An Antagonist Of Vitamin And Its Effect On The Formation Of Thrombin

Aspirin -Aspirin works by irreversibly inhibiting prostaglandin thromboxane A2 by irreversible acetylation of cyclooxygenase enzyme. This inhibition will result in diminished platelet aggregation.

According to Zeuthen, Lassen, and Husted (2003), the theoretical possibility of a transient hypercoaguable state “emerges from a decline in plasma levels of protein C and S, at a time when factors X and II levels are still high due to a longer half life, [which] may lead to a transient hypercoaguable state within the first 12 to 60 hours” of warfarin initiation. In this study, 40 patients who had atrial fibrillation lasting longer than 48 hours were enrolled, and were randomized to receive either warfarin or a LMWH as antithrombotic treatment. Patients with ulcer disease, a gastrointestinal bleed within the past five weeks, uncontrolled hypertension, pregnancy, thrombocytopenia, renal insufficiency, or blood coagulation disorders were excluded (Zeuthen et al., 2003). The study specified that two patients dropped out voluntarily, 21 patients received LMWH and 17 patients received warfarin with a goal international normalized ratio (INR) in the range of 2.0 to 3.0. According to Zeuthen et al. (2003), the method of measuring the possibility of a hypercoaguable state involved assessing markers that reflected the protein and factor activity during the initiation of warfarin and the initiation of a LMWH. The patients in the study were randomly treated with warfarin or LMWH, as discussed previously, for three consecutive days, and biochemical markers were measured at

5. Based on this study, apixaban is superior to warfarin, but why in the clinical setting, warfarin is still the first line medication to be used in atrial fibrillation patients?

While the prevention of a thrombotic event achieved by an anticoagulant, over- or under-dosing can give rise to excessive bleeding or severe clotting respectively, therefore closely link therapy with monitoring is essential. Several techniques have been developed to address the disadvantages of large sample volumes, by multiplexing of the assays in which various parameters or analytes are measured concurrently from a single sample.

Rivaroxaban is a factor Xa inhibitor that may be useful as a treatment for deep-vein thrombosis without the need monitoring that vitamin K antagonists like warfarin require. Standard treatment for acute deep-vein thrombosis consists of initial parenteral heparin with co-administration and followed use of vitamin K antagonists. However, vitamin K antagonists need to be monitored due to a high risk of bleeding.

These are the contact activation pathway (also known as the intrinsic pathway), and the tissue factor pathway (also known as the extrinsic pathway) which both lead to the same fundamental reactions that produce fibrin. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form. The coagulation factors are generally serine proteases (enzymes), which act by cleaving downstream proteins. The exceptions are FIII, FV, FVIII, FXIII. FIII, FV and FVIII are glycoproteins, and Factor XIII is a transglutaminase.

New strategies in anticoagulant therapy are developed over the last years. New anticoagulants are developed and also new indications have been identified for the already existing anticoagulants.

Heparin act by binding to the natural anticoagulant antithrombin, thereby consequently increasing the activation of thrombin by antithrombin and several others activated coagulation factors.

It’s produced by platelets (8). There are two types of thromboxane molecules; thromboxane A2, and thromboxane B2. TXA2 is needed for blood clotting whereas TXB2 is an inactive waste emptied in urine. Low dosage aspirin unlike Ibuprofen is an irreversible non-competitive inhibitor of the enzyme Cyclooxygenase(COX). COX exists just like thromboxane exists in 2 variations; COX 1 and COX 2. COX 1 is responsible of the protection of mucosa (inner layer of the stomach-used for secretion and absorption). COX2 is utilised to produce prostaglandins (chemical hormones made up of unsaturated fatty acid molecules) which are needed for platelet aggregation, and anti-inflammatory purposes (9). Aspirin is a non-selective inhibitor meaning it inhibits both Cyclooxygenase enzymes. It does this because of a complex, chemical process called Acetylation where an acetyl group forms a covalent bond with a serine group found in the active site of the COX enzyme. COX-2 enzymes are used to convert and develop arachidonic acid into prostaglandin H2 which in turn produces thromboxane A2 using an assisting enzyme called thromboxane A synthase. Therefore, by altering the active site of the enzyme it can no longer carry out its function meaning fewer thromboxane A2 is formed. Meaning very few platelets can perform aggregation and bind with fibrinogen net structure. The COX can’t

Targeting the FIX, FXI, and FXII appears to be a promising approach to decrease the atherothrombosis and thromboembolic events. However, in-depth knowledge of the proteins and other factors involved in the process of thrombus formation is crucial to design a safer and efficient therapeutic strategy by targeting these novel targets. The clinical trials are ongoing/recruiting the patients to understand the atherothrombosis, role of oral anticoagulants, and the influence of the proteins of the contact activation system on thrombus formation in human blood in a flow and static model (NCT02785718, FXI and FXII); embolization and degradation on collagen in a perfusion flow model (NCT01114074, FXI and FXII); randomized multicenter trial to

Binding of vWF to platelets is mediated primarily by the GpIb/IX/V complex. Collagen also binds to platelets via the GpIb/IX/V complex as well as through other collagen binding receptors on the platelet surface (like GpIa/IIa and GpVI). The GpIb/IX/V complex also binds to other proteins like thrombin and other proteins in the coagulation cascade and is critical for initial platelet response (50-52). These vWF/collagen bound platelets form a monolayer of activated platelets that secrete their granules and activate other platelets, which triggers the extension phase. Important mediators in this process include thromboxane A2 (inhibited by aspirin), ADP (inhibited by P2Y12-inhibitors) and thrombin ( inhibited by bivalirudin, dabigatran, heparin and low-molecular weight heparin) ( 53). The final downstream step of platelet activation is the expression of to bind other activated platelets (52,53). The platelet clot formation afterwards undergoes the stabilization phase, wherein the platelets form a close network. Several receptors have been implicated in this process, including the previously mentioned GPIIb/IIIa-receptors as well as CD40 and its ligand (CD40L) (51). The final step in thrombus formation is the activation of the coagulation cascade with the deposition of fibrin to stabilize the thrombus. This process is started by exposure of tissue factor to the coagulation system, thrombin generation and final conversion of insoluble fibrinogen into fibrin

Haemostasis occurs in three stages, vascular platelet phase, activation of coagulation cascade producing a clot and initiation of control mechanisms. Coagulation tests are used measure the functions associated with clotting, which involves drawing blood, chelating out the calcium and beginning the clot in a controlled environment, to discover if an individual has a clotting disorder or a factor deficiency. There are many disorders that cause problems with coagulation for example thrombophilia and haemophilia. (Hillyer 2009)

Coagulation is a process where there is a blood clot formation at the site of an injured blood vessel. Once there has been an injury to the blood vessel wall, vasoconstriction immediately occurs, and then we get primary haemostasis. Platelet activation occurs in this process and they adhere to the subendothelial complex. There is a formation of fibrin in this process and this leads to a haemostatic plug being formed at the site of injury. Secondary haemostasis also occurs simultaneously with primary haemostasis. In this process, tissue factors are involved in the initiation of the coagulation cascade. The end result of the coagulation cascade is the activation of thrombin. Thrombin is an important enzyme in haemostasis as it is needed for the conversion of fibrinogen to an insoluble fibrin monomer to form the matrix of the clot and also it is important for further platelet activation. (Khan and Dickerman, 2006; Hoffman, 2003; Clemetson, 2012; Arnout et al., 2006; Hawiger, 1987; Green, 2006)

Fibrin is the main structural component of the thrombus. The conversion of fibrinogen to fibrin by thrombin leads to one of the most remarkable processes in biology in which fibrin spontaneously forms a gel by producing fibers that grow longitudinally as well as laterally, with branch points forming and interconnecting the fibers leading to the formation of a 3-dimensional network that binds platelets and traps other blood cells. Even after the gel point, the architecture of the fibrin network can change quite dramatically.7 Other plasma proteins such as factor XIII, α2-antiplasmin, and fibronectin interact with the fibrin and alter its structural and functional properties. Once the fully organized thrombus is formed, its life span is determined by the resistance of the fibrin clot to proteolysis by plasmin. The generation of plasmin from plasminogen by tissue plasminogen activator is enhanced by the presence of fibrin, particularly after partial degradation by plasmin. The structure of the fibrin clot has been reported to significantly modulate both the rate of proteolysis of fibrin by plasmin as well as the rate of plasmin formation.8

Enoxaparin is a highly acidic mucopolysaccharide. It is an anticoagulant drug that is used primarily for prophylaxis of deep vein thrombosis (DVT) or for patients that exhibit pulmonary embolism (PE) that have underwent specific surgery. Enoxaparin functions as a serine-type endopeptidase inhibitor and targets antithrombin-III. It binds to it and creates a vertex that irreversibly inactivates clotting factor Xa. Enoxaparin binding to antithrombin-III also accelerates the activity of antithrombin-III which is a serine protease inhibitor that modulates the activation of blood coagulation. Enoxaparin inhibits the production of prothrombin to thrombin. Antithrombin-III inhibits thrombin, factors Xa, IXa, and XIa, as well as matripatase-3/TMPRSS7. With the presence of enoxaparin its inhibitory activity is increased greatly. With the Xa being catalyzed by the attachment of enoxaparin, the translation of prothrombin to thrombin is decreased.