Thrombosis Is The Formation Of A Thrombus Biology Essay

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Disturbed blood flow: Slow blood flow affects how anticoagulant factors are replenished and this leads to coagulation. This usually occurs during atrial fibrillation, immobility, venous obstruction during pregnancy etc.

Abnormal constituent of the blood: The blood contains more procoagulant than anticoagulant in certain conditions. E.g. During the late stage of pregnancy. 1

There are two classification of thrombosis and they are based on where the thrombus is formed.

Venous thrombosis: This is the formation of a thrombus within a vein; it can form in a deep vein (deep vein thrombosis) 2. Thrombus can break apart and lodge in other areas of the body causing another blockage. This is known as an embolus and it is called pulmonary embolism when it lodges in the lungs. 1

Arterial thrombosis: This is when a thrombus forms within an artery and it is usually as a result of atherosclerosis 1. If it formed in an artery leading to the heart, it can cause heart attack and if it causes ischemic stroke if it is in the artery leading to the brain.

A thrombus or blood clot is formed when the clotting mechanism (Haemostasis) is activated inappropriately i.e. in the absence of bleeding1. This mechanism is the formation of fibrin (blood coagulation), activation and aggregation of platelet and vasoconstriction.

Vasoconstriction: This is achieved by the release of a potent vasoconstrictor called endothelin from the endothelial cells. Epinephrine and serotonin are also released from the granules of activated platelet and the synthesis of thromboxane A2 from arachidonic acid by the activated platelet. Epinephrine, serotonin and thromboxane A2 are all powerful vasoconstrictors.

Activation and aggregation of platelets: During vascular injury, the endothelial is damaged and the subendothelial collagen is exposed 2. von Williebrand factor (vWf) is a protein secreted by platelet, vWf binds to the exposed subendothelial collagen and this causes platelet adhesion 1. This adhesion activates the platelet and causes:

- The release of granule contents which includes substances such as ADP, coagulation factors, etc.2

- The synthesis of thromboxane A2 (TXA2 ) which causes further platelet activation.

- Fibrinogen receptors exposure enabling fibrinogen to bind and form a cross link with nearby platelet. This is known as platelet aggregation 2.

This event of platelet aggregation and activation usually occurs in atherosclerosis because the artery is composed mainly of platelet.

Formation of fibrin (blood coagulation): blood coagulation is basically the conversion of soluble fibrinogen to insoluble fibrin strand by the action of thrombin 1. The blood contains substances that promote blood clotting known as procoagulant and are present in the inactive form. The insoluble fibrin is formed from a blood clotting cascade. The cascade is initiated by tissue damage and platelet activation which causes the mobilization of the clotting factors in the blood 1, 2. This cascade occurs over two pathways, the intrinsic (in vitro or contact) pathway and the extrinsic pathway (in vivo) pathway.

In the extrinsic pathway factor VII is activated by the tissue factor (factor III) and the activated factor VII (factor VIIa) activates factor X using Ca2+ . 7

In the intrinsic pathway, factor XII initiates the pathway by being activated when the blood comes in contact with a foreign surface. Activated factor XII activates factor XI which activates factor IX using Ca2+ . Factor IXa then activates factor X using Ca2+ . 7

The pathway common to both pathways involves the conversion of factor II (Prothrombin) to factor IIa (Thrombin) by factor Xa. Thrombin then converts fibrinogen (factor I) to fibrin (factor Ia). Fibrin then forms cross-linked fibrin clot by factor XIIIa. Factor II, VII, IX and X synthesis depends on vitamin K’s availability. 2,7

Aspirin

Aspirin acts as an antiplatelet by inhibiting platelet activity 4 and is used mainly in the treatment of arterial thrombosis. 2

Aspirin inhibits cyclo-oxygenase (COX) enzyme. There are two forms of the COX enzymes: COX-1 and COX-2. COX-1 is present in the platelet and both forms are present in the endothelium. Aspirin is able to inhibit COX enzyme because it uses its acetyl group to covalently bind to a serine residue in the enzyme’s active site.2 Platelets have no nucleus, so they are unable to resynthesize COX-1, This makes the action of aspirin on platelets permanent until the appearance of new platelets which takes 7-10days 1, 2. The action of aspirin on endothelial cells is not permanent because they have cells and can therefore regenerate the enzymes.2

COX enzyme is required for the conversion of arachidonic acid (AA) to prostaglandin G2 in platelets and prostaglandin H2 in the endothelium. Prostaglandin G2 produces thromboxane A2 in platelets and prostaglandin H2 produces prostacyclin in the endothelium. 2

Arachidonic acid (AA)

COX-1

COX-2

Aspirin

Aspirin

COX-1

Endothelium

Prostaglandin H2

Prostaglandin G2

Platelet

Prostacyclin is still synthesised because COX is regenerated

Prostacyclin

Thromboxane A2

Thromboxane cannot be synthesised

Thromboxane A2 promotes platelet aggregation and prostacyclin inhibits platelet aggregation. Aspirin inhibits both COX enzymes and therefore leads to less thromboxane A2 and prostacyclin synthesis but reduction in prostacyclin is not desirable. The reduction in prostacyclin is very minimal because the endothelium can regenerate the COX enzyme hence the reduction in thromboxane A2 synthesis dominates. 2

Low dose of aspirin is usually given because this decreases the synthesis of thromboxane A2 and does not really reduce the synthesis of prostacyclin1, 2 . If aspirin is given at higher doses the synthesis of prostacyclin would be affected and this would cancel out the effect of reducing the synthesis of thromboxane A2. 2

Low dose of aspirin (50 â€" 1500mg daily) is used in the treatment of myocardial infraction, unstable angina ischaemic stroke etc. 2. The long term use of aspirin in a dose of 75mg in cardiovascular disease is beneficial but extremely high blood pressure must be controlled before it is administered3. The main side effect of aspirin is gastrointestinal disturbances 1,2,3; this is because aspirin inhibits prostaglandin synthesis in the GI tract 2 hence the bleeding. This effect is dose related therefore a low dose of aspirin would reduce this or it may not occur.

Warfarin

Warfarin is an oral anticoagulant 3,5 and therefore prevents the process of blood coagulation. During the process of coagulation, factors II, VII, IX and X require gamma-carboxylation of their glutamic residue to enable binding to Ca2+ 2,.7 This is made possible by the action of vitamin K. The reduced form, Vitamin K hydroquinone is required for this gamma-carboxylation. Vitamin K reductase converts Vitamin K to the reduced form (vitamin K hydroquinone) and the oxidised form (vitamin K epoxide) back to vitamin K. 1 Basically, vitamin K reductase is needed for the recycling of vitamin K. Warfarin inhibits vitamin K reductase which leads to lack of the factors II, VII, IX, and X. 1

1

O2 + Co2 + Glutamic acid residues (in factors II, VII, IX, X)

Vitamin K hydroquinone

The inhibition of vitamin K reductase by warfarin leads to the deficiency of factors II, VII, IX and X hence blood cannot coagulate.

Vitamin K reductase

WARFARIN

Vitamin K

Vitamin K reductase

Vitamin K epoxide

Gamma-Carboxyglutamic acid residues (in factors II, VII, IX, X)

The absence of these factors means that the intrinsic, extrinsic and common pathway of the blood coagulation cascade cannot carry on. These factors have a long half-life (ranges from 6-10 hours) therefore the onset of action of warfarin is delayed because the clotting factors must be completely depleted for the anticoagulation effect can occur.1,2 Loading doses of warfarin are usually given and is used for prolonged therapy.2

Warfarin is used in the treatment of venous thrombosis, atrial fibrillation, pulmonary embolus, mural thrombus, etc. 2 The main side effect of warfarin is bleeding and the use of warfarin should be stopped if there is major bleeding. 5 Other side effects includes; vomiting, jaundice, diarrhoea etc. 5

Aspirin and warfarin are generally not used together because of an increased risk of bleeding but clinical studies have shown that the combination of low dose aspirin and warfarin led to less thromboembolic event in patient after mechanical valve replacement.6

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