Advances in the pathophysiology and treatment of heparin-induced thrombocytopenia

Abstract

Purpose of review: To review the recent developments in understanding the pathophysiology of heparin-induced thrombocytopenia (HIT) and in applying this knowledge to the treatment of patients with suspected and proven HIT.

Recent findings: HIT pathophysiology is dynamic and complex. HIT pathophysiology is initiated by four essential components--heparin (Hep), platelet factor 4 (PF4), IgG antibodies against the Hep-PF4 complex, and platelet FcγRIIa. HIT is propagated by activated platelets, monocytes, endothelial cells, and coagulation proteins. Insights into the unique HIT antibody response continue to emerge, but without consensus as to the relative roles of B cells, T cells, and antigen-presenting cells. Platelet activation via FcγRIIa, the sine qua non of HIT, has become much better appreciated. Therapy remains challenging for several reasons. Suspected HIT is more frequent than proven HIT, because of the widespread use of Hep and the inadequacies of current diagnostic tests and scoring systems. In proven HIT, approved treatments reduce but do not eliminate thrombosis, and have substantial bleeding risk. Rational novel therapeutic strategies, directed at the initiating steps in HIT pathophysiology and with potential combinations staged over time, are in various phases of development.

Summary: Progress continues in understanding the breadth of molecular and cellular players in HIT. Translation to improved diagnosis and treatment is needed.

FIGURE 1

The multiple steps of HIT disorder. After immunization, there is initiation (upper left) culminating in IC-mediated platelet activation, then propagation (lower right) marked by the central roles of thrombin. Thrombin feeds back to enhance cellular activation and cleaves fibrinogen to fibrin. GAG, glycosaminoglycan; HIT, heparin-induced thrombocytopenia; IC, immune complex; PF4, platelet factor 4; ULC, ultralarge complex.

FIGURE 2

A detailed view of HIT disorder and therapy. There are three potential routes to TF-mediated thrombin generation, resulting in the final step of platelet–fibrin thrombi. On the left, the locus of current therapy directed at thrombin generation and action (T1) is compared with alternative and combination novel therapies geared to formation of the IC (T2) or inhibition of IC-mediated platelet activation (T3). Hep, heparin; HIT, heparin-induced thrombocytopenia; IC, immune complex; PF4, platelet factor 4; TF, tissue factor.