Abstract

Anti-platelet factor 4 (PF4)/heparin antibodies (Abs) and activation of platelet FcyRlla are involved in the pathogenesis of heparin-induced thrombocytopenia (HIT). However, the actual basis of the observed thrombocytopenia and thrombosis are not well understood, and markers of risk or diagnosis and targeted therapies remain limited. This Project focuses on furthering our understanding of the cellular events underiying the thrombocytopenia and thrombosis in HIT. We believe that platelets, leukocytes and endothelium, and derived microparticles (MP) contribute to both the thrombocytopenia and thrombosis. In this Project, we propose three novel interrelated cellular mechanisms that underiie the thrombocytopenia and prothrombotic nature of HIT:

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL110860-01A1
Application #
8400935
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
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
$339,811
Indirect Cost
$126,001

  Institution

Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Cloutier, Nathalie; Allaeys, Isabelle; Marcoux, Genevieve et al. (2018) Platelets release pathogenic serotonin and return to circulation after immune complex-mediated sequestration. Proc Natl Acad Sci U S A 115:E1550-E1559
Rauova, Lubica; Arepally, Gowthami; Poncz, Mortimer et al. (2018) Molecular and cellular pathogenesis of heparin-induced thrombocytopenia (HIT). Autoimmun Rev 17:1046-1052
Khandelwal, Sanjay; Ravi, Joann; Rauova, Lubica et al. (2018) Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway. Blood 132:2431-2440
Gollomp, Kandace; Kim, Minna; Johnston, Ian et al. (2018) Neutrophil accumulation and NET release contribute to thrombosis in HIT. JCI Insight 3:
Cines, Douglas B; Levine, Lisa D (2017) Thrombocytopenia in pregnancy. Blood 130:2271-2277
Cines, Douglas B; Levine, Lisa D (2017) Thrombocytopenia in pregnancy. Hematology Am Soc Hematol Educ Program 2017:144-151
Ponomareva, A A; Nevzorova, T A; Mordakhanova, E R et al. (2017) Intracellular origin and ultrastructure of platelet-derived microparticles. J Thromb Haemost 15:1655-1667
Hayes, Vincent; Johnston, Ian; Arepally, Gowthami M et al. (2017) Endothelial antigen assembly leads to thrombotic complications in heparin-induced thrombocytopenia. J Clin Invest 127:1090-1098
Arepally, Gowthami M (2017) Heparin-induced thrombocytopenia. Blood 129:2864-2872
Nevzorova, Tatiana A; Zhao, Qingze; Lomakin, Yakov A et al. (2017) Single-Molecule Interactions of a Monoclonal Anti-DNA Antibody with DNA. Bionanoscience 7:132-147

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