Platelets and Platelet Granules

Platelets

• Platelets are cytoplasmic fragments originating from megakaryocytes in the bone marrow.
• Megakaryocytes remain in the bone marrow and release small pieces of cytoplasm into circulation as platelets.
• Platelets are anucleated and contain granules storing key molecules for clotting.
• On stained blood smears, platelets appear as small, purplish-pink structures.

Platelet Granules

• Platelets contain granules (dense and alpha granules), which are specialized storage compartments containing various substances necessary for their activation and function during clot formation.

Dense Granules

• Dense granules contain ADP, calcium, ATP, serotonin, and epinephrine.
• ADP is released upon platelet activation, promoting platelet aggregation by binding to P2Y12 receptors.
• ADP works with thromboxane A2 (TXA2) to enhance platelet adhesion and aggregation.
• Calcium helps activate enzymes and proteins involved in platelet shape change, aggregation, and the coagulation cascade.
• Calcium is also crucial for activating coagulation factors and platelet contraction during aggregation.

Alpha Granules

• Alpha granules contain clotting factors like fibrinogen and von Willebrand factor (vWF)
• Fibrinogen is converted to fibrin by thrombin, forming a mesh that stabilizes the platelet plug.
• vWF helps platelets adhere to exposed collagen and acts as a carrier for factor VIII
• Alpha granules also contain modulatory factors like platelet-derived growth factor (PDGF)

Significance of Granules in Platelet Function

• Both dense and alpha granules are vital for platelet activation and aggregation.
• ADP and calcium initiate platelet activation, while fibrinogen, vWF, and growth factors stabilize the clot and promote healing.
• Granule contents amplify the hemostatic response, especially ADP.
• Alpha granules contribute to clot integrity with clotting factors like fibrinogen and vWF.
• Growth factors from alpha granules stimulate blood vessel and tissue regeneration for proper healing.

Platelet Surface Receptors

• Platelets possess glycoprotein receptors for interacting with clotting factors and each other.
• Glycoprotein receptors play a vital part in platelet adhesion, activation, and aggregation.
• When a blood vessel is injured, vWF binds to GPIb on platelets, initiating adhesion to the damaged vessel wall.
• Upon platelet activation, GPIIb/IIIa receptors bind fibrinogen, connecting adjacent platelets.
• GPIIb/IIIa allows platelets to stick to each other and form aggregates

Endothelial Cells

• Endothelial cells lining blood vessels regulate hemostasis, preventing unnecessary clotting.
• Endothelial cells secrete:
  • Tissue Plasminogen Activator (tPA) promoting fibrinolysis
  • Vasodilators like Prostacyclin and Nitric Oxide, keeping vessels open
  • Adenosine Diphosphatase (ADPase) breaking down ADP
• Endothelial cells express Thrombomodulin, Heparin-like Molecules and Tissue Factor Pathway Inhibitor (TFPI) for anticoagulation.

Hemostasis Process

• Hemostasis process occurs in response to Injury

Hemostasis - Initial Response

• Vascular Spasm (Neurogenic Reflex & Vasoconstriction) upon injury.

Primary Hemostasis

• Platelet Plug Formation occurs, in three steps:
  • Adhesion: Platelets bind to von Willebrand factor (vWF) via Glycoprotein Ib (GpIb) receptor.
  • Platelet Activation: Platelets change shape leading to Granules release ADP and thromboxane A₂ to recruit more platelets.
  • Platelet Aggregation: Platelets bind to each other using Glycoprotein IIb/IIIa (GpIIb/IIIa) receptors.

Mnemonic

• “One binds first" → GpIb binds to vWF first.
• "Two-three" (GpIIb/IIIa) needed for aggregation.

Secondary Hemostasis

• Stable Clot Formation:
  • Tissue Factor is exposed, activating the coagulation cascade.
  • The coagulation cascade is a series of events that leads to formation of a stable blood clot after primary hemostasis
  • Thrombin is generated, converting fibrinogen to fibrin.

Clot Stabilization & Resolution

• Fibrin mesh strengthens the clot.
• Fibrinolysis occurs to restore normal blood flow.
• Plasmin breaks down fibrin into fibrin degradation products (FDPs), which dissolve the clot and allow the blood vessel to return to normal.