Figure 58-1 PATHOGENESIS OF HEPARIN-INDUCED THROMBOCYTOPENIA (HIT).

Heparin produces mild platelet activation, resulting in release of platelet factor 4 (PF4) from platelet α-granules and the formation of immunogenic PF4/heparin complexes. B lymphocytes generate IgG immunoglobulins that recognize the PF4/heparin complexes; the Fc “tails” of the IgG bind to platelet FcγIIa receptors, resulting in Fc receptor clustering and consequent “strong” platelet activation. Platelet-derived microparticles are generated that accelerate thrombin generation. The HIT antibodies also recognize PF4 bound to endothelial heparan sulfate, leading to immunoinjury that causes endothelial activation. Recent evidence suggests that HIT antibodies also activate monocytes. The greatly increased thrombin generation observed in HIT helps to explain its association with venous and arterial thrombosis, as well as some of its unusual clinical features (e.g., warfarin-induced venous limb gangrene, decompensated disseminated intravascular coagulation), and also provides a rationale for treatments that control thrombin generation (e.g., with indirect [antithrombin-dependent] or with direct thrombin inhibitors).

(Reprinted with permission from Greinacher A, Warkentin TE: Treatment of heparin-induced thrombocytopenia: An overview. In Warkentin TE, Greinacher A, editors: Heparin-induced thrombocytopenia, ed 4, New York, 2007, Informa Healthcare USA, p 287.)

Figure 58-2 CHARACTERISTIC TIMELINE OF HEPARIN-INDUCED THROMBOCYTOPENIA (HIT).

Anti-PF4/heparin antibodies (by enzyme immunoassay [EIA]) per postoperative day in 12 patients with HIT and 36 seropositive non-HIT control patients. A, Mean (±standard error of the mean [SEM]) optical density (OD) of anti-PF4/heparin antibodies detected using commercial immunoassay (EIA-GAM) that detects antibodies of all three immunoglobulin classes (IgG, IgA, IgM). HIT patients are indicated by , and seropositive non-HIT controls by . On each day beginning on postoperative day 6, there is a significant difference in the mean of the OD levels between the patients with HIT and the seropositive non-HIT controls (P < .05 by nonpaired t test). At the top of the figure, summary data for 12 HIT patient profiles are shown for four key events (first day of antibody detection, beginning of HIT-related platelet count fall, platelet count fall ≥50%, and thrombotic event), summarized as median (small purple squares within rectangles), interquartile range (rectangles), and range (ends of thin black lines). B, Mean (±SEM) OD values of anti-PF4/heparin antibodies detected using an in-house immunoassay (EIA-Ig) that detects antibodies of the individual immunoglobulin classes, IgG (red circles), IgA (green triangles), and IgM (blue inverted triangles) for HIT (solid symbols) and non-HIT (open symbols). On each postoperative day beginning on day 5, there is a significant difference in the mean of the OD units for the IgG immunoassay between the patients with HIT and the seropositive non-HIT controls (**P < .005 for days 6 to 10; *P < .05 for days 5, 11, and 12).

(From Warkentin TE, Sheppard JI, Moore JC, et al: Studies of the immune response in heparin-induced thrombocytopenia. Blood 113:4693, 2009.)