Klinisk kemi och koagulation
Karolinska Universitetssjukhuset, Solna, L2:05
171 76 Stockholm
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.
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.
- Crosstalk of coagulation and inflammation
- Mechanisms, diagnostics and therapy of Hereditary angioedema
- Therapeutics, functions and diagnostics of the prothrombotic and proinflammatory FXII-driven contact system
|Research area||Group leader|
|Cholesterol metabolism||Magnus Axelson|
|Contact activation system||Katrin Nickel|
|Fibrin and Fibrin meshworks||Margareta Blombäck|
|Quality control||Anders Kallner|
|Hemostasiological diagnostics||Jovan Antovic|
|Neutrophil Extracellular Traps (NETS)||Tobias Fuchs|
|Endothelial System Biology||Lynn Butler|
Utvalda publikationer (top 10)
Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection.
Nat Commun 2016 Sep;7():12616
Defective glycosylation of coagulation factor XII underlies hereditary angioedema type III.
J. Clin. Invest. 2015 Aug;125(8):3132-46
The polyphosphate-factor XII pathway drives coagulation in prostate cancer-associated thrombosis.
Blood 2015 Sep;126(11):1379-89
Plasma contact system activation drives anaphylaxis in severe mast cell-mediated allergic reactions.
J. Allergy Clin. Immunol. 2015 Apr;135(4):1031-43.e6
Activation of the factor XII-driven contact system in Alzheimer's disease patient and mouse model plasma.
Proc. Natl. Acad. Sci. U.S.A. 2015 Mar;112(13):4068-73
A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk.
Sci Transl Med 2014 Feb;6(222):222ra17
Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo.
Immunity 2011 Feb;34(2):258-68
Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo.
Cell 2009 Dec;139(6):1143-56
Targeting coagulation factor XII provides protection from pathological thrombosis in cerebral ischemia without interfering with hemostasis.
J. Exp. Med. 2006 Mar;203(3):513-8
Defective thrombus formation in mice lacking coagulation factor XII.
J. Exp. Med. 2005 Jul;202(2):271-81