Reactome: A Curated Pathway Database

Intrinsic Pathway of Fibrin Clot Formation (R-HSA-140837) [Homo sapiens]


The intrinsic pathway of blood clotting connects interactions among kininogen (high molecular weight kininogen, HK), prekallikrein (PK), and factor XII to the activation of clotting factor X by a series of reactions that is independent of the extrinsic pathway and that is not subject to inhibition by TFPI. It is thus essential for the prolongation of the clotting cascade: while the reactions of the extrinsic pathway appear to be sufficient to initiate clot formation, those of the intrinsic pathway are required to maintain it (Broze 1995; Davie et al. 1991; Monroe et al. 2002). The intrinsic pathway can be divided into three parts: 1) reactions involving interactions of kininogen, prekallikrein, and factor XII, leading to the activation of factor XII, 2) reactions involving factor XI, factor IX, factor VIII, and von Willebrand factor (vWF) leading to the activation of factors VIII and IX, and 3) reactions that inactivate factor XIIa and kallikrein.

Kininogen, prekallikrein, and factor XII were first identified as proteins needed for the rapid formation of clots when whole blood is exposed to negatively charged surfaces in vitro. Studies in vitro have identified several possible sets of interactions, in which small quantities of one or more of these proteins 'autoactivate' and then catalyze the formation of larger quantities of activated factors. Recent work, however, suggests that these factors form complexes on endothelial cell surfaces mediated by C1q binding protein (C1q bp), that the first activation event is the cleavage of prekallikrein by prolylcarboxypeptidase, and that the resulting kallikrein catalyzes the activation of factor XII (Schmaier 2004).

The second group of events, occurs in vivo on the surfaces of activated platelets (although most biochemical characterization of the reactions was originally done with purified proteins in solution). Factor XI binds to the platelet glycoprotein (GP) Ib:IX:V complex, where it can be activated by cleavage either by thrombin (generated by reactions of the common pathway) or by activated factor XII (generated in the first part of the intrinsic pathway). Activated factor XI in turn catalyzes the activation of factor IX. Simultaneously, factor VIII, complexed with vWF, is cleaved by thrombin, activating it and causing its release from vWF. Activated factors VIII and IX form a complex on the platelet surface that very efficiently converts factor X to activated factor X. (Activated factors X and V then form a complex that efficiently activates thrombin.)

While these two groups of events can be viewed as forming a single functional pathway (e.g., Davie et al. 1991), human clinical genetic data cast doubt on this view. Individuals deficient in kininogen, prekallikrein, or factor XII proteins exhibit normal blood clot formation in vivo. In contrast, deficiencies of factor XI can be associated with failure of blood clotting under some conditions, and deficiencies of vWF, factor VIII, or factor IX cause severe abnormalities - von Willebrand disease, hemophilia A, and hemophilia B, respectively. These data suggest that while the second group of events is essential for normal clot formation in vivo, the first group has a different function (e.g., Schmaier 2004).

Finally, reactions neutralize proteins activated in the first part of the intrinsic pathway. Kallikrein forms stable complexes with either C1 inhibitor (C1Inh) or with alpha2-macroglobulin, and factor XIIa forms stable complexes with C1Inh. The relevance of these neutralization events to the regulation of blood clotting is unclear, however. The physiological abnormalities observed in individuals who lack C1Inh appear to be due entirely to abnormalities of complement activation; blood clotting appears to proceed normally. This observation is consistent with the hypothesis, above, that factor XIIa plays a limited role in normal blood clotting under physiological conditions.

These events are outlined in the drawing: black arrows connect the substrates (inputs) and products (outputs) of individual reactions; blue lines connect activated enzymes to the reactions they catalyze.

Additional Information
Compartment extracellular region
GO Biological Process blood coagulation, intrinsic pathway (0007597)
Cross References
Database Identifier
BioModels Database BIOMD0000000340, BIOMD0000000338, BIOMD0000000339
Literature References
pubMedId Title Journal Year
7598447 Tissue factor pathway inhibitor and the revised theory of coagulation Annu Rev Med 1995
1931959 The coagulation cascade: initiation, maintenance, and regulation Biochemistry 1991
12231555 Platelets and thrombin generation Arterioscler Thromb Vasc Biol 2002
14691562 The physiologic basis of assembly and activation of the plasma kallikrein/kinin system Thromb Haemost 2004