2018A15 Describe platelets and their role in haemostasis.

Structure

·   Subcellular fragment

·   Biconvex, discoid

·   2-3μm greatest diameter

·   No nucleus, few organelles

·   Complex cytoskeleton

·   Many surface receptors

Life cycle

·   Thousands produced by each megakaryocyte

·   Stimulus for production is TPO

·   1/3 sequestered in the spleen

·   Normal life span 1/52

Secretions

(1) Alpha granules

·   Factors II, V, VII, XI, XIII (coag cascade)

·   vWF (activates platelets, binds and protects circulating factor VIII)

·   Fibronectin

·   TFPI

·   PAI-1

·   PDGF

(2) Dense granules

·   ADP: binds to P2Y₁ or P2Y₁₂ GPCR ↑cAMP, causes activation (inhibited by thienopyridines)

·   Serotonin: binds 5-HTR (various), causes activation and vasoconstriction

(3) Thromboxane A₂

·   Binds TXA₂ receptor (GPCR, ↑cAMP)

·   Causes activation and vasoconstriction (inhibited by aspirin)

Adhesion

·   Glycoprotein 1b-V-IX: binds vWF immobilized on collagen

·   GP Ia-IIa: binds collagen directly

·   GP VI: binds collagen directly

·   GP IIbIIIa: joins platelets via free vWF and fibrinogen, only once activated (inhibited by abciximab)

Stimuli for activation

·   Collagen binding

·   Paracrine binding: vWF, ADP, TXA₂

·   Coag factor: thrombin

Effects of activation

·   GP IIb-IIIa receptor changes to active conformation -> aggregation + activation

·   Secrete granules and TXA₂ -> aggregation + activation + vasoconstriction

·   Cytoskeletal contraction -> irregular shape with filopodia -> aggregation

·   Express phosphatidylserine (-ve charge)

Primary haemostasis

·   Vessel injury exposes platelet to subendothelial collagen

·   Platelet adhesion, activation, aggregation occur

·   Released mediators cause vasoconstriction, reducing blood flow

Promote secondary haemostasis

·   Platelet plug is backbone for coag cascade

·   Negatively charged phosphatidylserine supports clotting assembly

·   Secretion of α-granules with coag factors including vWF

Prevent premature fibrinolysis

·   Secretion of PAI-1: inhibits t-PA or u-PA

Prevent runaway anticoagulation

·   Secretion of TFPI: inhibits VIIa/TF, Xa

Stimulate wound healing

·   Secretion of PDGF