Coagulation

Coagulation is the thickening or congealing of any liquid into solid clots. This article is about a specific medical usage of the term with reference to human blood's mechanisms for forming scabs over wounds.

The coagulation of human blood is a fairly complex process by which liquid blood becomes solid clots. It is an important part of hemostasis where a damaged blood vessel is ultimately covered by a fibrin clot to stop hemorrhage. Disorders in coagulation can lead to increased hemorrhage on the one side and thrombosis and embolism on the other.

In brief

Ordinarily coagulation is initiated within seconds after an injury occurs when platelets form a plug at the site of injury. This is called primary hemostasis. Following this, various plasma components, called clotting factors respond (in a complex cascade) to form fibrin strands which strengthen the platelet plug.

The use of adsorbent chemicals, such as zeolite, and other hemostatic agents is also being explored for use in sealing severe injuries quickly.

Primary hemostasis

Primary hemostasis is initiated when platelets adhere, using a specific platelet collagen receptor glycoprotein Ia/IIa, to collagen fibers in vascular endothelium. This adhesion is stabilized by von Willebrand factor (vWF), which forms links between the platelet glycoprotein Ib/IX/X and collagen fibrils.

The platelets are then activated to secrete the contents of their granules in to the plasma, which causes a change in their shape. Fibrinogen, which links adjacent platelets by forming links via the glycoprotein IIb/IIIa.

Secondary hemostasis

The coagulation cascade

The coagulation cascade of secondary hemostasis has two pathways, the intrinsic and the extrinsic one, which join in a common pathway that leads to fibrin formation. The pathways are a series of reactions, in which a stable form of a protein is activated to become an enzyme which then catalyzes the next reaction in the cascade. Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form, ultimately resulting in cross-linked fibrin.

The coagulation reaction can be summarised into four reactions:

1. Intrinsic pathway: Formation of the primary complex on collagen by high molecular weight kininogen (HMWK), thrombin, a process that requires Factor Va. Factor V, like VIII, is activated in a positive feedback loop by thrombin itself. Thrombin has a large array of functions. Its main action is the conversion of fibrinogen to fibrin, the building block of a thrombus. In addition, it activates Factors VIII and V and their inhibitor Protein C, and it activates Factor XIII, which crosslinks fibrin polymers which form from activated monomers. In addition, thrombin activates platelets.

Most coagulation factors are serine proteases, which act by cleaving other proteins. Factor XIII is a transglutaminase. Protein C and S, too, are serine proteases.

Cofactors and inhibitors

Various substances are required for the proper functioning of the coagulation cascade:

• Calcium and phospholipid (a cell membrane constituent) are cofactors to the activation of factors VII, IX, X and II.
• Vitamin K is an essential factor to a hepatic decarboxylase that adds a second carboxyl group to glutamic acid residues on factors II, VII, IX and X, as well as Protein S and Protein C. Deficiency of vitamin K (e.g. in malabsorption) or use of inhibiting anticoagulants (warfarin, acenocoumarol and Protein C is an important inhibitor, which degrades F Va and F VIIIa. Its activation by thrombin requires Protein S. Deficiency of either leads to thrombophilia (a tendency to develop thrombosis). Impaired action of Protein C (activated Protein C resistance), for example by Factor V, "Leiden" variant, leads to a milder thrombosis tendency.
• Antithrombin is a serine protease inhibitor (serpin) that degrades the serine proteases thrombin and F Xa, as well as F XIIa, F XIa and F Xa. It is constantly active, but its adhesion to these factors is increased manifold by the presence of heparan sulfate (a glycosaminoglycan) or the medication class of heparins (different heparinoids increase affinity to F Xa, F IIa, or both). Deficiency (inborn or acquired, e.g. in proteinuria) of antithrombin leads to a severe thrombophilia.
• Tissue factor pathway inhibitor (TFPI) inhibits F VIIa-related activation of F IX and F X after its original initiation.

Testing of coagulation

The intrinsic pathway is initiated by activation of contact factors of plasma, and can be measured by the activated partial thromboplastin time (aPTT) test.

The extrinsic pathway is initiated by exposure of blood to "tissue factor" (a specific cellular lipoprotein), and can be measured by the prothrombin time (PT) test, sometimes reported as an INR value.

The common pathway is reached by completion of either or both of the above pathways, and results in the elaboration of thrombin.

If a coagulation factor is part of the intrinsic or extrinsic pathway, a deficiency of that factor will affect only one of the tests: thus hemophilia A, a deficiency of factor VIII, which is part of the intrinsic pathway, results in an abnormally prolonged PT test but a normal PTT test.

Disorders of hemostasis

• disorders of the platelet and vessel wall
  • immune thrombocytopenic purpura (ITP)
  • thrombotic thrombocytopenic purpura (TTP)
  • hemolytic-uremic syndrome (HUS)
  • Glanzmann's thrombasthenia
  • Bernard-Soulier syndrome (abnormal glycoprotein Ib-IX-V complex)
  • storage pool disorders
  • paroxysmal nocturnal hemoglobinuria
  • gray platelet syndrome: deficient alpha granules.
  • delta storage pool deficiency: deficient dense granules.
• disorders of coagulation and thrombosis
  • disseminated intravascular coagulation
  • factor deficiencies
    • hemophilia A
    • hemophilia B ("Christmas disease")
    • hemophilia C (Factor XI deficiency, mild bleeding tendency)
    • Von Willebrand disease (the commonest bleeding disorder)
  • factor inhibitors
• disorders predisposing to thrombosis
  • heparin-induced thrombocytopenia and thrombosis("white clot syndrome")
  • antiphospholipid syndrome
    • Lupus anticoagulant
    • anticardiolipin antibody
  • factor V Leiden
  • prothrombin mutation
  • protein C deficiency
  • protein S deficiency
  • antithrombin deficiency

Coagulation factors

Coagulation factors and related substances
Number and/or name	Function
I/fibrinogen	gels to form clot (fibrin)
II/prothrombin	activates I, V, VII, XIII, protein C, platelets
III	-
IV	-
V/proaccelerin	supports X, activates II
VI	-
VII/stable factor)	activates IX, X
VIII/antihemophilic factor)	supports IX, activates X
IX/Christmas factor	activates X
X/Stuart-Prower factor	activates II
XI/plasma thromboplastin antecedent)	activates XII and prekallikrein
XII/Hageman factor	activates XI, prekallikrein and fibrinolysis
XIII/fibrin-stabilizing factor	crosslinks fibrin
von Willebrand factor	binds VIII, mediates platelet adhesion
prekallikrein	activates XII and prekallikrein; cleaves HMWK
high molecular weight kininogen (HMWK)	supports reciprocal activation of XII, XI, and prekallikrein
fibronectin	mediates cell adhesion
antithrombin III	inhibits IIa, Xa, and other proteases; cofactor for heparin
heparin cofactor II	inhibits IIa, cofactor for heparin and dermatan sulfate ("minor antithrombin")
protein C	inactivates V and VIII
protein S	cofactor for activated protein C (APC, binds C4b-binding protein)
plasminogen	converts to plasmin, lyses fibrin and other proteins
alpha 2-antiplasmin	inhibits plasmin
prourokinase	activates plasminogen
tissue plasminogen activator (tPA)	activates plasminogen
plasminogen activator inhibitor I (PAI1)	inactivates tPA
APTT, INR (PT), TCT Other: factor assays, mixing test, antiphosholipid antibodies, genetic tests, dilute Russell viper venom test (dRVVT), bleeding time Cardiovascular system - Blood Red blood cells - White blood cells - Platelets - Blood plasma White blood cells Granulocytes (Neutrophil granulocytes, Eosinophil granulocytes, Basophil granulocytes) - Lymphocytes - Monocytes Coagulation To be filled - Fibrin - Thrombin - FVIII - FXII - vWF