The overall goal of this project is to develop a personalized approach to the diagnosis and treatment of human blood diseases where pathophysiology is driven by the alternative pathway of complement (APC). The APC is an important driver of thrombotic microangiopathies (TMA) including atypical hemolytic uremic syndrome (aHUS), post-transplant TMAs (ptTMA), hemolysis, elevated liver function tests, and low platelets (HELLP) syndrome and hypercoagulable states such as antiphospholipid antibody syndrome (APS) and catastrophic antiphospholipid antibody syndrome (CAPS). For this proposal we refer to these closely related diseases as ?complementopathies?. Germline mutations in the genes that regulate the APC are found in up to 50% of patients with aHUS and have also been reported in ptTMAs, HELLP, and APS/CAPS. Unfortunately, the functional consequence of these mutations is not always clear. Terminal complement inhibition with eculizumab is highly effective for treating aHUS but is not used routinely because of difficulty in distinguishing aHUS and thrombotic thrombocytopenic purpura (TTP) and because of the high cost of the drug (~$600,000) annually. There are case reports of eculizumab being effective in treating ptTMAs, HELLP, and APS/CAPS. Currently, the pathophysiology of HELLP syndrome, APS/CAPS, and ptTMAs remains obscure and there are no FDA approved drugs to treat these often fatal or highly morbid diseases. Recently, we developed a novel serum based assay, modified HAM test, which is highly sensitive and specific for detecting systemic activation of the APC; the assay is also highly effective in distinguishing aHUS from thrombotic thrombocytopenic purpura (TTP). We also demonstrate that continued administration of eculizumab is unnecessary in most aHUS cases if therapy is instituted rapidly. Our new preliminary data demonstrate that systemic activation of the APC is also a driver of the HELLP syndrome, APS/CAPS and ptTMAs. In this project we endeavor to solve the most pressing needs in the field of complement-driven TMAs (aHUS, HELLP, APS/CAPS etc) by: 1) establishing a rapid diagnosis; 2) predicting which patients will benefit most from complement inhibition (precision medicine); 3) linking the genotype and phenotype of complementopathies; and 4) defining ?innocent versus guilty? autoantibodies in APS/CAPS. Therefore, this laboratory research project is hypothesis-driven, translational, and goal-oriented. If successful, our proposal will open the door to precision medicine for TMAs and potentially APS/CAPS.

Public Health Relevance

The purpose of this laboratory-based proposal is to improve the diagnosis and treatment of complement-driven hematopoietic diseases (atypical hemolytic uremic syndrome, antiphospholipid antibody syndrome, post-transplant thrombotic microangiopathy, and HELLP syndrome. Specifically, we will develop a novel diagnostic assay to that will correlate with pathogenic mutations and autoantibodies in complementopathies and identify patients most likely to respond to complement inhibitors (precision medicine).

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hemostasis and Thrombosis Study Section (HT)
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Kindzelski, Andrei L
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Johns Hopkins University
Internal Medicine/Medicine
Schools of Medicine
United States
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Brodsky, Robert A (2017) Eculizumab: another breakthrough. Blood 129:922-923
Yuan, Xuan; Li, Zhe; Baines, Andrea C et al. (2017) A hypomorphic PIGA gene mutation causes severe defects in neuron development and susceptibility to complement-mediated toxicity in a human iPSC model. PLoS One 12:e0174074
Merrill, Samuel A; Brittingham, Zachary D; Yuan, Xuan et al. (2017) Eculizumab cessation in atypical hemolytic uremic syndrome. Blood 130:368-372
Yuan, Xuan; Gavriilaki, Eleni; Thanassi, Jane A et al. (2017) Small-molecule factor D inhibitors selectively block the alternative pathway of complement in paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Haematologica 102:466-475
Rotz, Seth J; Luebbering, Nathan; Dixon, Bradley P et al. (2017) In vitro evidence of complement activation in transplantation-associated thrombotic microangiopathy. Blood Adv 1:1632-1634
Baines, Andrea C; Brodsky, Robert A (2017) Complementopathies. Blood Rev 31:213-223
Vaught, Arthur J; Gavriilaki, Eleni; Hueppchen, Nancy et al. (2016) Direct evidence of complement activation in HELLP syndrome: A link to atypical hemolytic uremic syndrome. Exp Hematol 44:390-8