Deficiency of plasma ADAMTS13 activity, either hereditary or acquired, causes thrombotic thrombocytopenic purpura (TTP). However, the triggering events and mechanisms underlying the pathogenesis of TTP are not fully understood. Emerging data suggest that complement activation may be associated with both hemolytic uremic syndrome (HUS) and TTP.
In Aim 1, we propose to determine the effects of CFH on ADAMTS13- mediated VWF proteolysis and its adhesive function under flow. We will also determine the kinetics and mechanism of such interactions and how such an interaction affects complement activation/inactivation.
In Aim 2, we will determine the role of genetic or acquired deficiency of CFH on the occurrence, progression, and outcome of acquired TTP (with inhibitors) in murine models.
In Aim 3, we propose to determine the prevalence of mutations in genes in complement components and regulators in patients with acquired TTP patients with inhibitors. We pursue the hypothesis that by inhibiting complement activation with anti-complement therapy either alone or in combination with rADAMTS13 one can better prevent the onset and progression of the disease pathology or accelerate its recovery. The results of the proposed study will advance our understanding of the fundamental role of CFH in regulation of VWF function under physiological shear stress, shed new light on the mechanisms of acquired TTP, and provide invaluable tools for testing the efficacy of novel therapeutics.

Public Health Relevance

This project aims to understand the pathogenesis of thrombotic thrombocytopenic purpura (TTP) by determining the interactions between complement factor H (CFH) and von Willebrand factor and metalloprotease ADAMTS13. We propose to test the hypothesis that genetic or antibody-mediated inactivation of CFH and ADAMTS13 may have a cooperative role in pathogenesis of TTP. The results of the proposed study will shed new lights on the crosstalk between complement and hemostasis, and provide invaluable murine models for further testing novel therapeutic strategies of potentially fatal thrombotic microangiopathy including TTP and hemolytic uremic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL126724-03
Application #
9253436
Study Section
Special Emphasis Panel (ZRG1-VH-B (03)M)
Program Officer
Kindzelski, Andrei L
Project Start
2015-09-14
Project End
2019-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
3
Fiscal Year
2017
Total Cost
$455,395
Indirect Cost
$104,079
Name
University of Alabama Birmingham
Department
Pathology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Xiao, Juan; Feng, Yun; Li, Xueyin et al. (2017) Expression of ADAMTS13 in Normal and Abnormal Placentae and Its Potential Role in Angiogenesis and Placenta Development. Arterioscler Thromb Vasc Biol 37:1748-1756
Kim, Chong H; Simmons, Sierra C; Williams Iii, Lance A et al. (2017) ADAMTS13 test and/or PLASMIC clinical score in management of acquired thrombotic thrombocytopenic purpura: a cost-effective analysis. Transfusion 57:2609-2618
Saha, M; McDaniel, J K; Zheng, X L (2017) Thrombotic thrombocytopenic purpura: pathogenesis, diagnosis and potential novel therapeutics. J Thromb Haemost 15:1889-1900
Kumar, Monisha; Cao, Wenjing; McDaniel, Jenny K et al. (2017) Plasma ADAMTS13 activity and von Willebrand factor antigen and activity in patients with subarachnoid haemorrhage. Thromb Haemost 117:691-699
Ping, Zheng; Soni, Abha; Williams 3rd, Lance A et al. (2017) Mutations in Coagulation Factor VIII Are Associated with More Favorable Outcome in Patients with Cutaneous Melanoma. TH Open 1:e113-e121
Ueda, Yoshiyasu; Mohammed, Imran; Song, Delu et al. (2017) Murine systemic thrombophilia and hemolytic uremic syndrome from a factor H point mutation. Blood 129:1184-1196
Cao, W J; Zheng, X L (2017) Conformational quiescence of ADAMTS-13 prevents proteolytic promiscuity: comment. J Thromb Haemost 15:586-589
Ostertag, Eric M; Kacir, Stephen; Thiboutot, Michelle et al. (2016) ADAMTS13 autoantibodies cloned from patients with acquired thrombotic thrombocytopenic purpura: 1. Structural and functional characterization in vitro. Transfusion 56:1763-74
Zheng, Liang; Mao, Yingying; Abdelgawwad, Mohammad S et al. (2016) Therapeutic efficacy of the platelet glycoprotein Ib antagonist anfibatide in murine models of thrombotic thrombocytopenic purpura. Blood Adv 1:75-83
Cao, Wenjing; Pham, Huy P; Williams, Lance A et al. (2016) Human neutrophil peptides and complement factor Bb in pathogenesis of acquired thrombotic thrombocytopenic purpura. Haematologica 101:1319-1326

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