scholarly journals Platelet factor 4 polyanion immune complexes: heparin induced thrombocytopenia and vaccine-induced immune thrombotic thrombocytopenia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Payel Datta ◽  
Fuming Zhang ◽  
Jonathan S. Dordick ◽  
Robert J. Linhardt
Keyword(s):  
Drug Development ◽  
Immune Complexes ◽  
Sinus Thrombosis ◽  
Heparin Therapy ◽  
Platelet Factor 4 ◽  
Main Body ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Vein Thrombosis ◽  
Immune Mediated

Abstract Background This is a review article on heparin-induced thrombocytopenia, an adverse effect of heparin therapy, and vaccine-induced immune thrombotic thrombocytopenia, occurring in some patients administered certain coronavirus vaccines. Main body/text Immune-mediated thrombocytopenia occurs when specific antibodies bind to platelet factor 4 /heparin complexes. Platelet factor 4 is a naturally occurring chemokine, and under certain conditions, may complex with negatively charged molecules and polyanions, including heparin. The antibody-platelet factor 4/heparin complex may lead to platelet activation, accompanied by other cascading reactions, resulting in cerebral sinus thrombosis, deep vein thrombosis, lower limb arterial thrombosis, myocardial infarction, pulmonary embolism, skin necrosis, and thrombotic stroke. If untreated, heparin-induced thrombocytopenia can be life threatening. In parallel, rare incidents of spontaneous vaccine-induced immune thrombotic thrombocytopenia can also occur in some patients administered certain coronavirus vaccines. The role of platelet factor 4 in vaccine-induced thrombosis with thrombocytopenia syndrome further reinforces the importance the platelet factor 4/polyanion immune complexes and the complications that this might pose to susceptible individuals. These findings demonstrate, how auxiliary factors can complicate heparin therapy and drug development. An increasing interest in biomanufacturing heparins from non-animal sources has driven a growing interest in understanding the biology of immune-mediated heparin-induced thrombocytopenia, and therefore, the development of safe and effective biosynthetic heparins. Short conclusion In conclusion, these findings further reinforce the importance of the binding of platelet factor 4 with known and unknown polyanions, and the complications that these might pose to susceptible patients. In parallel, these findings also demonstrate how auxiliary factors can complicate the heparin drug development.

Heparin-induced thrombocytopenia: when a low platelet count is a mandate for anticoagulation

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 225-232 ◽  
Author(s):  
Thomas L. Ortel
Keyword(s):  
Platelet Count ◽  
Heparin Therapy ◽  
Severe Thrombocytopenia ◽  
Drug Induced ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Immune Mediated ◽  
Number Of Patients ◽  
Increased Risk ◽  
Antibody Levels

Abstract Heparin-induced thrombocytopenia (HIT) is an immune-mediated disorder caused by the development of antibodies to platelet factor 4 (PF4) and heparin. The thrombocytopenia is typically moderate, with a median platelet count nadir of ~50 to 60 × 109 platelets/L. Severe thrombocytopenia has been described in patients with HIT, and in these patients antibody levels are high and severe clinical outcomes have been reported (eg, disseminated intravascular coagulation with microvascular thrombosis). The timing of the thrombocytopenia in relation to the initiation of heparin therapy is critically important, with the platelet count beginning to drop within 5 to 10 days of starting heparin. A more rapid drop in the platelet count can occur in patients who have been recently exposed to heparin (within the preceding 3 months), due to preformed anti-heparin/PF4 antibodies. A delayed form of HIT has also been described that develops within days or weeks after the heparin has been discontinued. In contrast to other drug-induced thrombocytopenias, HIT is characterized by an increased risk for thromboembolic complications, primarily venous thromboembolism. Heparin and all heparin-containing products should be discontinued and an alternative, non-heparin anticoagulant initiated. Alternative agents that have been used effectively in patients with HIT include lepirudin, argatroban, bivalirudin, and danaparoid, although the last agent is not available in North America. Fondaparinux has been used in a small number of patients with HIT and generally appears to be safe. Warfarin therapy should not be initiated until the platelet count has recovered and the patient is systemically anticoagulated, and vitamin K should be administered to patients receiving warfarin at the time of diagnosis of HIT.

scholarly journals Platelet Activation in Heparin-Induced Thrombocytopenia is Followed by Platelet Death via Complex Apoptotic and Non-Apoptotic Pathways

2020 ◽  
Vol 21 (7) ◽  
pp. 2556
Author(s):  
Elmira R. Mordakhanova ◽  
Tatiana A. Nevzorova ◽  
Gulnaz E. Synbulatova ◽  
Lubica Rauova ◽  
John W. Weisel ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Immune Complexes ◽  
Gel Filtration ◽  
Human Platelets ◽  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Mitochondrial Membrane Depolarization ◽  
Low Platelet Count ◽  
Apoptotic Pathways

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction characterized by thrombocytopenia and a high risk for venous or arterial thrombosis. HIT is caused by antibodies that recognize complexes of platelet factor 4 and heparin. The pathogenic mechanisms of this condition are not fully understood. In this study, we used flow cytometry, fluorimetry, and Western blot analysis to study the direct effects of pathogenic immune complexes containing platelet factor 4 on human platelets isolated by gel-filtration. HIT-like pathogenic immune complexes initially caused pronounced activation of platelets detected by an increased expression of phosphatidylserine and P-selectin. This activation was mediated either directly through the FcγRIIA receptors or indirectly via protease-activated receptor 1 (PAR1) receptors due to thrombin generated on or near the surface of activated platelets. The immune activation was later followed by the biochemical signs of cell death, such as mitochondrial membrane depolarization, up-regulation of Bax, down-regulation of Bcl-XL, and moderate activation of procaspase 3 and increased calpain activity. The results show that platelet activation under the action of HIT-like immune complexes is accompanied by their death through complex apoptotic and calpain-dependent non-apoptotic pathways that may underlie the low platelet count in HIT.

Management of Heparin-Induced Thrombocytopenia and Heparin-Induced Thrombocytopenia and Thrombosis Syndrome

1997 ◽  
Vol 3 (1_suppl) ◽  
pp. S53-S63 ◽  
Author(s):  
Jeanine M. Walenga ◽  
Bruce E. Lewis ◽  
Debra A. Hoppensteadt ◽  
Jawed Fareed ◽  
Mamdouh Bakbos
Keyword(s):  
Antibody Titer ◽  
Platelet Factor 4 ◽  
Positive Patient ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Comprehensive Account ◽  
Immune Mediated ◽  
Life Threatening ◽  
Pros And Cons ◽  
Sensitivity Specificity

Summary: Heparin-induced thrombocytopenia (HIT) is an immune mediated response to heparin in which antibody driven thrombosis can have a dramatic life-threatening expression. There is much interest on this subject including studies on the pathophysiologic mechanism, the clinical managements of the initial stages of HIT versus the HIT-positive patient requiring continued anticoagulation versus the HIT patient with thrombosis, the pros and cons of available alterr~aci~~ anticoagulants, and the laboratory assays to aid in the diagnosis of HIT with particular reference to the sensitivity/specificity of the new heparin-platelet factor 4 antibody titer assay. A comprehensive account of these timely issues is given in this article.

scholarly journals A Case of Heparin-Induced Thrombocytopenia That Developed in the Therapeutic Course of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis

2019 ◽  
Vol 2019 ◽  
pp. 1-4
Author(s):  
Taketoshi Nonaka ◽  
Makoto Harada ◽  
Masahiko Sumi ◽  
Wataru Ishii ◽  
Tohru Ichikawa ◽  
...  
Keyword(s):  
Clinical Course ◽  
Systemic Vasculitis ◽  
Platelet Factor 4 ◽  
Organ Injury ◽  
Platelet Factor ◽  
Immunological Mechanism ◽  
Heparin Induced Thrombocytopenia ◽  
Vein Thrombosis ◽  
Leg Edema ◽  
Rapidly Progressive Renal Failure

Background. Heparin-induced thrombocytopenia (HIT) causes thrombocytopenia via an immunological mechanism, resulting in severe organ injury due to arterial-venous thrombosis. HIT often develops in hemodialysis patients owing to heparin use. Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic vasculitis, and cases of AAV complicated with HIT are rare. In addition, it mostly occurs in patients undergoing hemodialysis. Case Presentation. An 87-year-old woman presented with rapidly progressive renal failure and severe leg edema. She was diagnosed with AAV and treated with glucocorticoid and heparin calcium to prevent deep vein thrombosis. Eight days after the start of heparin calcium, her platelet count decreased and the anti-platelet factor 4-heparin complex antibody was strongly positive (>5.0 U/mL; the cutoff point of the anti-platelet factor 4-heparin complex antibody evaluated by the latex turbidity assay is 1.0 U/mL). She was diagnosed with HIT and treated with argatroban. Subsequently, her platelet counts increased gradually. Conclusion. We encountered a case of HIT that developed prior to the induction of hemodialysis in the clinical course of AAV. When AAV clinical course presents thrombocytopenia, the possibility of HIT should be considered.

scholarly journals Heparin-Induced Thrombocytopenia

2020 ◽  
Author(s):  
Gowthami M. Arepally ◽  
Anand Padmanabhan
Keyword(s):  
Risk Factors ◽  
Immune Complexes ◽  
Optimal Management ◽  
Cellular Mechanisms ◽  
Platelet Factor ◽  
Thrombotic Risk ◽  
Heparin Induced Thrombocytopenia ◽  
Factors Associated ◽  
Clinical Complications ◽  
Immune Mediated

Heparin-induced thrombocytopenia is an immune-mediated disorder caused by antibodies that recognize complexes of platelet factor 4 and heparin. Thrombosis is a central and unpredictable feature of this syndrome. Despite optimal management, disease morbidity and mortality from thrombosis remain high. The hypercoagulable state in heparin-induced thrombocytopenia is biologically distinct from other thrombophilic disorders in that clinical complications are directly attributable to circulating ultra-large immune complexes. In some individuals, ultra-large immune complexes elicit unchecked cellular procoagulant responses that culminate in thrombosis. To date, the clinical and biologic risk factors associated with thrombotic risk in heparin-induced thrombocytopenia remain elusive. This review will summarize our current understanding of thrombosis in heparin-induced thrombocytopenia with attention to its clinical features, cellular mechanisms, and its management.

scholarly journals Heparin induced thrombocytopenia type ii and myocardial infarction: Two case reports

2004 ◽  
Vol 132 (1-2) ◽  
pp. 33-37 ◽  
Author(s):  
Nebojsa Antonijevic ◽  
Milica Stanojevic ◽  
Jovan Perunicic ◽  
Milan Djokic ◽  
Danijela Mikovic ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heparin Therapy ◽  
Platelet Factor 4 ◽  
Cardiac Insufficiency ◽  
Inferior Wall ◽  
Type Ii ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Skin Changes ◽  
Therapeutic Measures

Heparin-induced thrombocytopenia (HIT) type II is an acquired thrombophylic state and life-threatening immune complication of a heparin treatment mainly clinically manifested by marked thrombocytopenia, frequently by arterial and venous thrombosis, and sometimes by skin changes. Functional assay as heparin aggregation test and 14C-serotonin release assays are used in diagnostics as well as antigen assays of which detection tests for heparin-platelet factor 4 antibodies are most frequently used. Considering the fact that there is no single reliable assays for HIT II detection available, sometimes it is necessary to combine both of the above-mentioned types of assays. We present the case of a 57-year-old patient with an acute anterior myocardial infarction with cardiac insufficiency of III and IV degree according to Killip, recurrent ventricular fibrillation and diabetes mellitus type II developing thrombocytopenia to 37x10 9/l accompanied with typical skin changes. The diagnosis was confirmed by the heparin aggregation test. The second patient aged 70 undergoing the treatment for anteroseptal myocardial infarction and reinfarction of the inferior wall complicated by a cardiogenic shock and acute right bundle branch block developed thrombocytopenia 59x10 9/I on the third day of the heparin therapy, with the remark that he had received a heparin therapy during the first infarction as well. Antibodies against heparin-platelet factor 4 were detected by particle gel ID-HPF4 immunoassay. In both patients, the disease had a lethal outcome despite all then available therapeutic measures applied. Further on we discuss advantages of certain types of tests, a therapy doctrine, need for urgent therapeutic measures, inclusive of the administration of anitithrombins, avoidance of harmful procedures like low-molecular-weight heparins administration and prophylactic platelet transfusion as well as preventive measures.

Prevalence, isotype, and functionality of antiheparin–platelet factor 4 antibodies in patients treated with heparin and clinically suspected for heparin-induced thrombocytopenia

2002 ◽  
Vol 105 (2) ◽  
pp. 117-123 ◽  
Author(s):  
Brian Untch ◽  
Sarfraz Ahmad ◽  
Walter P. Jeske ◽  
Harry L. Messmore ◽  
Debra A. Hoppensteadt ◽  
...  
Keyword(s):  
Platelet Factor 4 ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia

scholarly journals Heparin-induced thrombocytopenia: research and clinical updates

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 262-268 ◽  
Author(s):  
Oluwatoyosi Onwuemene ◽  
Gowthami M. Arepally
Keyword(s):  
Limited Data ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Diagnostic Strategies ◽  
Immune Mediated ◽  
Emerging Therapies ◽  
Current Perspective ◽  
Clinical Advances ◽  
A Current

Abstract Heparin-induced thrombocytopenia (HIT) remains an important diagnosis to consider in hospitalized patients developing thrombocytopenia. HIT is an immune-mediated prothrombotic disorder caused by antibodies to platelet factor 4 (PF4) and heparin. Recent basic scientific studies have advanced our understanding of disease pathogenesis through studies of the PF4/heparin structure, immune mechanisms, and cellular basis of thrombosis. Clinical advances have also occurred in areas of HIT prevention, description of disease variants, and diagnostic strategies. Emerging anticoagulants with the potential to change HIT treatment are evolving, although with limited data. This review will provide a current perspective on HIT pathogenesis, disease features, diagnostic strategies, and role of emerging therapies for the management of HIT.

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