Heparin-induced thrombocytopenia (HIT) is an iatrogenic complication associated with mild thrombocytopenia, but limb- and life-threatening thrombosis. The theme of this revised Program Project remains to understand the molecular mechanisms underlying HIT and to use that knowledge to develop new therapeutic approaches for its treatment. We believe that this is a timely proposal to combine several different, but highly interactive, efforts to advance our understanding and care of patients with HIT. There are four proposed Projects: Project 1: Cellular Events Underlying Thrombocytopenia and Thrombosis in HIT under Mortimer Poncz at the Children's Hospital of Philadelphia (CHOP) will examine the events that occur in vivo that lead to both the thrombocytopenia and prothrombotic state. Project 2: Pathogenic Antibodies in HIT under Douglas B. Cines at the University of Pennsylvania (UPENN) will better understand what distinguishes a pathogenic from a non-pathogenic anti-platelet factor 4 (PF4)/heparin Ab. Project 3: Immune Pathogenesis of HIT under Gowthami Arepally at Duke will study the physical characteristics of the PF4/heparin complex and the cellular basis of the pathogenic immune response in HIT. Project 4: Novel Therapeutics in HIT under Steven McKenzie at Thomas Jefferson University and Bruce Sachais at UPENN will study two novel strategies for early intervention to ameliorate this devastating disease on their own or in conjunction with present standard therapies. In addition to an administrative core, there are two cores involved. A Protein Core B under Lubica Rauova (CHOP) that will provide large quantities of human, mouse and specific mutant PF4s as well as large quantities of several HlT-like and control monoclonal Abs. This Core will also isolate batched large-scale HIT IgGs as well as individual HIT IgG samples from plasma isolated and processed by the Clinical Sample Core C under Dr. Cines. Core C will be responsible for identifying high likelihood of HIT patients at all three major adult programs, consent the individuals and obtain plasma from them as well as record their clinical and serological data. We believe that the proposed Projects are highly interactive. Advances and technologies developed within each will have great value to other Projects. Moreover the Cores will provide unique materials in large amounts and to high standards that will allow rapid scientific progress and easy crosstalk between projects. At the end of the 5 years of support, we believe that important fundamental and clinically useful information will have been generated for a disease that remains highly clinically relevant.

Public Health Relevance

This proposed Program Project focuses on the biology of heparin-induced thrombocytopenia (HIT), a devastating complication of heparin anticoagulation that leads to life-threatening clots and proposes to test novel therapies. The proposed studies will lead to a better understanding of HIT'S pathogenesis that may lead to new diagnostic risk assessment tests, and more effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL110860-01A1
Application #
8337972
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Kindzelski, Andrei L
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2012-09-01
Budget End
2013-06-30
Support Year
1
Fiscal Year
2012
Total Cost
$2,378,672
Indirect Cost
$882,003
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
McKenzie, Steven E; Sachais, Bruce S (2014) Advances in the pathophysiology and treatment of heparin-induced thrombocytopenia. Curr Opin Hematol 21:380-7
Cines, Douglas B; Lebedeva, Tatiana; Nagaswami, Chandrasekaran et al. (2014) Clot contraction: compression of erythrocytes into tightly packed polyhedra and redistribution of platelets and fibrin. Blood 123:1596-603
Yeung, Jennifer; Tourdot, Benjamin E; Fernandez-Perez, Pilar et al. (2014) Platelet 12-LOX is essential for Fc?RIIa-mediated platelet activation. Blood 124:2271-9
Cines, Douglas B; Cuker, Adam; Semple, John W (2014) Pathogenesis of immune thrombocytopenia. Presse Med 43:e49-59
Kowalska, M Anna; Zhao, Guohua; Zhai, Li et al. (2014) Modulation of protein C activation by histones, platelet factor 4, and heparinoids: new insights into activated protein C formation. Arterioscler Thromb Vasc Biol 34:120-6
Litvinov, Rustem I; Yarovoi, Serge V; Rauova, Lubica et al. (2013) Distinct specificity and single-molecule kinetics characterize the interaction of pathogenic and non-pathogenic antibodies against platelet factor 4-heparin complexes with platelet factor 4. J Biol Chem 288:33060-70
Zhi, Huiying; Rauova, Lubica; Hayes, Vincent et al. (2013) Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo. Blood 121:1858-67
Lee, Grace M; Arepally, Gowthami M (2013) Diagnosis and management of heparin-induced thrombocytopenia. Hematol Oncol Clin North Am 27:541-63
Lee, Grace M; Welsby, Ian J; Phillips-Bute, Barbara et al. (2013) High incidence of antibodies to protamine and protamine/heparin complexes in patients undergoing cardiopulmonary bypass. Blood 121:2828-35
Cuker, Adam; Rux, Ann H; Hinds, Jillian L et al. (2013) Novel diagnostic assays for heparin-induced thrombocytopenia. Blood 121:3727-32

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