Heparin-induced thrombocytopenia: research and clinical updates

Onwuemene, Oluwatoyosi A.; Arepally, Gowthami M.

doi:10.1182/asheducation-2016.1.262

Cited by 14 publications

(18 citation statements)

References 59 publications

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“…Heparin-induced thrombocytopenia (HIT) is a common autoimmune disorder that develops in ∼1–5% of patients treated with heparin. Affected individuals generally present with an otherwise unexplained absolute or relative thrombocytopenia, which is a harbinger of arterial or venous thrombosis, occurring in 20–50% of patients 1–3 .…”

Section: Introductionmentioning

confidence: 99%

Platelet factor 4-containing immune complexes induce platelet activation followed by calpain-dependent platelet death

Невзорова¹,

Mordakhanova²,

Daminova³

et al. 2019

Cell Death Discov.

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Heparin-induced thrombocytopenia (HIT) is a complication of heparin therapy sometimes associated with thrombosis. The hallmark of HIT is antibodies to the heparin/platelet factor 4 (PF4) complex that cause thrombocytopenia and thrombosis through platelet activation. Despite the clinical importance, the molecular mechanisms and late consequences of immune platelet activation are not fully understood. Here, we studied immediate and delayed effects of the complexes formed by human PF4 and HIT-like monoclonal mouse anti-human-PF4/heparin IgG antibodies (named KKO) on isolated human platelets in vitro. Direct platelet-activating effect of the KKO/PF4 complexes was corroborated by the overexpression of phosphatidylserine (PS) and P-selectin on the platelet surface. The immune platelet activation was accompanied by a decrease of the mitochondrial transmembrane potential (ΔΨm), concurrent with a significant gradual reduction of the ATP content in platelets, indicating disruption of energy metabolism. A combination of PS expression and mitochondrial depolarization induced by the PF4-containing immune complexes observed in a substantial fraction of platelets was considered as a sign of ongoing platelet death, as opposed to a subpopulation of activated live platelets with PS on the plasma membrane but normal ΔΨm. Both activated and dying platelets treated with KKO/PF4 formed procoagulant extracellular microvesicles bearing PS on their surface. Scanning and transmission electron microscopy revealed dramatic morphological changes of KKO/PF4-treated platelets, including their fragmentation, another indicator of cell death. Most of the effects of KKO/PF4 were prevented by an anti-FcγRII monoclonal antibody IV.3. The adverse functional and structural changes in platelets induced by the KKO/PF4 complexes were associated with strong time-dependent activation of calpain, but only trace cleavage of caspase 3. The results indicate that the pathogenic PF4-containing HIT-like immune complexes induce direct prothrombotic platelet activation via FcγRIIA receptors followed by non-apoptotic calpain-dependent death of platelets, which can be an important mechanism of thrombocytopenia during HIT development.

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Section: Introductionmentioning

confidence: 99%

Platelet factor 4-containing immune complexes induce platelet activation followed by calpain-dependent platelet death

Невзорова¹,

Mordakhanova²,

Daminova³

et al. 2019

Cell Death Discov.

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“…Heparin‐induced thrombocytopenia (HIT) is a life‐threatening thrombotic disorder commonly caused by the formation of anti‐heparin/platelet factor 4 (PF4) antibody immune complexes . Once diagnosed, the widely accepted standard of care involves cessation of the offending anticoagulant and initiation of a parenteral direct thrombin inhibitor (DTI); however, despite DTI use, HIT complications continue to occur with high rates of death, limb amputation, thrombosis, and bleeding .…”

Section: Introductionmentioning

confidence: 99%

Therapeutic plasma exchange for management of heparin‐induced thrombocytopenia: Results of an international practice survey

Onwuemene

Zantek

Rollins‐Raval

et al. 2019

J of Clinical Apheresis

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Introduction: Anti-heparin/platelet factor 4 antibody immune complexes resulting from heparin-induced thrombocytopenia (HIT) are removed by therapeutic plasma exchange (TPE). We sought to define TPE in HIT practice patterns using an international survey. Methods: A 31-item online survey was disseminated through the American Society for Apheresis. After institutional duplicate responses were eliminated, a descriptive analysis was performed. Results: The survey was completed by 94 respondents from 78 institutions in 18 countries. Twenty-nine institutions (37%) used TPE for HIT (YES cohort) and 49 (63%) did not (NO cohort). Most NO respondents (65%) cited "no requests received" as the most common reason for not using TPE. Of the 29 YES respondents, 10 (34%) gave incomplete information and were excluded from the final analysis, leaving 19 responses. Of these, 18 (95%) treated ≤10 HIT patients over a 2-year period. The most common indications were cardiovascular surgery (CS; 63%) and HIT-associated thrombosis (HT; 26%). The typical plasma volume processed was 1.0 (63% CS and 58% HT). For CS, the typical replacement fluid was plasma (42%) and for HT, it was determined on an individual basis (32%). For CS, patients were treated with a set number of TPE procedures (37%) or laboratory/clinical response (37%). For HT, the number of TPE procedures typically depended on laboratory/clinical response (42%).

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“…Despite the widespread use of direct oral anticoagulants (DOACs) and other parenteral anticoagulants, unfractionated heparin (UFH) still plays an important role in the management of hospitalized patients. Hence, understanding the pathophysiology and management of HIT is still very relevant to the treating physician 28 . HIT is a disease of multiple paradoxes.…”

Section: Heparin-induced Thrombocytopeniamentioning

confidence: 99%

Recent advances in understanding and management of acquired thrombocytopenia

Nagalla

Sarode

2018

F1000Res

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There are numerous congenital and acquired causes of thrombocytopenia. Thrombocytopenia could be a result of decreased bone marrow production, increased consumption, increased destruction, splenic sequestration or a combination of these causes. In this review, we have focused on some of the serious acquired causes of thrombocytopenia. There have been some significant advances in our understanding of the pathophysiology, diagnostic testing, and treatment of immune thrombocytopenia, heparin-induced thrombocytopenia, thrombotic thrombocytopenic purpura, and atypical hemolytic uremic syndrome over the past five years. These advances have resulted in a significant decrease in mortality and morbidity of patients with these disorders. Despite these advances, we are still faced with numerous unanswered questions in the pathophysiology and management of these complex thrombocytopenic disorders.

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Heparin-induced thrombocytopenia: research and clinical updates

Cited by 14 publications

References 59 publications

Platelet factor 4-containing immune complexes induce platelet activation followed by calpain-dependent platelet death

Platelet factor 4-containing immune complexes induce platelet activation followed by calpain-dependent platelet death

Therapeutic plasma exchange for management of heparin‐induced thrombocytopenia: Results of an international practice survey

Recent advances in understanding and management of acquired thrombocytopenia

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