Vascular System

Overview of the Vascular System in Hemostasis

• Definition: The vascular system, comprised of arteries, veins, and capillaries, is much more than just a network of pipes. It plays a dynamic and integral role in maintaining hemostasis, both at rest and in response to injury
• Key Roles
  • Provides a physical barrier to prevent blood loss after injury
  • Regulates blood flow to the site of injury
  • Releases substances that activate platelets and coagulation factors
  • Inhibits coagulation to prevent excessive clot formation
  • Participates in fibrinolysis to remove clots after tissue repair
• Components
  • Endothelial Cells: The inner lining of blood vessels
  • Subendothelial Matrix: Located beneath the endothelial cells, containing collagen, von Willebrand factor (vWF), and other substances

Endothelial Cells: The Gatekeepers of Hemostasis

Endothelial cells are the key regulators of hemostasis. They have both procoagulant and anticoagulant properties, maintaining a delicate balance to prevent both bleeding and thrombosis

• Intact Endothelium (Antithrombotic Properties)

  • Physical Barrier
    • Provides a smooth, non-thrombogenic surface that prevents platelets and coagulation factors from adhering to the vessel wall
  • Inhibition of Platelet Activation
    • Production of Prostacyclin (PGI2): PGI2 is a vasodilator and inhibits platelet activation and aggregation
    • Production of Nitric Oxide (NO): NO is a vasodilator and inhibits platelet adhesion and aggregation
    • CD39 (Ecto-ADPase): Degrades ADP, a potent platelet activator
  • Inhibition of Coagulation
    • Thrombomodulin: Binds to thrombin, converting it from a procoagulant to an anticoagulant enzyme that activates Protein C. Protein C then inhibits Factors Va and VIIIa
    • Heparan Sulfate: Binds to antithrombin, enhancing its ability to inhibit thrombin and other coagulation factors (IXa, Xa, XIa, XIIa)
    • Tissue Factor Pathway Inhibitor (TFPI): Inhibits the Tissue Factor-VIIa complex, preventing the initiation of the extrinsic pathway of coagulation
  • Promotion of Fibrinolysis
    • Tissue Plasminogen Activator (tPA): Released by endothelial cells to activate plasminogen and promote fibrinolysis

• Injured Endothelium (Procoagulant Properties)

  • Exposure of Subendothelial Matrix
    • Damage to the endothelium exposes the underlying subendothelial matrix, which contains collagen and von Willebrand factor (vWF)
    • Collagen: Activates platelets and initiates the intrinsic pathway of coagulation
    • vWF: Binds to platelet GPIb/IX/V, mediating platelet adhesion to the damaged vessel wall
  • Tissue Factor (TF) Expression
    • Endothelial cells express tissue factor (TF) on their surface upon activation by inflammatory cytokines or other stimuli
    • TF initiates the extrinsic pathway of coagulation
  • Inhibition of Natural Anticoagulants
    • Damaged endothelial cells reduce their production of thrombomodulin, heparan sulfate, and TFPI, diminishing their anticoagulant properties
  • Release of Platelet Activating Factors
    • von Willebrand Factor (vWF): vWF is released from Weibel-Palade bodies in endothelial cells
    • Platelet Activating Factor (PAF): Some endothelial cells can synthesize and release PAF

The Subendothelial Matrix: A Scaffold for Hemostasis

The subendothelial matrix is a complex layer located beneath the endothelial cells that contains various proteins and substances that play a crucial role in hemostasis

• Collagen

  • Provides a surface for platelet adhesion and activation
  • Binds to platelet glycoprotein VI (GPVI), initiating intracellular signaling pathways that lead to platelet activation and aggregation
  • Also activates the intrinsic pathway of coagulation by activating Factor XII

• von Willebrand Factor (vWF)

  • Binds to platelet GPIb/IX/V, mediating platelet adhesion to the damaged vessel wall
  • Especially important under high shear stress conditions, such as in small arteries and arterioles
  • Also binds to Factor VIII, protecting it from degradation

• Other Components

  • Fibronectin, laminin, and other adhesive proteins that contribute to platelet adhesion and cell migration

Regulation of Blood Flow: Vasoconstriction & Vasodilation

The vascular system regulates blood flow to the site of injury through vasoconstriction and vasodilation:

• Vasoconstriction

  • Immediate response to vascular injury
  • Reduces blood flow to the injured area, limiting blood loss and promoting platelet adhesion
  • Mediated by:
    • Endothelin-1: A potent vasoconstrictor released by endothelial cells
    • Thromboxane A2 (TxA2): Released by activated platelets
    • Nervous system reflexes

• Vasodilation

  • Occurs later in the hemostatic process to promote tissue repair and angiogenesis (formation of new blood vessels)
  • Mediated by:
    • Nitric Oxide (NO): Released by endothelial cells
    • Prostacyclin (PGI2): Released by endothelial cells
    • Vascular endothelial growth factor (VEGF): Promotes angiogenesis

Angiogenesis

• Definition: The formation of new blood vessels from pre-existing vessels
• Role in Hemostasis and Wound Healing
  • Provides nutrients and oxygen to the healing tissue
  • Removes waste products
• Regulation
  • Vascular Endothelial Growth Factor (VEGF): The primary driver of angiogenesis
  • Other growth factors and cytokines: Also involved in regulating angiogenesis