Target molecules recognized by platelet-reactive antibodies. The role played by rare platelet-specific antigens as triggers for neonatal alloimmune thrombocytopenia (NATP) will be characterized by studying mother/father pairs of unresolved NATP cases. Recombinant target proteins will be developed to facilitate NATP diagnosis. The biology of a newly identified genetic trait (high-expression of blood group A and B antigens on platelets) and its significance in platelet transfusion and neonatal thrombocytopenia will be examined. The 5b (HNA-3a) neutrophil/platelet alloantigen, a cause of fatal transfusion reactions in patients transfused with anti-5b, will be characterized. Drug-induced immune cytopenia (DIIC) induced by drugs other than heparin. Mechanisms by which drugs induce drug-dependent antibodies, promote binding of these antibodies to their targets and cause blood cell destruction will be examined at a molecular level. The importance of drug metabolites as triggers for these antibodies will be defined. The possibility that drug-dependent antibodies specific for markers on endothelial cells influence the clinical course of DIIC will be explored. Improved methods for diagnosis of DIIC will be developed. Heparin-induced thrombocytopenia/ thrombosis (HIT). Studies will be undertaken in a large cohort of patients suspected of having HIT to resolve the question of whether antibodies specific for IL-8, a CXC chemokine homologous to PF4, have a role in pathogenesis. Pathogenesis of other immune-mediated platelet disorders. Patients with other immune-mediated platelet disorders relevant to the objectives of this grant will be studies as time and resources permit.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL013629-36
Application #
6927974
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Ganguly, Pankaj
Project Start
1970-06-01
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
36
Fiscal Year
2005
Total Cost
$474,182
Indirect Cost
Name
Bloodcenter of Wisconsin, Inc.
Department
Type
DUNS #
057163172
City
Milwaukee
State
WI
Country
United States
Zip Code
53233
Jones, Curtis G; Pechauer, Shannon M; Curtis, Brian R et al. (2018) Normal plasma IgG inhibits HIT antibody-mediated platelet activation: implications for therapeutic plasma exchange. Blood 131:703-706
Curtis, Brian R; Hsu, Yen-Michael S; Podoltsev, Nikolai et al. (2018) Patients treated with oxaliplatin are at risk for thrombocytopenia caused by multiple drug-dependent antibodies. Blood 131:1486-1489
Jones, Curtis G; Pechauer, Shannon M; Curtis, Brian R et al. (2017) A Platelet Factor 4-Dependent Platelet Activation Assay Facilitates Early Detection of Pathogenic Heparin-Induced Thrombocytopenia Antibodies. Chest 152:e77-e80
Padmanabhan, Anand; Jones, Curtis G; Pechauer, Shannon M et al. (2017) IVIg for Treatment of Severe Refractory Heparin-Induced Thrombocytopenia. Chest 152:478-485
Bougie, Daniel W; Nayak, Dhirendra; Aster, Richard H (2016) Immune destruction of human platelets in the NOD/scid mouse. Transfusion 56:2648-2649
Fuentes, Rudy E; Zaitsev, Sergei; Ahn, Hyun Sook et al. (2016) A chimeric platelet-targeted urokinase prodrug selectively blocks new thrombus formation. J Clin Invest 126:483-94
Padmanabhan, Anand; Jones, Curtis G; Curtis, Brian R et al. (2016) A Novel PF4-Dependent Platelet Activation Assay Identifies Patients Likely to Have Heparin-Induced Thrombocytopenia/Thrombosis. Chest 150:506-15
Falk, Gavin; Winans, Charles G; Bowens, Krista et al. (2016) An unexpected development after surgery-post-transfusion purpura! Am J Hematol 91:848-51
Padmanabhan, Anand; Jones, Curtis G; Bougie, Daniel W et al. (2015) A modified PF4-dependent, CD62p expression assay selectively detects serotonin-releasing antibodies in patients suspected of HIT. Thromb Haemost 114:1322-3
Sullivan, Mia J; Peterson, Julie; McFarland, Janice G et al. (2015) A new low-frequency alloantigen (Kha(b) ) located on platelet glycoprotein IIIa as a cause of maternal sensitization leading to neonatal alloimmune thrombocytopenia. Transfusion 55:1584-5

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