Heparin Induced Thrombocytopenia

A common adverse drug reaction is heparin-induced thrombocytopenia (HIT). The patho-genesis of HIT begins with the formation of antibodies (typically IgG), against platelet factor 4 (PF4), a protein released from platelet granules that binds to and inactivates heparin (55). IgG-heparin-PF4 complexes bind to platelet immunoglobin Fc receptors (FCy Rlla), leading to rapid uptake by splenic macrophages and thrombocytopenia. In addition, FCy Rlla-mediated platelet activation accelerates thrombin generation, contributing to an acquired hypercoaguable state. The risk of developing HIT is dependent upon many variables, including dose and duration of heparin exposure, heparin formulation (unfractionated ^ low molecular weight heparin, bovine > porcine), and clinical setting (orthopedic surgery > cardiac surgery > medical patients) (56). Thrombocytope-nia rarely is severe enough to cause bleeding, but thrombotic complications occur in up to 50% of the HIT patients (57).

Although 7.5% to 50% of the patients exposed to heparin form PF4 antibodies, most do not become thrombocytopenic or develop thrombotic complications (56). In addition, when exposed to heparin and serum-containing PF4 antibodies, the degree of platelet activation varies widely among normal donors. Investigations into this variable platelet response have focused on the G507A polymorphism in the platelet FCy RIIa receptor that substitutes histidine (H), for arginine (R), at amino acid position 131. When exposed to HIT-positive serum in vitro, platelets homozygous for 131 H/H polymorphism are more reactive than platelets homozygous for 131 R/R (58), suggesting that the G507A polymorphism could be a risk factor for HIT and thrombotic complications. Five published studies have compared the frequency of FCy RIIa R/H 131 polymorphism in HIT patients and controls with inconsistent findings. Three reported a significant increase in H131 frequency (58-60), one no difference (61), and one an increase in A131 frequency compared with the control populations (62). PF4 polymorphisms are another potential source of genetic predisposition for developing HIT. However, no polymorphisms were found when 10 HIT patients and 10 control PF4 sequences were compared (63).

Thus, currently, there are no convincing candidate gene polymorphisms to explain the variable clinical consequences of heparin-PF4 immune complex interaction with platelets.

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