Canadian Blood Services
Platform Director and Scientist for Hematology, Cancer and Immunological Diseases
Keenan Research Centre for Biomedical Science – St. Michael's Hospital
Laboratory Medicine and Pathobiology – University of Toronto
Medicine – University of Toronto
Physiology – University of Toronto
- Doctor of Philosophy, University of Manitoba
- MD, Anhui Medical University, China
- Master of Science, Anhui Medical University, China
Keenan Research Centre for Biomedical Research
St. Michael's Hospital
209 Victoria Street
Toronto, ON, Canada M5B 1W8
416-864-6060 ext. 6758
Hemostasis and Thrombosis - finding the right balance
A complex system of cells, proteins and signaling molecules in the blood and blood vessels maintain a delicate balance between bleeding (hemostasis) and clotting (thrombosis). Dr. Heyu Ni’s laboratory investigates the role(s) of adhesion molecules involved in clot formation and their implications for hemostasis (including bleeding disorders) and thrombotic diseases (including heart attack and stroke).
Why is this important?
Understanding the cellular and molecular mechanisms of hemostasis and thrombotic diseases could lead to the development of new therapies as well as diagnostic tools to control bleeding disorders and cardiovascular diseases, such as heart attack and stroke, which are the leading cause of mortality and morbidity worldwide.
While completing his post-doctoral fellowship at Harvard, Dr. Heyu Ni established an intravital microscopy thrombosis model to study thrombus formation in real time in live mice. Through direct monitoring of platelet adhesion and aggregation in vivo, the group was the first to observe that platelet aggregation and thrombus formation still occur in mice lacking both von Willebrand factor (VWF) and fibrinogen (Fg), two proteins previously thought to be essential for thrombus formation. This surprising discovery challenged the established theory of thrombosis and suggested that other unidentified molecule(s) were also involved in thrombosis and hemostasis and may provide novel targets for anti-thrombotic therapies. Dr. Ni’s team is in the process of identifying these mystery molecules using several state-of-the-art techniques such as proteomics and confocal intravital microscopy. In particular, the work focuses on the role of adhesion molecules such as the beta3 integrin (e.g. GPIIbIIIa) and GPIb alpha complexes.
- Hou Y, Carrim N, Wang Y, Gallant RC, Marshall AH, Ni H: Platelets in hemostasis and thrombosis: Novel mechanisms of fibrinogen-independent platelet aggregation and fibronectin-mediated protein wave of hemostasis. J Biomed Res 2015; doi: 10.7555/JBR.29.20150121 [Epub ahead of print].
- Wang Y, Reheman A, Spring CM, Kalantari J, Marshall AH, Wolberg AS, Gross PL, Weitz JI, Rand ML, Mosher DF, Freedman J, Ni H: Plasma fibronectin supports hemostasis and regulates thrombosis. J Clin Invest 2014; 124:4281-4293.
- Reheman A, Xu X, Reddy E, Ni H: Targeting activated platelets and fibrinolysis: hitting two birds with one stone. Circ Res 2014; 114:1070-1073.
- Fedorov K, Blaszykowski C, Sheikh S, Reheman A, Romaschin A, Ni H, Thompson M: Prevention of thrombogenesis from whole human blood on plastic polymer by ultrathin monoethylene glycol silane adlayer. Langmuir 2014; 30:3217-3222.
- Lei X, Reheman A, Hou Y, Zhou H, Wang Y, Marshall AH, Liang C, Dai X, Li BX, Vanhoorelbeke K, Ni H: Anfibatide, a novel GPIb complex antagonist, inhibits platelet adhesion and thrombus formation in vitro and in vivo in murine models of thrombosis. Thromb Haemost 2014; 111:279-289.
- Murphy AJ, Bijl N, Yvan-Charvet L, Welch CB, Bhagwat N, Reheman A, Wang Y, Levine R, Ni H, Tall AR, Wang N: Cholesterol efflux in megakaryocyte progenitors suppresses platelet production and thrombosis. Nat Med. 2013; 19:586-594.
- Wang Y, Andrews M, Lang S, Jin JW, Cameron-Vendrig A, Zhu G, Reheman A, Ni H: Platelets in Thrombosis and Hemostasis: Old Topic with New Mechanisms. Cardiovascular & Haematological Disorders - Drug Targets 2012; 12:126-132.
- Dunne E, Spring CM, Reheman A, Jin W, Berndt MC, Newman DK, Newman PJ, Ni H Kenny D: Cadherin 6 has a functional role in platelet aggregation and thrombus formation. Arterioscl Throm Vas 2012; 32:1724-1731.
- Patel S, Huang YW, Reheman A, Pluthero FG, Chaturvedi S, Mukovozov IM, Tole S, Liu GY, Li L, Durocher Y, Ni H, Kahr WH, Robinson LA: The cell motility modulator Slit2 is a potent inhibitor of platelet function. Circulation 2012; 126:1385-1395.
- Yang Y, Shi Z, Reheman A, Jin JW, Li C, Wang Y, Andrews MC, Chen P, Zhu G, Ling W, Ni H: Plant food delphinidin-3-glucoside significantly inhibits platelet activation and thrombosis: Novel protective roles against cardiovascular diseases. PLoS One 2012;7:e37323.
Understanding Diseases to Optimize Transfusion Practice
Dr. Heyu Ni’s laboratory studies allo- and auto-immune diseases related to bleeding disorders such as immune thrombocytopenia (ITP) and fetal and neonatal alloimmune thrombocytopenic purpura (FNAIT). These diseases are characterized by the presence of antibodies that target platelet antigens and result in a loss of platelets, which in turn can lead to uncontrolled bleeding and, in rare cases, death.
Why is this important?
These studies help us understand immune diseases and their treatment and could lead to more appropriate clinical practice of both diagnosis and treatment.
While ITP and FNAITP are characterized by immune-mediated destruction of platelets, how and why these diseases occur isn’t clear. Dr. Ni’s group has investigated how ITP mediated by anti-beta3 integrin (GPIIbIIIa) and anti-GPIb antibodies differ, and have found that these two antibody specificities may respond to therapy differently. The group recently conducted a retrospective study in adults with ITP and concluded that patients with autoantibodies targeting the platelet surface protein GPIIb/IIIa respond well to intravenous immunoglobulin G (IVIG) and steroid therapies, but those with autoantibodies targeting platelet GPIb/IX do not. This has important implications for human ITP and potential screening of patients in order to successfully treat this disease. IVIG, which is provided to Canadian physicians by Canadian Blood Services, is limited in supply and is an expensive treatment option. A better understanding of the mechanism by which IVIG works and development of alternative therapies to IVIG would benefit patients and the blood system in general.
Dr. Ni’s group developed the first animal model of FNAIT, characterizing the disease and its response to IVIG therapy. Currently, the laboratory is studying the molecular and cellular basis of ITP, the maternal immune responses to fetal platelet antigens and the roles of anti-angiogenesis and apoptosis in the pathogenesis of FNAIT.
- Li J, van der Wal DE, Zhu G, Xu M, Yougbaré I, Ma L, Vadasz B, Carrim N, Grozovsky R, Ruan M, Zhu L, Zeng Q, Tao L, Zhai ZM, Peng J, Hou M, Leytin V, Freedman J, Hoffmeister KM, Ni H: Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia. Nat Commun2015; 6:7737.
- Yougbaré I, Lang S, Yang H, Chen P, Zhao X, Tai WS, Zdravic D, Vadasz B, Li C, Piran S, Marshall A, Zhu G, Tiller H, Killie MK, Boyd S, Leong-Poi H, Wen XY, Skogen B, Adamson SL, Freedman J, Ni H: Maternal anti-platelet β3 integrins impair angiogenesis and cause intracranial hemorrhage. J Clin Invest 2015; 125:1545-1556.
- Ma L, Simpson E, Li J, Xuan M, Xu M, Baker L, Shi Y, Yougbaré I, Wang X, Zhu G, Chen P, Prud’homme G, Lazarus AH, Freedman J, Ni H: CD8+ T cells are predominantly protective and required for effective steroid therapy in murine models of immune thrombocytopenia. Blood 2015; 126:247-256.
- Ni H: ResearchUnit: Novel discovery reveals new diagnostic markers and treatment targets for bleeding disorder. 2015; Transfusionmedicine.ca website.
- Ni H: ResearchUnit: Platelets vs. blood vessels: What causes bleeding in fetuses and newborns with FNAIT? 2015; Transfusionmedicine.ca website.
- Li J, Callum JL, LinY, Zhou Y, Zhu G, Ni H: Severe platelet desialylation in a patient with glycoprotein Ib/IX antibody-mediated immune thrombocytopenia and fatal pulmonary hemorrhage. Haematologica 2014; 99:e61-63.
- Peng J, Ma S‐H, Liu J, Hou Y, Liu X‐M, Niu T, Xu R‐R, Guo C‐S, Wang X‐M, Cheng Y‐F, Ni H, Hou M: Association of autoantibody specificity and response to intravenous immunoglobulin G therapy in immune thrombocytopenia: a multicenter cohort study. J Thromb Haemost 2014; 12:497-504.
- Guo L, Yang L, Speck E, Aslam R, Kim M, McKenzie C, Lazarus A, Ni H, Hou M, Freedman J, Semple J: Allogeneic platelet transfusions prevent murine T cell-mediated immune thrombocytopenia (ITP). Blood 2014; 123:422-427.
- Li C, Chen P, Zhou H, Vadasz B, Ma L, Lang S, Freedman J, Ni H: Co-stimulation with lipopolysaccharide or polyinosinic: polycytidylic acid enhances the immune response against platelet antigens in murine models of fetal and neonatal alloimmune thrombocytopenia. Thromb Haemostasis 2013; 110:1250-1258.
- Ni H: Influence of the anticoagulant on detection of the ITP anti-platelet GPIIb/IIIa and GPIbalpha antibodies on based modified MAIPA. Acta Universitatis Medicinalis Anhui 2013; 48:832-834.
- Nishimoto T, Satoh T, Simpson EK, Ni H, Kuwana M: Predominant autoantibody response to GPIb/IX in a regulatory T-cell-deficient mouse model for immune thrombocytopenia. J Thromb Haemost 2013; 11:369-372.
- Aslam R, Hu Y, Gebremeskel S, Segel GB, Speck ER, Guo L, Kim M, Ni H, Freedman J, Semple JW: Thymic retention of CD4+CD25+FoxP3+ T regulatory cells is associated with their peripheral deficiency and thrombocytopenia in a murine model of immune thrombocytopenia (ITP). Blood 2012; 120:2127-2132.
- Tiller H, Kjaer Killie M, Chen P, Eksteen M, Husebekk A, Skogen B, Kjeldsen‐Kragh J, Ni H: Toward a prophylaxis against fetal and neonatal alloimmune thrombocytopenia: induction of antibody‐mediated immune suppression and prevention of severe clinical complications in a murine model. Transfusion 2012; 52:1446-1457.
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