Medicine & USMLE

Platelet Plug Formation

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Platelet Disorders
  1. Platelet Plug Formation
  2. Bernard-Soulier Syndrome
  3. Glanzmann Thrombasthenia
  4. Immune Thrombocytopenic Purpura (ITP)
  5. Thrombotic Thrombocytopenic Purpura (TTP)
  6. Hemolytic Uremic Syndrome (HUS)

Summary

Platelet plug formation, also known as primary hemostasis, is the first of two processes required to form a blood clot. This process occurs over many different steps.

Platelet plug formation begins with injury to a vessel wall, which exposes collagen to circulating blood. Transient vasoconstriction also occurs at the site of injury, which enables von Willebrand Factor or vWF to bind to the exposed collagen.

Next, a circulating platelet adheres to the vWF via its Gp1b receptor. The interaction between vWF and Gp1b receptors on platelets can be stimulated in laboratory settings by the addition of ristocetin. After adhering to vWF, the platelet releases ADP, TXA2, and calcium ions, all of which play important roles in later hemostasis.

Notably, this release attracts other circulating platelets to the injury site, where they become activated upon ADP-receptor binding. After activation, these platelets express Gp2b/3a on their surfaces. Circulating fibrinogen then acts as a bridge to link platelets together via their Gp2b/3a receptors. The end result is aggregation into a platelet plug, which serves to block blood flow to the injury site and prevent blood loss. This platelet plug is later stabilized by the coagulation cascade to form a stable blood clot.

As you might expect, the formation of a platelet plug is stimulated by vasoconstriction, TXA2, and activated platelets - since all of these factors play a role in this formation pathway. In contrast, nitrous oxide and PGI2 both work as important inhibitors of platelet plug formation.

Key Points

  • Platelet Plug Formation
    • Also known as primary hemostasis
      • First step of blood clot formation
      • Coagulation cascade is known as secondary hemostasis
    • Injury exposes collagen (subendothelial) and matrix
      • Transient vasoconstriction
        • Via neural stimulation reflex and endothelin (released by damaged endothelial cells)
        • Works to slow blood flow, increasing time for vWF and platelets to bind
      • vWF binds to exposed collagen
        • vWF from Weibel-Palade bodies in endothelial cells and alpha-granules of platelets
    • Platelet adhere to vWF via GpIb to damaged vessel wall
      • Platelet activates and degranulates after binding to release:
        • ADP
          • Stimulates activation of nearby platelets (see below)
        • Thromboxane A2 (TXA2)
          • Also stimulates platelet activation
          • Aspirin blocks TXA2 by preventing its synthesis by COX
        • Calcium (Ca2+)
          • Stimulates coagulation cascade (secondary hemostasis) and improves stability of platelet plug
        • Von Willebrand Factor (vWF)
          • Found in alpha-granules of platelets, contributes to even more adhesion
      • Ristocetin activates vWF to bind GpIb
        • Used in ristocetin cofactor assay to diagnose vWD (deficiency of vWF) and Bernard-Soulier syndrome (deficiency of GpIb)
    • Nearby platelets activate
      • ADP binding to ADP-receptor (P2Y12 receptor) induces GpIIb/IIIa expression on surface
        • Clopidogrel, prasugrel, and ticlopidine block ADP-receptor to reduce GPIIb/IIIa expression
        • Abciximab, eptifibatide, and tirofiban block GpIIb/IIIa directly
      • Activated platelets also undergo conformational change
        • Spread out in shape to become wider, allowing more blockage of flow and more surface for adhesion
    • Platelets aggregate into a plug
      • Fibrinogen links platelets together via GpIIb/IIIa
        • This is a temporary platelet plug, unstable and easily dislodged
        • Requires fibrinogen to be converted into fibrin to stabilize blood clot (via secondary hemostasis)
        • Fibrinogen is derived from dense granules of platelets
      • Maintenance of platelet plug is a balance between
        • Pro-aggregation factors
          • TXA2
            • released by platelets, stimulates activation
          • Decreased blood flow
            • Slowing blood flow allows more platelets to interact with the surface
          • Increased platelet aggregation
            • Blocking vessel lumen to slow blood flow
          • Platelet-activating factor (PAF)
        • Anti-aggregation factors
          • PGI2 and NO (released by endothelial cells)
            • Work to vasodilate blood vessels, thereby increasing blood flow and decreasing platelet adhesion
          • Increased blood flow
          • Decreased platelet aggregation
    • Monitoring
      • Bleeding time (BT)
        • Measures time to platelet plug