The role of low frequency platelet-specific antigens as triggers for neonatal alloimmune thrombocytopenia (NATP) will be characterized more fully. Improved methods for detecting and identifying the responsible antibodies will be developed. The significance of """"""""high-expression"""""""" of A/B antigens on platelets in NATP and other aspects or transfusion medicine will be defined. Molecular properties of the HNA-3a (5b) neutrophil antigen, an important trigger for transfusion-related acute lung injury (TRALI) will be determined. Drug-induced immune thrombocytopenia (DITP) (non-heparin). Mechanisms by which drugs induce drug-dependent antibodies (DDAbs) and promote binding of DDAbs to their targets will be characterized at the molecular level using both human DDAbs and murine monoclonal DDAbs that mimic their human counterparts. A unique NOD/scid mouse model will be used to define mechanisms of in vivo destruction of human platelets by human and murine DDAbs and to characterize drug metabolites capable of triggering DITP. A murine model of DITP will be explored. Improved methods for identifying agents responsible for immune cytopenia in individual patients will be developed. Heparin-induced thrombocytopenia (HIT). HIT is an important cause of morbidity and mortality in patients treated with this otherwise useful anticoagulant. We propose to address important unresolved questions concerning performance of diagnostic testing and interpretation of test results to improve diagnosis and management. Immune-mediated blood disorders and other types of drug sensitivity are a major cause of morbidity and mortality. The proposed studies will lead to a better understanding of causation and improved diagnosis and treatment.

Public Health Relevance

Immune-mediated thrombocytopenias and other blood disorders are a major cause of morbidity and mortality. The proposed studies will lead to a better understanding of causation and to improved diagnosis and treatment.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL013629-39A1
Application #
7647727
Study Section
Special Emphasis Panel (ZRG1-HEMT-D (01))
Program Officer
Kindzelski, Andrei L
Project Start
1970-06-01
Project End
2012-04-30
Budget Start
2009-06-15
Budget End
2010-04-30
Support Year
39
Fiscal Year
2009
Total Cost
$514,210
Indirect Cost
Name
Bloodcenter of Wisconsin, Inc.
Department
Type
DUNS #
057163172
City
Milwaukee
State
WI
Country
United States
Zip Code
53233
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. (2018) Normal plasma IgG inhibits HIT antibody-mediated platelet activation: implications for therapeutic plasma exchange. Blood 131:703-706
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

Showing the most recent 10 out of 131 publications