Atlas One · Cellular · Anucleate / Haemostatic / Bone Marrow Derived
Shed as cytoplasmic fragments from polyploid megakaryocytes under TPO → Mpl → JAK2/STAT5 signalling
Structure and Granules
| Compartment | Contents | Released by | Function |
|---|---|---|---|
| α-granules (~60 per platelet) | Fibrinogen, vWF, P-selectin (GMP-140), PDGF, TGF-β, PF4 (CXCL4), Factor V, thrombospondin, β-thromboglobulin | Thrombin, collagen, ADP | Adhesion; coagulation (fibrinogen, FV); growth factor release; P-selectin → leukocyte adhesion (inflammation) |
| Dense (δ) granules (~4–8 per platelet) | ADP, ATP, serotonin (5-HT), polyphosphates, calcium, pyrophosphate | Collagen, thrombin, ADP | ADP → P2Y1/P2Y12 autocrine/paracrine activation; serotonin → vasoconstriction; polyphosphates → contact pathway |
| Lysosomes | Acid hydrolases | Strong activation | ECM remodelling; bactericidal |
| Open canalicular system (OCS) | Internal membrane reservoir; connected to plasma membrane | — | Surface area expansion on activation; granule secretion channel; GPIb-IX-V storage |
| Dense tubular system (DTS) | Sequestered Ca²⁺; COX-1; TXA₂ synthase | IP₃-mediated | IP₃-mediated Ca²⁺ release on activation; TXA₂ synthesis |
Function
Primary haemostasis: adhesion → activation → aggregation; secondary: procoagulant surface
Platelet Activation Cascade
┌───────────────────────────────────────────────────────────────────┐
│ VASCULAR INJURY — subendothelial collagen + vWF exposed │
└───────────────────────────────────────────────────────────────────┘
│ │
▼ ▼
vWF–GPIb-IX-V Collagen–GPVI
(High-shear adhesion) (FcR γ-chain → Syk → LAT → PLCγ2)
→ filamin A linking ↓
→ actin cytoskeleton IP₃ → Ca²⁺ release (DTS)
reorganisation DAG → PKC activation
│ ↓
└─────────── Ca²⁺ ───────►│
│
CalDAG-GEFI → Rap1b-GTP
│
Talin-1 + Kindlin-3 → αIIbβ3 inside-out activation
│
▼
αIIbβ3 (GPIIb/IIIa) — high affinity for:
Fibrinogen (bridges platelets: aggregation)
vWF, fibronectin, vitronectin
│
Autocrine amplification: │
ADP → P2Y12 (Gi → ↓cAMP) │ P2Y1 (Gq → PLCβ → Ca²⁺)
TXA₂ → TP receptor (Gq) │
Thrombin → PAR1 + PAR4 (Gq) │
▼
STABLE PLATELET PLUG
Procoagulant surface (Scott syndrome if absent):
TMEM16F (ANO6) scramblase → phosphatidylserine (PS) exposed on outer leaflet
PS surface → Tenase complex (VIIIa-IXa-Ca²⁺-PS): X → Xa × ~10⁵ faster
PS surface → Prothrombinase (Va-Xa-Ca²⁺-PS): Prothrombin → Thrombin × ~10⁵
Thrombin → Fibrinogen → Fibrin clot (secondary haemostasis)
Key Platelet Surface Receptors
| Receptor | Ligand | Copies/platelet | Signalling |
|---|---|---|---|
| GPIb-IX-V (VWR) | vWF (A1 domain); thrombin; P-selectin | ~25,000 GPIbα | Filamin A → actin; 14-3-3ζ; PI3Kβ |
| GPVI | Collagen (CRP); fibrin; laminin | ~2,000–3,000 | FcR γ-chain → Syk → LAT → PLCγ2 → Ca²⁺/PKC/Rap1b |
| αIIbβ3 (GPIIb/IIIa) | Fibrinogen, vWF, fibronectin | 40,000–80,000 | Outside-in: FAK, Src, PI3K → cytoskeleton/clot retraction |
| P2Y12 (ADP-R) | ADP | ~400–500 | Gi → ↓cAMP → ↓PKA → ↓VASP-p → ↑αIIbβ3 activity |
| PAR1 + PAR4 (Thrombin-R) | Thrombin (tethered ligand) | ~2,000 PAR1 | Gq → PLCβ → IP₃/DAG → Ca²⁺/PKC |
| TP receptor (TXA₂-R) | TXA₂ (COX-1 product) | ~1,000–2,000 | Gq/G12/13 → PLCβ / RhoA → shape change |
Pathology
| Disorder | Mechanism | Signs | Treatment |
|---|---|---|---|
| Immune thrombocytopenia (ITP) | Anti-GPIb or anti-αIIbβ3 IgG → platelet opsonisation → splenic destruction; ↓ megakaryocyte production | Petechiae, purpura, mucosal bleeding; PLT <100×10⁹/L; no splenomegaly | Corticosteroids; IVIG; rituximab; TPO-RAs (eltrombopag, romiplostim); splenectomy |
| Heparin-induced thrombocytopenia (HIT) | IgG anti-PF4/heparin complex → FcγRIIa on platelets → platelet activation + thrombin generation → thrombosis despite thrombocytopenia | PLT fall ≥50% after heparin day 5–10; thrombosis (venous > arterial); 4Ts score | Stop heparin; argatroban or bivalirudin (direct thrombin inhibitors); avoid warfarin until PLT normalised |
| Glanzmann thrombasthenia | αIIbβ3 (ITGA2B/ITGB3) deficiency or dysfunction | Mucocutaneous bleeding from birth; prolonged BT; absent platelet aggregation to all agonists; normal PLT count/morphology | Recombinant FVIIa; platelet transfusion; HLA-matched if alloimmunised; gene therapy trials |
| Bernard-Soulier syndrome | GPIb-IX-V (GP1BA/GP1BB/GP9) deficiency | Giant platelets (MPV ↑↑); moderate thrombocytopenia; absent aggregation to ristocetin; mucocutaneous bleeding | Platelet transfusion; DDAVP; rFVIIa; gene therapy trials |
| Essential thrombocythaemia (ET) | JAK2 V617F (~55%), CALR exon 9 (~25%), MPL mutations → constitutive TPO/JAK2 → megakaryocyte clonal expansion | PLT >450×10⁹/L; thrombosis (microvascular: erythromelalgia; macrovascular: MI/stroke/DVT); transformation to MF/AML rare | Aspirin (low risk); hydroxycarbamide/anagrelide (high risk); ruxolitinib (JAK1/2 inhibitor) |
| Thrombotic thrombocytopenic purpura (TTP) | ADAMTS13 deficiency (congenital or anti-ADAMTS13 IgG) → ultra-large vWF multimers → platelet-rich thrombi in microvasculature | MAHA + thrombocytopenia + fever + neurological + renal (pentad); ADAMTS13 <10% activity | Therapeutic plasma exchange; caplacizumab (anti-vWF A1 nanobody); rituximab; immunosuppression |
Antiplatelet Therapy
| Drug | Target | Mechanism | Key Trials / Use |
|---|---|---|---|
| Aspirin | COX-1 Ser529 | Irreversible acetylation → ↓ TXA₂ synthesis for platelet lifetime; anucleate platelets cannot regenerate COX-1 | ACS, AF (secondary); low-dose 75–100 mg/day; ASCEND/ARRIVE trials (primary prevention not beneficial in low-risk) |
| Clopidogrel | P2Y12 | Prodrug → hepatic CYP2C19 → active thiol metabolite → irreversible P2Y12 blockade; CYP2C19 poor metabolisers (7–14%) reduced efficacy | ACS, PCI (with aspirin — CURE, PCI-CURE); stroke secondary prevention |
| Prasugrel | P2Y12 | Prodrug → more reliable CYP3A4/hydrolase activation; irreversible; faster onset; ↑ bleeding vs. clopidogrel | ACS-PCI (TRITON-TIMI 38); avoid if prior TIA/stroke, age >75, <60 kg |
| Ticagrelor | P2Y12 | Direct-acting; reversible; no prodrug conversion; allosteric P2Y12 binding; faster offset → less bleeding with missed doses | ACS ± PCI (PLATO); also reduces mortality in STEMI (PLATO subgroup) |
| Abciximab / eptifibatide / tirofiban | αIIbβ3 (GPIIb/IIIa) | Block fibrinogen binding site; IV only; parenteral for high-risk PCI; largely replaced by P2Y12 inhibitors | EPIC, ESPRIT trials; still used in thrombotic complications during PCI |
Connections
References
- Italiano JE, Shivdasani RA. "Megakaryocytes and beyond: the birth of platelets." J Thromb Haemost 2003;1:1174–1182.
- Offermanns S. "Activation of platelet function through G protein-coupled receptors." Circ Res 2006;99:1293–1304.
- Wallentin L, et al. (PLATO). "Ticagrelor versus clopidogrel in patients with acute coronary syndromes." N Engl J Med 2009;361:1045–1057.
- Swisher KK, Kojouri K, George JN. "Thrombotic thrombocytopenic purpura." In: Williams Hematology, 9th ed., 2016.
- Boehlen F, Fontana P. "Platelet inhibitors." Semin Vasc Med 2005;5:187–196.