The contact activation and kallikrein/kinin systems: pathophysiologic and physiologic activities

Abstract

Summary. The contact activation system (CAS) and kallikrein/kinin system (KKS) are older recognized biochemical pathways that include several proteins that skirt the fringes of the blood coagulation, fibrinolytic, complement and renin-angiotensin fields. These proteins initially were proposed as part of the hemostatic pathways because their deficiencies are associated with prolonged clinical assays. However, the absence of bleeding states with deficiencies of factor XII (FXII), prekallikrein (PK) and high-molecular-weight kininogen indicates that the CAS and KKS do not contribute to hemostasis. Since the discovery of the Hageman factor 60 years ago much has been learned about the biochemistry, cell biology and animal physiology of these proteins. The CAS is a pathophysiologic surface defense mechanism against foreign proteins, organisms and artificial materials. The KKS is an inflammatory response mechanism. Targeting their activation through FXIIa or plasma kallikrein inhibition when blood interacts with the artificial surfaces of modern interventional medicine or in acute attacks of hereditary angioedema restores vascular homeostasis. FXII/ FXIIa and products that arise with PK deficiency also offer novel ways to reduce arterial and venous thrombosis without an effect on hemostasis. In summary, there is revived interest in the CAS and KKS due to better understanding of their activities. The new appreciation of these systems will lead to several new therapies for a variety of medical disorders.

Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice

“…Third, we considered changes in the kinin/kallikrein pathway as a mechanism by which low FXII may modulate spontaneous VT. 31 We investigated the impact of low FXII on edema. Edema in the masseter and mandibular area is a clear macroscopically visible feature of spontaneous thrombosis.…”

Cross Talk Pathways Between Coagulation and Inflammation

“…With this information, novel insights are providing unique opportunities for the development of safer approaches to treat thrombo-inflammatory disorders. 176 The contact activation system and the kallikrein-kinin system, often referred to collectively as the plasma contact system, is required for rapid generation of enzymatic activity on the surface of pathological surfaces, damaged cells, and invading pathogens and can trigger coagulation and inflammation. The key components are factor XII, plasma prekallikrein (PPK), and high molecular weight kininogen (HK).…”

Making thrombolysis safer in stroke

“…PKal and FXIIa should, therefore, be considered targets for drug development to improve the safety of fibrinolytic therapy. Although traditionally classified as parts of the intrinsic pathway of blood coagulation, PPK and FXII are not required for hemostasis, 7 and specific PKal Conflict-of-interest disclosure: D.G. has received consultant fees from several pharmaceutical companies (Aronora, Bayer, Dyax, Ionis, Merck, Novartis, Ono) with an interest in inhibition of contact activation proteases for therapeutic purposes.…”

“…6 The KKS includes the plasma proteins PPK and FXII. 7 When the KKS is activated, PPK and FXII are converted to the enzymes PKal and FXIIa (see figure, red arrows). Among its functions, PKal catalyzes cleavage of a third component of the KKS, highmolecular-weight kininogen, generating the peptide BK (see figure, green arrow).…”

“…BK induces vasodilatation and increases vascular permeability and edema formation. 6,7 Infusion of tPA into patients with myocardial infarction increases PKal and BK generation. 8 Local production of BK in a stroke patient receiving tPA could contribute to loss of blood vessel and blood-brain barrier integrity, leading to tissue damage and increased risk of hemorrhagic transformation.…”