Tracking down contact activation – from coagulation in vitro to inflammation in vivo

Abstract

Summary The contact system is a volatile and versatile enzyme system in blood plasma that responds to the presence of nonphysiological surface materials by spontaneous generation of enzymatic activity. In subsequent steps, it can trigger blood coagulation and is responsible for the generation of the proinflammatory peptide bradykinin. The physiological role of the contact system is presently unknown, but it is commonly used to trigger coagulation in a diagnostic setting. In this three‐part review, we will first describe the molecular mechanisms that drive contact activation on nonphysiological materials. Next, we will summarize and compare a number of bioassays, which are commonly used to investigate the contact system in health and disease. Finally, we will discuss recent findings from both fundamental and clinical studies on the contributions of contact system to cardiovascular, infectious, and inflammatory disease.

A comparison of the effects of factor XII deficiency and prekallikrein deficiency on thrombus formation

“…The zymogens FXII and PK and the non-enzymatic cofactor HK comprise the plasma kallikrein-kinin system [1–4]. FXII was identified as a plasma constituent missing in a patient with a defect in surface-induced plasma coagulation, but with no symptoms of a bleeding disorder [25].…”

“…FXII was identified as a plasma constituent missing in a patient with a defect in surface-induced plasma coagulation, but with no symptoms of a bleeding disorder [25]. It is now clear that FXII is not required for hemostasis [1–4,25]. While relatively few patients with PK or HK deficiency have been described, these conditions, like FXII deficiency, are not associated with a bleeding diathesis [25,36,37].…”

“…Factor XIIa (FXIIa) is a plasma protease that contributes to a number of host-defense processes, including thrombin generation and inflammation [1–4]. Conversion of zymogen factor XII (FXII) to factor XIIa may be initiated when blood is exposed to a variety of compounds and surfaces including polyanions released from activated platelets and damaged tissues [5–8], cell walls and membranes of microbial pathogens [9], and materials used in medical devices [10,11].…”

Pathophysiology of Hereditary Angioedema

“…1). 33 In vitro activation of the contact system is used to measure activated partial thromboplastin time (aPTT), while the best characterized event associated with its in vivo activation is angioedema due to C1-INH deficiency. It has been shown that the increase in BK plasma levels during attacks is due to local production of BK as a result of inappropriate activation of systems controlled by C1-INH.…”

“…43 Experimental results have shown that FXII may pivot contact system activation in vivo similar to the mechanism observed in vitro, suggesting that the enzymatic activity of FXII may initiate contact activation. 33,44 Moreover, other studies have shown that FXII can be activated in vivo by substances such as platelets polyphosphates and heparin-activated mast cells, thus ensuring efficient activation of the contact system. 45,46 Thus, it is possible that these mechanisms of contact activation specifically contribute to angioedema formation.…”