The contact system of blood coagulation

In 1975, three individuals were described with deficiency of high molecular weight kininogen (HK), a precursor of BK. All had a prolonged activated partial thromboplastin time (APTT), a surface-activated clinical coagulation screening test. Studies on the plasma kallikrein-kinin system first focused on defining the procoagulant property of HK, despite the fact that 1) none of these individuals had a hemorrhagic state and 2) it was already known that factor XII and prekallikrein deficiencies were not associated with bleeding. Factor XII and prekallikrein are required for enzymatic cleavage of HK. These plasma proteins together were grouped as the 'contact system' because of the requirement for an artificial surface for their efficient activation (Table 1).

Factor XII is produced by a single gene on chromosome 5. Activation of factor XII by plasma kal-likrein, trypsin or plasmin results in an enzyme with a decreasing size, a decrease in its artificial surface-binding properties, and a decrease in its coagulant activity. There are two major forms of activated factor XII: an 80 kDa protein consisting of two disulfide-linked polypeptide chains (factor Xlla), and factor XII fragment (factor Xllf) a 28-30 kDa protein fragment derived from factor Xlla by removal of its heavy chain. Factor Xllf has no artificial surface-binding properties but retains its enzymatic ability to activate prekallikrein and the first component of the complement CI.

Prekallikrein (PK) is produced by a single gene on chromosome 4. When prekallikrein is cleaved and activated to kallikrein by either factor Xlla or factor Xllf, the active enzyme is composed of two disulfide-linked subunits: a heavy chain of approximately

Table 1 Kallikrein-kinin system

Glycoprotein Molecular weight

Factor XII 80

Factor Xllf 28

Prekallikrein (PK) 88

High molecular weight kininogen (HK) 120

Low molecular weight kininogen (LK) 65

52 kDa and a light chain which occurs as one of two variants of approximately 36 and 33 kDa. At least 75% of PK circulates bound noncovalently to HK. In the absence of factor XII, prekallikrein in vitro will not become activated on an artificial surface.

The human kininogens, HK and low molecular weight kininogen (LK) are proteins with multiple associated activities. HK and LK are the products of a single gene on chromosome 3 as a result of alternative mRNA splicing. HK has been divided into six domains. Domain 1 (which binds calcium) and D2 and D3 (which inhibit cysteine proteases including cathepsins and calpain) form the heavy chain. D4 contains BK. These domains are common to both HK and LK. D5H which binds to artificial surfaces and D6 which binds to prekallikrein and factor XI, form the unique light chain of HK. The function of D5l, the unique light chain of LK, is not known. The activation of the contact system can be better understood on the basis of the multiple interactions between HK and LK with cells, although the in vivo activating agent(s) remains unknown. Both HK and LK are known to bind to platelets, neutrophils and endothelial cells through D3, D4 and D5. On the platelet surface HK inhibits the binding of thrombin and its subsequent induction of platelet aggregation by binding to GPIb. On the neutrophil surface HK inhibits adhesion by competing with fibrinogen for binding to CDllb/CD18 (Mac-1). HK binds to several receptors on endothelial cells which mediate BK release and fibrinolysis (See below).

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