Blood Coagulation Cascade, Prothrombin and Fibrinogen

Hemostasis is the mechanism to prevent blood loss. It is a fast acting system that has multiple steps to reduce blood loss, temporarily and then permanently plug the leak until the integrity of the blood vessel is restored. There are four main phases to hemostasis with the blood coagulation phase following vascular constriction (first phase) and then the platelet plug (second phase).

Almost the entire hemostatic mechanism is regulated by various chemicals that are in constant circulation in the blood stream. These chemicals are known as procoagulants but are prevented from acting until there is injury to the blood vessels by another set of chemicals known as anticoagulants. In the normal healthy state, the anticoagulants dominate but once there is injury to the blood vessels, the procoagulants are activated and promote blood clotting.

What is coagulation?

Blood coagulation is the process of forming a blood clot. It follows the development of a platelet plug as part of hemostasis and is essentially a continuation of the platelet phase. Blood coagulation does not just start immediately after the formation of a platelet plug but is rather the consequence of a series of steps that commences with vessel injury. The coagulation process involves 12 clotting factors (11 different specialized chemicals and calcium) which act on each other to lead to clot formation and this is known as the coagulation cascade.

Coagulation Process

The process of forming a blood clot can be broadly divided into two pathways :

• Extrinsic pathway which is mediated by factors outside of the blood released during injury.
• Intrinsic pathway which is mediated by factors within the blood coming into contact with the damaged area.

The pathways involved the series of chemical reactions known as the coagulation cascade. If one chemical (blood clotting factor) is missing or fails to act appropriately, the entire cascade can be disrupted and the formation of a blood clot may not occur or arise very slowly. These types of disruption is seen with various blood clotting disorders.

The aim of both the extrinsic and intrinsic pathway is to yield PROTHROMBIN ACTIVATOR.

The extrinsic-intrinsic model of blood clotting has in recent years given way to a new cell-based model of clotting. This has revealed that the intrinsic pathway does not just follow the successful completion of the extrinsic pathways but rather that factors initiated with cell injury trigger both pathways almost simultaneously. Nevertheless, the net result of all the processes is to conclude with the formation of a blood clot.

The two pathways achieve three essential steps :

• Initiating a number of chemicals known as prothrombin activator
• Conversion of prothrombin into thrombin by prothrobin activator
• Conversion of fibrinogen into fibrin by thrombin

Fibrin are long strands of protein which then form a mesh network securing the platelets laid down in the previous phases of hemostasis and trapping other blood cells and components to form a blood clot.

Extrinsic Pathway

When the blood vessel wall is damaged, the tissue releases tissue factor also known as tissue thromboplastin (Factor III). This is the start of the coagulation cascade.

• Factor III (tissue thromboplastin) activates Factor VII (activated = VIIa). Calcium is also involved in the activation (calcium-dependent step).
• Activated Factor VII (VIIa) then activates Factor X (activated = Xa).
• Activated Factor X (Xa) + Factor V* + platelet phospholipids = Prothrombin Activator.
• Prothrombin Activator works with calcium to convert prothrombin into thrombin.

* It is important to note that Factor V is only activated by thrombin. Therefore initially the Prothrombin Activator complex is still capable of converting prothrombin into thrombin even with the inactive Factor V component but becomes much more efficient once the Factor V is activated.

Intrinsic Pathway

This pathway is triggered by the blood coming into contact with the collagen into damaged vessel wall. It may also be triggered by trauma to the blood cells in an otherwise intact blood vessel. These two trigger factors then activate Factor XII (XIIa).

• Activated Factor XII (XIIa) along with the other clotting factors prekallikrein and kininogen activate Factor XI (activated = Factor XIa).
• Activated Factor XI (XIa) then works with calcium to activate Factor IX (IXa).
• Activated Factor IX (IXa) along with calcium and Factor VIII ** (activated by thrombin to yield Factor VIIIa) then activated Factor X (Xa). Platelet phospholipids also contribute to this step.
• Activated Factor X (Xa) + Factor V** + platelet phospholipids = Prothrombin Activator.
• Prothrombin Activator works with calcium to convert prothrombin into thrombin.

** As explained above Factor V is only activated by thrombin yet Prothrombin Activator can function with inactive Function V albeit not as efficiently. Similarly Factor VIII needs thrombin to become activated.

Extrinsic vs Intrinsic Pathway

As outlined above, both the extrinsic and intrinsic pathways utilize different blood clotting factors to  yield Prothrombin Activator. Despite this, both pathways are necessary for rapid clotting and and maintaining the blood clot until the blood vessel wall heals. The difference between these two pathways though is time – extrinsic pathway happens within seconds. It is not only rapid but capable of involving large quantities of the relevant clotting factors to yield a large clot if necessary. The intrinsic pathway is much slower taking minutes to yield Prothrombin Activator.

Prothrombin

Prothrombin is one of the proteins in constant circulation in the blood. It is manufactured by the liver and requires vitamin K. Since the body is constantly plugging small tears throughout the system everyday, prothrombin is rapidly used up. If the liver does not produce thrombin for one or two days, blood clotting is compromised. As explained above the extrinsic and intrinsic pathways yield Prothrombin Activator. This converts prothrombin into thrombin. Thrombin is essentially an enzyme  that then converts fibrinogen into fibrin.

Fibrinogen

Fibrinogen is a protein formed by the liver. When thrombin acts on it, fibrinogen is converted into a lighter protein known as fibrin. Many fibrin molecules can attach to each other to form long fibrin strands. These strands are then laid down over the platelet plug (second phase of hemostasis) to secure the platelets, trap blood cells and more firmly seal the area. This is essentially a blood clot.