Role of Heparin-Dependent Antigens in Immune Heparin-Induced Thrombocytopenia

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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Role of Sulfated Polysaccharides in the Pathogenesis?of Heparin-Induced Thrombocytopenia

Heparin-Induced Thrombocytopenia - Fundamental and Clinical Cardiology Series ◽

10.3109/9781420045093.007 ◽

2007 ◽

pp. 167-186 ◽

Cited By ~ 4

Author(s):

Susanne Alban ◽

Andreas Greinacher

Keyword(s):

Sulfated Polysaccharides ◽

Heparin Induced Thrombocytopenia

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Heparin induced thrombocytopenia

Hämostaseologie ◽

10.5482/hamo-15-04-0013 ◽

2015 ◽

Vol 35 (04) ◽

pp. 372-375 ◽

Cited By ~ 1

Author(s):

N. A. Viniou ◽

P. Diamantopoulos ◽

J. Barbetseas ◽

E. A. Sanidas

Keyword(s):

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Treatment Options ◽

Factor Xa ◽

Additional Treatment ◽

Thrombin Inhibitors ◽

Factor Xa Inhibitors ◽

Clinical Aspects ◽

Heparin Induced Thrombocytopenia

SummaryHeparin induced thrombocytopenia (HIT) is a prothrombotic syndrome initiated by platelet-activating auto-antibodies with potentially devastating complications. Once the diagnosis of HIT is suspected, discontinuation of heparin and treatment with an alternative anticoagulant are mandatory. While established drugs for HIT are no longer available, parenteral factor Xa inhibitors, thrombin inhibitors and perhaps the direct oral anticoagulants provide additional treatment options. The aim of this review was to highlight the current clinical aspects regarding HIT focusing on the role of novel medications.

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Importance of the FcγRIIa-Arg/His-131 Polymorphism in Heparin-induced Thrombocytopenia Diagnosis

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614938 ◽

1998 ◽

Vol 79 (03) ◽

pp. 523-528 ◽

Cited By ~ 38

Author(s):

Raphaël Saffroy ◽

Dominique Lasne ◽

Gilles Chatellier ◽

Martine Aiach ◽

Francine Rendu ◽

...

Keyword(s):

Serotonin Release ◽

Positive Answer ◽

Control Group ◽

Normal Donor ◽

Heparin Induced Thrombocytopenia ◽

Weak Association ◽

Healthy Control ◽

Release Assay ◽

The Mean

SummaryHeparin-induced thrombocytopenia (HIT) involves heparin-dependent antibodies which induce platelet activation. In the present study, we searched for a relationship between the polymorphism of the Fc receptor (FcγRIIa) and the development of HIT. In this purpose, all the donors were genotyped for their FcγRIIA and HIT patients were selected on the basis of at least one positive answer by 14C-serotonin release assay (SRA). The frequency distribution of the FcγRIIa polymorphism in the HIT patient group was similar to that observed in the healthy control group. Moreover, a statistical analysis taking into account our results and those of 3 previously published studies, suggested at most only a weak association between HIT and the FcγRIIa-131 polymorphism.Laboratory tests used to diagnose HIT rely on the activation of normal donor platelets but fail to detect every HIT positive patient. We determined the role of FcγRIIa-131 polymorphism on the reactivity of control platelets to HIT plasmas. When control platelet FcγRIIa-131 was of Arg/Arg form, only 47% of the HIT plasmas were positive by SRA, compared to 81% and 74% for His/His or His/Arg forms, respectively. We also compared the level of anti PF4/heparin antibodies in the HIT plasmas with the response obtained by SRA. The mean anti PF4/heparin antibodies level in HIT plasma was significantly lower in negative SRA than in positive tests when using control platelets from FcγRIIa-Arg/Arg131 and heterozygous donors. Thus, the variability of control platelets to respond to HIT plasmas in the SRA test is related to both the FcγRIIa-131 polymorphism, and to the amount of anti PF4/heparin antibodies.

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Role of sulfated polysaccharides and other polyanions in the pathogenesis of heparin-induced thrombocytopenia

Heparin-Induced Thrombocytopenia ◽

10.3109/9781841848617-10 ◽

2012 ◽

pp. 193-220

Keyword(s):

Sulfated Polysaccharides ◽

Heparin Induced Thrombocytopenia

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Risk factors for heparin-induced thrombocytopenia: Focus on Fcγ receptors

Thrombosis and Haemostasis ◽

10.1160/th16-02-0109 ◽

2016 ◽

Vol 116 (11) ◽

pp. 799-805 ◽

Cited By ~ 27

Author(s):

Jérôme Rollin ◽

Claire Pouplard ◽

Yves Gruel

Keyword(s):

Risk Factors ◽

Tyrosine Phosphatase ◽

Inhibitory Effect ◽

Igg Antibodies ◽

Fcγ Receptors ◽

Heparin Induced Thrombocytopenia ◽

Thrombosis Risk ◽

Immune Mediated ◽

Healthy Donors

SummaryFcγ receptors have critical roles in the pathophysiology of heparin-induced thrombocytopenia (HIT), a severe immune-mediated complication of heparin treatment. Activation of platelets, monocytes and neutrophils by platelet-activating anti-PF4/heparin IgG antibodies results in thrombocytopenia, hypercoagulability and thrombosis in susceptible patients, effects that depend on FcγRIIA. In addition, FcγRIIIA receptors probably contribute to clearance of platelets sensitised by HIT immune complexes. FcγRI has also been reported to be involved in monocyte activation by HIT IgG antibodies and synthesis of tissue factor. This review focuses on the role of these FcγRs in HIT pathophysiology, including the potential influence of several gene variations associated with variable risk of HIT and related thrombosis. In particular, the 276P and 326Q alleles of CD148, a protein tyrosine phosphatase that regulates FcγRIIA signalling, are associated with a lower risk of HIT, and platelets from healthy donors expressing these alleles are hyporesponsive to anti-PF4/H antibodies. It was also recently demonstrated that the risk of thrombosis is higher in HIT patients expressing the R isoform of the FcγRIIA H131R polymorphism, with HIT antibodies shown to activate RR platelets more efficiently, mainly explained by an inhibitory effect of normal IgG2, which bound to the FcγRIIA 131H isoform more efficiently. Environmental risk factors probably interact with these gene polymorphisms affecting FcγRs, thereby increasing thrombosis risk in HIT.

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