Heparin-Induced Thrombocytopenia: A Review of New Concepts in Pathogenesis, Diagnosis, and Management

Abstract

Knowledge on heparin-induced thrombocytopenia keeps increasing. Recent progress on diagnosis and management as well as several discoveries concerning its pathogenesis have been made. However, many aspects of heparin-induced thrombocytopenia remain partly unknown, and exact application of these new insights still need to be addressed. This article reviews the main new concepts in pathogenesis, diagnosis, and management of heparin-induced thrombocytopenia.

Keywords: Bayesian diagnostic thinking; diagnosis; heparin-induced thrombocytopenia (HIT); immune PF4/heparin/antibody complexes; intravenous immunoglobulins (IVIG); management; new concepts; pathogenesis; therapeutic plasma exchange.

Figure 1

Pathophysiology of HIT. Platelets are activated by ultralarge complexes (ULCs) of PF4 and heparin via FcγRIIa. The activation leads to PF4 release, aggregation, P-selectin expression, and to production of procoagulant microparticles. After platelet activation, PF4 is in excess compared to heparin and can bind to endogenous glycosaminoglycans (GAG) on endothelial cells, monocytes, and neutrophils. Complexes of PF4 and GAG are recognized by HIT antibodies with consecutive activation of the cells. The activation of monocytes and endothelial cells leads to thrombin generation via expression of tissue factor (TF) and microparticles with TF (TF-MP), with further activation of platelets, creating a positive feedback loop. Moreover, the activation of endothelial cells leads to von Willebrand factor (VWF) secretion, on which PF4 binds, creating a Fc-rich surface, which leads to further activation of platelets. Activation of neutrophils leads to NETosis offering a Fc-rich surface with further activation of platelets and supporting thrombin generation (see text).