Coagulation | Why is Coagulation Important? | Coagulation Disorders

Coagulation in simpler words is the clotting of blood. It is a process by which liquid blood changes into a gel or semi-solid form, which is called as a clot.

coagulation

Why is Coagulation Important?

Coagulation is a necessary process that enables the blood to plug and heal a wound. It is the body’s way to stop unwanted bleeding. Coagulation overlaps with the immune system; coagulation can physically trap invading microorganisms in blood clots.

Also, some of the products of the coagulation system contribute to the innate immune system by increasing vascular permeability and acting as chemotactic agents for phagocytic cells. Some of the products of the coagulation system are antimicrobial. Specific acute proteins of inflammation are involved in the coagulation system.

Read More- Everything You Need to Know About Cell and Its Parts

Coagulation Cascade: How Coagulation Works?

The formation of a clot is mostly referred to as secondary haemostasis as it forms the second stage in the process of arresting the loss of blood from a ruptured vessel. Primary haemostasis or first stage involves blood vessel constriction (vasoconstriction) and platelet aggregation at the site of injury.

The mechanism of coagulation is a cascade that involves activation, adhesion, and aggregation of platelets, along with deposition and maturation of fibrin. Clotting occurs in a sequence that involves the interaction of numerous blood components, which are called coagulation factors.

Coagulation initiates through the activation of two separate pathways, termed as extrinsic and intrinsic pathways. Both pathways lead to the production of factor X. The activation of this factor X begins the common pathway of coagulation, which leads to the formation of a clot.

  • Primary Haemostasis

Underlying collagen is exposed when the endothelium is damaged to circulating platelets, which bind to collagen with collagen-specific glycoprotein Ia/IIa surface receptors.

This binding gets stronger further by von Willebrand factor that is released from the endothelium and platelets. It makes additional links between the platelets’ glycoprotein Ib/IX/V and the collagen fibrils.

This localization of platelets promotes collagen interaction with platelet glycoprotein VI. Binding of collagen with glycoprotein VI triggers a cascade that results in the activation of platelet integrins. Activated integrins enhance the tight binding of platelets to the extracellular matrix. This process carries out the adhesion of platelets to the site of injury.

Activated platelets release the contents of stored granules into the blood plasma which activate additional platelets.

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  • Secondary Haemostasis

It has two initial pathways, and both lead to fibrin formation. These are the contact activation pathway (termed as the intrinsic pathway), and the tissue factor pathway (termed as the extrinsic pathway).

Tissue factor (Extrinsic pathway) is considered as a primary pathway for the initiation of blood coagulation. The pathways are a series of various reactions, in which a zymogen that is inactive enzyme precursor of a serine protease and its glycoprotein co-factor get activated to become active components which then catalyze the next reaction.

Ultimately resulting in cross-linked fibrin. The tissue factor (extrinsic) and contact activation (intrinsic) pathways both activate the final common pathway of factor X, thrombin and fibrin.

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  • Tissue Factor Pathway (Extrinsic Pathway)

Tissue factor pathway serves to generate a process by which thrombin is released very rapidly. FVIIa circulates in a higher amount than other activated coagulation factors. The extrinsic pathway is the shorter pathway in the secondary haemostasis.

When the vessel is damaged, the endothelial cells release tissue factor that further activates factor VII to factor VIIa. Factor VIIa activates factor X into factor Xa. The extrinsic pathway is measured as the prothrombin time (PT) clinically.

  • Contact Activation Pathway (Intrinsic Pathway)

This pathway is the longer one in secondary haemostasis. It begins with the activation of Factor XII, i.e. a zymogen- an inactivated serine protease that becomes Factor XIIA, i.e. activated serine protease after coming into contact with endothelial collagen during the endothelial damage.
Factor XIIA acting as a catalyst activates factor XI to Factor XIA. Factor XIA further activates factor IX to factor IXA. Factor IXA acts as a catalyst for turning factor X into factor Xa. It is known as a cascade.

Further down the cascade, the concentration of that factor increases in the blood. The intrinsic pathway is measured as the partial thromboplastin time (PTT).

  • Final Common Pathway

This pathway starts at factor X which is further activated to factor Xa. It is quite a complicated reaction. Tenase cleaves factor X into factor Xa. Tenase has two forms: extrinsic that consists of factor VII, factor III, and Ca2+, or intrinsic, consisting of cofactor factor VIII, factor IXA, a phospholipid, and Ca2+. Once factor Xa is activated, it goes on to activate factor II, i.e. prothrombin into factor IIa, i.e. thrombin.

Also, factor Xa needs factor V as a cofactor to cleave prothrombin into thrombin. Factor IIa goes on to activate fibrinogen into fibrin. Thrombin also activates other factors in the intrinsic pathway as well as cofactors V and VIII and factor XIII. Fibrin subunits get together to form fibrin strands, and factor XIII forms a fibrin mesh which helps to stabilize the platelet plug.

Coagulation Disorders 

  • Haemophilia-A is the most common form of haemophilia that is associated with the deficiency of factor VIII.
  • Haemophilia B also knows as Christmas disease is secondary to lack of factor IX.
  • Haemophilia C is found in 1% of the population and occurs due to deficiency of factor XI.
  • Haemophilia is X linked recessive disorder. The severity of the bleeding is directly related to the coagulation factors’ level.
  • Von Willebrand disease is the autosomal dominant inherited disorder that occurs due to an abnormality in the production of von Willebrand factor (vWF), which can be qualitative or quantitative. vWF serves as a carrier molecule for factor VIII coagulant protein. The most common sign of the condition is abnormal bleeding.

Anti-Coagulants: 

Anticoagulants are termed as blood thinners. They are chemical substances that help in the prevention or reduction of blood coagulation, prolonging the clotting time. They generally include Non-VKA Oral Anticoagulants (NOACs), heparins and Vitamin K Antagonists. They all have a different mode of action.

The use of anticoagulants may be associated with an enhanced risk of occult or overt bleeding from any tissue or organ leading to post haemorrhagic anaemia due to the pharmacological mode of action.

  • Vitamin K Antagonists (VKA)

Such as Warfarin are a group of substances that reduce blood clotting by decreasing the action of vitamin K. Vitamin K is required for the proper synthesis of certain clotting factors in the liver.

  • Non-VKA Oral Anticoagulants (NOACs)

  • Rivaroxaban

It is a direct Factor Xa inhibitor which works by inhibiting Factor Xa, a protein which helps the formation of blood clots. It’s usually administrated orally and comes in a tablet form. It should be swallowed whole.

  • Edoxaban

It is a direct Factor Xa inhibitor that works by inhibiting Factor Xa, a protein that helps blood clots to be formed. It comes in a tablet form, administrated orally and can be taken with or without food.

  • Apixaban

It is also a direct Factor Xa inhibitor oral anticoagulant which works by inhibiting Factor Xa.

  • Dabigatran

It is a direct thrombin inhibitor oral anticoagulant that works by inhibiting the action of thrombin. It usually comes in the capsule form and swallowed whole with or without food.

3. Heparin

It is used to treat and prevent deep vein thrombosis, pulmonary embolism as well as arterial thromboembolism. It’s used in heart attacks and unstable angina treatment. It is administrated by injection into a vein or under the skin.

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