Hemodynamic disorders


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Hemodynamic disorders

  1. 1. HEMODYNAMIC DISORDERS, THROMBOSIS, & SHOCKEDEMASixty percent of lean body weight is water, 2/3 intracellular & 1/3 is in extracellular. Thelatter is mostly interstitial fluid; only 5% of total body water is in blood plasma.Edema refers to” increased fluid in the interstitial tissue spaces.”Hydrothorax, hydropericardium, or hydroperitoneum (ascites) refer to fluid collectionin the respective body cavity.Anasarca is a severe and generalized edema with profound subcutaneous tissue swelling.Mechanisms of edema:The movement of fluid between vascular and interstitial spaces is controlled mainly bythe opposing effects of vascular hydrostatic pressure and plasma colloid osmoticpressure. Normally, the exit of fluid into the interstitium from the arteriolar end of themicrocirculation is nearly balanced by inflow at the venular end; the lymphatics drain asmall residual amount of excess interstitial fluid. Either increased capillary pressure ordiminished colloid osmotic pressure can result in increased interstitial fluid. Asextravascular fluid accumulates in either case, the increased tissue hydrostatic and plasmaosmotic pressures eventually achieve a new equilibrium, and water re-enters the venules.Excess interstitial edema fluid is removed by lymphatic drainage, ultimately returning tothe bloodstream via the thoracic duct; clearly, lymphatic obstruction (e.g., due toscarring or tumor) can also impair fluid drainage and cause edema. Sodium and waterretention due to renal disease can also cause edema. The mechanism of inflammatoryedema mostly involves increased vascular permeability;The edema fluid may be either a transudate or exudate.A transudate occurs with volume or pressure overload, or under conditions of reducedplasma protein; it is typically protein-poor with a specific gravity less than 1.012.An exudate occurs due to increased vascular permeability in inflammation. It is protein-rich with a specific gravity greater than 1.020.The principal causes of non-inflammatory edema are:1. Increased Hydrostatic PressureThis is either localized or generalized (systemic)Localized increases in intravascular pressure can result from impaired venous return; forexample, deep venous thrombosis of leg veins can cause edema restricted to the distalportion of the affected leg, liver cirrhosis ascites, acute LVF pulmonary edema.Generalized increases in venous pressure, with resultant systemic edema, occur mostcommonly in congestive heart failure, with involvement of the right ventricular cardiacfunction.Although increased venous hydrostatic pressure is contributory, the pathogenesis ofcardiac edema is more complex. In congestive heart failure, reduced cardiac output leadsto reduced renal perfusion. Renal hypoperfusion in turn triggers the renin-angiotensin-aldosterone axis, inducing sodium and water retention by the kidneys (secondaryaldosteronism). This mechanism normally functions to increase intravascular volume and1
  2. 2. thereby improve cardiac output to restore normal renal perfusion. However, if the failingheart cannot increase cardiac output, the extra fluid load causes increased venouspressure and, eventually, edema. Unless cardiac output is restored or renal water retentionreduced (e.g., by salt restriction, diuretics, or aldosterone antagonists), a cycle of renalfluid retention and worsening edema ensues.2. Reduced Plasma Osmotic PressureAlbumin is the most important serum protein responsible for maintaining intravascularcolloid osmotic pressure. Reduced osmotic pressure occurs when there is reducedsynthesis or loss of this plasma protein from the circulation. Albumin loss is exemplifiedby the nephrotic syndrome (glomerular capillary walls become leaky) that is associatedwith generalized edema. Reduced albumin synthesis occurs in the setting of diffuse liverdiseases (e.g., cirrhosis) or protein malnutrition. In all the above reduced plasmaosmotic pressure leads to a net movement of fluid into the interstitial tissues.3. Lymphatic ObstructionImpaired lymphatic drainage and consequent lymphedema is usually localized; it canresult from inflammatory or neoplastic obstruction. The parasitic infection filariasis cancause extensive inguinal lymphatic and lymph node fibrosis. The resultant edema of theexternal genitalia and lower limbs can be so massive that it has been likened to the limbsof an elephant (elephantiasis). Cancer of the breast can be treated by resection and/orirradiation of the associated axillary lymph nodes; the resultant scarring and loss oflymphatic drainage can cause severe upper extremity edema. In breast carcinomainfiltration and obstruction of superficial lymphatics can also cause edema of theoverlying skin, the so-called peau dorange (orange peel) appearance. Such a finely pittedsurface results from an accentuation of depressions in the skin at the site of hair follicles.4. Sodium and Water RetentionSalt retention can also be a primary cause of edema. Increased salt-with the obligateaccompanying water-causes both increased hydrostatic pressure (due to expansion of theintravascular volume) and reduced vascular osmotic pressure. Salt retention can occurwith any impairment of renal function, as in poststreptococcal glomerulonephritis andacute renal failure.Pathologic features of edemaEdema is most easily recognized grossly. Microscopically, edema fluid is reflectedprimarily as a clearing and separation of the extracellular matrix elements. Although anyorgan or tissue in the body may be involved, edema is most commonly encountered insubcutaneous tissues, lungs, and brain.Subcutaneous edema• This can be diffuse or more prominent in regions with high hydrostatic pressures; theultimate distribution depends on the underlying etiology.• Even diffuse edema is usually more prominent in certain body areas as a result of theeffects of gravity- dependent edema (e.g., involving the legs when standing, orinvolving the sacrum when recumbent). Dependent edema is a prominent feature ofcardiac failure, particularly of the right ventricle.• Edema due to renal dysfunction or nephrotic syndrome is generally more severe thancardiac edema and affects all parts of the body equally. Nevertheless, severe edema2
  3. 3. early in the disease course can still manifest disproportionately in tissues with a looseconnective tissue matrix (e.g., the eyelids, causing periorbital edema).Finger pressure over significantly edematous subcutaneous tissue displaces the interstitialfluid and leaves a finger-shaped depression, so-called pitting edema.Pulmonary edema• This is a common clinical problem that is encountered witha. left ventricular failure (most frequent association)b. renal failurec. acute respiratory distress syndrome (ARDS)d. pulmonary infectionse. hypersensitivity reactionsGross features• The lungs typically heavy• Sectioning reveals frothy, sometimes blood-tinged fluid representing a mixture of air,edema fluid, and extravasated red cells.Microscopic features• The alveolar spaces are filled with pale pink edema fluid• There is congestion of the capillaries within the alveolar walls due to the increase invenous pressure.Brain Edema• This may be localized to sites of focal injury (e.g., infarct, abscesses or neoplasms) ormay be generalized, as in encephalitis, hypertensive crises, or obstruction to the brainsvenous outflow. Trauma may result in local or generalized edema, depending on thenature and extent of the injury.Gross featuresWith generalized edema, the brain is grossly swollen with narrowed sulci and distendedflattened gyri due to compression against the unyielding skull.Clinical significance of edemaSubcutaneous tissue edema in cardiac or renal failure is important primarily because itindicates underlying disease; however, when significant it can also impair wound healingor the clearance of infection. Pulmonary edema can cause death by interfering withnormal ventilation. In chronic venous congestion of the lung, edema fluid in the alveolarspaces also creates a favorable environment for bacterial infection. Brain edema isserious and can be rapidly fatal due to increased intracranial pressure. Marked Edema ofthe larynx may cause suffocationHYPEREMIA AND CONGESTIONThe terms hyperemia and congestion both indicate a local increased volume of blood in aparticular tissue. Hyperemia is an active process resulting from augmented blood flowdue to arteriolar dilation (e.g., at sites of inflammation or in skeletal muscle duringexercise). The affected tissue is redder than normal because of engorgement withoxygenated blood. Congestion is a passive process resulting from impaired venousreturn out of a tissue. It may occur systemically, as in heart failure (right ventricularfailure or congestive HF), or it may be local, resulting from an isolated venous3
  4. 4. obstruction. The tissue has a blue-red color (cyanosis), especially as worseningcongestion leads to accumulation of deoxygenated hemoglobin in the affected tissues.Congestion of capillary beds is closely related to the development of edema, so thatcongestion and edema commonly occur together. In long-standing congestion, calledchronic passive congestion, the stasis of poorly oxygenated blood causes chronichypoxia, which in turn can result in degeneration or death of parenchymal cells andsubsequent tissue fibrosis. Capillary rupture at such sites of chronic congestion can alsocause small foci of hemorrhage; phagocytosis and catabolism of the erythrocyte debriscan result in accumulations of hemosiderin-laden macrophages.Localized venous congestion:A. Pulmonary venous congestion: Occurs in Left sided heart (ventricular) failure and inmitral valve stenosisB. venous outflow obstruction: Occurs in1. Venous thrombosis of major vein e.g. thrombosis of lower limb veins congestion+ swelling of lower limb2. Cirrhosis of the liver  portal hypertension  congestive splenomegaly, ascites,esophageal varices and hemorrhoids3. Mechanical compression of veins e.g. strangulated hernia, volvulus small intestine,torsion of ovary/testisMorphological changes in chronic venous congestion of the liver:Gross appearance: The liver is enlarged and firm in consistency. Its cut surface shows amottled appearance of dark areas (of centrilobular zones congestion), and pale peripheral(peri-portal) areas, similating the appearance of the cut surface of a nutmeg, hence theterm “nutmeg liver”.Microscopically, the central vein and the central ends of the sinusoids appear distendedand packed with red cells. The hepatic cells in the center of the lobule undergodegeneration and sometimes necrosis as a result of the anoxia and the pressureeffects of congested (dilated) sinusoids. The hepatic cells at the periphery ofthe lobule (around portal tracts) are either normal or show mild form of injurysuch as fatty changes.Morphological changes in Chronic venous congestion of the LungsGrossly: The lungs are heavy, dark red in color and firm in consistency.MicroscopicallyThe alveolar capillaries and venules are dilated, and packed with red cells. Some of thealveolar capillaries rupture leading to intra-alveolar hemorrhage. Macrophages move intothe alveolar spaces to engulf the red cells and store the iron in hemoglobin ashemosiderin granules. These macrophages are called heart failure cells because of their4
  5. 5. common association in heart failure. Some of the excess iron is deposited in interstitialtissue stimulating fibrosis and causing brown induration of the lung. In consequence ofthe venous congestion a transudate collects in the alveolar spaces (edema fluid), whichmicroscopically appears as pale eosinophilic homogeneous material.HEMORRHAGEHemorrhage is “extravasation of blood from vessels into the extravascular space”.• Capillary bleeding can occur under conditions of chronic congestion or capillaritis.• Hemorrhagic diatheses refer to an increased tendency to hemorrhage (usually withinsignificant injury). This occurs in a wide variety of clinical disorders.• Rupture of a large artery or vein results in severe hemorrhage, and is almost alwaysdue to1. Vascular injury, including trauma,2. Ruptured aneurismal dilatation (e.g. atherosclerotic aortic aneurysm)3. inflammatory or neoplastic erosion of the vessel wall• Hemorrhage can be external to or confined within a tissue.Hematoma refers to any localized accumulation of blood. Hematomas can be relativelyinsignificant (e.g., a bruise) or can be due to massive bleeding as to cause death (e.g., amassive retroperitoneal hematoma resulting from rupture of a dissecting aortic aneurysm.Petechiae are minute (1- to 2-mm) hemorrhages into skin, mucous membranes, or serosalsurfaces and are typically associated with1. Low platelet counts (thrombocytopenia)2. Defective platelet function.3. Locally increased intravascular pressure4. Clotting factor deficiencies.Purpura is raised slightly larger than petechiae (3- to 5-mm) hemorrhages and can beassociated with many of the same disorders that cause petechiae; in addition, purpura canoccur with trauma, vascular inflammation (vasculitis), or increased vascular fragility.Ecchymoses are larger (1- to 2-cm) subcutaneous hematomas (bruises). The erythrocytesin these local hemorrhages are phagocytosed and degraded by macrophages; thehemoglobin (red-blue color) is enzymatically converted into bilirubin (blue-green color)and eventually into hemosiderin (golden-brown), accounting for the characteristic colorchanges in a hematoma.Large accumulations of blood in one or another of the body cavities are calledHemothorax, hemopericardium, hemoperitoneum, or hemarthrosis refer to largeaccumulation of blood in the pleural, pericardial, peritoneal or synovial cavitiesrespectively.Clinical significance of hemorrhageThis depends on: 1- The volume of blood loss, 2-Its rate, and 3-Its locationRapid loss (internal or external) of as much as 20% of the blood volume or slow losses ofeven larger amounts may have little impact in healthy adults; greater losses, however, cancause hemorrhagic (hypovolemic) shock. The site of hemorrhage is also important;bleeding that would be trivial in the subcutaneous tissues may cause death if located in5
  6. 6. the brain. Finally, chronic or recurrent external blood loss (e.g., a peptic ulcer ormenstrual bleeding) causes a net loss of iron, frequently culminating in an iron deficiencyanemia.THROMBOSISNormally the blood is kept in a fluid state with rapid formation of a plug at the site ofinjury. This is normal hemostasis. The pathologic opposite to hemostasis is thrombosis;it can be considered an inappropriate activation of normal hemostatic processes.Thrombosis is defined as the formation of a solid or semi-solid mass from theconstituents of the blood within the vascular system during life. The mass itself iscalled a thrombus.Both hemostasis and thrombosis involve three components:1. Vascular wall2. Platelets3. Coagulation cascadePathogenesis of thrombosisThere are three predisposing factors for thrombus formation (Virchows triad):1. Endothelial injury2. Stasis or turbulence of blood flow3. Blood hypercoagulability (Changes in the composition of blood)Endothelial injuryA. Mechanical injury such as , pressure, ruptue or tortion of the vesselB. Degeneration of vascular endothelium at sites of1. Atherosclerosis e.g. of the coronaries, cerebral arteries and aorta.2. Aneurysm e.g. aortic aneurysm3. endothelium overlying a myocardial infarction.C. Inflammatory processes as in Phlebitis , Arteritis, and inflammation of heart valves.However, it is important to note that endothelium need not be denuded or physicallydisrupted to contribute to the development of thrombosis; any disturbance in the balanceof the prothrombotic and antithrombotic activities of endothelium can influence localclotting events. Thus, dysfunctional endothelium may elaborate greater amounts ofprocoagulant factors (e.g., platelet adhesion molecules, tissue factor, plasminogenactivator inhibitors) or may synthesize reduced amounts of anticoagulant effectors.Significant endothelial dysfunction in the absence of endothelial cell loss may occur in:1. Hypertension 4. Hypercholesterolemia2. Turbulent flow over scarred valves 5. Radiation3. Bacterial endotoxins 6. Products absorbed from cigarette smokeAlterations in Normal Blood FlowTurbulence contributes to arterial and cardiac thrombosis by causing endothelial injuryor dysfunction, as well as by forming countercurrents and local pockets of stasis.Stasis is a major contributor to the development of venous thrombi.Stasis and turbulence therefore:1. Disrupt laminar flow and bring platelets into contact with the endothelium6
  7. 7. 2. Prevent dilution of activated clotting factors by fresh-flowing blood3. Retard the inflow of clotting factor inhibitors and permit the buildup of thrombi4. Promote endothelial cell activation, resulting in local thrombosis, leukocyte adhesion,etc.Turbulence and stasis contribute to thrombosis in several other clinical settings:• Ulcerated atherosclerotic plaques not only expose subendothelial ECM but also causeturbulence• Aneurysms (abnormal dilations) of the aorta & other arteries create local stasis andconsequently a fertile site for thrombosis.• Myocardial infarction. Mural thrombi may form over infarcted non-contractilemyocardium, or within ventricular aneurysm complicating old MI, due to stasis andlocal turbulance• Mitral valve stenosis (e.g., after rheumatic heart disease) results in left atrial dilation.In conjunction with atrial fibrillation, a dilated atrium is a site of profound stasis and aprime location for development of thrombi.• Hyperviscosity syndromes (such as polycythemia) increase resistance to flow andcause small vessel stasis• The deformed red cells in sickle cell anemia cause vascular occlusions, with theresultant stasis also predisposing to thrombosis.HypercoagulabilityHypercoagulability is defined as any alteration of the coagulation pathways thatpredisposes to thrombosis, and it can be divided into primary (genetic) and secondary(acquired) disorders.Causes of the primary (inherited) hypercoagulable states include most commonlymutations in the factor V gene and the prothrombin gene.The pathogenesis of acquired thrombotic diatheses is frequently multifactorial & include• Cardiac failure, major surgery or trauma: In addition to hypercoagulability (increasedplatelets and they become stickier, increased clotting factors), stasis or vascularinjury may be more important.• Oral contraceptive use & pregnancy: probably related to the hyperestrogenic state thatis associated with increased hepatic synthesis of coagulation factors and reducedsynthesis of antithrombin III.• Disseminated cancers, release of procoagulant tumor products predisposes tothrombosis.• Advancing age: is associated with hypercoagulability & this has been attributed toincreasing platelet aggregation and reduced endothelial PGI2 release.• Smoking & obesity promote hypercoagulability by unknown mechanisms.• The antiphospholipid antibody syndrome comprise recurrent thrombosis, repeatedabortions, cardiac valve vegetations and thrombocytopenia. It is associated withautoantibodies directed against plasma proteins (e.g. prothrombin) which would bindto anionic phospholipids (cardiolipin). These antibodies induce a hypercoagulablestate, by platelet activation or by interfering with endothelial cell production of PGI2.There are two types of anti-phospholipid antibody syndrome.1. Primary (idiopathic)7
  8. 8. 2. Secondary to a well-defined autoimmune disease, such as systemic lupuserythematosus.Pathological features of thrombosis• Thrombi can develop anywhere in the cardiovascular system (e.g., in cardiacchambers, on valves, or in arteries, veins, or capillaries).• The size and shape of a thrombus depend on the site of origin and the cause. Arterial orcardiac thrombi typically begin at sites of endothelial injury or turbulence; venousthrombi characteristically occur at sites of stasis.• Thrombi are focally attached to the underlying vascular surface; arterial thrombi tendto grow (propagate) in a retrograde direction from the point of attachment, whilevenous thrombi extend in the direction of blood flow (thus both tend to propagatetoward the heart).• The propagating portion of a thrombus tends to be poorly attached and therefore proneto fragmentation, generating an embolus especially in venous thrombi.• Thrombi can have grossly (and microscopically) apparent laminations called lines ofZahn; these represent pale platelet and fibrin layers alternating with darkererythrocyte-rich layers. Their presence can distinguish ante-mortem thrombosis fromthe non-laminated postmortem clots that occur after death. Such lines are lessprominent in venous thrombi compared to arterial ones.• Venous thrombi are formed in the sluggish venous flow & thus tend to contain moreenmeshed erythrocytes and are therefore called red, or stasis, thrombi. They usuallyresemble statically coagulated blood. Never the less, careful evaluation of venousthrombi generally reveals ill-defined laminations.• Postmortem clots can sometimes be mistaken at autopsy for venous thrombi. However,postmortem "thrombi" are gelatinous, with a dark red dependent portion where redcells have settled by gravity, and a yellow "chicken fat" supernatant, and they areusually not attached to the underlying wall. In contrast, red thrombi are firmer and arefocally attached, and sectioning reveals strands of gray fibrin.• Thrombi occurring in heart chambers or in the aortic lumen are designated muralthrombi. Abnormal myocardial contraction (resulting from arrhythmias or myocardialinfarction) or endomyocardial injury (caused by myocarditis, catheter trauma)promotes cardiac mural thrombi, while ulcerated atherosclerotic plaques andaneurismal dilation promote aortic thrombosis.• Arterial thrombi are frequently occlusive. Arterial thrombi are usually superimposedon an atherosclerotic plaque, however, other vascular injury (vasculitis, trauma) can beinvolved.• Venous thrombosis (phlebothrombosis) is almost invariably occlusive, and thethrombus can create a long cast of the lumen; venous thrombosis is largely the result ofstasis. The veins of the lower extremities are most commonly affected (90% of venousthromboses); however, venous thrombi can occur in the upper extremities, periprostaticplexus, or ovarian and periuterine veins; under special circumstances they may befound in the dural sinuses, portal vein, or hepatic vein.8
  9. 9. • Thrombi on heart valves are called vegetations (as in rheumatic valvulitis). Bacterial orfungal blood-borne infections can cause valve damage, subsequently leading to largethrombotic masses (infective endocarditis).Fate of the ThrombusIn the ensuing days or weeks after the formation of thrombi, they undergo somecombination of the following four events:1. Propagation: thrombi may accumulate additional platelets and fibrin, eventuallycausing vessel obstruction.2. Embolization: thrombi may dislodge or fragment and are transported elsewhere in thevasculature.3. Dissolution is the result of fibrinolytic activation, which leads to rapid shrinkage andeven total lysis of recent thrombi. Old thrombi are resistant to proteolysis. This isclinically significant because therapeutic administration of fibrinolytic agents (in thesetting of acute coronary thrombosis) is generally effective only within a few hours ofthrombus formation.4. Organization and recanalization: Older thrombi become organized by the ingrowth ofendothelial cells, smooth muscle cells, and fibroblasts into the fibrin-rich clot. Capillarychannels are eventually formed that can create conduits along the length of the thrombusand thereby re-establish the continuity of the original lumen. Although the channels maynot successfully restore significant flow to many obstructed vessels, recanalization canpotentially convert a thrombus into a vascularized mass of connective tissue that iseventually incorporated into the vessel wall and remains as a subendothelial swelling.Eventually, with contraction of the mesenchymal cells only a fibrous lump may remain tomark the original thrombus site. Occasionally, instead of organizing, the center of athrombus undergoes enzymatic digestion, presumably because of the release of lysosomalenzymes from trapped leukocytes and platelets.Clinical significance of venous & arterial thrombosisThrombi are significant because they1. Cause obstruction of arteries and veins2. Are potential sources of emboli.Which effect is most important depends on the site of thrombosis.Venous thrombi can cause congestion and edema in vascular beds distal to anobstruction, but they are most troublesome for their capacity to embolize to the lungs andcause death.While arterial thrombi can embolize and even cause downstream tissue infarction, theirrole in vascular obstruction at critical sites (e.g., coronary and cerebral vessels) is muchmore 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 whenthere are varicosities. Such superficial thrombi can cause local congestion, swelling, pain,and tenderness along the course of the involved vein, but they rarely embolize.Nevertheless, the local edema and impaired venous drainage do predispose the overlyingskin to infections from minor trauma and to the development of varicose ulcers.9
  10. 10. Deep venous 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. Although theymay cause local pain and edema, the venous obstruction may be rapidly offset bycollateral bypass channels. Consequently, deep venous thromboses are entirelyasymptomatic in approximately 50% of patients and are recognized in retrospect onlyafter they have embolized to the lung.Deep venous thrombosis can complicate :1. Advanced age, bed rest, and immobilization all increase the risk of deep venousthrombosis because reduced physical activity diminishes the milking action of muscles inthe lower leg and so slows venous return.2. Cardiac failure causes stasis in the venous circulation.3. Trauma, surgery, and burns usually result in reduced physical activity, injury tovessels and release of procoagulant substances from tissues.4. Peripartum and postpartum states; in addition to the potential for amniotic fluidinfusion into the circulation during parturition, late pregnancy and the postpartum periodare associated with hypercoagulability.5. Hypercoagulable states .6. Disseminated cancers: tumor-associated procoagulant release increases the risk ofthromboembolic phenomena (including migratory thrombophlebitis).Arterial ThrombosisAtherosclerosis is a major initiator of thromboses, because it is associated with loss ofendothelial integrity and abnormal vascular flow.Myocardial infarction may be complicated by cardiac mural thrombi as a result ofdyskinetic 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.Arterial aneurysms (e.g. aortic) are frequently filled by thrombi.In addition to the obstructive consequences, cardiac and aortic mural thrombi can alsoembolize peripherally. Virtually any tissue can be affected, but brain, kidneys, and spleenare prime targets because of their large volume of blood flow.EMBOLISMAn embolus is a detached intravascular solid, liquid, or gaseous mass that is carried bythe blood to a site distant from its point of origin.Forms of emboli1. Thromboemboli: representing a dislodged thrombus or part of it. This type virtuallyconstitutes 99% of all emboli. Thus, unless otherwise specified, an embolism should beconsidered to be thrombotic in origin.Rare forms of emboli include2. Fat emboli consisting of fat droplets3. Air emboli consisting of bubbles of air or nitrogen4. Atherosclerotic emboli (cholesterol emboli) consisting of athermatous debris5. Tumor emboli made up of fragments of a tumor6. Bone marrow emboli: consisting of bits of bone marrow7. Foreign body emboli as bullets or shrapnel .10
  11. 11. Inevitably, emboli lodge in vessels too small to permit further passage, resulting in partialor complete vascular occlusion. The consequences of thromboembolism include ischemicnecrosis (infarction) of downstream tissue.Depending on the site of origin, emboli may lodge anywhere in the vascular tree; theclinical outcomes are best understood from the standpoint of whether emboli lodge in thepulmonary or systemic circulations.PULMONARY THROMBO-EMBOLISMThis has an incidence of 25/100,000 hospitalized patients. It is considered the mostcommon preventable cause of death in hospitalized patients. In more than 95% of cases,venous emboli originate from deep leg vein thrombi above the level of the knee such asthe popliteal, femoral, or iliac veins. These emboli are carried through progressivelylarger channels and pass through the right side of the heart before entering the pulmonaryarterial circulation.Depending on its size, the embolus may settle within1. The main pulmonary trunk2. Across the bifurcation (saddle embolus)3. The main pulmonary arteries4. The medium sized pulmonary arteries5. Pass out into the smaller branching arteries or arteriolesFrequently, there are multiple emboli, perhaps sequentially, or as a shower of smalleremboli from a single large thrombus; The patient who has had one pulmonary embolus isat high risk of having more.6. Rarely, an embolus can pass through an interatrial or interventricular defect, therebyentering the systemic circulation (paradoxical or crossing embolism).CLINICAL OUTCOME OF PULMONARY THROMBO-EMBOLISMDepends on1. Severity of occlusiona. Size of pulmonary artery occludedb. Number of occluding emboli2. Cardio-respiratory status of the patient• Most pulmonary emboli (60% to 80%) are clinically silent because they are small.They eventually become organized and become incorporated into the vascular wall.• Sudden death due to cardiovascular collapse or right ventricular failure (corpulmonale) (incidence 5%), occurs when 60% or more of the pulmonary circulation isobstructed with emboli. This is also described as massive pulmonary embolism.• Embolic obstruction of medium-sized arteries can cause pulmonary hemorrhage (10%)but usually not pulmonary infarction because the lung has a dual blood supply and theintact bronchial arterial circulation continues to supply blood to the area. However, asimilar embolus in the setting of left-sided cardiac failure (and resultant sluggishbronchial artery blood flow) may result in a large infarct (10% incidence).• Many emboli occurring over a period of time may cause pulmonary hypertension withright ventricular failure. This is an uncommon event.SYSTEMIC THROMBO-EMBOLISMThis refers to emboli in the arterial circulation. Sources include11
  12. 12. 1. Intracardiac mural thrombi (80%) that complicatea. infarction of the left ventricular wall (70%)b. dilated left atria (e.g., secondary to mitral valve disease) (25%).2. Aortic aneurysms3. Ulcerated atherosclerotic plaques4. Valvular vegetations.5. A very small fraction of systemic emboli appear to arise in veins but end up in thearterial circulation, through interventricular or interatrial septal defects ( paradoxicalemboli).6- 10-15% are of unknown origin.The major sites for arteriolar embolization are1. The lower extremities (75%)2. The brain (10%)3. The intestines (mesenteric vessels), kidneys, and spleen.4. The upper limbs are the least common sitesClinical significanceThe consequences of embolization in a tissue depend on1. Vulnerability of the tissue to ischemia2. Caliber of the occluded vessel3. The efficiency of the collateral blood supplyGenerally speaking, arterial embolization causes infarction of the affected tissues.Emboli from cases of infective (bacterial) endocarditis à septic infarcts (abscesses)Fat & bone marrow embolismAlthough fat and marrow embolism occurs in some 90% of individuals with severeskeletal injuries including major fractures, only about 10% of such patients show anyclinical findings. The Fat embolism syndrome is characterized by pulmonaryinsufficiency, neurologic symptoms, anemia, thrombocytopenia, & globules of fat in theurine; it is fatal in about 10% of cases. The pathogenesis of this syndrome involves bothmechanical obstruction & biochemical injury. It may further be complicated by DIC.Air EmbolismGas bubbles or Air may enter the circulation during obstetric procedures (air insufflationof tubes) or as a consequence of chest wall injury. Generally, more than 100 ml of air arerequired to produce a clinical effect; bubbles can coalesce to form frothy massessufficiently large to occlude major vessels. A particular form of gas embolism, calleddecompression sickness, occurs when Deep-sea divers and underwater constructionworkers are brought to the surface quickly.Amniotic Fluid EmbolismAmniotic fluid embolism is a grave but uncommon complication of labor (1 in 50,000deliveries). It has a mortality rate of up to 40%. The underlying cause is entry of amnioticfluid into the maternal circulation via a tear in the placental membranes with the fluidgaining access into ruptured uterine veins. Classically, there is marked pulmonary edemaand diffuse alveolar damage, with the pulmonary microcirculation containing squamous12
  13. 13. cells and hair shed from fetal skin, and mucin derived from the fetal respiratory orgastrointestinal tracts. DIC may also occur.INFARCTIONThis is defined as “localized area of ischemic cell necrosis in a living organ or tissue,resulting most often from sudden reduction or cessation of its arterial blood supply oroccasionally its venous drainage”Causes of vascular obstruction1. Nearly 99% of all infarcts result from thrombotic or embolic events, and almost allresult from arterial occlusion.Uncommon causes include2. Expansion of atheromatous plaques by intraplaque hemorrhage3. Spasm of coronary arteries4. Pressure on a vessel from outside- Tumor- Fibrous adhesions- Narrow mouthed hernia sac5. Twisting (torsion) of the pedicle of mobile organ e.g. loop of small intestine(volvulus), ovary and testis.External pressure and torsion (causes 4 and 5) usually interfere with venous drainage,since veins are more readily compressed than arteries.Gross features• Infarcts are classified on the basis of their color (reflecting the amount of hemorrhage)into red (hemorrhagic) or white (pale, anemic). They are also classified according tothe presence or absence of microbial infection into septic or bland.• Red infarcts occur1. with venous occlusions (such as in ovarian torsion)2. in loose tissues (such as lung) that allow blood to collect in the infarcted zone3. in tissues with dual circulations such as lung and small intestine, permitting flow ofblood from an unobstructed parallel supply into a necrotic area (such perfusion not beingsufficient to rescue the ischemic tissues)4. in tissues that were previously congested because of sluggish venous outflow5. when flow is re-established to a site of previous arterial occlusion and necrosis (e.g.,fragmentation of an occlusive embolus or angioplasty of a thrombotic lesion).• White infarcts occur with arterial occlusions or in solid organs (such as heart, spleen,and kidney), where the solidity of the tissue limits the amount of hemorrhage that canseep into the area of ischemic necrosis from adjoining capillary beds.• All infarcts tend to be wedge shaped, with the occluded vessel at the apex and theperiphery of the organ forming the base; when the base is a serosal surface there can bean overlying fibrinous inflammation and exudate.• At the outset, all infarcts are poorly defined and slightly hemorrhagic. The margins ofboth types of infarcts tend to become better defined with time by a narrow rim ofcongestion attributable to inflammation at the edge of the lesion (line of demarcation).• In solid organs, the relatively few extravasated red cells are lysed, with the releasedhemoglobin remaining in the form of hemosiderin. Thus, such infarcts become13
  14. 14. progressively paler and sharply defined with time. While in spongy organs, thehemorrhage is too extensive so it doen’t pale, but in few days, it becomes firmer andbrowner, reflecting the accumulation of hemosiderin pigment.• Infarcts within the brain could be pale or hemorrhagic.Microscopic featuresThe dominant histologic characteristic of infarction is ischemic coagulative necrosis.The brain is an exception in that ischemic tissue injury in the central nervous systemresults in liquefactive necrosis.• An inflammatory response begins to develop along the margins of infarcts within a fewhours and is usually well defined within 1 to 2 days.• Eventually the inflammatory response is followed by a reparative response beginningin the preserved margins.• In stable or labile tissues, parenchymal regeneration can occur at the periphery, whereunderlying stromal architecture is spared. However, most infarcts are ultimatelyreplaced by scar. This, depending on the size of the infarct, may take several months.• Septic infarctions occur when bacterial vegetations from a heart valve embolize, whenmicrobes seed an area of necrotic tissue, or when infarction occurs in an alreadyinfected area. In these cases the infarct is converted into an abscess.Factors That Influence Development of an Infarct1- Nature of the Vascular SupplyThe most important factor that determines whether occlusion of a vessel will causedamage is the presence or absence of an alternative blood supply. For example, lungshave a dual pulmonary and bronchial artery blood supply; thus, obstruction of smallpulmonary artery or arterioles does not cause infarction in an otherwise healthyindividual with an intact bronchial circulation. Similarly, the liver, with its dual hepaticartery and portal vein circulation, and the hand and forearm, with their dual radial andulnar arterial supply, are all relatively resistant to infarction. In contrast, renal and splenictissues are supplied by end arteries, and obstruction of such vessels generally causesinfarction.2- Rate of Development of OcclusionSlowly developing occlusions are less likely to cause infarction because they providetime for the development of collateral vessels. For example, small interarteriolaranastomoses ( normally with minimal functional flow) interconnect the three majorcoronary arteries in the heart. If one of the coronaries is slowly occluded (e.g., byatherosclerotic plaque), flow within this collateral circulation may increase sufficiently toprevent infarction, even though the major coronary artery is eventually occluded.3- Vulnerability of tissue to HypoxiaThe susceptibility of a tissue to hypoxia influences the likelihood of infarction. Neuronsundergo irreversible damage when deprived of their blood supply for only 3 to 4 minutes.Myocardial cells, though more resistant to hypoxic damage than neurons, are also quitesensitive and die after only 20 to 30 minutes of ischemia. In contrast, skeletal muscles &fibroblasts within a limb may remain viable after many hours of ischemia.4- Oxygen Content of BloodThe partial pressure of oxygen in blood also determines the outcome of vascularocclusion. Partial flow obstruction of a small vessel in an anemic or cyanotic patientmight lead to tissue infarction, whereas it would be without effect under conditions of14
  15. 15. normal oxygen tension. In this way congestive heart failure, with impaired flow flow andventilation, could cause infarction in the setting of an otherwise inconsequentialblockage.Clinical significance of infarction• Tissue infarction is a common and extremely important cause of clinical illness.More than half of all deaths are caused by cardiovascular disease, and most of these aredue to myocardial or cerebral infarction.• Pulmonary infarction is a common complication in several clinical settings• Ischemic necrosis of the extremities (gangrene) is a serious problem in thediabetics.SHOCKShock in essence is a state of systemic hypoperfusion that is caused either by reducedcardiac output or by reduced effective circulating blood volume. The end results arehypotension, impaired tissue perfusion, and cellular hypoxia. It is the final commonpathway for a number of potentially lethal clinical events. Although the hypoxic andmetabolic effects of hypoperfusion initially cause only reversible cellular injury,persistence of shock eventually causes irreversible tissue injury and can culminate in thedeath of the patient.Categories of shockA. CardiogenicB. HypovolemicC. SepticD. Neurogenic – less commonE. Anaphylactic- less commonPathogenesis & clinical examplesCardiogenic shock is due to myocardial pump failure resulting from intrinsic myocardialdamage, extrinsic pressure, or obstruction to outflow. Examples include• Myocardial infarction• Ventricular rupture• Arrhythmia• Cardiac tamponade• Pulmonary embolismHypovolemic shock is due to inadequate blood or plasma volume. Examples include• Hemorrhage (external or internal)• Fluid loss (e.g., severe continuous vomiting &/or diarrhea, extensive burns)Septic shock is due to peripheral vasodilation and pooling of blood; endothelialactivation/injury; leukocyte-induced damage; disseminated intravascular coagulation;activation of cytokine cascades. Examples include:• Overwhelming microbial infections- Endotoxic shock- Gram-positive septicemia- Fungal sepsis15
  16. 16. Neurogenic shock is due to loss of vascular tone and peripheral pooling of blood.Examples include• Anesthetic accidents• Spinal cord injuryAnaphylactic shock is caused by an Ig E mediated (type I) hypersensitivity reaction. Inthese situations, acute severe widespread vasodilation with subsequent pooling of theblood results in tissue hypoperfusion and cellular anoxia. Examples include drugsanaphylaxis.Pathogenesis of Septic ShockSeptic shock ranks first among the causes of death in intensive care units (25% to 50%mortality rate), and is particularly seen in immunocompromised patients (secondary tochemotherapy, immunosuppression, or HIV infection).Most cases of septic shock (70%) are caused by endotoxin-producing gram-negativebacilli-hence the term endotoxic shock. Endotoxins are bacterial wall lipopolysaccharides(LPS). Analogous molecules in the walls of gram-positive bacteria and fungi can alsoelicit septic shock. These microbial products will attach to receptors on monocytes,macrophages and neutrophils resulting in their activation and production of potentcytokines such as IL-1 and TNF. These cytokines in high levels result in:1. Systemic vasodilation (hypotension)2. Diminished myocardial contractility3. Widespread endothelial injury and activation, causing systemic leukocyte adhesion anddiffuse alveolar capillary damage in the lung (ARDS)4. Activate the coagulation system causing disseminated intravascular coagulation (DIC)The hypoperfusion resulting from the combined effects of widespread vasodilation,myocardial pump failure, and DIC causes multiorgan system failure that affects the liver,kidneys, and central nervous system, among others. Unless the underlying infection (andLPS overload) is rapidly brought under control, the patient usually dies.Stages of ShockShock is a progressive disorder that if uncorrected passes into deeper levels ofhomodynamic/metabolic deterioration that eventuates in death. Unless the insult ismassive and rapidly lethal (e.g., a massive hemorrhage from a ruptured aortic aneurysm),shock tends to evolve through three stages. These stages have been documented mostclearly in hypovolemic shock but are common to other forms as well:1- Nonprogressive (compensated) stage during which reflex compensatory mechanismsare activated and perfusion of vital organs is maintained. Various neurohumoralmechanisms help maintain cardiac output and blood pressure near normal levels. The aimis maintain enough blood supply to vital organs. A number of compensatory mechanismsare set into motion, these include1. Arteriolar constriction leading to increase in peripheral vascular resistance & henceblood pressure.2. Increase in heart rate leading to increase in cardiac output.3. Renal conservation of fluids to increase intravascular volume; this occurs througha. Increase secretion of antidiuretic hormone (ADH).16
  17. 17. b. Activation of renin/angiotensin/aldosterone axis.Cutaneous vasoconstriction is responsible for the characteristic coolness and pallor ofskin in shock (although septic shock may initially cause cutaneous vasodilation and thuspresent with warm, flushed skin). Coronary and cerebral vessels are less sensitive to thesympathetic response and thus maintain relatively normal caliber, blood flow, andoxygen delivery.2- Progressive (decompensated) stage characterized by tissue hypoperfusion and onset ofworsening circulatory and metabolic imbalances if the cause is not dealt with or theclinical condition of the patient worsens e.g. hypovolemia in the elderly complicated byMI. During this stage there is widespread tissue hypoxia causing intracellular shift intoanaerobic glycolysis, with excessive production of lactic acid. The resultant metaboliclactic acidosis causes arteriolar dilation, and blood begins to pool in the microcirculation.Peripheral pooling reduces the cardiac output and exposes endothelial cells to anoxicinjury with subsequent DIC. With widespread tissue hypoxia, vital organs are affectedand begin to fail.3- Irreversible stage; Unless there is intervention, the process eventually enters anirreversible stage when the resulting hemodynamic & biochemical abnormalities havecaused cellular and tissue injury so severe that even if these are corrected, survival is notpossible. Widespread cell injury is reflected in lysosomal enzyme leakage, furtheraggravating the shock state. Myocardial contractile function worsens, in part because ofnitric acid synthesis. If ischemic bowel allows intestinal flora to enter the circulation,endotoxic shock may also be superimposed. At this point, the patient has complete renalshutdown due to ischemic acute tubular necrosis, and, despite intensive correctingmeasures, the patient may die.Pathologic features• The cellular and tissue changes induced by shock are essentially those of hypoxicinjury, due to some combination of hypoperfusion and microvascular thrombosis.• Ischemic and metabolic injuries that threaten life are those of the brain, heart, lungsand kidney. However, changes are also frequent in the GIT, liver and adrenals.• The brain: show changes collectively known as hypoxic encephalopathy.• The heart: Foci of hemorrhage and necrosis are seen in the sub-epicardial and sub-endocardial regions of the myocardium.• The lungs: the changes are referred to as shock lung or adult respiratory distresssyndrome (ARDS). These changes are in essence those of pulmonary edema and fibrindeposition on the alveolar walls.• The kidneys: the tubules are affected principally and the changes are referred to asacute tubular necrosis.17