Tissue Factor Pathway
ISTH Core Curriculum 10.1 – Hypercoagulable States, 17.1 – Oncology
November 30, 2016 15:00 - 16:00 UTC
Tilman Hackeng "TFPI and the Coagulation Pathway"
Nigel Mackman "TF in Inflammation and Infection"
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Tilman Hackeng (1962) studied chemistry with major biochemistry at the University of Utrecht, The Netherlands. He obtained his Ph.D. with Prof. Bouma at the same University in 1993 on studying protein C/protein S anticoagulant activities on endothelial cells. Shortly after, he left for The Scripps Research Institute, La Jolla, CA, USA, were he worked in the laboratories of Profs. Griffin (Molecular & Experimental Medicine) and Kent (Chemistry). In 1998 he returned to the Netherlands as a Research Fellow of the Royal Netherlands Academy of Arts and Sciences (KNAW) at the Department of Biochemistry with Prof. Rosing at the Cardiovascular Research Institute of the University Maastricht (CARIM). In 2001 he was awarded a senior researcher status and fellowship from the KNAW, followed by a VIDI personal grant from the Netherlands Organisation for Scientific Research in 2002.
Currently, he is head of the Department of Biochemistry, board member of CARIM and vice director of CARIM. His group studies the anticoagulant protein C/protein S/TFPI pathways and applies total chemical protein synthesis to structure-function analysis of coagulation proteins. In addition his group designs and synthesizes peptide/protein-based contrast agents for targeted molecular imaging of thrombotic disease. He has published 134 Wi-1 papers with an average impact factor of 6.8 and an h-index of 40 (WoS). He has supervised 17 PhD students.
He is section editor at Thrombosis & Haemostasis, editorial board member at Thrombosis Journal, and reviewer at Blood; the Journal of Thrombosis and Haemostasis; Angewandte Chemie International Edition; Thrombosis Research; Bioconjugate Chemistry; Tetrahedron Letters; BBA - Molecular Basis of Disease; International Journal of Molecular Sciences; Arteriosclerosis Thrombosis and Vascular Biology; Bioorganic & Medicinal Chemistry; Haemophilia; and the Journal of the American Chemical Society.
He and his research group have been awarded ISTH young investigator awards in 1991 (Hackeng); 1995 (Hackeng); 2003 (Koenen); 2003 (Seré); 2011 (Winckers); 2013 (Winckers); 2013 (Peraramelli), an ASH Travel Award in 1996 (Hackeng); the Novo Haemostasis award in 2005 (Seré & Hackeng), NVTH awards for scientific excellence in 2007 (Maurissen); 2011 (Winckers); 2011 (Peraramelli). He has received the ISTH Ratnoff MacFarlane Plenary award in 2013. In addition, he has given more than 40 invited lectures at international conferences.
As a member of professional organisations he is involved in the International Society on Thrombosis and Haemostasis as co-chair of the SSC Plasma Coagulation Inhibitors from 2009-2013, as regular abstract reviewer, as member of the Local Organizing Committee ISTH 2013, and as member of the International advisory board and Scientific topic program member at ISTH 2017. In addition he is past treasurer and past president of the Netherlands Society on Thrombosis and Hemostasis (NVTH). He is member of the American Chemical Society and the Royal Netherlands Society of Chemistry, and he became elected member of the Royal Netherlands Society of Sciences and Humanities (KHMW) in 2014.
In my early career, I studied bacterial pathogenesis. For the past 25 years, I have been studying tissue factor (TF), which is the primary cellular initiator of the blood coagulation cascade. I cloned the human TF gene in 1989 and characterized the transcription factor binding sites that regulate TF gene expression in difference cell types. My lab studies the role of TF, coagulation proteases and protease activated receptors (PARs) in hemostasis, thrombosis, inflammation, ischemia-reperfusion injury, cancer, sickle cell disease, viral infection and atherosclerosis. We have generated several unique mice that have altered levels of TF for these studies. We found that mice with reduced levels of TF exhibit spontaneous bleeding in certain tissues and this led us to propose a model of tissue-specific hemostasis. We have determined that TF expression by both monocytes and non-hematopoietic cells leads to activation of coagulation during endotoxemia. In addition, TF, coagulation proteases and PARs contribute to acute injury and remodeling following cardiac ischemia-reperfusion injury. Currently, we are studying the role of tumor-derived TF-positive microparticles in venous thrombosis in mouse models of pancreatic cancer. Our studies suggest that elevated levels of TF-positive microparticles are a novel biomarker for venous thrombosis in cancer patients. Hyperlipidemia also induces monocyte TF expression and release of TF-positive microparticles that might enhance thrombosis after rupture of an atherosclerotic plaque. Recently, we have demonstrated that TF activates coagulation and enhances inflammation in a mouse model of sickle cell disease. Our most recent studies have revealed that the TF-thrombin-PAR-1 pathway plays a role in the innate response to viral infection. Recent studies have demonstrated a role of TF and PAR2 in diet induced obesity. We are currently studying the mechanism by which this pathway contributes to obesity and insulin resistance. I have trained 24 postdoctoral fellows, 4 medical students and 1 graduate student. Currently, I supervise 4 postdoctoral fellows and 1 MD/PhD graduate student.
In 2007, I moved to UNC-Chapel Hill. My primary appointment is in Medicine, but I also have joint appointments in the Departments of Pharmacology and Pathology and Laboratory Medicine, which allows me to accept graduate students. I am Director of the UNC McAllister Heart Institute, which runs a joint symposium once a year with the Integrative Biology Program. I am co-Director of the Thrombosis and Hemostasis Program, which has a large number of members and runs an active seminar program.