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Thrombosis complete
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- 2. THROMBOSIS Definition: • Thrombosis isthe process of formation of solid mass in circulation from the constituents of flowing blood; the mass itself is called a thrombus. THROMBUS.
- 3. • Haemostatic plugsare the blood clots formed in healthy individuals at the site of bleeding e.g. in injury to the blood vessel. • Haemostatic plugs are useful as they stop escape of blood and plasma, whereas thrombi developing in the unruptured cardiovascular system may be life- threatening by causing one of the following harmful effects: 1. Ischaemic injury: Thrombi may decrease or stop the blood supply to part of an organ or tissue and cause ischaemia which may subsequently result in infarction. 2. Thromboembolism: Thrombus or its part may get dislodged and be carried along in the bloodstream as embolus to lodge in a distant vessel.
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- 6. Pathophysiology/Thrombogenesis • Human beingspossess inbuilt system by which the blood remains in fluid state normally and guards against the hazards of thrombosis and hemorrhage. • However, injury to the blood vessel initiates thrombogenesis.
- 7. • Virchow describedthree primary events which predispose to thrombus formation (Virchow’s triad): ENDOTHELIAL INJURY ALTERED BLOOD FLOW VIRCHOW’S TRIAD HYPERCOAGULABILITY
- 8. • Virchow's Triad •Activation of Platelets • Activation of Clotting System THROMBOSIS.
- 9. Events in THROMBOGENESIS 1.ENDOTHELIAL INJURY 2. ROLE OF PLATELETS 3. ROLE OF COAGULATION SYSTEM 4. ALTERATION OF BLOOD FLOW 5. HYPERCOAGULABLE STATES (THROMBOPHILIA)
- 10. 1. ENDOTHELIAL INJURY INTACTENDOTHELIUM 1. Protects the flowing blood from Thrombogenic influence of Subendothelium. 2. Releases Anti-thrombotic factors (thrombosis Inhibitory factors) • Heparin-like substance which accelerates the action of antithrombin III and inactivates some other clotting factors. • Thrombomodulin which converts thrombin into activator of protein C, an anticoagulant. • Inhibitors of platelet aggregation: ADPase, PGI2, NO. • Tissue plasminogen activator which accelerates fibrinolytic activity.
- 11. N.O PLATELETS PGI2 PREVENTS PLATELETS ADHESION HEPARIN SULPHATE ANTITHROMBIN III INACTIVATES THROMBIN XA IXa THROMBIN THROMBOMODULIN PROTEIN-C DIGESTSVA, VIIIA ADPase TISSUE PLASMINOGEN ACTIVATOR INACTIVE PLASMINOGEN ACTIVE PLASMIN ENZYME BREAKDOWN OF FIBRIN STRANDS TO FIBRIN SPLIT PRODUCTS (FSP).
- 12. INTACT ENDOTHELIUM 3. Releasesa few prothrombotic factors which have procoagulant properties (thrombosis favoring factors) as under: a) Thromboplastin or 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. • Vascular injuryexposes the subendothelial extracellular matrix or ECM which is thrombogenic and thus plays an important role in initiating thrombosis. • Endothelial injury is of major significance in the formation of arterial thrombi and thrombi of the heart, especially of the left ventricle.
- 14. • A numberof factors and conditions may cause vascular injury and predispose to the formation of thrombi. These are as under: Ulcerated plaques in advanced atherosclerosis. Haemodynamic stress in hypertension. Arterial diseases. Diabetes mellitus. Endogenous chemical agents such as hypercholesterolaemia, endotoxins. Exogenous chemical agents such as cigarette smoke.
- 15. ULCERATED PLAQUES IN ADVANCEDATHEROSCLEROSIS.
- 16. HAEMODYNAMIC STRESS INHYPERTENSION.
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- 18. 2. ROLE OFPLATELETS • Following endothelial cell injury, platelets come to play a central role in normal haemostasis as well as in thrombosis. • The sequence of events is as under i) Platelet adhesion ii) Platelet release reaction iii) Platelet aggregation
- 19. I) PLATELET ADHESION •Glycoprotein Ib (GpIb) receptor on the platelets recognises the site of endothelial injury and the circulating platelets adhere to exposed subendothelial ECM (primary aggregation). • von Willebrand’s factor (vWF), synthesised by the endothelial cells binds to GpIb and forms a firm adhesion of platelets with ECM.
- 20. Thus, • Deficiency ofvWF leads to von Willebrand’s disease • Absence of GpIb lead to Bernard-Soulier disease would result in defective platelet adhesion and cause abnormal bleeding.
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- 23. platelet Platelet adhesion (PRIMARY AGGREGATION) ThromboxaneA-2 (A vasoconstrictor) Gp1b receptors
- 24. II) PLATELET RELEASEREACTION • Activated platelets then undergo release reaction by which the platelet granules are released to the exterior. • Two main types of platelet granules are released: A) DENSE BODIES: release - ADP (adenosine diphosphate), - ionic calcium, - 5-HT (serotonin), histamine and epinephrine. • Release of contents of dense bodies are more important since ADP is further an activator of platelets, and calcium is required in the coagulation cascade.
- 25. B) ALPHA GRANULES:Their release produces - Fibrinogen, - Fibronectin, - Platelet-derived growth factor (PDGF), - Platelet factor 4 (an antiheparin) and - Thrombospondin.
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- 27. iii) 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.
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- 29. 3. ROLE OFCOAGULATION SYSTEM • Coagulation mechanism is the conversion of the plasma fibrinogen into solid mass of fibrin. SOLUBLE FIBRINOGEN INSOLUBLE FIBRIN.
- 30. COAGULATION PATHWAYS • INTRINSICPATHWAY • EXTRINSIC PATHWAY
- 31. INTRINSIC PATHWAY • Theintrinsic pathway is activated by trauma inside the vascular system, and is activated by platelets, exposed endothelium or collagen. • This pathway is slower than the extrinsic pathway. • It involves factors XII, XI, IX, VIII
- 32. • In theintrinsic pathway, contact with abnormal surface (e.g. ECM in the subendothelium) leads to activation of factor XII and the sequential interactions of factors XI, IX, VIII.
- 33. XII XIIa ` XI XIa IX IXa Ca++ X Xa VIII, PF3,Ca++ Ca++, V, PF3 PROTHROMBIN THROMBIN(II a) FIBRINOGEN FIBRINS
- 34. EXTRINSIC PATHWAY • Theextrinsic pathway is activated by external trauma that causes blood to escape from the vascular system. • Tissue damage results in release of tissue factor or thromboplastin. • Tissue factor on interaction with factor VII activates factor X.
- 35. TISSUE FACTOR X Xa TISSUE FACTOR VII,Ca++ Ca++, V, PF3 PROTHROMBIN THROMBIN (II a) FIBRINOGEN FIBRINS
- 36. Regulation of coagulationsystem Normally, the blood is kept in fluid state and the coagulation system is kept in check by controlling mechanisms. These are as under: i) Protease inhibitors: These act on coagulation factors so as to oppose the formation of thrombin e.g. antithrombin III, protein C. ii) Fibrinolytic system: Plasmin, a potent fibrinolytic enzyme, is formed by the action of plasminogen activator on plasminogen present in the normal plasma. - Plasmin so formed acts on fibrin to destroy the clot and produces fibrin split products (FSP).
- 37. 4. ALTERATION OFBLOOD FLOW • Normally, there is axial flow of blood in which the most rapidly-moving central stream consists of leucocytes and red cells. • The platelets are present in the slow-moving laminar stream adjacent to the central stream while the peripheral stream consists of most slow-moving cell-free plasma close to endothelial layer
- 38. NORMAL AXIAL FLOWOF BLOOD Formed elements (LEUCOCYTES+RBC+ PLATELETS
- 39. MARGINATION AND PAVEMENTINGOF BLOOD ELEMENTS
- 41. • Turbulence andstasis causes THROMBOSIS (Turbulence means unequal flow while stasis means slowing.) • When blood slows down, the blood cells including platelets marginate to the periphery and form a kind of pavement close to endothelium (margination and pavementing)
- 42. • Formation ofarterial and cardiac thrombi is facilitated by turbulence in the blood flow, while stasis initiates the venous thrombi even without evidence of endothelial injury.
- 43. 5. HYPERCOAGULABLE STATES(THROMBOPHILIA) • Thrombophilia or hypercoagulable states are a group of conditions having increased risk or predisposition to develop venous thrombosis. • These conditions may be - Hereditary (or primary) - Acquired (or secondary)
- 46. Fate of Thrombus •1. RESOLUTION • 2. ORGANISATION • 3. PROPAGATION • 4. THROMBOEMBOLISM
- 48. 1. RESOLUTION • Thrombusactivates the fibrinolytic system with consequent release of plasmin which may dissolve the thrombus completely resulting in resolution. • Usually, lysis is complete in small venous thrombi while large thrombi may not be dissolved. • Fibrinolytic activity can be accentuated by Administration of thrombolytic substances (e.g. urokinase, streptokinase), especially in the early stage when fibrin is in monomeric form e.g. thromobytic therapy in early stage acute myocardial infarction.
- 51. 2. ORGANISATION ANDRECANALISATION • Thrombi may be invaded by fibroblast and endothelial cells. • Thus, fibrovascular granulation tissue is formed which subsequently becomes dense and less vascular and is covered over by endothelial cells. • The thrombus in this way is excluded from the vascular lumen and becomes part of vessel wall.(ORGANISATION)
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- 53. • The thrombusis now converted to fibrous connective tissue. • This scar tissue may shrink with time allowing for re-establishment of blood flow through the recanalized vessel.(RECANALISATION)
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- 55. 3. PROPAGATION • Thethrombus may enlarge in size due to more and more deposition from the constituents of flowing blood. • In this way, it may ultimately cause obstruction of some important vessel.
- 57. 4. THROMBOEMBOLISM • Thethrombi in early stage and infected thrombi are quite friable and may get detached from the vessel wall. • These are released in part or completely in blood-stream as emboli which produce ill- effects at the site of their lodgment
- 59. Different types ofThrombosis • Thrombosis is normally categorized by where it occurs in the body. • Within these categories, it may be classified further. 1. Venous Thrombosis 2. Arterial Thrombosis
- 60. Feature Arterial ThrombiVenous Thrombi Blood flow Rapidly flowing Coronary Artery, Aorta Slow moving blood Deep Veins of Leg Thrombogenesis Endothelial Cell Injury Venous Stasis Development Usually Mural Usually Occlusivemay and may propagate in both Directions. Macroscopic Appearance Grey-White Lines of Zahn Red Blue Lines of Zahn Microscopic Appearance Distinct lines of Zahn composed of platelets, fibrin with entangled red and white blood Cells Lines of Zahn with more abundant red cells Effects Ischemia leading to Infarcts Thrombo-embolism, Oedema, Skin Ulcers, Poor wound healing DISTINGUISHING FEATURES OF ARTERIAL AND VENOUS THROMBI.
- 61. • Mural thrombi(non-occlusive) are thrombi that adhere to the wall of a blood vessel. • Occlusive thrombi are thrombi that completely occlude the blood vessel.
- 64. DISTINGUISHING FEATURES OFANTEMORTEM THROMBUS AND POSTMORTEM CLOT