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THROMBOSIS

THROMBOSIS. Dr NISHA T G Assistant Professor. DEFINITION PATHOPHYSIOLOGY ORIGIN OF THROMBI AT DIFFERENT SITES FATE OF THROMBUS CLINICAL EFFECTS. Definition. Thrombosis is the process of formation of solid mass in circulation from the constituents of the blood.

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THROMBOSIS

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  1. THROMBOSIS Dr NISHA T G Assistant Professor

  2. DEFINITION • PATHOPHYSIOLOGY • ORIGIN OF THROMBI AT DIFFERENT SITES • FATE OF THROMBUS • CLINICAL EFFECTS

  3. Definition • Thrombosis is the process of formation of solid mass in circulation from the constituents of the blood. • The mass itself is called THROMBUS.

  4. Blood clot is the mass of coagulated blood formed in vitro e.g. in a test tube. • Haematomais the extravascular accumulation of blood clot e.g. into the tissues. • Haemostatic plugs are the blood clots formed in healthy individuals at the site of bleeding e.g. in injury to the blood vessel  simplest form of thrombosis.

  5. Mechanism of Thrombosis • Human beings possess inbuilt system by which the blood remains in fluid state normally and guards against the hazards of thrombosis and haemorrhage. • Injury to the blood vessel initiates haemostatic repair mechanism or thrombogenesis.

  6. PATHOPHYSIOLOGY

  7. Virchow’s Triad Virchow described three primary events which predispose to the formation of thrombosis. 1)Endothelial injury. 2)Alteration in flow of blood. 3)Hypercoagulability of blood.

  8. Major factors in pathophysiology of thrombus formation

  9. Endothelial Injury • The integrity of blood vessel wall is important for maintaining normal blood flow.

  10. An intact endothelium has the following functions: i] Protects the flowing blood from the thrombogenic influence of subendothelium. ii] Elaborates few anti-thrombotic factors like heparin-like substance, thrombomodulin, inhibitors of platelet aggregation like ADPase, PGI2 or prostacyclin & tissue plasminogen activator . iii] It also releases a few prothrombotic factorslike thromboplastin, von Willerbrand’s factor, platelet activating factor & inhibitor of plasminogen activator.

  11. anti-thrombotic factors a) Heparin-like substance which accelerates the action of antithrombinIII and inactivates some other clotting factors. b) Thrombomodulinwhich converts thrombin into activator of protein C, an anticoagulant. c) Inhibitors of platelet aggregation such as ADPase, PGI2 or prostacyclin. d) Tissue plasminogen activator which accelerates the fibrinolyticactivity.

  12. prothrombotic factors a) Thromboplastinor tissue factor released from endothelial cells. b) von Willebrand factor that causes adherence of platelets to the subendothelium. c) Platelet activating factor which is activator and aggregator of platelets. d) Inhibitor of plasminogen activator that suppresses fibrinolysis.

  13. Anticoagulant properties of normal endothelium (left) and procoagulant properties of injured or activated endothelium (right).

  14. Vascular injury also causes vasoconstriction of small blood vessels to reduce blood flow

  15. Endothelial injury is of major significance in the formation of • arterial thrombi and • thrombi of the heart, especially of the left ventricle.

  16. Conditions which may cause vascular injury: • Endothelial injury in myocardial infarction, myocarditis, cardiac surgery, prosthetic valves • Ulcerated plaques in advanced atherosclerosis • Haemodynamic stress in hypertension • Arterial diseases • Diabetes mellitus • Endogenous chemical agents such as hypercholestrolaemia, endotoxins • Exogenous chemicals like cigarette smoke.

  17. Role of Platelets in Thrombosis Sequence of events in thrombosis: • Platelet adhesion. • Platelet release reaction. • Platelet aggregation.

  18. Platelet adhesion • The platelets in circulation recognise the site of endothelial injury and adhere to exposed subendothelial collagen(primary aggregation). • VWF is required for such adhesion between platelets and collagen.

  19. Normal non-activated platelets have open canalicular system with cytoplasmic organelles dispersed throughout the cytoplasm.

  20. During the early adhesion process, there is dilatation of canalicular system with formation of pseudopods and cytoplasmic organelles shift to the center of cell.

  21. Platelet release reaction The activated platelets then undergo release reaction by which the platelet granules are released to the exterior.

  22. Two main types of granules: • Alpha granules containing fibrinogen, PDGF, PF4, fibronectin and cationic proteins. • Dense bodies containing ADP(adenosine diphosphate), ionic calcium, 5-HT(serotonin), histamin and epinephrine.

  23. Platelet aggregation • Following release of ADP, a potent platelet aggregating agent  aggregation of additional platelets takes place(secondary aggregation). • This results in formation of temporary haemostatic plug. • However, stable haemostatic plug is formed by the action of fibrin, thrombin and thromboxane A2.

  24. Platelet adhesion and aggregation.Von Willebrandfactor functions as an adhesion bridge between subendothelial collagen and the glycoprotein Ib (GpIb) platelet receptor. Platelet aggregation is accomplished by fibrinogen binding to platelet GpIIb-IIIa receptors on different platelets.

  25. Role of coagulation system • Coagulation mechanism is the conversion of the plasma fibrinogen into solid mass of fibrin. • This system is involved in both haemostatic process and thrombosis.

  26. Regulation of coagulation system Blood is kept in fluid state normally and coagulation system kept in check by controlling mechanisms. a) Protease inhibitors b) Fibrinolytic system. • These act on coagulation factors so as to oppose the formation of thrombin e.g. antithrombin III, protein C, C1 inactivator, α1-antitrypsin, α2-macroglobulin. • Plasmin, a potent fibrinolytic enzyme, is formed by the action of plasminogen activator on plasminogen present in the normal plasma.

  27. Two types of plasminogen activators (PA) are identified: • Tissue-type PAderived from endothelial cells and leucocytes. • Urokinase-like PA present in the plasma. • Plasmin so formed acts on fibrin to destroy the clot and produces fibrin split products (FSP).

  28. Alteration of Blood Flow • Normally axial flow of blood. • Most rapidly moving central stream  consists of leucocytes and red cells. • Platelets are present in the slow moving laminar stream adjacent to the central stream. • Peripheral stream consists of most slowly moving cell-free plasma close to the endothelial layer.

  29. Normal Axial Flow

  30. The intact endothelial lining of blood vessels normally repels platelets and inhibits clot formation through secretion of numerous inhibitory substances.

  31. In turbulence and stasis, the normal axial flow of blood is disturbed so that the platelets come into contact with the endothelium. • Turbulence may actually injure the endothelium resulting in deposition of platelet and fibrin.

  32. Formation of arterial and cardiac thrombi is facilitated by turbulence in the blood flow. • While stasis initiates the venous thrombi even without evidence of endothelial injury.

  33. Hypercoagulability of Blood Occurence of thrombosis is explained on the basis of hypercoagulability of blood in some conditions like: • Nephrotic syndrome • Advanced cancers • Extensive trauma • Burns • During puerperium.

  34. Changes in blood which cause hypercoagulability 1] Increase in coagulation factorseg: fibrinogen, prothrombin, factor VIIa, VIIIa, Xa. 2] Increase in platelet count and adhesiveness. 3] Decrease levels of coagulation inhibitorseg: antithrombin III, fibrin split products.

  35. Predisposing Factors • Primary(Genetic) • Secondary(Aquired)

  36. Primary(Genetic): • Common: • Factor V mutation • Prothrombin mutation • Increased levels of factors Vlll, lX, Xl etc • Rare: • Antithrombin lll deficiency, • Protein C deficiency, • Protein S deficiency

  37. Secondary(Aquired) High risk for thrombosis: -Prolonged bedrest or immobilization, -MI, AF, Cancer, DIC, -Prosthetic cardiac valves -Tissue injury (surgery, fracture, burn) -Antiphospholipid antibody syndrome -Heparin induced thrombocytopenia

  38. Lower risk for Thrombosis -Cardiomyopathy, -Nephrotic syndrome, -Hyperestrogenic states(pregnancy, postpartum) -Oral contraceptive pills -Sickle cell anaemia -Smoking etc

  39. THROMBOSIS - PART 2

  40. Morphologic Features • Thrombosis may occur in the heart, arteries, veins and the capillaries. • Arterial thrombi produce ischaemiaand infarction • Cardiac and venous thrombi cause embolism.

  41. General morphological features GROSSLY: • Thrombi may be of various shapes, sizes and composition depending upon the site of origin. • Arterial thrombi White & mural • Venous thrombi Red & occlusive

  42. GROSSLY…. • Mixed or laminated thrombi are also common and consist of alternate white and red layers called lines of Zahn. Red thrombiWhite thrombi Soft Firm Red Pale Gelatinous

  43. Microscopy • Microscopy shows the presence of lines of Zahn • Formed by • alternate layers of light staining aggregated platelets admixed with fibrin meshwork and • dark staining layer of red cells, leucocytes, and platelets.

  44. Thrombus in an artery. The thrombus is adherent to the arterial wall and is seen occluding most of the lumen. It shows lines of Zahn composed of granular-looking platelets and fibrin meshwork with entangled red cells and leucocytes.

  45. MICROSCOPIC VIEW OF THROMBUS

  46. CLASSIFICATION OF THROMBUS

  47. CLASSIFICATION • Cardiac • Arterial • Venous • Capillary

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