Contact activation pathway

The other pathway that leads to thrombin formation is by the intrinsic pathway, also termed the contact activation pathway; the name derived from its intriguing initiation mechanism where factor XII undergoes auto-activation triggered by the contact with a surface interface. Ratnoff et al was the first to discover factor XII in 1955 and named it Hageman factor, from the name of the first studied patient with factor XII deficiency. The deficiency was brought to attention when neither blood nor plasma from Mr. Hageman coagulated properly during incubation in test tubes [23]. These primary findings have lead to the unveiling of the contact activation system, regulated by three plasma proteins; factor XII, prekallikrein (PK) and high molecular weight kininogen (HMWK). The pathway is initiated as factor XII binds to a surface and thereby undergoes spontaneous cleavage of its single peptide chain, rendering the zymogen into a fully active serine protease comprised of two polypeptide chains held together by a disulfide bond [24]. Three separate sites on the factor XII molecule have been characterized and proposed to facilitate its important interactions with surfaces [25-27]. The activated factor XII on the surface converts both factor XI and prekallikrein to their activated forms, factor XIa and kallikrein respectively. Factor XII is also a substrate for kallikrein and the pair thereby forms a short reciprocal activation loop, enabling rapid activation of the intrinsic pathway  [28]. Factor XI is not the exclusive substrate for factor XIIa but can also be activated by thrombin and factor XIa [29], and it is the activation by thrombin that is considered to be the physiological relevant pathway since deficiency of factor XI but not that of factor XII results in bleeding tendencies [30, 31]. Factor XI activity are enhanced by association with the platelet membrane [32], and it has been demonstrated that the GPIb-IX-V receptor facilitate binding of factor XI to the platelet surface [33]. Also, the interaction of factor XI and prekallikrein with surfaces are to a large extent mediated by HMWK. The dual function of HMWK; forming complex with factor XI and prekallikrein and binding to surfaces are both crucial for its procoagulant role in coagulation. It has been shown that inhibition of one or the other function by directed monoclonal antibody blocking results in a complete loss of the procoagulant property of HMWK [34]. HMWK is also cleaved during the contact activation process by kallikrein, liberating bradykinin [35], a peptide mediator that induces anti-thrombotic responses in the vascular tissue [36]. The intrinsic pathway activation is propagated downstreams by factor XIa, subsequently activating the vitamin K-dependent zymogen factor IX [37]. Facor IX then activates factor X, the factor that links the intrinsic and extrinsic pathways. Prothrombin can then be converted into active thrombin by the activated factor Xa. However, this initial thrombin formation is limited to proceed at a slow rate since both factor IXa and factor Xa lack their respective cofactor, factor VIIIa and factor Va. Thrombin, but also factor X can convert the pro-cofactors into active cofactors, facilitating the formation of the FIXa:FVIIIa (intrinsic Xase) and the FXa:FVa (prothrombinase) complex on a phospholipid surface [38, 39].  This complex formation is essential for rapid formation of thrombin; its necessity reflected by a ~50,000 fold increase in enzymatic activity for factor XIa [38], and a ~1,000 fold increase for factor Xa [17].  As both complexes become functional, large amounts of thrombin will be generated, converting fibrinogen into fibrin, ultimately resulting in fibrin network formation.
The physiological role of factor XII in haemostasis and thrombosis have for a long time been a subject for investigation, especially since deficiencies in factors VIII, IX and XI from the intrinsic pathway cause bleeding disorders [40], while a deficiency in the first factor in this pathway, factor XII, does not cause any bleeding [23, 31]. Recently a patophysiological role for FXII in thrombosis was proposed as it was showed that FXII-deficient mice do have defective thrombus formation in arterial beds and are protected against thromboembolism induced by collagen and epinephrine [41]. The authors furthermore speculated that FXII-driven thrombin generation might proceed on the platelet surface.
Naturally occurring surfaces that can facilitate the autoactivation of factor XII have also been thoroughly investigated. A recent report presented results that indicate that FXII might be activated by polyphosphate anions released by activated platelets [42].  Another exogenous source of contact activation may be the lipopolysaccharides found on the surface of bacteria during sepsis [43, 44]. Exposed collagen is also a proposed endogenous activator of FXII, and although reported results have pointed both in favor and against this concept, the consensus is that collagen type I, that is found in the subendothelial matrix can facilitate autoactivation of FXII [41, 45, 46].