**2. Epidemiology and pathogenesis**

HIT is a rare complication of heparin therapy primarily affecting the surgical population. It occurs in 1-2% of cardiovascular surgery patients, 3%-10% of orthopaedic surgery patients and in less than 1% of obstetrical patients. It is higher in the orthopaedic population since they usually require prolonged treatment with heparin for DVT prophylaxis following surgery. Within the cardiac surgical population, patients who require implantation of a left ventricular assist device are at very high risk of developing HIT (> 10%). The incidence of HIT in patients treated in medical wards is usually very low (< 0.25%).

HIT develops primarily in patients treated with unfractionated heparin (UFH) but it can also develop in patients treated with low molecular weight heparins (LMWH) however the probability is significantly lower. The classical presentation of HIT might be confusing since the thrombocytopenia is usually not severe (a drop of 50-60% when compared to pre-op values) and the dominating clinical symptoms are usually related to thrombo-embolic complications. The final diagnosis can be confirmed only by additional, relatively complicated laboratory tests, which usually take several days to complete. In the meantime, if HIT is suspected, treatment should be initiated based on strong clinical indications.

HIT is an immune reaction associated with the formation of antibodies directed against heparin-Platelet Factor 4 (PF-4) complexes. Once heparin is administered to a patient, platelets release PF-4, which binds heparin. The heparin-PF-4 complex is highly immunogenic and initiates formation of antibodies, which belong to many subgroups (IgG, IgM and IgA). Among these classes of immunoglobulins, only IgG is capable of triggering the reaction responsible for HIT. The immune system of the patient develops sensitivity (memory) to complexes of heparin-PF-4. When a second dose of heparin is given (even a small amount) it causes platelet degranulation and release of PF-4. Antibodies then bind to the complexes (Fab fragment) and to the surface of platelets (Fc fragment) initiating a cascade of events that result in further platelet activation and release of large amounts of PF-4 along with further platelet aggregation and thrombin generation. Strong activation of thrombin leads to clot formation and subsequent thrombo-embolic events. PF-4 can also bind to other substances, which are chemicaly similar to heparin. They belong to a group of molecules called glycosaminoglycans (GAGs). Many GAGs are present on the surface of the endothelial cells. This interaction amplifies the reaction leading to further platelet activation and aggregation, inflammation and propagates clot formation. The above described sequence of events presents clinically as thrombocytopenia accompanied by thrombotic complications. 80% of embolic events take place in the venous system while the remaining 20% occur in the arterial system. Rarely, HIT presents as a systemic reaction, for example disseminated intravascular coagulation (DIC). Therefore, HIT should be considered as a pro-thrombotic disorder leading to venous or major arterial thrombosis with potentially life-threatening consequences.

Antibodies against heparin-PF-4 are usually detectable for up to 3 months after the last heparin exposure. After the antibodies disappear the patient can be safely treated with heparin again.
