8 platelets and hemostasis

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  • ET- endothelin, 5ht- 5 hydroxytryptamine
  • 8 platelets and hemostasis

    1. 1. Platelet or Thrombocyte Physiology
    2. 2. Platelet or Thrombocyte Physiology Shape: Biconvex disk like, diameter about 2~4 µm, average cubage 8 µm3.  Complicated structure: under the electronic microscope, there are α-granule, dense body, lysin peroxide enzyme, opening tubular system, dense tubular system, canaliculus,etc.  Dense body: It contains ADP, ATP, 5-HT, Ca2+, epinephrine,etc.  Source: Platelet comes from megakaryocyte fractionlet release in the marrow. 
    3. 3. Normal Value and Function of Platelet     Normal value: 100×109 ~ 300×109, range from 6%~10% Normal changes: more number in the afternoon than in the morning, more in winter than in spring, more in the venous blood than capillary, after sport↑ , pregnacy ↑ . *Functions: 1. It maintains capillary endothelial cells smooth and integrated (repairing endothelium and providing nutrition). 2. It is involved in physiological hemostasis. Platelet and clinic relation: decrease of platelet, abnormal immune reaction, will results in hemorrhage or bleeding, purpuric symptom.
    4. 4. How low is too low?  150,000 - 50,000: no symptoms  50,000 - 20,000: first symptoms  20,000-10,000: potentially lifethreatening  <10,000: risk for spontaneous intracranial hemorrhage
    5. 5. Platelet Hypofunction- Symptoms mucocutaneous bleeding, ie “Oozing and bruising”  epistaxis  gum bleeding  bruising  heavy menses  Petechiae  Post-surgical bleeding 
    6. 6. Platelet Forming and Regulation  Platelet forming: Birth place is bone marrow, originating from hemopoietic stem cells, and differentiating into burst forming unitmegakaryocyte, BFU-MK, then continuously into CFU-MK, and into megakaryocyte , into fractionlet release to the blood requiring 8~10 days. >(one megakaryocyte can produce 200~7700 platelet).
    7. 7. 8
    8. 8. Development      Platelet are derived from bone marrow cell called megakaryocytes Megakaryocytes are large cells These megakaryocytes remain outside the vascular sinus in the bone marrow They throw out a part of their cytoplasm like pseudopodium, through the wall of sinusoids. These pseudopodia are broken off in such a way that the individual fragment is surrounded by unit membrane and are washed away by blood stream These fragment with unit membrane are platelets Each megakaryocyte liberate several thousand platelets Destruction   Platelets are destroyed by tissue macrophages More than half are destroyed by tissue macrophages of spleen and remaining by macrophage of other tissue
    9. 9. Platelet Production Platelet production is regulated by thrombopoietin (TPO).  TPO synthesis is static  Thrombopoietin binds to the surface of megakaryocytes and platelets-   only free TPO stimulates platelet production Therefore, platelet mass negatively regulates free TPO and further platelet production
    10. 10. Platelet Forming and Regulation  Regulation: Protein, Mpl, expressed by c-mpl (oncogene) exists in CD34+ located at hemopoietic stem cells/ >committed progenitors, megakaryocyte and platelet, found by Methin in 1993, and its ligand named thrombopoietin, TPO was discovered in 1994 which promoted hemopoietic stem cells differentiating into megakaryocyte as hemopoietic stem cells positive regulating factor.
    11. 11. Life- Span and Breakage of Platelet  Life-span: Averagely, 7~14 days in the blood. It can be consumed when it displays physiological functions.  Breakage: Aged platelet can be processed by phagocytosis in liver, spleen and lymphatic node.
    12. 12. IV. Physiological Hemostasis  *Definition: The process from vessel bleeding to automatic hemostasia.  *Bleeding time: The time from vessel bleeding to automatic hemostasia. Normal time is 1~3 min and it is longer when platelet decrease.  Process of hemostasis: 1. Blood vessel contraction or convulsion (induced by neuroreflex; 5-hydroxytryptamine,5-HT; thromboxane A2, TXA2; endothelin, ET ) 2. Platelet thrombosis forming (made by platelet adhesion, aggregation, release and contraction) 3. fibrin, clot forming and maintenance (made by blood coagulation activation)
    13. 13. Physiological Hemostasis
    14. 14. 1.Endocrine functions of vessel endothelial cells a. Material related to hemostasis are basal membrane, collagen (III, IV), microfibril, elastin, laminin, ectonectin, fibronectin, von Willebrand factor (vWF), protein enzyme, protein enzyme inhibitor, adhesive amylose, etc. b. Anticoagulative material: They are prostacyclin (PGI 2), endotheliumderived relaxing factor (EDRF or nitric oxide, NO), tissue-type plasminogen activator (tPA), uPA, ADPase, ATIII, heparin sulfate, protein C, thrombomomodulin (TM), plasminogen activator (PA). c. Promoting coagulative material: Tissue factor, vWF, blood clotting factor V, plasminogen activator inhibitor (PAI-1, PAI-2, ATIII), TNFα, interleukin-1 (IL-1). d. Vessel constricting and relaxing modulators: endothelin-1 (ET-1), EDRF (NO), PGI2, etc.
    15. 15. Roles of Vessel Endothelial Cells in Physiological Hemostasis Roles are close related to its endocrine functions a. Vessel endothelium serves as barrier between under endothelial structure (namely, collagen) and blood. As soon as collagen expose to blood, hemostasis of platelet is immediately activated to form thrombus blocking wounded vessels. b. Platelet activation can releases constrictive factors (TXA2, ET-1, 5HT, etc) making vessel convulsion, lasting about 60 sec. c. Stimulated vessel endothelial cells release coagulative factors and Promoting coagulative material to realize, speed up blood coagulation. At the same time, cells also release anticoagulative factors and fibrinolysis material to modify blood coagulation.
    16. 16. Inactive Platelet Under the electronic microscope
    17. 17. Activated Platelet for Hemostasis Under the electronic microscope
    18. 18. 2.Physiological Characteristics of Platelet  Thrombocyte adhesion: its membrane glycoprotein (GP, GPIb/IX and GPIIa/IIIb), collagen (underendothelial structure), vWF (plasma component), fibrinogen are involved in adhesion. Mechanism: Exposed collagen+vWF → vWF changes → platelet membrane glycoprotein+changed vWF → Thrombocyte adhesion.  Thrombocyte aggregation: induced by physiological factors such as ADP, thromboxane A2 (TXA2), epinephrine, 5-HT, histamine, collagen, thrombin, prostacyclin,etc and by pathological factors like bacteria, virus, immune complex, drugs, etc. The process can be separated into two phases: phase one is reversible aggregation and phase two irreversible aggregation. Both phases require Ca2+, fibrinogen and energy consumption. Mechanism : Various factors+corresponding receptors on the platelet → changes in the second messenger within platelet → cAMP↓ , Ip3↑ , Ca2+↑ , cGMP↑→ platelet aggregation.
    19. 19. 2.Physiological Characteristics of Platelet  Thrombocyte release: ADP, ATP, 5-HT, Ca2+ released from dense body, and β-platelet globin, PF4, vWF, fibrinogen, PFV, PDGF, thrombin sensitive protein from α-granule, and acid protein hydrolyzed enzyme, tissue hydrolyzed enzyme from lysosome.  Thrombocyte contraction: Loose platelet thrombus could turn into compact platelet thrombus by Ca2+ release and cytoskeleton movement (filament/canaliculus) within platelet.
    20. 20. Two Phases of Physiological Hemostasis First Phase Second Phase
    21. 21. Roles of Platelet in Hemostasis  Activation of platelet: Stimulus brings about thrombocyte adhesion, aggregation, release and contraction.  Loose platelet thrombus forming: First phase of hemostasis.  Blood coagulation activation by platelet: Fibrin net forming, second phase of hemostasis.
    22. 22. Roles of Platelet in Hemostasis  *Roles of platelet in hemostasis: 1. Activated platelets supply lecithoid (phospholipid) surface for blood clotting factor and involve in activating factor X and prothrombin. 2. Surface of platelet membrane combine with many blood clotting factor, such as fibrinogen, FV, FXI, FXIII to speed up coagulation. 3. Activated platelets release α-granule which contains fibrinogen to intensify fibrin forming and blood coagulation. 4. Activated platelets contract clot with its contractive protein to solidify blood coagulation.
    23. 23. Mechanism1 of Platelet in Hemostasis
    24. 24. Mechanism2 of Platelet in Hemostasis
    25. 25. 3.Blood Coagulation Blood Clotting Factor  Definition: The process of blood flow from flowing liquid to gel or gelatin.  Serum: Light yellow fluid after blood coagulation.  Difference between serum and plasma mainly consists in no fibrinogen in serum.  Blood coagulation is a series of complicated biochemical reactions with various enzymes.
    26. 26. 3.Blood Coagulation Blood Clotting Factor    Blood clotting factor: Material which are directly involved in blood coagulation. There are 12 factors named Roman numerals, Blood clotting enzymes have two type: inactive and activated type [FII, FVII, FIX, Fx, FXI, FXII, FXIII].
    27. 27. Blood Clotting Factor Factor Name Chromsome Plasma Concentration I Fibrinogen 3000 II Prothrombin 100 III Tissue factor IV Ca2+ 100 V Proaccelerin 10 Ⅶ Proconvertin 0.5 Ⅷ Antihemophilic factor,AHF 0.1 Ⅸ Plasma thromboplastic 5 component,PTC(Christmas factor) Ⅹ Stuart-Prower Factor 10 Ⅺ Plasma thromoboplastin 5 antecedent,PTA Ⅻ Contact factor or Hageman factor 40 XIII Fibrin-stabilizing factor 10 - High-molecular weight 80 kininogen,HMW-K - Prekallikrein,Pre-K or Fletcher factor 35 Synthesizing Half life site Liver 4~5 d Liver (with Vit K) 3d Endothelial cell Endothelial cell, platelet 12~15 h Liver (with Vit K) 4~7 h Liver 8~10 h Liver (with Vit K) 24 h site 4 11 1 13 Ⅹ Ⅹ Liver (with Vit K) Liver 13 4 2d 2~3 d Liver Liver, platelet Liver 24 h 8d - 5 6,1 3 Liver - 4
    28. 28. Blood Coagulation    Intrinsic pathway of blood coagulation: All blood clotting factors involved in blood coagulation come from blood. Eyewinker surface with negative charges (collagenin) on the endothelium of blood vessel activates blood FXII as beginning of coagulation named surface activation. Extrinsic pathway of blood coagulation: Stimulus activates tissue factor (FIII) as beginning of coagulation. Extrinsic pathway of blood coagulation is faster than intrinsic pathway of blood coagulation because its steps are more simple. *Basic steps of blood coagulation [typical positive feedback]: Prothrombin activator forming [FXa-Va-Ca 2+-phospholipid] Step 1 Prothrombin  thrombin Step 2 Fibrinogen fibrin (clot) Step 3 Hemophilia A, B, C in the clinic results from deficiency of FVIII, FIX, FXI in the blood, respectively.
    29. 29. Process of Blood Coagulation Extrinsic pathway Intrinsic pathway ( ( Tissue Factor , TF ) Eyewinker surface ) TF+Ⅶ Ⅶ-TF Ⅹa ⅦaTF Ca2+ PL Ⅸ Ca2+ , PL Ca 2+ Ⅻa CL: cross linking fibrin HK: high molecular weight kininogen Ⅺa Ⅹa Ⅴa Ⅱ Ca2+ PL ⅩⅢ Ⅱa Subendothelium K: kallikrein PK Ca2+ Ⅷ PL a PL: phospholipid PK: prekallikrein S K Ⅸa Ⅹ S: H K Ⅺ Ca2+ Ⅻ Ⅰ Ⅰa ⅩⅢa Ca2+ CL Ⅰa
    30. 30. Mechanism of Blood Coagulation
    31. 31. Anticoagulative system in blood  Cellular anticoagulative system: Liver cell and reticular endothelial cell could engulf blood clotting factor, tissue factor, prothrombin complex and soluble fibrin monomer.  Humoral anticoagulative system: 1. Amino acid protease inhibitors in blood include antithrombin III, Clinhibitor, α1 antitrypsin, α2 antiplasmin, α2 huge globin, heparin coenzyme II, protease nexin-1 (PN-1) to combine with FIXa, FXa, FXIa, FXIIa and thrombin and then inactivate them for anticoagulation. Heparin can intensify functions of antithrombin III. 2. Protein C system are protein C (PC), thrombomodulin (TM), protein S and Protein C inhibitors. Main functions of PC consist in ①It inactivates FVa, FVIIIa with phospholipid and Ca 2+; ②It blocks FXa combining with platelet phospholipid membrane to reduce prothrombin activation; ③It stimulates plasminogen activators release to trigger fibrinolysis; ④ Protein S is a coenzyme of PC and greatly intensify functions of PC.
    32. 32. Anticoagulative system in blood  3. Tissue factor pathway inhibitor (TFPI) mainly coming from vessel endothelial cells inhibits FXa and inactivates FVIIa-TF complex to block extrinsic pathway of coagulation with negative feed back. 4. Heparin used in the clinic widely is due to ①It combines with antithrombin III to increase functions of antithrombin III; ②It stimulates vessel endothelial cell greatly releasing TFPI and other anticoagulative material; ③It intensifies PC activation and stimulates vessel endothelial cell releasing plasminogen activators to increase fibrinolysis. [lower molecular weight heparin is less hemorrhage]
    33. 33. 4.Fibrinolysis  Fibrinolytic system is involved in fibrinolysis, tissue repair and vessel rebirth.  Two fibrinolytic systems: cellular one and plasma one. The former is leucocyte, macrophage, endothelial cell, mesothelial cell and platelet to engulf and digest fibrin. The latter is plasminogen activators (PA) and its inhibitors (PAI), plasminogen, plasmin.  Basic steps: Endothelial cells (Extrinsic pathway ) (Urokinase, uPA) uPA tPA Plasminogen Kallikrein (Intrinsic pathway) PAI-1 α2-antiplasmin α2-huge globin Fibrin or fibrinogen Cl-inhibitors uPAG Plasmin Fibrin dissolution
    34. 34. Blood Coagulation and Fibrinolysis
    35. 35. Antifibrinolysis: Fibrinolytic Inhibitors and Its Functions  Main fibrinolytic inhibitors: They are plasminogen activator inhibitor type-1 (PAI-1, in platelet), α2antiplasmin (in liver), α2-huge globin, α1-antitrypsin, antithrombin III, alexin C1 inhibitor.  PAI-1 synthesis and release: PAI-1 made by endothelial cell, smooth muscular cell, mesothelial cell, megakaryocyte is stored in platelet with inactive form. Some factors such as thrombin, IL-1, TNFα, etc stimulate its release from platelet.
    36. 36. Antifibrinolysis: Fibrinolytic Inhibitors and Its Functions  PAI-1 function: It inhibits tPA (tissue-type plasminogen activator) limiting local fibrinolysis of thrombus.  α2-antiplasmin characteristics: (1) Quick effect, (2) Inhibit plasminogen adhering to fibrin; (3) Combine with fibrin αchain and block fibrinolysis  Clinic relation: Innate deficiency of α2-antiplasmin often brings about serious hemorrhage.
    37. 37. Thank you

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