Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.
Prothrombin is encoded in the human by the F2 gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin.
Antithrombin (AT) is a small glycoprotein that inactivates several enzymes of the coagulation system. It is a 464-amino-acid protein produced by the liver. It contains three disulfide bonds and a total of four possible glycosylation sites. α-Antithrombin is the dominant form of antithrombin found in blood plasma and has an oligosaccharide occupying each of its four glycosylation sites. A single glycosylation site remains consistently un-occupied in the minor form of antithrombin, β-antithrombin. Its activity is increased manyfold by the anticoagulant drug heparin, which enhances the binding of antithrombin to factor IIa (thrombin) and factor Xa.
Coagulation factor VIII is an essential blood clotting protein. In humans, it is encoded by F8 gene. Defects in this gene result in hemophilia A, an X-linked bleeding disorder.
Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and, in the treatment of venous thromboembolism, and the treatment of myocardial infarction.
Coagulation factor VII is a protein involved in coagulation and, in humans, is encoded by 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.
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintaining the permeability of blood vessel walls in humans and other animals. Activated protein C (APC) performs these operations primarily by proteolytically inactivating proteins Factor Va and Factor VIIIa. APC is classified as a serine protease since it contains a residue of serine in its active site. In humans, protein C is encoded by the PROC gene, which is found on chromosome 2.
Coagulation factor X, or Stuart factor, is an enzyme of the coagulation cascade, encoded in humans by F10 gene. It is a serine endopeptidase. Factor X is synthesized in the liver and requires vitamin K for its synthesis.
Hirudin is a naturally occurring peptide in the salivary glands of blood-sucking leeches that has a blood anticoagulant property. This is essential for the leeches' habit of feeding on blood, since it keeps a host's blood flowing after the worm's initial puncture of the skin.
The prothrombinase enzyme complex consists of factor Xa (a serine protease) and factor Va (a protein cofactor). The complex assembles on negatively charged phospholipid membranes in the presence of calcium ions. The prothrombinase complex catalyzes the conversion of prothrombin (factor II), an inactive zymogen, to thrombin (factor IIa), an active serine protease. The activation of thrombin is a critical reaction in the coagulation cascade, which functions to regulate hemostasis in the body. To produce thrombin, the prothrombinase complex cleaves two peptide bonds in prothrombin, one after Arg271 and the other after Arg320. Although it has been shown that factor Xa can activate prothrombin when unassociated with the prothrombinase complex, the rate of thrombin formation is severely decreased under such circumstances. The prothrombinase complex can catalyze the activation of prothrombin at a rate 3 x 105-fold faster than can factor Xa alone. Thus, the prothrombinase complex is required for the efficient production of activated thrombin and also for adequate hemostasis.
Tissue factor pathway inhibitor is a single-chain polypeptide which can reversibly inhibit factor Xa (Xa). While Xa is inhibited, the Xa-TFPI complex can subsequently also inhibit the FVIIa-tissue factor complex. TFPI contributes significantly to the inhibition of Xa in vivo, despite being present at concentrations of only 2.5 nM.
Heparin cofactor II (HCII), a protein encoded by the SERPIND1 gene, is a coagulation factor that inhibits IIa, and is a cofactor for heparin and dermatan sulfate.
β2-glycoprotein 1, also known as beta-2 glycoprotein 1 and Apolipoprotein H (Apo-H), is a 38 kDa multifunctional plasma protein that in humans is encoded by the APOH gene. One of its functions is to bind cardiolipin. When bound, the structure of cardiolipin and β2-GP1 both undergo large changes in structure. Within the structure of Apo-H is a stretch of positively charged amino acids, Lys-Asn-Lys-Glu-Lys-Lys, are involved in phospholipid binding.
In autoimmune disease, anti-apolipoprotein H (AAHA) antibodies, also called anti-β2 glycoprotein I antibodies, comprise a subset of anti-cardiolipin antibodies and lupus anticoagulant. These antibodies are involved in sclerosis and are strongly associated with thrombotic forms of lupus. As a result, AAHA are strongly implicated in autoimmune deep vein thrombosis.
Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma. It is an experimental drug that acts as an anticoagulant and antithrombotic to prevent venous thromboembolism after a major orthopaedic surgery, stroke in patients with atrial fibrillation and possibly ischemic events in acute coronary syndrome. It is used in form of the maleate. The development of darexaban was discontinued in September 2011.
Direct thrombin inhibitors (DTIs) are a class of anticoagulant drugs that can be used to prevent and treat embolisms and blood clots caused by various diseases. They inhibit thrombin, a serine protease which affects the coagulation cascade in many ways. DTIs have undergone rapid development since the 90's. With technological advances in genetic engineering the production of recombinant hirudin was made possible which opened the door to this new group of drugs. Before the use of DTIs the therapy and prophylaxis for anticoagulation had stayed the same for over 50 years with the use of heparin derivatives and warfarin which have some well known disadvantages. DTIs are still under development, but the research focus has shifted towards factor Xa inhibitors, or even dual thrombin and fXa inhibitors that have a broader mechanism of action by both inhibiting factor IIa (thrombin) and Xa. A recent review of patents and literature on thrombin inhibitors has demonstrated that the development of allosteric and multi-mechanism inhibitors might lead the way to a safer anticoagulant.
CU-2010 and CU-2020 are synthetic compounds that act as serine protease inhibitors. These were developed in 2010 to replace the use of aprotinin during and after cardiac surgery, including surgeries with cardiopulmonary bypass which cause blood loss and hemorrhagic complications. CU-2010 and CU-2020 were developed to avoid many issues associated with the use of aprotinin, including the risk of an allergic reaction and infection. Since the isolation of aprotinin is expensive, a drug with a simpler synthesis was desired.
Four drugs from the class of direct Xa inhibitors are marketed worldwide. Rivaroxaban (Xarelto) was the first approved FXa inhibitor to become commercially available in Europe and Canada in 2008. The second one was apixaban (Eliquis), approved in Europe in 2011 and in the United States in 2012. The third one edoxaban was approved in Japan in 2011 and in Europe and the US in 2015. Betrixaban (Bevyxxa) was approved in the US in 2017.
Prothrombin fragment 1+2 (F1+2), also written as prothrombin fragment 1.2 (F1.2), is a polypeptide fragment of prothrombin generated by the in vivo cleavage of prothrombin into thrombin by the enzyme prothrombinase. It is released from the N-terminus of prothrombin. F1+2 is a marker of thrombin generation and hence of coagulation activation. It is considered the best marker of in vivo thrombin generation.
Hendrik Coenraad"Coen"Hemker is a Dutch biochemist and academic administrator. He was one of the founders of Maastricht University and was its rector magnificus from 1982 to 1984. He was a professor of biochemistry from 1975 until 1999. In his research he has mainly studied thrombosis and hemostasis.
