The research group Clinical and Experimental Hemostaseology focuses on various basic and translational research projects related to thrombosis and hemostasis.

Members:

• PD Dr. med. Katharina Holstein (Physican)
• Dr. med. Christina Rolling (Physican)
• Dr. med. Minna Voigtländer (Physican)

• Carina Lehr (BTA)
• Judith Regenhardt (BTA)
• Anita Schulenkorf (BTA)

Contact information:

Prof. Dr. med. Florian Langer (Head)
Outpatient coagulation clinic and hemophilia center
II Medical Clinic and Polyclinic
Center for Oncology
University Hospital Hamburg-Eppendorf
Martinistr. 52
20246 Hamburg
Germany

Phone: 040-7410-50664 / -52453
Fax: 040-7410-55193
Email: langer@uke.de

Current and future research projects:

• Mechanisms of coagulation activation in malignancy
  Clotting abnormalities contribute to morbidity and mortality in patients with solid tumors or hematologic malignancies. Our research group is interested in the cellular and molecular mechanisms underlying paraneoplastic coagulation activation. Of particular interest in this regard is the role of tissue factor (TF), the principal initiator of the extrinsic coagulation pathway that is variably expressed by tumor cells and cells of the tumor microenvironment. TF is also released into the bloodstream as a soluble molecule or in association with subcellular membrane vesicles, so-called plasma microparticles, and could thus be used as a diagnostic tool or predictive biomarker. TF-dependent coagulation activation contributes not only to the pathogenesis of cancer-associated thrombosis or complex coagulopathies such as DIC, but also to cancer progression by promoting angiogenesis, primary tumor growth and hematogenous metastasis.

• Posttranslational regulation of the TF-dependent coagulation pathway
  The clotting cascade is regulated on many different levels. While at sites of vessel injury, all components of the extrinsic coagulation pathway must be in place to secure wound sealing (hemostasis), tight control of the TF pathway is required under physiological conditions to prevent pathological clot formation (thrombosis). It is well established that TF resides in a predominantly non-coagulant (i.e. inactive or cryptic) form on intact cells. The molecular mechanisms that underlie cellular TF activation have not been completely resolved. In addition to the translocation of negatively charged phospholipids from the inner to the outer membrane leaflet (e.g. in the context of apoptosis), the posttranslational modification of an intramolecular allosteric disulfide bond within the TF extracellular domain appears to be critically involved in this process. A key enzyme modulating this disulfide bond is protein disulfide isomerase (PDI). In additional research projects, the posttranslational regulation of TF activity by leukocyte-derived proteases is investigated.

• Acquired von Willebrand syndrome in acute leukemias and monoclonal gammopathies Patients with acute leukemia or monoclonal gammopathy have an increased risk of bleeding, which is typically caused by multiple patient- and disease-related factors. Among the letter, quantitative and/or qualitative abnormalities of plasma von Willebrand factor (vWF), which mediates the adhesion of platelets to the injured vessel wall, appear to play an important role. For instance, in patients with plasma cell dyscrasias (e.g. MGUS or multiple myeloma), various pathomechanisms may contribute to the development of an acquired von Willebrand syndrome (AVWS). The specific aims of ongoing research projects are to prospectively determine the prevalence of AVWS in patients with acute leukemias or plasma cell dyscrasias and to further define the underlying pathomechanisms. The overall goal is to improve both diagnosis and treatment of hemorrhagic complications in patients with hematological malignancies.

• Monitoring of antiplatelet therapy
  Pharmacological inhibition of platelet cyclooxygenase-1 (by acetylsalicylic acid, ASA) and the ADP receptor, P2Y12 (e.g. by clopidogrel), is used for the treatment and secondary prevention of cardio- and cerebrovascular thrombosis. The pharmacodynamic effects of these anti-platelet agents are subject to significant intra- and inter-individual variability. The specific aims of ongoing research projects are the characterization of compensatory signaling pathways leading to the attenuation or complete abolishment of pharmacological platelet inhibition and the validation of various platelet function tests used to assess the effects of ASA and ADP receptor antagonists.

• Variability in bleeding severity in hemophilia: causes and consequences
  Hemophilia A and B are X-linked, recessive bleeding disorders caused by congenital factor VIII or IX deficiency, respectively. Although the bleeding tendency largely depends on residual FVIII (FVIII:C) or FIX (FIX:C) clotting activity, there is tremendous heterogeneity in bleeding frequency and severity among individuals with similar FVIII:C or FIX:C plasma levels. It is therefore likely that additional factors modulate thrombin generation and fibrin deposition in patients with congenital hemophilia A or B. Various ongoing research projects are based on the hypothesis that hemostasis in patients with hemophilia is largely based on the activity of the extrinsic coagulation pathway, particularly, since leukocyte production of tissue factor (TF) and the shedding of TF-bearing microvesicles, e.g. as a consequence of inflammatory stimuli, are subject to tremendous inter-individual variability. In addition, platelets appear to modulate TF-dependent hemostasis through the provision of various factors, including protein disulfide isomerase (PDI). Besides detailed characterization of these mechanisms in patients with congenital hemophilia, findings will be correlated with clinically relevant endpoints such as the severity and frequency of bleeding events and the prevalence of hemophilic arthropathy. Furthermore, the effects of (pyscho)social and socioeconomic factors on treatment outcome and quality of life are of particular interest.

• Prof. Dr. Reinhard Schneppenheim, Dr. Johanna Schrum, Dr. Wolf Hassenpflug, Klinik und Poliklinik für Pädiatrische Hämatologie und Onkologie, UKE
• Prof. Dr. Dr. Thomas Renné, Dr. Katrin Nickel, Dr. Tobias Fuchs, Institut für Klinische Chemie und Laboratoriumsmedizin, UKE
• Dr. Sylvia von Mackensen, Institut für Medizinische Psychologie, UKE
• Prof. Dr. Ulrich Budde, Dr. Rita Dittmer, Dr. Sonja Schneppenheim, MEDILYS Laborgesellschaft mbH, Gerinnungslabor, Hamburg
• Dr. Ali Amirkhosravi, Florida Hospital Center for Thrombosis Research, Orlando, FL, USA
• Prof. Dr. Wolfram Ruf, Centrum für Thrombose und Hämostase (CTH), Universitätsmedizin Mainz, und Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA