**2. Pathophysiology**

The pathophysiologic mechanism of HIT II is mediated by the formation of heparin-platelet factor 4 (PF4) complexes. The PF4 is a positively charged heterodimer found in platelet alpha granules, and heparin is a negatively charged molecule. The formation of heparin-PF4 complex results in the change in the tertiary structure of the PF4 and exposure of neo-peptide, which elicits the formation of antibodies, usually IgG isotype. The immune heparin-PF4-IgG complexes activate platelets via Fc y IIa receptors. The antibodies may bind to monocytes, which then release tissue factor, the most potent blood clotting factor. Activated platelets release procoagulant microparticles and PF4. Antibodies recognize the complexes, bind to the endothelial cells, and activate the coagulation cascade, which leads to the formation of thrombin and eventually thrombosis. The ability of HIT antibodies to strongly activate platelets even in the absence of heparin may cause heparin-independent HIT II [7–9].

HIT II is most often caused by IgG antibodies targeting heparin-PF4 complex. In patients with HIT antibodies present in the blood, re-administration of heparin causes a rapid decrease in the platelet counts (within hours) to extremely low values. In heparin-treated patients, platelet count should be monitored before and during therapy. Before the specific laboratory evidence of anti-heparin antibodies, the probability of HIT should be determined using clinical laboratory indicators.
