Pathogenesis of HIT Treatment Implications

HIT is caused by antibodies that usually recognize multimolecular complexes of platelet factor 4 (PF4) and heparin. HIT can be viewed as a syndrome of in vivo thrombin generation that results from the activation of platelets, endothelium, monocytes, and coagulation pathways (Warkentin and Kelton, 1994; Greinacher, 1995; Warkentin, 2003; Warkentin et al., 1998) (Fig. 1) (see Chapters 4-9). Given this model of pathogenesis, therapy for acute HIT should focus on the following issues: (1) rapid reduction of increased thrombin generation; (2) treatment of HIT-associated thrombosis, and (3) interruption of the immune response and heparin-dependent platelet activation (i.e., discontinuation of heparin). In most patients with HIT, effective pharmacological therapy for thrombosis will involve an agent that rapidly controls thrombin generation, although in some situations, additional adjunctive treatments may be necessary (e.g., surgical thromboembolectomy).

An increasingly recognized treatment issue involves patients with detectable anti-PF4/heparin antibodies but no platelet count reduction or other clinical evidence of HIT. With increased testing for HIT antibodies, it is now clear that many patients develop anti-PF4/heparin antibodies without developing clinical HIT (see Chapters 3 and 10). In these patients, it seems acceptable to continue heparin treatment but to monitor the platelet counts carefully ("watch-and-wait" strategy).

Several studies of heparin administration in the contexts of acute coronary syndrome, cardiac surgery, and hemodialysis have suggested that presence of anti-PF4/heparin antibodies confer adverse prognosis (increased cardiovascular events) even in the absence of clinically evident HIT (Mattioli et al., 2000; Williams et al., 2003; Mascelli et al., 2004a,b; Bennett-Guerrero et al., 2005; Pena de la Vega et al., 2005). However, whether this reflects true pathogenicity of these antibodies in the presence of heparin ("forme fruste" HIT) or whether the presence of antibodies represents simply a surrogate marker for other adverse prognostic markers

Heparan sulfate B-lymphocyte Endothelial cell

Hepa

Heparin Resting platelet

GPIIb/IIIa Fc receptor

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