Contact activation system

Contact Activation System (CAS) is a critical component of the innate immune system and the coagulation cascade, playing a pivotal role in inflammation, blood coagulation, and wound healing. The system is initiated when blood comes into contact with negatively charged surfaces, leading to a series of enzymatic reactions that ultimately result in blood clot formation and activation of inflammatory pathways.

Overview

The contact activation system is initiated through the activation of Factor XII (Hageman factor), a plasma protein. Upon encountering negatively charged surfaces, such as those presented by bacterial cell walls, damaged tissue, or artificial surfaces like those found in medical devices, Factor XII undergoes a conformational change and becomes activated (Factor XIIa). This activation marks the start of a cascade involving several other components, including prekallikrein (PK) and high molecular weight kininogen (HK), leading to further activation of the coagulation cascade and the generation of bradykinin, a potent vasodilator involved in inflammatory responses.

Components

The contact activation system consists of the following key components:

• Factor XII: Initiates the cascade upon activation.
• Prekallikrein (PK): Activated by Factor XIIa to kallikrein, which in turn can further activate Factor XII and cleave HK to release bradykinin.
• High Molecular Weight Kininogen (HK): Serves as a cofactor for the activation of prekallikrein and the generation of bradykinin.

Pathway

The activation pathway of the contact system can be summarized as follows: 1. Activation of Factor XII to Factor XIIa upon contact with negatively charged surfaces. 2. Factor XIIa activates prekallikrein to kallikrein. 3. Kallikrein activates more Factor XII, amplifying the response, and cleaves HK to release bradykinin. 4. Bradykinin promotes inflammation, increases vascular permeability, and induces pain.

Additionally, Factor XIIa can initiate the intrinsic pathway of the coagulation cascade by converting Factor XI to Factor XIa, further promoting clot formation.

Clinical Significance

The contact activation system has been implicated in various clinical conditions, including hereditary angioedema, due to excessive bradykinin production, and in the development of thrombosis associated with artificial surfaces used in medical devices. Inhibitors of the contact system components, particularly targeting Factor XIIa, are under investigation for their potential therapeutic benefits in preventing thrombosis without increasing bleeding risk, offering a promising avenue for anticoagulant therapy.

Research Directions

Current research is focused on elucidating the precise mechanisms by which the contact activation system contributes to disease and identifying potential therapeutic targets within the cascade. The development of novel inhibitors that can selectively block components of the contact system without affecting the overall hemostatic balance is a key area of interest.