HEMODYNAMIC DISORDERS Edema 60 of lean body weight

HEMODYNAMIC DISORDERS

Edema 60% of lean body weight is water; two thirds of this water is intracellular, remainder is in the extracellular space, mostly interstitial fluid. EDEMA signifies increased fluid in the interstitial tissue spaces. Depending on the site, fluid collections are variously designated hydrothorax, hydropericardium, and hydroperitoneum (ascites). Anasarca: severe, generalized edema with profound subcutaneous tissue swelling.

Pathophysiologic Categories of Edema Increased Hydrostatic Pressure Impaired venous return Congestive heart failure Constrictive pericarditis Ascites (liver cirrhosis) Venous obstruction or compression Thrombosis External pressure (e. g. , mass) Lower extremity inactivity with prolonged dependency Arteriolar dilation Heat Neurohumoral dysregulation

Reduced Plasma Osmotic Pressure (Hypoproteinemia) Protein-losing glomerulopathies (nephrotic syndrome) Liver cirrhosis (ascites) Malnutrition Protein-losing gastroenteropathy Lymphatic Obstruction Inflammatory Neoplastic Postsurgical Postirradiation

Sodium Retention Excessive salt intake with renal insufficiency Increased tubular reabsorption of sodium Renal hypoperfusion Increased renin-angiotensin-aldosterone secretion Inflammation Acute inflammation Chronic inflammation Angiogenesis

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Types of edema Transdate: protein poor (<3 gm/dl) fluid with specific gravity of <1. 012 due to imbalances in normal hemodynamic forces e. g. congestive heart failure, liver and renal disease etc. Exudate - protein rich (>3 gm/dl) fluid with a specific gravity of >1. 020 results from endothelial damage and alteration of vasular permeability e. g. inflammatory and immunologic pathology.

Hyperemia & Congestion Hyperemia is an active process resulting from tissue inflow because of arteriolar dilation, e. g. skeletal muscle during exercise or at sites of inflammation. The affected tissue is redder because of the engorgement of vessels with oxygenated blood. Congestion is a passive process resulting from impaired outflow from a tissue. It may be systemic e. g. cardiac failure, or local e. g. an isolated venous obstruction. The tissue has a blue-red color (cyanosis), due to accumulation of deoxygenated hemoglobin in the affected tissues.

Morphology: lung The cut surfaces are hemorrhagic and wet. LUNGS: Microscopically, acute pulmonary congestion is characterized by alveolar capillaries engorged with blood, alveolar septal edema and/or focal intra-alveolar hemorrhage. In chronic pulmonary congestion, the septa are thickened and fibrotic, and the alveolar spaces may contain numerous hemosiderinladen macrophages (heart failure cells).

Morphology: liver In acute hepatic congestion: central vein and sinusoids are distended with blood with or without central hepatocyte degeneration. In chronic passive congestion of the liver: on cut surface central regions of the hepatic lobules are red-brown and surrounded by zones of uncongested tan liver (nutmeg liver). Microscopically: centrilobular necrosis with loss of hepatocytes, hemorrhage and hemosiderinladen macrophages. Long-standing cases (most commonly associated with heart failure), hepatic fibrosis (cardiac cirrhosis) may develope.

Hemorrhage Hemorrhage generally indicates extravasation of blood due to vessel rupture Hematoma: accumulation of blood within tissue. Petechiae: Minute 1 - to 2 -mm hemorrhages into skin, mucous membranes, or serosal surfaces.

Purpura: Slightly larger (≥ 3 mm) hemorrhages. Ecchymoses: Larger (>1 to 2 cm) subcutaneous hematomas (i. e. , bruises). Large accumulations of blood in one or another of the body cavities are called hemothorax, hemopericardium, hemoperitoneum, or hemarthrosis (in joints).

Thrombosis It represents hemostasis in the intact vascular system. It is a process by which a thrombus is formed. A thrombus is a solid mass of blood constituents which developes in artery or vein. Is intravascular coagulation of blood often causing sinificant interuption to blood flow.

Pathogenesis Three primary influences predispose to thrombus formation, the so-called Virchow triad: (1) endothelial injury (2) stasis or turbulence of blood flow (3) blood hypercoagulability In other words it results from interaction platelets, damaged endothelial cells and the coagulation cascade.

Figure 4 -13 Virchow triad in thrombosis. Endothelial integrity is the single most important factor. Note that injury to endothelial cells can affect local blood flow and/or coagulability; abnormal blood flow (stasis or turbulence) can, in turn, cause endothelial injury. The elements of the triad may act independently or may combine to cause thrombus formation. Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 1 April 2005 07: 37 PM) © 2005 Elsevier

Primary (Genetic) Hypercoagulable States Mutation in factor V gene (factor V Leiden) Mutation in prothrombin gene Mutation in methyltetrahydrofolate gene ) Antithrombin III deficiency Protein C deficiency Protein S deficiency Fibrinolysis defects

Secondary(Acquired) Hypercoaguable States High risk for thrombosis Prolonged bed rest or immobilization Myocardial infarction, Atrial fibrillation Tissue damage (surgery, fracture, burns) Cancer Prosthetic cardiac valves Disseminated intravascular coagulation Heparin-induced thrombocytopenia Antiphospholipid antibody syndrome (lupus anticoagulant syndrome) Lower risk for thrombosis Cardiomyopathy, Nephrotic syndrome, Hyperestrogenic states (pregnancy), Oral contraceptive use, Sickle cell anemia, Smoking.

Pathogenesis contd. 1) platelets - maintain the integrity of the vascular endothelium. -participate in endothelial repair through the contirbution of PDGF -form platelet plugs -promote the coagulation cascade through the platelet phospholipid complex.

Pathogenesis contd 2) Endothelial cells - are resistant to the thrombogenic influence of platelets and coagulation proteins. Intact endothelial cells act to modulate several aspects of hemostasis and oppose coagulation after injury by thromboresistance.

Pathogenesis contd 3) Coagulation Cascade The coagulation cascade constitutes the third component of the hemostatic process and is a major contributor to thrombosis. The coagulation cascade is essentially a series of enzymatic conversions, turning inactive proenzymes into activated enzymes and culminating in the formation of thrombin.

Pathogenesis contd 3) Coagulation Cascade contd. Thrombin then converts the soluble plasma protein fibrinogen precursor into the insoluble fibrous protein fibrin. -intrinsic pathway -extrinsic pathway

Pathogenesis contd 3) Coagulation Cascade contd. Besides inducing coagulation, activation of the clotting cascade also sets into motion a fibrinolytic cascade that limits the size of the final clot. This is primarily accomplished by the generation of plasmin. Plasmin is derived from enzymatic breakdown of its inactive circulating precursor plasminogen, either by a factor XIIdependent pathway or by two distinct types of plasminogen activators

Fibrinolysis (thrombus dissolution) Runs concurrently with thrombogenesis. Restores blood flow in vessels occluded by a thrombus and facilitates healing after inflammation and injury. The proenzyme plasminogen is converted by proteolysis to plasmin, the most important fibrinolytic protease. Plasmin split fibrin.

Thrombotic disorders - can be anti-thrombotic (hemorrhagic), leading to pathologic bleeding states such as hemophilia, Christmas disease and von Willebrand disease. - can also be prothrombotic, leading to hypercoagulability with pathologic thrombosis.

Hereditary Thrombophilia Is a prothrombotic familial syndrome. Charecterized by recurrent venous thrombosis and thromboembolism Can be caused by deficiency of antithrombotic proteins including antithrombin 3, protein C, and protien S.

Antiphospholipid antibody syndrome Is a prothrombotic disorder charecterized by autoantibodies directed against a number of protein antigens complexed to phospholipids Is further charecterized by recurrent venous and arterial thromboembolism, fetal loss, thrombocytopenia and a variety of neurological manifestations.

Antiphospholipid antibody syndrome It is most often diagnosed because of an incidental finding of prolonged PTT. It is sometimes associated Systemic Lupus Erythematosus and so this antibody is also known as lupus anticoagulant.

Disseminated intravascular coagulation Is both prothrombotic and antithrombotic disorder characterized by widespread thrombosis and hemorrhage resulting from the consumption of platelets and coagulation factors.

Morphology of thrombus Thrombi may develop anywhere in the cardiovascular system, the cardiac chambers, valve cusps, arteries, veins, or capillaries. They vary in size and shape, depending on the site of origin. Arterial or cardiac thrombi usually begin at a site of endothelial injury (e. g. , atherosclerotic plaque) or turbulence (vessel bifurcation) Venous thrombi characteristically occur in sites of stasis.

Arterial & Venous Thrombi Arterial thrombi grow in a retrograde direction from the point of attachment Venous thrombi extend in the direction of blood flow (i. e. , toward the heart). The propagating tail of either thrombi may not be well attached (particularly in veins) is prone to fragmentation, creating an embolus.

Thrombi (cont. ) When formed in the heart or aorta, thrombi may have grossly (and microscopically) apparent laminations, called lines of Zahn; these are produced by alternating pale layers of platelets admixed with some fibrin and darker layers containing more red cells. When arterial thrombi arise in heart chambers or in the aortic lumen, they usually adhere to the wall of the underlying structure and are termed mural thrombi.

Arterial thrombi are usually occlusive most common sites in descending order, are coronary, cerebral, and femoral arteries. It is usually superimposed on an atherosclerotic plaque and are firmly adherent to the injured arterial wall and are gray-white and friable, composed of a tangled mesh of platelets, fibrin, erythrocytes, and degenerating leukocytes.

Venous thrombosis Also called phlebothrombosis, is almost invariably occlusive thrombus often takes the shape of the vein. Because these thrombi form in a relatively static environment, they contain more enmeshed erythrocytes and are therefore known as red, or stasis thrombi. Phlebothrombosis most commonly affects the veins of the lower extremities (90% of cases).

Postmortem clots At autopsy, postmortem clots may be confused for venous thrombi. Postmortem clots are gelatinous with a dark red dependent portion where red cells have settled by gravity and a yellow chicken fat supernatant resembling melted and clotted chicken fat. They are not attached to the underlying wall. Red thrombi are firmer, almost always have a point of attachment, and on transection reveal vague strands of pale gray fibrin.

Thrombi on Heart Valves Bacterial or fungal blood-borne infections may result in the development of large thrombotic masses on heart valves, called as vegetations (infective endocarditis). Sterile vegetations can also develop on noninfected valves in patients with hypercoagulable states, socalled nonbacterial thrombotic endocarditis. Less commonly, noninfective, verrucous (Libman. Sacks) endocarditis attributable to elevated levels of circulating immune complexes may occur in patients with systemic lupus erythematosus

Figure 4 -15 Potential outcomes of venous thrombosis. Downloaded from: Robbins & Cotran Pathologic

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. Almost all emboli represent some part of a dislodged thrombus, hence the commonly used term thromboembolism.

Embolism (cont. ) The emboli ultimately lodge in vessels too small to permit further passage, resulting in partial or complete vascular occlusion leading to ischemic necrosis of distal tissue, (infarction). Depending on the site of origin, emboli may lodge in the pulmonary or systemic circulations.

PULMONARY THROMBOEMBOLISM Depending on size of embolus, it may occlude main pulmonary artery, or impact across the bifurcation (saddle embolus), or pass out into the smaller, branching arterioles Rarely, embolus may pass through an interatrial or interventricular defect to gain access to the systemic circulation (paradoxical embolism).

PULMONARY THROMBOEMBOLISM (cont. ) Most pulmonary emboli (60% to 80%) are clinically silent because they are small. Sudden death, right heart failure (cor pulmonale), or CVS occurs when 60% or more of the pulmonary circulation is obstructed with emboli. Embolic obstruction of small end-arteriolar pulmonary branches may result in infarction.

SYSTEMIC THROMBOEMBOLISM refers to emboli traveling within the arterial circulation. Most (80%) arise from intracardiac mural thrombi. The major sites for arteriolar embolization are the lower extremities (75%) and the brain (10%). The consequences of systemic emboli depend on the extent of collateral vascular supply in the affected tissue, the tissue's vulnerability to ischemia, and the caliber of the vessel occluded; in general, arterial emboli cause infarction of tissues supplied by the artery

$FAT EMBOLISM Microscopic fat globules may be found in the circulation after fractures of$

FAT EMBOLISM Microscopic fat globules may be found in the circulation after fractures of long bones (which have fatty marrow) or, rarely, in soft tissue trauma and burns. Fat is released by marrow or adipose tissue injury and enters the circulation through rupture of the blood vessels. Less than 10% of patients with fat embolism have any clinical findings. Fat embolism syndrome is characterized by pulmonary insufficiency, neurologic symptoms, anemia, and thrombocytopenia.

AIR EMBOLISM Gas bubbles within the circulation can obstruct vascular flow (and cause distal ischemic injury) acting as thrombotic masses. Bubbles may coalesce to form frothy masses sufficiently large to occlude major vessels. Air may enter the circulation during obstetric procedures or as a consequence of chest wall injury. An excess of 100 cc is required to have a clinical effect.

Decompression sickness Occurs when individuals are exposed to sudden changes in atmospheric pressure. Scuba and deep sea divers, underwater construction workers, and individuals in unpressurized aircraft in rapid ascent are all at risk.

Decompression sickness (cont. ) When air is breathed at high pressure (e. g. , during a deep sea dive), increased amounts of gas (particularly nitrogen) become dissolved in the blood and tissues. If the diver then ascends (depressurizes) too rapidly, the nitrogen expands in the tissues and bubbles out of solution in the blood to form gas emboli. ‘Bends’ and ‘chokes’.

Decompression sickness (cont. ) Treatment: placing the individual in a compression chamber where the barometric pressure may be raised, thus forcing the gas bubbles back into solution followed by subsequent slow decompression. A more chronic form of decompression sickness is called caisson disease in which, persistence of gas emboli in the skeletal system leads to multiple foci of ischemic necrosis; the more common sites are the heads of the femurs, tibia, and humeri.

AMNIOTIC FLUID EMBOLISM A grave and uncommon complication of labor and the immediate postpartum period, characterized by sudden severe dyspnea, cyanosis, and hypotensive shock, followed by seizures and coma. If the patient survives the initial crisis, pulmonary edema develops, along with DIC, owing to release of thrombogenic substances from amniotic.

AMNIOTIC FLUID EMBOLISM (cont. ) Caused by infusion of amniotic fluid or fetal tissue into the maternal circulation via a tear in the placental membranes or rupture of uterine veins. Microscopy: presence in the pulmonary microcirculation of squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa, and mucin derived from the fetal respiratory or gastrointestinal tract. Marked pulmonary edema and diffuse alveolar damage are also present. Systemic fibrin thrombi indicative of DIC can also be seen.

INFARCTION An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage in a particular tissue e. g. myocardial, cerebral, pulmonary and bowel infarction. Most infarcts result from thrombotic or embolic events, and almost all result from arterial occlusion. Although venous thrombosis may cause infarction, it more often merely induces venous obstruction and congestion.

Morphology Infarcts are classified on the basis of their color (reflecting the amount of hemorrhage) and the presence or absence of microbial infection. Therefore, infarcts may be either red (hemorrhagic) or white (anemic) and may be either septic or bland.

Red Infarcts Red (hemorrhagic) infarcts occur with venous occlusions (such as in ovarian torsion) in loose tissues (such as lung), and in tissues with dual circulations (e. g. , lung and small intestine), permitting flow of blood from the unobstructed vessel into the affected zone

White Infarct White (anemic) infarcts occur with arterial occlusions in solid organs with end-arterial circulation (such as heart, spleen, and kidney), where the solidity of the tissue limits the amount of hemorrhage that can seep into the area of ischemic necrosis from adjoining capillary beds.

Morphology Gross: Most infarcts are wedge-shaped, with the occluded vessel at the apex and the periphery of the organ forming the base. Micro: An inflammatory response begins along the margins of infarcts within a few hours and is usually well defined within 1 or 2 days, followed by gradual degradation of the dead tissue with phagocytosis of the cellular debris by neutrophils and macrophages. Most infarcts are ultimately replaced by scar tissue.

Septic Infarct Septic infarctions may develop when embolization occurs by fragmentation of a bacterial vegetation from a heart valve or when microbes seed an area of necrotic tissue. The septic infarct is converted into an abscess, with a correspondingly greater inflammatory response

Infarct (cont. ) The consequences of a vascular occlusion can range from no or minimal effect, all the way up to death of a tissue or even the individual. The major determinants include: (1) the nature of the vascular supply; (2) the rate of development of the occlusion; (3) the vulnerability of a given tissue to hypoxia; and (4) the blood oxygen content.

SHOCK Shock, or cardiovascular collapse, is the final common pathway for a number of potentially lethal clinical events, including severe hemorrhage, extensive trauma or burns, large myocardial infarction, massive pulmonary embolism, and microbial sepsis.

In shock there is systemic hypoperfusion caused by reduction either in cardiac output or in the effective circulating blood volume. The end results are hypotension, followed by impaired tissue perfusion and cellular hypoxia. Initially the cellular injury is reversible, persistence of shock eventually causes irreversible tissue injury.

Types of shock. Cardiogenic shock results from myocardial pump failure e. g intrinsic myocardial infarction, ventricular arrhythmias. Hypovolemic shock results from loss of blood or plasma volume e. g. hemorrhage, fluid loss from severe burns, or trauma. Septic shock is caused by systemic microbial infection. Most commonly due to gram-negative infections (endotoxic shock), but it can also occur with gram-positive and fungal infections.

Neurogenic shock: anesthetic accident or spinal cord injury can lead to loss of vascular tone and peripheral pooling of blood. Anaphylactic shock: initiated by a generalized Ig. E-mediated hypersensitivity response, is associated with systemic vasodilation and increased vascular permeability.

Septic/Endotoxic Shock Septic shock results from spread and expansion of an initially localized infection (e. g. , abscess, peritonitis, pneumonia) into the bloodstream. Most cases of septic shock (approximately 70%) are caused by endotoxin-producing gramnegative bacilli. Endotoxins are bacterial wall lipopolysaccharides (LPSs) that are released when the cell walls are degraded (e. g. , in an inflammatory response).

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Stages of Shock If uncorrected, leads to death. Unless insult is massive and lethal (e. g. a massive hemorrhage), shock tends to evolve through three general phases. A nonprogressive phase: reflex compensatory mechanisms are activated and perfusion of vital organs is maintained A progressive stage: tissue hypoperfusion and onset of worsening circulatory and metabolic imbalances, including acidosis An irreversible stage: sets in after body has incurred cellular and tissue injury so severe that even if the hemodynamic defects are corrected, survival is not possible.

Morphology The cellular and tissue changes induced by shock are essentially those of hypoxic injury, since shock is characterized by failure of multiple organ systems, the cellular changes may appear in any tissue. They are particularly evident in brain, heart, lungs, kidneys, adrenals, and gastrointestinal tract.

Morphology of shock (cont. ) brain - ischemic encephalopathy heart - coagulation necrosis, may exhibit subendocardial hemorrhage and/or contraction band necrosis. kidneys - tubular ischemic injury (acute tubular necrosis, therefore oliguria, and electrolyte disturbances constitute major clinical problems. lungs are seldom affected in pure hypovolemic shock because they are resistant to hypoxic injury. When shock is caused by bacterial sepsis or trauma, however, changes of diffuse alveolar damage may appear, the so-called shock lung

Clinical Course. In hypovolemic and cardiogenic shock, the patient presents with hypotension; a weak, rapid pulse; tachypnea; and cool, clammy, cyanotic skin. In septic shock, the skin may initially be warm and flushed because of peripheral vasodilation. As shock progresses, electrolyte disturbances and metabolic acidosis (lactic acidosis) complicate the situation followed by progressive fall in urine output.

Prognosis The prognosis varies with the origin of shock and its duration. 80% to 90% of young, otherwise healthy patients with hypovolemic shock survive with appropriate management, whereas cardiogenic shock associated with extensive myocardial infarction and gramnegative shock carry mortality rates of up to 75%, even with the best care currently available.