Platelets: Functions in Health and Disease
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This document discusses platelets, including their history, formation, structure, functions, and role in hemostasis. Platelets are formed from megakaryocytes in the bone marrow and released into circulation. They are anuclear cell fragments that help form blood clots to stop bleeding. Platelets adhere to sites of vessel injury, become activated, and aggregate to form a platelet plug. They also release chemicals that promote coagulation and wound healing. Disorders can occur if platelets are dysfunctional or in inadequate numbers.
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Platelets: Functions in Health and Disease
- 1. PLATELETS IN HEALTH AND DISEASE Dr.AnuPriya J
- 2. SCHEME • Introduction • History • Formation • Structure • Properties • Functions • Role in hemostasis • Platelet function tests • Antiplatelet drugs • Platelet disorders • Transfusion
- 3. Introduction • Blood is a complex fluid consisting of plasma and of formed elements – red blood cells, white blood cells & platelets. • Platelets are small, anuclear, cytoplasmic fragments of megakaryocytes • Normal platelet count – 1.5 to 4 L / mm3 of blood
- 4. • Platelets survive in circulation for about 8-10 days • Removal -by the mononuclear phagocyte system -spleen plays a major role • Half life – about 5 days Introduction
- 5. History • Hewson - in 1780 - very small undefined particles in blood. • Max Schultze in 1865 - these particles must be degenerate and disintegrated leukocytes – as they showed a granular appearance. • Riess in 1872 and Laptschinski in 1874 - leucocytes - mainly during infectious diseases – are the origin of the Schultze's corpuscles.
- 6. • George Hayem between the years 1878 and 1879 - related to erythrocytes - considered as their precursors - the term “haematoblasts” • Neumann -1880 - stated they were artifacts derived from red cells following an incorrect technique of venipuncture . History
- 7. • Giulio Bizzozzero - the first - in 1882 - clearly establish the significance of the particles- the third morphological element of blood, totally unrelated to white and red cells - gave a more precise description • Bizzozzero named these elements “piastrine”, i.e. small plates • Wright - Between 1906 and 1910 - identified bone marrow megakaryocytes as precursors of blood platelets – first to use the term “platelets” History
- 8. • The invention of the aggregometer by Born in 1962 provided a valuable instrument to study platelet function and responsiveness to agonists • In 1964, David-Ferreira published the first paper concerning platelet ultrastructure analyzed by means of electron microscopy. History
- 9. • The late 20th century - the definition and characterization of many platelet receptors - the analysis of molecular mechanisms involved in signal transduction - the introduction of anti-platelet treatments • Recent – collection, storage & transfusion History
- 10. Formation Pluripotent stem cells Committed stem cells CFU-Mega Megakaryoblast Basophil megakaryocyte Granular megakaryocyte Mature megakaryocyte Platelets Thrombopoiesis CFU - GEMM CFU- MegE CFU- Mega TPO
- 12. Formation • Thrombopoiesis – formation of platelets • Regulated by - Thrombopoietin - Interleukin (IL-1,IL-3,IL-6,IL-11) - GM-CSF • Each megakaryocyte produces between 1,000 to 3,000 platelets during its lifetime. • An average of 1011 platelets are produced daily in a healthy adult.
- 13. •Small, granulated, anuclear, discoid •Diameter - 2 to 3 μm •Volume - 8 fl •Size - One fourth of red cells Structure
- 15. Properties
- 16. Functions • Temporary hemostasis • Blood coagulation • Clot retraction • Phagocytosis • Storage & transport • Wound healing & Vascular growth
- 19. Adhesion • VWF – GpIb/IX/V • Collagen – GpIa/IIa • Fibronectin & Laminin – GpIc/IIa • Collagen – GpVI Role in hemostasis
- 21. Activation & Release Platelet agonists bind with specific membrane receptors ↓ G protein activation ↓ Activation of Phospholipase C ↓ Membrane inositol phospholipids ↓ IP3 , DAG Role in hemostasis
- 22. IP3 • A calcium ionophore • Causes calcium to enter the cytosol from the dense tubular system ( an internal platelet reservoir) and from the platelet exterior • A rising cytosolic calcium concentration Role in hemostasis
- 23. Calcium Rising cytosolic calcium concentration ↓ Activation of myosin light chain kinase ↓ Phosphorylation of myosin light chain ↓ Reorientation of cytoskeletal proteins ↓ Platelet shape change,secretion and contraction Role in hemostasis
- 24. Calcium • Contraction of the actin microfilaments – movement of granules to the open canalicular system – release • Calcium and platelet agonists also activates phospholipase A2 Role in hemostasis
- 25. Activation & Release G protein activation and calcium ↓ Activation of Phospholipase A2 ↓ Membrane phosphatidylcholine ↓ Arachidonic acid ↓COX PGH2 ↓ Thromboxane synthase TXA2 Role in hemostasis
- 26. • PGH2 – a cofactor enhancing the ability of collagen to function as a platelet agonist • TXA2 – binds to a specific platelet membrane receptor – resultant activation of Phospholipase C – amplification of platelet activation through further generation of IP3,DAG Role in hemostasis
- 27. • Activated platelets change shape from disc to tiny sphere with numerous projecting pseudopods • Activated platelets exocytose the contents of their dense storage granules and alpha granules • Platelet activating factor (PAF) – cytokine – neutrophils, monocytes & platelets ; produced from membrane lipids; acts via G proteins Role in hemostasis
- 28. • Locally damaged red cells also release ADP which further activates the platelets • Thrombospondin and Thrombonectin – facilitate contractile system activity – promote exocytosis of granular contents. • Thrombospondin – binds to fibrinogen n GP IV receptor secondary phase of aggregation – larger, firmer aggregates Role in hemostasis
- 32. • Platelet activation – increased platelet coagulant activity • Synthesize coagulation factor V • Platelet phospholipids - Platelet factor 3 and 4 - accelerate the formation of Va, VIIIa • Va – conversion of prothrombin to thrombin • Platelets play a major role in formation of intrinsic prothrombin activator – clot formation Role in hemostasis
- 33. XII XIIa XI XIa IXaIX X Xa VIIIaVIII VII VIIa X Prothrombin Intrinsic Pathway Extrinsic Pathway VaV Thrombin Fibrinogen Fibrin monomer Blood Coagulation Cascade Collagen, HMW Kininogen, Kallikrein ↓ HMW Kininogen Platelet phospholipids Calcium Platelet phospholipids Calcium Calcium XIIIaXIII Stable fibrin polymer(clot) Release of tissue factor (Tissue thromboplastin) Platelet phospholipids Calcium
- 35. The activated platelets incorporated in the clot rearrange and contract their intracellular actin/myosin cytoskeleton. The intracellular actin network - internal part of GpIIb/IIIa fibrinogen receptor. The external part of GpIIb/IIIa - the fibrin network of the clot As a result of platelet contractile force on the fibrin network, the formed clot will compact on itself and hence reduce its total volume. Role in hemostasis Clot retraction
- 36. Platelet factor 4 Platelet derived growth factor(PDGF) Transforming growth factor β • Chemoattractants for WBCs, Smooth muscle cells & fibroblasts. • Activate these cells and accelerate wound healing. • PDGF – Potent mitogen for vascular smooth muscle. Role in hemostasis Wound healing
- 37. Platelet function tests • Platelet count • Bleeding time • Platelet aggregation test • Platelet adhesiveness test • Clot retraction time
- 39. Bernard-Soulier Syndrome (Giant Platelet Syndrome) • Discovered by Jean Bernard and Jean-Pierre Soulier, 1948 • Abnormality of the platelet glycoprotein Ib-IX-V complex, receptor for vWF – platelets cannot adhere • Inherited in autosomal recessive manner • Large platelets on peripheral blood smear • Normal count, Prolonged bleeding time • Decreased or absent glass bead retention • Platelets aggregate wt physiological agonists but fail to aggregate wt ristocetin (similar to Von Willebrand disease)
- 40. Glanzmann's thrombasthenia • Platelets lack GPIIb/IIIa; hence, no fibrinogen binding can occur • Inherited in autosomal recessive manner • Normal morphology and count • Platelets less able to aggregate ; defective clot retraction • Bleeding time is significantly prolonged • Platelets do not aggregate with all aggregating agents but they aggregate with ristocetin.
- 41. Granule defects • δ storage pool disease – dense body deficiency • α granule deficiency – grey platelet syndrome • αδ storage pool disease • δ storage pool disease - Autosomal dominant - Absence of dense bodies - Seen in association with certain inherited disorders
- 42. Gray platelet syndrome • A rare condition caused by a reduction or absence of the platelet alpha granules, or of the proteins contained in these granules Pseudo gray platelet syndrome • Platelets in blood collected into EDTA appear gray and agranular compared with platelets from citrated blood. • EDTA-exposed platelets show extensive activation, with loss of storage granule contents and pseudopod formation
- 43. Von Willebrand disease (vWD) • Most common hereditary coagulation abnormality • Arises from a qualitative or quantitative deficiency of vWF • Hereditary – type 1, type 2, type 3. • Acquired • Normal count, Prolonged bleeding time • Deficiency of factor VIII activity in the plasma • Platelets aggregate wt physiological agonists but fail to aggregate wt ristocetin • Desmopressin – type 1 and 2 - stimulates release of VWF from Weibel-Palade bodies of endothelial cells • vWF replacement therapy – type 3 disease
- 44. Thrombocytopenia • Pseudothrombocytopenia • Decrease Production – Marrow Damage • Aplasia • Drugs • Malignancy • Radiation – Congenital Defects – Ineffective Production • B12, Folic Acid Def
- 45. • Increase Destruction Non Immune • Disseminated Intravascular Coagulation • Thrombotic Thrombocytopenic Purpura • HELLP syndrome Immune • Idiopathic Thrombocytopenic Purpura • Heparin Induced Thrombocytopenia • SLE, AIDS • Thrombotic Thrombocytopenic Purpura • Neonatal • Post transfusion Thrombocytopenia
- 46. Idiopathic Thrombocytopenic Purpura • Autoimmune • IgG autoantibody mediated platelet destruction • Thrombocytopenia with normal or increased number of megakaryocytes • Diagnosis of exclusion • Childhood/Adult onset • Children – Acute; H/O viral infection , self-limiting • Adults – F > M; Chronic; longer course • 80% respond to Oral prednisolone – 3 months – if no response – Splenectomy • Intravenous immunoglobulin or Immunosuppressive drugs
- 47. Dengue hemorrhagic fever • Characterized by severe thrombocytopenia with bleeding manifestations • Severity depends on the dengue virus subtype • Concomitant infection with more than one subtype • Dengue virus 2 – most severe – direct binding, ultramicroscopic changes • Cytotoxic factor ; increased proinflammatory cytokines • Plasma leakage – decreased plasma proteins – decreased fibrinogen • PLATELET TRANSFUSION • FRESH FROZEN PLASMA
- 48. Transfusion • Platelets collected by apheresis – intermittent/continuous flow cell separator. • Single donor / Random donor platelet concentrate • Storage - 20-24ᵒ C under constant agitation – 5 days • Neither group specific or Rh specific – cross matching not needed • Indications – thrombocytopenia • Contraindications – Immune mediated thrombocytopenia
- 49. Post transfusion • 5-7 days after transfusion • Allo antibodies • Anti-P1A1 [Antigen located on gp IIIa subunit] • Anti-Baka (Leka) [Antigen located on gp IIb subunit] • Self – limiting ; 3-6 weeks • High dose intravenous immunoglobulin – treatment of choice
- 50. References • Boron & Boulpaep - Medical Physiology, 2nd Edition • Ganong's Review Of Medical Physiology, 24th Edition • Best & Taylor's Physiological Basis Of Medical Practice, 13/ E. • Dacie And Lewis Practical Haematology 11th Edition • de Gruchy's Clinical Haematology In Medical Practice, 5th Ed • Arthropod borne viral diseases – Current status and research – D.Raghunath Rao, C.Durga Rao • Textbook of Medical Physiology G K Pal 2 E • Internet references
- 54. • Alfred Donne -1842 «globulin du chyle» (that is to say small globules derived from plasma) a sort of small globular, pale, opaline corpuscles visible in blood. • Later described by Beale in 1850 as particles of «germinal matter» and by Zimmermann in 1860 as «small corpuscles»
- 56. Clot retraction After the clot has been formed, the activated platelets incorporated in the clot rearrange and contract their intracellular actin/myosin cytoskeleton. The intracellular actin network is connected to the internal part of the integrin αIIbβ3 fibrinogen receptor. Following coagulation, the external part of αIIbβ3 will have bound to the fibrin network of the clot, and therefore, as a result of platelet contractile force on the fibrin network, the formed clot will compact on itself and hence reduce its total volume. The mechanism is termed clot retraction. Role in hemostasis
Notas del editor
- PAF – a phospholipid produced from membrane lipids
- Thrombospondin – secondary irrev phase of platelet aggregation – bind to fibrinogen n GP IV receptor – reinforces the fibrin glue of aggregation Platelet shape change – reversible – when inducing stimuli are weak & transient, the platelet may revert to its unstimulated appearance
- Disrupting the fibrin binding capability of platelets with the use of integrin αIIbβ3 inhibitors results in a complete loss of clot retraction. Clot retraction can also be inhibited by the use of cytochalsin E, a cell permeable metabolite of fungal origin that prevents intracellular actin rearrangement