Increased risk of thrombosis in FcγRIIA 131RR patients with HIT due to defective control of platelet activation by plasma IgG2

Rollin, Jérôme; Pouplard, Claire; Sung, Hsueh Cheng; Leroux, Dorothée; Saada, Armand; Gouilleux-Gruart, Valérie; Thibault, Gilles; Gruel, Yves

doi:10.1182/blood-2014-09-594515

Cited by 79 publications

(103 citation statements)

References 37 publications

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“…PEA and SRA reactivities were completely inhibited in the presence of 100 U/mL UFH, confirming that platelet activation was mediated by HIT antibodies (data not shown). Previous work has shown that patients with arginine at amino acid position 131 in the activating IgG receptor on platelets, FcγRIIa, are more likely to experience more severe HIT (thrombosis) due to the inability of normal IgG 2 present in plasma to compete with HIT antibodies for binding to the receptor . Patients with histidine at aa131 in FcγRIIa, on the other hand, are competent to be bound by both normal IgG 2 and IgG 1 , leading to greater protection from HIT antibody‐mediated platelet activation.…”

Section: Case Presentation/resultsmentioning

confidence: 99%

Use of intravenous immunoglobulin G to treat spontaneous heparin‐induced thrombocytopenia

et al. 2018

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BACKGROUND Spontaneous heparin‐induced thrombocytopenia (HIT) is a rare but serious prothrombotic syndrome characterized by thrombosis, thrombocytopenia, and strong platelet‐activating HIT antibodies in the absence of heparin exposure, and is frequently characterized by a suboptimal response to standard therapies. Here, we present the first report of intravenous immunoglobulin G (IVIG) use in a patient with spontaneous HIT. STUDY DESIGN AND METHODS Patient information, including demographic, clinical, and laboratory results, were obtained from the electronic medical record. Laboratory testing was performed in the serotonin release assay, platelet factor 4 (PF4)‐dependent P‐selectin expression assay, and PF4/polyvinylsulfonate enzyme‐linked immunosorbent assay to study the impact of IVIG on HIT antibody‐mediated platelet activation. The patient was also genotyped for a polymorphism in the IgG receptor on platelets, FcγRIIa, at amino acid position 131. RESULTS A 30‐year‐old man had a thrombotic stroke and thrombocytopenia and strong HIT serologies in the absence of proximate heparin use. Direct thrombin inhibitor therapy was not associated with a prompt response. Due to severity and extent of thrombosis and persistent thrombocytopenia, he was treated with high‐dose IVIG. This treatment was associated with rapid and sustained normalization of platelet counts and a gradual improvement in thrombotic complications. Platelet activation induced by HIT antibodies in the PF4‐dependent P‐selectin expression assay (low PF4) was significantly lower after IVIG treatment, correlating well with platelet rise. Consistent with the severity of thrombosis, the patient was found to possess the 131HR polymorphism in FcγRIIa. CONCLUSION These results suggest that IVIG may be a useful adjunctive therapy in spontaneous HIT.

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Section: Case Presentation/resultsmentioning

confidence: 99%

Use of intravenous immunoglobulin G to treat spontaneous heparin‐induced thrombocytopenia

et al. 2018

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“…All assays were performed on the same day with platelets from each of the unselected donors tested, and the data obtained confirmed that SRA is the most sensitive functional assay to detect platelet‐activating PF4‐specific antibodies. Indeed, the sensitivity of SRA to high, intermediate, and low concentrations of 5B9 was ≥95%, and SRA was also positive with 9 of the 10 samples from patients with “likely HIT.” The use of washed platelets is likely essential for explaining the excellent performance of SRA, because the removal of plasma abolishes any competition between HIT antibodies and donors' IgG for binding to platelet FcγRIIA receptors . This benefit of washing platelets probably explains why heparin‐induced activation assay (HIPA), performed with WP collected from four independent donors and under stirring in microtiter plates, is also considered a gold standard for HIT diagnosis .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of functional assays for the diagnosis of heparin induced thrombocytopenia using 5B9, a monoclonal IgG that mimics human antibodies

Vayne

Guéry

Charuel

et al. 2020

Journal of Thrombosis and Haemostasis

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Background Serotonin release assay (SRA) is considered as the “gold standard” for detecting pathogenic heparin‐induced thrombocytopenia (HIT) antibodies. However, this method is time consuming, expensive, and uses radioelements. Heparin‐induced multiple electrode aggregometry (HIMEA), light transmission aggregometry (LTA) with platelet rich plasma (PRP) or washed platelets (WP), adenosine triphosphate (ATP) release, and flow cytometry (FC) are available alternatives. Objectives To evaluate the performance of these assays, comparatively with SRA, for detecting HIT antibodies, using 5B9, a monoclonal IgG fully mimicking human HIT antibodies. Patients/Methods Heparin‐dependent platelet activation induced by 5B9 (50/20/10 µg/mL) was evaluated by all assays performed on the same day using platelets from 20 healthy donors. The three methods exhibiting the highest sensitivity to 5B9 were then assessed by testing samples from patients with either likely (n = 10), or indeterminate/unlikely HIT (n = 10). Results All methods exhibited good sensitivity for detecting 5B9 50 µg/mL, but only SRA and HIMEA were positive with 100% of donors using 5B9 20 µg/mL, followed by FC (83%). SRA detected 5B9 10 μg/mL with 90% of donors, while HIMEA and FC were positive in 45% and 44% of cases, respectively. Whereas SRA was positive with 9/10 samples from likely HIT, HIMEA and FC were positive with 6 and 7 of them, respectively. Neither SRA nor HIMEA was positive with indeterminate/unlikely HIT samples, while FC was positive or doubtful in three cases. Conclusions Serotonin release assay likely remains the most sensitive and specific assay for detecting platelet activating HIT antibodies, but HIMEA or FC are potential alternatives, despite being less performant.

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“…Several European groups made major contributions to the pathogenesis of DITPs 229 and developed test systems and treatment recommendations. Access of physicians and patients to appropriate laboratory testing is well developed in some European countries (e.g.…”

Section: European Research Contributionsmentioning

confidence: 99%

The European Hematology Association Roadmap for European Hematology Research: a consensus document

et al. 2016

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T he European Hematology Association (EHA) Roadmap for European Hematology Research highlights major achievements in diagnosis and treatment of blood disorders and identifies the greatest unmet clinical and scientific needs in those areas to enable better funded, more focused European hematology research. Initiated by the EHA, around 300 experts contributed to the consensus document, which will help European policy makers, research funders, research organizations, researchers, and patient groups make better informed decisions on hematology research. It also aims to raise public awareness of the burden of blood disorders on European society, which purely in economic terms is estimated at €23 billion per year, a level of cost that is not matched in current European hematology research funding. In recent decades, hematology research has improved our fundamental understanding of the biology of blood disorders, and has improved diagnostics and treatments, sometimes in revolutionary ways. This progress highlights the potential of focused basic research programs such as this EHA Roadmap. The EHA Roadmap identifies nine 'sections' in hematology: normal hematopoiesis, malignant lymphoid and myeloid diseases, anemias and related diseases, platelet disorders, blood coagulation and hemostatic disorders, transfusion medicine, infections in hematology, and hematopoietic stem cell transplantation. These sections span 60 smaller groups of diseases or disorders. The EHA Roadmap identifies priorities and needs across the field of hematology, including those to develop targeted therapies based on genomic profiling and chemical biology, to eradicate minimal residual malignant disease, and to develop cellular immunotherapies, combination treatments, gene therapies, hematopoietic stem cell treatments, and treatments that are better tolerated by elderly patients.

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Increased risk of thrombosis in FcγRIIA 131RR patients with HIT due to defective control of platelet activation by plasma IgG2

Abstract: Key Points Normal IgG and IgG2 differentially inhibit HIT antibody-dependent platelet activation according to the FcγRIIA H131R polymorphism. This variable effect of IgG and IgG2 probably explains the higher risk of thrombosis in patients homozygous for the FcγRIIA 131R allele.

Cited by 79 publications

References 37 publications

Use of intravenous immunoglobulin G to treat spontaneous heparin‐induced thrombocytopenia

Use of intravenous immunoglobulin G to treat spontaneous heparin‐induced thrombocytopenia

Evaluation of functional assays for the diagnosis of heparin induced thrombocytopenia using 5B9, a monoclonal IgG that mimics human antibodies

The European Hematology Association Roadmap for European Hematology Research: a consensus document

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