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Thrombosis

Thrombosis. Asim K. Duttaroy ERN 3110. Vessels. Coagulation Proteins. Platelets. Fibrinolysis/Inhibitors. Homeostasis. State of fluid equilibrium within the blood vessels. Hemostasis. Arrest of bleeding Events preventing excessive blood loss

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Thrombosis

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  1. Thrombosis Asim K. Duttaroy ERN 3110

  2. Vessels Coagulation Proteins Platelets Fibrinolysis/Inhibitors Homeostasis State of fluid equilibrium within the blood vessels

  3. Hemostasis • Arrest of bleeding • Events preventing excessive blood loss • Vascular spasm: Vasoconstriction of damaged blood vessels • Platelet plug formation • Coagulation or blood clotting

  4. Functions of Blood • Transport of: • Gases, nutrients, waste products • Processed molecules • Regulatory molecules • Regulation of pH and osmosis • Maintenance of body temperature • Protection against foreign substances • Clot formation

  5. Composition of Blood

  6. HEMOSTASIS • VASCULAR SPASM • PLATELET PLUG • BLOOD COAGULATION (will talk later) • GROWTH OF FIBROUS TISSUE IN CLOT • Fibrinolysis (will talk later)

  7. What is thrombosis? • Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system • When a thrombus occupies more than 75% of cross-sectional area of the lumen of an artery, blood flow to the tissue supplied is reduced enough to cause of symptoms because of decreased oxygen supply and accumulation of lactic acid. • More than 90% obstruction can result in anoxi, complete deprivation of oxygen, and the infarction , a mode of cell death

  8. Thrombosis • Arterial Thrombosis : • Adherence of platelets to arterial walls - White in color - Often associated with MI, stroke and ischemia • Venous Thrombosis : • Develops in areas of stagnated blood flow (deep vein thrombosis), Red in color- Associated with Congestive Heart Failure, Cancer, Surgery.

  9. Slide 3 of 28

  10. Haemostasis: • Vasoconstriction • Platelet activation • Haemostatic plug • Coagulation • Stable clot formation • Clot dissolution

  11. BLOOD COAGULATION Thrombin Fibrin Monomers Fibrinogen Ca+2, factor XIII Fibrin threads

  12. Coagulation: • Fibrinogen to Fibrin – Coag. Cascade • Several factors – proenzymes-activation. • Enzyme amplication – • Plasma, Endothelium & Platelets • Stable hemostatic plug. • Clot lysis – starts soon after clot formation.

  13. BV Injury Contact/ Tissue Factor Neural Coagulation Cascade Blood Vessel Constriction Platelet Aggregation Primary hemostatic plug Reduced Blood flow Platelet Activation Fibrin formation Stable Hemostatic Plug Haemostasis overview:

  14. NORMAL HAEMOSTASIS • formation of the platelet plug • coagulation = fibrin formation • clot retraction • fibrinolysis • RESOLUTION

  15. PLATELETS AND ARTERIAL THROMBOSIS platelet and coagulation activation within blood vessel Thrombus “a mass of blood constituents formed within the vascular system” “inappropriate haemostasis” ?

  16. Overlap of Vascular Disease in Patients With Atherothrombosis Ischemic stroke Unstable angina MI PAD Platelet adhesion, activation, and aggregation Plaque rupture Thrombus formation Vascular events (MI, stroke, or CV death) Ness J, Aronow WS. J Am Geriatr Soc. 1999;47:1255-1256. Schafer AI. Am J Med. 1996;101:199-209.

  17. How do we know platelets are important in CVD? • Platelets are present in atherosclerosis, thrombosis, embolism i.e. at early and late stages of cardiovascular disease • Activated platelets are present in circulation of patients with cardiovascular disease • Modification of platelet activity affects the development and progression of cardiovascular disease

  18. What are platelets?

  19. Platelets in cardiovascular disease • What are Platelets? • Role in Health : how do they work? • Role in Disease • bleeding disorders • atherosclerosis • arterial thrombosis • thrombo-embolism • Techniques for the study of platelets • Anti-platelet Therapy in Cardiovascular Disease

  20. Normal Function of Platelets • Haemostasis • Preventing bleeding from wounds • Integrity and repair of the vessel wall

  21. Haemostatic role of platelets in health: how do they work? • Platelets circulate in a resting, inactive state • Must become activated • Must stick together = Aggregation

  22. Disk-shaped cell fragments produced in the megakaryocytes Mature Platelet Megakaryocyte Bone Marrow What are Platelets?

  23. Quantity - 200,000 - 400,000/mm3 Life Span - 10 days 33% pooling 67% in the circulation Spleen Megakaryocyte Storage and Circulation

  24. lipidbilayer Glycoprotein receptors

  25. Fig. 16-10

  26. Platelet Plug Formation

  27. Platelet Aggregation Fibrinogen binding to Glycoprotein IIb-IIIa on activated platelets

  28. Factors that activate platelets ADP Thrombin Collagen 5-hydroxytryptamine (serotonin) Thromboxane A2 Mechanical stimuli Many stimuli Several different receptors Multiple signalling pathways

  29. ADP Aggregation Aggregation Aggregation GpIIb/IIIa GpIIb/IIIa GpIIb/IIIa GpIIb/IIIa GpIIb/IIIa GpIIb/IIIa Adrenaline Adhesion Adhesion vWF Endothelium Exposed Collagen Platelet Activation Pathways COLLAGEN THROMBIN ADP GpIIb/IIIa Platelet GpIb Adrenaline Adhesion

  30. Slide 23 of 79

  31. Targets for anti-platelet therapy Thrombin inhibitors ADP ADP receptor antagonists Clopidogrel II receptor THROMBIN receptor COX-1 Aspirin Signalling Phosphodiesterase inhibitors dipyridamole AA NSAIDs pathways TXA2 GPIIb - IIIa Fibrinogen Receptor Antagonists Fibrinogen

  32. Insulin Resistance Hypertension Dyslipidemia Atherosclerosis Hypercoagulability Hyperglycemia • Coronary arteries • Carotid arteries • Cerebral arteries • Aorta • Peripheral arteries Hyperinsulinemia Inflammation Impaired Fibrinolysis Endothelial Dysfunction Multiple Factors Associated With Obesity Give Rise to Increased Risk of CVD Primary Metabolic Disturbance Intermediate Vascular Disease Risk Factor Intravascular Pathology Clinical Event Hyperactivity of Platelets plays central role Overnutrition CVD

  33. Slide 27 of 79

  34. Plaques Tissue factor, VIIa

  35. Effects of spices on platelet function Effects on platelets Spice Reduced TxA2 generation, Reduced AA incorporation to membrane PL Garlic Reduced TXA2 and 12-Lipoxygenase products Onion Ginger Reduced Aggregation Cloves Antiaggregatory, Reduces cyclooxygenase and lipoxygnease products Cumin Inhibits AA-induced Aggregation Reduced TxA2 generation, Reduced AA incorporation to membrane PL Tumeric

  36. In vitro anti-aggregatory properties of fruit extracts

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