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Clotting mechanism

factors and clotting

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Clotting mechanism

  1. 1. CLOTTING MECHANISM 1 Done By A Mahesh Kumar 1st Year Pg student Dept of Pedodontics Drs S&N SIDS
  2. 2. Contents 2  Thrombocytes  Thrombocytopoiesis  Hemostasis  Coagulation of blood  Fibrinolysis  Bleeding time  Clotting time  Plasma  Plasma proteins
  3. 3. THROMBOCYTES : • Greek : Thrombus : Clot; Cyte: Cell. • Platelets are not whole cells. ( since they don’t have nuclear component ) • It posses a cell membrane – covered by fragments of cytoplasm that are liberated from megakaryocytes. 3
  4. 4. • Small disk shaped fragments of granule containing cytoplasm with diameter 2µm – 3µm. • The number varies from 1,50,000 – 4,00,000/cumm. • Spherical or rod shaped - Active form Oval or disc shaped – Inactive form 4
  5. 5. • Life span: 8 to 11 days (median value of 10 days) • Platelets are destroyed by tissue macrophage system in spleen 5
  6. 6. LM • Small, irregular with fine cytoplasmic processes • Cytoplasmic granules are often visible • Central portion – granulomere (purple colored material) • Outer region stains a transparent pale blue - hyalomere 6
  7. 7. ULTRASTRUCTURE OF PLATELETS Peripheral zone Exterior coat(glycocalyx), cell membrane, open canalicular system Sol-gel zone Microfilaments, circumferential microtubules, dense tubular system Organelle zone Alpha granules, dense granules, mitochondria, lysosomes 7
  8. 8. 8
  9. 9. OPEN CANALICULAR SYSTEM 1. Tubules communicate with the platelet surface. 2. This system is wide and tortuous . 3. Provides a major conduit for the release of number of important secretory substances to the exterior of the platelet. DENSE TUBULAR SYSTEM 1. Lumen of the tubules consists of electron dense material and hence the name. 2. This system is narrow and is derived from the endoplasmic reticulum. 3. Function is unknown. 4. Has a role in sequester calcium ions that are involved in regulating the platelet’s internal contractile activities. 9
  10. 10. Alpha Delta Lambda Most numerous. 300-500 nm diameter Less number & Smaller size. similar to lysosomes Contains: Fibrinogen Coagulation factors Plasminogen PDGF Contains ADP, ATP, Serotonin and histamine contains several hydrolytic enzymes. Important role 1. initial phase of vessel repair, 2. blood coagulation & 3. platelet aggregation. Important Role in : 1. Facilitate platelet adhesion and 2. Vasoconstriction in the area of injured vessel Important Role in : 1. Clot resorption in later stages of vessel repair. 10
  11. 11. THROMBOCYTOPOIESIS • Identifiable stages are 1. Megakaryoblast 2. Promegakaryocyte 3. Megakaryocyte 4. Platelets. • Unique feature in thrombocytopoiesis is endomitosis. • Endomitosis : Nuclear division with cytoplasmic maturation without cell division. 11
  12. 12. 12
  13. 13. As cell matures from Megakaryoblast to Megakaryocyte : there is • gradual increase in cell size • Number of nuclear lobes • Red-Pink granules • Gradual decrease in cytoplasmic basophilia 13
  14. 14. Megakaryocyte • Most abundant cells of platelet series in marrow • Large & contain numerous nuclear lobes with dense nuclear chromatin, small aggregates of granules in cytoplasm • On maturation : Megakaryocytes extend pseudopods through the walls of marrow sinusoids and individual platelets break off in to the peripheral circulation • Thrombopoietin controls the maturation of megakaryocytes 14
  15. 15. PROPERTIES Adhesiveness 1. Property of sticking to a rough surface. 2. The factors are: Collagen, thrombin, ADP, Thromboxane A2, Calcium ions, Von willebrand’s Factors, P selectin Aggregation 1. Grouping of platelets. 2. The factor responsible are : Platelet activating Factor ( secreted by neutrophills & Monocytes.), ADP, Thromboxane A2 Agglutination 1. Clumping of platelets. 2. The factor responsible are : Platelet agglutinins & Platelet Activating Factor. 15
  16. 16. FUNCTIONS Blood clotting Responsible for formation clot by intrinsic & extrinsic pathway through Prothrombin activator. Clot retraction Clot contraction & oozing of serum out is called clot retraction. It is by contractile proteins like myosin & thrombosthenin in cytoplasm of platelets. Role in repair of ruptured blood vessel PDGF formed in cytoplasm of platelets is useful for the repair of the endothelium. Role in defense mechanism By agglutination property; Platelets encircle the foreign body and destroy through phagocytosis. 16
  17. 17. HEMOSTASIS • Set of process that regulate 2 important functions. 1. They maintain blood in a fluid, clot – free state in normal vessels. 2. They are poised to induce a rapid and localized hemostatic plug at a site of vascular injury. 17
  18. 18. • Physiologic form of blood coagulation is termed as hemostasis. • Pathologic counter part of it is Thrombosis ( happens in unsevered vessel i.e., normal vessel.) 18
  19. 19. Blood doesn't clot in vascular channel due to Antithrombin III Heparin Protein C & S Thrombomodulin Alpha -2 macroglobulin. These factors inactivate the activated factors. 1. Vascular endothelium prevents activation of clotting factors. 2. High blood flow prevents accumulation of activated clotting factor 19
  20. 20. VASOCONSTRICTION 20
  21. 21. PRIMARY HEMOSTASIS 21
  22. 22. SECONDARY HEMOSTASIS 22
  23. 23. THROMBUS AND ANTITHROMBOTIC EVENTS 23
  24. 24. Injury to blood vessel and damage to endothelium EXPOSURE OF COLLAGEN Adherence of platelets to collagen Activation of platelets Von willebrand’s Factor Secretion of serotonin Secretion of ADP & TXN Formation of Prothrombin Activatior VASOCONSTRICTION Formation of platelet plug Blood clotting. Aggregation of platelets PAF HEMOSTASI S 24
  25. 25. • “Process in which blood looses its fluidity and becomes a jelly like mass few minutes after it is shed out.” • Clotting factors are responsible in the process of coagulation of blood. COAGULATION OF BLOOD 25
  26. 26. • Clotting mechanism occurs in 3 stages: 1. Formation of Prothrombin Activator. 2. Conversion of prothrombin into thrombin. 3. Conversion of fibrinogen into fibrin 26
  27. 27. Factor No. Nomenclature I Fibrinogen II Prothrombin III Thromboplastin ( Tissue Factor) IV Calcium V Labile factor ( Pro accelerin / Accelerator globulin.) VI Presence has not been proved. VII Stable factor VIII Anti hemophillic Factor IX Christmas Factor X Stuart Prower Factor XI Plasma thromboplastin Antecedent XII Hegman factor ( contact Factor) XIII Fibrin Stabilizing Factor ( fibrinase.) 27
  28. 28. Formation of Prothrombin Activator • Blood clot commences with the formation of PROTHROMBIN ACTIVATOR. • Prothrombrin activator formation occurs in 2 pathways 28
  29. 29. 29 The two final phases in the haemostatic process, plasma coagulation with the formation of a fibrin clot, and fibrinolysis leading to the dissolution of fibrin clots, are reviewed. Coagulation may be initiated either by reactions occurring between components of the blood alone, the intrinsic pathway, or by reactions which also involve tissue components, termed the extrinsic pathway.
  30. 30. Extrinsic Pathway 1. Formed from the injured tissues. 2. Formation of prothrombin activator is initiated by the tissue thromboplastin. Intrinsic Pathway 1. Formed with in the blood itself. 2. Formation of prothrombin activator is initiated by platelets. 30
  31. 31. Extrinsic pathway Tissue trauma Tissue thromboplastin Factor VII Factor X Xa Ca Thrombin FactorV Prothrombin activator31
  32. 32. INTRINSIC PATHWAY Endothelial damage + Collagen exposure XII XII a Kinogen Platelets prekallikrein XI XI a Ca Phospholipid IX IX a VIII & Ca X Xa32
  33. 33. Stage 2 Ca Prothrombin Thrombin Stage 3 Fibrinogen a Fibrinogen Polymerization Loose strands of fibrin XIII, Ca Prothrombin activator Fibrin Tight blood clot 33
  34. 34. FIBRINOLYSIS • Lysis of blood clot inside the blood vessel is termed as fibrinolysis. • It requires a substance called plasmin / fibrinolysin. 34
  35. 35. 35 The key component in fibrinolysis is plasminogen, which under the influence of various activators is converted to plasmin. Plasmin is a serine protease and its main in vivo target is fibrin. Alpha 2antiplasmin and a fast acting inhibitor of tissue plasminogen activator are the most important inhibitors.
  36. 36. Damaged tissue and endothelium Lysosomal enzymes Thrombomodulin + Thrombin Thrombomodulin – thrombin complex Protein C Activated Protein C Protein S :: Cofactor Inactivates V and VII Inactivation of t- PA inhibitor Activation of t- PA Thrombin urokinase PA Plasminogen Plasmin Lysis of clot 36
  37. 37. ANTICOAGULANTS 1. Heparin 2. Coumarin derivatives – dicoumoral and warfarin 3. EDTA 4. Oxalate compounds 5. Citrates 37
  38. 38. PROCOAGULANTS 1. Thrombin 2. Some snake venom 3. Extracts of lungs and thymus 4. Sodium calcium alginate 5. Oxidized cellulose 38
  39. 39. LAB INVESTIGATIONS Bleeding time Clotting time Prothrombin time Activated Partial Thromboplastin time Thrombin Test Capillary Resistance test by Hess Platelet count Clot retraction Time. 39
  40. 40. BLEEDING TIME DUKE’S METHOD IVY’S METHOD Ear lobe is pricked and escaping blood is dried every 30 seconds on the edge of a circle. The forearm is punctured after the application of BP cuff over the upper arm and BP raised to 40mm Hg. Here the arrest of bleeding is from platelet plug formation Normal value is 2-6 minutes. Normal value is 2-6 minutes. 40
  41. 41. 41
  42. 42. Prolonged bleeding time • Thrombocytopenia • Von-Willebrand’s disease • Purpura • Antiplatelet medication – Aspirin • Uraemia • Myeloproliferative disorders • Leukaemias • DIC 42
  43. 43. CLOTTING TIME Glass Capillary tube method (Wright’s) Lee & White Method Finger is pricked and blood is allowed to flow in capillary tube of 15 cm length. 3-5ml of blood is taken in 3 test tubes kept in a bath at 37ºc. A small bit of tube is carefully broken till the thread of clotted blood appears Test tube is tilted at every 30 seconds and checked for the solidification of blood. Normal value by this method is 3-7 minutes. Normal value by this method is 4- 11 minutes at 37oc. Prolonged in Hemophilia 43
  44. 44. PROTHROMBIN TIME Quick’s One stage Method: In a test tube 0.2ml of Commerical Thromboplastin containing calcium is kept at 37°c. After 30 seconds, 0.1ml of plasma is added from a pippete and stop watch is started. The test tube kept in water bath and shaken constantly. The test tube is tilted to find out the appearance of clot The normal value is 11-16 seconds. This is test for extrinsic pathway. 44
  45. 45. Prolonged prothrombin time • Hypoprothrombinaemia • Afibrinogenaemia • Vit K Deficiency. • VII, X, V, II, I deficiency • Dicoumarol therapy 45
  46. 46. ACTIVATED PARTIAL THROMBOPLASTIN TIME PROCEDURE 0.1ml of plasma kept at 37ºc is mixed with 0.2ml of thromboplastin and Kaolin Kaolin activate XII. And is kept in a bath for 37ºc for about 10 minutes. & at the end point 0.025ml of CaCl2 is added. Normal value 30-40 seconds. This test used to find out the deficiency of VIII and IX. 47
  47. 47. Prolonged APTT is seen in • Deficiency of VIII, IX • DIC • Heparin • Liver disease • Vit K deficiency 48
  48. 48. THROMBIN TIME This test is test for conversion of fibrinogen to fibrin Add 0.1ml of thrombin + CaCl2 mixture to 0.1ml of citrated platelet poor plasma. Normal value 8-12 seconds. 49
  49. 49. Prolonged thrombin time is seen in • Disorders of fibrinogen – afibrinogenaemia, hypofibrinogenaemia, dysfibrinogenaemia • Presence of heparin in plasma • Chronic liver disease 50
  50. 50. CAPILLARY RESISTANCE TEST OF HESS This test is done to check for resistance of capillary endothelium or capillary fragility test. BP cuff is applied on the arm & pressure is raised to 80mm of Hg for about 5 minutes. Capillaries leak the blood leading to appearance of minute hemmorhagic spots called petechia. When there is more than 10 such spots – indicates diminished resistance of capillary endothelium. 51
  51. 51. Defective capillary fragility is seen in • Thrombocytopenia • Defective platelet function • Vascular purpura • Thrombasthenia 52
  52. 52. THROMBOCYTOPENIA • Splenomegaly • X-ray Radiation • Aplastic Anemia • Pernicious anemia • Allergy 53
  53. 53. THROMBOCYTOSIS • >4,00,000/mm3 • Leukemia • Hodgkin’s disease • Polycythemia Vera • Splenectomy • Stress • Adrenaline injection 54
  54. 54. PLASMA • Water 91-92% • Solids 8-9% Solids Organic Inorganic 55
  55. 55. Organic substances • Proteins : Albumin, Globulin, Fibrinogen • Carbohydrates : Glucose • Fats : Neutral fats, Phospholipids, Cholesterol • Non protein nitrogenous substances : ammonia, creatine, creatinine, xanthine, hypoxanthine, urea, uric acid • Hormones & antibodies • Enzymes : amylase, carbonic anhydrase, alkaline phosphatase, acid phosphatase, lipase, esterase, protease, transaminase 56
  56. 56. Inorganic substances Na, Ca, K, Mg, Cl, I, Fe, PO4, Cu Gases O2, CO2 Serum = Plasma - Fibrinogen 57
  57. 57. Cholesterol up to 200mg/dl Plasma proteins 6.4 to 8.3 gm/dl Bilirubin 0.5 to 1.5 mg/dl Iron 50 to 150 micro gram/dl Copper 100 to 200mg/dl Calcium 9 to 11 mg/dl Sodium 135 to 145mg /dl Potassium 3.5 to 5.0 mg/dl Magnesium 1.5 to 2.0 mg/dl Chloride 100 to 110 mg/dl Bicarbonate 22 to 26 mg/dl 58
  58. 58. Plasma proteins : Total proteins 7.3 gm% (6.4-8.3) Serum albumin 4.7gm% Serum globulin 2.3 gm% Fibrinogen 0.3 gm% 59
  59. 59. Origin of Plasma Proteins : In embryo : mesenchymal cells First albumin is synthesized In adults : mostly from reticuloendothelial cells of liver Also synthesized by spleen, bone marrow, disintegrating blood cells ϒglobulin – B lymphocytes 60
  60. 60. FUNCTIONS OF PLASMA PROTEINS : 1. Role in coagulation of blood 2. Role in defense mechanism of body 3. Role in transport mechanism 4. Role in maintenance of osmotic pressure of blood 5. Role in acid base regulation 61
  61. 61. 6. Role in viscosity of blood 7. Role in ESR 8. Role in suspension stability of RBC 9. Role as reserve proteins 10. Role in production of trephone substances 62
  62. 62. Separation of Plasma Proteins 1. Precipitation method 2. Salting out method 3. Electrophoretic method 4. Cohn’s fractional precipitation method 5. Ultra centrifugation method 6. Immunoelectrophoretic method 63
  63. 63. Plasmapheresis : • Experimental procedure done in animals to demonstrate the importance of plasma proteins • Demonstrate the synthesis of plasma proteins by the liver 64
  64. 64. Plasma proteins Condition when it increases Condition when it decreases Albumin Dehydration Malnutrition , Cirrhoses of liver , Burns , Hypothyroid disease , Nephrosis Globulin Cirrhosis of liver, Chronic infections , Nephrosis, Rheumatoid arthritis Emphysema , Acute hemolytic anemia. Fibrinogen Acute infections , Stroke , Trauma. Liver dysfunction , steroids , use of phenol a/g ratio Hypothyroidism , excess of glucocorticoids , hypogamma globunemia Liver dysfunction 65
  65. 65. REFERENCES : 1. Ham’s Histology – 9th edition – David H Cormack 2. Text book of Medical Physiology- 10th edition- Guyton & Hall 3. Concise Medical Physiology- 4th edition- Chaudhuri 4. Essentials of Hematology; Shirish M Kawthalkar 5. Essentials of Medical physiology-3rd edition-Sembulingam 6. Scand J Gastroenterol Suppl. Coagulation and fibrinolysis 1987;137:118. 7. Narla Mohandas and Patrick G. Gallagher. Red cell membrane: past, present, and future. Blood 2008; 112: 3939-48 66
  66. 66. 8. Michael Fo¨ller1, Stephan M. Huber2 and Florian Lang. Erythrocyte Programmed Cell Death. Life 2008; 60(10): 661– 668 9. Petra Kleinbongard et all. Red blood cells express a functional endothelial nitric oxide synthase. Blood 2006; 107: 2943-2951 10.Veronique Witko-Sarsat et al. Neutrophils: Molecules, Functions and Pathophysiological Aspects. Laboratory investigations 2000; 80(5): 617-653 11.SM Rashmi et al. Neutrophils in health and disease: An overview. J Oral Maxillofac Pathol 2006; 10: 3-8 12. Per venge. What is the role of eosinophil?. Thorax 1990; 45: 161- 163 67
  67. 67. THANK YOU 68
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