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1.2.3 Bacterial infection Experimental bacterial infection with Escherichia coli in primates causes hypotension. At high, lethal dosages, this hypotension is irreversible and accompanied by significant consumption of HK. Correspondingly, PK-C1inh complexes in plasma increase, which is indicative for contact system activation. During non-lethal challenges, reversible hypotension occurs. Also here, HK is consumed and PK-C1inh complex levels rise, but not as pronounced as during lethal challenges. While FXII antigen levels remained equal during both types of challenges, an inhibitory monoclonal antibody against FXII effectively blocked contact system activation. This indicates that minute levels of FXIIa can cause significant downstream effects. Animals that were treated with this antibody also showed decreased complement activation, diminished degranulation of neutrophils, and increased survival36, 37. These observations clearly show that the contact system is involved during bacteremia in a coagulation-independent manner. 1.2.4 The contact system during acute phase reactions During acute-phase reactions (inflammation), FXII levels become lowered, while PPK312 and HK levels increase38. The lowered expression of FXII is explained by the inhibiting effect of interleukin-6 on the production of FXII by hepatocytes39. Hence, the changes of contact system proteins in cardiovascular disease may in part be attributed to ongoing acute phase reactions30. 1.2.5 Angioedema In the search for the physiological role of the contact system, lessons can be learned from pathological increases in contact system activity. C1inh controls the contact system enzymes: persons that are deficient in C1inh develop periodical episodes of painful and localized tissue swelling. These may occur in the facial area, hands, feet, but also the intestine and upper airways. These swellings are associated with (locally) increased BK levels, PK- or FXIIa-inhibitor complexes, and cHK. This indicates that increased contact system activation is the underlying cause of angioedema. Infusion of recombinant C1inh, lysine analogs or inhibitors of the kinin B2 receptor can be used for these patients. Interestingly, substitution mutations in the proline-rich region of FXII also cause angioedema, while C1inh activity is normal40. The mechanism behind these mutations is unknown and the trigger that precedes the episodes remains elusive. 1.3 Outline of this thesis This thesis will focus on the plasma contact system, with special attention to the role of factor XII (FXII). The contact system is linked to blood coagulation by the activation of FXI, as well as to inflammation by the production of the inflammatory peptide bradykinin. It has been implicated in multiple disease states, but its natural activation mechanism as well as its physiological role are unknown. Prior to this thesis, the availability of sensitive and specific assays for the study of contact system components in blood was limited. The aim of the work in this thesis is to elucidate the natural mechanism for activation of the contact system, using newly developed analytical methods.
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