Sep 22(1).pdf

9/22/2023 Fig. 2‐20 Ecchymotic hemorrhages (ecchymoses), subcutis, rabbit. Ecchymoses result from moderate injury to endothelial cells in the capillary beds. (Courtesy Dr. D.A. Mosier, College of Veterinary Medicine, Kansas State University.) 1 Fig. 2‐19 Hemorrhage, anticoagulant (warfarin‐contai...

9/22/2023 Fig. 2‐20 Ecchymotic hemorrhages (ecchymoses), subcutis, rabbit. Ecchymoses result from moderate injury to endothelial cells in the capillary beds. (Courtesy Dr. D.A. Mosier, College of Veterinary Medicine, Kansas State University.) 1 Fig. 2‐19 Hemorrhage, anticoagulant (warfarin‐containing) rodenticide toxicosis, skin and subcutis, medial aspect of the right hindleg, dog. There is a large area of extensive hemorrhage in the subcutis. This lesion was attributed to decreased production of coagulation factors II, VII, IX, and X and proteins C and S resulting from a deficiency of vitamin K induced by warfarin. (Courtesy Dr. D.A. Mosier, College of Veterinary Medicine, Kansas State University.) Fig. 2‐21 Suffusive hemorrhage, serosa, stomach, dog. Suffusive hemorrhage results from severe injury to endothelial cells in the capillary beds. (Courtesy Dr. D.A. Mosier, College of Veterinary Medicine, Kansas State University.) 2 Hemostasis and Thrombosis • Normal hemostasis is a consequence of tightly regulated processes that maintain blood in a fluid, clot‐free state in normal vessels while inducing the rapid formation of a localized hemostatic plug at the site of vascular injury • Thrombosis, the pathologic form of hemostasis, involves blood clot (thrombus) formation in uninjured vessels or thrombotic occlusion of a vessel after minor injury • Both involve 3 components: the vascular wall, platelets, and the coagulation cascade 3 1 9/22/2023 The cascade happens but then a feedback loop happens to break down fibrin to prevent excessive clotting 4 Normal Hemostasis • After injury, local neurohumoral factors induce transient vasoconstriction • Reflex neurogenic responses • Endothelin (endothelium‐derived vasoconstrictor) • Endothelial injury exposes highly thrombogenic subendothelial ECM, allowing platelets to adhere and be activated • Activated platelets can undergo conformational change and release granules • Tissue factor (aka factor III and thromboplastin) is also exposed at the site of injury • a pro‐coagulant glycoprotein synthesized by the endothelium • Acts with factor VII as major in vivo pathway to activate the s coagulation cascade and generate thrombin • Thrombin cleaves fibrinogen into insoluble fibrin and recruits more platelets and stimulates their granule release  secondary hemostasis • Permanent plug forms and grows  stimulates tissue plasminogen activator to limit the clot 5 Platelets • After vessel injury, platelets encounter ECM constituents and other proteins not normally exposed when endothelium in intact • Platelets adhere to subendothelial collagen by means of vWF acting as a bridge between platelet surface receptors (GpIb) and exposed collagen If aberration in receptor • ligand process, then… von Willebrand disease….Lack of clotting • Contact with these ECM constituents causes platelets to undergo three reactions: adhesion and shape change, secretion, and aggregation 6 Platelets are fragments with no nucleus of megakaryocytes vWBF is a bridge for platelets to adhere to surface receptors GPLB and exposed collagen 2 9/22/2023 Platelet Activation and Aggregation • Platelets possess alpha‐granules (contain P‐selectin) and dense (delta) granules (contain calcium and ADP) • • • • After adhesion to ECM, platelets become activated  secretion Calcium is cofactor required by coagulation proteins ADP is a potent mediator of further platelet aggregation AND promotes further degranulation Platelet activation increases plasmalemma surface expression of phospholipid complexes • Provide binding site for calcium and coagulation factors • Activated platelets synthesize thromboxane A2 • ADP and TXA2 together drive an autocatalytic process resulting in formation of the primary hemostatic plug • Granules in platelets which contain prothrombotic, pro coagulant etc. TXA2 increases platelet aggregation and induces vasoconstriction 7 Granules contain pro coagulant proteins Thrombosis • There are three principal influences on thrombus formation Vitreotriad 8 Thrombosis • Endothelial injury in itself can lead to thrombosis • Loss of endothelium leads to exposure of ECM, adhesion of platelets, release of tissue factor, depletion of PGI2, and plasminogen activators • Stasis or turbulence in blood flow • Disrupt laminar flow and bring platelets into contact with endothelium, prevent dilution of activated clotting factors, retard inflow of clotting factor inhibitors, and promote endothelial cell activation, resulting in local thrombi • Turbulence contributes to arterial and cardiac thrombosis by causing endothelial injury • Stasis is a major contributor to venous thrombi • Aneurysms are abnormal aortic and arterial dilations; these create local stasis and thrombosis • Blood hypercoagulability • An alteration in coagulation pathways that predisposes to thrombosis • Primary (genetic) or secondary (acquired) disorders 9 Blood turbulence, Damage to endothelial, And alteration in coagulation pathways 3 9/22/2023 Thrombus can form anywhere. Arterial and cardiac thrombus begin at the site of endothelial injury or turbulence Venous thrombus occur at site of stasis or occlusion or emboli, could be parasitic emboli too. Morphologic Features of Thrombi • Thrombi can develop anywhere in the cardiovascular system • Chambers of heart, on valves, in arteries, veins or capillaries • Arterial or cardiac thrombi typically begin at sites of endothelial injury or turbulence • Venous thrombi typically occur at sites of stasis • Thrombi are focally attached to the underlying vascular surface and tend to propagate toward the heart • Propagating portion often is less well attached and therefore prone to break or fragment  embolus • Thrombi can have grossly and microscopically apparent laminations, aka lines of Zahn • represent layers of pale platelets and fibrin alternating with darker layers of erythrocytes • Represent thrombosis in the face of flowing blood, i.e. antemortem • Thrombi on heart valves are called vegetations • Bacteria or fungi circulating in the blood can seed the edges of damaged heart valves leading to large thrombotic masses, condition termed vegetative valvular endocarditis 10 Arterial versus Venous Thrombosis Arterial thrombosis • Frequently occlusive • Produced by platelet and coagulation activation • Occurs at sites of endothelial or vessel injury. • Can embolize and cause downstream tissue infarction, especially brain, kidneys and spleen Tissue infarct white in color, blood stoppage, ischemic damage and necrosis, grossly it looks pale Tissue infarct ischemic injury) Venous thrombosis More occlusive • aka phlebothrombosis • Invariably occlusive. Stopping return of blood to main system • Form in segments where there is sluggish venous circulation • Contain abundant RBCs, therefore are red, called red or stasis thrombi Red in color because of pooling of blood in p articulate organ • Veins of lower extremities most commonly affected • Cause congestion and edema in vascular beds distal to an obstruction, or can embolize to the lung Pulmonary thrombosis. Mainly takes place because of where its going. Whenever vessels are very tortuous, then in those places the venous thrombus will get lodges, its pressure dependent. Veins of lower extremities are most prone. Causes edema 11 Deep Vein thrombus can emboli in lung because the blood goes from right side to the pulmonary artery to lung, so emboli get lodged in lung Artery which has arterial thrombus • Fig. 2‐27 Arterial thrombus, lines of Zahn, cranial mesenteric artery, horse. Cardiac and larger arterial thrombi often have a laminated appearance characterized by alternating layers of platelets (white‐gray) and fibrin (white) intermixed with erythrocytes and leukocytes (lines of Zahn). These lines are the result of rapid blood flow in the heart and arteries/arterioles that favors the deposition of fibrin and platelets and the exclusion of erythrocytes from the thrombus. This horse had verminous arteritis (Strongylus vulgaris fourth stage larvae) in the affected artery. (Courtesy Dr. P.N. Nation, University of Alberta; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia.) 12 4 9/22/2023 Bone marrow Makes platelets through Megakaryocyte cells Megakaryocyte Hematopoietic cells Pulmonary embolism originating from bone marrow because of the adipocytes from marrow fat bone marrow embolus because of adipocytes and cells similar to hematopoietic Cells from bone marrow. 13 Lamination of the thrombus 14 Eventually what will happen is you will see small cavernous, recanulization of that thrombus, lined by new endothelial cells. Tunica intimate completely lost Elastin stains black by van. Hesin Stain 15 This is an artery and how we know this is because of the smooth muscle Elastin is present in large arteries Von geison stain stains elastin BLACK 5 9/22/2023 16 Lowe extremity deep vein thrombosis, This is lung. Lodges in pulmonary. Saddle thrombosis Arterial infarct Fig. 2‐38 Infarction due to arterial obstruction. Arterial obstruction results in loss of blood flow to downstream tissue, resulting in abrupt coagulative necrosis. The amount of necrosis depends on factors such as the type and prior health of the tissue affected, its metabolic rate (neurons versus myocytes and fibroblasts), and amount of collateral circulation or alternative blood supply. 1, Normal arterial flow; 2, arterial flow obstructed by an arterial thrombus. (Courtesy Dr. D.A. Mosier and L. Schooley, College of Veterinary Medicine, Kansas State University.) Fig. 2-40 Acute pale infarcts, kidney, rabbit. Multiple, pale white to tan pyramidal-shaped infarcts extend from the renal cortex to the medulla. The infarcts bulge above the capsular surface (center top), indicative of acute cell swelling. The glistening areas on the right are highlights from the photographic lamps. (Courtesy Dr. M.D. McGavin, College of Veterinary Medicine, University of Tennessee.) 17 Venous Infarct Fig. 2-41 Infarction due to venous obstruction. Venous obstruction results in stagnation of blood flow and reduction or loss of venous return. There is progressive ischemia and ultimately coagulative necrosis of the tissue upstream of the site of vessel obstruction. The amount of necrosis depends on factors such as the type and prior health of the tissue affected, metabolic rate, and amount of collateral circulation or alternative blood supply. 1, Venous return to a larger vein (note the valve) obstructed by a mass (M); 2, normal venous return to a larger vein. (Courtesy Dr. D.A. Mosier and L. Schooley, College of Veterinary Medicine, Kansas State University.) Fig. 2‐39 Acute hemorrhagic infarct, kidney, dog. There is a focal wedge‐shaped hemorrhagic area of cortical necrosis. The capsular surface of the infarct bulges above that of the adjacent normal kidney, indicating acute cell swelling and hemorrhage. (Courtesy Dr. W. Crowell, College of Veterinary Medicine, The University of Georgia; and Noah’s Arkive, College of Veterinary Medicine, The University of Georgia.) 18 6 9/22/2023 Venous infarct 19 Arterial infarct Normal color 20 • Fig. 2‐42 Venous infarction, small intestinal volvulus, pig. Note the intensely congested loops of small intestine undergoing early venous infarction. The veins have been compressed by a volvulus that has compressed the veins but not the arteries, thus preventing the venous return. If the volvulus had rotated further, it would also have compressed the arteries. (Courtesy Dr. D.A. Mosier, College of Veterinary Medicine, Kansas State University.) 21 7 9/22/2023 Fate of the Thrombosis • Propagation – thrombi accumulate platelets and fibrin causing vessel obstruction • Embolization‐ thrombi dislodge or fragment and are transported elsewhere in the vasculature • Dissolution ‐ thrombi are removed by fibrinolytic activity • Organization and recanalization – thrombi induce inflammation and fibrosis (organization) and can eventually recanalize (re‐establish some flow), or be incorporated into a thickened vessel wall 22 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 • 99% are part of a dislodged thrombus, referred to as thromboembolism • Rare forms of emboli include fat droplets, air or nitrogen bubbles, or atherosclerotic debris (cholesterol emboli) • Issue is that emboli inevitably lodge in vessels too small to permit further passage  partial or complete vascular occlusion  ischemic necrosis (infarction) of downstream tissues • Clinical outcomes depend on the anatomic location where emboli lodge and extent of regional ischemia 23 Types of Thromboembolism • Pulmonary Thromboembolism • In >95% of cases, venous emboli originate from deep leg vein thrombi (above the level of the knee) • most are clinically silent because they are small and eventually incorporate into the vascular wall • Sudden death, right ventricular failure, (cor pulmonare) or cardiovascular collapse occurs when 60% of pulmonary circulation is obstructed • this can occur when an embolus is large enough to occlude a main pulmonary artery • Can cause pulmonary hypertension with right ventricular failure Thrombus that impacts across a bifurcation is known as a saddle thrombus 24 8 9/22/2023 Intracardial mural thrombi, thrombi are originate from endocardial wall • Systemic Thromboembolism Has to do with left side (arterial circulation side) • refers to embolism in the arterial circulation • Most (80%) arise from intracardial mural thrombi, in particular left ventricular wall infarcts • Remainder originate from aortic aneurysms, thrombi on ulcerated artherosclerotic plaques, or fragmentation of valvular vegetations • Major sites for arteriolar embolism are lower extremities and brain • Air Embolism • May occur during obsteric procedures or chest wall injury • Decompression sickness Pleura will rupture. • Amniotic Fluid Embolism • Complication of labor and immediate postpartum period • Caused by entry of amniotic fluid into the maternal circulation via tear in the placental membranes and rupture of uterine veins 25 • Fat Embolism • Microscopic fat globules found after long bone fracture or soft tissue trauma…in fewer than 10% of patients • Fat enters circulation as a result of rupture of bone marrow sinusoids • Fat microemboli occlude pulmonary and cerebral microvasculature • Fat embolism syndrome characterized by pulmonary insufficiency, neurologic syndromes, anemia and thrombocytopenia…fatal in about 10% of cases 26 Infarction • An infarct is an area of ischemic necrosis caused by occlusion of either the arterial supply or venous drainage in a particular tissue • Infarcts are classified on the basis of their color (reflecting the amount of hemorrhage) and the presence or absence of microbial infection • Red (hemorrhagic) or white (anemic) • Septic (microbes present) or bland (microbes absent) • All infarcts tend to be wedge‐shaped, with the occluded vessel at the apex and the periphery of the organ forming the base 27 9 9/22/2023 • Ischemic coagulative necrosis is the dominant histologic characteristic of infarction • Exception: brain, where ischemic injury results in liquefactive necrosis • Inflammatory response develops at the margins of infarcts within a few hours • Most often infarcts ultimately replaced by scar (fibrous tissue) • Septic infarctions occur when bacterial vegetations from a heart valve embolize or microbes seed an area of necrotic tissue • Inflammatory response converts the initial infarct into an abscess 28 Factors that Influence Development of an Infarct • Nature of vascular supply • availability of alternate blood supply, such as in lungs and liver, will determine whether occlusion will cause damage • Rate of development of the occlusion • Slowly developing occlusions are less likely to cause infarction because they provide time for the development of alternative perfusion pathways (i.e. atherosclerosis in coronary artery) • Vulnerability to hypoxia • Neurons undergo irreversible damage if deprived of blood for 3‐4 min • Myocardial cells die after 20‐30 min • Fibroblasts viable after hours of ischemia • Oxygen content of the blood • Partial flow obstruction of a small vessel in an anemic or cyanotic patient may lead to infarction, whereas would be without effect under normal oxygen tension 29 Shock Either due to reduced cardiac output or reduced circulating blood volume • Shock is the final common pathway for a number of potentially lethal events including… • severe hemorrhage extensive trauma or burns, extensive myocardial infarction, massive pulmonary embolism, microbial sepsis • Shock gives rise to systemic hypoperfusion • Key pathophysiologic event regardless of cause • Results from either reduced cardiac output or reduced circulating blood volume Brain and heart are most sensitive • End results of shock are hypotension, impaired tissue perfusion (i.e. tissue hypoperfusion), and cellular hypoxia Systemic hypoperfusion. Hypotension, impaired tissue perfusion which leads to then hypoxia 30 10 9/22/2023 Hypovolemic shock, Cardio genie shock Septic shock - gram negative microbe causing endotoxic shock Categories of Shock • 3 general categories of shock • Cardiogenic shock results from failure of cardiac pump • Myocardial infarction, ventricular arrythmias, outflow obstruction • Hypovolemic shock results from loss of blood or plasma volume • Hemorrhage, extensive burns • Septic shock is caused by microbial infection • Most commonly gram‐negative infections (endotoxic shock) • Less common are neurogenic and anaphylactic shock • Neurogenic shock results from loss of vascular tone leading to peripheral blood pooling You need neurogenic system for contraction and rhythm circulation in circulatory system. If any thing occurs in the subdural space, loss of vascular tone • Anaphylactic shock results from systemic vasodilation and increased vascular permeability mediated by IgE hypersensitivity reaction Immune system will either caused localized vasoconstriction or systemic/extensive Vasodilation 31 Morphology of Shock • Cellular and tissue changes induced by shock are essentially those of hypoxic injury due to hypoperfusion and thrombosis of microvasculature • Shock is characterized by failure of many organ systems (multiorgan system failure); morphologic changes may appear in any tissue, particularly the brain, heart, kidneys, adrenal glands and GI tract • Septic shock results from host innate immune response to bacterial or fungal cell molecules; mediated by TLRs causing widespread (i.e. systemic) production of cytokines, TNF and IL‐1, leading to system‐wide endothelial and leukocyte activation • Clinical triad of septic shock is hypotension, DIC and Disseminated intravascular coagulopathy metabolic disturbances 32 Stages of Shock • Nonprogressive stage: the initial stage during which reflex compensatory mechanisms are activated and perfusion of vital organs is maintained • Progressive stage: characterized by tissue hypoperfusion and onset of worsening circulatory and metabolic imbalances • Irreversible stage: occurs after the body has incurred cellular and tissue injury so severe that even if the hemodynamic defects are corrected, survival is not possible 33 11