Blood Clotting (definition)
Blood clotting, or coagulation, is a process in which blood changes its state from a free-flowing liquid to a semi-solid gel resulting in stopping or preventing the loss of blood from the damaged blood vessels.
List of 13 Blood clotting factors –
Factor I (FI): Fibrinogen
Factor II (FII): Prothrombin
Factor III (FIII): Tissue thromboplastin
Factor IV (FIV): Calcium
Factor V (FV): Proaccelerin, labile factor
Factor VI (FVI): Unassigned
Factor VII (FVII): Stable factor, proconvertin
Factor VIII (FVIII): Antihemophilic factor
Factor IX (FIX): Christmas factor
Factor X (FX): Stuart-power factor
Factor XI (FXI): Plasma thromboplastin antecedent
Factor XII (FXII): Hageman factor
Factor XIII (FXIII): Fibrin-stabilizing factor.
Mechanism or process of blood clotting
The mechanism or process of blood clotting can be described briefly in 2 main stages:
1. Primary hemostasis: Formation of a weak platelet plug.
2. Secondary hemostasis: Stabilizing the weak platelet plug into a clot by the fibrin network.
1. Primary Hemostasis:
It is the formation of a weak platelet plug, which is achieved in four different phases:
(ii) platelet adhesion
(iii) platelet activation
(iv) platelet aggregation.
It is the initial response to any vessel injury. Vasospasm of the blood vessels develops first in response to any injury of the vasculature. This vasospasm, in turn, stimulates vasoconstriction. Vasoconstriction is primarily mediated by endothelin-1 which is a strong vasoconstrictor, it is synthesized by the damaged endothelium. Damaged endothelium exposes sub-endothelial collagen, von Willebrand factor (vWF) and releases ATP, and inflammatory mediators. Von Willebrand Factor (or vWF) is synthesized by megakaryocytes which later gets stored in granules of platelets. Weibel-Palade bodies of the endothelium also synthesize vWF. It is the combination of exposure of Von Willebrand Factor (or vWF), ATP, subendothelial collagen and inflammatory mediators which provide the gateway into the second phase of primary hemostasis, platelet adhesion.
(ii) Platelet adhesion
It is the process by which platelets attach to the exposed subendothelial vWF. After vascular damage, platelets begin to roll along the vessel walls and adhere (or sticks) to areas of exposed subendothelial collagen and vWF. Platelet membranes are rich in G protein (Gp) receptors which are present within the phospholipid bilayer. Specifically, it is Gp Ib-IX receptor on platelets that binds to vWF within the endothelium which creates the initial connection between the two. Once bound, a variety of events occur in the third phase of primary hemostasis to activate the platelet.
(iii) Platelet activation
It consists of platelets undergoing two specific events once they have adhered to the exposed vWF (i.e. the damaged vessel site). First, platelets will undergo an irreversible change in shape from a smooth disc to multi-pseudopodal plugs, which greatly increases their surface area. Second, platelets secrete their cytoplasmic granules.
Platelet activation is mediated via thrombin by two mechanisms. Thrombin directly activates platelets via proteolytic cleavage by binding the protease-activated receptor. Thrombin also stimulates platelet granule release which includes serotonin, platelet activating factor, and Adenosine Diphosphate (ADP). ADP is one of the most important physiological agonist which is stored specifically in the dense granules of platelets. When ADP is released, it binds to P2Y1 and P2Y12 receptors on platelet membranes. P2Y1 induces the pseudopod shape change and aids in aggregation of platelets. P2Y12 plays an important role in inducing the clotting cascade. When Adenosine diphosphate (or ADP) binds to its receptors, it induces Gp IIb/IIIa complex expression at the platelet membrane surface. The Gp IIb/IIIa complex is a calcium-dependent collagen receptor which is necessary for platelet-to-endothelial adherence and platelet-to-platelet aggregation. Simultaneously, platelets synthesize Thromboxane A2 (TXA2). TXA2 further increases vasoconstriction and platelet aggregation. The process of platelet activation forms the local environment for platelet aggregation.
It starts once platelets have been activated. Once activated, the Gp IIb/IIIa receptors adhere to vWF and fibrinogen. Fibrinogen is found in the circulation and forms a connection between the Gp IIb/IIIa receptors of platelets to interconnect them with each other. This ultimately forms the weak platelet plug.
Thus, the primary hemostasis allows the culmination of a weak platelet plug to temporarily protect from hemorrhage until further stabilization of fibrinogen to fibrin via thrombin occurs in secondary hemostasis.
2. Secondary Hemostasis:
It involves the clotting factors acting in a cascade to ultimately stabilize the weak platelet plug. This is accomplished by completing three tasks:
(i) triggering activation of clotting factors,
(ii) conversion of prothrombin to thrombin, and
(iii) conversion of fibrinogen to fibrin.
These tasks are initially completed by 1 of 2 pathways; the extrinsic pathway and the intrinsic pathway, which converge at the activation of factor X and then complete their tasks via the common pathway. Please note that calcium ions are required for the entire process of secondary hemostasis.
Pathways involved in blood clotting (coagulation of blood) are :-
The extrinsic pathway
This pathway includes tissue factor (TF) and factor VII (FVII). It starts when TF binds to FVII, activating FVII to factor VIIa (FVIIa), forming a TF-FVIIa complex. This complex, in turn, activates factor X (FX), (the TF-FVIIa complex can also activate factor IX of the intrinsic pathway). Once Factor X gets activated into FXa by TF-FVIIa complex, the cascade continues down the common pathway.
The intrinsic pathway
This pathway includes Hageman factor (FXII), factor I (FXI), factor IX (FIX), and factor VIII (FVIII). The process is initiated when FXII comes in contact with the exposed subendothelial collagen and gets activated into FXIIa. Similarly, FXIIa activates FXI to FXIa, and FXIa activates FIX to FIXa. FIXa performs its work in combination with activated factor VIII (FVIIIa) to activate factor X. Once Factor X is activated by FIXa-FVIIIa complex, the cascade continues down the common pathway.
The common pathway
It starts via the activation of Factor Xa. Factor Xa combines with Factor Va and calcium on phospholipid surfaces to create a prothrombinase complex ultimately activating prothrombin (or Factor II) into thrombin. This activation of thrombin occurs via serine protease cleaving of prothrombin. Now, thrombin activates factor XIIIa (FXIIIa). FXIIIa crosslinks with fibrin forming the stabilized clot. Calcium ions also plays a very important role in this process.
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