Coagulation

Coagulation pathways.

Coagulation is "the process of the interaction of blood coagulation factors that results in an insoluble fibrin clot."

Coagulation, along with platelet activation, leads to hemostasis.

Biochemistry

Coagulation and cofactors

Pathway	Diagnostic test	Blood coagulation factor	Half-life	Abnormalities
Intrinsic	Partial thromboplastin time (PTT)	Factor VIII (Antihemophilic factor)
		Factor IX	24 hours	Liver failure, heparin, warfarin therapy, Vitamin K deficiency
		Factor X	40 hours	Liver failure, heparin, warfarin therapy, Vitamin K deficiency
		Factor XI		Liver failure
		Factor XII		Liver failure
Extrinsic	Prothrombin time (PT)	Factor VII (Proconvertin; Stable factor)	5-7 hours	Liver failure, warfarin therapy, Vitamin K deficiency
		Factor X	40 hours	Liver failure
Final Common Pathway	PT & PTT	Factor I (fibrinogen)		Liver failure
		Factor II (prothrombin)	3 days	Liver failure, warfarin therapy, Vitamin K deficiency
Notes: Factor X is a member of both the intrinsic and extrinsic pathways and, as with abnormalities of the final common pathway, affects both the partial thromboplastin time and the prothrombin time

Details and figures depicting the coagulation pathways are available online at the National Library of Medicine.

Production of coagulation factors

All coagulation factors are produced in the liver except for von Willebrand's factor which is made in blood vessels and the spleen.

The synthesis of coagulation factors II, VII, IX, and X and proteins C and S is dependent on vitamin K. The half-lives of the cofactors range from five to seven hours for factor VII to 3 days for factor II (prothrombin).

Disorders of coagulation

Blood coagulation disorders are "hemorrhagic and thrombotic disorders that occur as a consequence of abnormalities in blood coagulation due to a variety of factors such as coagulation protein disorders; blood platelet disorders; blood protein disorders or nutritional conditions."

Factor I deficiency

Deficiency of Factor I (fibrinogen) may be inherited (afibrinogenemia) or acquired.

Factor II deficiency

Deficiency of Factor II (prothrombin) leads to hypoprothrombinemia. The defiency may be acquired in due to prothrombin antibodies.

Factor V deficiency

Factor V deficiency is a "(known as proaccelerin or accelerator globulin or labile factor) leading to a rare hemorrhagic tendency known as Owren's disease or parahemophilia. It varies greatly in severity. Factor V deficiency is an autosomal recessive trait."

Factor VIII deficiency

Hemophilia, an usually genetic deficiency of certain factors necessary for coagulation, is of two major types:

• Hemophilia A (HA), the most common form, involving Factor VIII (FVIII) deficiency
• Hemophilia B (HB), also called Christmas disease, due to a deficiency of Factor IX (FIX)
• Acquired hemophilia, an autoimmune disease that targets Factor VIII

Factor X deficiency

Factor X deficiency is a "blood coagulation disorder usually inherited as an autosomal recessive trait, though it can be acquired. It is characterized by defective activity in both the intrinsic and extrinsic pathways, impaired thromboplastin time, and impaired prothrombin consumption."

Multiple factor deficiencies

Multiple factor deficiencies may be present in disease, or produced deliberately in treating diseases of the coagulation system.

Cirrhosis

Liver failure and cirrhosis affects all coagulation factors except von Willebrand's factor and Factor VIII.

Surprisingly, patients with liver failure are not at reduced risk of embolism and thrombosis. The risk of thrombosis and embolism among patients with liver failure correlates with the partial thromboplastin time and not the International Normalized Ratio. Fatal pulmonary embolism has been reported, and may be due to reduction in synthesis by the liver of protein C, protein S, and antithrombin III and compared to reduction in coagulation factors.

Disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) affects all coagulation factors.

Treatment of coagulation-related diseases

Preventing inappropriate coagulation

Anticoagulants are medications use to prevent coagulation and embolism and thrombosis.

Heparin therapy

Heparin therapy primarily affects Factors IX and X of the intrinsic pathway.

The effect of heparin is monitored by the partial thromboplastin time. However, it can affect the prothrombin time as well. and extend the prothrombin time by one to two seconds.

Warfarin therapy

Warfarin therapy reduces the vitamin K dependent cofactors II, VII, IX, and X and the vitamin K dependent Protein C. The level of factor II is thought to most influence coagulation. The levels of factor VII and Protein C fall the fastest after warfarin is started. With the exception of Factor IX, these factors are from either the extrinsic pathway or the final common pathway.

The effect of warfarin is measured by the prothrombin time (or the International Normalized Ratio derived from the prothrombin time) although warfarin can also affect the partial thromboplastin time.

Reversing inappropriate coagulation

Thrombolytic drugs are used to dissolve harmful clots caused either by a disorder of coagulation, or of an internal traumatic event, such as a myocardial infarction, where a clot is blocking necessary blood flow. They are proteins, produced by recombinant DNA technologies, or extracted from bacterial or human cell cultures.

Most cause the proenzyme, plasminogen, presented in plasma, to the active enzyme plasmin. Plasmin then dissolves fibrin and inactivates other proteins involved in coagulation, principally fibrinogen. The main tbrombolytics used in clinical practice are urokinase, streptokinase, or one of several forms of tissue plasminogen activator (TPA). The TPA variants include alteplase, Reteplase, and tenecteplase.

While thrombolysis can be extremely effective, truly modifying and reversing the disease process, they are absolutely contraindicated in an actively bleeding patient, and have relative contraindications in patients at high risk of hemorrhage. Indications for thrombolyis include:

• myocardial infarction
• deep vein thrombosis (DVT)
• ischemic stroke

In stroke, for example, it is utterly essential that the cause is confirmed to be ischemia rather than hemorrhage. Making this distinction often requires cerebral angiography.

Treating inadequate coagulation

Hemophilia

Synthetic FVIII and FIX are available, and can be used for prophylaxis and treatment of acute hemorrhage. Other drugs can counter the inhibition in acquired hemophilia, or help accelerate coagulation in acute hemorrhage.