Heparin-Induced Thrombocytopenia. Part I
Frequency of Thromboembolic Events
There is conflicting information in the published dataconcerning the frequency of thromboembolic events in patients with HIT. Early retrospective studies reported a frequency rate .60%, although this may have reflected the fact that the condition was often not recognized before complications occurred In prospective studies of HIT, only small numbers of patients have developed thrombotic complications. When data from the adequately designed studies are pooled, the risk of thrombosis in patients with HIT is estimated at 30% The frequency may vary dramatically with the baseline risk of thrombosis in the patient group. In the study of patients receiving heparin for thromboprophylaxis after hip surgery, 8 (88.9%) of the 9 patients with HIT had one or more thrombotic events as compared with 117 (17.8%) of the 656 patients without HIT. Data from a recent, carefully performed, retrospective study suggest that the risk of thrombotic events may persist for several weeks after exposure to heparin . In this study of 62 patients diagnosed initially with isolated HIT, .50% experienced thrombotic complications over the ensuing 30 days.
Pathophysiology
Type II HIT is an immune-mediated reaction most commonly caused by an immunoglobulin (Ig) G antibody that binds to platelets in the presence of heparin and causes platelet activation. Heparin-dependent IgM and IgA antibodies have also been described, and recent evidence suggests that they too may induce type II HIT
The antigen. Despite the important role of heparin in initiating and sustaining the syndrome, it has not been possible to directly demonstrate an interaction between the antibody and heparin alone. In 1992, it was shown that the majority of antibodies generated in HIT recognized a complex between heparin and platelet factor 4 (PF4) . The antibody is not specific for heparin, but reacts with other sulfated polysaccharides bound to PF4. This cross reactivity increases with size and negative charge of the polysaccharide In up to 25% of cases the antibody does not recognize the polysaccharide–PF4 complex, indicating that antigens other than PF4 are responsible for some cases of HIT. These antigens remain unidentified.
The antibody response. The heparin-dependent IgG generally becomes detectable after 5 to 7 days of heparin therapy. Patients preexposed to heparin may develop HIT sooner after institution of therapy than those receiving heparin for the first time, suggestive of an anamnestic response. However, almost all of these reported events have occurred within days to weeks of the index exposure, when the heparinassociated IgG is usually still detectable in the circulation and is presumably responsible for the thrombocytopenia. It is noteworthy that patients with cardiac disease requiring percutaneous or surgical interventions have frequently been exposed to heparin within this time frame. One case of recurrent HIT, documented years after the initial episode, reported a time course comparable to the index event, consistent with the mounting of a second primary immune response and absence of immunologic memory.