Thrombosis, Embolism and Infarction

1. Thrombosis, Embolism and Infarction Dr. Raid Jastania

2. Hemostasis and Thrombosis • Hemostasis is the physiological process of maintaining blood in fluid state and formation of hemostatic plug at site of vessel injury. • Thrombosis is the pathological process of blood clotting in uninjured vessel or exagurated response to minimal injury. • Components: • Vessel wall • Platelets • Coagulation pathways

3. Normal Hemostasis: • Vessel injury - brief period of arteriolar vasoconstriction (neurogenic reflex ,endothelin) • Endothelial injury exposes ECM (highly thrombogenic material). • Platelets adhere to endothelial cells and ECM, and are activated. They release their secretory granules. Platelet aggregation occurs forming hemostatic plug (Primary hemostasis) • Tissue factor (produced by endothelium) activates coagulation - formation of thrombin which act of finbrinogen to form fibrin (secondary Hemostsis)

4. Normal Hemostasis: • The process continues to form the permanent plug formed by polymerized fibrin and platelet aggregates. • At the same time tissue plasminogen activator (t-PA) is formed and it limits hemostatic plug. • Fibrinolysis is also activated to limit heostatic plug to the site of injury.

5. Thrombosis: • Thrombosis is the pathological process of blood clotting in uninjured vessel or an exaggerated blood clotting response to minimal injury. • Virchow Triad: (factors predisposing thrombosis) • Endothelial injury • Blood stasis or turbulence of blood flow • Blood hypercoagulability

6. Endothelial Injury • An important factor in arterial thrombosis. • Occurs in myocardial infarction, ulcerated atherosclerosis, trauma, and inflammatory disease of vessels. • Endothelial dysfunction is also a predisposing factor for thrombosis. Eg. Hypertension, bacterial endotoxins, hypercholestrolemia, radiation, cigarette smoking. • Loss of endothelium will expose the ECM and hence activation of platelets and thrombosis.

7. Blood Stasis and Turbulence of Flow • Turbulence enhances endothelial injury. • Stasis enhances venous thrombosis. • Both result in: • Bringing platelets close to endothelium • Accumulation of clotting factors • Prevent clotting factors inhibitors • Endothelial activation • Example: aortic aneurysm, MI, valve stenosis, rheumatic heart disease, hyperviscosity, sickle cell disease.

8. Hypercoagulability • It is an alteration in coagulation leading to thrombosis. • Primary: (genetic) • Factor V mutation • Antithrombin III deficiency • Secondary: • Prolonged immobilization • Cancer • Lupus anticoagulant • Nephrotic syndrome • Contraceptive pills • Smoking

9. Hypercoagulability • Heparin-induced Thrombocytopenia: • When heparin is administered it induces the formation of antibodies that bind platelets and activate them. • Antiphospholipid syndrome (Lupus anticoagulant): • Antibodies to phospholipid (eg. Cardiolipin) • In-vitro: it inhibits coagulation • In-vivo: it induces coagulation

10. Thrombosis • May develop in the heart, arteries, veins and capillaries. • Arterial thrombi and cardiac thrombi occur at site of endothelial injury or turbulence of flow. • Venous thrombi occur in areas of blood stasis. • Thrombi usually are attached to the underlying vessel wall (mural thrombi) • Arterial thrombi grow back to the heart. • Venous thrombi grow toward the heart.

11. Thrombosis • Arterial thrombi are firmly attached to the wall and show lines of Zahn (layers of fibrin and platelets alternate with layers of RBC and WBC. • Venous thrombi do no show clear lamination. • In the heart: common causes: MI, dilated cardiomyopathy, arrhythmia, myocarditis, or valvular disease.

12. Thrombosis • In arteries: common causes: atherosclerosis, and aneurysm. • Arterial thrombi usually occlude the lumen, common in coronary, cerebral, and femoral arteries. • Venous thrombi (phlebothrombosis) are almost always occlusive, Red thrombi, 90% occur in lower extremities.

13. Fate of thrombus • Propagation (progression) • Embolization • Lysis 4.Organization and recanalization (inflammation and fibrosis)

14. Venous Thrombosis: • Superficial: eg. Saphenous vein • Local congesion, edema, swelling, pain, tenderness, ischemia, risk of infection • Rarely embolize • Deep Vein Thrombosis: eg. Popliteal, femoral, iliac veins. • Can embolize • There is a lot of collaterals so the congestion and edema are not prominent. • 50% are asymptomatic.

15. Venous Thrombosis • Blood stasis is common predisposing factor for venous thrombosis. Eg. Heart failure, surgery, trauma, burn, pregnancy, cancer (Trousseau syndrome)

16. Cardiac and arterial thrombi • MI, valve disease, arrhythmia, atherosclerosis • Possible embolism to brain, kidneys, spleen.

17. Disseminated Intravascular Coagulation • Sudden widespread fibrin thrombi in the microcirculation • Occurs in pregnancy, and with malignancy. • Leading to circulatory insufficiency: brain , lung, heart, kidneys • Leading to consumption of platelets and clotting factors and risk of bleeding.

18. Embolism • Detached intravascular solid, liquid or gaseous mass carried by blood to a distant site. • Types: Thrombus 90%, fat, air, cholesterol, tumor, bone marrow, foreign body • Occlusion of vessels and ischemia/infarction

19. Pulmonary Thromboembolism • 20-25/ 100,000 of hospital patients • 95% coming from DVT (above knee) • may occlude main pulmonary artery (Saddle embolus) • or in small branches of vessels (multiple) • Paradoxical embolus: cardiac embolus passing to the right side through septal defect.

20. Pulmonary Thromboembolism • 20-25/ 100,000 of hospital patients • 95% coming from DVT (above knee) • may occlude main pulmonary artery (Saddle embolus) • or in small branches of vessels (multiple) • Paradoxical embolus: cardiac embolus passing to the right side through septal defect.

21. Pulmonary Thromboembolism • 60-80% are asymptomatic • most organize • can lead to cor pulmonale, sudden death. • Result in hemorrhage, and rarely infarction • Obstruction of small vessels lead to small infarctions • Multiple emboli may lead to pulmonary hypertension

22. Fat EmbolismAir EmbolismAmniotic Fluid Embolism

23. Infarction • Ischemic necrosis caused by occlusion of arterial or venous vessles. • Example: MI, cerebral infarction, pulmonary infarct, bowel infract, gangrene • 99% due to thrombosis, mostly arterial • Can be: • Vasospasm • External pressure • Trauma • Twisting of organs eg. Testicular torsion • Edema

24. Infarction • Venous infarct occurs in organs with single venous outflow. Eg. Testis, ovary • Types: Red infarct, white infarct, septic infarct • Red infarct: • Due to venous occlusion • In loose tissue eg. Lung • Organs with dual circulation • In tissues that have be previously congested • White infarct • Arterial occlusion of solid organs, eg. Heart, kidneys, spleen

25. Infarction • Infarction is usually wedge shape surrounded by rim of hyperemia • Hemosiderin pigment may accumulate following hemorrhage • Necrosis is of coagulative type (except brain: liquifactive) • Inflammation within few hours • Repair process

26. Factors influencing development of Infarct • Nature of the blood supply • Dual: lung, liver, hands • End-arterial: spleen, kidneys • Rate of occlusion: • Eg. Atherosclerosis of coronary arteries is gradual slow process

27. Factors influencing development of Infarct 3. Vulnerability to hypoxia • Neuron: 3-4 minutes • Heart: 20-30 minutes • Fibrous tissue: hours 4. Oxygen content of the blood • Eg. Heart failure patient have low oxygen concentration in blood

29. Normal Endothelium • Endothelial cells are activated by injury, infection, plasma mediators and cytokines. They have pro-thrombotic and anti-thrombotic functions.

30. Anti-thrombotic properties: • Anti-platelet effect: • Non activated platelets do not adhere to endothelium. • PGI2, and NO (produced by endothelium) prevent platelet adhesion • Anticoagulant properties: • Heparin-like molecule activate anti-thrombin III • Thrombomodulin binds thrombin which activate protein C (anticoagulant) • Fibrinolytic properties: • Endothelium synthesize t-PA (fibrinolysis)

31. Pro-thrombotic properties: • Von Willebrand factor: • It enhances binding of platelets to ECM. • Tissue factor • Produced by endothelium, it activates extrinsic clotting pathway • Plasminogen activator inhibitors (PAI)

32. Normal Platelets • Platelets contain • Alpha-granules: P-selectin, fibrinogen, fibronectin, factor V, factor VIII, PDGF,TGF-alpha. • Delta-granules: ATP, ADP, Ca, histamine, epinephrine

33. Normal Platelets • On encountering ECM: • 1. Platelets adhere to ECM (collagen) mediated by vWF. • 2. Secrete their granules • 3.Platelets aggregate: forming the primary hemostatic plug which is reversible. With the action of thrombin, platelet contraction occur and the plug becomes irreversible (secondary hemostatic plug)

34. Normal Platelets • PGI2 inhibits platelet aggregation • Thromboxane A2 (TXA2) enhances platelet aggregation • Aspirin inhibits the synthesis of TXA2

35. Normal coagulation Cascade • It is series of enzymatic conversions turning inactive proenzymes to active forms. • They lead to formation of thrombin • Thrombin converts fibrinogen to fibrin. • Each reaction needs: enzyme, substrate, cofactor, phospholipid complex, Ca ions • Two pathways: extrinsic and intrinsic: both lead to activation of factor X.

36. Intrinsic pathway is activated by activation of Hageman factor (factor XII). • Extrinsic pathway is activated by tissue factor. • The process is controlled by anticoagulants: • Antithrombins (eg. Antithrombin III). It is activated by binding to Heparin-like molecule on endothelium. • Protein C and S (vit K dependent) they inactivate factors Va and VIIIa.

37. Fibrinolytic cascade: • While coagulation occurs • Factor XII or tissue plasminogen activator (t-PA) act on plasminogen to form plasmin. • Plasmin start the process of fibrin lysis an the production of fibrin degradation produces. • The function of plasmin is controlled (opposed) by plasminogen activator inhibitor (PAI) and alph2-antiplasmin.