The Science of Coagulation

Introduction

Normally, blood flows through the blood vessels in fluid form. However, the blood lost through a ruptured blood vessel gradually becomes a jelly-like blob, hardening into a solid mass within a few minutes. In physiology, this phenomenon is called blood coagulation. In short, coagulation means the clotting of blood. Any abnormalities in the body’s blood coagulation mechanism can have serious effects on health and may lead to serious complications if undiagnosed. These disorders can either be hereditary or acquired over a period of a lifetime. If left untreated, some conditions can also prove to be life-threatening. Treatment and management of coagulation-related disorders are possible and commonly involve anticoagulant or procoagulant drugs.

Significance of Coagulation

Formation of blood plug at the site of injury prevents extensive blood loss, simultaneously preventing any foreign particles from invading the body. Coagulation also marks the beginning of the wound healing process. Thus, coagulation plays an important role in managing a closed blood circulatory system in invertebrates with a high-pressure circulatory system. Some byproducts of blood coagulation are also known to contribute to a stronger immunity system by enhancing vascular permeability and serving as chemotactic agents.

Coagulation factors

Blood Coagulation is a complex system consisting of platelets, endothelial cells and blood-clotting proteins. It is a gradual process involving the interaction of different components present in blood or tissue fluids sequentially. These components are called coagulation factors (Zymogens) and are identified by Roman numerals starting from Factor I to Factor XIII, except Factor VI, which does not exist. Refer to Table 1 for the list of all factors contributing to coagulation.

Table 1
Factor I	Fibrinogen
Factor II	Prothrombin
Factor III	Thromboplastin
Factor IV	Calcium
Factor V	Proaccelerin/Labile factor
Factor VII	Proconvertin /stable factor
Factor VIII	Antihemophilic Factor A/ Antihemophilic Globulin
Factor IX	Antihemophilic Factor B/ Plasma Thromboplastin component
Factor X	Stuart Prower Factor
Factor XI	Plasma thromboplastin antecedent
Factor XII	Hageman Factor/ Contact factor/ Glass factor
Factor XIII	Fibrin stabilising factor
HMW-K/ HK	High molecular weight kininogen/ Fitzgerald factor
Pre-Ka	Prekallikrein/ Fletcher factor
Ka	kallikrein
PL	Platelet Phospholipids

Overview of Coagulation Mechanism

Prevention or stoppage of blood loss from a damaged blood vessel is called hemostasis. Blood clotting is referred to as secondary hemostasis, as it is the second stage in the process of arresting the loss of blood from the injured site. Primary hemostasis involves the blood vessel constriction and platelet aggregation, resulting in the formation of the temporary plug at the site of vessel injury.  Coagulation involves three prominent steps. These are-

1. Formation of Prothrombin activator.
2. Conversion of Prothrombin to Thrombin.
3. Conversion of Fibrinogen to Fibrin.

The formation of a Prothrombin activator may begin by activating two separate pathways, extrinsic and intrinsic pathways.  The extrinsic pathway begins with the trauma to the vascular wall or tissues outside the blood vessel. This pathway starts with Factor VII. The intrinsic pathway begins in the blood after the blood is exposed to collagen in the traumatised vascular wall or due to the contact of blood with a negatively charged surface such as glass. It starts with Factor XII. Although a different trigger activates each pathway, they merge at the stage where factor X is involved during the coagulation cascade of reactions. At this stage, the common pathway begins, which contributes to the formation of Thrombin from Prothrombin (Factor II), an enzyme that facilitates blood clotting by converting fibrinogen (Factor I) to fibrin clot.

Coagulation Disorders 

Dysfunctional coagulation is caused due to the inability of the body to control the formation of blood clots, resulting in either too much clotting (Thrombosis) or too little clotting (haemorrhage). Haemorrhage leads to abnormal bleeding and easy bruising, whereas thrombosis is characterised by the formation of multiple unwanted blood clots. The severity of the condition is directly proportional to the level of coagulation factors. Following are some common coagulation disorders:

Von Willebrand disease

It is a congenital abnormality caused by the deficiency of the Von Willebrand factor.  A person suffering from this disease experiences abnormal bleeding and difficulty in forming clots. Also, the time required in such cases for the formation of a clot is longer than normal. Symptoms include easy bruising, epistaxis (nasal bleeding), hemarthrosis (joint bleeding), rectal bleeding, heavy menstrual bleeding, bleeding from the mouth and haemorrhage on trivial injuries etc. 

Haemophilia

Haemophilia is also a clotting disorder similar to Von Willebrand disease in which patients suffer from abnormal bleeding or extensive blood loss due to difficulty in clot formation. It is more common in males, as it is a recessive X-linked genetic disorder passed to offspring via the X chromosome. This occurs due to the deficiency of certain other coagulation factors and is further classified accordingly.

• Haemophilia A: Haemophilia A, Also known as classic Haemophilia, occurs due to the deficiency of factor VIII/antihemophilic factor. This is the most common deficiency encountered among hemophilic people. Symptoms observed with this deficiency are similar to those occurring due to Von Willebrand factor deficiency, characterised by non-stop bleeding
• Haemophilia B/ Christmas disease: Occurs due to Factor IX deficiency 
• Haemophilia C: It is a comparatively rare condition that occurs due to factor XI deficiency. It is also called Rosenthal syndrome

Fibrinogen deficiency

This rare deficiency occurs due to the missing or reduced factor I, which plays an important role in generating fibrin. The three main types of fibrinogen deficiency are-

• Afibrinogenemia- Complete deficiency of fibrinogen
• Hypofibrinogenemia – Fibrinogen is produced in reduced quantities 
• Dysfibrinogenemia – The amount of fibrinogen produced is normal, but it does not function as expected

Thrombosis

When the blood flow in blood vessels gets obstructed due to the formation of blood clots independent of any injury, this condition is termed thrombosis. 

Liver disease

Severe liver diseases are often associated with coagulopathy. Since the liver is responsible for discarding as well as for synthesising most of the clotting factors, a malfunctioning liver may also lead to the development of disseminated intravascular coagulation syndrome, where clots are formed in abnormal locations. This is a form of acquired coagulation disorder.

Anticoagulants

Normal coagulation occurs when there is the perfect balance between procoagulant activity and the anticoagulant system. Naturally occurring anticoagulants in the body regulate the procoagulant activity in the blood, helping localised thrombus formation. Antithrombin and Tissue factor plasminogen inhibitors are the two main parts of the natural anticoagulant system.  Antithrombin is the main inhibitor of thrombin, whose enzymatic activity is enhanced in the presence of heparin, while Tissue factor plasminogen inhibitor is a polypeptide produced by endothelial cells and acts as a natural inhibitor of the extrinsic pathway. In cases where blood coagulationdoes not work properly, anticoagulant drugs or antiplatelet medicine are administered to manage the abnormal clotting. Also termed as blood thinners, these are chemical substances that assist in preventing blood coagulationor prolonging the process of clotting. Apixaban, Heparin, Edoxaban, Rivaroxaban, Dabigatran and Warfarin etc. are examples of anticoagulants. Antiplatelet drugs include Aspirin, Prasugrel, Clopidogrel and Ticagrelor etc. Coagulation in vertebrates is a very important phenomenon assisting in keeping a closed blood circulatory system, especially with the body’s evolved high-pressure circulation. It is achieved through a complex set of self-regulating cascading reactions involving different coagulation factors. Any deficiency in the contributing factors may result in coagulation disorders with mild to severe symptoms. They can be congenital, such as Haemophilia or acquired, such as disseminated intravascular coagulation syndrome. In cases of abnormal bleeding, such as in Haemophilia, procoagulant drugs or hormone therapy may be used to help the formation of clots. On the contrary, in cases where too much blood clotting is observed, external drugs such as anticoagulants or antiplatelet agents are used to maintain free blood flow and prevent resultant situations such as strokes etc. 

Conclusion

Coagulation means the clotting of blood. Any abnormalities in the body’s blood coagulation mechanism can have serious effects on health and may lead to serious complications if undiagnosed.Prevention or stoppage of blood loss from a damaged blood vessel is called haemostasis. Blood clotting is referred to as secondary haemostasis.