Hemodynamic disorder 1.pdf

Hemodynamic Disorders, Thrombosis, and Shock The health of cells and tissues depends ,on an intact circulation to deliver oxygen and remove wastes and on normal fluid homeostasis. Normal fluid homeostasis also means maintaining blood as a liquid until clot formation i...

Hemodynamic Disorders, Thrombosis, and Shock The health of cells and tissues depends ,on an intact circulation to deliver oxygen and remove wastes and on normal fluid homeostasis. Normal fluid homeostasis also means maintaining blood as a liquid until clot formation is mandatory. HEMOSTASIS AND THROMBOSIS Normal hemostasis is a consequence of tightly regulated processes that maintain blood in a fluid, clot-free state in normal vessels while inducing the rapid formation of a localized hemostatic plug at the site of vascular injury. Both hemostasis and thrombosis involve three components: the vascular wall, platelets, and the coagulation cascade. Endothelium Endothelial cells modulate several (and frequently opposing) aspects of normal hemostasis. The balance between endothelial anti- and prothrombotic activities determines whether thrombus formation, propagation, or dissolution occurs. At baseline, endothelial cells exhibit antiplatelet, anticoagulant, and fibrinolytic properties; however, they are capable (after injury or activation) of exhibiting numerous procoagulant activities. Antithrombotic Properties Antiplatelet Effects Anticoagulant effects Fibrinolytic effects. Under most circumstances, endothelial cells maintain an environment that promotes liquid blood flow by blocking platelet adhesion and aggregation, by inhibiting the coagulation cascade, and by lysing blood clots. Antiplatelete An intact endothelium prevents platelets (and plasma coagulation factors) from interacting with the highly thrombogenic subendothelial ECM. prostacyclin (PGI2) and nitric oxide. adenosine diphosphatase Anticoagulant Effects heparin-like molecules and thrombomodulin. Fibrinolytic Properties plasminogen activator (t-PA) Prothrombotic Properties Platelet effects: Recall that endothelial injury leads to adhesion of platelets to the underlying extracellular matrix; this is facilitated by endothelial production of von Willebrand factor (vWF). Procoagulant effects. Endothelial cells are also induced by bacterial endotoxin or by cytokines (e.g., tumor necrosis factor [TNF] or interleukin-1 [IL-1]) to synthesize tissue factor, which, activates the extrinsic clotting cascade. Antifibrinolytic effects. Endothelial cells also secrete inhibitors of plasminogen activator (PAIs) Platelets Platelets play a central role in normal hemostasis. Platelet Adhesion :Adhesion to ECM is mediated largely via interactions with vWF acting as a bridge between platelet surface receptors (e.g., GpIb) and exposed collagen. Secretion (Release Reaction) Secretion of both granule types occurs soon after adhesion. Release of dense body contents (δ granules, contain adenine nucleotides (ADP and ATP), ionized calcium, histamine, serotonin, and epinephrine) platelet activation increases surface expression of phospholipid complexes. Platelet Aggregation Aggregation follows platelet adhesion and granule release. In addition to ADP, platelet-synthesized thromboxane A2 is also an important stimulus for platelet aggregation. ADP and TXA2 promotes formation of an enlarging platelet aggregate, the primary hemostatic plug. This primary aggregation is reversible. However, with activation of the coagulation cascade, the generation of thrombin results in two processes that make an irreversible hemostatic plug. Thrombin binds to a platelet surface receptor (protease-activated receptor, or PAR); in association with ADP and TXA2, this interaction induces further platelet aggregation. Platelet contraction follows, creating an irreversibly fused mass of platelets ("viscous metamorphosis") constituting the definitive secondary hemostatic plug. Concurrently, thrombin converts fibrinogen to fibrin within and about the platelet plug, contributing to the overall stability of the clot Coagulation Cascade The coagulation cascade is essentially an amplifying series of enzymatic conversions; each step in the process proteolytically cleaves an inactive proenzyme into an activated enzyme, eventually culminating in thrombin. Thrombin converts the soluble plasma protein fibrinogen into fibrin monomers that polymerize into an insoluble gel; this gel encases platelets and other circulating cells in the definitive secondary hemostatic plug. Once activated, the coagulation cascade must be restricted to the local site of vascular injury to prevent runaway clotting of the entire vascular tree. In addition to the restriction of factor activation to sites of exposed phospholipids, three categories of natural anticoagulants function to control clotting: antithrombins, proteins C and S, and tissue factor pathway inhibitor (TFPI). Antithrombins (e.g., antithrombin III) inhibit the activity of thrombin and other serine proteases, factors IXa, Xa, XIa, and XIIa. ).Proteins C and S are two vitamin K-dependent proteins that inactivate the cofactors Va and VIIIa. Activation of the clotting cascade also sets into motion a fibrinolytic cascade that moderates the size of the ultimate clot. Fibrinolysis is largely accomplished by the enzymatic activity of plasmin, which breaks down fibrin and interferes with its polymerization. Plasmin is generated by enzymatic degradation of the inactive circulating precursor plasminogen either by a factor XII-dependent pathway or by plasminogen activators. Urokinase-like PA (u-PA) is PA present in plasma and in various tissues; it can activate plasmin in the fluid phase. To prevent excess plasmin from lysing thrombi indiscriminately elsewhere in the body, free plasmin rapidly forms a complex with circulating α2-antiplasmin and is inactivated The coagulation assay can be assessed by PT, PTT and INR. Fibrinolysis is largely accomplished by the enzymatic activity of plasmin, which breaks down fibrin and interferes with its polymerization. Plasmin is generated by enzymatic degradation of the inactive circulating precursor plasminogen either by a factor XII-dependent pathway or by plasminogen activators (The most important of the PAs is t-PA). Thrombosis Pathogenesis There are three primary influences on thrombus formation (called Virchow's triad): (1) endothelial injury, (2) stasis or turbulence of blood flow, and (3) blood hypercoagulability Endothelial Injury It is particularly important for thrombus formation occurring in the heart or in the arterial circulation. it is important to note that endothelium need not be denuded or physically disrupted to contribute to the development of thrombosis; any perturbation in the dynamic balance of the prothrombotic and antithrombotic activities of endothelium can influence local clotting events Alterations in Normal Blood Flow Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury or dysfunction, as well as by forming countercurrents and local pockets of stasis; stasis is a major contributor to the development of venous thrombi. Hypercoagulability It is loosely defined as any alteration of the coagulation pathways that predisposes to thrombosis, and it can be divided into primary (genetic) and secondary (acquired) disorders  Primary 1. Mutation in factor V gene (factor V Leiden) 2. Mutation in prothrombin gene 3. Antithrombin III deficiency Secondary 1. Prolonged bedrest or immobilization 2. Myocardial infarction 3. Atrial fibrillation 4. Cancer 5. Disseminated intravascular coagulation 6. Tissue damage (surgery, fracture, burns) 7. Others. Morphology Thrombi can develop anywhere in the cardiovascular system (e.g., in cardiac chambers, on valves, or in arteries, veins, or capillaries). The size and shape of a thrombus depend on the site of origin and the cause Thrombi are focally attached to the underlying vascular surface; arterial thrombi tend to grow in a retrograde direction from the point of attachment, while venous thrombi extend in the direction of blood flow (thus both tend to propagate toward the heart). Thrombi can have grossly (and microscopically) apparent laminations called lines of Zahn. Thrombi occurring in heart chambers or in the aortic lumen are designated mural thrombi. Arterial thrombi are frequently occlusive and are produced by platelet and coagulation activation; they are typically a friable meshwork of platelets, fibrin, erythrocytes, and degenerating leukocytes. Venous thrombosis (phlebothrombosis) is almost invariably occlusive, and the thrombus can create a long cast of the lumen; venous thrombosis is largely the result of activation of the coagulation cascade, and platelets play a secondary role. Because these thrombi form in the sluggish venous circulation, they also tend to contain more enmeshed erythrocytes and are therefore called red, or stasis, thrombi.. Fate of the Thrombus Propagation. Embolization.. Dissolution. Organization and recanalization. Thrombus in the left and right ventricular apices, overlying white fibrous scar. Low-power view of an artery with an old thrombus. A, H&E-stained section. B, Stain for elastic tissue. Clinical Correlations: Venous versus Arterial Thrombosis Thrombi are significant because they cause obstruction of arteries and veins and are potential sources of emboli. Venous thrombi can cause congestion and edema in vascular beds distal to an obstruction, but they are most worrisome for their capacity to embolize to the lungs and cause death.Conversely, while arterial thrombi can embolize and even cause downstream tissue infarction, their role in vascular obstruction at critical sites (e.g., coronary and cerebral vessels) is much more significant clinically. Venous Thrombosis (Phlebothrombosis) Most venous thrombi occur in the superficial or deep veins of the leg. Superficial venous thrombi usually occur in the saphenous system, particularly when there are varicosities. Such superficial thrombi can cause local congestion, swelling, pain, and tenderness along the course of the involved vein, but they rarely embolize. Deep thrombi in the larger leg veins at or above the knee joint (e.g., popliteal, femoral, and iliac veins) are more serious because they may embolize. Deep venous thrombosis can occur with stasis or in a variety of hypercoagulable states. Cardiac and Arterial Thrombosis Atherosclerosis is a major initiator of thromboses, because it is associated with loss of endothelial integrity and abnormal vascular flow. Cardiac mural thrombi can occur in the setting of myocardial infarction related to dyskinetic myocardial contraction as well as damage to the adjacent endocardium. Rheumatic heart disease can cause atrial mural thrombi due to mitral valve stenosis, followed by left atrial dilation and concurrent atrial fibrillation. EMBOLISM An embolus is a detached intravascular solid, liquid, or gaseous mass that is carried by the blood to a site distant from its point of origin. Virtually 99% of all emboli represent some part of a dislodged thrombus, hence the term thromboembolism. Rare forms of emboli include fat droplets, bubbles of air or nitrogen, atherosclerotic debris (cholesterol emboli), tumor fragments, bits of bone marrow, or foreign bodies such as bullets. The consequences of thromboembolism include ischemic necrosis (infarction) of downstream tissue. Pulmonary Thromboembolism Pulmonary embolism has an incidence of 20 to 25 per 100,000 hospitalized patients. Although the rate of fatal pulmonary emboli (as assessed at autopsy) has declined from 6% to 2% over the last quarter century, pulmonary embolism still causes about 200,000 deaths per year in the United States. In more than 95% of cases, venous emboli originate from deep leg vein thrombi above the level of the knee. the patient who has had one pulmonary embolus is at high risk of having more. Most pulmonary emboli (60% to 80%) are clinically silent because they are small. Sudden death, right ventricular failure (cor pulmonale), or cardiovascular collapse occurs when 60% or more of the pulmonary circulation is obstructed with emboli. Embolic obstruction of medium-sized arteries can cause pulmonary hemorrhage. Many emboli occurring over a period of time may cause pulmonary hypertension with right ventricular failure. Systemic Thromboembolism Systemic thromboembolism refers to emboli in the arterial circulation. Most (80%) arise from intracardiac mural thrombi, two-thirds of which are associated with left ventricular wall infarcts and another quarter with dilated left atria (e.g., secondary to mitral valve disease). The major sites for arteriolar embolization are the lower extremities (75%) and the brain (10%), with the intestines, kidneys, and spleen affected to a lesser extent. Deep veins thrombosis Predisposing factors: 1. Immobility and bed rest. 2. Pregnancy and post-partum state. 3. Post-operative. 4. Sever burns. 5. Heart failure. 6. Disseminated cancer. High risk patients must be identified and offered prophylaxis. Heparin subcutaneously. Leg compression during surgery. Treatment of DVT: Intravenous heparin. Warfarin. Fat Embolism Microscopic fat globules can be found in the circulation after fractures of long bones (which contain fatty marrow) or after soft-tissue trauma. Fat enters the circulation by rupture of the marrow vascular sinusoids or rupture of venules in injured tissues. Fat embolism syndrome is characterized by pulmonary insufficiency, neurologic symptoms, anemia, and thrombocytopenia; it is fatal in about 10% of cases. Air Embolism Gas bubbles within the circulation can obstruct vascular flow (and cause distal ischemic injury) almost as readily as thrombotic masses can. Air may enter the circulation during obstetric procedures or as a consequence of chest wall injury. Generally, more than 100 mL of air are required to produce a clinical effect; bubbles can coalesce to form frothy masses sufficiently large to occlude major vessels. Amniotic Fluid Embolism Amniotic fluid embolism is a grave but fortunately uncommon complication of labor and the immediate postpartum period (1 in 50,000 deliveries). It has a mortality rate in excess of 20% to 40%.