Heparin-Induced Thrombocytopenia. Part 2
Platelet activation. In HIT, IgG binds to the antigenic complex (usually heparin–PF4) on the platelet surface, with the activation of platelets through the Fc receptor (FcgRII). Platelets from patients with HIT express increased numbers of Fc receptors on their surface. These platelets show an increased tendency to aggregate in the presence of heparindependent antibodies. Recent evidence suggests that genetic polymorphisms of the Fc receptor, specifically the presence of the Fcg RIIA allele, may be associated with a predisposition to HIT. Binding of the HIT-IgG to the Fc receptor results in platelet granule release, thromboxane generation, strong platelet aggregation and microparticle release (see late discussion).
A recent report suggests that both IgM and IgA can induce HIT complicated by thrombosis. As platelets are not known to carry a receptor for IgM or IgA Fc, this suggests that in these instances, platelet activation occurs through Fcindependent mechanisms.
Activation of coagulation. Depletions in the levels of the coagulation factor inhibitors protein C, heparin cofactor II and antithrombin III have been reported in patients during the thrombocytopenic phase of HIT and normalize after resolution of the thrombocytopenia. Disseminated intravascular coagulation is also seen, although not commonly
The heparin-associated platelet activation and aggregation consequent on production of the antibody are associated with the generation of platelet-derived microparticles with procoagulant activity, and this, possibly together with endothelial activation (see later discussion), may contribute to the generalized activation of the coagulation cascade.
Endothelial cell activation. In vitro studies have provided suggestive evidence that endothelial cell activation may contribute to the pathophysiologic sequelae of HIT. Serum samples from patients with HIT have increased amounts of IgG, IgM and IgA on endothelial cells, stimulating the release of tissue factor. The binding of both IgG and IgM HIT antibodies to endothelial cells requires the presence of PF4 but not heparin. Binding is reduced when the cells are incubated with heparinase, suggesting that this interaction is mediated in part by endogenous heparin-like molecules such as heparan sulfate found on the surface of endothelial cells.
However, the in vivo contribution of endothelial cell activation and procoagulant activity to the thrombotic sequelae of HIT has been challenged for several reasons.
Pathophysiology of HIT syndrome. In susceptible subjects, heparin bound to PF4 results in an antibody response. An IgG antibody directed against a heparin–PF4 complex binds platelets through the Fc receptor. This results in platelet activation and microparticle formation. Platelet-rich thrombi form at sites of preexisting pathology (arterial thrombotic events in patients with atherosclerotic vascular disease) or sites of endothelial injury (e.g., deep venous thrombosis in patients undergoing orthopedic surgery) risk of thrombosis generally decreases quickly after cessation of heparin, despite the fact that the antibody can often be demonstrated for several weeks. In addition, thromboemboli tend to be located at sites of vascular injury rather than being diffusely distributed throughout the vascular tree suggesting that endothelial disruption rather than integrity may provide the focus for the thrombogenic response.