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Hematology

Physiology

Hemostasis is a highly regulated, dynamic physiological process designed to maintain blood in a fluid state within intact vessels while inducing a rapid and localized response to vascular injury to minimize blood loss. This system relies on a delicate balance between procoagulant forces (clot promotion) and anticoagulant/fibrinolytic forces (clot inhibition and dissolution). The process is generally conceptualized in stages: the vascular response, primary hemostasis (platelet plug formation), secondary hemostasis (fibrin clot formation), and fibrinolysis (clot removal)

Vascular System

The vascular endothelium is not merely an inert tubing system but the primary regulator of hemostasis. Under normal physiological conditions, the intact endothelium maintains an antithrombotic environment to ensure blood fluidity. However, upon injury, the vessel wall undergoes immediate structural and biochemical changes to become prothrombotic, initiating the hemostatic response

0.0.1 Key Vascular Functions

  • Antithrombotic Properties (Intact Endothelium)
    • Physical Barrier: Prevents contact between platelets/coagulation factors and the subendothelial matrix
    • Platelet Inhibition: Secretes Prostacyclin (PGI2) and Nitric Oxide (NO) to inhibit platelet activation and cause vasodilation. Ecto-ADPase (CD39) degrades ADP to prevent platelet aggregation
    • Anticoagulation: Expresses Thrombomodulin (activates Protein C), Heparan Sulfate (enhances Antithrombin), and Tissue Factor Pathway Inhibitor (TFPI)
    • Fibrinolytic Promotion: Synthesizes Tissue Plasminogen Activator (tPA)
  • Prothrombotic Properties (Injured Endothelium)
    • Vasoconstriction: mediated by Endothelin-1 and neural reflexes to reduce blood flow to the injury site
    • Exposure of Subendothelium: Reveals collagen (binds Platelet GPVI and activates Factor XII) and von Willebrand Factor (binds Platelet GPIb/IX/V)
    • Tissue Factor Expression: Exposed endothelial cells and subendothelial fibroblasts express Tissue Factor (TF) to initiate the extrinsic coagulation pathway
    • Secretion: Releases stored vWF from Weibel-Palade bodies to assist adhesion

Coagulation Pathways (Secondary Hemostasis)

Secondary hemostasis involves the activation of the coagulation cascade, a series of enzymatic reactions that transform circulating zymogens (inactive precursors) into active serine proteases. The ultimate goal of this cascade is the conversion of fibrinogen (Factor I) into a stable fibrin clot. While classically taught as two separate pathways (Intrinsic and Extrinsic) converging on a Common pathway - a model essential for interpreting lab tests like PT and aPTT - physiological coagulation is best understood via the Cell-Based Model (Initiation, Amplification, and Propagation)

Coagulation Cascade

  • Extrinsic Pathway (Tissue Factor Pathway)
    • The primary in vivo initiator of coagulation
    • Triggered by the release of Tissue Factor (Factor III) from damaged tissue
    • TF binds with Factor VII to form the TF-VIIa complex, which activates Factor X
    • Assessed in the laboratory by the Prothrombin Time (PT)
  • Intrinsic Pathway (Contact Activation Pathway)
    • Initiated by contact with negatively charged surfaces (collagen, phospholipids)
    • Involves Factors XII, XI, IX, and VIII
    • Factor IXa complexed with cofactor VIIIa activates Factor X
    • Assessed in the laboratory by the Activated Partial Thromboplastin Time (aPTT)
  • Common Pathway
    • The convergence point where Factor Xa, complexed with cofactor Va (Prothrombinase Complex), converts Prothrombin (Factor II) to Thrombin (Factor IIa)
    • Thrombin cleaves Fibrinogen (Factor I) into fibrin monomers, which polymerize
    • Factor XIIIa (activated by thrombin) cross-links these monomers to stabilize the clot
  • Vitamin K Dependence
    • Factors II, VII, IX, and X, as well as Protein C and Protein S, require Vitamin K for gamma-carboxylation. This process allows these factors to bind calcium and adhere to phospholipid surfaces
    • Warfarin therapy targets this mechanism

Natural Anticoagulants

  • Antithrombin: Inhibits Thrombin and Factors Xa, IXa, XIa, and XIIa (activity enhanced by Heparin)
  • Protein C Pathway: Thrombin-Thrombomodulin complex activates Protein C. Activated Protein C (APC), with Protein S, inactivates cofactors Va and VIIIa
  • TFPI: Inhibits the TF-VIIa complex

Fibrinolytic Pathways

Fibrinolysis is the enzymatic breakdown of the fibrin clot, a crucial process to restore vascular patency once tissue repair is underway. This system must be tightly regulated to prevent premature clot dissolution (bleeding) or persistence of thrombi (thrombosis)

Mechanism of Fibrinolysis

  • Activation: Plasminogen (an inactive zymogen trapped within the clot) is converted to Plasmin by activators
    • Tissue Plasminogen Activator (tPA): Released by endothelial cells; highly specific for fibrin-bound plasminogen
    • Urokinase Plasminogen Activator (uPA): Active in extravascular tissue
    • Streptokinase: Exogenous bacterial activator used therapeutically
  • Action of Plasmin: Plasmin is a potent serine protease that digests fibrin into Fibrin Degradation Products (FDPs), including D-dimers, X, Y, and E fragments. Plasmin can also degrade fibrinogen and Factors V and VIII if not regulated
  • Regulation (Inhibition)
    • Plasminogen Activator Inhibitor-1 (PAI-1): The primary inhibitor of tPA and uPA
    • Alpha-2-Antiplasmin: Rapidly binds and neutralizes free circulating plasmin to prevent systemic fibrinolysis
    • TAFI (Thrombin Activatable Fibrinolysis Inhibitor): Modifies fibrin to make it resistant to plasmin
  • Clinical Marker: The D-dimer assay specifically measures cross-linked fibrin fragments, distinguishing fibrinolysis (clot breakdown) from fibrinogenolysis. Elevated levels are seen in DIC, DVT, and PE