L06: Haemostasis 1 – Platelets

Haemostasis is the physiological process that arrests bleeding after vessel injury. It operates through three integrated mechanisms: vascular response, primary haemostasis (platelet plug formation), and secondary haemostasis (coagulation cascade). Together these produce a stable clot that seals the breach while limiting thrombosis to the site of injury.

Immediately after vascular injury, reflex vasoconstriction reduces blood flow and limits blood loss. Exposed subendothelial collagen then triggers platelet adhesion. Platelets do not normally adhere to intact endothelium, which actively produces prostacyclin (PGI₂) and nitric oxide to maintain platelet quiescence. Damage disrupts this inhibitory environment and exposes collagen and tissue factor.

Von Willebrand factor (vWF) is essential for platelet adhesion under conditions of high shear stress. vWF is a large multimeric glycoprotein secreted by endothelial cells and stored in Weibel-Palade bodies. At sites of injury, vWF unfolds and bridges between exposed collagen and platelet surface glycoprotein Ib (GPIb), tethering platelets to the vessel wall. Platelet glycoprotein VI (GPVI) and integrin α2β1 then bind collagen directly, stabilising adhesion.

Adherent platelets become activated. Activation involves a shape change (from discoid to spiny spheres), release of granule contents, and expression of phosphatidylserine on the outer membrane leaflet (providing a surface for coagulation factor assembly). Dense granules release ADP and serotonin; alpha granules release fibrinogen, vWF, and platelet factor 4. ADP binds P2Y₁ and P2Y₁₂ receptors on neighbouring platelets, amplifying activation. Activated platelets produce thromboxane A₂ (TXA₂) from arachidonic acid via cyclooxygenase-1 (COX-1); TXA₂ is a potent platelet activator and vasoconstrictor.

Activated platelets aggregate through fibrinogen bridges linking GPIIb/IIIa (integrin αIIbβ3) receptors on adjacent platelets. This forms the primary platelet plug, which is soft and reversible. Secondary haemostasis (the coagulation cascade) generates thrombin, which cleaves fibrinogen to fibrin, reinforcing the plug into a stable clot.

Platelets are anucleate fragments derived from megakaryocytes in the bone marrow. Thrombopoietin (TPO), produced by the liver and kidneys, drives megakaryocyte differentiation and platelet production. Normal platelet count is 150–400 × 10⁹/L; lifespan is approximately 10 days, and senescent platelets are cleared by the spleen.

Thrombocytopenia (platelet count below 150 × 10⁹/L) causes mucocutaneous bleeding: petechiae, purpura, and epistaxis. Causes include: immune thrombocytopenic purpura (ITP, autoantibodies against GPIIb/IIIa), disseminated intravascular coagulation (DIC, consumption), bone marrow failure (aplasia, infiltration by leukaemia), and hypersplenism.

Laboratory assessment of platelet function uses the platelet function analyser-100 (PFA-100), which measures closure time as blood flows through a collagen-coated membrane with ADP or adrenaline apertures. Prolonged closure time indicates platelet dysfunction or vWD.

Antiplatelet drugs exploit platelet activation pathways. Aspirin irreversibly acetylates COX-1, blocking TXA₂ synthesis for the platelet's entire lifespan (10 days). Because platelets cannot synthesise new COX-1, the effect is irreversible, and antiplatelet activity persists until new platelets are produced. Clopidogrel (and prasugrel, ticagrelor) block the P2Y₁₂ ADP receptor, preventing ADP-mediated amplification of platelet activation. These drugs are used in combination (dual antiplatelet therapy) after acute coronary syndromes and coronary stenting.