Evolving concepts of pathogenesis of heparin-induced thrombocytopenia: Diagnostic and therapeutic implications

Heparin-induced thrombocytopenia (HIT) is an immune reaction to heparin. It often causes severe thrombosis which may lead to limb gangrene and thrombosis-associated death. The concept of its pathogenesis has been evolving during the past five decades. Initially, HIT was thought to be caused by disseminated intravascular coagulation. Later it became clear that HIT was mediated by an immune mechanism whereby an IgG antibody induced platelet aggregation, release of procoagulant materials and consequently thrombus formation. The antigen comprises Platelet Factor 4 (PF4) and heparin which have a tendency to form ultralarge complexes. The HIT immune response has atypical features. IgG antibody appears early without IgM precedence and lasts transiently. One explanation is that there is prior priming by bacterial infection. Another unique characteristic is that it is processed as if it is a particulate antigen involving complement activation and B cells. Antigen-presenting cells/monocytes are also involved but the role of T cells is controversial. Recent advances have provided new insights into the underlying mechanisms of HIT-related thrombosis. Previously, platelets were believed to play a central role; their activation and consequently the induction of blood coagulation was the basis of the hypercoagulability in HIT. More recently, several studies have provided clear evidence that neutrophil and NETosis, monocytes and endothelial cells contribute significantly to the thrombosis in HIT. These new insights may result in development of better diagnostic laboratory assays and more effective treatments for HIT.