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PLATELETS IN HEALTH AND DISEASE
Dr.AnuPriya J
SCHEME
• Introduction
• History
• Formation
• Structure
• Properties
• Functions
• Role in hemostasis
• Platelet function ...
Introduction
• Blood is a complex fluid consisting of plasma and of formed
elements – red blood cells, white blood cells &...
• Platelets survive in circulation for about 8-10 days
• Removal -by the mononuclear phagocyte system
-spleen plays a majo...
History
• Hewson - in 1780 - very small undefined particles in blood.
• Max Schultze in 1865 - these particles must be deg...
• George Hayem between the years 1878 and 1879 - related to
erythrocytes - considered as their precursors - the term
“haem...
• Giulio Bizzozzero - the first - in 1882 - clearly establish the
significance of the particles- the third morphological e...
• The invention of the aggregometer by Born in 1962 provided a
valuable instrument to study platelet function and
responsi...
• The late 20th century
- the definition and characterization of many platelet receptors
- the analysis of molecular mecha...
Formation
Pluripotent stem cells
Committed stem cells
CFU-Mega
Megakaryoblast
Basophil megakaryocyte
Granular megakaryocyt...
Formation
• Thrombopoiesis – formation of platelets
• Regulated by
- Thrombopoietin
- Interleukin (IL-1,IL-3,IL-6,IL-11)
-...
•Small, granulated,
anuclear, discoid
•Diameter - 2 to 3 μm
•Volume - 8 fl
•Size - One fourth of
red cells
Structure
Granular contents
VWF
Properties
Functions
• Temporary hemostasis
• Blood coagulation
• Clot retraction
• Phagocytosis
• Storage & transport
• Wound healin...
Role in hemostasis
Role in hemostasis
 Adhesion
• VWF – GpIb/IX/V
• Collagen – GpIa/IIa
• Fibronectin & Laminin – GpIc/IIa
• Collagen – GpVI
Role in hemostasis
Role in hemostasis
 Activation & Release
Platelet agonists bind with specific membrane receptors
↓
G protein activation
↓
Activation of Phos...
 IP3
• A calcium ionophore
• Causes calcium to enter the cytosol from the dense tubular
system ( an internal platelet res...
 Calcium
Rising cytosolic calcium concentration
↓
Activation of myosin light chain kinase
↓
Phosphorylation of myosin lig...
 Calcium
• Contraction of the actin microfilaments – movement of
granules to the open canalicular system – release
• Calc...
 Activation & Release
G protein activation and calcium
↓
Activation of Phospholipase A2
↓
Membrane phosphatidylcholine
↓
...
• PGH2 – a cofactor enhancing the ability of collagen to function
as a platelet agonist
• TXA2 – binds to a specific plate...
• Activated platelets change shape from disc to tiny sphere with
numerous projecting pseudopods
• Activated platelets exoc...
• Locally damaged red cells also release ADP which further
activates the platelets
• Thrombospondin and Thrombonectin – fa...
Role in hemostasis
Role in hemostasis
Role in hemostasis
• Platelet activation – increased platelet coagulant activity
• Synthesize coagulation factor V
• Platelet phospholipids -...
XII XIIa
XI XIa
IXaIX
X Xa
VIIIaVIII
VII VIIa
X
Prothrombin
Intrinsic Pathway Extrinsic Pathway
VaV
Thrombin
Fibrinogen Fi...
Role in hemostasis
 The activated platelets incorporated in the clot rearrange and
contract their intracellular actin/myosin cytoskeleton.
...
 Platelet factor 4
 Platelet derived growth factor(PDGF)
 Transforming growth factor β
• Chemoattractants for WBCs, Smo...
Platelet function tests
• Platelet count
• Bleeding time
• Platelet aggregation test
• Platelet adhesiveness test
• Clot r...
Antiplatelet drugs
Bernard-Soulier Syndrome
(Giant Platelet Syndrome)
• Discovered by Jean Bernard and Jean-Pierre Soulier, 1948
• Abnormalit...
Glanzmann's thrombasthenia
• Platelets lack GPIIb/IIIa; hence, no fibrinogen binding can
occur
• Inherited in autosomal re...
Granule defects
• δ storage pool disease – dense body deficiency
• α granule deficiency – grey platelet syndrome
• αδ stor...
Gray platelet syndrome
• A rare condition caused by a reduction or absence of the
platelet alpha granules, or of the prote...
Von Willebrand disease (vWD)
• Most common hereditary coagulation abnormality
• Arises from a qualitative or quantitative ...
Thrombocytopenia
• Pseudothrombocytopenia
• Decrease Production
– Marrow Damage
• Aplasia
• Drugs
• Malignancy
• Radiation...
• Increase Destruction
Non Immune
• Disseminated Intravascular Coagulation
• Thrombotic Thrombocytopenic Purpura
• HELLP ...
Idiopathic Thrombocytopenic Purpura
• Autoimmune
• IgG autoantibody mediated platelet destruction
• Thrombocytopenia with ...
Dengue hemorrhagic fever
• Characterized by severe thrombocytopenia with bleeding
manifestations
• Severity depends on the...
Transfusion
• Platelets collected by apheresis – intermittent/continuous
flow cell separator.
• Single donor / Random dono...
Post transfusion
• 5-7 days after transfusion
• Allo antibodies
• Anti-P1A1 [Antigen located on gp IIIa subunit]
• Anti-Ba...
References
• Boron & Boulpaep - Medical Physiology, 2nd Edition
• Ganong's Review Of Medical Physiology, 24th Edition
• Be...
• Alfred Donne -1842 «globulin du chyle» (that is to say small
globules derived from plasma) a sort of small globular, pal...
Role in hemostasis
Clot retraction
 After the clot has been formed, the activated platelets
incorporated in the clot rearrange and contract ...
Platelets in health & disease - AJ
Platelets in health & disease - AJ
Platelets in health & disease - AJ
Platelets in health & disease - AJ
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  • 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
  • Transcript of "Platelets in health & disease - AJ "

    1. 1. PLATELETS IN HEALTH AND DISEASE Dr.AnuPriya J
    2. 2. SCHEME • Introduction • History • Formation • Structure • Properties • Functions • Role in hemostasis • Platelet function tests • Antiplatelet drugs • Platelet disorders • Transfusion
    3. 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. 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. 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. 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. 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. 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. 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. 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
    11. 11. 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.
    12. 12. •Small, granulated, anuclear, discoid •Diameter - 2 to 3 μm •Volume - 8 fl •Size - One fourth of red cells Structure
    13. 13. Granular contents VWF
    14. 14. Properties
    15. 15. Functions • Temporary hemostasis • Blood coagulation • Clot retraction • Phagocytosis • Storage & transport • Wound healing & Vascular growth
    16. 16. Role in hemostasis
    17. 17. Role in hemostasis
    18. 18.  Adhesion • VWF – GpIb/IX/V • Collagen – GpIa/IIa • Fibronectin & Laminin – GpIc/IIa • Collagen – GpVI Role in hemostasis
    19. 19. Role in hemostasis
    20. 20.  Activation & Release Platelet agonists bind with specific membrane receptors ↓ G protein activation ↓ Activation of Phospholipase C ↓ Membrane inositol phospholipids ↓ IP3 , DAG Role in hemostasis
    21. 21.  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
    22. 22.  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
    23. 23.  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
    24. 24.  Activation & Release G protein activation and calcium ↓ Activation of Phospholipase A2 ↓ Membrane phosphatidylcholine ↓ Arachidonic acid ↓COX PGH2 ↓ Thromboxane synthase TXA2 Role in hemostasis
    25. 25. • 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
    26. 26. • 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
    27. 27. • 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
    28. 28. Role in hemostasis
    29. 29. Role in hemostasis
    30. 30. Role in hemostasis
    31. 31. • 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
    32. 32. 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
    33. 33. Role in hemostasis
    34. 34.  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
    35. 35.  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
    36. 36. Platelet function tests • Platelet count • Bleeding time • Platelet aggregation test • Platelet adhesiveness test • Clot retraction time
    37. 37. Antiplatelet drugs
    38. 38. 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)
    39. 39. 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.
    40. 40. 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
    41. 41. 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
    42. 42. 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
    43. 43. Thrombocytopenia • Pseudothrombocytopenia • Decrease Production – Marrow Damage • Aplasia • Drugs • Malignancy • Radiation – Congenital Defects – Ineffective Production • B12, Folic Acid Def
    44. 44. • 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
    45. 45. 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
    46. 46. 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
    47. 47. 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
    48. 48. 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
    49. 49. 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
    50. 50. • 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»
    51. 51. Role in hemostasis
    52. 52. 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
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