Blood Coagulation Basics | Zoology Optional Notes for UPSC PDF Download

Blood Coagulation and Platelet-Mediated Primary Haemostasis

1. Defense Mechanisms Against Bleeding: Blood coagulation and platelet-mediated primary haemostasis serve as crucial defense mechanisms against bleeding.

2. Trigger for Coagulation System: The coagulation system is triggered when there is endothelial rupture, exposing blood to extravascular tissue.

3. Coordination with Platelet Plug Formation: Coagulation responses are coordinated with the formation of the platelet plug, which initially occludes the vascular lesion.

   

4. Anticoagulant Mechanisms: Anticoagulant mechanisms play a crucial role in controlling coagulation. Under normal conditions, these mechanisms prevail over procoagulant forces.

5. Natural Balance: A delicate balance exists between procoagulant and anticoagulant systems. This balance is essential for maintaining normal hemostasis.

6. Genetic or Acquired Factors: Disturbances in the natural balance can occur due to genetic or acquired factors.

7. Consequences of Imbalance: Imbalances in the procoagulant and anticoagulant systems may lead to bleeding disorders or thrombotic diseases.

8. Coordinated Response: The responses of the coagulation system and platelet plug formation are intricately coordinated to prevent excessive bleeding while maintaining vascular integrity.

9. Controlled Coagulation: Anticoagulant mechanisms ensure careful control of the coagulation process, preventing it from becoming excessive or uncontrolled.

10. Clinical Implications: Understanding the balance and regulation of these hemostatic mechanisms is crucial for diagnosing and managing bleeding or thrombotic disorders in clinical settings.

The coagulation pathway is a complex series of reactions that plays a crucial role in preventing bleeding. Thrombin, a key effector enzyme, is central to this system and performs various important functions, including platelet activation and the conversion of fibrinogen to a fibrin network. The generation of thrombin is a highly regulated process involving a series of ordered reactions collectively referred to as blood coagulation.

Key Components of the Coagulation Pathway

1. Tissue Factor (TF):

   • TF is a membrane protein abundantly present in cells surrounding the vascular bed.
   • It binds both zymogen and activated forms of factor VII (factor VIIa).
   • Coagulation is triggered when factor VIIa binds to TF, converting factors IX and X to their active forms (IXa and Xa).
   • Feedback amplification occurs through the activation of factor VII by factors VIIa, IXa, and Xa.

2. Prothrombinase Complex:

   • Prothrombin is activated to thrombin by the prothrombinase complex.
   • The complex consists of the phospholipid-bound complex between the enzyme factor Xa and its cofactor, activated factor V (Va).
   • Thrombin feedback amplifies the system by activating factors V, VIII, and XI.

3. Thrombin Generation:

   • Maximum thrombin generation occurs after the formation of the fibrin clot.
   • Thrombin is essential for additional fibrin generation and activates factor XIII and thrombin-activatable fibrinolysis inhibitor.
   • Activated factor XIII (XIIIa) stabilizes the clot by covalent crosslinking of fibrin.
   • Thrombin-activatable fibrinolysis inhibitor prevents further fibrinolytic attack.

4. Phosphatidylserine:

   • Phosphatidylserine is a negatively charged phospholipid required for the assembly of the tenase and prothrombinase complexes.
   • During platelet activation, phosphatidylserine is translocated from the inner layer to the outer layer of the plasma cell membrane.

5. Coagulation Proteins in Circulating Blood:

   • Concentrations of coagulation proteins vary based on their specific roles in the pathway.
   • Fibrinogen is the predominant clotting factor, and its concentration is significantly higher than other factors.
   • The assembly of enzyme-cofactor complexes on phospholipid surfaces increases the local concentration of coagulation components.

6. Role of Vitamin K-Dependent Proteins:

   • The enzymes and substrates involved in coagulation are vitamin K-dependent proteins.
   • Antagonists of vitamin K, used in anticoagulant therapy, inhibit the correct folding of the proteins, affecting their interaction with phospholipid membranes.

7. In Vivo Importance of Coagulation Factors:

   • Knock-out mice technology has helped elucidate the relative importance of various coagulation factors in vivo.
   • Tissue factor deficiency leads to embryonic death, emphasizing its crucial role in development.
   • Deficiencies of other factors, such as VII, V, prothrombin, IX, and VIII, have different impacts on embryonic development and postnatal life.

Understanding these intricate details of the coagulation pathway is essential for developing therapies and interventions for bleeding or thrombotic disorders.

Regulation of Blood Coagulation by Anticoagulant Pathways

1. Tissue-Factor-Pathway Inhibitor (TFPI):

   • Inhibits reactions involving tissue factor and factor VIIa.
   • Mostly bound to LDL in plasma or to heparan sulfate when associated with endothelial cells.
   • Lack of TFPI may not be compatible with life, as demonstrated in knock-out mice.

2. Antithrombin:

   • Inhibits most enzymes generated during coagulation, preferentially targeting free enzymes.
   • Inhibits serine proteases and is previously known as antithrombin III.
   • Antithrombin is an inefficient inhibitor itself, but its activity is stimulated by heparin and heparin-like molecules on endothelial cell surfaces.
   • Heparin is used therapeutically as an anticoagulant by enhancing antithrombin's inhibitory function.

3. Protein C Anticoagulant System:

   • Regulates coagulation by modulating the activity of cofactors factors VIIIa and Va.
   • Protein C, a vitamin-K-dependent zymogen, is activated on intact endothelial cells by thrombin bound to thrombomodulin.
   • Thrombin has dual functions—procoagulant at sites of vascular disruption and anticoagulant in an intact vascular system.
   • Activated Protein C (APC) cleaves phospholipid-membrane-bound cofactors Va and VIIIa, inhibiting the coagulation system.
   • Protein S, a vitamin-K-dependent cofactor, supports APC's anticoagulant activity.
   • APC and free protein S form a membrane-bound complex, cleaving factors VIIIa and Va, even within fully assembled tenase and prothrombinase complexes.
   • Factor V can function both as a procoagulant (factor Va) and an anticoagulant cofactor after limited proteolysis by thrombin or factor Xa.

4. Role of Factor V:

   • APC can cleave intact factor V, leading to the generation of anticoagulant factor V.
   • Factor V serves as both a procoagulant (factor Va) and an anticoagulant cofactor.
   • The anticoagulant potential of factor V is crucial in the regulation of the tenase complex by APC and protein S.

Physiological Importance:

• Severe thromboembolic disease is associated with homozygous deficiency of protein C in both humans and mice.
• Mice lacking a functional thrombomodulin gene exhibit even more severe disease, leading to lethality during embryogenesis, emphasizing the critical role of the protein C system in regulating coagulation.

Understanding the delicate balance between procoagulant and anticoagulant mechanisms is essential for maintaining hemostasis and preventing excessive bleeding or thrombotic diseases. Dysregulation of these pathways can lead to severe clinical consequences.

Inherited and Acquired Coagulation Disorders

1. Inherited Disorders: a. Hemophilia A (Factor VIII Deficiency) and Hemophilia B (Factor IX Deficiency): - Rare bleeding disorders with a prevalence of about one in 10,000. - Genes for both factors are on the X chromosome, affecting only males; females are carriers. - Severe hemophilia is associated with less than 1% of the normal plasma concentration of either factor, while moderate and mild forms have higher concentrations. - Symptoms include bleeding episodes affecting joints, muscles, organs, and the brain. - Joint bleeding (haemarthrosis) is characteristic, leading to chronic arthropathy. - Symptoms usually appear in early childhood.

   b. von Willebrand's Disease: - Caused by quantitative or qualitative defects in von Willebrand factor, leading to a primary haemostasis defect. - Results in deficient adhesion of platelets to subendothelial collagen. - Bleeding symptoms, affecting skin and mucous membranes, start soon after birth. - Clinically heterogeneous with three major categories (Type I, Type II, and Type III) distinguished based on severity and genetic inheritance.

2. Acquired Disorders: a. Autoantibody-Mediated Disorders: - Autoantibodies against coagulation factors, often directed against factor VIII or V. - Mainly affects elderly individuals. - Associated bleeding tendency can be severe and life-threatening. - Molecular mechanisms involved in autoantibody generation are not fully understood.

   b. Vitamin K-Related Bleeding Disorders: - Related to vitamin K requirement in coagulation protein biosynthesis. - Conditions with malabsorption of vitamin K can lead to deficient
   -carboxylation of coagulation proteins, resulting in an increased bleeding tendency. - Deficiency of vitamin K due to excessive intake of antagonists (e.g., warfarin) or severe liver disease can also cause bleeding.

   c. Disseminated Intravascular Coagulation (DIC): - Associated with the consumption of platelets and coagulation factors due to widespread pathological proteolysis. - Activated by severe infections, septicaemia, malignant disease, trauma, surgery, or pregnancy. - Results in microvascular thrombosis and disturbances in capillary circulation.

Laboratory Investigations for Bleeding Disorders

• Initial Tests:
  • Platelet counts, bleeding time, activated partial thromboplastin time (APTT), and prothrombin time (PT).
• Further Tests for Primary Hemostatic Disorders:
  • Functional platelet tests, immunological and functional assays for von Willebrand factor.
• Coagulation Disorder Confirmation:
  • Specific functional and immunological testing for coagulation factors, particularly factors VIII and IX in hemophilia.
• Autoantibody-Mediated Disorders Diagnosis:
  • Based on inhibition in clotting tests by the antibodies.
  • Specific coagulation or immunological tests for identifying the recognized factor.

Note: The comprehensive laboratory diagnosis involves a combination of tests to identify the specific coagulation factor deficiency or dysfunction, providing crucial information for appropriate management and treatment strategies.