B8 The contact system in liver: an interface of inflammation, innate immunity and coagulation

B8_April 2014

Principal Investigator:
Prof. Dr. med. Dr. rer. nat. Thomas Renné
Institut für Klinische Chemie und Laboratoriumsmedizin
Universitätsklinikum Hamburg-Eppendorf
Martinistr. 52
20246 Hamburg
Tel.: +49-40-7410-52981
E-Mail: t.renne@uke.de

Project description

Coagulation and inflammation are considered as two distinct pathologies but they closely interact at multiple levels. Understanding the role of coagulation in inflammation and the impact of inflammation on coagulation will introduce new perspectives to improve diagnostics and therapies for both disease states.

Coagulation factor XII (FXII) is synthesized by hepatocytes, secreted into plasma and gets activated by “contact” to charged surfaces. Despite its crucial importance for generating fibrin in vitro, it is widely accepted that FXII does not contribute to hemostasis (coagulation mechanism that prevents blood loss from injuries), since FXII-deficiency is not associated with excessive bleeding.

B8 in 60 SecondsVideoarchiv

online seit 21.02.2014
Ein Thrombus an den Oxygenatormembranen einer speziellen Herz-Lungenmaschine
Figure 1: A thrombus at the oxygenating membranes of a special heart-lung machine (Kjell Hultenby, Karolinska Stockholm)

Our laboratory developed the first murine knockout model of FXII. Thrombus formation in FXII-/- mice was largely defective and the animals were protected from experimental thrombotic disease without interfering with hemostasis. We have identified polyphosphate (an inorganic polymer), as in vivo FXII activator with implications on the initiation of thrombosis and infection-associated edema. We recently have developed the FXII neutralizing antibody 3F7 that interferes with FXII-mediated inflammatory and procoagulant pathologies in preclinical models.

The goal of this proposal is to define the in vivo functions of FXII and its activator polyphosphate for liver inflammatory and infectious disease states. The sum of these studies will indicate in vivo FXII functions not previously appreciated and will result in a new therapeutic approach to anti-inflammation and selective thrombi-protection.

Related news:

Nickel KF, Long AT, Fuchs TA, Butler LM, Renné T

Factor XII as a Therapeutic Target in Thromboembolic and Inflammatory Diseases
Arterioscler Thromb Vasc Biol. 2017 Jan;37(1):13-20. doi: 10.1161/ATVBAHA.116.308595.

Labberton L, Kenne E, Long AT, Nickel KF, Di Gennaro A, Rigg RA, Hernandez JS,Butler L, Maas C, Stavrou EX, Renné T

Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection
Nat Commun. 2016 Sep 6;7:12616. doi:10.1038/ncomms12616

Long AT, Kenne E, Jung R, Fuchs TA, Renné T

Contact system revisited: an interface between inflammation, coagulation, and innate immunity
J Thromb Haemost. 2016 Mar;14(3):427-37. doi: 10.1111/jth.13235. Epub 2016 Feb 9. Review.

Worm M, Köhler EC, Panda R, Long A, Butler LM, Stavrou EX, Nickel KF, Fuchs TA, Renné T

The factor XIIa blocking antibody 3F7: a safe anticoagulant with anti-inflammatory activities
Ann Transl Med. 2015 Oct;3(17):247. doi:10.3978/j.issn.2305-5839.2015.09.07. Review.