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 inhibitor Inhibits plasmin Antiplasmin deficiency
Antithrombin Antithrombin III, AT, ATIII Inhibits Factor IIa, Xa, and other proteases Antithrombin III deficiency
Cancer Procoagulant Pathological factor X activator linked to thrombosis in cancer
Factor I FI, Fibrinogen Blood clot formation (Fibrin) Congenital afibrinogenemia,
Familial renal amyloidosis
Factor II FII, Prothrombin Factor IIa activates I, X, VII, VIII, XI, XIII, protein C, platelets Prothrombin G20210A,
Thrombophilia
Factor III FIII, Tissue Factor, Tissue Thromboplastin Co-factor of VIIa (formerly known as Factor III)
Factor IV FIV, Calcium Required for coagulation factors to bind to phospholipid (formerly known as factor IV)
Factor V FV, Proaccelerin, Labile factor Cofactor of X with which it forms prothrombinase complex Activated protein C resistance
Factor VI FVI, Factor Va Unassigned
Factor VII FVII, Stable Factor, Proconvertin Activates Factor IX, X Congenital proconvertin / Factor VII Deficiency
Factor VIII FVIII, Antihemophilic Factor A, AHF Cofactor of IX with which it forms tenase complex Haemophilia A
Factor IX FIX, Antihemophilic factor B, Christmas Factor Activates Factor X, forms tenase complex with Factor VIII Haemophilia B
Factor X FX, Stuart-Prower Factor Activates Factor II, forms prothrombinase complex with Factor V Congenital Factor X deficiency
Factor XI FXI, Plasma Thromboplastin Antecedent Activates Factor IX Haemophilia C
Factor XII FXII, Hageman Factor Activates Factor XI, VII and Prekallikrein Hereditary angioedema type III
Factor XIII FXIII, Fibrin-Stabilizing Factor Crosslinks Fibrin Congenital Factor XIIIa/b deficiency
Fibronectin Mediates cell adhesion Glomerulopathy with fibronectin deposits
Heparin Cofactor II HCII Inhibits Factor IIa, cofactor for heparin and dermatan sulfate (“minor antithrombin”) Heparin cofactor II deficiency
High Molecular Weight Kininogen HMWK, HK, Fitzgerald Factor Supports reciprocal activation of Factor XII, XI, and prekallikrein Kininogen deficiency
Plasminogen  PLG Converts to plasmin, lyses fibrin and other proteins Plasminogen deficiency
type I (ligneous conjunctivitis)
Plasminogen Activator Inhibitor-1 PAI1, PAI-1 Inactivates tPA & urokinase (endothelial PAI) Plasminogen activator inhibitor-1 deficiency
Plasminogen Activator Inhibitor-2 PAI2, PAI-2 Inactivates tPA & urokinase (placental PAI)
Prekallikrein Fletcher Factor Activates Factor XII and prekallikrein; cleaves HMWK Prekallikrein/Fletcher Factor deficiency
Protein C PC, autoprothrombin IIA, Factor XIV Inactivates Factor Va and VIIIa Protein C deficiency
Protein S PS Cofactor for activated protein C (APC, inactive when bound to C4b-binding protein) Protein S deficiency
Protein Z PZ, PROZ Mediates thrombin adhesion to phospholipids and stimulates degradation of factor X by ZPI Protein Z deficiency
Protein Z-related Protease Inhibitor ZPI Degrades Factors X (in presence of protein Z) and XI (independently)
Tissue Plasminogen Activator tPA Activates plasminogen Familial hyperfibrinolysis and thrombophilia
Urokinase UK Activates plasminogen Quebec platelet disorder
von Willebrand Factor vWF Binds to Factor VIII, mediates platelet adhesion von 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