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 (PF4)/heparin antibodies, nor the thromboembolic complications of HIT. Genes implicated in HIT and PF4/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.

The Challenge of Diagnosing Heparin-Induced Thrombocytopenia with Negative Immunologic and Functional Assays

“…Our patient had several risk factors for HIT including unfractionated heparin use, duration of treatment, therapeutic dosing, and increased age [2,13]. This patient's platelets rose from 63 to 85 after the heparin was initially stopped for 3 days but dropped to 60 following re-initiation of heparin.…”

Individual variation in unfractionated heparin dosing after pediatric cardiac surgery

“…Previous studies have reported that 20%–30% of the inter-individual differences in drug metabolism and drug response were estimated to be due to genetic variations 35 , 36 . Until now, no pharmacogenomic studies related to heparin therapy have been conducted, except for heparin-induced thrombocytopenia 37 – 39 . Including genetic factors could improve the prediction of interindividual variabilities and will be the next step to consider.…”

Elucidation of Cellular Contributions to Heparin-Induced Thrombocytopenia Using Omic Approaches

“…Mutations in the FcγRIIa receptor have been shown to be associated with both HIT and HITT (Karnes 2018). The polymorphism H131R in the IgG binding region of FcγRIIa receptor has been associated with HIT in several populations, but a meta-analysis showed no difference in HIT between the wild-type and 131R variant (Trikalinos et al, 2001).…”

“…These PF4/heparin antibodies then engage with platelets, leading to platelet activation and ultimately thrombocytopenia. Despite extensive research efforts towards understanding the immunopathology of HIT, fundamental knowledge gaps persist regarding HIT etiology (Cuker 2011;Greinacher et al, 2011;Karnes 2018). The HIT immunogen, the roles of antigen presenting cells and T-cells, and the B cell subtypes that produce the antibody remain unknown (Arepally 2017).…”