Pharmacogenetics to prevent heparin-induced thrombocytopenia: what do we know?

Abstract

Heparin-induced thrombocytopenia (HIT) is a life-threatening, immune-mediated adverse reaction to heparin anticoagulants. The inability to predict HIT represents a considerable liability associated with heparin administration. Genetic studies of HIT are challenging due to the scarcity of true HIT cases, potential for misclassification, and many environmental risk factors. Genetic studies have not consistently identified risk alleles for HIT, the production of platelet factor 4/heparin antibodies or the thromboembolic complications of HIT. Genes implicated in HIT and platelet factor 4/heparin antibody levels include FCGR2A, TDAG8, HLA-DR and others. Compelling evidence also suggests that the FCGR2A H131R polymorphism is associated with HIT-related thrombosis. There is a need for well-powered, multiethnic studies with laboratory confirmation of HIT, detailed patient- and drug-specific data, and inclusion of both serologic and thromboembolic outcomes. Genomic biomarkers identified from such studies offer the possibility of shifting current clinical practice paradigms from early detection and treatment to prevention.

Keywords: anticoagulant; biomarker; genetics; genome-wide association study; heparin; heparin-induced thrombocytopenia; low molecular weight heparin; pharmacogenomics.

Figure 1.. The pathogenesis of heparin-induced thrombocytopenia is characterized by gaps in our knowledge.

Genomic biomarkers have the potential to answer critical questions at every stage of HIT pathogenesis, including the predisposing immunogen, the cellular source of antibodies, the identification of pathogenic IgG antibodies and the mechanisms of thrombosis. Similarly, the clinical progression of patient who will eventually develop HIT is characterized by various unmet clinical needs. Genomic biomarkers have the potential to meet many of the unmet clinical needs for HIT, including limitations in the clinical utility of platelet count monitoring, PF4/heparin antibody testing, functional assay testing and limited treatment options. APC: Antigen-presenting cell; FcγRIIA: Platelet FcγRIIa receptor; HIPA: Heparin-induced platelet aggregation; HIT: Heparin-induced thrombocytopenia; IVIG: Intravenous immunoglobulin; NOAC: New oral anticoagulant; PF4: Platelet factor 4; SRA: Serotonin release assay.