Coagulation

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Summary

  • To ensure that blood vessels don’t break when there is a cause of injury, a blood clot is crucial
  • Blood clotting can also prevent you from bleeding to death which also protects you from bacterial and virial infection
  • The process by which a blood clot is formed is called the coagulation cascade that involves a set of complex of reactions
  • Principle events: clotting factors cause platelets to become sticky and adhere to the damaged region which forms a solid plug
  • Clotting factors trigger the conversion of the inactive prothrombin into the activated enzyme thrombin
  • Thrombin catalyses the conversion of soluble plasma protein fibrinogen into an insoluble fibrous form called fibrin
  • Fibrin strands form a mesh of fibres around the platelet plug that traps the blood cells to form a temporarily blood clot
  • Calcium and vitamin K is essentially required for the progression and acceleration for the blood coagulation process

Basic theory

There are two types of cardiovascular diseases: blood clotting and atherosclerosis.

A damage to a blood vessel causes the blood vessel lumen to initially shrink and causes less blood to leak out. This process is known as vasoconstriction. Simultaneously cell fragments in the blood called platelets stick together along with the blood proteins to form a clot.

Blood coagulation is a process that controls bleeding when a blood vessel is damaged. This process involves a group of proteins that are known as blood clotting factors. There are twelve clotting factors that are numbered with roman numerals and also have a common name.

The prevention of blood loss is known as haemostasis. Damage to a blood vessel leads to a series of steps that as follows:

  • Vasoconstriction: the narrowing of the lumen of the blood vessel reduces blood flow which is caused by the constriction of the smooth muscle within the wall of vessels. The degree of constriction depends on the severity of trauma to the vascular endothelial wall. The constriction can last for many minutes, or hours during which time the processes of platelet plugging and blood coagulation can take place.
  • Platelet activation: Platelets become activated when a tissue is damaged. When they come in contact with the damaged vascular surface, specifically the collagen fibres where they join together to form a temporarily platelet plug, to block the blood flow.
  • Blood clot formation: platelets along with fibrin fibres and blood cells form a meshwork that is stronger than the platelet plug that lasts longer to stop bleeding.

Blood platelets aggregation and activation

To save a damaged tissue, blood consists small cell fragments known as platelets. This causes the blood to clot around the damage part of the vessel. Platelets are also called thrombocytes that are shaped as miniature discs which are formed in the bone marrow.

Damage to a blood vessel exposes the lumen of the vessel to the collagen in its wall. Overall vessels collagen is present within the walls of vessels. Collagen is an abundant protein in the body that provides rigidity to the cell wall to stand the pressure that is forming inside the vessel. A cut through the vessel causes the collagen to be exposed to the blood. When platelets are exposed to the wall and come into contact with collagen they change their shape from normal disc shape they are within the blood to discs with long thin projections. The change in the platelet shape enables the blood platelets to become more sticky to the collagen and other blood cells within the vessel. This change therefore has activated the platelets that then releases chemicals that help prevent bleeding that are usually hormones that are able to act to nearby blood vessels and cause them to vasoconstrict, the narrowing of the blood vessels, reducing the blood flow. This causes for less blood to flow to this area where the blood can then be diverted to other areas that need the blood to prevent huge blood loss.

The need for clotting

Within the blood there is substances that promote blood clotting that are known as pro-coagulants and substances the inhibit called anti-coagulants. To maintain homeostasis of the blood the balance between these two groups are very necessary.

For the normal circulation of blood anti-coagulants are predominate however, when there is a rupture to the blood vessel the pro-coagulants override the anti-coagulants and the blood clot develops through a clotting cascade. The clotting cascade is series of enzyme controlled reactions that are summarized below:

Blood clotting

Conversion of prothrombin to thrombin

Prothrombin is a plasma protein found in the blood that is continuously formed by the liver. It has a high molecular weight and deficiency in Vitamin K or damage to the liver can disturb the blood clotting mechanism leading to an increase in bleeding. It’s an unstable protein that is broken down into smaller compounds like thrombin. This occurs in the presence of sufficient calcium ions and prothrombin activator when there is a damage to a blood vessel. Simultaneously there is aggregation of platelets at the site which aid in the conversion of prothrombin to thrombin (Figure 1).

2nd step: conversion of fibrinogen to fibrin

Fibrinogen is also a high molecular weight soluble plasma protein. Thrombin acts as a weak proteolytic enzyme that removes four peptides from a single molecule of fibrinogen. This reaction leads to the formation of fibrin monomers that have the capability to polymerize and form insoluble fibrin fibres (Figure 1).

Formation of the clot

These fibrin fibres initially have weak non-covalent hydrogen bonding and newly formed fibres are not cross linked. After a few minutes fibrin stabilizing factors which are also activated by thrombin, causes there to be multiple cross-linkages between the fibrin fibres and platelets that further strengthens the meshwork. The meshwork constituents fibrin fibres, blood cells, platelets and plasma. This leads to the formation of a blood clot. The fibrin fibres of the blood clot also adhere to the damaged surface of a blood vessel thus preventing any further blood loss.

Figure 1 simplified schematic of the blood coagulation cascade

Blood Clotting in more detail

The coagulation cascade is summarised and often classified into three pathways: extrinsic pathway, intrinsic pathway and the common pathway (Figure 2).

Extrinsic pathway

The extrinsic pathway is initiated with the trauma to the vascular wall and the surrounding tissues. It involves certain tissue factors that are released outside the blood vessel

Intrinsic pathway

This pathway as the name suggests starts with trauma to the blood itself or exposure of blood to collagen of the vascular walls and thereby initiating the clotting cascade.

The common pathway

The common pathway is the interaction between the extrinsic and intrinsic pathway where both pathways eventually produce prothrombin activator. The prothrombin activators triggers the conversion of prothrombin to thrombin ultimately leading to the conversion of fibrinogen to fibrin.

Figure 2 illustrating the three pathways that make the classical blood coagulation pathway

The removal of the blood clot

When a blood clot is formed and has served its function there is a need to remove the clot for the correct circulation of blood. This is to ensure that none of the blood clots formed become too large to block the inside of the blood vessel.
The removal of the blood clot also known as fibrinolysis is the process that causes the blood clot to become dissolved by another plasma protein called plasmin. Plasmin is a proteolytic enzyme that is normally present in an inactivated form called plasminogen. The plasmin digests the fibrin fibres into smaller pieces that can be further broken down by other enzymes and excreted out from the body

Disorders

A disturbance in the clotting cascade or the deficiency in the production of clotting factors can lead to a variety of different disorders summarised below:

  • Haemophilia’s – is the abnormality and deficiency of factor VIII (classical haemophilia) and is a genetic disorder. This disorder is most common in males.
  • Thrombocytopenia – is the presence of very low number of platelets in the blood. They have an increase tendency to bleed from smaller vessels rather than large vessels like in haemophilia.
  • Vitamin K deficiency – This causes there to be a decrease in the production of certain clotting factors within the liver. For example: prothrombin, factor VII, IX and X. This is a rare condition.

Anticoagulating mechanisms in the body

To prevent excessive coagulation, the body has its own way: the endothelium discourages clot formation due to its smoothness when there is no injury. In addition there is no exposure of collagen to activate the clotting cascade. The body has natural anticoagulants which are present within the blood. For example antithrombin III, heparin and protein C.

References and further reading

[1]. https://commons.wikimedia.org/w/index.php?curid=19094276
[2]. Stevanovic, Nikola. (2019). Guyton and Hall Textbook of Medical Physiology – 12th-Ed.
[3]. Palta S, Saroa R, Palta A. Overview of the coagulation system. Indian J Anaesth. 2014;58(5):515–523. doi:10.4103/0019-5049.144643
[4]. https://www.sciencedirect.com/topics/medicine-and-dentistry/blood-clotting
[5]. https://en.wikipedia.org/wiki/Coagulation