L40 Thrombosis Note PDF

L40 Thrombosis ILOs By the end of this lecture, students will be able to 1. Compare between blood clot and thrombus as regards pathogenesis, morphology, and clinical settings. 2. Explain the pathophysiology of thrombosis in relation to corresponding clinical settings. 3. Categorize thrombi according...

L40 Thrombosis ILOs By the end of this lecture, students will be able to 1. Compare between blood clot and thrombus as regards pathogenesis, morphology, and clinical settings. 2. Explain the pathophysiology of thrombosis in relation to corresponding clinical settings. 3. Categorize thrombi according to location, morphology, and clinical effects. 4. Explain fate and complications of thrombus in relation to location and size. Thrombosis is the process of the formation of solid mass in circulation from the constituents of flowing blood; the mass itself is called a thrombus. It occurs due to the pathological activation of blood clotting in uninjured vasculature, within an intact blood vessel, during life. A blood clot; is a process that involves only the conversion of soluble fibrinogen to insoluble polymerized fibrin without the activation of platelets. It may occur in the following situations; a. Coagulation of blood in vitro e.g., in a test tube. b. Coagulated blood after death. c. Hematoma; extravascular accumulation of blood e.g. into the tissues. d. Hemostatic plugs; where the blood clots form in healthy individuals at the site of injury to the blood vessel. A blood clot is loosely attached to the vascular wall, does not detach and circulate, and looks red, soft, and jelly-like. Etiology and pathogenesis of thrombosis; The primary abnormalities that lead to thrombosis are (1) endothelial injury, (2) stasis or turbulent blood flow, and (3) hypercoagulability of the blood, the so-called Virchow triad. 1) Endothelial injury; Normally, Endothelial cells (ECs) exhibit platelet inhibitory effect, anticoagulant, and fibrinolytic properties. However, after injury or activation, ECs exhibit procoagulant function. The balance between EC antithrombotic and prothrombotic activities determines whether thrombus formation, propagation, or dissolution occurs. EC injury usually underlies thrombus formation in the heart and the arterial circulation, where the high rates of blood flow impede clot formation. Endothelial injury; a) Exposes the subendothelial extracellular matrix (ECM) which is thrombogenic and thus plays an important role in initiating hemostasis as well as thrombosis. b) Leads to platelet activation that almost inevitably Causes of endothelial injury; i) Endocardial injury in myocardial infarction, myocarditis, cardiac surgery, and prosthetic valves. ii) Endothelial injury; complicated atherosclerosis plaques. iii) Endothelial dysfunction; Hemodynamic stress in hypertension or turbulent blood flow. iv) Other; endotoxin, radiation, cigarette smoke, and Diabetes mellitus. 2) Alterations in normal blood flow. Normally, there is an axial laminar 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 the endothelial layer. Stasis (stagnation or slow circulation) and turbulence (that forms eddy currents with local pockets of stasis) predispose to the formation of thrombi through the following actions: a) Disrupt laminar flow and bring platelets into contact with the endothelium. b) Prevent dilution of activated clotting factors by flowing blood. c) Retard the inflow of clotting inhibitors. d) Promote Endothelial Cell activation. - Stasis causes thrombosis in the venous circulation as in prolonged recumbency, bandages, outside pressure, or systemic congestion. Hyperviscosity syndromes (e.g., polycythemia) or deformed erythrocytes (e.g., sickle cell anemia) result in small vessel stasis and also predispose to thrombosis. - Turbulence causes thrombosis in the arterial circulation, cardiac chambers (healed myocardial infarction), and arterial aneurysms as well as endothelial injury (atherosclerosis). 3) Hypercoagulability; It is loosely defined as any alteration of the coagulation pathways that predisposes to thrombosis. It contributes less frequently to thrombosis but is critical in certain conditions. A. Heritable hypercoagulable states: Factor V gene mutations are the most common, as well as deficiencies of antithrombin III, protein C, or protein S. B. Acquired hypercoagulable states: Risk factors: Advancing age, Prolonged bed rest, or immobilization (e.g., in a plaster cast, long-distance travel), Cigarette smoking, and Obesity. Predisposing clinical conditions: a) Heart diseases (e.g. myocardial infarction, Congestive Heart Failure, rheumatic mitral stenosis, cardiomyopathy) b) Vascular diseases (e.g. atherosclerosis, aneurysms of the aorta and other vessels, varicosities of leg veins) c) Hypercoagulable conditions (e.g. disseminated cancers that can release procoagulant products) d) Late pregnancy and puerperium e) Oral contraceptives or the hyperestrogenic state of pregnancy can cause hypercoagulability via increased hepatic synthesis of coagulation factors and reduced synthesis of antithrombin III. Origin and location of thrombi; Cardiac thrombi; Common locations; may form in any of the chambers of the heart and on the valve cusps. The main pathogenetic mechanism for cardiac thrombi is endothelial cell injury and abnormal blood flow; stasis e.g., stenosis and turbulence e.g. aneurysm. Clinical associations of cardiac thrombi; I.Left atrium; in mitral stenosis and atrial fibrillation. II.Left ventricle; in healed myocardial infarction and apical aneurysm. III.On mitral and aortic valves (vegetation) seen in infective endocarditis, rheumatic fever, and non-bacterial thrombotic endocarditis. Arterial thrombi; Common locations; in the aorta, coronary, carotid, cerebral, iliac, femoral, renal, and mesenteric arteries. The main pathogenetic mechanism is endothelial cell injury e.g. in atherosclerosis and turbulence e.g. aneurysm. Clinical associations of arterial thrombi; a) Aorta: atherosclerosis, aneurysms, arteritis. b) Coronary, cerebral, renal, mesenteric arteries: atherosclerosis, vasculitis. c) Arteries of limbs: atherosclerosis, diabetes mellitus, Buerger’s disease, Raynaud’s disease. Venous thrombosis; Common locations; most commonly affects the veins of the lower extremities followed by femoral and iliac veins. The main pathogenetic mechanism is stasis and hypercoagulability. Clinical associations of venous thrombi; a) Deep veins of lower limbs: [deep vein thrombosis (DVT)], Popliteal (>90% of cases), femoral, and iliac veins. DVT occurs in multiple clinical settings: Advanced age, bed rest, or immobilization, Congestive heart failure, surgery, and burns, postpartum states or malignancy-associated procoagulant release. b) Superficial veins of lower limb; varicose veins (usually affects superficial veins). c) Pulmonary veins: congestive heart failure, pulmonary hypertension. d) Mesenteric veins: volvulus, intestinal obstruction. Morphology Grossly; thrombi may be of various shapes, sizes, and compositions depending upon the site of origin. The composition of a thrombus is determined by the rate of flow of blood i.e. whether it is formed in the rapid arterial and cardiac circulation or the slow-moving flow in veins. Arterial and cardiac (mural) thrombi have gross and microscopic laminations (lines of Zahn) produced by pale layers of platelets and fibrin alternating with darker erythrocyte-rich layers. According to the size of affected vessel it may be occlusive or mura). Venous thrombi (phlebothrombosis) typically contain abundant erythrocytes among sparse fibrin strands (red or stasis thrombi). Venous thrombi are propagating. Valve thrombosis (vegetations): may occur as loose, friable, infected polypoid masses (as in infective endocarditis) or as firmly attached, pin-head-sized masses (e.g.... rheumatic valvulitis). Thrombi look red-brown and granular. Thrombi are firmly attached at their site of origin and typically propagate toward the heart. Microscopically, Thrombi are mainly composed of layers of platelets and fibrin alternating with layers of blood constituents. Fate of the thrombus If a patient survives the immediate effects of a thrombus, some combination of the following occurs: Dissolution by fibrinolytic activity. Thrombus activates the fibrinolytic system with the consequent release of plasmin which may dissolve the thrombus ultimately resulting in resolution (Usually, in small veins), whereas, thrombi in thrombi large veins may not be dissolved. Organization and recanalization. Phagocytic cells (neutrophils and macrophages) phagocytose fibrin and cell debris. Capillaries grow into the thrombus creating granulation tissue that grow into fibrous tissue and is covered over by endothelial cells and it either lead to a thrombus incorporated into vascular lumen or create multiple vascular channels to re-establish the blood flow. Propagation. Due to more deposition from the constituents of flowing blood. Embolism. Detached thrombi may circulate with the blood-stream and become impacted in distant sites.