HAEMODYNAMIC DISORDERS Presentation for AE-FUNAI Medical Students PDF

HAEMODYNAMIC DISORDERS Presented by Dr. Emmanuel Kunle Abudu (MBBS, M.Sc, FMCPath) Professor and Consultant Pathologist To 400L MEDICAL STUDENTS (STREAM B & C) OF ALEX EKWUEME FEDERAL UNIVERSITY  Course Objectives Define...

HAEMODYNAMIC DISORDERS Presented by Dr. Emmanuel Kunle Abudu (MBBS, M.Sc, FMCPath) Professor and Consultant Pathologist To 400L MEDICAL STUDENTS (STREAM B & C) OF ALEX EKWUEME FEDERAL UNIVERSITY  Course Objectives Define the terms “Oedema”, “hyperaemia”, and “haemorrhage”. Explain how the processes of Oedema, hyperaemia, and hemorrhage occur. Define the terms “haemostasis” and “thrombosis”. Explain how the processes of haemostasis and thrombosis occur. Define the term Define the term ischemia “ischemia”, “ infarction”, “embolism and shock ” and “shock”. Explain how the processes of ischemia, infarction, embolism and shock occur. Describe the histological changes that occur in each of the following: Oedema, hyperaemia, haemorrhage, haemostasis, thrombosis, ischemia, infarction, embolism and shock. Describe the different types of shock which occur and the aetiology of each. List clinical examples of shock  GOALS AND OBJECTIVES AT THE END OF THE LECTURE YOU SHOULD BE ABLE TO DEFINE: THROMBOSIS, EMBOLISM, INFARCT (BOTH RED AND PALE), COAGULATIVE NECROSIS, OEDEMA, SHOCK, HYPERAEMIA, CONGESTION, HAEMORRHAGE, HAEMATOMA, PETECHIAE IDENTIFY PATHOLOGICALLY THROMBOSIS (VENOUS AND ARTERIAL), EMBOLISM, INFARCTION, CONGESTION, OEDEMA, AND THE TISSUE CHANGES RELATED TO SHOCK  GOALS AND OBJECTIVES 2 UNDERSTAND THE PATHOPHYSIOLOGY OF: NORMAL HAEMOSTASIS THE NORMAL VESSEL WALL CONSTITUENTS AND HOW THEY INTERACT WITH THE CIRCULATING BLOOD HYPERCOAGUABLE STATES INCLUDING PRIMARY (FACTOR V LEIDEN MUTATION, PROTEIN C AND S DEFICIENCY) AND SECONDARY ACQUIRED HYPERCOAGUABLE STATES THROMBOSIS (INCLUDING VIRCHOW’S TRIAD OF THROMBOSIS) POTENTIAL FATES OF THROMBI EMBOLISM (THROMBOEMBOLI, PARADOXICAL EMBOLI, FAT EMBOLI, AMNIOTIC FLUID EMBOLI, FOREIGN BODY EMBOLI) January 2007  GOALS AND OBJECTIVES 3 DISTINGUISH THE DIFFERENCE IN PATHOPHYSIOLOGY BETWEEN RED AND PALE (WHITE) INFARCTS UNDERSTAND THE PATHOPHYSIOLOGY OF HAEMORRHAGIC SHOCK, CARDIOGENIC SHOCK, SEPTIC SHOCK, ANAPHYLACTIC SHOCK January 2007 NORMAL HEAMOSTASIS WE ARE NOT COMPOSED OF STATIC PIPES THAT TRANSMIT BLOOD SO WE PLUMBER’S TOOL MUST BEGIN OUR DISCUSSION WITH AN UNDERSTANDING OF HOW THE NORMAL VESSEL CONSTITUENTS INTERACT WITH BLOOD NORMALLY! NORMAL HAEMOSTASIS: MAINTAINS BLOOD IN A FLUID STATE AND PRODUCES A LOCAL HEAMOSTATIC PLUG AT SITES OF VASCULAR INJURY January 2007 NORMAL HAEMOSTASIS 1. Integrity of small blood vessels 2. Adequate numbers of platelets 3. Normal amounts of coagulation factors 4. Normal amounts of coagulation inhibitors 5. Adequate amounts of calcium ions in the blood January 2007 THE VESSEL CONSTITUENTS AND COAGULATION ENDOTHELIAL CELLS ARE ORRRR PROTHROMBOTIC ANTITHROMBOTIC PRO-PLATELET ADHESION – VWF ANTIPLATELET EFFECTS PROCOAGULANT – ACTIVATED TO SECRETE TISSUE FACTOR ANTICOAGULANT EFFECTS ANTIFIBRINOLYTIC – INHIBITORS OF PLASMINOGEN ACTIVATORS THAT FIBRINOLYTIC EFFECTS DEPRESS FIBRINOLYSIS January 2007  HAEMOSTASIS AND PLATELETS PLAY A CENTRAL ROLE IN HAEMOSTASIS CYTOPLASMIC FRAGMENTS FROM MEGAKARYOCYTES AFTER VASCULAR INJURY: PLATELETS ADHERE M PLATELETS SECRETE GRANULE PRODUCTS PLATELETS AGGREGATE PRIMARY HEMOSTATIC PLUG January 2007  Figure 4-6 Diagrammatic representation of the normal hemostatic process. A, After vascular injury, local neurohumoral factors induce a transient vasoconstriction. B, Platelets adhere to exposed extracellular matrix (ECM) via von Willebrand factor (vWF) and are activated, undergoing a shape change and granule release; released adenosine diphosphate (ADP) and thromboxane A2 (TxA2) lead to further platelet aggregation to form the primary haemostatic plug. C, Local activation of the coagulation cascade (involving tissue factor and platelet phospholipids) results in fibrin polymerization, "cementing" the platelets into a definitive secondary haemostatic plug. D, Counter-regulatory mechanisms, such as release of tissue type plasminogen activator (t-PA) (fibrinolytic) and thrombomodulin (interfering with the coagulation cascade), limit the hemostatic process to the site of injury. January 2007 Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 31 January 2005 07:03 PM) © 2005 Elsevier January 2007 Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 31 January 2005 07:03 PM) © 2005 Elsevier January 2007 Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 31 January 2005 07:03 PM) © 2005 Elsevier  Introduction Normal fluid homeostasis depends on: maintenance of vessel wall integrity intravascular pressure osmolarity within certain physiologic ranges Normal fluid homeostasis means maintaining blood as a liquid until such time as injury necessitates clot formation  Review 60% lean body weight is water. 2/3 intracellular and the reminder found in extracellular space mostly as interstitial fluid, 5% found in blood plasma. 3 major fluid compartments: Intracellular fluid (ICF):fluid within cells (cytosol) Extracellular fluid (ECF):fluid outside of cells, A) interstitial fluid: fluid surrounding the cells B) plasma: fluid compartment of the blood  Oedema Oedema: abnormal increased fluid in interstitial tissue spaces and natural body cavities. Fluid in cavities is designated special names: hydrothorax, hydropericardium , hydropericardium, hydroperitoneum (ascites) Anasarca is severe, generalized edema with profound subcutaneous tissue swelling. Exudate: Increased vascular permeability leads to inflammatory oedema that is rich in proteins. Transudate: Oedema due to haemodynamic derangements that is protein poor.  Causes of Edema Classified under 5 broad categories: Increased hydrostatic pressure Reduced plasma oncotic pressure Lymphatic obstruction Sodium retention Inflammation Oedema: Opposing effects of vascular hydrostatic pressure and plasma Colloid osmotic pressure govern movement of fluid between vascular and interstitial spaces Fluid exits from arteriole into interstitial space, balanced by inflow from venule, excess interstitial fluid is drained by lymphatics  Causes of Edema 1) INCREASED HYDROSTATIC PRESSURE: a) Impaired venous return: i) Congestive heart failure ii) Constrictive pericarditis iii) Ascites (liver cirrhosis) iv) Venous obstruction or compression: Thrombosis External pressure (e.g., mass) Lower extremity inactivity with prolonged dependency b) Arteriolar dilation: Heat Neurohumoral dysregulation  Causes of Edema contd 2) REDUCED PLASMA OSMOTIC PRESSURE (HYPOPROTEINEMIA): Protein-losing glomerulopathies (nephrotic syndrome) Liver cirrhosis (ascites) Malnutrition Protein-losing gastroenteropathy 3) LYMPHATIC OBSTRUCTION: Inflammatory Neoplastic Postsurgical Postirradiation  Causes of Oedema contd 4) SODIUM RETENTION: Excessive salt intake with renal insufficiency. Increased tubular reabsorption of sodium. Renal hypoperfusion. Increased renin-angiotensin-aldosterone secretion. 5) INFLAMMATION: Acute inflammation Chronic inflammation Angiogenesis  Morphology Oedema is easily recognized grossly; microscopically, it is appreciated as clearing and separation of the extracellular matrix and subtle cell swelling. Any organ or tissue can be involved, but oedema is most commonly seen in subcutaneous tissues, the lungs, and the brain. Subcutaneous oedema can be diffuse or more conspicuous in regions with high hydrostatic pressures. In most cases the distribution is influenced by gravity and is termed dependent oedema (e.g., the legs when standing, the sacrum when recumbent). Finger pressure over substantially oedematous subcutaneous tissue displaces the interstitial fluid and leaves a depression, a sign called pitting edema. Oedema as a result of renal dysfunction can affect all parts of the body. With pulmonary oedema, the lungs are often two to three times their normal weight, and sectioning yields frothy, blood-tinged fluid—a mixture of air, oedema, and extravasated red cells. Brain oedema can be localized or generalized depending on the nature and extent of the pathologic process or injury. With generalized edema the brain is grossly swollen with narrowed sulci; distended gyri show evidence of compression against the unyielding skull  Edema - Morphology Easily identified grossly. Microscopically – subtle cell swelling with clearing and separation of extracellular matrix. Depending on degree of oedema, there can be devastating effects on the brain, heart, lungs and kidneys. Subcutaneous: can be diffuse or conspicuous. Dependent: distribution influenced by Gravity. Pitting edema: finger pressure over oedematous tissue displaces interstitial fluid leaving a depression.  Oedema - Morphology It often initially manifests in tissues with loose connective tissue matrix, such as the eyelids; periorbital oedema is thus a characteristic finding in severe renal disease. Pulmonary edema: seen in renal failure, ARDS. Lungs 2-3x weight Sectioning of lungs yields frothy, blood-tinged fluid—a mixture of air, oedema, and extravasated red cells. Brain edema (Cerebral edema): localised or diffuse seen in infection / trauma. With generalized edema the brain is grossly swollen with narrowed sulci; distended gyri show evidence of compression against the unyielding skull  HYPERAEMIA & CONGESTION - Both are due to increased blood volume in particular tissue S/N Features Hyperaemia Congestion 1 Nature Active process Passive process 2 Anatomic site Arterioles Veins/venules 3 Aetiology Arteriolar dilatation, Impaired tissue outflow, venous obstruction, 4 Pathogenesis Engorgement of vessels with Appearance with accumulation oxygenated blood of deoxygenated blood 5 Gross appearance Red (erythema) Cyanotic (bluish) 6 Anatomic distribution Usually local It can be systemic (e.g cardiac failure) or local (e.g isolated venous obstruction) 7. Oedema Rare Common  Congestion Occurs commonly with oedema due to increased fluid transudation as a result of the increased volumes and pressures. In long-standing chronic passive congestion, stasis of poorly oxygenated blood can lead to hypoxia, potentially resulting in ischemic tissue injury and scarring. Capillary rupture may occur at sites of chronic congestion leading to haemorrhage and subsequent catabolism of extravasated red cells can leave residual telltale clusters of haemosiderin-laden macrophages.  Congestion- Morphology The cut surfaces of congested tissues are often discolored or cyanotic. Microscopically, acute pulmonary congestion exhibits engorged alveolar capillaries often with alveolar septal oedema and focal intra-alveolar haemorrhage. In chronic pulmonary congestion, the septa are thickened and fibrotic, and the alveoli contain numerous haemosiderin-laden macrophages (heart failure cells).  Congestion- Morphology contd In acute hepatic congestion, the central vein and sinusoids are distended; centrilobular hepatocytes can be frankly ischemic while the periportal hepatocytes—better oxygenated because of proximity to hepatic arterioles—may only develop fatty change. In chronic passive hepatic congestion, the centrilobular regions are grossly red-brown and slightly depressed and are accentuated against the surrounding zones of uncongested tan liver (nutmeg liver). Microscopically, there is centrilobular haemorrhage, haemosiderin-laden macrophages, and degeneration of hepatocytes. The centrilobular area is at the distal end of the blood supply to the liver, thus, it is prone to undergo necrosis in impaired blood supply.  Haemorrhage Defines as extravasation of blood due to vessel rupture into the extravascular space. Causes: conditions of chronic congestion; Haemorrhagic diatheses. Vascular injury, including trauma, atherosclerosis, or inflammatory or neoplastic erosion of the vessel wall May manifest in a variety of patterns depending on size, extent, location of bleeding May be external or within tissue (haematoma) May be insignificant (bruise) May be fatal – massive haematoma  Haemorrhage Minute 1 – 2 mm diameter into skin (petechial) associated with locally increased intravascular pressure, low platelet count, defective platelet function or clotting defects > 3mm called purpura associated with same disorders as petechiae, may be due to trauma, vascular inflammation or increased vascular fragility Larger (> 1 – 2 cm) subcutaneous haematomas called ecchymoses usually seen after trauma Erythrocytes get degraded phagocytosed by macrophages, haemoglobin (red-blue) conveted to bilirubin (blue-green) and event Determining the Age of a Bruise by its Color Color of Bruise Age of Bruise Red (Swollen, tender) 0- 2 days Bluish -red, red purple purple 2-55 days days Green 5-7 days Yellow 7-10 days Brown 10-14 days No further bruising 2-4 wks  Haemorrhage contd Extensive haemorrhage due to extensive breakdown of red cells may lead to jaundice Large accumulations of blood in one or another of body cavities are called: Haemothorax Haemopericardium Haemoperitoneum Haemarthrosis Clinical Significance The clinical significance of haemorrhage depends on the volume and rate of bleeding. Blood loss of up to 20% may have little impact on healthy adults Greater loss may lead to shock Site of bleeding e.g in brain may lead to an increase in pressure and herniation Chronic bleeding may lead to anemia  Haemostasis and Thrombosis Haemostasis is a result of well regulated processes. Aimed at maintenance of blood in fluid, clot free state in normal vessels. Induce rapid, localize haemostatic plug at the site of vascular injury. Is achieved via the vascular wall, activity of platelets and the coagulation cascade Endothelium: Endothelial cells modulate several (and frequently opposing) aspects of normal haemostasis. 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 pro-coagulant activities. Endothelium can be activated by infectious agents, by haemodynamic factors, by plasma mediators, and (most significantly) by cytokines.  Haemostasis and Thrombosis Antithrombotic properties: Antiplatelet properties Properties: endothelial prostacyclin (PGI2) and nitric oxide Anticoagulatant Properties: Heparin-like molecules and thrombomodulin. The heparin-like molecules act indirectly; they are cofactors that allow antithrombin III to inactivate thrombin, factor Xa, and several other coagulation factors (see later). Thrombomodulin also acts indirectly; it binds to thrombin, converting it from a procoagulant to an anticoagulant capable of activating the anticoagulant protein C. Activated protein C, in turn, inhibits clotting by proteolytic cleavage of factors Va and VIIIa; it requires protein S, synthesized by endothelial cells, as a cofactor. Antifibrinolytic Properties: Endothelial cells synthesize tissue plasminogen activator (t-PA), promoting fibrinolytic activity to clear fibrin deposits from endothelial surfaces.  Haemostasis and Thrombosis Pro-thrombotic properties: Prothrombotic with activities that affect platelets, coagulation proteins, and the fibrinolytic system. Endothelial injury results in platelet adhesion to subendothelial collagen; this occurs through von Willebrand factor (vWF), an essential cofactor for binding platelets to collagen and other surfaces. Cytokines such as tumour necrosis factor (TNF) or interleukin-1 (IL-1) as well as bacterial endotoxin all induce endothelial cell production of tissue factor; tissue factor activates the extrinsic clotting pathway. By binding activated IXa and Xa, endothelial cells augment the catalytic activities of these coagulation factors. Endothelial cells also secrete plasminogen activator inhibitors (PAIs), which depress fibrinolysis  Haemostasis and thrombosis Thrombosis: Formation of an intravascular solid or semisolid mass (thrombus) comprised of blood constituents. Embolism – occlusion of the artery by an embolus. An embolus is a material within a vessel capable of blocking its lumen. Thrombi, atheromatous material, tumour cells, fat, gas, amniotic fluid, foreign body materials  Thrombosis Defined as inappropriate activation of normal haemostatic processes in uninjured vasculature or thrombotic occlusion of a vessel after relatively minor injury. May develop anywhere in the cardio-vascular system. Physiological clot formation is essential for life. Abnormal situations in which clot is not formed or formed in excess are both dangerous. Virchow’s Triad in Thrombosis: a) Endothelial damage: Leads to ↓ inhibition of coagulation & local fibrinolysis b) 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 in the development of venous thrombi. Normal blood flow is laminar such that the platelets (and other blood cellular elements) flow centrally in the vessel lumen, separated from endothelium by a slower moving layer of plasma.  Thrombosis Stasis and turbulence therefore: i) Promote endothelial activation, enhancing procoagulant activity, leukocyte adhesion through flow-induced changes in endothelial cell gene expression. ii) Disrupt laminar flow and bring platelets into contact with the endothelium. Iii) Prevent washout and dilution of activated clotting factors by fresh flowing blood and the inflow of clotting factor inhibitors. Venous stasis (abnormal blood flow): Inhibits immobilization, clearance & dilution of coagulation factors. c) Hypercoagulability: A) Inherited - point mutations in the Factor V gene and prothrombin gene are the most common. Antithrombin III deficiency Protein C deficiency Protein S deficiency B) Acquired  Thrombosis contd i) Endothelial injury Endocardium - Myocardial infarction, rheumatism, endocarditis. Intima - atherosclerosis and ulcerated plaque, vasculitis, bacterial endotoxins Hypercholesterolemia, smoking etc Hypercholesterolemia smoking etc they all lead to exposure. They all lead to exposure of subendothelial collagen. II) Alteration in blood flow Turbulence and stasis. Platelets come into contact with endothelium, prevent dilution of clotting factors Plaques, MI, aneurysm, Polycythemia, sickle cell anaemia.  Thrombosis contd Iii) Hypercoagulability High Risk for Thrombosis Prolonged bed rest or immobilization Myocardial infarction Atrial fibrillation Tissue injury (surgery, fracture, burn) Cancer Prosthetic cardiac valves Disseminated intravascular coagulation Heparin-induced thrombocytopenia Antiphospholipid antibody syndrome Lower Risk for Thrombosis Cardiomyopathy Nephrotic syndrome Hyperestrogenic states (pregnancy and postpartum) Oral contraceptive use Sickle cell anemia Smoking  Fate of a thrombus Propagation – may accumulate more platelets and fibrin leading to vessel obstruction Embolization – thrombi may dislodge and travel to other sites in the vasculature Dissolution – may be removed by fibrinolytic activity Organisation & recanalization – thrombi may induce inflammation and fibrosis (organization), reestablish vascular (recanalization) flow or may be incorporated into a thickened vascular wall  Thrombosis- Morphology S/N Features Postmortem clots Antemortem venous thrombi 1 Appearance A dark red dependent portion where red Red cells have settled by gravity and a yellow “chicken fat” upper portion 2 Consistency Gelatinous Friable and firmer 3 Attachment to blood They are usually not attached to the Focally attached vessel wall underlying wall 4 Shape Takes after shape of the blood vessel Do not take after shape of the blood vessel 5 Lines of Zahn. Absent Present  Thrombosis- Morphology contd 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 thrombi depend on the site of origin and the cause. Arterial or cardiac thrombi usually begin at sites of turbulence or endothelial injury; venous thrombi characteristically occur at sites of stasis. Thrombi are focally attached to the underlying vascular surface; arterial thrombi tend to grow retrograde from the point of attachment, while venous thrombi extend in the direction of blood flow (thus both propagate toward the heart). Thrombi occurring in heart chambers or in the aortic lumen are designated mural thrombi. Abnormal myocardial contraction (arrhythmias, dilated cardiomyopathy, or myocardial infarction) or endomyocardial injury (myocarditis or catheter trauma) promotes cardiac mural thrombi, while ulcerated atherosclerotic plaque and aneurysmal dilation are the precursors of aortic thrombus  Thrombosis- Morphology contd Arterial thrombi are frequently occlusive; the most common sites in decreasing order of frequency are the coronary, cerebral, and femoral arteries. They typically consist of a friable meshwork of platelets, fibrin, red cells, and degenerating leukocytes. Venous thrombosis (phlebothrombosis) is almost invariably occlusive, with the thrombus forming a long cast of the lumen. Because these thrombi form in the sluggish venous circulation, they tend to contain more enmeshed red cells (and relatively few platelets) and are therefore known as red, or stasis, thrombi. The veins of the lower extremities are most commonly involved (90% of cases); however, upper extremities, periprostatic plexus, or the ovarian and periuterine veins can also develop venous thrombi. Under special circumstances, they can also occur in the dural sinuses, portal vein, or hepatic vein.  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 term thromboembolism. Rare forms of emboli include fat droplets, nitrogen bubbles, atherosclerotic debris (cholesterol emboli), tumor fragments, bone marrow, or even foreign bodies. Depending on where they originate, emboli can lodge anywhere in the vascular tree; the clinical outcomes are best understood based on whether emboli lodge in the pulmonary or systemic circulations. Types of Embolism Pulmonary Systemic Fat Embolism Air Embolism Amniotic Fluid Embolism  PULMONARY EMBOLISM Embolism of pulmonary artery Depending on the size of the embolus, it can occlude the main pulmonary artery, straddle the pulmonary artery bifurcation (saddle embolus), or pass out into the smaller, branching arteries. Frequently there are multiple emboli, perhaps sequentially or as a shower of smaller emboli from a single large mass; in general, the patient who has had one PE is at high risk of having more. Rarely, an embolus can pass through an interatrial or interventricular defect and gain access to the systemic circulation (paradoxical embolism). If 60% of the pulmonary vasculature is blocked, the heart cannot pump blood through the lungs. Blockage of middle-sized arteries cause breathlessness, developing of infarctions and haemoptysis. Minor pulmonary embolism: may be asymptomatic or causes pleuritic chest pain and breathlessness.  Clinicopathological correlations Most pulmonary emboli (60% to 80%) are clinically silent because they are small and can be incorporated into the vascular wall. Sudden death, right heart failure (cor pulmonale), or cardiovascular collapse occurs when emboli obstruct 60% or more of the pulmonary circulation. Embolic obstruction of medium-sized arteries with subsequent vascular rupture can result in pulmonary haemorrhage but usually does not cause pulmonary infarction. A similar embolus in the setting of left-sided cardiac failure (and compromised bronchial artery flow) can result in infarction. Embolic obstruction of small end-arteriolar pulmonary branches usually does result in haemorrhage or infarction. Multiple emboli over time may cause pulmonary hypertension and right ventricular failure.  SYSTEMIC THROMBOEMBOLISM It 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 left atrial dilation and fibrillation. 10% originate from aortic aneurysms, thrombi on ulcerated atherosclerotic plaques, or fragmentation of a valvular vegetation, with a small fraction due to paradoxical emboli; 10% to 15% of systemic emboli are of unknown origin. In contrast to venous emboli, which tend to lodge primarily in one vascular bed (the lung), arterial emboli can travel to a wide variety of sites; the point of arrest depends on the source and the relative amount of blood flow that downstream tissues receive. Major sites for arteriolar embolization are the lower extremities (75%) and the brain (10%), with the intestines, kidneys, spleen, and upper extremities involved to a lesser extent. The consequences of embolization in a tissue depend on its vulnerability to ischemia, the caliber of the occluded vessel, and whether there is a collateral blood supply; Generally, arterial emboli cause infarction of the affected tissues.  FAT AND MARROW EMBOLISM Microscopic fat globules—with or without associated haematopoietic marrow elements in the circulation and impacted in the pulmonary vasculature following fractures of long bones or soft tissue trauma and burns. Mechanism is via the rupture of the marrow vascular sinusoids or venules. Fat embolism occurs in some 90% of individuals with severe skeletal injuries + symptoms. Fat embolism syndrome occurs in the minority of patients who become symptomatic (15%). It is characterized by pulmonary insufficiency, neurologic symptoms, anemia, and thrombocytopenia with petechial rash. Typically, 1 to 3 days after injury there is a sudden onset of tachypnea, dyspnoea, and tachycardia; irritability and restlessness can progress to delirium or coma. Its pathogenesis probably involves both mechanical obstruction and biochemical injury. i) Fat microemboli and associated red cell and platelet aggregates can occlude the pulmonary and cerebral microvasculature. ii) Release of free fatty acids from the fat globules exacerbates the situation by causing local toxic injury to endothelium, and platelet activation and granulocyte recruitment (with free radical, protease, and eicosanoid release) complete the vascular assault.  AIR EMBOLISM Gas bubbles within the circulation can coalesce to form frothy masses that obstruct vascular flow (and cause distal ischemic injury). Causes: in a coronary artery during bypass surgery, or introduced into the cerebral circulation by neurosurgery in the “sitting position,” during obstetric or laparoscopic procedures, or as a consequence of chest wall injury. Generally, > 100 cc of air are required to have a clinical effect in the pulmonary circulation. Decompression sickness, occurs when individuals experience sudden decreases in atmospheric pressure. e.g Scuba and deep sea divers, underwater construction workers, and individuals in unpressurized aircraft in rapid ascent are all at risk. When air is breathed at high pressure (e.g., during a deep sea dive), increased amounts of gas (particularly nitrogen) are dissolved in the blood and tissues. If the diver then ascends (depressurizes) too rapidly, the nitrogen comes out of solution in the tissues and the blood. The rapid formation of gas bubbles within skeletal muscles and supporting tissues in and about joints is responsible for the painful condition called the bends. In the lungs, gas bubbles in the vasculature cause edema, hemorrhage, and focal atelectasis or emphysema, leading to a form of respiratory distress called the chokes. In caisson disease, persistence of gas emboli in the skeletal system leads to multiple foci of ischemic necrosis; the more common sites are the femoral heads, tibia, and humeri.  AMNIOTIC FLUID EMBOLISM Amniotic fluid embolism is an ominous complication of labour and the immediate postpartum period. The onset is characterized by sudden severe dyspnoea, cyanosis, and shock, followed by neurologic impairment ranging from headache to seizures and coma. If the patient survives the initial crisis, pulmonary edema typically develops, along with (in half the patients) DIC, as a result of release of thrombogenic substances from the amniotic fluid. The underlying cause is the infusion of amniotic fluid or fetal tissue into the maternal circulation via a tear in the placental membranes or rupture of uterine veins. Classic findings include the presence of squamous cells shed from fetal skin, lanugo hair, fat from vernix caseosa, and mucin derived from the fetal respiratory or gastrointestinal tract in the maternal pulmonary microvasculature. Other findings include marked pulmonary edema, diffuse alveolar damage, and the presence of fibrin thrombi in many vascular beds due to DIC.  Infarction An area of ischemic necrosis caused by occlusion of either the arterial supply or the venous drainage in a particular tissue. Commonly seen: Myocardial, cerebral, pulmonary, bowel, extremities 99% from thrombotic / embolic events Others from local vasospasm, expansion of atheroma, extrinsic compression of a vessel (e.g. tumor), torsion, volvulus, oedema.  Infarct - Classification i) Histologically: Ischemic coagulative necrosis Liquefactive necrosis Scar tissue II) Morphologically into: Infarcts are classified on the basis of their color (reflecting the amount of hemorrhage) and the presence or absence of microbial infection. Infarcts may be either red (hemorrhagic) or white (anemic). Infarcts may be either septic or bland. Usually wedge-shaped with occluded vessel at the apex and the periphery of the organ forming the base  Red infarcts (1) with venous occlusions (such as in ovarian torsion); 2) in loose tissues (such as lung) that allow blood to collect in the infarcted zone; (3) in tissues with dual circulations such as lung and small intestine, permitting flow of blood from an unobstructed parallel supply into a necrotic area (such perfusion not being sufficient to rescue the ischemic tissues); (4) in tissues that were previously congested because of sluggish venous outflow; (5) 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 haemorrhage that can seep into the area of ischemic necrosis from adjoining capillary beds.  Morphology All infarcts tend to be wedge shaped, with the occluded vessel at the apex and the periphery of the organ forming the base; when the base is a serosal surface there can be an overlying fibrinous exudate. At the outset, all infarcts are poorly defined and slightly hemorrhagic. The margins of both types of infarcts tend to become better defined with time by a narrow rim of congestion attributable to inflammation at the edge of the lesion. In solid organs, the relatively few extravasated red cells are lysed, with the released haemoglobin remaining in the form of haemosiderin. Thus, infarcts resulting from arterial occlusions typically become progressively more pale and sharply defined with time. In spongy organs, by comparison, the haemorrhage is too extensive to permit the lesion ever to become pale. Over the course of a few days, however, it does become firmer and browner, reflecting the accumulation of haemosiderin pigment. The dominant histologic characteristic of infarction is ischemic coagulative necrosis + Inflammatory reaction. to these generalizations; ischemic tissue injury in the central nervous system results in liquefactive necrosis. Septic infarctions occur when bacterial vegetations from a heart valve embolize or when microbes seed an area of necrotic tissue which can lead to an abscess, with marked inflammatory response + organization  Infarction contd Factors that Influence Development of an Infarct: i) Nature of the vascular supply Ii) Rate of development of occlusion Iii) The vulnerability of the given tissue to Hypoxia Iv) Blood oxygen content Some Definitions SVR (Systemic Vascular Resistance): the resistance the left ventricle must pump against to eject its volume. This resistance is created by the systemic arteries and arterioles. ↑ SVR: vasoconstriction, HPTN, cardiogenic shock ↓SVR: vasodilatation, septic shock  Definitions Definitions CO (Cardiac Output):The volume of blood ejected from the ventricle over 1 minute. Formula: Heart Rate x Stroke Volume = CO Normal Value 4- 6 L/ min ↓ CO: MI, shock, ↓HR, ↓SV, hypovolaemia, valvular heart dz ↑ CO: HPTN, pulmonary oedema, ↓Vascular resistance Definitions SV (Stroke volume):The volume of blood ejected by the ventricle with each heartbeat. Blood Pressure “ is the hydrostatic pressure exerted by blood on the walls of a blood vessel” BP = CO x SVR BP = blood pressure CO = cardiac output (HR x SV) SVR = systemic vascular resistance  SHOCK What is Shock? Is a condition where the perfusion of organs is too low to meet the metabolic demands and leads to anaerobic metabolism. In other words, blood flow (pressure) and oxygen delivery to the body is too low Occurs when the cardiovascular system fails to perfuse tissues adequately. Widespread impairment of cellular metabolism Can progress to organ failure and death If the blood pressure is low, then either the: CO is low or the SVR is low  Classification of Shock Classified by cause, principal pathophysiologic process or clinical manifestation: Cardiogenic Neurogenic Anaphylactic Septic Hypovolemic Cardiogenic Shock Due to heart failure from any cause Usually hard to treat As CO ↓, renal and hypothalamic adaptive responses maintain or ↑ BV BP is maintained by vasoconstriction Compensation keeps BP & CO fairly normal at cost of Myocardium hyperfunctioning eg myocardial infarction  Shock contd Hypovolemic Shock Caused by: Loss of whole blood Loss of plasma Loss of interstitial fluid Begins to develop when intravascular volume is decreased by 15 % Initially offset by compensatory mechanisms If fluid or blood loss is great or continuing, compensation will Fail Nutrient delivery impaired – cellular metabolism falls e.g burns  Shock contd Neurogenic Shock/Vasogenic shock Widespread, massive vasodilatation due to imbalance between parasympathetic and sympathetic stimulation of vascular smooth muscle. Parasympathetic over stimulation or sympathetic under stimulation Extreme persistent vasodilatation and neurogenic shock Creates relative hypovolaemia Blood volume not changed – space increased e.g brain damage, spinal anaesthesia Anaphylactic Shock Widespread hypersensitivity reaction Similar to neurogenic – massive vasodilatation Begins as allergic reaction Extravascular and intravascular effects Sudden onset  Shock contd Septic Shock Endpoint of a continuum of progressive dysfunction Bacteremia, sepsis, severe sepsis, septic shock Gram negative, gram positive bacteria, fungi High- mortality rate Begins with infection, toxins act as triggering agents Triggering molecules cause host to initiate a pro-inflammatory response. Compensatory anti-inflammatory response follows End – result mixed antagonistic response follows  Cellular Alterations in shock Many diverse signs and symptoms Cells function or malfunction at different stages of metabolic impairment Non specific subjective complaints Observable and measurable signs BP, CO, urinary output decreased (usually) Respiratory rate increased Variable indicators Dyspnoea, diaphoresis, altered sensorium  Pathophysiology of shock Impairment of Cellular Metabolism Final common pathway for all types of shock: Impairment of oxygen use Impairment of glucose use Impairment of oxygen use Cells not receiving or cant use oxygen Cardiogenic – CO is too low Hypovolemic – delivery impaired Neurogenic, anaphylactic and septic – vascular resistance – too low Septic – hypoxia made more worse by fever Impairment of Glucose Use Same reasons as inadequate oxygen delivery In addition with septic and anaphylactic glucose metabolism is increased or disrupted due to fever or bacteria. Cells switch to glycogen, protein & fat Loss of proteins – organ failure.  Stages of Shock i) Compensatory stage The CO is insufficient to meet the metabolic needs of the body but not low enough to produce symptoms Patient is alert, anxious, altered mental status, increased respiration Due to release of catecholamines ↑HR, ↑CO, vasoconstriction, BP within normal limit (WNL) or slight ↓  Stages of Shock contd ii) Progressive stage Unfavorable signs and symptoms become more favorable to you. Oliguria, ↓BP, ↑HR, system dysfunction begins If shock irreversible at this stage, death results iii) Irreversible Stage During this stage no matter what is done, the outcome is death There is myocardial depression There is massive capillary dilatation Blood remains pooled in the extremities Patient succumbs (dies)  Disseminated Intravascular Coagulation Sudden or insidious onset of widespread fibrin thrombi in the microcirculation More visible on microscopic rather than gross examination, can occur diffusely affection vital organs There is rapid consumption of platelets and coagulation proteins Fibrinolytic mechanisms activated resulting in bleeding May be seen as obstetric or advanced malignancy complications  DISSEMINATED INTRAVASCULAR COAGULATION (DIC) DIC is an acute, subacute, or chronic thrombohaemorrhagic disorder characterized by the excessive activation of coagulation, which leads to the formation of thrombi in the microvasculature of the body. It occurs as a secondary complication of many different disorders leading to consumption of platelets, fibrin, and coagulation factors and, secondarily, activation of fibrinolysis. Sometimes the coagulopathy is localized to a specific organ or tissue. DIC can present with signs and symptoms relating to the tissue hypoxia and infarction caused by the myriad microthrombi; with haemorrhage caused by the depletion of factors required for haemostasis and the activation of fibrinolytic mechanisms; or both. Classification: Acute Subacute Chronic  Etiology and Pathogenesis. DIC is not a primary disease. It is a coagulopathy that occurs secondary to a variety of clinical conditions. Clotting can be initiated by either of two pathways: (1) the extrinsic pathway, which is triggered by the release of tissue factor (“tissue thromboplastin”); and (2) the intrinsic pathway, which involves the activation of factor XII by surface contact with collagen or other negatively charged substances. Both pathways, through a series of intermediate steps, result in the generation of thrombin, which in turn converts fibrinogen to fibrin. At the site of injury, thrombin further augments local fibrin deposition by directly activating the intrinsic pathway and factors that inhibit fibrinolysis  Etiology and Pathogenesis contd. Once clotting is initiated, it is critically important that it be limited to the site of injury. Thrombin is converted to an anticoagulant through binding to thrombomodulin in the blood vessels. The thrombin-thrombomodulin complex activates protein C, which is an important inhibitor of two procoagulants, factor V and factor VIII. Other activated coagulation factors are removed from the circulation by the liver, and plasmin. DIC could result from pathologic activation of the extrinsic and/or intrinsic pathways of coagulation or the impairment of clot-inhibiting mechanisms. Two major mechanisms trigger DIC: (1) release of tissue factor or thromboplastic substances into the circulation, and (2) widespread injury to the endothelial cells. Thromboplastic substances can be derived from a variety of sources, such as the placenta in obstetric complications and the cytoplasmic granules of acute promyelocytic leukemia cells. Mucus released from certain adenocarcinomas can directly activate factor X, independent of factor VII.  Etiology and Pathogenesis contd. Endothelial injury can initiate DIC in several ways. Injuries that cause endothelial cell necrosis expose the subendothelial matrix, leading to the activation of platelets and both arms of the coagulation pathway. Subtle endothelial injuries can promote procoagulant activity e.gTNF and enhancing membrane expression of tissue factor. TNF induces endothelial cells to express tissue factor on their cell surfaces and to decrease the expression of thrombomodulin, shifting the checks and balances that govern hemostasis towards coagulation. In addition, TNF upregulates the expression of adhesion molecules on endothelial cells, thereby promoting the adhesion of leukocytes, which can damage endothelial cells by releasing reactive oxygen species and preformed proteases. Widespread endothelial injury may also be produced by deposition of antigen-antibody complexes (e.g., systemic lupus erythematosus), temperature extremes (e.g., heat stroke, burns), or microorganisms (e.g., meningococci, rickettsiae).  Etiology and Pathogenesis contd. DIC is most likely to be associated with obstetric complications, malignant neoplasms, sepsis, and major trauma. In bacterial infections endotoxins can injure endothelial cells and inhibit the expression of thrombomodulin directly or through production of TNF; stimulate the release of thromboplastins from inflammatory cells; and activate factor XII. Antigen-antibody complexes formed in response to the infection can activate the classical complement pathway, giving rise to complement fragments that secondarily activate both platelets and granulocytes. In massive trauma, extensive surgery, and severe burns, the major trigger is the release of tissue thromboplastins. In obstetric conditions, thromboplastins derived from the placenta, dead retained fetus, or amniotic fluid may enter the circulation. Hypoxia, acidosis, and shock, which often coexist in very ill patients, can also cause widespread endothelial injury, and supervening infections can complicate the problems further. Among cancers, acute promyelocytic leukemia and adenocarcinomas of the lung, pancreas, colon, and stomach are most frequently associated with DIC. The possible consequences of DIC are twofold: Firstly, there is widespread deposition of fibrin within the microcirculation leading to ischemia of the more severely affected or more vulnerable organs and a microangiopathic hemolytic anemia, which results from the fragmentation of red cells as they squeeze through the narrowed microvasculature. Secondly, the consumption of platelets and clotting factors and the activation of plasminogen leads to a hqemorrhagic diathesis. Plasmin not only cleaves fibrin, but it also digests factors V and VIII, thereby reducing their concentration further. In addition, fibrin degradation products resulting from fibrinolysis inhibit platelet aggregation, fibrin polymerization, and thrombin.  Morphology. Thrombi are most often found in the brain, heart, lungs, kidneys, adrenals, spleen, and liver, in decreasing order of frequency, but any tissue can be affected. Affected kidneys may have small thrombi in the glomeruli that evoke only reactive swelling of endothelial cells or, in severe cases, microinfarcts or even bilateral renal cortical necrosis. Numerous fibrin thrombi may be found in alveolar capillaries, sometimes associated with pulmonary edema and fibrin exudation, creating “hyaline membranes” reminiscent of acute respiratory distress syndrome. In the central nervous system, fibrin thrombi can cause microinfarcts, occasionally complicated by simultaneous hemorrhage. In meningococcemia, fibrin thrombi within the microcirculation of the adrenal cortex are the probable basis for the massive adrenal hemorrhages seen in Waterhouse-Friderichsen syndrome. Sheehan postpartum pituitary necrosis is a form of DIC complicating labor and delivery. In toxemia of pregnancy, the placenta exhibits widespread microthrombi, providing a plausible explanation for the premature atrophy of the cytotrophoblast and syncytiotrophoblast that is encountered in this condition.  Clinical Features. The onset can be fulminant, as in endotoxic shock or amniotic fluid embolism, or insidious and chronic, as in cases of carcinomatosis or retention of a dead fetus. Overall, about 50% of the affected are obstetric patients having complications of pregnancy. About 33% of the affected patients have carcinomatosis. The potential clinical presentations: microangiopathic hemolytic anemia; dyspnea, cyanosis, and respiratory failure; convulsions and coma; oliguria and acute renal failure; and sudden or progressive circulatory failure and shock. In general, acute DIC, associated with obstetric complications or major trauma is dominated by a bleeding diathesis, whereas chronic DIC, such as occurs in cancer patients, tends to present with thrombotic complications. The diagnosis is based on clinical observation and laboratory studies, including measurement of fibrinogen levels, platelets, the PT and PTT, and fibrin degradation products. The prognosis is highly variable and largely depends on the underlying disorder. The only definitive treatment is to remove or treat the inciting cause.  Tutorial Questions What is hemostasis? How is hemostasis regulated? Describe Virchow’s triad List some hypercoaguability states What is a thrombus? What is an emboli? Describe the fate of a thrombus? Describe air embolism How does each of the types of embolism occur? What is infarction? How is infarction classified? What are the factors that influence the development of an infarction? What does normal fluid homeostasis depend on? What are some complications that may arise due to a disruption in fluid homeostasis? Define edema What are some causes of edema?  Tutorial Questions What is hyperemia? What is congestion? What is hemorrhage? Describe the pathophysiology of the changes that occur in the evolution of a bruise Define the following terms: Petechiae Purpura Hematoma Ecchymoses List down differences between arteries and veins. What is blood pressure? What are the factors that control blood pressure? What is shock? What are the different types of shock? Briefly describe what happens in each of the different types How many stages of shock are there? Describe each stage of shock.  Tutorial Questions What are some physiological changes that occur during shock? What are some signs and symptoms of shock? What are some causes of shock? List the mortality rates of shock Tutorial Scenario J.T. 27 yr old was involved in a road traffic accident. He suffered a frontal contusion, fractured clavicle & ribs, extensive abrasions on his arms, sides, legs, back & buttocks. He was tachycardiac, hypotensive, unresponsive and ventilating poorly when admitted. He was placed on a ventilator and given IV fluids. He responded well to the fluids well to the fluids his BP , his BP ↑, and UO ↑. Based on his history and response, what sort of shock was he experiencing? Justify your answer Because of his many open wounds and invasive line, he is at a risk for sepsis and septic shock. What clinical findings would suggest that this complication has developed? THANK YOU FOR LISTENING