Blood Coagulation

Abstract

The blood coagulation system acts in concert with the platelets to seal damaged blood vessels by the formation of a clot that consists of aggregated platelets interwoven with fibrin. Coagulation is initiated by the subendothelial membrane protein tissue factor and proceeds through a highly regulated proteolytic cascade to the production of thrombin and the fibrin clot. Although stoppage of blood leakage is the primary purpose of the coagulation system, many of the direct products of coagulation have additional functions that involve communicating with surrounding cells and crosstalk with other biochemical systems (i.e. inflammation and immunity). These secondary roles of the coagulation system products are vital for regeneration of tissue normalcy and overall homeostasis. Dysregulation of any of these coagulant system functions can lead to various clinical pathologies.

Key Concepts:

  • The initiator of coagulation, tissue factor, surrounds the vasculature in a protective haemostatic envelope.

  • The cascade design and feedback reactions in blood coagulation serve to rapidly amplify and dampen the response to create a burst of activity rather than a prolonged response.

  • Coagulation throw‐off products serve to signal the surrounding tissue to protect against pathogen invasion as well as initiate wound healing.

Keywords: clotting factors; tissue factor; protease inhibitors; platelets; endothelial cells

Figure 1.

The initiation of clotting by tissue factor (TF): parallel pathways to factor Xa formation, and the feedback role of factor Xa in TF–VIIa generation. Blue arrows denote the action of an enzyme (e.g. TF–VIIa, IXa) in catalysing the reaction pointed to; green arrows indicate the proteolytic reaction being catalysed. Species shown beside an arrow (here, VIIIa and anionic phospholipid, PL) denote required cofactors.

Figure 2.

Prothrombin activation. Activated platelets (P) provide the necessary cofactors, anionic phospholipid (–) and factor Va, required for maximum efficiency of the proteolytic action of factor Xa on prothrombin.

Figure 3.

Fibrin formation and initial polymerisation. Thrombin (IIa) cleaves fibrinopeptides from the central N‐termini of the A α and B β chains of fibrinogen. The ‘fibrin monomer’ formed polymerises to form an initial half‐staggered two‐chain protofibril of fibrin.

Figure 4.

Role of γ‐carboxyglutamic acid (Gla) in the calcium ion‐dependent binding of vitamin K‐dependent factors to anionic phospholipid. Anionic headgroups (e.g. phosphatidylserine) are shown as red circles (–) and neutral headgroups (e.g. phosphatidylcholine) as pink. The protein's peptide chain, on the right, has a pair of Gla residues in sequence.

Figure 5.

Positive feedback controls (red arrows). Activation of TF–VII by factor Xa is essential in initiating the system. Thrombin activates the required cofactors, factors V and VIII. Blue and green arrows are as in Figure .

Figure 6.

Negative feedback controls (red arrows). Inhibition of tissue factor (TF)–VIIa by tissue factor pathway inhibitor (TFPI) first requires reaction with factor Xa, the TFPI–Xa complex formed being the inhibitor of TF–VIIa. The protein C pathway, initiated by thrombin in the presence of thrombomodulin, entails the proteolytic inactivation of factors VIIIa and Va by activated protein C (APC). Protein S plays a cofactor role. Blue and green arrows are as in Figure .

Figure 7.

Crosstalk with other systems. The blood coagulation reactions produce numerous throw‐off products whose presence and levels have the capacity to provide considerable information to surrounding tissue as to the extent and nature of the damage. It is not surprising therefore that some of these throw‐off products have been demonstrated to have secondary roles in linking coagulation with inflammation, immunity and tissue repair/restructuring. The cycle of injury/recovery is affected at nearly all stages by coagulation products: initial triggering and then stoppage of blood loss, signalling cells for cytokine release in proportion to the coagulation response and finally the delicate coordination of procoagulation and anticoagulation during fibrinolysis and wound healing. EC, endothelial cell; ECM, extracellular matrix and TF, tissue factor.

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Further Reading

Amara U, Rittirsch D, Flierl M et al. (2008) Interaction between the coagulation and complement system. In: Lambris JD (ed.) Advances in Experimental Medicine and Biology: Current Topics in Complement II, vol. 632, pp. 68–76. New York: Springer‐Verlag.

Chu AJ (2006) Tissue factor upregulation drives a thrombosis‐inflammation circuit in relation to cardiovascular complications. Cell Biochemistry and Function 24: 173–192.

Levi M and van der Poll T (2010) Inflammation and coagulation. Critical Care Medicine 38: S26–S34.

Mackman N (2009) The many faces of tissue factor. Journal of Thrombosis and Haemostasis 7: 136–139.

Opal SM and Esmon CT (2003) Bench‐to‐bedside review: functional relationships between coagulation and the innate immune response and their respective roles in the pathogenesis of sepsis. Critical Care 7: 23–28.

Riewald M and Ruf W (2003) Science review: role of coagulation protease cascades in sepsis. Critical Care 7: 123–129.

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Neuenschwander, Pierre F, and Jesty, Jolyon(Feb 2011) Blood Coagulation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000904.pub3]