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Proteins involved in Blood Coagulation

The information on 21 proteins involved in blood coagulation pathway is as follows:

Fibrinogen (factor I) consists of three polypeptide chains - alpha, beta and gamma. It is converted to fibrin (factor Ia) by thrombin (factor IIa). Fibrin forms a mesh around the wound ultimately leading to blood clot. The inherited disorders caused due to mutations in fibrinogen include afibrinogenemia (complete lack of fibrinogen), hypofibrinogenemia (reduced levels of fibrinogen) and  hyperfibrinogenemia (dysfunctional fibrinogen). These individuals suffer from thromboembolism.

The gene for factor I is located on the fourth chromosome.

Prothrombin (factor II) is a vitamin K-dependent serine protease. It is enzymatically cleaved to thrombin by activated factor X (FXa). Thrombin converts soluble fibrinogen into insoluble fibrin. It also activates factors V, VIII, XI and XIII. Thrombin along with thrombomodulin present on endothelial cell surfaces form a complex that converts protein C to activated protein C (APC). Individuals with prothrombin deficiency have hemorrhagic diathesis. Patients may also suffer from dysprothrombinemia or hypoprothrombinemia. Female patients may suffer from menorrhagia.

The gene for thrombin is located on the eleventh chromosome (11p11-q12).

Tissue factor (factor III) is also called as platelet tissue factor. It is found on the outside of blood vessels and is not exposed to the bloodstream. It initiates the extrinsic pathway at the site of injury. It functions as a high-affinity receptor for factor VII. It acts as a cofactor in the factor VIIa-catalyzed activation of factor X to FXa.

The gene for tissue factor is located on the first chromosome.

Factor V is also referred to as proaccelerin or labile factor.  It is enzymatically inactive and acts as a cofactor to the serine protease FXa, which in the presence of calcium ions and an appropriate phospholipid (PL) membrane surface enhances the activation of prothrombin to thrombin. Factor V Leiden mutation causes factor V deficiency or parahemophilia, which is a rare bleeding disorder. It may also lead to myocardial infarction and deep vein thrombosis.

The gene for factor V is located on the first chromosome (1q21-q25).

Factor VII is vitamin K-dependent serine protease. It initiates coagulation by activating factors IX and X simultaneously with tissue factor in the extrinsic pathway. Its deficiency may lead to epitaxis, menorrhagia, hematomas, hemarthrosis, digestive tract or cerebral haemorrhages.

The gene for factor VII is located on the thirteenth chromosome (13q34-qter).

Factor VIII is also known as anti-hemophilic factor (AHF). It is a cofactor in the activation of factor X to FXa, which is catalyzed by factor IXa in the presence of calcium and phospholipids. Mutations in the factor VIII gene results in hemophilia A. It is also called classical hemophilia, an X-linked recessive coagulation disorder. It is the most common type of hemophilia. Pateints suffer from clinical manifestations in their early childhood; spontaneous and traumatic bleeds continue throughout their life.

The gene for factor VIII is located on the long arm of X chromosome (Xq28).

Factor IX is also known as Christmas factor. It is a proenzyme serine protease, which in the presence of calcium activates factor X. Its deficiency cause hemophilia B or Christmas disease. Although, the clinical symptoms of hemophilia A and B are similar, hemophilia B is less severe than hemophilia A. High antigen or activity levels of factor IX is associated with an increased risk of thromboembolism.

The gene for factor IX is located on the X chromosome (Xq27.1-q27.2).

Factor X is also known as Stuart-Prower factor. In the presence of calcium and phospholipid, it functions in both intrinsic and extrinsic pathway of blood coagulation. Factor X is activated to FXa by factors IX and VII. It is the first member of the common pathway of blood coagulation. FXa cleaves prothrombin to thrombin. Its deficiency may cause bleeding diathesis and hemorrhages. Patients commonly suffer from epitaxis, gastrointestinal bleeds and hemarthrosis. Women with factor X deficiency may be susceptible to miscarriages. 

The gene for factor X is located on the thirteenth chromosome (13q32-qter).

Factor XI is also known as plasma thromboplastin antecedent. It is a serine protease zymogen which is activated to factor XIa by factor XIIa. Deficiency in factor XI causes injury-related bleeding. The disorder is sometimes referred to as hemophilia C. Individuals with severe deficiency do not show excessive bleeding conditions and hemorrhage normally occurs after trauma or surgery. Female patients may experience menorrhagia and prolonged bleeding after childbirth.

The gene for factor XI is located on the distal end on the long arm of fourth chromosome (4q35). 

Factor XII is a plasma protein, also known as Hageman factor. It is the zymogen form of factor XIIa, which activates factor XI and prekallikrein. Its deficiency does not cause excessive hemorrhage due to lack of involvement of factor XIIa in thrombin formation. However, it may increase the risk of thrombosis, due to inadequate activation of the fibrinolytic pathway.

The gene for factor XII is located on the tip of the long arm of the fifth chromosome (5q33-qter).

Factor XIII or fibrin stabilizing factor is the proenzyme form of plasma transglutaminase. It is composed of two subunits- alpha (A) and beta (B). It is activated by thrombin into factor XIIIa in presence of calcium. It forms ε-(γ-glutamyl)-lysyl bonds between the fibrin chains and stabilizes the blood clot. Thus, it reduces the sensitivity of the clot to degradation by proteases. Genetic defects in the factor XIII gene leads to lifelong bleeding diathesis. Patients may also suffer from intercranial bleeding and death.

The gene for F13A is located on the sixth chromosome (6p24-25). The F13B gene is located on the long arm of first chromosome (1q32-32.1).

Antithrombin is also termed antithrombin III. It is an important natural inhibitor of the activated serine proteases of the coagulation system. It majorly inhibits factors Xa, IXa and thrombin. It also has inhibitory effects on factors XIIa, XIa and the complex of factor VIIa and tissue factor. Its activity is accelerated in the presence of heparin. Based on the functional and immunological assays, there are two types of antithrombin deficiency: type I and type II. Type I deficiency is characterized by reduction in the levels of antithrombin available to inactivate the coagulation factors. In case of type II deficiency, the amount of antithrombin present is normal, but it does not function properly. Patients suffer from recurrent venous thrombosis and pulmonary embolism.

The gene for antithrombin is located on the first chromosome (1q23-25).

Protein C is a serine protease enzyme. Its function is to inactivate factors Va and VIIIa. It is activated by thrombin to activated protein C (APC). APC along with protein S degrades factors Va and VIIIa. Protein C deficiency is a rare genetic disorder that causes venous thrombosis. There are two types of protein C deficiency: type I and type II. Type I deficiency results from an inadequate amount of protein C whereas type II deficiency is characterized by defective protein C molecules. Patients may suffer from arterial and venous thrombosis.

The PROC gene is located on the second chromosome (2q13-q14).

Protein S is a vitamin K-dependent plasma glycoprotein. It acts as a cofactor to protein C, thus enhancing the inactivation of factors Va and VIIIa. Mutations in the PROS1 gene can lead to protein S deficiency which increases the risk of thrombosis. There are three types of protein S deficiency: type I, type II and type III. Type I deficiency is characterized by inadequate amount of both free and total protein S levels. Type II deficiency is characterized by normal protein S levels but reduction in functional activity of protein S. Type III deficiency is characterized by low amount of free protein S.

The PROS1 gene for protein S is located on the third chromosome.

Protein Z plays a role in the degradation of factor Xa.

The PROZ gene is located on the thirteenth chromosome (13q34).

von Willebrand factor (vWF) is a multimeric glycoprotein involved in hemostasis. It supports binding of platelets to the site of injury by forming a bridge between collagen matrix and platelet-surface receptor complex. Hereditary or acquired defects of vWF lead to von Willebrand disease. Patients may suffer from bleeding diathesis, menorrhagia and gastrointestinal bleeding.

The gene for vWF is located on short arm of the twelfth chromosome.

Plasminogen is a glycoprotein which circulates as proenzyme. It is converted to plasmin by tissue plasminogen activator (tPA or PLAT) in the presence of a fibrin clot. The main function of plasmin is to dissolve the fibrin of blood clots. Plasminogen plays important role in wound healing and the maintenance of liver homeostasis. Deficiency in plasmin may lead to thrombosis, as clots are not degraded adequately.

The PLG gene for plasminogen is located on sixth chromosome. The PLAT gene for tPA is located on the eighth chromosome.

Heparin cofactor II is a serine protease inhibitor. It inhibits thrombin and factor X. It is a cofactor for heparin and dermatan sulphate. Mutations in this gene are associated with heparin cofactor II deficiency, which can lead to increased thrombin generation and a hypercoagulable state.

The gene SERPIND1 for HC-II is located on chromosome 22 (22q11).

Kallikrein is a serine protease. It exists in an inactive form called prekallikrein, which is converted to kallikrein by factor XIIa. Kallikrein cleaves kininogen releasing brandykinin.

The gene for plasma kallikrein is located on the fourth chromosome (4q34-q35).

High-molecular-weight kininogen (HMWK) is also called as the Williams-Fitzgerald-Flaujeac factor. It is enzymatically inactive and functions as a cofactor for the activation of kallikrein and factor XII. Kinins such as brandykinin are released from kininogen upon activation of plasma kallikrein.

The gene for HMWK is located on the third chromosome (3q26).

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