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Dennis RL, Dorsey D, Scott M, Shaban A, Himes S. Atypical Chest Pain Leading to the Diagnosis of Acute Promyelocytic Leukemia: A Case Report. Cureus 2025; 17:e77196. [PMID: 39925599 PMCID: PMC11806940 DOI: 10.7759/cureus.77196] [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: 12/14/2024] [Accepted: 01/09/2025] [Indexed: 02/11/2025] Open
Abstract
Acute promyelocytic leukemia (APML) is a rare leukemia that leads to complications of renal toxicity, infections, leukocytosis, hemorrhaging, and disseminated intravascular coagulation, which is fatal. APML normally presents with bruising, bleeding, weakness, and infections. Patients can present with chest pain and shortness of breath due to coagulopathy. The workup for APML usually occurs when patients' labs return with leukocytosis and thrombocytopenia. Here, we report a case of a 75-year-old female with a past medical history of bronchiectasis, hypertension, and rheumatic fever who presented with chest pain and shortness of breath with elevated troponins and a normal EKG. The patient had worsened thrombocytopenia, leukocytosis, and an elevated D-dimer that did not resolve with steroids. The following report presents a patient diagnosed with APML with the initial symptoms of chest pain and shortness of breath without signs of acute coronary syndrome, leading to the diagnosis and treatment with ATRA.
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Affiliation(s)
- Roy L Dennis
- Internal Medicine, Oklahoma State University Medical Center, Tulsa, USA
- Internal Medicine, Edward Via College of Osteopathic Medicine (VCOM) Carolinas, Spartanburg, USA
| | - Dade Dorsey
- Emergency Medicine, Oklahoma State University Medical Center, Tulsa, USA
- Emergency Medicine, Oklahoma State University College of Osteopathic Medicine, Tulsa, USA
| | - Mitchell Scott
- Internal Medicine, Oklahoma State University Medical Center, Tulsa, USA
| | - Ahmed Shaban
- Internal Medicine, Oklahoma State University Medical Center, Tulsa, USA
| | - Seraphim Himes
- Internal Medicine, Oklahoma State University Medical Center, Tulsa, USA
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2
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Hisada Y. Dysregulated hemostasis in acute promyelocytic leukemia. Int J Hematol 2024; 119:526-531. [PMID: 38341391 DOI: 10.1007/s12185-024-03708-0] [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: 11/30/2023] [Revised: 12/26/2023] [Accepted: 01/04/2024] [Indexed: 02/12/2024]
Abstract
Acute promyelocytic leukemia (APL) is associated with a high incidence of early death, which occurs within 30 days of diagnosis. The major cause of early death in APL is severe bleeding, particularly intracranial bleeding. Although APL is known to be associated with activation of coagulation, hyperfibrinolysis, and thrombocytopenia, the precise mechanisms that cause bleeding have not yet been elucidated. I propose that a combination of four pathways may contribute to bleeding in APL: (1) tissue factor, (2) the urokinase plasminogen activator/urokinase plasminogen activator receptor, (3) the annexin A2/S100A100/tissue plasminogen activator, and (4) the podoplanin/C-type lectin-like receptor 2. A better understanding of these pathways will identify new biomarkers to determine which APL patients are at high risk of bleeding and allow the development of new treatments for APL-associated bleeding.
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Affiliation(s)
- Yohei Hisada
- UNC Blood Research Center, Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, 116 Manning Drive, 8004 Mary Ellen Jones Bldg, Campus Box #7035, Chapel Hill, NC, 27599, USA.
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3
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Wolff L, Khzouri T. Coagulation intravasculaire disséminée : mise au point. Rev Med Interne 2024; 45:271-278. [PMID: 38575440 DOI: 10.1016/j.revmed.2024.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 02/27/2024] [Accepted: 03/07/2024] [Indexed: 04/06/2024]
Affiliation(s)
- L Wolff
- Service de réanimation polyvalente du groupe hospitalier intercommunal Le Raincy Montfermeil, 10, rue du Général Leclerc, 93370 Montfermeil, France.
| | - T Khzouri
- Service de réanimation polyvalente du groupe hospitalier intercommunal Le Raincy Montfermeil, 10, rue du Général Leclerc, 93370 Montfermeil, France.
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4
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Wada T, Gando S. Phenotypes of Disseminated Intravascular Coagulation. Thromb Haemost 2024; 124:181-191. [PMID: 37657485 PMCID: PMC10890912 DOI: 10.1055/a-2165-1142] [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: 07/30/2023] [Accepted: 08/30/2023] [Indexed: 09/03/2023]
Abstract
Two phenotypes of disseminated intravascular coagulation (DIC) are systematically reviewed. DIC is classified into thrombotic and fibrinolytic phenotypes characterized by thrombosis and hemorrhage, respectively. Major pathology of DIC with thrombotic phenotype is the activation of coagulation, insufficient anticoagulation with endothelial injury, and plasminogen activator inhibitor-1-mediated inhibition of fibrinolysis, leading to microvascular fibrin thrombosis and organ dysfunction. DIC with fibrinolytic phenotype is defined as massive thrombin generation commonly observed in any type of DIC, combined with systemic pathologic hyperfibrinogenolysis caused by underlying disorder that results in severe bleeding due to excessive plasmin formation. Three major pathomechanisms of systemic hyperfibrinogenolysis have been considered: (1) acceleration of tissue-type plasminogen activator (t-PA) release from hypoxic endothelial cells and t-PA-rich storage pools, (2) enhancement of the conversion of plasminogen to plasmin due to specific proteins and receptors that are expressed on cancer cells and endothelial cells, and (3) alternative pathways of fibrinolysis. DIC with fibrinolytic phenotype can be diagnosed by DIC diagnosis followed by the recognition of systemic pathologic hyperfibrin(ogen)olysis. Low fibrinogen levels, high fibrinogen and fibrin degradation products (FDPs), and the FDP/D-dimer ratio are important for the diagnosis of systemic pathologic hyperfibrin(ogen)olysis. Currently, evidence-based treatment strategies for DIC with fibrinolytic phenotypes are lacking. Tranexamic acid appears to be one of the few methods to be effective in the treatment of systemic pathologic hyperfibrin(ogen)olysis. International cooperation for the elucidation of pathomechanisms, establishment of diagnostic criteria, and treatment strategies for DIC with fibrinolytic phenotype are urgent issues in the field of thrombosis and hemostasis.
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Affiliation(s)
- Takeshi Wada
- Department of Anesthesiology and Critical Care Medicine, Division of Acute and Critical Care Medicine, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Satoshi Gando
- Department of Anesthesiology and Critical Care Medicine, Division of Acute and Critical Care Medicine, Hokkaido University Faculty of Medicine, Sapporo, Japan
- Department of Acute and Critical Care Medicine, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan
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Tonutti A, Scarfò I, La Canna G, Selmi C, De Santis M. Diagnostic Work-Up in Patients with Nonbacterial Thrombotic Endocarditis. J Clin Med 2023; 12:5819. [PMID: 37762758 PMCID: PMC10532023 DOI: 10.3390/jcm12185819] [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: 07/25/2023] [Revised: 08/23/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Nonbacterial thrombotic endocarditis (NBTE) is a form of endocarditis that occurs in patients with predisposing conditions, including malignancies, autoimmune diseases (particularly antiphospholipid antibody syndrome, which accounts for the majority of lupus-associated cases), and coagulation disturbances for which the correlation with classical determinants is unclear. The condition is commonly referred to as "marantic", "verrucous", or Libman-Sacks endocarditis, although these are not synonymous, representing clinical-pathological nuances. The clinical presentation of NBTE involves embolic events, while local valvular complications, generally regurgitation, are typically less frequent and milder compared to infective forms of endocarditis. In the past, the diagnosis of NBTE relied on post mortem examinations, while at present, the diagnosis is primarily based on echocardiography, with the priority of excluding infective endocarditis through comprehensive microbiological and serological tests. As in other forms of endocarditis, besides pathology, transesophageal echocardiography remains the diagnostic standard, while other imaging techniques hold promise as adjunctive tools for early diagnosis and differentiation from infective vegetations. These include cardiac MRI and 18FDG-PET/CT, which already represents a major diagnostic criterion of infective endocarditis in specific settings. We will herein provide a comprehensive review of the current knowledge on the clinics and therapeutics of NBTE, with a specific focus on the diagnostic tools.
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Affiliation(s)
- Antonio Tonutti
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy; (A.T.); (C.S.)
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
| | - Iside Scarfò
- Applied Diagnostic Echocardiography Unit, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (I.S.); (G.L.C.)
| | - Giovanni La Canna
- Applied Diagnostic Echocardiography Unit, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy; (I.S.); (G.L.C.)
| | - Carlo Selmi
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy; (A.T.); (C.S.)
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
| | - Maria De Santis
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Italy; (A.T.); (C.S.)
- Rheumatology and Clinical Immunology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
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Hermsen J, Hambley B. The Coagulopathy of Acute Promyelocytic Leukemia: An Updated Review of Pathophysiology, Risk Stratification, and Clinical Management. Cancers (Basel) 2023; 15:3477. [PMID: 37444587 DOI: 10.3390/cancers15133477] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 06/21/2023] [Accepted: 06/28/2023] [Indexed: 07/15/2023] Open
Abstract
Acute promyelocytic leukemia (APL) has a well-established mechanism and a long-term prognosis that exceeds that of any other acute leukemia. These improving outcomes are due, in part, to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), two targeted and highly active agents in this disease. However, there remains a considerable morbidity and mortality risk in APL secondary to clinically significant hemorrhagic and/or thrombotic events. Prevention and treatment of these coagulopathic complications remain significant impediments to further progress in optimizing outcomes for patients with APL. Moreover, the relative rarity of APL hinders adequately powered randomized controlled trials for evaluating APL coagulopathy management strategies. This review draws from peer-reviewed works falling between initial descriptions of APL in 1957 and work published prior to January 2023 and provides an updated overview of the pathophysiology of hemorrhagic and thrombotic complications in APL, outlines risk stratification parameters, and compiles current clinical best practices. An improved understanding of the pathophysiologic mechanisms driving hemorrhage and thrombosis along with the completion of well-designed trials of management strategies will assist clinicians in developing interventions that mitigate these devastating complications in an otherwise largely curable disease.
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Affiliation(s)
- Jack Hermsen
- University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Bryan Hambley
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, 3125 Eden Ave, Cincinnati, OH 45267, USA
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Kanamoto R, Oda T, Akaiwa K, Nakamura K, Tayama E. Total arch replacement for the enhanced-fibrinolytic-type disseminated intravascular coagulation patient with endoleak after thoracic endovascular aortic repair for aortic dissection. GENERAL THORACIC AND CARDIOVASCULAR SURGERY CASES 2023; 2:34. [PMID: 39516939 PMCID: PMC11533607 DOI: 10.1186/s44215-023-00046-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 01/22/2023] [Indexed: 11/16/2024]
Abstract
BACKGROUND Endoleaks after stent graft treatment can cause disseminated intravascular coagulation (DIC), leading to a bleeding tendency. CASE PRESENTATION A 69-year-old man received thoracic endovascular aortic repair (TEVAR) for acute type B aortic dissection. After that, he developed bleeding tendency, and the diameter of his distal aortic arch increased. We diagnosed him with enhanced fibrinolytic-type DIC associated with a type Ia endoleak. We decided to perform a total arch replacement for the endoleak closure. To reduce the risk of massive bleeding, transfusion of fresh frozen plasma and platelets, oral tranexamic acid, and intravenous recombinant human soluble thrombomodulin were administered in the perioperative period. According to the multidisciplinary approach, the DIC improved, and the patient recovered. CONCLUSION We successfully treated an endoleak-related DIC patient with bleeding tendency and combined correction for coagulopathy with supportive treatments.
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Affiliation(s)
- Ryo Kanamoto
- Division of Cardiovascular Surgery, Omura Municipal Hospital, 133-22 Kogashima-Cho, Omura-Shi, Nagasaki, 856-8561, Japan.
| | - Takeshi Oda
- Division of Cardiovascular Surgery, Omura Municipal Hospital, 133-22 Kogashima-Cho, Omura-Shi, Nagasaki, 856-8561, Japan
| | - Keiichi Akaiwa
- Division of Cardiovascular Surgery, Omura Municipal Hospital, 133-22 Kogashima-Cho, Omura-Shi, Nagasaki, 856-8561, Japan
| | - Katsuhiko Nakamura
- Division of Cardiovascular Surgery, Omura Municipal Hospital, 133-22 Kogashima-Cho, Omura-Shi, Nagasaki, 856-8561, Japan
| | - Eiki Tayama
- Department of Cardiovascular Surgery, Department of Surgery, Kurume University School of Medicine, Kurume, Fukuoka, Japan
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8
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Benoit TM, Gundermann S. [Devil with angel wings - when vitamin A saves lives]. Dtsch Med Wochenschr 2023; 148:396-399. [PMID: 36940690 DOI: 10.1055/a-2038-9745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/23/2023]
Abstract
ANAMNESIS AND CLINICAL EXAMINATION A 40-year-old male patient presented to our emergency department with a new onset of hemorrhagic diathesis. Clinically, there were marked bleeding stigmata with extensive ecchymosis in the thigh area and oral mucosal hemorrhage with otherwise general well-being. DIAGNOSTICS The coagulation diagnostics performed were consistent with the picture of disseminated intravascular consumption coagulopathy. Microscopic blood count also revealed 74% morphologically atypical promyelocytes. DIAGNOSIS, THERAPY, AND CLINICAL COURSE Bone marrow investigation confirmed the diagnosis of a microgranular variant of acute promyelocytic leukemia. In addition to coagulation optimization, therapy with all-trans retinoic acid (ATRA) was initiated immediately. Subsequently, arsenic trioxide (ATO) and the anthracycline idarubicin were added. No severe complications occurred in the following course of treatment. Moreover, the patient is currently in complete remission regarding acute promyelocytes leukemia. CONCLUSIONS Acute promyelocytic leukemia accounts for approximately 10-15% of all acute myeloid leukemias. Often, association with marked coagulation abnormalities due to disseminated intravascular consumption coagulopathy, which is present at diagnosis, APL becomes fatal if untreated. Rapid therapy initiation with ATRA and coagulation optimization, initiated as soon as the diagnosis is suspected, are crucial for prognosis.
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Affiliation(s)
- Tobias Matthieu Benoit
- Klinik für Medizinische Onkologie und Hämatologie, Universitätsspital Zürich, Zürich, Schweiz
| | - Stefan Gundermann
- Klinik für Medizinische Onkologie und Hämatologie, Universitätsspital Zürich, Zürich, Schweiz
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9
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Jiang M, Wan JH, Tu Y, Shen Y, Kong FC, Zhang ZL. Angioimmunoblastic T-cell lymphoma induced hemophagocytic lymphohistiocytosis and disseminated intravascular coagulopathy: A case report. World J Clin Cases 2023; 11:1086-1093. [PMID: 36874426 PMCID: PMC9979290 DOI: 10.12998/wjcc.v11.i5.1086] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/25/2022] [Accepted: 01/28/2023] [Indexed: 02/14/2023] Open
Abstract
BACKGROUND Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma, with heterogenous clinical manifestations and poor prognosis. Here, we report a case of AITL induced hemophagocytic lymphohistiocytosis (HLH) and disseminated intravascular coagulopathy (DIC).
CASE SUMMARY An 83-year-old man presented with fever and purpura of both lower limbs for one month. Groin lymph node puncture and flow cytometry indicated a diagnosis of AITL. Bone marrow examination and other laboratory related indexes indicated DIC and HLH. The patient rapidly succumbed to gastrointestinal bleeding and septic shock.
CONCLUSION This is the first reported case of AITL induced HLH and DIC. AITL is more aggressive in older adults. In addition to male gender, mediastinal lymphadenopathy, anaemia, and sustained high level of neutrophil-to-lymphocyte ratio may indicate a greater risk of death. Early diagnosis, early detection of severe complications, and prompt and effective treatment are vital.
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Affiliation(s)
- Mei Jiang
- Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jing-Hua Wan
- Clinical Laboratory, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Yi Tu
- Department of Pathology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Yan Shen
- Department of Anesthesia, Medical College of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Fan-Cong Kong
- Department of Hematology, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Zhang-Lin Zhang
- Department of Transfusion, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
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Zhang N, Miao XJ, Shuai YR, Yao H, Fan FY, Liu YL. Family Aggregation of Hematological Malignancies Discovered from an Acute Myeloid Leukemia Patient with STK11 and THBD Gene Mutation. Case Rep Oncol 2023; 16:734-738. [PMID: 37900785 PMCID: PMC10601766 DOI: 10.1159/000532003] [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: 02/09/2023] [Accepted: 07/03/2023] [Indexed: 10/31/2023] Open
Abstract
Acute myeloid leukemia (AML) is a large class of heterogeneous hematological malignancies with the highest incidence rate in acute leukemia. Its pathogenesis is still unclear, which may be related to genetics. According to the latest AML NCCN guidelines, genes involved in AML family genetic changes include RUNX1, ANKRD26, CEBPA. Finding new genes related to AML genetics is of great significance for predicting the prognosis of patients, developing targeted drugs, and selecting transplant donors. Here, we report a case of adult female AML patient whose three relatives suffered from hematological malignancies, including Waldenstrom macroglobulinemia, NK/T-cell lymphoma, and angioimmunoblastic T-cell lymphoma. The screen for genetic susceptibility genes related to blood and immune system diseases was carried out, and the result showed that the patient herself, her son, her daughter, and her two cousins all had STK11 p.F354L and/or THBD p.D486Y mutations. At present, there is no research or case report on the relationship between STK11/THBD and family aggregation of hematological malignancies. We report for the first time that an AML patient with STK11 and THBD mutations has a family aggregation of hematological malignancies, and consider that STK11 and THBD may be related to family genetic changes which ultimately cause the family aggregation of hematological malignancies.
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Affiliation(s)
- Nan Zhang
- Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Chengdu, China
| | - Xiao-Juan Miao
- Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Chengdu, China
| | - Yan-Rong Shuai
- Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Chengdu, China
| | - Hao Yao
- Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Chengdu, China
| | - Fang-Yi Fan
- Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Chengdu, China
| | - Yi-Lan Liu
- Department of Hematology, People's Liberation Army The General Hospital of Western Theater Command, Chengdu, China
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11
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Alnuaimy SL, Shamoon RP. Disseminated intravascular coagulation in a cohort of adult acute leukemia patients: a single center experience. Blood Coagul Fibrinolysis 2023; 34:28-32. [PMID: 36239573 DOI: 10.1097/mbc.0000000000001172] [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: 01/20/2023]
Abstract
OBJECTIVES We aimed to detect the incidence of disseminated intravascular coagulation (DIC) in patients with acute leukemia (AL) and find out its association with types of AL and patients' clinical and pathological parameters. METHODS In this prospective study, 59 newly diagnosed adults with AL were clinically examined and screened for DIC presentation time. Coagulation tests, including prothrombin time, activated partial thromboplastin time, fibrinogen level, D-dimer, antithrombin, and protein C and protein S levels were all assessed. The International Society for Thrombosis and Hemostasis scoring system was adopted to diagnose overt DIC. RESULTS The age of the studied patients ranged from 15 to 81 years with a median of 41 years; male to female ratio was 1.1:1. acute myeloid leukemia (AML) constituted 64.4% of the total cases (38 patients). DIC was detected in 28 patients (47.5%); its incidence was higher in AML than in acute lymphoblastic leukemia (ALL) (52.6% vs. 38.1%). Overt DIC was significantly associated with bleeding manifestations, duration of symptoms, and leukocytosis ( P -values = 0.050, 0.044, and 0.003, respectively). Bleeding events were encountered in 50.8% of patients (25 AML and 5 ALL patients). Bleeding was associated significantly with leukocytosis, thrombocytopenia, and low fibrinogen level. Thrombosis was found in two patients (3.4%) at presentation. CONCLUSIONS Overt DIC was common in patients with AL at presentation, mostly in AML. Routine testing for coagulopathy in newly diagnosed AL patients will possibly aid in improving the overall patients' survival.
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Affiliation(s)
- Sarah L Alnuaimy
- Department of Haematology, Nanakali Hemato-Oncology Teaching Center
| | - Rawand P Shamoon
- Department of Haematology, Nanakali Hemato-Oncology Teaching Center
- Department of Pathology, College of Medicine, Hawler Medical University, Erbil, Iraq
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12
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Khan ER, Islam A, Jamal CY, Karim MA, Rahman AA, Hafiz MG, Khaleque A. Outcome and complications of pediatric acute promyelocytic leukemia in Bangladesh. Pediatr Hematol Oncol 2022; 39:406-417. [PMID: 34986070 DOI: 10.1080/08880018.2021.2002486] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Pediatric acute promyelocytic leukemia (APL) is one of the most curable subtypes of acute myeloid leukemia of childhood. But it may have many early complications, especially in developing countries. This study aims to describe the outcome and complications of pediatric APL patients in Bangladesh. This prospective observational study was conducted in the pediatric hematology and oncology department of Bangabandhu Sheikh Mujib Medical University, Dhaka from September 2017 to March 2019. In this study, PML:RAR-α (Promyelocytic leukemia-retinoic acid receptor-α) positive APL cases were included and observed while being treated with risk-directed ATRA (All-trans-retinoic acid) based chemotherapy. Among twenty PML:RAR-α positive APL cases, 13 children were in the high risk group and hemorrhagic manifestations were present in 95% of patients. Post-induction remission was achieved in 85% of the patients. 3-year overall survival was 70% (45-85% with 95% confidence interval). There was no refractory disease or relapses. Neutropenic sepsis was the most common complication and also the most common cause of mortality. In Bangladesh, the 3-year overall survival of pediatric APL is 70% (45-85% with 95% CI). Post-chemotherapy neutropenic sepsis is the most common complication and also the most common cause of mortality in this potentially curable malignancy in Bangladesh.
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Affiliation(s)
- Eshita Reza Khan
- Department of Pediatrics, Mugda Medical College Hospital, Dhaka, Bangladesh
| | - Afiqul Islam
- Department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Chowdhury Yakub Jamal
- Department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Md Anwarul Karim
- Department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Atm Atikur Rahman
- Department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Md Golam Hafiz
- Department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Abdul Khaleque
- Department of Pediatric Hematology and Oncology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
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13
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Geyer-Roberts E, Akhand T, Blanco A, Jose R, Chowdhury N, Ea M, Gutierrez E, Balbuena J, Anagnostis S, Henderson C, Fazio A, Burpee A, Jacobs RJ. Disseminated Intravascular Coagulation in Varying Age Groups Based on Clinical Conditions. Cureus 2022; 14:e24362. [PMID: 35611030 PMCID: PMC9124292 DOI: 10.7759/cureus.24362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 04/21/2022] [Indexed: 11/22/2022] Open
Abstract
Disseminated intravascular coagulation (DIC) is a serious syndrome characterized by the systemic activation of blood coagulation resulting in the thrombosis of vessels leading to organ dysfunction and severe bleeding. When physicians try to treat DIC, it is imperative to diagnose and treat the underlying conditions. Anyone can be affected by DIC, but vulnerable groups such as pediatric populations, pregnant women and the elderly may be at higher risk. In this review, the current literature on DIC in pregnancy, the pediatric population, and the elderly is reported. This review also highlights the similarities and differences in the etiology, clinical presentation, diagnosis, and management of DIC in the aforementioned groups (i.e., pediatrics, pregnant women, and the elderly). Findings from this study may help increase awareness about various presentations of DIC in these groups to facilitate rapid recognition of symptoms leading to correct diagnoses.
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14
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Therapeutic Strategies for Disseminated Intravascular Coagulation Associated with Aortic Aneurysm. Int J Mol Sci 2022; 23:ijms23031296. [PMID: 35163216 PMCID: PMC8836167 DOI: 10.3390/ijms23031296] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/05/2022] [Accepted: 01/22/2022] [Indexed: 01/22/2023] Open
Abstract
Aortic aneurysms are sometimes associated with enhanced-fibrinolytic-type disseminated intravascular coagulation (DIC). In enhanced-fibrinolytic-type DIC, both coagulation and fibrinolysis are markedly activated. Typical cases show decreased platelet counts and fibrinogen levels, increased concentrations of fibrin/fibrinogen degradation products (FDP) and D-dimer, and increased FDP/D-dimer ratios. Thrombin-antithrombin complex or prothrombin fragment 1 + 2, as markers of coagulation activation, and plasmin-α2 plasmin inhibitor complex, a marker of fibrinolytic activation, are all markedly increased. Prolongation of prothrombin time (PT) is not so obvious, and the activated partial thromboplastin time (APTT) is rather shortened in some cases. As a result, DIC can be neither diagnosed nor excluded based on PT and APTT alone. Many of the factors involved in coagulation and fibrinolysis activation are serine proteases. Treatment of enhanced-fibrinolytic-type DIC requires consideration of how to control the function of these serine proteases. The cornerstone of DIC treatment is treatment of the underlying pathology. However, in some cases surgery is either not possible or exacerbates the DIC associated with aortic aneurysm. In such cases, pharmacotherapy becomes even more important. Unfractionated heparin, other heparins, synthetic protease inhibitors, recombinant thrombomodulin, and direct oral anticoagulants (DOACs) are agents that inhibit serine proteases, and all are effective against DIC. Inhibition of activated coagulation factors by anticoagulants is key to the treatment of DIC. Among them, DOACs can be taken orally and is useful for outpatient treatment. Combination therapy of heparin and nafamostat allows fine-adjustment of anticoagulant and antifibrinolytic effects. While warfarin is an anticoagulant, this agent is ineffective in the treatment of DIC because it inhibits the production of coagulation factors as substrates without inhibiting activated coagulation factors. In addition, monotherapy using tranexamic acid in cases of enhanced-fibrinolytic-type DIC may induce fatal thrombosis. If tranexamic acid is needed for DIC, combination with anticoagulant therapy is of critical importance.
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Yashim N, Obazee D, Ajani O, Abiodun P, Ajani L, Sanni F. Comparative study of hemostasis file in newly diagnosed leukemia patients and healthy persons at the Hematology and Blood Transfusion Department, National Hospital, Abuja. BLDE UNIVERSITY JOURNAL OF HEALTH SCIENCES 2022. [DOI: 10.4103/bjhs.bjhs_35_21] [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
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Hambley BC, Tomuleasa C, Ghiaur G. Coagulopathy in Acute Promyelocytic Leukemia: Can We Go Beyond Supportive Care? Front Med (Lausanne) 2021; 8:722614. [PMID: 34485349 PMCID: PMC8415964 DOI: 10.3389/fmed.2021.722614] [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: 06/09/2021] [Accepted: 07/26/2021] [Indexed: 11/24/2022] Open
Abstract
Acute promyelocytic leukemia (APL) is characterized by frequent complications due to a distinct coagulopathy. While advances in treatments have improved long-term survival, hemorrhagic and thrombotic complications remain the most common causes of death and morbidity. Improved understanding of the mechanisms of the coagulopathy associated with APL may lead to therapeutic interventions to mitigate the risk of hemorrhage and thrombosis.
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Affiliation(s)
- Bryan C Hambley
- Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Ciprian Tomuleasa
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.,Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj Napoca, Romania.,Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania
| | - Gabriel Ghiaur
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania.,Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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Sanz MA, Montesinos P. Advances in the management of coagulopathy in acute promyelocytic leukemia. Thromb Res 2021; 191 Suppl 1:S63-S67. [PMID: 32736781 DOI: 10.1016/s0049-3848(20)30399-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 01/13/2020] [Accepted: 01/14/2020] [Indexed: 12/13/2022]
Abstract
Since the introduction of all-trans retinoic acid and, more recently, arsenic trioxide into the therapy of acute promyelocytic leukemia (APL), significant improvements in patient outcomes have been achieved, and this disease has become the most curable subtype of acute myeloid leukemia. However, while primary leukemia resistance has virtually disappeared, a sizable fraction of APL patients still die before or during induction therapy. Hemorrhagic death still remains the major problem during this early phase of treatment and, to a lesser extent, deaths due to infection, differentiation syndrome and other causes. Patients with APL typically present with a range of laboratory abnormalities consistent with the diagnosis of disseminated intravascular coagulation and hyperfibrinolysis. This APL-associated coagulopathy, as a result of a dysregulation of the hemostatic system due to the imbalance between procoagulant, anticoagulant and profibrinolytic mechanisms, may show a variety of clinical manifestations, ranging from minimal bleeding or localized thrombosis to lethal or life-threatening hemorrhages or thrombotic events that sometimes occur concomitantly. Hemorrhagic events are the most common cause of death associated with APL coagulopathy, but thrombosis, a less recognized and probably underestimated life-threatening manifestation of the thrombo-hemorrhagic syndrome, is also a non-negligible cause of morbidity and mortality in patients with APL. In this article, we aim to discuss recent advances in the knowledge of pathogenesis, predictors of thrombo-hemorrhagic events, management of coagulopathy associated with APL and the controversial issues that still persist.
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Affiliation(s)
- Miguel A Sanz
- Hospital Universitario y Politécnico La Fe, Valencia, Spain.
| | - Pau Montesinos
- Hospital Universitario y Politécnico La Fe, Valencia, Spain
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Pei Y, Shi M, Song J, Niu X, Wei S, Dou L, Xiao M, Li D, Xu F, Bai Y, Sun K. Absolute Circulating Leukemic Cells as a Risk Factor for Early Bleeding Events in Patients with Non-High-Risk Acute Promyelocytic Leukemia. Cancer Manag Res 2021; 13:4135-4146. [PMID: 34045900 PMCID: PMC8149285 DOI: 10.2147/cmar.s309138] [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: 03/02/2021] [Accepted: 04/25/2021] [Indexed: 11/23/2022] Open
Abstract
Background Hemorrhagic complications are the most common cause of early death in patients with APL and remain a major challenge in the management of APL. Early fatal bleeding events occur not only in high-risk but also in non-high-risk acute promyelocytic leukemia (APL) patients with normal or low WBC counts. Objectives and Methods To demonstrate the role of the absolute number of circulating leukemic cells in early bleeding events in APL patients. Clinical and laboratory characteristics of 149 patients newly diagnosed with APL were obtained from medical records and retrospectively investigated. Results In this study, circulating absolute leukemic cells were positively correlated with the WBC count (r=0.9813, p<0.001) in all patients with APL, and importantly, they were strongly associated with significant bleeding events in non-high-risk patients. Multivariate logistic regression analysis showed that the absolute number of leukemia cells was an independent risk factor for significant bleeding events in APL patients. A cut-off value of 2.59×109/L for circulating leukemic cells to predict significant bleeding events in APL patients was obtained by ROC curve analysis. We further confirmed that the significant bleeding rate of patients with non-high-risk APL was statistically increased when the absolute number of circulating leukemic cells was ≥2.59×109/L. Conclusion Circulating leukemic cell content has great clinical value for predicting early bleeding events in APL patients, especially in non-high-risk APL.
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Affiliation(s)
- Yanru Pei
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Henan, People's Republic of China
| | - Mingyue Shi
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Henan, People's Republic of China
| | - Juanjuan Song
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Henan, People's Republic of China
| | - Xiaona Niu
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Henan, People's Republic of China
| | - Shengjie Wei
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Henan, People's Republic of China
| | - Liurui Dou
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Henan, People's Republic of China
| | - Mengyu Xiao
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Henan, People's Republic of China
| | - Dan Li
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Henan, People's Republic of China
| | - Fangfang Xu
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Henan, People's Republic of China
| | - Yanliang Bai
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Henan, People's Republic of China
| | - Kai Sun
- Department of Hematology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Henan, People's Republic of China
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Kondo T, Takahashi M, Yamasaki G, Sugimoto M, Kuse A, Morichika M, Nakagawa K, Sakurada M, Asano M, Ueno Y. Immunohistochemical analysis of thrombomodulin expression in myocardial tissue from autopsy cases of ischemic heart disease. Leg Med (Tokyo) 2021; 51:101897. [PMID: 33940278 DOI: 10.1016/j.legalmed.2021.101897] [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: 01/20/2021] [Revised: 04/07/2021] [Accepted: 04/17/2021] [Indexed: 10/21/2022]
Abstract
Thrombomodulin is a transmembrane glycoprotein that is ubiquitously expressed on the surface of vascular endothelial cells. Thrombomodulin exerts its anticoagulant effects by combining with thrombin, activating protein C, and inactivating the coagulation factors FVa and FVIIIa. Clinically, thrombomodulin is also known as a marker of vascular injury because it circulates freely in response to endothelial injury. In this study, myocardial tissue from cases of ischemic heart disease was subjected to immunohistochemistry by thrombomodulin. We examined 40 neutral-formalin-fixed, paraffin-embedded myocardial tissue samples from autopsy cases that were diagnosed with ischemic heart disease (within 48 h postmortem). Thrombomodulin expression was observed in vascular endothelial cells between myocardial cells and in mesothelial cells of the epicardium. In necrotic myocardium, diffusion of thrombomodulin, which reflected endothelial injury, was observed. Upregulated thrombomodulin expression was observed around myocardial cells under ongoing remodeling, which suggested endothelial proliferation in these locations. Completed fibrotic foci of the myocardium did not show upregulated thrombomodulin expression. In a mouse model of acute myocardial infarction, the same phenomena as that found in human samples were observed by immunohistochemistry of thrombomodulin. Immunostaining of thrombomodulin, as a marker for endothelial injury or myocardial remodeling, may be useful for supplementing conventional staining techniques in the diagnosis of ischemic heart disease in forensic pathology.
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Affiliation(s)
- Takeshi Kondo
- Division of Legal Medicine, Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan.
| | - Motonori Takahashi
- Division of Legal Medicine, Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Gentaro Yamasaki
- Division of Legal Medicine, Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Marie Sugimoto
- Division of Legal Medicine, Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Azumi Kuse
- Division of Legal Medicine, Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Mai Morichika
- Division of Legal Medicine, Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kanako Nakagawa
- Division of Legal Medicine, Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Makoto Sakurada
- Division of Legal Medicine, Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan; Forensic Science Laboratory, Hyogo Prefectural Police Headquarters, Kobe, Japan
| | - Migiwa Asano
- Department of Legal Medicine, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yasuhiro Ueno
- Division of Legal Medicine, Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Kobe, Japan
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Thakar SD, Hassan OM, Gill MK. Acute macular neuroretinopathy associated with acute promyelocytic leukemia. Am J Ophthalmol Case Rep 2021; 22:101044. [PMID: 33718659 PMCID: PMC7933699 DOI: 10.1016/j.ajoc.2021.101044] [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: 09/15/2020] [Revised: 11/11/2020] [Accepted: 02/20/2021] [Indexed: 11/03/2022] Open
Abstract
Purpose To describe the first reported case of acute macular neuroretinopathy (AMN) associated with acute promyelocytic leukemia in a young Asian-Indian male. Observations We review the clinical and multimodal imaging findings in our patient that are characteristic of AMN. Conclusions and importance Ophthalmologists should be aware of the association of leukemia with AMN and consider hematologic work-up when assessing patients with AMN without the prototypical history or risk factors.
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Affiliation(s)
- Sudip D Thakar
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Omar M Hassan
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Manjot K Gill
- Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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21
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Wang Z, Jiang L, Yan H, Xu Z, Luo P. Adverse events associated with nilotinib in chronic myeloid leukemia: mechanisms and management strategies. Expert Rev Clin Pharmacol 2021; 14:445-456. [PMID: 33618586 DOI: 10.1080/17512433.2021.1894129] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Introduction: Nilotinib is a second-generation tyrosine kinase inhibitor (TKI) targeting BCR/ABL, which is used for the first-line treatment of newly diagnosed chronic myeloid leukemia (CML) patients and the second-line treatment of most CML patients who are resistant or intolerant to prior therapy that includes imatinib. In addition to common adverse reactions, long-term use of nilotinib shows some toxicities that are different from those of occurring during other BCR/ABL TKI treatments, such as cardiovascular toxicity. It is life-threatening, which would affect not only the choice of initial treatment of CML patients but also the safety of long-term medication.Areas covered: Through searching literature and reports from PubMed and clinical trials, here we review a profile of the adverse effects induced by nilotinib. We also discuss the potential molecular toxicological mechanisms and clinical management, which may provide strategies to prevent or intervene the toxicity associated with nilotinib.Expert opinion: Severe adverse effects associated with nilotinib limit its long-term clinical application. However, the exact mechanisms underlying these toxicities remain unclear. Future research should focus on the developing strategies to reduce the toxicities of nilotinib as well as to avoid similar toxicity in the development of new drugs.
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Affiliation(s)
- Zeng Wang
- Department of Colorectal Pharmacy, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China
| | - Liyu Jiang
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hao Yan
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Zhifei Xu
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Peihua Luo
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Fatal Intracerebral Hemorrhage During "Muay Thai" in a 21-Year-Old Man With Undiagnosed Acute Myeloid Leukemia: Spontaneous or Posttraumatic Hemorrhage? Am J Forensic Med Pathol 2021; 41:213-216. [PMID: 32541393 DOI: 10.1097/paf.0000000000000575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Acute myeloid leukemia (AML) is characterized by the rapid growth of abnormal white blood cells in the bone marrow that interferes with the production of normal blood cells. This disease is burdened by a high risk of bleeding complications involving central nervous system hemorrhages, purpura, gingival bleeding, and gastrointestinal bleeding. In this article, the authors report a case of a fatal intracerebral hemorrhage in a 21-year-old man who was affected by an undiagnosed AML. The subject practiced a combat sport (Muay Thai), and 2 days before his last training, he was involved in a fight where the aggressor punched him in the face; however, after the fight, he did not claim of any symptoms. The current case highlights the importance of the role of the forensic pathologist because only through a careful and complete circumstantial, autoptic, and histological analysis it is possible to date the origin of a cerebral hemorrhage and establish whether it is spontaneous or posttraumatic in subjects with undiagnosed preexisting diseases. Through an integrated study, it is also important to date the lesion and identify the traumatic event responsible of the bleeding. Finally, this case has a relevant clinical importance relatively to sports medicine, where it would be appropriate that athletes undergo blood test as a preventive measure. In fact, in presence of an acute hematological disease, such as AML, even mild traumatic injuries may be fatal.
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Ikezoe T. Advances in the diagnosis and treatment of disseminated intravascular coagulation in haematological malignancies. Int J Hematol 2020; 113:34-44. [PMID: 32902759 DOI: 10.1007/s12185-020-02992-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 08/22/2020] [Accepted: 08/28/2020] [Indexed: 11/26/2022]
Abstract
Haematological malignancies, including acute leukaemia and non-Hodgkin lymphoma, are one of the underlying diseases that frequently cause disseminated intravascular coagulation (DIC), an acquired thrombotic disorder. Concomitant DIC is associated with the severity of the underlying disease and poor prognosis. The Japanese Society on Thrombosis and Hemostasis released the new DIC diagnostic criteria in 2017. This criteria include coagulation markers such as soluble fibrin and the thrombin-antithrombin complex to more accurately evaluate the hypercoagulable state in patients. Among several groups of anticoagulants available, recombinant human soluble thrombomodulin is most frequently used to treat DIC caused by haematological malignancies in Japan. DIC is remitted in parallel with the improvement of the underlying haematological diseases; thus, there is room for debate regarding whether the treatment of DIC would improve the prognosis of patients. Haematopoietic stem cell transplantation as well as the recently introduced chimeric antigen receptor (CAR)-T-cell therapy are innovative therapies to produce a cure in a subset of patients with haematological malignancies. However, coagulopathy frequently occurs after these therapies, which limits the success of the treatment. For example, DIC is noted in approximately 50% of patients after CAT-T-cell therapy in conjunction with cytokine release syndrome. Hematopoietic stem cell transplantation (HSCT) causes endotheliitis, which triggers coagulopathy and the development of potentially lethal complications, such as sinusoidal obstruction syndrome/veno-occlusive disease and transplant-associated thrombotic microangiopathy. This review article describes the pathogenesis, clinical manifestation, diagnosis, and treatment of DIC caused by haematological malignancies, CAR-T-cell therapy, and HSCT.
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Affiliation(s)
- Takayuki Ikezoe
- Department of Haematology, Fukushima Medical University, Fukushima, 960-1295, Japan.
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Kongstad C, Mikkelsen TS, Hvas AM. Disseminated intravascular coagulation in children with cancer: A systematic review. Pediatr Hematol Oncol 2020; 37:390-411. [PMID: 32202958 DOI: 10.1080/08880018.2020.1733717] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Disseminated intravascular coagulation (DIC) may complicate malignant disease. Numerous studies have investigated this association in adults, however only sparse knowledge exists on DIC in pediatric cancer patients. The objective of this article was to systematically review the literature regarding DIC in pediatric malignancies. PubMed and Embase were searched for relevant articles on January 31, 2020. In total, 6,070 articles were identified out of which 24 articles met inclusion and exclusion criteria. These were included in the qualitative synthesis. The National Institutes of Health's Quality Assessment Tools was used to assess bias in the included articles. The studies were of only moderate quality mainly based on medical charts and demonstrated high heterogeneity, especially as regards to diagnostic criteria. DIC was reported most frequently in patients with acute leukemia, particularly the subtype acute promyelocytic leukemia (APL). Standard coagulation parameters were used as diagnostic laboratory tests supporting the diagnosis of DIC. Hemorrhage was the predominant clinical manifestation, whereas thromboembolic events and organ failure were reported less frequently. Unfractionated heparin, platelet concentrate and fresh frozen plasma were the most frequently used supportive treatment agents. Hemorrhage accounted for the majority of deaths in children with acute leukemia and solid tumors. In conclusion, only a limited number of studies, being heterogenous and of moderate quality, have investigated DIC in pediatric malignancy. Notably, this entity seems to be complicated mainly by hemorrhage. High quality studies are needed to evaluate diagnosis, clinical manifestations and optimal treatment of DIC in childhood cancers.
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Affiliation(s)
- Christine Kongstad
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
| | - Torben Stamm Mikkelsen
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Anne-Mette Hvas
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark
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Naymagon L, Mascarenhas J. Hemorrhage in acute promyelocytic leukemia: Can it be predicted and prevented? Leuk Res 2020; 94:106356. [PMID: 32445941 DOI: 10.1016/j.leukres.2020.106356] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/11/2020] [Accepted: 04/17/2020] [Indexed: 12/13/2022]
Abstract
Hemorrhagic death is the leading cause of treatment failure in acute promyelocytic leukemia (APL). Our ability to identify patients at greatest risk of hemorrhage, and to actively prevent hemorrhage, remains limited. Nevertheless, some data is available to guide contemporary clinical practice and future investigation. Circulating disease burden, best represented by the peripheral WBC / blast count, is the most consistent predictor of major and fatal bleeding risk. In contrast, laboratory markers of disseminated intravascular coagulation (DIC) appear to be poor predictors. A number of interventions have been posited to reduce bleeding risk. Prompt initiation of all-trans retinoic acid (ATRA), avoidance of invasive procedures, transfusion support, and cytoreduction all have theoretical merit. Though they lack strong evidence to support their benefit with respect to bleeding, they are associated with limited risks, and are therefore advisable. Low-dose therapeutic heparin and antifibrinolytics have not shown the ability to positively modify bleeding risk, and heparin has been associated with harm. Thrombomodulin has shown promise in limited retrospective studies however further prospective data are needed. rFVIIa may have a role in cases of life-threatening bleeding however evidence is largely anecdotal. Additional studies evaluating the above interventions, and investigating other potential interventions are needed.
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Affiliation(s)
- Leonard Naymagon
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
| | - John Mascarenhas
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Kawano N, Wada H, Uchiyama T, Kawasugi K, Madoiwa S, Takezako N, Suzuki K, Seki Y, Ikezoe T, Hattori T, Okamoto K. Analysis of the association between resolution of disseminated intravascular coagulation (DIC) and treatment outcomes in post-marketing surveillance of thrombomodulin alpha for DIC with infectious disease and with hematological malignancy by organ failure. Thromb J 2020; 18:2. [PMID: 32047363 PMCID: PMC7006199 DOI: 10.1186/s12959-020-0216-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Accepted: 01/28/2020] [Indexed: 12/29/2022] Open
Abstract
Background Although disseminated intravascular coagulation (DIC) is life-threatening, any organ failure associated with DIC resolution and outcomes have been unclear. Patients and methods A total of 2795 DIC patients (infection: 1990, hematological malignancy: 805) were analyzed in the post-marketing surveillance of thrombomodulin alpha (TM-α). The background factors of sequential organ failure assessment (SOFA) and antithrombin (AT) were investigated in DIC with infectious disease for their association with DIC resolution and outcome using κ statistics, indicating DIC resolution and survival or DIC non-resolution and non-survival. The same analyses were performed for total bilirubin, creatinine, lactate dehydrogenase, and underlying disease in DIC with hematological malignancy. Results In DIC with infectious disease, higher SOFA score severity was closely correlated with lower overall survival in both the DIC resolution and non-resolution groups, but AT activity was not. κ coefficients were 0.234, 0.295, and 0.311 for the SOFA score 0-6, 7-12, and 13-24 groups, respectively. In DIC with hematological malignancy, κ coefficients of total bilirubin were 0.251 and 0.434, and those of creatinine were 0.283 and 0.437 in the normal and abnormal groups, respectively, showing better concordance in the abnormal group than in the normal. Other factors had poor concordance. Conclusion In DIC with infectious disease, DIC resolution is an important therapeutic target in patients who have higher SOFA score severity. In DIC with hematological malignancy, DIC resolution is similarly important in patients with abnormality of bilirubin and/or creatinine. Trial registration The clinical characteristics and treatment outcomes of patients with DIC treated with TM-α between May 2008 and April 2010 were retrospectively analyzed by subgroup analysis of the post-marketing surveillance data.
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Affiliation(s)
- Noriaki Kawano
- Department of Internal Medicine, Miyazaki Prefectural Miyazaki Hospital, 5-30 Kitatakamatsu, Miyazaki, 880-8510 Japan
| | - Hideo Wada
- Department of General Medicine, Mie Prefectural General Medical Center, Mie, Japan
| | - Toshimasa Uchiyama
- Department of Laboratory Medicine, National Hospital Organization Takasaki General Medical Center, Gunma, Japan
| | - Kazuo Kawasugi
- 4Faculty of Medical Technology, Teikyo University, Tokyo, Japan
| | - Seiji Madoiwa
- 5Department of Clinical Laboratory Medicine, Tokyo Saiseikai Central Hospital, Tokyo, Japan
| | - Naoki Takezako
- 6Department of Hematology, National Hospital Organization Disaster Medical Center, Tokyo, Japan
| | - Kei Suzuki
- 7Emergency and Critical Care Center, Mie University Hospital, Mie, Japan
| | - Yoshinobu Seki
- 8Department of Hematology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Takayuki Ikezoe
- 9Department of Hematology, Fukushima Medical University, Fukushima, Japan
| | - Tsuyoshi Hattori
- 10Department of Medical Affairs, Asahi Kasei Pharma Corporation, Tokyo, Japan
| | - Kohji Okamoto
- Department of Surgery, Center for Gastroenterology and Liver Disease, Kitakyushu City Yahata Hospital, Fukuoka, Japan
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Circulating intranuclear proteins may play a role in development of disseminated intravascular coagulation in individuals with acute leukemia. Int J Hematol 2019; 111:378-387. [PMID: 31848990 DOI: 10.1007/s12185-019-02798-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 12/05/2019] [Accepted: 12/06/2019] [Indexed: 10/25/2022]
Abstract
Intranuclear proteins, including high mobility group box 1 (HMGB1) and histone H3, released from inflammatory cells activate platelets and the coagulation systems, leading to development of disseminated intravascular coagulation (DIC) in individuals with sepsis. These observations prompted us to hypothesize that HMGB1 and histone H3 liberated from leukemia cells undergoing apoptosis after chemotherapy might play a role in development of DIC. To test this hypothesis, we prospectively measured plasma levels of coagulation markers and intranuclear proteins in patients with newly diagnosed acute leukemia (n = 17) before and after chemotherapy. Ten of 17 patients were diagnosed with DIC at the time of diagnosis of leukemia. Serum levels of HMGB1 and histone H3 were significantly higher in patients with DIC than in non-DIC patients. Of note, seven patients developed DIC or experienced exacerbation of coagulopathy after administration of anti-leukemic agents. Intriguingly, an increase in levels of HMGB1 and histone H3 were detected in five of seven patients. These findings suggest that intranuclear proteins spontaneously released from leukemia cells may play a role in development of leukemia-related DIC. Additionally, remission induction chemotherapy causes apoptosis of leukemia cells, leading to forced release of intranuclear proteins, which may exacerbate coagulopathy.
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Ader D, Durrani M, Blazar E. Disseminated Intravascular Coagulation With Purpura Fulminans Presentation of Acute Promyelocytic Leukemia. Clin Pract Cases Emerg Med 2019; 3:446-448. [PMID: 31763615 PMCID: PMC6861048 DOI: 10.5811/cpcem.2019.7.43632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 07/13/2019] [Accepted: 07/23/2019] [Indexed: 11/11/2022] Open
Abstract
A 47-year-old male presented to the emergency department with 12 hours of nausea, vomiting, abdominal pain, and a widespread skin eruption with mottled, irregular, purpuric lesions with subsequent rapid decompensation. Laboratory analysis revealed thrombocytopenia, bandemia, elevated metamyelocytes, abnormal coagulation panel, decreased fibrinogen, elevated fibrin split products, renal dysfunction, bacterial rods, dohle bodies, and toxic granulation. Acute promyelocytic leukemia (APML) was confirmed via bone marrow biopsy, flow cytometry, and fluorescence in situ hybridization analysis. Disseminated intravascular coagulation (DIC) may be the initial presentation of APML. When treated promptly, APML can achieve high remission rates; however, conditions such as DIC continue to increase mortality requiring early recognition to improve survival rates.
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Affiliation(s)
- Douglas Ader
- Inspira Medical Center, Department of Emergency Medicine, Vineland, New Jersey
| | - Muhammad Durrani
- Inspira Medical Center, Department of Emergency Medicine, Vineland, New Jersey
| | - Eric Blazar
- Inspira Medical Center, Department of Emergency Medicine, Vineland, New Jersey
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Kunak RL, Rojiani A, Savage NM. Educational Case: Acute Promyelocytic Leukemia With PML-RARA. Acad Pathol 2019; 6:2374289519875647. [PMID: 31555723 PMCID: PMC6753509 DOI: 10.1177/2374289519875647] [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: 05/13/2019] [Revised: 07/19/2019] [Accepted: 08/10/2019] [Indexed: 11/21/2022] Open
Abstract
The following fictional case is intended as a learning tool within the Pathology
Competencies for Medical Education (PCME), a set of national standards for teaching
pathology. These are divided into three basic competencies: Disease Mechanisms and
Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology.
For additional information, and a full list of learning objectives for all three
competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.
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Affiliation(s)
- Rebecca L Kunak
- Department of Pathology, Medical College of Georgia, Augusta University Medical Center, Augusta, GA, USA
| | - Amyn Rojiani
- Department of Pathology, Medical College of Georgia, Augusta University Medical Center, Augusta, GA, USA
| | - Natasha M Savage
- Department of Pathology, Medical College of Georgia, Augusta University Medical Center, Augusta, GA, USA
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Kuwano A, Kohjima M, Suzuki H, Yamasaki A, Ohashi T, Imoto K, Kurokawa M, Morita Y, Kato M, Ogawa Y. Recombinant human soluble thrombomodulin ameliorates acetaminophen-induced liver toxicity in mice. Exp Ther Med 2019; 18:1323-1330. [PMID: 31316624 DOI: 10.3892/etm.2019.7665] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 05/21/2019] [Indexed: 12/13/2022] Open
Abstract
Recombinant human soluble thrombomodulin alpha (rhTM) has been developed as an anticoagulant with anti-inflammatory activity. Notably, acetaminophen (APAP) -induced liver disease (AILI) is caused by direct metabolite-induced hepatotoxicity as well as hepatic hyper-coagulation. To evaluate the utility of anticoagulant for the treatment of AILI, rhTM was administered in a mouse AILI model and liver damage was analyzed. AILI was induced in 8-week-old mice by intraperitoneal injection of APAP. rhTM (20 mg/kg) or placebo was injected at the same time as APAP administration. Serum alanine aminotransferase, fibrin degradation products and high-mobility group box 1 levels were significantly decreased in the rhTM-treated group compared with the control group. Furthermore, rhTM reduced the necrotic area and fibrin deposition in liver sections. rhTM suppressed the mRNA expression of heme oxygenase-1, plasminogen activator inhibitor type-1, tissue factors, and inflammatory cytokines compared with the control group. rhTM did not change the hepatic GSH content at 2 h after APAP injection, but restored them at 4 h after the insult. rhTM ameliorated liver damage in mice with AILI, probably via the improvement in liver perfusion induced by it's anticoagulant acitivity, which can lead to the suppression of secondary liver damage.
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Affiliation(s)
- Akifumi Kuwano
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Motoyuki Kohjima
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Hideo Suzuki
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Akihiro Yamasaki
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Tomoko Ohashi
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Koji Imoto
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Miho Kurokawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yusuke Morita
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.,Department of Molecular and Cellular Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.,CREST, Japan Agency for Medical Research and Development, Tokyo 100-0004, Japan
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31
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Sanz MA, Fenaux P, Tallman MS, Estey EH, Löwenberg B, Naoe T, Lengfelder E, Döhner H, Burnett AK, Chen SJ, Mathews V, Iland H, Rego E, Kantarjian H, Adès L, Avvisati G, Montesinos P, Platzbecker U, Ravandi F, Russell NH, Lo-Coco F. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood 2019; 133:1630-1643. [PMID: 30803991 PMCID: PMC6509567 DOI: 10.1182/blood-2019-01-894980] [Citation(s) in RCA: 405] [Impact Index Per Article: 67.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 02/20/2019] [Indexed: 12/17/2022] Open
Abstract
Since the comprehensive recommendations for the management of acute promyelocytic leukemia (APL) reported in 2009, several studies have provided important insights, particularly regarding the role of arsenic trioxide (ATO) in frontline therapy. Ten years later, a European LeukemiaNet expert panel has reviewed the recent advances in the management of APL in both frontline and relapse settings in order to develop updated evidence- and expert opinion-based recommendations on the management of this disease. Together with providing current indications on genetic diagnosis, modern risk-adapted frontline therapy, and salvage treatment, the review contains specific recommendations for the identification and management of the most important complications such as the bleeding disorder APL differentiation syndrome, QT prolongation, and other all-trans retinoic acid- and ATO-related toxicities, as well as recommendations for molecular assessment of the response to treatment. Finally, the approach to special situations is also discussed, including management of APL in children, elderly patients, and pregnant women. The most important challenges remaining in APL include early death, which still occurs before and during induction therapy, and optimizing treatment in patients with high-risk disease.
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Affiliation(s)
- Miguel A Sanz
- Departamento de Hematologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain
- Department of Medicine, University of Valencia, Valencia, Spain
- Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos III, Madrid, Spain
| | - Pierre Fenaux
- Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France
- Department of Hematology, Université Paris Diderot, Paris, France
| | | | | | - Bob Löwenberg
- Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Tomoki Naoe
- National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Eva Lengfelder
- Department of Haematology, University Hospital Mannheim, University of Heidelberg, Mannheim, Germany
| | - Hartmut Döhner
- Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany
| | - Alan K Burnett
- Department of Haematology, Glasgow University, Glasgow, United Kingdom
| | - Sai-Juan Chen
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Vikram Mathews
- Department of Hematology, Christian Medical College, Vellore, India
| | - Harry Iland
- Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Eduardo Rego
- Hematology Division and
- Clinical Oncology Division, Department of Internal Medicine, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Hagop Kantarjian
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Lionel Adès
- Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France
- Department of Hematology, Université Paris Diderot, Paris, France
| | | | - Pau Montesinos
- Departamento de Hematologia, Hospital Universitari i Politècnic La Fe, Valencia, Spain
- Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos III, Madrid, Spain
| | - Uwe Platzbecker
- Medical Clinic and Polyclinic I, Hematology and Cellular Therapy, University Hospital Leipzig, Leipzig, Germany
| | - Farhad Ravandi
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Nigel H Russell
- Centre for Clinical Haematology, Department of Haematology, Nottingham University Hospital, Nottingham, United Kingdom; and
| | - Francesco Lo-Coco
- Department of Biomedicine and Prevention, Tor Vergata University of Rome, Rome, Italy
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Shimizu M, Konishi A, Nomura S. Examination of biomarker expressions in sepsis-related DIC patients. Int J Gen Med 2018; 11:353-361. [PMID: 30254480 PMCID: PMC6140747 DOI: 10.2147/ijgm.s173684] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Disseminated avascular coagulation (DIC) is the main cause of death among patients with sepsis. In particular, low platelet count is predictive of poor outcome. However, the significance of platelet activation in patients with sepsis-related DIC is poorly understood. To determine the characteristics of platelet-related abnormality in patients with sepsis-related DIC, we assessed the expression levels of several biomarkers. METHODS Plasma levels of biomarkers, including cytokines, chemokines, soluble selectins, platelet-derived microparticles (PDMPs), soluble vascular adhesion molecule 1, and high mobility group box protein 1 were measured by enzyme-linked immunosorbent assay at baseline and after 4, 7, 14, and 21 days of DIC treatment. RESULTS Differences in platelet activation and in the elevation of activated platelet-related PDMPs and of soluble P-selectin were seen between patients suffering from sepsis and hematologic malignancy with DIC. In addition, the elevation of interleukin (IL)-6 and thrombopoietin (TPO) was significant in sepsis patients with DIC. Furthermore, IL-6 and TPO promoted platelet activation in vitro. CONCLUSION Assessment of PDMPs, sP-selectin, IL-6, and TPO may be beneficial in the primary prevention of multi-organ failure in sepsis patients with DIC.
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Affiliation(s)
- Michiomi Shimizu
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan,
| | - Akiko Konishi
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan,
| | - Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan,
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Balmages A, Dinglasan J, Osborn MB. Severe Intracranial Hemorrhage at Initial Presentation of Acute Myelogenous Leukemia. Clin Pract Cases Emerg Med 2018; 2:203-206. [PMID: 30083633 PMCID: PMC6075489 DOI: 10.5811/cpcem.2018.4.37881] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 04/02/2018] [Accepted: 04/19/2018] [Indexed: 12/26/2022] Open
Abstract
Intracranial hemorrhage (ICH) is the second leading cause of mortality among patients diagnosed with acute myelogenous leukemia (AML). The bone marrow failure associated with AML produces dysfunctional platelets, which significantly increases the risk of hemorrhagic complications within this population. In this report we discuss the case of a previously healthy female patient, newly diagnosed with AML, who rapidly developed fatal ICH.
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Affiliation(s)
| | - Joseph Dinglasan
- Mission Hospital, Department of Emergency Medicine, Mission Viejo, California
| | - Megan Boysen Osborn
- University of California Irvine Health, Department of Emergency Medicine, Orange, California
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In vitro studies on the role of recombinant human soluble thrombomodulin in the context of retinoic acid mediated APL differentiation syndrome. Leuk Res 2017; 63:1-9. [PMID: 29055789 DOI: 10.1016/j.leukres.2017.10.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2017] [Revised: 09/25/2017] [Accepted: 10/17/2017] [Indexed: 12/29/2022]
Abstract
Recombinant human soluble thrombomodulin (rTM) is a newly developed anti-coagulant approved for treatment of disseminated intravascular coagulation (DIC) in Japan. rTM exerts anti-inflammatory and cytoprotective functions via its lectin-like and epidermal growth factor-like domains, respectively. In this study, we retrospectively reviewed the treatment of 21 consecutive patients with coagulopathy, complicated by acute promyelocytic leukemia (APL), with all-trans retinoic acid (ATRA) with or without combination with rTM. Surprisingly, none of the 14 rTM-treated patients developed retinoic acid (RA)-related differentiation syndrome (DS). The co-culture of vascular endothelial cell-derived EA.hy926 and APL-derived NB4 cells in the presence of RA increased production of tumor necrosis factor alpha (TNF-α) in culture media, in parallel with activation of p38 mitogen-activated protein kinase and increased levels of intracellular adhesion molecule 1 (ICAM1) in EA.hy926 cells. This was also associated with increased levels of the phosphorylated forms of VE-cadherin and enhanced vascular permeability of EA.hy926 monolayers. Importantly, addition of rTM to this co-culture system inhibited the RA-induced phosphorylation of p38 and VE-cadherin and decreased ICAM1 and vascular permeability in EA.hy926 cells, without a decrease inthe levels of TNF-α. Taken together, use of rTM may be a promising treatment strategy to prevent DS in APL patients who receive ATRA.
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Sukegawa M, Wang X, Nishioka C, Pan B, Xu K, Ohkawara H, Hamasaki Y, Mita M, Nakamura K, Okamoto M, Shimura H, Ohta M, Ikezoe T. The BCR/ABL tyrosine kinase inhibitor, nilotinib, stimulates expression of IL-1β in vascular endothelium in association with downregulation of miR-3p. Leuk Res 2017; 58:83-90. [PMID: 28501737 DOI: 10.1016/j.leukres.2017.05.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 05/03/2017] [Accepted: 05/05/2017] [Indexed: 10/19/2022]
Abstract
BCR/ABL tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis for in dividuals with chronic myeloid leukemia (CML). However, many patients treated with TKIs suffer from TKI-related complications. In particular, vascular events such as peripheral artery occlusive disease have become aserious clinical problem for patients who receive the TKI, nilotinib. At present, the molecular mechanisms by which TKIs cause vascular endothelial cell insults remain unknown.This study explored the effects of the TKIs, imatinib, nilotinib and dasatinib, on vascular endothelial cells in vitro, and found that only nilotinib induced expression of interleukin-1β (IL-1β) by vascular endothelial cells. Nilotinib-induced IL-1β expression stimulated the adhesion of monocytes to vascular endothelial cells in association with an increase in levels of adhesion molecules. MicroRNA database searching identified miR-3121-3p binding sites in the 3'-UTR of the IL-1β gene. Exposure of endothelial cells to nilotinib caused downregulation of miR-3121-3p in these cells. Importantly, forced-expression of miR-3121-3p counteracted nilotinib-induced expression of IL-1β. Importantly, serum levels if IL-1β were significantly elevated in CML patients receiving nilotinib (n=14) compared to those receiving other TKIs (n=16) (3.76±1.22pg/ml vs 0.27±0.77pg/ml, p<0.05). Taken together, our data suggest that nilotinib decreases levels of miR-3121-3p resulting in an increase in expression of IL-1β and adhesion molecules in vascular endothelial cells. The miR-3121-3p/IL-1β axis could be a potential target to prevent vascular events in CML patients with high risk of vascular events.
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Affiliation(s)
- Masumi Sukegawa
- Department of Hematology, Fukushima Medical University, Hikarigaoka-1, Fukushima 960-1295, Japan
| | - Xiangmin Wang
- Department of Hematology, Fukushima Medical University, Hikarigaoka-1, Fukushima 960-1295, Japan; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99,West Huaihai Road, 221002 Xuzhou, China
| | - Chie Nishioka
- Department of Hematology and Respiratory Medicine, Kochi University, Oko-cho, Nankoku, Kochi 783-8505, Japan
| | - Bin Pan
- Department of Hematology, Fukushima Medical University, Hikarigaoka-1, Fukushima 960-1295, Japan; Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99,West Huaihai Road, 221002 Xuzhou, China
| | - Kailin Xu
- Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, No. 99,West Huaihai Road, 221002 Xuzhou, China
| | - Hiroshi Ohkawara
- Department of Hematology, Fukushima Medical University, Hikarigaoka-1, Fukushima 960-1295, Japan
| | - Yoichi Hamasaki
- Department of Hematology, Iwaki Kyoritsu General Hospital, Iwaki, Fukushima 973-8402 Japan
| | - Masayuki Mita
- Department of Hematology, Shirakawa Kosei General Hospital, Shirakawa, 961-0005 Fukushima, Japan
| | - Kenichi Nakamura
- Department of Hematology, Shirakawa Kosei General Hospital, Shirakawa, 961-0005 Fukushima, Japan
| | - Masatoshi Okamoto
- Department of Hematology, YUASA Foundation Jusendo General Hospital, Koriyama, Fukushima 963-8585, Japan
| | - Hiromi Shimura
- Department of Laboratory Medicine, Fukushima Medical University, Hikarigaoka-1, Fukushima 960-1295, Japan
| | - Masatsugu Ohta
- Department of Hematology, Fukushima Medical University Aizu Medical Center, Aizuwakamatsu, 969-3492 Fukushima, Japan
| | - Takayuki Ikezoe
- Department of Hematology, Fukushima Medical University, Hikarigaoka-1, Fukushima 960-1295, Japan.
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Pan B, Wang X, Kojima S, Nishioka C, Yokoyama A, Honda G, Xu K, Ikezoe T. The Fifth Epidermal Growth Factor–like Region of Thrombomodulin Alleviates Murine Graft-versus-Host Disease in a G-Protein Coupled Receptor 15 Dependent Manner. Biol Blood Marrow Transplant 2017; 23:746-756. [DOI: 10.1016/j.bbmt.2017.02.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Accepted: 02/01/2017] [Indexed: 01/04/2023]
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Shahmarvand N, Oak JS, Cascio MJ, Alcasid M, Goodman E, Medeiros BC, Arber DA, Zehnder JL, Ohgami RS. A study of disseminated intravascular coagulation in acute leukemia reveals markedly elevated D-dimer levels are a sensitive indicator of acute promyelocytic leukemia. Int J Lab Hematol 2017; 39:375-383. [DOI: 10.1111/ijlh.12636] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 01/07/2017] [Indexed: 11/29/2022]
Affiliation(s)
| | - J. S. Oak
- Stanford University; Stanford CA USA
| | - M. J. Cascio
- Oregon Health and Science University; Portland OR USA
| | | | - E. Goodman
- Virginia Office of the Chief Medical Examiner; Roanoke VA USA
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Ikezoe T, Yang J, Nishioka C, Umezawa K, Yokoyama A. Thrombomodulin blocks calcineurin inhibitor-induced vascular permeability via inhibition of Src/VE-cadherin axis. Bone Marrow Transplant 2016; 52:245-251. [PMID: 27643869 DOI: 10.1038/bmt.2016.241] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 07/31/2016] [Accepted: 08/04/2016] [Indexed: 01/02/2023]
Abstract
Recombinant human soluble thrombomodulin (rTM) counteracted capillary leakage and alleviated edema in individuals with sinusoidal obstruction syndrome and engraftment syndrome after hematopoietic stem cell transplantation. We previously showed that rTM increased levels of antiapoptotic protein Mcl-1 and protected endothelial cells from calcineurin inhibitor cyclosporine A (CsA)-induced apoptosis. However, the molecular mechanisms by which rTM enhances barrier function in vascular endothelial cells remain unknown. Here we show that exposure of vascular endothelial EA.hy926 cells to CsA induced phosphorylation of Src/vascular endothelial cadherin (VE-cadherin) and translocation of VE-cadherin from cell surface to cytoplasm, resulting in an increase in vascular permeability. In addition, CsA increased production of inflammatory cytokines, including interleukin (IL)-1β and IL-6, associated with an increase in nuclear levels of nuclear factor-κB (NF-κB) which also enhanced vascular permeability. Importantly, the fourth and fifth regions of epidermal growth factor-like domain of TM (TME45) attenuated CsA-induced p-Src/VE-cadherin and vascular permeability in parallel with a decrease in nuclear levels of NF-κB and cytokine production in EA.hy926 cells. In conclusion, TM, especially TME45, maintains vascular integrity, at least in part, via Src signaling.
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Affiliation(s)
- T Ikezoe
- Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan.,Department of Hematology, Fukushima Medical University, Fukushima, Japan
| | - J Yang
- Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan
| | - C Nishioka
- Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan
| | - K Umezawa
- Department of Molecular Target Medicine Screening, School of Medicine, Aichi Medical University, Aichi, Japan
| | - A Yokoyama
- Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Kochi, Japan
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Matsunari Y, Sugimoto M, Doi M, Matsui H, Kawaguchi M. Functional characterization of tissue factor in von Willebrand factor-dependent thrombus formation under whole blood flow conditions. Int J Hematol 2016; 104:661-668. [PMID: 27562418 DOI: 10.1007/s12185-016-2086-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Revised: 08/17/2016] [Accepted: 08/22/2016] [Indexed: 11/29/2022]
Abstract
Von Willebrand factor (VWF) plays an important role in mediating platelet adhesion and aggregation under high shear rate conditions. Such platelet aggregates are strengthened by fibrin-network formation triggered by tissue factor (TF). However, little is known about the role of TF in VWF-dependent thrombus formation under blood flow conditions. We evaluated TF in thrombus formation on immobilized VWF under whole blood flow conditions in an in vitro perfusion chamber system. Surface-immobilized TF amplified intra-thrombus fibrin generation significantly under both low and high shear flow conditions, while TF in sample blood showed no appreciable effects. Furthermore, immobilized TF enhanced VWF-dependent platelet adhesion and aggregation significantly under high shear rates. Neutrophil cathepsin G and elastase increased significantly intra-thrombus fibrin deposition on immobilized VWF-TF complex, suggesting the involvement of leukocyte inflammatory responses in VWF/TF-dependent mural thrombogenesis under these flow conditions. These results reveal a functional link between VWF and TF under whole blood flow conditions, in which surface-immobilized TF and VWF mutually contribute to mural thrombus formation, which is essential for normal hemostasis. By contrast, TF circulating in blood may be involved in systemic hypercoagulability, as seen in sepsis caused by severe microbial infection, in which neutrophil inflammatory responses may be active.
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Affiliation(s)
- Yasunori Matsunari
- Department of Anesthesiology, Nara Medical University, Kashihara, Nara, Japan
| | - Mitsuhiko Sugimoto
- Department of Regulatory Medicine for Thrombosis, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan.
| | - Masaaki Doi
- Department of Regulatory Medicine for Thrombosis, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan
| | - Hideto Matsui
- Department of Regulatory Medicine for Thrombosis, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8521, Japan
| | - Masahiko Kawaguchi
- Department of Anesthesiology, Nara Medical University, Kashihara, Nara, Japan
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Abstract
An 8-year-old boy developed anorexia, fatigue, and fever. Laboratory examination revealed a high white blood cell (WBC) count of 145×10/μL with 97.5% abnormal promyelocytic cells that contained Auer bodies. Faggot cells were seen. He was diagnosed with acute promyelocytic leukemia. Later, a chromosome analysis showed 46,XY,t(15;17)(q22;q12). Promyelocytic Leukemia-retinoic acid receptor α-fused gene and chimeric mRNA were confirmed by fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction, respectively. He was complicated with disseminated intravascular coagulation (DIC) and his fibrin and fibrinogen degradation product at the onset was 37.6 μg/mL. Human recombinant thrombomodulin (rTM) was started for DIC. After dexamethasone was administered at a dose of 8 mg/m to prevent all-trans retinoic acid syndrome on day 1, all-trans retinoic acid was started at a dose of 45 mg/m on day 4. Cytarabine (100 mg/m/d) and daunorubicin (45 mg/m/d) were started on day 9. The WBC count gradually increased to 270×10/μL on day 8, and then decreased beginning on day 9. DIC improved after the initiation of chemotherapy and only minor petechia was noted. DIC did not become worse even after rTM was stopped on day 8. The risk of DIC and bleeding is high in the early stage of treatment for acute promyelocytic leukemia, especially in patients with a high WBC count. In our patient, rTM may have prevented fatal DIC and made it possible to safely administer induction chemotherapy.
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Ichikawa K, Edahiro Y, Gotoh A, Iiduka K, Komatsu N, Koike M. Co-occurrence of hyperleukocytosis and elevated fibrin-fibrinogen degradation product levels is a risk factor for early intracranial hemorrhage in patients with de novo acute leukemia. Int J Hematol 2016; 104:612-620. [PMID: 27456463 DOI: 10.1007/s12185-016-2072-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2016] [Revised: 07/19/2016] [Accepted: 07/19/2016] [Indexed: 11/24/2022]
Abstract
Early intracranial hemorrhage (eICH) is a potentially fatal complication of acute leukemia. We analyzed risk factors for eICH in patients with de novo acute leukemia. Ninety-one de novo acute leukemia patients at our institution between September 2003 and June 2014 were included. Of the 91 patients, eight (8.8 %) and 83 were included in the eICH and non-eICH groups, respectively. Univariate analysis demonstrated that white blood cell (WBC) count (P = 0.018), fibrin-fibrinogen degradation product (FDP) level (P = 0.0075), co-occurrence of WBC ≥50,000/µl and FDP level >40 µg/ml (P < 0.001), and fever (P = 0.248) were all significant predictors of eICH at the 0.25 level. In a subsequent multivariate analysis involving these parameters, only the combination of hyperleukocytosis and elevated FDP levels was found to be significant at the 0.05 level. A significant difference in the duration of the overall survival (OS) period was detected between patients that did and did not exhibit the combination of hyperleukocytosis and elevated FDP levels (P < 0.001). Co-occurrence of hyperleukocytosis and elevated FDP levels is a significant risk factor for eICH in patients with de novo acute leukemia and has a significant adverse affect on OS.
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Affiliation(s)
- Kunimoto Ichikawa
- Sakura Life Clinic, ABY Building 1F, 4-12-10, Ishihara, Sumida-ward, Tokyo, 130-0011, Japan.
| | - Yoko Edahiro
- Division of Hematology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Akihiko Gotoh
- Division of Hematology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Kazuhide Iiduka
- Department of Hematology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Norio Komatsu
- Division of Hematology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Michiaki Koike
- Department of Hematology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
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Azuma Y, Nakaya A, Hotta M, Fujita S, Tsubokura Y, Yoshimura H, Satake A, Ishii K, Ito T, Nomura S. Disseminated intravascular coagulation observed following treatment with gemtuzumab ozogamicin for relapsed/refractory acute promyelocytic leukemia. Mol Clin Oncol 2016; 5:31-34. [PMID: 27330760 PMCID: PMC4906953 DOI: 10.3892/mco.2016.864] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 04/07/2016] [Indexed: 11/06/2022] Open
Abstract
Gemtuzumab ozogamicin (GO) is a recombinant humanized immunoglobulin G4 anti-cluster of differentiation (CD)33 monoclonal antibody conjugated to N-acetyl-γ calicheamicin dimethylhydrazide, a naturally potent antibiotic. It has been introduced for the treatment of acute promyelocytic leukemia (APL), since large quantities of CD33 are commonly expressed on the surface of APL cells. The present study reported two cases with prominent disseminated intravascular coagulation (DIC), which was transiently observed following treatment with GO with relapsed/refractory APL. Very limited information exists regarding DIC occurring following GO, and its mechanism remains to be elucidated. In the present study, recombinant human soluble thrombomodulin was used for DIC treatment, and the patients recovered promptly. Since DIC is the most serious adverse event associated with GO treatment, elucidation of its mechanism and establishment of a treatment strategy are warranted.
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Affiliation(s)
- Yoshiko Azuma
- The First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Aya Nakaya
- The First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Masaaki Hotta
- The First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Shinya Fujita
- The First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Yukie Tsubokura
- The First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Hideaki Yoshimura
- The First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Atsushi Satake
- The First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Kazuyoshi Ishii
- The First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Tomoki Ito
- The First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Shosaku Nomura
- The First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
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Whatʼs new in the pathogenesis of the coagulopathy in acute promyelocytic leukemia? Curr Opin Hematol 2016; 23:121-6. [DOI: 10.1097/moh.0000000000000221] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Asphyxia by Drowning Induces Massive Bleeding Due To Hyperfibrinolytic Disseminated Intravascular Coagulation. Crit Care Med 2016; 43:2394-402. [PMID: 26327200 PMCID: PMC4603369 DOI: 10.1097/ccm.0000000000001273] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE To date, no study has systematically investigated the impact of drowning-induced asphyxia on hemostasis. Our objective was to test the hypothesis that asphyxia induces bleeding by hyperfibrinolytic disseminated intravascular coagulation. DESIGN Observational study. SETTING A 2,100-bed tertiary care facility in Vienna, Austria, Europe. PATIENTS All cases of drowning-induced asphyxia (n=49) were compared with other patients with cardiopulmonary resuscitation (n=116) and to patients with acute promyelocytic leukemia (n=83). Six drowning victims were investigated prospectively. To study the mechanism, a forearm-ischemia model was used in 20 volunteers to investigate whether hypoxia releases tissue plasminogen activator. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Eighty percent of patients with drowning-induced asphyxia developed overt disseminated intravascular coagulation within 24 hours. When compared with nondrowning cardiac arrest patients, drowning patients had a 13 times higher prevalence of overt disseminated intravascular coagulation at admission (55% vs 4%; p<0.001). Despite comparable disseminated intravascular coagulation scores, acute promyelocytic leukemia patients had higher fibrinogen but lower d-dimer levels and platelet counts than drowning patients (p<0.001). Drowning victims had a three-fold longer activated partial thromboplastin time (124 s; p<0.001) than both nondrowning cardiac arrest and acute promyelocytic leukemia patients. Hyperfibrinolysis was reflected by up to 1,000-fold increased d-dimer levels, greater than 5-fold elevated plasmin antiplasmin levels, and a complete absence of thrombelastometric clotting patterns, which was reversed by antifibrinolytics and heparinase. Thirty minutes of forearm-ischemia increased tissue plasminogen activator 31-fold (p<0.001). CONCLUSIONS The vast majority of drowning patients develops overt hyperfibrinolytic disseminated intravascular coagulation, partly caused by hypoxia induced tissue plasminogen activator release. Antifibrinolytics and heparinase partially reverse the abnormal clotting patterns. Severe activated partial thromboplastin time prolongation may be a marker of combined hyperfibrinolytic afibrinogenemia and autoheparinization in drowning-related asphyxia.
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Chi S, Ikezoe T. Disseminated intravascular coagulation in non-Hodgkin lymphoma. Int J Hematol 2015; 102:413-9. [DOI: 10.1007/s12185-015-1854-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 08/03/2015] [Accepted: 08/04/2015] [Indexed: 12/01/2022]
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Martí‐Carvajal AJ, Anand V, Solà I. Treatment for disseminated intravascular coagulation in patients with acute and chronic leukemia. Cochrane Database Syst Rev 2015; 2015:CD008562. [PMID: 26107113 PMCID: PMC7173718 DOI: 10.1002/14651858.cd008562.pub3] [Citation(s) in RCA: 10] [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] [Indexed: 12/16/2022]
Abstract
BACKGROUND Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by systemic intravascular activation of coagulation, leading to deposition of fibrin in the bloodstream. It may occur in patients with acute and chronic leukemia and is particularly associated with acute promyelocytic leukemia (a subtype of acute myeloid leukemia). OBJECTIVES To assess the clinical benefits and harms of any pharmacological intervention for treating DIC in patients with acute or chronic leukemia. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2015, Issue 05), MEDLINE (1946 to 7 May 2015), LILACS (1982 to 7 May 2015) and African Index Medicus (7 May 2015). There was no language restrictions. We sought additional randomized controlled trials (RCTs) from the World Health Organization International Clinical Trials Registry Platform and the reference lists of primary studies identified. SELECTION CRITERIA RCTs assessing the clinical benefits and harms of interventions for treating DIC in patients with acute and chronic leukemia. DATA COLLECTION AND ANALYSIS Two review authors independently performed trial selection, 'Risk of bias' assessment and data extraction. Primary outcomes were overall mortality, in-hospital mortality from any cause (15-day and 30-day) and adverse events. MAIN RESULTS In this Cochrane Review update we did not include any new RCT compared with the first review version. Accordingly, four RCTs (388 participants) met the inclusion criteria. These trials evaluated the human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate. Included trials reported data on mortality and bleeding. The studies were conducted in Japan, Italy and the Netherlands. We classified the included trials as: 1) including patients with or without leukemia which did not report data for the leukemia subgroup (366 participants); and 2) only including patients with leukemia (22 participants). Overall, the risk of bias of the included trials was high, since the trial authors did not provide a detailed description about trial design and execution.According to the GRADE recommendations, we judged the overall quality of the body of evidence for all prefixed outcomes as 'very low', due to methodological limitations and very small sample size.One trial, including 10 participants with leukemia and comparing dermatan sulphate with heparin, reported no deaths during trial treatment.In terms of bleeding data, we were unable to pool results from two studies that were only conducted with leukemia patients due to the inconsistency in the measurement and reporting of this outcome. One trial, including 12 participants with leukemia, found very low quality evidence that tranexamic acid can reduce the cumulative hemorrhagic score in participants compared with those assigned to placebo (P = 0.0015, very low quality evidence). On the contrary, there is no evidence that dermatan sulphate compared with placebo reduces new events of hemorrhagic diathesis (1/5 (20%) versus 2/5 (40%); RR 0.50; 95% CI 0.06 to 3.91; P = 0.51, very low quality evidence).No thromboembolic complications were reported in either trial that included patients with leukemia only (very low quality evidence). The safety profile was inconclusive.The included trials did not assess overall mortality, resolution of respiratory failure, renal failure or shock. AUTHORS' CONCLUSIONS Due to a lack of new RCTs, our conclusions in this Cochrane Review update are the same as the previous review version. We included four RCTs which reported mortality and bleeding data. It is not possible to determine whether human activated protein C, recombinant human soluble thrombomodulin, tranexamic acid and dermatan sulphate are effective or harmful for patients presenting with DIC related to acute or chronic leukemia. The quality of the evidence was low to very low. Therefore, prescription of these interventions for treating DIC in patients with acute and chronic leukemia can neither be supported nor rejected, unless new evidence from a large high-quality trial alters this conclusion.
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Affiliation(s)
| | - Vidhu Anand
- University of MinnesotaDepartment of Medicine420 Delaware Street SEMayo Mail Code 195MinneapolisMNUSA55455
| | - Ivan Solà
- CIBER Epidemiología y Salud Pública (CIBERESP)Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau)Sant Antoni Maria Claret 171 ‐ Edifici Casa de ConvalescènciaBarcelonaCatalunyaSpain08041
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47
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Ikezoe T. Thrombomodulin/activated protein C system in septic disseminated intravascular coagulation. J Intensive Care 2015; 3:1. [PMID: 25705426 PMCID: PMC4336127 DOI: 10.1186/s40560-014-0050-7] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Accepted: 08/14/2014] [Indexed: 11/10/2022] Open
Abstract
The thrombomodulin (TM)/activated protein C (APC) system plays an important role in maintaining the homeostasis of thrombosis and hemostasis and maintaining vascular integrity in vivo. TM expressed on vascular endothelium binds to thrombin, forming a 1:1 complex and acts as an anticoagulant. In addition, the thrombin-TM complex activates protein C to produce APC, which inactivates factors VIIIa and Va in the presence of protein S, thereby inhibiting further thrombin formation. Intriguingly, APC possesses anti-inflammatory as well as cytoprotective activities. Moreover, the extracellular domain of TM also possesses APC-independent anti-inflammatory and cytoprotective activities. Of note, the TM/APC system is compromised in disseminated intravascular coagulation (DIC) caused by sepsis due to various mechanisms, including cleavage of cell-surface TM by exaggerated cytokines and proteases produced by activated inflammatory cells. Thus, it is reasonable to assume that reconstitution of the TM/APC system by recombinant proteins would alleviate sepsis and DIC. On the basis of the success of the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, the FDA approved the use of recombinant human APC (rhAPC) for severe sepsis patients in 2002. However, subsequent clinical trials failed to show clinical benefits for rhAPC, and an increased incidence of hemorrhage-related adverse events was noted, which prompted the industry to withdraw rhAPC from the market. On the other hand, recombinant human soluble TM (rTM) has been used for treatment of individuals with DIC since 2008 in Japan, and a phase III clinical trial evaluating the efficacy of rTM in severe sepsis patients with coagulopathy is now ongoing in the USA, South America, Asia, Australia, European Union, and other countries. This review article discusses the molecular mechanisms by which the TM/APC system produces anticoagulant as well as anti-inflammatory and cytoprotective activities in septic DIC patients.
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Affiliation(s)
- Takayuki Ikezoe
- Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi, 783-8505 Japan
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48
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Ikezoe T, Yang J, Nishioka C, Yokoyama A. Thrombomodulin alleviates murine GVHD in association with an increase in the proportion of regulatory T cells in the spleen. Bone Marrow Transplant 2014; 50:113-20. [PMID: 25243628 DOI: 10.1038/bmt.2014.208] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 08/03/2014] [Accepted: 08/08/2014] [Indexed: 01/08/2023]
Abstract
Recombinant human soluble thrombomodulin (rTM), a potent anticoagulant, has been used for the treatment of disseminated intravascular coagulation in Japan since 2008. Interestingly, rTM possesses anti-inflammatory and cytoprotective functions. This study examined whether rTM alleviates GVHD in a murine hematopoietic SCT (HSCT) model. Use of rTM significantly improved the survival of mice on day 28 of transplantation (survival rate 70% in rTM - treated mice vs 35% in control, P<0.05) in association with a significant decrease in plasma levels of IL-6, IFN-γ and high-mobility group B1 DNA-binding protein on day 7 of HSCT. Intriguingly, the proportion of regulatory T cells in the spleen was significantly increased in rTM-treated mice on day 7 of transplantation compared with control diluent-treated mice. In addition, elevated plasma levels of TM and fibrin/fibrinogen degradation product were noted in HSCT-recipient mice, suggesting coagulopathy caused by endothelial cell damage in this GVHD model. The use of rTM potently decreased these levels. Importantly, rTM did not hamper the anti-GVL and engraftment of hematopoietic cells. Taken together, the use of rTM may prevent GVHD and serve as a potential therapeutic strategy to improve clinical outcomes in individuals who receive HSCT.
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Affiliation(s)
- T Ikezoe
- Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Japan
| | - J Yang
- Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Japan
| | - C Nishioka
- Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Japan
| | - A Yokoyama
- Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Japan
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