Coagulation is the process of forming clots in which blood changes from liquid to gel to stop bleeding. It results in a condition known as hemostasis, which is the process of preventing blood bleeding and keeping the blood in damaged blood vessels. It is the opposite of haemorrhage.
It begins instantly after damage to the endothelial lining of the blood vessel. The process of coagulation involves activation, adhesion, clustering of platelets and deposition of fibrin. It is a cascade of events that is catalysed by enzymes and various proteinaceous factors.
Mechanism
Platelet activation
As soon as the endothelium lining of the blood vessel is damaged, the circulating platelets are exposed to the underlying collagen and bind to the glycoprotein Ia/IIa surface receptors. This binding is strengthened by the vWF factor (Factor XVI) that is released by the endothelium and platelets. The platelets are localised in the extracellular matrix and promote the interaction of collagen with platelet glycoprotein VI, which results in the activation of platelet integrins. These integrins bind platelets tightly to the extracellular matrix and promote the adhesion of platelets to the site of injury. This brings primary hemostasis.
Coagulation cascade
The coagulation cascade, or secondary hemostasis has two pathways – intrinsic and extrinsic that lead to fibrin formation. The cascade involves three main steps, formation of prothrombin activator, conversion of prothrombin to thrombin and conversion of fibrinogen to fibrin.
Prothrombin activation
- Extrinsic pathway: Also known as the tissue factor (TF) pathway. In this process, tissue or thromboplastin factors are released by the damaged vessels. These released factors, in turn, activate factor VII to VIIa, which leads to the activation of factors X to Xa in the presence of calcium ions.
- Intrinsic pathway: It is the longer pathway that activates plasma factor XII to XIIa, after the exposure of blood to collagen from the damaged endothelium. XIIa, which is a serine protease, activates factor XI to XIa, which in turn activates factors IX to IXa in the presence of calcium ions.
- Common pathway: The factors Xa, V, phospholipids and calcium ions become the prothrombin activator and begin the cascade of coagulation.
Conversion of prothrombin to thrombin
Prothrombin, also known as factor II is the inactive form of the enzyme protein thrombin. It is synthesised in the liver in the presence of Vitamin K. The prothrombin is converted to thrombin by the prothrombin activator formed in the common pathway. Thrombin promotes its own formation, i.e. it is a proteolytic enzyme. It activates factors VIII, V and XIII, which helps in the formation of the prothrombin factor.
Conversion of fibrinogen into fibrin
Fibrinogen, also known as factor I, is converted into its active form fibrin by thrombin. Thrombin forms monomers of fibrin that polymerise to form long fibrin threads. These threads are stabilised by factor XIII, also known as the fibrin stabilising factor. This factor forms cross-linking between the fibrin threads to stabilise it in the presence of calcium ions. A fibrin mesh is formed that traps the solid clot made up of formed elements such as erythrocytes, leukocytes and platelets.
Regulators of Coagulation
- Vitamin K: Vitamin K adds a carboxyl group to factors II, VII, IX and X, which enables them to bind to Ca2+ and activate the clotting cascade.
- Antithrombin: It is a serine protease inhibitor that degrades the factors thrombin IXa, Xa, XIa and XIIa. It is a naturally occurring anticoagulant in our body.
- Tissue Factor Pathway Inhibitor (TFPI): TFPI limits the activity of tissue factors and, in turn, limits factor VII and X.
- Plasmin: Plasminogen is a protein that is synthesised in the liver. Plasmin is produced by the proteolytic cleavage of plasminogen. It cleaves fibrin into degradation products that inhibit excessive fibrin formation.
- Prostacyclin: It is released by the endothelium that lowers the cytosolic levels of calcium ions, which eventually inhibit the coagulation cascade.
Disorders
Haemophilia is the major bleeding disorder found in humans. It is an inherited disorder that is caused by mutations in genes responsible for making clotting factors. The genes for clotting factors are found on X chromosomes. Males have XY sex chromosomes, whereas females have XX sex chromosomes. Males are usually affected with haemophilia because they have mutations on X chromosomes. Females are less affected by haemophilia because they have two X chromosomes, and it is a recessive disorder, so they are the carriers of disease that transmit the disease to their offspring.
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