Coagulation Pathways

Overview of Coagulation Pathways

• Definition: The process by which the body stops bleeding, involving a complex interplay of blood vessels, platelets, and coagulation factors
• Phases of Hemostasis:
  • Primary Hemostasis: Formation of a temporary platelet plug at the site of vascular injury
  • Secondary Hemostasis: Activation of the coagulation cascade, leading to the formation of a stable fibrin clot
  • Fibrinolysis: Breakdown of the fibrin clot once the vessel has healed
• Coagulation Pathways: A series of enzymatic reactions involving coagulation factors that ultimately result in the formation of fibrin

Components of the Coagulation System

• Coagulation Factors:
  • Most are serine proteases (enzymes that cleave peptide bonds in proteins)
  • Synthesized primarily in the liver
  • Circulate in the blood in an inactive form (zymogens)
  • Activated by specific activators or by other coagulation factors
  • Numbered with Roman numerals (e.g., Factor I, Factor II, Factor III)
• Cofactors:
  • Non-enzymatic proteins that enhance the activity of coagulation factors
  • Examples: Factor V, Factor VIII, Tissue Factor (Factor III)
• Calcium (Ca2+):
  • Essential for the activity of several coagulation factors (e.g., Factors II, VII, IX, X)
• Phospholipids:
  • Provide a surface for the assembly of coagulation complexes
  • Platelet membranes and activated endothelial cells provide phospholipid surfaces

The Coagulation Cascade

The coagulation cascade is traditionally divided into three pathways: the intrinsic pathway, the extrinsic pathway, and the common pathway

• Intrinsic Pathway: (Also known as the Contact Activation Pathway)

  • Initiated by factors within the blood
  • Involves Factors XII, XI, IX, and VIII
  • Steps:
    1. Factor XII is activated to Factor XIIa upon contact with negatively charged surfaces (e.g., collagen, phospholipids)
    2. Factor XIIa activates Factor XI to Factor XIa
    3. Factor XIa activates Factor IX to Factor IXa
    4. Factor IXa, along with its cofactor Factor VIIIa, forms a complex on the platelet surface that activates Factor X

• Extrinsic Pathway: (Also known as the Tissue Factor Pathway)

  • Initiated by factors outside the blood, specifically tissue factor (TF)
  • Involves Tissue Factor (Factor III) and Factor VII
  • Steps:
    1. Tissue factor (TF) is exposed at the site of vascular injury
    2. Factor VII binds to TF, forming the TF-VIIa complex
    3. The TF-VIIa complex activates Factor X to Factor Xa

• Common Pathway:

  • The final pathway in the coagulation cascade, leading to the formation of fibrin
  • Involves Factors X, V, II (prothrombin), and I (fibrinogen)
  • Steps:
    1. Factor Xa, along with its cofactor Factor Va, forms the prothrombinase complex on the platelet surface
    2. The prothrombinase complex converts prothrombin (Factor II) to thrombin (Factor IIa)
    3. Thrombin converts fibrinogen (Factor I) to fibrin monomers
    4. Fibrin monomers spontaneously polymerize to form a fibrin polymer (a loose, unstable clot)

• Note:

  • This traditional division into pathways is useful for understanding the steps involved, but it’s important to recognize that the coagulation cascade is a highly interconnected system with significant cross-talk between the pathways.
  • In vivo, the extrinsic pathway is considered the primary initiator of coagulation

Stabilization of the Fibrin Clot

• Factor XIIIa (Fibrin-Stabilizing Factor):
  • A transglutaminase that cross-links fibrin monomers, forming a stable, insoluble fibrin clot
  • Activated by thrombin
  • Cross-linking of fibrin provides strength and stability to the clot, making it resistant to degradation by plasmin

Cell-Based Model of Coagulation

A more modern model of coagulation emphasizes the role of cells (tissue factor-bearing cells and platelets) in regulating the coagulation process. It divides coagulation into three phases:

• Initiation:
  • Occurs on tissue factor-bearing cells (e.g., subendothelial cells) at the site of vascular injury
  • TF binds to Factor VIIa, forming the TF-VIIa complex
  • TF-VIIa activates Factor X and Factor IX
  • Small amounts of thrombin are generated
• Amplification:
  • Occurs on the platelet surface
  • Thrombin activates platelets and coagulation factors (Factors XI, VIII, and V)
  • Activated platelets provide a phospholipid surface for the assembly of coagulation complexes
• Propagation:
  • Formation of large amounts of thrombin on the platelet surface
  • Factor IXa and Factor VIIIa form a complex that efficiently activates Factor X
  • Factor Xa and Factor Va form the prothrombinase complex, which converts prothrombin to thrombin
  • Thrombin activates fibrinogen to fibrin, leading to clot formation

Natural Anticoagulant Mechanisms

To prevent excessive clot formation and thrombosis, the body has several natural anticoagulant mechanisms:

• Antithrombin:
  • A serine protease inhibitor (serpin) that inhibits thrombin and other coagulation factors (e.g., Factors IXa, Xa, XIa, XIIa)
  • Heparin enhances the activity of antithrombin
• Protein C Pathway:
  • Thrombin binds to thrombomodulin, an endothelial cell receptor
  • The thrombin-thrombomodulin complex activates protein C
  • Activated protein C (APC), along with its cofactor protein S, inactivates Factors Va and VIIIa, inhibiting thrombin generation
• Tissue Factor Pathway Inhibitor (TFPI):
  • Inhibits the TF-VIIa complex, preventing the initiation of coagulation

Vitamin K-Dependent Coagulation Factors

• Vitamin K is a required cofactor for the carboxylation of certain glutamate residues on Factors II (prothrombin), VII, IX, and X, as well as proteins C and S
• Carboxylation is necessary for these proteins to bind calcium and become fully functional
• Vitamin K deficiency or warfarin (Coumadin) inhibits this carboxylation process, leading to decreased levels of functional coagulation factors

Laboratory Testing

• Prothrombin Time (PT):
  • Measures the function of the extrinsic and common pathways
  • Prolonged PT indicates a deficiency or dysfunction of one or more factors in these pathways (e.g., Factor VII, Factor X, Factor V, prothrombin, fibrinogen)
  • Used to monitor warfarin therapy
• Activated Partial Thromboplastin Time (aPTT):
  • Measures the function of the intrinsic and common pathways
  • Prolonged aPTT indicates a deficiency or dysfunction of one or more factors in these pathways (e.g., Factors XII, XI, IX, VIII, X, V, prothrombin, fibrinogen)
  • Used to monitor heparin therapy
• Mixing Studies:
  • Used to differentiate factor deficiencies from factor inhibitors
  • Plasma from a normal individual is mixed with the patient’s plasma
  • If the aPTT or PT corrects with mixing, it suggests a factor deficiency
  • If the aPTT or PT does not correct with mixing, it suggests the presence of a factor inhibitor (e.g., lupus anticoagulant, factor VIII inhibitor)
• Individual Factor Assays:
  • Measure the activity of specific coagulation factors
  • Used to identify specific factor deficiencies (e.g., Factor VIII deficiency in hemophilia A, Factor IX deficiency in hemophilia B)
• Fibrinogen Assay:
  • Measures the concentration of fibrinogen in the plasma
  • Decreased in DIC or severe liver disease
• D-dimer Assay:
  • Measures the level of D-dimer, a fibrin degradation product
  • Elevated in DIC, pulmonary embolism (PE), deep vein thrombosis (DVT), and other thrombotic conditions

Key Terms

• Hemostasis: The process of stopping bleeding
• Coagulation Cascade: A series of enzymatic reactions leading to fibrin formation
• Coagulation Factors: Proteins involved in the coagulation cascade
• Thrombin: A key enzyme that converts fibrinogen to fibrin
• Fibrinogen: A protein that is converted to fibrin, the main component of a blood clot
• Fibrin: An insoluble protein that forms the meshwork of a blood clot
• Prothrombin Time (PT): Test of the extrinsic and common pathways
• Activated Partial Thromboplastin Time (aPTT): Test of the intrinsic and common pathways
• Disseminated Intravascular Coagulation (DIC): A life-threatening condition with widespread clotting and bleeding