Coagulation (clotting) is the process by which blood changes from a liquid to a gel, forming a clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism of coagulation involves activation, adhesion, and aggregation of platelets along with deposition and maturation of fibrin. Disorders of coagulation can result in bleeding (hemorrhage or bruising) or obstructive clotting (thrombosis).


Coagulation Cascade

diapharma chromogenic clotting elisa assay test kit

The coagulation cascade of secondary hemostasis has two initial pathways which lead to fibrin formation:

  • contact activation pathway (intrinsic pathway)
  • tissue factor pathway (extrinsic pathway)

The primary pathway for the initiation of blood coagulation is the tissue factor (extrinsic) pathway. Both the tissue factor and contact activation pathways both activate the “final common pathway” of factor X, thrombin and fibrin.

The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin.

The coagulation factors are generally serine proteases (enzymes), which act by cleaving downstream proteins, with some exceptions. FVIII and FV are glycoproteins, and Factor XIII is a transglutaminase. The coagulation factors circulate as inactive zymogens.


Tissue Factor Pathway (Extrinsic Pathway)

The main role of the tissue factor pathway is to generate a “thrombin burst”, a process by which thrombin, the most important constituent of the coagulation cascade in terms of its feedback activation roles, is released very rapidly. FVIIa circulates in a higher amount than any other activated coagulation factor. The process includes the following steps:

  • Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor (TF) expressed on tissue-factor-bearing cells (stromal fibroblasts and leukocytes), forming an activated complex (TF-FVIIa).
  • TF-FVIIa activates FIX and FX.
  • FVII is itself activated by thrombin, FXIa, FXII and FXa.
  • The activation of FX (to form FXa) by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI).
  • FXa and its co-factor FVa form the prothrombinase complex, which activates prothrombin to thrombin.
  • Thrombin then activates other components of the coagulation cascade, including FV and FVIII (which forms a complex with FIX), and activates and releases FVIII from being bound to vWF.
  • FVIIIa is the co-factor of FIXa, and together they form the “tenase” complex, which activates FX

Contact Activation Pathway (Intrinsic Pathway)

The contact activation pathway begins with formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and FXII (Hageman factor).

  • Prekallikrein is converted to kallikrein and FXII becomes FXIIa.
  • FXIIa converts FXI into FXIa.
  • Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa.

The minor role that the contact activation pathway has in initiating clot formation can be illustrated by the fact that subjects with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding disorder. Instead, contact activation system seems to be more involved in inflammation, and innate immunity.


Final Common Pathway

coagulation intrinsic extrinsic common pathway clot formation

Following activation by the contact factor or tissue factor pathways, the coagulation cascade is maintained in a prothrombotic state by the continued activation of FVIII and FIX to form the tenase complex, until it is down-regulated by the anticoagulant pathways.


Coagulation Factors

Factor / name

Alternate name

Function

Associated Genetic Disorders

Alpha 2-Antiplasmin α2-antiplasmin,   plasmin inhibitorInhibits plasminAntiplasmin deficiency
AntithrombinAntithrombin III, AT, ATIIIInhibits Factor IIa, Xa, and other proteasesAntithrombin III deficiency
Cancer ProcoagulantPathological factor X activatorlinked to thrombosis in cancer
Factor IFI, FibrinogenBlood clot formation (Fibrin)Congenital afibrinogenemia,
Familial renal amyloidosis
Factor IIFII, ProthrombinFactor IIa activates I, X, VII, VIII, XI, XIII, protein C, plateletsProthrombin G20210A,
Thrombophilia
Factor IIIFIII, Tissue Factor, Tissue ThromboplastinCo-factor of VIIa (formerly known as Factor III)
Factor IVFIV, CalciumRequired for coagulation factors to bind to phospholipid (formerly known as factor IV)
Factor VFV, Proaccelerin, Labile factorCofactor of X with which it forms prothrombinase complexActivated protein C resistance
Factor VIFVI, Factor VaUnassigned
Factor VIIFVII, Stable Factor, ProconvertinActivates Factor IX, XCongenital proconvertin / Factor VII Deficiency
Factor VIIIFVIII, Antihemophilic Factor A, AHFCofactor of IX with which it forms tenase complexHaemophilia A
Factor IXFIX, Antihemophilic factor B, Christmas FactorActivates Factor X, forms tenase complex with Factor VIIIHaemophilia B
Factor XFX, Stuart-Prower FactorActivates Factor II, forms prothrombinase complex with Factor VCongenital Factor X deficiency
Factor XIFXI, Plasma Thromboplastin AntecedentActivates Factor IXHaemophilia C
Factor XIIFXII, Hageman FactorActivates Factor XI, VII and PrekallikreinHereditary angioedema type III
Factor XIIIFXIII, Fibrin-Stabilizing FactorCrosslinks FibrinCongenital Factor XIIIa/b deficiency
FibronectinMediates cell adhesionGlomerulopathy with fibronectin deposits
Heparin Cofactor IIHCIIInhibits Factor IIa, cofactor for heparin and dermatan sulfate (“minor antithrombin”)Heparin cofactor II deficiency
High Molecular Weight KininogenHMWK, HK, Fitzgerald FactorSupports reciprocal activation of Factor XII, XI, and prekallikreinKininogen deficiency
Plasminogen PLGConverts to plasmin, lyses fibrin and other proteinsPlasminogen deficiency
type I (ligneous conjunctivitis)
Plasminogen Activator Inhibitor-1PAI1, PAI-1Inactivates tPA & urokinase (endothelial PAI)Plasminogen activator inhibitor-1 deficiency
Plasminogen Activator Inhibitor-2PAI2, PAI-2Inactivates tPA & urokinase (placental PAI)
PrekallikreinFletcher FactorActivates Factor XII and prekallikrein; cleaves HMWKPrekallikrein/Fletcher Factor deficiency
Protein CPC, autoprothrombin IIA, Factor XIVInactivates Factor Va and VIIIaProtein C deficiency
Protein SPSCofactor for activated protein C (APC, inactive when bound to C4b-binding protein)Protein S deficiency
Protein ZPZ, PROZMediates thrombin adhesion to phospholipids and stimulates degradation of factor X by ZPIProtein Z deficiency
Protein Z-related Protease InhibitorZPIDegrades Factors X (in presence of protein Z) and XI (independently)
Tissue Plasminogen ActivatortPAActivates plasminogenFamilial hyperfibrinolysis and thrombophilia
UrokinaseUKActivates plasminogenQuebec platelet disorder
von Willebrand FactorvWFBinds to Factor VIII, mediates platelet adhesionvon Willebrand disease

 


Cofactors

  • Calcium and phospholipid
  • Vitamin K

Regulators

  • Protein C
  • Antithrombin
  • Tissue factor pathway inhibitor (TFPI)
  • Plasmin
  • Prostacyclin (PGI2)

View the Diapharma special coagulation presentation