The Blood Coagulation Pathway and related Disorders

Blood clotting, also known as hemostasis, is a fascinating and intricate process that ensures our bodies can effectively respond to injuries and prevent excessive bleeding. It involves a complex network of interactions, called the coagulation pathways. These pathways consist of a series of enzymatic reactions, triggered by the release of substances called clotting factors that ultimately lead to formation of blood clots.

Examples of clotting factors include :

• Fibrinogen
• Platelets
• Calcium

The release of these clotting factors is regulated by a number of different mechanisms, including the presence of certain proteins in the blood, the pH of the blood, and the temperature of the blood. In this blog post, we will delve into the coagulation pathways, exploring the key clotting factors involved and shedding light on how these pathways contribute to maintaining hemostasis in the human body

There are two main pathways that contribute to blood clot formation - The extrinsic and intrinsic coagulation pathways. In the extrinsic pathway, tissue factor, released from damaged tissue, initiates clot formation. On the other hand, the intrinsic pathway is activated by contact between blood and exposed surfaces, such as collagen in the blood vessel wall. Let;s look into both these pathways in detail

The intrinsic pathway, also known as the contact activation pathway, is one of the two primary pathways involved in blood coagulation. It plays a crucial role in amplifying the coagulation process and is activated when blood comes into contact with certain surfaces, such as collagen in the blood vessel wall. Other activators include kallikrein and high molecular weight kininogen (HMWK). The intrinsic clotting factors and the steps involved are explained below.

1. Factor XII (Hageman Factor): The intrinsic pathway is initiated by the activation of Factor XII, also known as Hageman Factor. Factor XII circulates in the blood as an inactive enzyme. Upon contact with an exposed surface, such as collagen, kallikrein (converted from prekallikrein when complexed with collagen) and high molecular weight kininogen (HMWK), in the blood vessel wall, it undergoes a conformational change and becomes activated as Factor XIIa.

2. Factor XI: Activated Factor XIIa then converts Factor XI into its active form, Factor XIa. This conversion occurs on the surface of platelets or other negatively charged substances present at the site of injury.

3. Factor IX: Factor XIa acts as an enzyme and cleaves inactive Factor IX into its active form, Factor IXa. This step occurs in the presence of calcium ions.

4. Factor VIII: Once activated, Factor IXa forms a complex with Factor VIII, a cofactor that stabilizes and enhances the activity of Factor IXa. This complex is known as the Factor IXa-Factor VIIIa complex. HMWK also interacts with this complex, further assisting in the activation of Factor XI.

5. Factor X Activation: The Factor IXa-Factor VIIIa complex, along with calcium ions, activates Factor X, converting it into its active form, Factor Xa. This activation takes place on the surface of a phospholipid membrane. Activation of Factor X leads into the common pathway.

Extrinsic Blood Coagulation Pathway, also known as the Tissue Factor Pathway, is another pathway of blood clotting. In the extrinsic pathway, clotting is triggered by factors other than tissue damage. For example, if you cut yourself, chemicals released from your white blood cells will activate factor VII, which starts the cascade of reactions that leads to clot formation. The extrinsic clotting factors and the steps involved are explained below.

1. Tissue Factor (TF): The extrinsic pathway, also known as the tissue factor pathway, is initiated by the release of tissue factor (TF), also called Factor III, from damaged cells outside the blood vessels, such as in the surrounding tissue. TF is not normally exposed to the bloodstream but becomes exposed during tissue injury or trauma.

2. Tissue Factor-Factor VII Complex: When tissue damage occurs, TF binds to and forms a complex with Factor VII, a plasma protein. This complex is referred to as the tissue factor-Factor VIIa complex. Factor VII is normally present in an inactive form in the blood. However, when it binds to TF, it undergoes a conformational change and becomes activated as Factor VIIa.

3. Activation of Factor X: The tissue factor-Factor VIIa complex serves as a catalyst for the activation of Factor X, which is a key enzyme in the coagulation cascade. The complex activates Factor X by cleaving it, converting it from its inactive form to its active form, Factor Xa. Activation of Factor X leads into the common pathway.

4. Common Pathway: Once Factor X is activated, it joins the common pathway of coagulation. Factor Xa combines with Factor V and calcium ions to form the prothrombinase complex, which acts as an enzyme to convert prothrombin (Factor II) into thrombin (activated Factor II).

5. Thrombin and Fibrin Formation: Thrombin, the active form of prothrombin, plays a central role in coagulation. It converts fibrinogen (Factor I) into fibrin, which forms a meshwork of insoluble fibers. Thrombin then activates factor XIII, which cross-links fibrin monomers, stabilizing the clot. The fibrin meshwork traps platelets and red blood cells, forming a stable blood clot at the site of injury.

The common pathway is the final pathway of blood clotting. In this pathway, clotting is triggered by the presence of calcium ions in the blood. Calcium ions are needed for the activation of factor XII and factor VII. They also play a role in the activation of factor IX and factor X. The common pathway is activated when any of the other pathways are triggered; known as the common pathway because it involves all of the clotting factors. The common pathway begins when factor XII (FXII) is activated by contact with a foreign surface. This FXII then activates FXI, which in turn activates FIX. FIX then activates FX, which then activates prothrombin. Prothrombin is then converted to thrombin by FVIIa, and thrombin converts fibrinogen to fibrin. The fibrin then polymerizes to form a clot.

The intrinsic pathway amplifies the coagulation process by activating additional clotting factors. It plays a significant role in maintaining hemostasis and ensuring appropriate clot formation. The extrinsic pathway provides a rapid response to tissue injury and is considered the primary trigger for initiating clot formation. It bypasses several steps involved in the intrinsic pathway, allowing for a swift and efficient coagulation response. It's important to note that while the extrinsic pathway primarily relies on tissue factor and Factor VII, it also interacts with other clotting factors and components of the common pathway to ensure proper coagulation. The extrinsic pathway and intrinsic pathway work in tandem to form a cohesive response to tissue injury and maintain hemostasis in the body.

The blood coagulation cascade is a vital process that helps to prevent excessive bleeding. There are many diseases that can arise from dysregulation of the blood coagulation cascade.

Hemophilia is a disorder in which there is a deficiency of one of the clotting factors. This can lead to excessive bleeding and easy bruising.

Heamophilia A (classical hemophilia) is a disorder in which there is a deficiency of factor VIII. This can lead to easy bruising, excessive bleeding, and joint damage. Heamophilia A id due to a mutation in the FVIII gene, resulting in the production of a defective or missing protein.

Heamophilia B (Christmas hemophilia) in which there is a deficiency of factor IX. This can lead to easy bruising, excessive bleeding, and joint damage. Hemophilia B is due to a mutation in the FIX gene, resulting in the production of a defective or missing protein.

Von Willebrand disease is the most common inherited bleeding disorder, caused by a deficiency or dysfunction of von Willebrand factor (vWF). vWF plays a crucial role in platelet adhesion and stabilizing factor VIII in the blood. Symptoms can vary from mild to severe and include nosebleeds, easy bruising, heavy or prolonged menstrual bleeding, and excessive bleeding after dental procedures or surgery.

Thrombocytopenia refers to a low platelet count in the blood. Platelets are essential for blood clotting, so a reduced count can lead to excessive bleeding or easy bruising. Thrombocytopenia can be caused by various factors, including autoimmune disorders, medications, viral infections, bone marrow disorders, or certain cancers.

APS is an autoimmune disorder where the immune system mistakenly produces antibodies against certain phospholipids, leading to abnormal blood clotting. This can result in recurrent blood clots in arteries or veins, such as deep vein thrombosis or stroke, as well as pregnancy complications like recurrent miscarriages or pre-eclampsia.

Hypercoagulable states, also known as thrombophilia or hypercoagulability, refer to conditions or factors that increase the risk of excessive blood clotting (thrombosis) within the blood vessels. These conditions can be inherited (genetic) or acquired, and they disrupt the balance between procoagulant and anticoagulant factors, leading to an increased tendency to form blood clots. Some Clinical Manifestations are:

1. Deep Vein Thrombosis (DVT): DVT occurs when a blood clot forms in one of the deep veins, typically in the leg. It is often associated with prolonged immobility, surgery, trauma, cancer, pregnancy, obesity, or inherited clotting disorders. DVT can lead to pain, swelling, warmth, and redness in the affected leg. If a clot dislodges and travels to the lungs, it can cause a potentially life-threatening condition called a pulmonary embolism.
2. Pulmonary Embolism (PE): PE occurs when a blood clot, usually originating from a deep vein in the leg (DVT), travels to the lungs and blocks blood flow. Symptoms include sudden shortness of breath, chest pain, rapid heart rate, coughing up blood, and sometimes fainting. PE requires immediate medical attention as it can be life-threatening.
3. Disseminated Intravascular Coagulation (DIC): DIC is a serious condition characterized by abnormal blood clotting and excessive bleeding occurring simultaneously. It is often secondary to an underlying condition such as sepsis, trauma, cancer, or complications during pregnancy. DIC can lead to organ damage, bleeding from various sites, and potentially life-threatening complications.