Genetic, Demographic and Laboratory Predictors of Anti-PF4/Heparin Antibody Response in Heparin-Induced Thrombocytopenia

Abstract

The adverse drug reaction, heparin-induced thrombocytopenia (HIT), is an antibody mediated response against the anticoagulant drug heparin. HIT is a potentially catastrophic immune response with limb- and life-threatening complications. The immune response is initiated by binding of heparin to endogenous platelet factor 4 proteins (PF4), generating a neoepitope recognized by immunoglobin G antibodies. These anti-PF4/heparin antibodies form ultra large complexes that bind to the low affinity IgG Fc region receptor II a (FCγRIIa) on the surface of platelets, neutrophils, and monocytes. Anti-PF4/heparin antibodies are necessary for HIT to occur, but only a proportion of heparin-treated patients develop detectable antibody titers. Adding to the complexity of HIT, while antibodies are necessary, not all antibody positive individuals progress to full-blown HIT. Furthermore, some HIT patients experience the paradoxical manifestation of thrombosis due to a drug prescribed for its anticoagulant properties. This multi-staged disease progression creates a serious burden for heparin-therapy, particularly given the fact that clinicians currently are unable to identify which patients will progress from being anti-PF4/heparin antibody positive to manifesting the symptoms of full-blown HIT and furthermore which HIT patients will have thromboembolic complications. The work encompassed in this dissertation sought to further understand potential genetic, demographic, and clinical factors that affected a patient’s risk of HIT. As our understanding of HIT pathogenesis is still not fully resolved, investigation of potential influential factors in HIT pathogenesis is warranted. Given the small proportion of heparin-treated patients who progress to HIT, genetic predispositions may be a factor in disease progression. However, limited work has been conducted on the genetic influence in HIT. Additionally, little is known of the potential influences of demographic and clinical factors that play a role in a person’s progression from heparin-treated to antibody positive to full-blown HIT. Some demographic factors such as age, body mass index and gender, and clinical factors such as surgery, diabetes status and dosing have been associated with HIT status, but replication and validation of many associations are lacking. Furthermore, speculation of other factors such as chronically altered metal cation milieu, prior bacterial infections, and immune cell tolerance breakdown, among others, have been speculated to influence HIT risk but findings remain sparse. Specifically, as antibodies are necessary but not sufficient for HIT to occur, the focus of the work presented here was the identification of risk factors related to the antibody response seen in HIT. The results of these studies further the understanding of HIT pathogenesis, by identifying associations of genetic polymorphisms, demographic factors and physiologically relevant cations on the antibody response seen in HIT. These results, and further identification of HIT associated variables, could eventually be used to identify patients at risk for HIT prior to heparin initiation