Patients with HIV-1 infection can develop severe thrombocytopenia which is likely due to both 1) impaired platelet production and 2) enhanced immunologic platelet destruction. We are currently working on enhaned platelet destruction.



Platelets from thrombocytopenic patients have considerable deposits of IgG, IgM, and C3C4 on their surface, which is likely due to deposition of immune complexes from their plasma which contain the same components. Immune complexes contain HIV-1-related antibodies: anti-gp120, anti-CD4, and anti-p24 in the absence of antigens. These antibodies are complexed to anti-F(ab'')2 Ab''s and anti-idiotype Ab''s. Immune complexes also have high affinity anti-platelet IgG (Kd 0.8 to 1.8 nM) . The anti-platelet IgG is specific for the platelet integrin, GPIIIa, and correlates inversely with thrombocytopenia (r=0.7; p<0.001).

The anti-platelet antibody is directed against an immunodominat GPIIa49-66 epitope and fragments platelets in the abssence of complement. This Ab induces platelet oxidation/fragmentation through an NADPH oxidase and 12-Lipoxygenase pathway. We are currently directing our attention to the etiology of this immunodonant Ab--proposing that it is due to moleclar mimickry, i.e. cross-reactivity between anti-HIV Ab''s and antiplatelet Ab.

We are also working on the role of thrombin and thrombosis in tumor growth, metastasis and angiogenesis. Most tumor cells have constitutively-active tissue factor on their surface which is capable of generating thrombin. Thrombin enhances tumor adhesion to platelets, fibronectin and Von Willebrand factor which serves to protect the tumor from host destruction. Thrombin also stimulates tumor growth in vitro and tumor growth and metastasis iin vivo. Hirudin, a potent anti-thrombin agent inhibits tumor growth in vivo as well as tumor seeding into the blod and tumor metastasis into the lungs an other organs.