Plasma Kallikrein-Kinin System

30 June 2006
Oslo Kongressenter, Norway

Chairman:  K. R. McCrae, USA
Co-Chairs: D. Gailani , USA ; A. H. Schmaier, USA

The 2006 SSC plasma kallikrein-kinin subcommittee was attended by approximately 20 individuals. Several discussions were presented, as outlined below:

Dr. Alvin Schmaier discussed the interactions of high molecular weight kininogen with endothelial cells, and its binding to a multiprotein complex consisting of uPAR, gC1qR and CK1. The activation of prekallikrein on cell surfaces by prolylcarboxypeptidase was reviewed and updated. The mechanisms by which BKB2R deficient mice are protected from thrombosis was discussed in detail. The working hypothesis for this observation involves increased levels of Ang >II interacting with AT2R, which are upregulated in several tissues, leading to vasodilation, increased NO and PGI2. Also, preliminary evidence suggests that BK1-5 may impair platelet function.

Dr. Thomas Renne discussed clinical studies on hereditary angioedema, including a new Type III variant that may result from a Thr347Lys mutation in FXII, leading to increased FXIIa proteolytic activity. The remainder of the presentation focused on thrombosis in the FXII deficient mouse, which is not prone to increased bleeding, but fails to form occlusive thrombi. The latter observation appears to result from failure to stabilize the initial platelet aggregates at the site of vessel damage. These mice also have markedly smaller infarcts in and induced stroke model, with less vessel occlusion. The relationship of these observations to the human situation was discussed at length by the audience.

Dr David Gailani update his work on mice deficient in FXII, FXI or FIX, in particular those deficient in FXI. These mice are protected from thrombosis to an extent caused only by high concentrations of heparin in the range of 200 U/ml. These animals display both decreased fibrin deposition as well as decreased platelet consumption in thrombosis induced by FeCl3. Interesting studies designed to test the hypothesis that FIX deficiency would protect against the pathology of plg deficiency were presented, based on crosses of mice deficient in both. These mice did have increased survival compared to plg deficiency alone. However, FXI deficiency worsens the outcome in plg deficient mice, and crossed mice develop a marked inflammatory process in the lung. Finally, a discussion of the genetics of human FXI deficiency was presented, with findings suggesting that specific FXI mutations may impair FXI secretion in a dominant manner by forming heterodimers with normal FXI monomers and impairing cellular secretion.

Dr. Robert Colman was scheduled to speak but was unable to attend the SSC meeting.

Dr. Keith McCrae presented additional information concerning the mechanisms by which two chain HK impairs angiogenesis and causes apoptosis of proliferating endothelial cells. This process is associated with enhanced cellular oxidant stress, and may also involve activation of cellular MMPs. Studies describing kininogen deficient mice were also presented. The first of two kininogen genes have been deleted, yielding viable mice. Studies suggest that this gene is solely responsible for plasma kininogen, and that though gene 2 is transcribed it appears to yield little if any protein. Possible reasons for this were discussed. Future studies with these mice were discussed with other members of the subcommittee.

Dr. David Pritchard discussed studies of several forms of FXIIa in acute cardiac ischemia. Two forms of FXIIa were measured-FXIIaA and FXIIaR. The latter is available only after release by chemical treatment of plasma. The biochemical nature of these forms of FXIIa have not yet been characterized in detail. However, in the RACS study, upper quartile levels of FXIIaR are strongly associated with risk of recurrent MI within 30 days. Moreover, high levels of FXIIaA are associated with increased risk for 30 day mortality as well as death and recurrent MI at 1 year. The implications of these findings and the biochemical nature of FXIIaA and FXIIaR were discussed at length by the subcommittee.

Dr Zia Shariat-Madar discussed the implication of sepsis to activation of the KKS. In particular he reported that HK binds with significant affinity to bacterial LPS at physiological pH. This is blocked by the HKH20 peptide. The sentinel observation was that LPS appears to increase the expression of prolycarboxypeptidase by human endothelial cells, suggesting one mechanism whereby the kallikrein-kinin system may undergo enhanced activation in sepsis.

At the conclusion of the meeting the possibility of developing a FXII plasma standard was raised. Dr. McCrae will discuss these further with several subcommittee members and the subcommittee will consider this objective over the coming year.

Submitted by Keith McCrae 7/01/06