Coagulation-3 steps: initiation, propagation and fibrin formation.

Soluble blood coagulation factors are critical components in the formation of a thrombus.

Hepatic cells principal site of synthesis of coagulation factors

Other cells, such as endothelial cells, also have an important role in hemostasis and thrombosis.

The coagulation cascade is characterized by the sequential activation of three vitamin K-dependent serine proteases factor VII, factorIX, and factorX, and therir cofactor complexes tissue factor, factor VIII and Factor V.

Factor VIII acts as an essential cofactor for factor IX in the intrinsic cascade, amplifying factor IX activity.

Factor VIII is a heterodimer composed of a heavy chain and a light chain stabilized by noncovalent interactions between the light chain and von Willebrand factor.

Von Willebrand factor interacts with factor VIII and stabilize it and inhibits factor VIII binding to phospholipids, thereby increasing the half-life of factor VIII.

Intrinsic pathway initiated by factor XII.

The instrinsic pathwy starts when blood comes in contact with a variety of negatively charged surfaces-including non-physiological materials such as glass, kaolin, and ellagic acid.

When factor XII binds to these surfaces it undergoes a conformational change in factor XII that allows it to activate prekallikrein.

Prekllikrein activates Factor XII, producing a positive feedback loop that amplifies the system and leads to activation of factor XI and cleaves high molecular weight kininogen by kallikrein.

Cleavage of kininogen produces the inflammatory mediator bradykinin.

While contact activation is part of the activated partial thromboplastin time severe deficiencies in factor XII, prekallikrein and kininogen do not produce a bleeding diathesis.

Extrinsic pathway initiated by factor VIIa/tissue factor (TF).

The intrinsic and extrinsic pathways converge on a common pathway at the level of factor Xa/factor Va, the prothrombin complex.

The coagulation complex requires phospholipid and calcium for activity.

Deficiencies in factor XII not associated with significant hemorrhage.

Deficiency in factor XI may or may not be associated with hemorrhage.

Deficiencies in factor VIII and IX consistently associated with hemorrhage.

Triggered by Factor VIIa/tissue factor (TF) complex, which then activates Factors IX and X.

Propagated by Factors IXa and Xa together with their cofactors, Factor VIIIa and Va, respectively.

Factor Xa formed on the TF bearing cells interacts with its cofactor Va to form prothrombinase complexes and generates a small amount of thrombin.

Activity of factor Xa formed by factor VIIa/TF complex is restricted to TF bearing cell, because factor Xa that dissociates from the cell surface is rapidly inhibited by TFPI or antithrombin.

Factor IXa can diffuse to nearby platelets because it is not inhibited by TFPI and is inhibited more slowly by antithrombin than factor Xa.

Factor IXa activated by factor VIIa/TF does not play a significant role in initiation phase of coagulation, but it can diffuse to nearby platelets and can bind to surface receptors interacting with cofactor factor VIIIa and activate factor X on the platelet surface.

Fibrin formation is effected by thrombin which converts fibrinogen to fibrin and activates Factor XIII, which stabilizes the fibrin network by covalently cross linking adjacent fibrin monomers.

Amplified by thrombin which activates Factors V and VIII and is a platelet agonist.

Most coagulation factors can leave the vascular space and their activated peptides are found in the lymph.

Likely that most extravascular tissue factor is bound to factor VIIa even in the absence of an injury and that low levels of factor IXa and Xa and thrombin are produced on tissue factor bearing cells at all times.

Platelets have a major role in localizing clotting reactions to the site of injury as they adhere and aggregate where TF is exposed.

Platelets provide the surface for thrombin needed for hemostasis during the propagation phase of coagulation.

Platelet localization and activation mediated von Willebrand factor, thrombin, platelet receptors, and blood vessel components such as collagen.

Acquired disorders of coagulation include: decreased coagulation factor synthesis,increased clearance of coagulation factors, caused by consumption, hemodilution or an immune effect, inhibition of coagulation enzymatic activity, liver disease, vitamin K inhibitors, use of oral novel anticoagulants, factor Xa inhibitors, direct thrombin inhibitors, antiplatelet agents, uremia, DIC, acquired von Willebrand disease, acquired hemophilia,and trauma induced coagulopathy.

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