.,Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas
| | - Ganesh Rao
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
| | - Chad J Creighton
- Dan L Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, Texas.,Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Joshua D Wythe
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas.,Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas.,Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas.,Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas
| | - Benjamin Deneen
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas.,Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas.,Department of Neurosurgery, Baylor College of Medicine, Houston, Texas
| |
Collapse
|
46
|
Mandel JJ, Youssef M, Yust-Katz S, Patel AJ, Jalali A, Li Z, Wu J, Ludmir EB, de Groot JF. IDH mutation status and the development of venous thromboembolism in astrocytoma patients. J Neurol Sci 2021; 427:117538. [PMID: 34146775 DOI: 10.1016/j.jns.2021.117538] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/21/2021] [Accepted: 06/10/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Venous thromboembolism (VTE) is a very common adverse event for astrocytoma patients, but validation of proposed risk biomarkers has been elusive. We examine whether the status of the isocitrate dehydrogenase (IDH) gene is a risk factor for the development of venous thromboembolism (VTE) in astrocytoma patients. METHODS We conducted a retrospective chart review of 282 astrocytoma patients enrolled in the PROACTIVE (Prospective Assessment of Correlative Biomarker) study at MD Anderson Cancer Center (MDACC) from 9/1/2000 until 12/31/2013. RESULTS We identified 282 astrocytoma patients consisting of 49 IDH mutant astrocytomas and 233 IDH wildtype astrocytomas. Glioblastoma was the initial histopathologic diagnosis in 30 (61.2%) of the IDH mutated astrocytomas compared to 227(97.4%) of the IDH wild type astrocytomas. VTE was identified in 52 (18.4%) of patients. VTE was diagnosed in 7 (14.3%) of the IDH mutated astrocytomas compared to 45(19.3%) of the IDH wild type astrocytoma s (p = 0.4094). Median time to VTE from diagnosis was 2.71 months. Median time to VTE from diagnosis was 2.6 months for IDH mutated astrocytomas compared to 3.06 months for the IDH wild type astrocytomas (p = 0.8663). CONCLUSIONS IDH gene status did not appear as a significant risk factor for the development of venous thromboembolism (VTE) in our cohort of astrocytoma patients. Further research into potential biomarkers for VTE may be warranted.
Collapse
Affiliation(s)
- Jacob J Mandel
- Baylor College of Medicine, Department of Neurology and Neurosurgery, One Baylor Plaza, MS NB302, Houston, TX 77030, United States of America
| | | | - Shlomit Yust-Katz
- Rabin Medical Center, Department of Neurosurgery, 39 Jabotinski St, Petah Tikva, Israel; Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Akash J Patel
- Baylor College of Medicine, Department of Neurology and Neurosurgery, One Baylor Plaza, MS NB302, Houston, TX 77030, United States of America
| | - Ali Jalali
- Baylor College of Medicine, Department of Neurology and Neurosurgery, One Baylor Plaza, MS NB302, Houston, TX 77030, United States of America
| | - Ziyi Li
- The University of Texas MD Anderson Cancer Center, Department of Biostatistics, Unit 1409, P. O. Box 301402, Houston, TX 77230-1402, United States of America
| | - Jimin Wu
- The University of Texas MD Anderson Cancer Center, Department of Biostatistics, Unit 1409, P. O. Box 301402, Houston, TX 77230-1402, United States of America
| | - Ethan B Ludmir
- The University of Texas MD Anderson Cancer Center, Division of Radiation Oncology - Unit 1422, 1400 Pressler St., FCT6.5000, Houston, TX 77030, United States of America
| | - John F de Groot
- The University of Texas MD Anderson Cancer Center, Department of Neuro-Oncology, Unit 431, 1515 Holcombe Blvd, Houston, TX 77030-4009, United States of America.
| |
Collapse
|
47
|
Naeem K, Bhargava M, Bohl M, Porter RW. Posterior Fossa Hemorrhage Following the Use of Low-Molecular-Weight Heparin: Lessons Learned and Recommendations for the Treatment and Prophylaxis of Postoperative Venous Thromboembolism. Cureus 2021; 13:e15404. [PMID: 34249552 PMCID: PMC8253580 DOI: 10.7759/cureus.15404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 04/30/2021] [Indexed: 11/16/2022] Open
Abstract
Introduction Venous thromboembolism (VTE) is the most common preventable cause of morbidity and mortality among neurosurgery patients. Several studies have concluded that the use of chemical prophylaxis among patients undergoing a craniotomy reduces the incidence of VTE, and it is presumed to be safe. However, these studies do not differentiate between a supratentorial and posterior fossa craniotomy. Furthermore, the prophylactic or therapeutic use of low-molecular-weight heparin (LMWH) has been reported to increase the risk of intracranial hemorrhage. In this study, we describe the clinical details and outcomes for all patients who underwent posterior fossa craniotomy and developed posterior fossa hemorrhage secondary to postoperative use of LMWH during the study period. We also propose recommendations pertaining to postoperative heparin use after posterior fossa surgeries. Methods Data were retrospectively collected for patients presenting with posterior fossa hemorrhage following anticoagulant use among those who previously underwent posterior fossa craniotomy by the senior author (R.W.P.) from January 1, 2011, through December 31, 2018. Results We identified five patients who experienced postoperative hemorrhage while receiving LMWH in the initial setting of posterior fossa craniotomy. After hemorrhaging, four patients had low Glasgow Outcome Scale (GOS) scores (≤3) and failed to return to their baseline neurological status. These four patients had a Glasgow Coma Scale (GCS) score of 15/15 in the immediate postoperative period and received heparin within 72 hours of surgery. Conclusions Based on our findings, there is a possible association between the increased risk of hemorrhage and the early postoperative use of LMWH. The debilitating outcomes among the majority of these patients warrant the cautious use and further investigation of postoperative LMWH to appropriately quantify the risk. Further comparative studies with a larger sample size are required to provide insight into the pathophysiology of our findings.
Collapse
Affiliation(s)
- Komal Naeem
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, USA
| | - Malika Bhargava
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, USA
| | - Michael Bohl
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, USA
| | - Randall W Porter
- Department of Neurosurgery, Barrow Neurological Institute, Phoenix, USA
| |
Collapse
|
48
|
Zoccarato M, Nardetto L, Basile AM, Giometto B, Zagonel V, Lombardi G. Seizures, Edema, Thrombosis, and Hemorrhages: An Update Review on the Medical Management of Gliomas. Front Oncol 2021; 11:617966. [PMID: 33828976 PMCID: PMC8019972 DOI: 10.3389/fonc.2021.617966] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 02/04/2021] [Indexed: 12/21/2022] Open
Abstract
Patients affected with gliomas develop a complex set of clinical manifestations that deeply impact on quality of life and overall survival. Brain tumor-related epilepsy is frequently the first manifestation of gliomas or may occur during the course of disease; the underlying mechanisms have not been fully explained and depend on both patient and tumor factors. Novel treatment options derive from the growing use of third-generation antiepileptic drugs. Vasogenic edema and elevated intracranial pressure cause a considerable burden of symptoms, especially in high-grade glioma, requiring an adequate use of corticosteroids. Patients with gliomas present with an elevated risk of tumor-associated venous thromboembolism whose prophylaxis and treatment are challenging, considering also the availability of new oral anticoagulant drugs. Moreover, intracerebral hemorrhages can complicate the course of the illness both due to tumor-specific characteristics, patient comorbidities, and side effects of antithrombotic and antitumoral therapies. This paper aims to review recent advances in these clinical issues, discussing the medical management of gliomas through an updated literature review.
Collapse
Affiliation(s)
- Marco Zoccarato
- Neurology Unit, O.S.A., Azienda Ospedale-Università, Padua, Italy
| | - Lucia Nardetto
- Neurology Unit, O.S.A., Azienda Ospedale-Università, Padua, Italy
| | | | - Bruno Giometto
- Neurology Unit, Trento Hospital, Azienda Provinciale per i Servizi Sanitari (APSS) di Trento, Trento, Italy
| | - Vittorina Zagonel
- Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCSS, Padua, Italy
| | - Giuseppe Lombardi
- Department of Oncology, Oncology 1, Veneto Institute of Oncology IOV-IRCSS, Padua, Italy
| |
Collapse
|
49
|
Pandit S, Wasekar N, Badarkhe G, Ramesh Y, Nagarkar R. Cerebral venous thrombosis in nucleophosmin gene-mutated acute myeloid leukemia: A rare case report. JOURNAL OF APPLIED HEMATOLOGY 2021. [DOI: 10.4103/joah.joah_224_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
|
50
|
Leiva O, Newcomb R, Connors JM, Al-Samkari H. Cancer and thrombosis: new insights to an old problem. JOURNAL DE MÉDECINE VASCULAIRE 2020; 45:6S8-6S16. [PMID: 33276943 DOI: 10.1016/s2542-4513(20)30514-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Venous thromboembolism (VTE) is a common complication in patients with cancer and portends a poor prognosis. Our understanding of the underlying pathophysiology of VTE in cancer has advanced since Trousseau first described hypercoagulability in patients with malignancy and Virchow described his famous triad of thrombosis formation. Malignancy itself induces a thrombophilic state by increasing the risk of venous stasis, endothelial injury and an imbalance of pro and anti-thrombotic factors leading to a hypercoaguable state. Additional insults to this thrombotic balance are introduced by patient-specific, treatment related and tumor-specific factors. The importance of understanding the factors associated with increased thrombosis in cancer is paramount in order to adequately identify patients who will benefit from thromboprophylaxis.
Collapse
Affiliation(s)
- O Leiva
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - R Newcomb
- Division of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - J M Connors
- Hematology Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - H Al-Samkari
- Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
| |
Collapse
|