Coagulation

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	Coagulation Coagulation 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 blood loss. Disorders in coagulation can lead to hemorrhage, thrombosis, or embolism. 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.

Primary hemostasis

Primary hemostasis is initiated when platelets adhere, using a specific platelet collagen receptor glycoprotein Ia/IIa, to collagen fibers in vascular epithelium. This adhesion is stabilized by von Willebrand's factor which forms links between the platelet glycoprotein Ib/IX 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.

The different pathways of the coagulation cascade.

The coagulation cascade

The coagulation cascade of secondary hemostasis is traditionally divided into three parts: the final common pathway, the intrinsic pathway (abnormal in ) and the extrinsic pathway. 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 intrinsic pathway is initiated by activation of contact factors of plasma, and can be measured by the prothrombin time (PT) test, sometime reported as an INR value.

The extrinsic pathway is initiated by exposure of blood to "tissue factor" (a specific cellular lipoprotein), and can be measured by the activated partial thromboplastin time (PTT) test.

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[?]
  - gray platelet syndrome: deficient alpha granules.
  - delta storage pool deficiency: deficient dense granules.
disorders of coagulation and thrombosis
- factor deficiencies
- factor inhibitors
disorders predisposing to thrombosis
- Lupus anticoagulant[?] (causes thrombosis rather than hemorrhage)
- antiphospholipid syndrome

Coagulation factors

I fibrinogen gels to form clot
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 and prekallikrein
XIII fibrin-stabilizing factor crosslinks fibrin and other proteins
von Willebrand factor (vWF) Factor VIII-related antigen binds VIII, mediates platelet adhesion

prekallikrein activates XII and prekallikrein; cleaves high molecular weigh kininogen
high molecular weight kininogen supports reciprocal activation of XII, CI, and prekallikrein
fibronectin mediates cell adhesion
antithrombin III major antithrombin inhibits IIa, Xa, and other proteases; cofactror for heparin
heparin cofactor II minor antithrombin inhibits IIa, cofactor for heparin and dermatan sulfate
protein C[?] inactivates V and VIII
protein S cofactor for protein Ca, binds C4b-binding protein
plasminogen lyses fibrin and other proteins
alpha-2-antiplasmin inhibits plasmin
prourokinase activates plasminogen
tissue plasminogen activator[?] (TPA) activates plasminogen
plasminogen activator inhibitor I inactivates TPA
plasminogen activator inhibitor II inactivates urokinase

Laboratory tests of coagulation

Common: APTT, INR (PT), TCT
Other: factor assays, mixing test, Lupus anticoagulant, genetic tests, dilute Russell viper[?] venom test (dRVVT), bleeding time

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