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Factor XII and the contact system:
cross-talk between thrombosis and inflammation

Objective

Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system. 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. 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.

The current investigations will explore roles of the FXII-driven contact system at the intersection of procoagulant and proinflammatory pathways using genetically altered murine models. We aim to understand activation, regulation and functions of the system for ischemic heart disease, vascular leakage in Hereditary angioedema, allergic airway inflammation as well as procoagulant reactions driven by bacterial infections in skin and lung.

A key aspect of this proposal will be analysis of common principles, interactions and cross-talk between coagulation and inflammation, to identify novel therapeutic targets. Elucidating the FXII-driven contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory diseases.

Field of science

  • /medical and health sciences/health sciences/inflammatory diseases
  • /natural sciences/biological sciences/biochemistry

Call for proposal

ERC-2012-StG_20111109
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

KAROLINSKA INSTITUTET
Address
Nobels Vag 5
17177 Stockholm
Sweden
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 252 980
Principal investigator
Hans Thomas Renné (Prof.)
Administrative Contact
Therese Kindaker (Mrs.)

Beneficiaries (2)

KAROLINSKA INSTITUTET
Sweden
EU contribution
€ 1 252 980
Address
Nobels Vag 5
17177 Stockholm
Activity type
Higher or Secondary Education Establishments
Principal investigator
Hans Thomas Renné (Prof.)
Administrative Contact
Therese Kindaker (Mrs.)
UNIVERSITAETSKLINIKUM HAMBURG-EPPENDORF
Germany
EU contribution
€ 235 800
Address
Martinistrasse 52
20251 Hamburg
Activity type
Higher or Secondary Education Establishments
Administrative Contact
Susanne Holzhüter (Ms.)