Clinical Chemistry & Blood Coagulation - Thomas RennÚ
Department of Molecular Medicine and Surgery
Research Group Leader
Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of thrombotic disorders affecting the cardiovascular system. Thrombosis - localized clotting of the blood - may occur in the arterial or the venous circulation and has a major medical impact. Acute arterial thrombosis is the proximal cause of most cases of myocardial infarction (heart attack) and of about 80% of strokes, collectively the most common cause of death in the developed world.
Factor XII (FXII, Hageman factor) is a plasma protease that initiates the contact system. This system starts a cascade of procoagulant and proinflammatory reactions via the intrinsic pathway of coagulation, and the bradykinin-producing kallikrein-kinin system, respectively (Figure 1). The biochemistry of the contact system in vitro is well understood, however its in vivo functions are just beginning to emerge.
We have previously demonstrated that FXII is essential for thrombus formation while being dispensable for hemostatic processes that terminate blood loss. Challenging the dogma of a coagulation balance, targeting factor XII protected from cerebral ischemia without interfering with hemostasis. In contrast, excess FXII activity is associated with a life threatening inflammatory disorder, Hereditary angioedema. We recently have identified platelet polyphosphate (an inorganic polymer) and mast cell heparin as in vivo FXII activators with implications on the initiation of thrombosis and edema.
A key aspect of our work is the analysis of common principles, and cross-talk between coagulation and inflammation, to establish new biomarkers and bioassays and to identify novel therapeutic targets.
Figure 1: The factor XII (FXII)-driven contact system. Contact with negatively charged surfaces activates coagulation factor XII (FXII) on leukocytes, bacteria, endothelial cells, and thrombocytes and initiates pro-coagulant and pro-inflammatory protease cascades. FXII triggers fibrin formation through the factor XI (FXI)-driven intrinsic pathway of blood coagulation. Activated FXII initiates the kallikrein-kinin system that generates the pro-inflammatory peptide hormone bradykinin by plasma kallikrein (PK)-mediated cleavage of high molecular weight kininogen (HK). BK triggers intracellular signaling events that increase vascular leakage by Ena/VASP-mediated rearrangements of the endothelial cytoskeleton.
The FXII-driven contact system provides an excellent platform to test basic principles of coagulation and inflammation with new perspectives to improve diagnostics and therapies of thrombotic, inflammatory, infectious and allergic diseases. Insight into contact system functions offers the unique opportunity to develop "safe anticoagulant drugs" that interfere with thrombosis and lack the bleeding risk of all currently used anticoagulant medications. FXII inhibitors will also have beneficial anti-inflammatory potency and block edema formation with crucial clinical implications.
- In vivo functions and diagnostics of the prothrombotic and proinflammatory FXII-driven contact system
- Mechanisms, diagnostics and therapy of Hereditary angioedema
- Role of Ena/VASP proteins for vascular permeability and angiogenesis
|Research Area||Group leader|
|Cholesterol metabolism||Magnus Axelson|
|Contact activation system||Coen Maas/Katrin Nickel|
|Fibrin and Fibrin meshworks||Margareta Blombńck|
|Quality control||Anders Kallner|
|Fibrin modifications||Jan Svensson|
|Hemostasiological diagnostics||Jovan Antovic|