2018A15 Describe platelets and their role in haemostasis.

· Intro: structure, life cycle, secretion

· Platelet activation process

· Function: each aspect of coagulation

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