SCIENTIFIC SUBCOMMITTEE SESSION
7 July 2007 Palexpo, Geneva, Switzerland

Plasma Kallikrein-Kinin System

Chair: K. McCrae ( USA)
Co-Chairs D. Gailani ( USA), T. Rennè ( Germany), A. Schmaier ( USA)

The Kallikrein-Kinin subcommittee met on July 7, 2007 in the Mont-Blanc room of Palexpo. The session was extremely well attended, with more than 80 participants, surely a new record for this subcommittee. The session was introduced by the current chair, Dr. McCrae who reviewed the procedure for an ISTH publication, and suggested the possibility of the group preparing a manuscript on the role of the KKS in thrombosis. Follow up with specific group members will be obtained after the meeting.

The meeting then proceded with a number of scientific publications, each of which was followed by a lively discussion. A brief synopsis of these presentations is provided below.

Dr. Keith McCrae discussed the role of kininogen in the regulation of angiogenesis, particularly with respect to the newly developed mouse model in which one of the two kininogen genes has been deleted. These animals display abnormalities in angiogenesis and tumor growth, though the underlying mechanisms have not yet been defined.

Dr. Alvin Schmaier discussed the mechanisms by which BKB2 receptor deficient mice are protected from thrombosis. These include the increased generation of the BK derived peptide RPPGF, which inhibits thrombin and thrombin signaling through PARs, as well as increased generation of NO and PGI2 mediated through the AT2R. He also described preliminary studies in the PRCP deficient mouse, which is prothrombotic.

Dr. Thomas Renne discussed a number of studies relating to the KKS and thrombosis. A number of studies were presented demonstrating that deficiency of FXI and FXII reduced cerebral damage in stroke models. He also discussed the role of naturally occurring polyphosphates as physiologic activators of FXII, and described studies demonstrating that FXII deficiency was protective in a murine model of polyphosphate-induced lethal pulmonary embolism.

Dr. Heiko Herwald discussed the role of the KKS in gram positive and gram negative bacterial infections. Bacteria activate several KKS system proteins, including factor XII and HK, and elevated levels of activated factors and BK are observed in sepsis. Moreover, HK derived peptides, including the HKH20 peptide are potent antibacterial agents, with killing activity similar to that of defensins.

Dr. Jonas Emsley discussed structural aspects of FXI and prekallikrein. Several aspects of the crystal structures of these proteins account for their similarity and differences. For example, a gly(FXI)-cys (PK) difference at position 321 explains the ability of FXI, but not PK, to dimerize. Activation of PK by prolylcarboxypeptidase was difficult to explain on a purely structural basis given the location of the putative PRCP cleavage site on PK.

Dr. Robert Colman discussed the role of HK domain 5 on angiogenesis and inflammation. Studies in a 3D collagen-fibrin gel system suggested that the major antiangiogenic mechanism of HKa reflects its ability to inhibit endothelial cell migration rather than induce endothelial cell apoptosis. This may be mediated through ERK activation. In terms of inflammation, HKa induced the secretion of multiple cytokines from monocytes, including MCP-1 and IL-8. The receptor for these activities has not been defined, but signaling through jnk, NFKB and p38 MAPK, but not ERK, appears to be involved.

Dr. David Pritchard discussed studies using a new antibody that is highly specific for FXIIa. Whether this antibody reacts with FXIIa from other species has not yet been determined, though it stains fixed tissue strongly for FXIIa. The relevance of FXIIa measurements in a number of ACS studies were also described. Interesting, the fourth quartile of FXIIa is an independent risk factor for death in most of these studies, and has strongest prognostic activity n the subgroup of patients presenting with chest pain, but without increased tropomyosin in plasma—i.e. those in whom acute MI was ruled out.

Dr Jose’ W.P. Govers-Riemslag discussed the topic of whether the KKS system is relevant to clinical thrombosis. Discrepant results for this question have been described in a number of clinical studies. The hypothesis that a U-shaped curve may account for these abnormalities was presented. At low FXIIa levels, fibrinolysis may be decreased, while at high levels coagulant processes are significantly stimulated. For FXII in the middle quartiles, risk may not be significantly changed.

A brief discussion was held at the end of the meeting on whether the KKS subcommittee would be the appropriate subcommittee to champion a C1 esterase inhibitor standardization project. It was felt that this would be appropriate.