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Haemophilia A is a blood clotting disorder caused by a genetic deficiency in clotting factor VIII, thereby resulting in significant susceptibility to bleeding, both internally and externally. This condition occurs almost exclusively in males born to carrier mothers due to X-linked recessive inheritance. Nevertheless, rare isolated cases do emerge from de novo (spontaneous) mutations.
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.
Fibrinogen is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clot. Fibrin clots function primarily to occlude blood vessels to stop bleeding. Fibrin also binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, limits clotting. Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby promotes revascularization and wound healing.
Thrombotic thrombocytopenic purpura (TTP) is a blood disorder that results in blood clots forming in small blood vessels throughout the body. This results in a low platelet count, low red blood cells due to their breakdown, and often kidney, heart, and brain dysfunction. Symptoms may include large bruises, fever, weakness, shortness of breath, confusion, and headache. Repeated episodes may occur.
Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme of the serine protease class. In humans, factor XII is encoded by the F12 gene.
Coagulation factor VII is one of the proteins that causes blood to clot in the coagulation cascade, and in humans is coded for by the gene F7. It is an enzyme of the serine protease class. Once bound to tissue factor released from damaged tissues, it is converted to factor VIIa, which in turn activates factor IX and factor X.
Factor IX is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes haemophilia B. It was discovered in 1952 after a young boy named Stephen Christmas was found to be lacking this exact factor, leading to haemophilia.
Factor XIII or fibrin stabilizing factor is a zymogen found in blood of humans and some other animals. It is activated by thrombin to factor XIIIa. Factor XIIIa is an enzyme of the blood coagulation system that crosslinks fibrin. Deficiency of XIII worsens clot stability and increases bleeding tendency.
Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Such abnormalities can be identified in 50% of people who have an episode of thrombosis that was not provoked by other causes. A significant proportion of the population has a detectable thrombophilic abnormality, but most of these develop thrombosis only in the presence of an additional risk factor.
Fresh frozen plasma (FFP) is a blood product made from the liquid portion of whole blood. It is used to treat conditions in which there are low blood clotting factors or low levels of other blood proteins. It may also be used as the replacement fluid in plasma exchange. Using ABO compatible plasma, while not required, may be recommended. Use as a volume expander is not recommended. It is given by slow injection into a vein.
Congenital afibrinogenemia is a rare, genetically inherited blood fibrinogen disorder in which the blood does not clot normally due to the lack of fibrinogen, a blood protein necessary for coagulation. This disorder is autosomal recessive, meaning that two unaffected parents can have a child with the disorder. The lack of fibrinogen expresses itself with excessive and, at times, uncontrollable bleeding.
Hypoprothrombinemia is a rare blood disorder in which a deficiency in immunoreactive prothrombin, produced in the liver, results in an impaired blood clotting reaction, leading to an increased physiological risk for spontaneous bleeding. This condition can be observed in the gastrointestinal system, cranial vault, and superficial integumentary system, affecting both the male and female population. Prothrombin is a critical protein that is involved in the process of hemostasis, as well as illustrating procoagulant activities. This condition is characterized as an autosomal recessive inheritance congenital coagulation disorder affecting 1 per 2,000,000 of the population, worldwide, but is also attributed as acquired.
Warfarin-induced skin necrosis is a condition in which skin and subcutaneous tissue necrosis occurs due to acquired protein C deficiency following treatment with anti-vitamin K anticoagulants.
Factor XIII deficiency occurs exceedingly rarely, causing a severe bleeding tendency. The incidence is one in a million to one in five million people, with higher incidence in areas with consanguineous marriage such as Iran that has the highest global incidence of the disorder. Most are due to mutations in the A subunit gene. This mutation is inherited in an autosomal recessive fashion.
The human gene VKORC1 encodes for the enzyme, Vitamin K epOxide Reductase Complex (VKORC) subunit 1. This enzymatic protein complex is responsible for reducing vitamin K 2,3-epoxide to its active form, which is important for effective clotting (coagulation). In humans, mutations in this gene can be associated with deficiencies in vitamin-K-dependent clotting factors.
Recombinant factor VIIa, also known as eptacog alfa (INN), and sold under the brand name Novoseven, among others, is a form of blood factor VII that has been manufactured via recombinant technology. It is administered via an injection into a vein.
Turoctocog alfa is a recombinant antihemophilic factor VIII used for the treatment of and prophylaxis of bleeding patients with haemophilia A. It is marketed by Novo Nordisk. It was approved in the United States, the European Union, and Japan in 2013.
Factor I deficiency, also known as fibrinogen deficiency, is a rare inherited bleeding disorder related to fibrinogen function in the blood coagulation cascade. It is typically subclassified into four distinct fibrinogen disorders: afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia.
Factor XII deficiency is a deficiency in the production of factor XII (FXII), a plasma glycoprotein and clotting factor that participates in the coagulation cascade and activates factor XI. FXII appears to be not essential for blood clotting, as individuals with this condition are usually asymptomatic and form blood clots in vivo. FXII deficiency tends to be identified during presurgical laboratory screening for bleeding disorders.
Congenital hypofibrinogenemia is a rare disorder in which one of the three genes responsible for producing fibrinogen, a critical blood clotting factor, is unable to make a functional fibrinogen glycoprotein because of an inherited mutation. In consequence, liver cells, the normal site of fibrinogen production, make small amounts of this critical coagulation protein, blood levels of fibrinogen are low, and individuals with the disorder may develop a coagulopathy, i.e. a diathesis or propensity to experience episodes of abnormal bleeding. However, individuals with congenital hypofibrinogenemia may also have episodes of abnormal blood clot formation, i.e. thrombosis. This seemingly paradoxical propensity to develop thrombosis in a disorder causing a decrease in a critical protein for blood clotting may be due to the function of fibrin to promote the lysis or disintegration of blood clots. Lower levels of fibrin may reduce the lysis of early fibrin strand depositions and thereby allow these depositions to develop into clots.
References
- 1 2 NHS New Drugs Online Report for catridecacog Archived 2015-07-03 at the Wayback Machine Page accessed July 2, 2015
- ↑ Catridecacog: First drug to treat rare genetic blood clotting disorder. The Pharmacist February 01, 2014
- Korte W (9 July 2014). "Catridecacog: a breakthrough in the treatment of congenital factor XIII A-subunit deficiency?". J Blood Med . 5: 107–13. doi: 10.2147/JBM.S35395 . PMC 4096448 . PMID 25031548.
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CNDO-210 and Catridecacog were discontinued due to safety concerns and lack of efficacy, respectively.
