Coagulation, let's make it easy

Basic principles

Coagulation is a dynamic process, the mechanism of which includes multiple components and aims to stop bleeding and maintain homeostasis of the body. The complex balance between the coagulation and fibrinolytic systems aims to minimize bleeding, while preventing excessive thrombus formation and dissolution of the clot after complete tissue repair. Hemostasis in blood clotting can be divided into four main stages:

1. Primary hemostasis begins with vasoconstriction and platelet plug formation, with platelets being the key component of primary hemostasis. It is triggered by injury to the vessel wall and access to the subendothelial collagen. At the site of injury, vasoconstriction occurs to reduce blood flow. Von Willebrand factor adheres platelets to the subendothelial collagen to ensure tissue adhesion. Platelets aggregate with each other, either with the help of fibrinogen, or directly to the tissue collagen layer, forming a platelet plug.

2. Secondary hemostasis can be divided into three phases. The initiation phase begins with the activation of coagulation factors and the formation of thrombin. Coagulation begins with the release of tissue factor (TF) from damaged tissue cells, endothelial cells, and monocytes. TF and factor VIIa form a complex that activates small amounts of factors IX and X. Factor XII (and other "contact" factors) play a minor role in the activation of factor XI.

During the amplification phase, thrombin activates not only platelets but also factor V into Va, factor VIII is activated to VIIIa, FXI to FXIa.

In the propagation phase, the complex formed by TF and factor VIIa activates factor IX, producing additional factor Xa. Factor IXa together with factor VIIIa form the so-called tenase complex, which activates factor X into Xa. Thus, the large amount of factor Xa and Va together with calcium and activated platelets form the prothrombin complex, which converts prothrombin into large amounts of thrombin.

3. Formation and stabilization of a fibrin clot occurs when thrombin converts fibrinogen into fibrin monomers, which polymerize to form a soluble clot. Thrombin then activates factor XIII, which binds the fibrin monomers and stabilizes the clot.

4. Inhibition of coagulation is associated with the formation of thrombin and the breakdown of the fibrin clot (fibrinolysis). Simultaneously with clot formation, the coagulation process is also switched off to limit the extent of thrombus formation. This occurs when thrombin binds to the membrane receptor thrombomodulin and activates the natural anticoagulant protein C. With the help of its cofactor protein S, it inhibits factors Va and VIIIa, slowing the coagulation process. Thrombin bound to thrombomodulin becomes inactive. The endogenous anticoagulant, antithrombin, as well as factor Xa also inhibit its activity. Tissue plasminogen activator (t-PA) converts plasminogen to plasmin, which breaks down cross-linked fibrin into several fibrin degradation products, the smallest of which is D-dimer.

   

   
   

   

Blood clotting cascade

The blood coagulation cascade itself is activated in two ways, intrinsic and extrinsic, which in turn meet at a certain point to convert fibrinogen into fibrin. Many of the enzymes and enzyme complexes involved in the activation of the individual steps of coagulation require Ca2+. When the integrity of a cell is disrupted, a Ca2+-mediated reaction is activated, which helps transport procoagulants to the cell wall. This can significantly increase the rate of the coagulation reaction. Cytokines, thrombin and hypoxia can also stimulate the formation of additional parts of granulocytes and erythrocytes, which help coagulation. The formed clot and possible fibrinolysis can occur at the site of injury, but in polytraumatism they can also form in a place in the body that does not have an injury. In these cases, we can talk about serious thrombosis or coagulopathy, which are life-threatening conditions.

Until the beginning of World War II, only fibrinogen, prothrombin, thromboplastin and calcium were known as clotting factors. As medicine progressed, the others were discovered. In the currently existing nomenclature of clotting factors, some of them are named after the first diagnosed patient suffering from a congenital deficiency of the respective factor.

Name	Synonym
Factor I	fibrinogen
Factor II	prothrombin
Factor III	tissue factor
Factor IV	calcium
Factor V	proaccelerin, labile factor
Factor VI	old name of Factor Va
Factor VII	proconvertin, stable factor
Factor VIII	antihemophilic factor A
Factor IX	antihemophilic factor B
Factor X	Stuart-Prower factor
Factor XI	plasma thromboplastin antecedent
Factor XII	Hagemen factor
Factor XIII	fibrin stabilizing factor

Many coagulation factors exist as inactive zymogens that are activated after limited proteolysis. Tissue factor (TF), FV, and FVIII function as cofactors. The vitamin K-dependent coagulation factors require vitamin K to perform their functions. These are prothrombin, FVII, factor IX (FIX), and factor X (FX). Natural anticoagulants, such as protein C, are also vitamin K-dependent factors.

The mechanism by which coagulation allows for hemostasis is a series of activations of clotting factors. The intrinsic pathway consists of factors I, II, IX, X, XI, and XII. The extrinsic pathway consists of factors I, II, VII, and X. Factor VII is called the stable factor. The common pathway consists of factors I, II, V, VIII, and X. The intrinsic pathway is activated by exposed endothelial collagen, and the extrinsic pathway is activated by tissue factor released by endothelial cells after they are damaged.

Intrinsic pathway ( factor activation)

This pathway is the longer pathway of secondary hemostasis. It begins with the activation of factor XII (zymogen, inactivated serine protease) into factor XIIA (activated serine protease) by endothelial collagen, which is released upon endothelial damage. Factor XIIA acts as a catalyst for the activation of factor XI to factor XIA. In this manner, the cascade is activated until factor X reaches factor Xa. Once activated, a factor continues to activate many more factors in subsequent steps. As you move further down the cascade, the concentration of that factor increases in the blood. For example, the concentration of factor IX is greater than that of factor XI. When factor II is activated by either the intrinsic or extrinsic pathway, it can amplify the intrinsic pathway by providing positive feedback to factors V, VII, VIII, XI, XIII. This makes factor XII less critical; patients can actually clot well without factor XII. The intrinsic pathway is measured clinically as the partial thromboplastin time (PTT).

External path (tissue factor)

The extrinsic pathway is the shorter route of secondary hemostasis. Once we have a blood vessel injury, endothelial cells release tissue factor, which further activates factor VII to factor VIIa. Factor VIIa in turn activates factor X to factor Xa. This is the point at which both the extrinsic and intrinsic pathways become one. The extrinsic pathway is measured clinically as the prothrombin time (PT).

Common path

This pathway begins with factor X, which is activated to factor Xa. The process of activating factor Xa is a complex reaction, but once activated, it continues to activate factor II (prothrombin) to factor IIa (thrombin). Factor Xa also requires factor V as a cofactor to cleave prothrombin to thrombin. Factor IIa (thrombin) continues to activate fibrinogen to fibrin. Thrombin also activates other factors in the intrinsic pathway. Fibrin subunits assemble to form fibrin strands, and factor XIII acts on the fibrin strands to form a fibrin mesh. This mesh helps stabilize the platelet plug.

Negative feedback

To prevent hypercoagulation, which causes widespread thrombosis, there are certain processes that keep the coagulation cascade in check. Since thrombin acts as a procoagulant, it also acts as a negative feedback loop by activating plasminogen to plasmin and stimulating the production of antithrombin (AT). Plasmin acts directly on the fibrin network and degrades it. AT reduces the production of thrombin from prothrombin and reduces the amount of activated factor X.

Activated protein C and antithrombin are natural anticoagulants that also act to prevent coagulation.

Organs responsible for blood clotting

One of the organs closely involved in the coagulation process is the liver. The liver is responsible for the formation of factors I, II, V, VII, VIII, IX, X, XI, XIII and proteins C and S. Factor VIII is produced by the vascular endothelium.

Liver disease can cause a deficiency of coagulation factors and lead to bleeding. Decreased coagulation factors usually indicate severe liver damage. Factor VII has the shortest half-life, which results in an elevated PT first in liver disease. Coagulopathy in liver disease is treated with fresh frozen plasma.

Conclusion

Given the traumatism in our patients and the associated frequent complications in coagulation, as well as congenital abnormalities of blood clotting, a better knowledge and understanding of hemostasis would help us in our daily work.

References:

1. Physiology, Coagulation Pathway; Raheel Chaudhry; Syed Muhammad Usama; Hani M. Babiker

2. Monitoring and intervention for the critically ill small animal; Rebecca Kirby, Andrew Linklater

3. Back to basics: the coagulation pathway; Seonyang Park1* and Joo Kyung Park

4. Picture from Osmosis.org

5. Bloody easy; www.transfusionontario.org