We have discovered a novel mechanism for platelet lysis and clearance in HIV-I-ITP patients, which is complement independent and induced by H202/free radicals. The Ab is directed against an immunodominant platelet GPIIla49-66 epitope and sequestered within serum immune complexes. Other Ab's against GPIIla do not have this effect. A rabbit Ab raised against GPIIla49-66 has the same effect. The mechanism of H202/free radical induction is via an apparent NADPH oxidase pathway in platelets since it is inoperative in NADPH oxidase deficient mice (p47phox(-/-) and gp91phox(-/-)) and dependent upon a functioning platelet 12-1ipoxygenase. I. Analyze the Presence of a Functioning NADPH Oxidase Pathway in Platelets. 2. Analyze the Mechanism of the Requirement of Platelet 12-Lipoxygenase for Ab-induced Platelet fragmentation. 3. Determine whether NADPH oxidase/ROS induced platelet fragmentation is a unique effect of anti- GPIIla49-66 Ab in HIV-I-ITP patients or a general mechanism for other platelet destructive disorders. 4. Determine whether anti-GPIIla49-66 is a result of molecular mimicry with antigen of infectious origin or its products.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hemostasis and Thrombosis Study Section (HT)
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Ganguly, Pankaj
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New York University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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Zhang, Wei; Nardi, Michael A; Borkowsky, William et al. (2009) Role of molecular mimicry of hepatitis C virus protein with platelet GPIIIa in hepatitis C-related immunologic thrombocytopenia. Blood 113:4086-93
Li, Zongdong; Nardi, Michael A; Li, Yong-Sheng et al. (2009) C-terminal ADAMTS-18 fragment induces oxidative platelet fragmentation, dissolves platelet aggregates, and protects against carotid artery occlusion and cerebral stroke. Blood 113:6051-60
Hu, Liang; Ibrahim, Sherif; Liu, Cynthia et al. (2009) Thrombin induces tumor cell cycle activation and spontaneous growth by down-regulation of p27Kip1, in association with the up-regulation of Skp2 and MiR-222. Cancer Res 69:3374-81
Hu, Liang; Roth, Jennifer M; Brooks, Peter et al. (2008) Twist is required for thrombin-induced tumor angiogenesis and growth. Cancer Res 68:4296-302
Hu, Liang; Roth, Jennifer M; Brooks, Peter et al. (2008) Thrombin up-regulates cathepsin D which enhances angiogenesis, growth, and metastasis. Cancer Res 68:4666-73
Li, Zongdong; Nardi, Michael A; Wu, Jing et al. (2008) Platelet fragmentation requires a specific structural conformation of human monoclonal antibody against beta3 integrin. J Biol Chem 283:3224-30
Nardi, Michael A; Gor, Yelena; Feinmark, Steven J et al. (2007) Platelet particle formation by anti GPIIIa49-66 Ab, Ca2+ ionophore A23187, and phorbol myristate acetate is induced by reactive oxygen species and inhibited by dexamethasone blockade of platelet phospholipase A2, 12-lipoxygenase, and NADPH oxidase. Blood 110:1989-96
Caunt, Maresa; Hu, Liang; Tang, Thomas et al. (2006) Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis. Cancer Res 66:4125-32
Li, Zongdong; Nardi, Michael A; Karpatkin, Simon (2005) Role of molecular mimicry to HIV-1 peptides in HIV-1-related immunologic thrombocytopenia. Blood 106:572-6
Hu, Liang; Lee, Merlin; Campbell, Wendy et al. (2004) Role of endogenous thrombin in tumor implantation, seeding, and spontaneous metastasis. Blood 104:2746-51

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