**2. Pathophysiology**

Heparin is a negatively-charged, highly sulfated glycosaminoglycan that occurs naturally in the body. It was discovered nearly one century ago (Howell & Holt, 1918) and shortly thereafter was used in the medical profession for thromboprophylaxis in post-operative patients (Crafoord, 1936). Amongst the qualities that made it an attractive option for physicians were its immediate onset of action and its short half-life. During the first three decades of its use in the medical field, case reports and series of patients developing thrombosis while on heparin began to emerge in the literature, a phenomenon known as HIT (e.g. Weismann & Tobin, 1958; Roberts et al., 1963). Over the last several decades much has been learned about heparin and the mechanisms that are responsible for this disorder.

Physiologically, two types of thrombocytopenia due to heparin exposure have been described. Non-immune heparin-associated thrombocytopenia, historically referred to as HIT type I, describes a response that is self-limiting and rarely causes major complications. Non-immune HIT occurs in 10% to 30% of patients who receive heparin and typically emerges within 4 days of exposure (Jang & Hursting, 2005). Platelet counts do not normally fall below 100K/uL. Heparin use does not need to be discontinued and no treatment is needed (Chong, 2003).

Currently the term HIT is used to denote what has been historically called HIT type 2. HIT occurs when, following heparin administration, platelet factor 4 (PF4) binds to heparin to form heparin/PF4 complexes. The body identifies these complexes as abnormal and, in response, develops antibodies. Specifically immunoglobulin G (IgG), M (IgM) and/or A (IgA) antibodies are formed. IgG is pathogenic, and binding of the IgG antibodies to the heparin/PF4 complexes results in platelet activation and aggregation. This causes thrombin generation, resulting in thrombotic events. Activated platelet aggregates are removed prematurely from circulation, which leads to development of thrombocytopenia, the main criteria for diagnosis of HIT (Warkentin et al., 1994a; Untch et al., 2002). The heparin/PF4 antibodies (also known as chemokine CXCL4) are typically activated within 5-14 days of heparin exposure, though delayed-onset cases have been reported (Warkentin & Kelton, 2001a). In patients who have a recent history of heparin use, however, significant platelet activation can occur more rapidly after reintroducing a heparin-containing product (Warkentin & Kelton, 2001b). This may be because HIT antibodies are transient and can remain in the body for up to four months after withdrawal of heparin (Lubenow et al., 2002).

Though the exact mechanisms of action are unclear, endothelial cells and monocytes also seem to play a role in the procoagulant state associated with HIT (Blank et al., 2002; Pouplard et al., 2001; Rauova et al., 2010; Arepally & Mayer, 2001). Many processes still remain unexplained in HIT, including the inability of some anti-heparin/PF4 IgG molecules to cause platelet activation (Warkentin, 2005) and the role of individual biological differences in predisposing to development of the disease. There is evidence that the length of the heparin molecule chain may positively correlate with the potential for HIT. Since LMWH's are formed from smaller molecules, this could explain why there is less immunogenic potential in these derived forms of heparin (Gruel et al., 2003). Furthermore, there may be a role of other glycosaminoglycans that are found on the surface of platelets, which may cross-react with heparin/PF4 antibodies and more directly cause thrombus formation (Rauova et al., 2006).
