2nd Year Pathology 2010 Vascular Disturbances III Infarction & Shock

2nd Year Pathology 2010 Infarction

2nd Year Pathology 2010 Infarction Tissue necrosis due to ischaemia  vascular insufficiency of any cause  usually arterial occlusion due to thrombosis/embolism Mainly due to oxygen deficiency, but toxin accumulation & reperfusion injury may contribute Number of determining factors  Size of vessel and size of vascular territory  Partial / total vascular occlusion  Duration of ischaemia

2nd Year Pathology 2010 Appearance of Infarct  Wedge-shaped  Occluded vessel at apex  Periphery of organ forms base  If extends to serosal surface, often overlying fibrinous exudate  Lateral margins blurred due to collateral blood supply

2nd Year Pathology 2010 Appearance of Infarct ARTERY OCCLUSION NORMAL TISSUE INFARCTED TISSUE SURFACE FIBRINOUS EXUDATE ILL-DEFINED INFARCT BORDERS

2nd Year Pathology 2010 Types of Infarct Red (haemorrhagic) infarcts 1. Venous occlusion/congestion e.g. torsion 2. Loose tissues where haemorrhage can occur and blood can collect in infarcted zone e.g. lung 3. Tissues with dual blood supply e.g. lung small intestine (permitting blood flow from unobstructed vessel into infarcted zone – note flow is insufficient to rescue ischaemia) 4. Tissues that were previously congested due to sluggish venous outflow 5. When flow is re-established e.g. fragmentation of an occlusive embolus, angioplasty White infarcts 1. arterial occlusion 2. solid tissues, where haemorrhage limited e.g. spleen, heart, kidney

2nd Year Pathology 2010 Types of Infarct Red pulmonary infarcts - dual pulmonary / bronchial arterial supply

2nd Year Pathology 2010 Types of Infarct White splenic infarct

2nd Year Pathology 2010 Event Sequence 1. Coagulative necrosis 2. Infiltration by neutrophils 3. Infiltration by macrophages 4. Phagocytosis of debris 5. Granulation tissue formation 6. Scar formation

2nd Year Pathology 2010 Event Sequence Day

2nd Year Pathology 2010 TimeMicroscopic FeaturesGross Features 0 – 4 hrNone 4 – 12 hrEarly coagulation necrosis (nucleus: pyknosis, cytoplasm: eosinophilia) None 12 – 24 hrFurther necrosis, haemorrhage, early neutrophil infiltrate Dark mottling 1 – 3 daysMarked neutrophil infiltrate and necrosis Mottled with yellow-tan necrotic centre 3 – 7 daysEarly phagocytosis of dead cells by macrophages (at border) Hyperaemic border, central yellow-tan softening 7 – 10 daysWell-developed phagocytosis, early granulation tissue formation Maximal yellow-tan softening, depressed red-tan margins 10 – 14 daysWell-developed granulation tissue, early collagen deposition Red-gray depressed infarct borders 2 – 8 wkIncreased collagen deposition, decreased cellularity Grey-white scar progresses from border toward centre > 2 monthsAcellular collagenous scarDense gray scar

2nd Year Pathology 2010 Infarct, day 0 Fibre eosinophilia & contraction band necrosis

2nd Year Pathology 2010 Infarct, day 1 Haemorrhage, necrosis and early neutrophil infiltrate

2nd Year Pathology 2010 Infarct, day 3 Myocyte necrosis, pyknosis and marked neutrophil infiltrate

2nd Year Pathology 2010 Infarct, day 7 Yellow necrotic infarct with hyperaemic border

2nd Year Pathology 2010 Infarct, day 10 Granulation tissue after macrophage phagocytosis of infarcted cells

2nd Year Pathology 2010 Infarct, day 90+ Subendocardial acellular fibrous scar

2nd Year Pathology 2010 Infarct Development Dependent on a number of factors  Nature of vascular supply Dual supply e.g. lungs, liver End arteries e.g. kidneys, spleen  Rate of vascular occlusion Time for development of collateral circulation  Vulnerability to hypoxia Neurons – 2-3mins, Myocardium – 20-30mins, Fibroblasts – hours.  Oxygen content of blood Anaemia, cyanosis, congestive heart failure  Can result in infarction due to otherwise inconsequential blockage  Size of vessel and size of vascular territory  Partial / total vascular occlusion  Duration of ischaemia

2nd Year Pathology 2010 Reperfusion Injury Possible effects of re-establishing blood flow:  prevention of all necrosis  salvage of reversibly injured cells  accentuation of damage to irreversibly injured cells  new cellular damage Latter two constitute reperfusion injury  Accentuated or new damage due to re-establishing blood flow  Many effects of ischaemic injury only seen when perfusion re-established

2nd Year Pathology 2010 Reperfusion Injury Can result in accelerated transition through stages of infarct development Timing of infarcts unreliable post reperfusion Inevitable if reperfusion occurs after optimum salvage time e.g. usually 6 hours after myocardial infarct Characterised histologically by:  Marked haemorrhage  Marked contraction band necrosis

2nd Year Pathology 2010 Reperfusion Injury Causes:  delivery of oxygen and calcium ions to damaged tissue  interior of cells with damaged cell membranes exposed to high Ca ++ conc  cell lysis  generation of oxygen-dependent free radicals by damaged cells and phagocytes  cell lysis  accentuation of O2-dependent damage Anti-oxidants have only small effect on tissue loss  Acceleration of damage to irreversibly damaged cells more than new cellular damage

2nd Year Pathology 2010 Shock

2nd Year Pathology 2010 Shock (cardiovascular collapse) Final Common Pathway for a umber of potentially lethal clinical events:  Severe Haemorrhage  Burns  Trauma  Large MI  (massive) Pulmonary Embolism  Microbial Sepsis

2nd Year Pathology 2010 Shock (cardiovascular collapse) Circulatory failure resulting in inadequate tissue perfusion (systemic hypoperfusion) Results in:  hypotension  impaired tissue perfusion  cellular hypoxia  reversible cellular injury  irreversible cell injury and cell death

2nd Year Pathology 2010 Types of Shock Cardiogenic - due to myocardial pump failure  Intrinsic damage (MI)  Ventricular arrhythmias  Extrinsic compression (Tamponade)  Outflow obstruction (e.g. pulmonary embolism) Hypovolaemic - due to loss of blood or plasma volume  Haemorrhage  Fluid Loss from severe burns  Trauma

2nd Year Pathology 2010 Septic  Systemic microbial infection Neurogenic  Loss of vascular tone – spinal cord injury Anaphylactic  Generalised IgE hypersensitivity response- systemic vasodilation - due to reduction in effective circulating blood volume peripheral pooling secondary to vasodilation and leakage of fluid due to increased vascular permeability

2nd Year Pathology 2010 Types of Shock Cardiogenic  myocardial pump failure  e.g. myocardial infarction, ventricular rupture, ventricular arrhythmia, cardiac tamponade, pulmonary embolism Hypovolaemic  loss of blood or plasma volume  e.g. haemorrhage, trauma, burns, vomiting, diarrhoea

2nd Year Pathology 2010 Types of Shock Neurogenic shock  peripheral pooling of blood due to loss of vascular tone  e.g. anaesthetic accident / spinal cord injury Anaphylactic shock  systemic IgE-mediated hypersensitivity reaction to allergens e.g. bee stings, peanut  release of mast cell mediators  systemic vasodilation and increased vascular permeability

2nd Year Pathology 2010 Types of Shock Septic shock  overwhelming microbial infection  gram negative sepsis due to lipopolysaccharide (LPS / endotoxin) in walls  gram-positive / fungal septicaemia due to molecules similar to LPS in walls  Super-antigen release

2nd Year Pathology 2010 Septic Shock Usually due to lipopolysaccharide (LPS/endotoxin) in walls of gram negative bacteria LPS consists of fatty acid core and complex carbohydrate coat Similar molecules in walls of gram positive bacteria or fungi results in  endothelial damage  complement activation  activation of macrophages with cytokine release

2nd Year Pathology 2010

Event Sequence Low doses : Local effects of LPS & primary mediators (IL-1, TNF)  Complement activation by LPS  Monocyte/macrophage activation by LPS binding to surface receptors production of low doses of IL- 1 and TNF  Endothelial cell activation by IL-1 & TNF production of IL-6 & 8 by endothelium increased adhesion molecule expression  Recruitment of inflammatory cells and cytokine cascade

2nd Year Pathology 2010 Event Sequence Intermediate doses: Local effects of LPS & secondary mediators (NO, PAF) Systemic effects of primary mediators (IL-1, TNF)  Endothelial cell injury by LPS triggering of coagulation cascade increased vascular permeability production of secondary mediators by endothelium  Local vasodilation due to secondary mediators: nitric oxide, platelet activating factor  Systemic effects of IL-1 and TNF Fever Acute-phase reactant production (CRP, fibrinogen)

2nd Year Pathology 2010 Event Sequence High doses Systemic effects of LPS, primary & secondary mediators  Widespread endothelial cell injury (LPS, cytokines) Acute respiratory distress syndrome  Widespread activation of coagulation (LPS, cytokines) Disseminated intravascular coagulation  Peripheral vasodilation, decreased cardiac contractility (NO) Hypotension Multiorgan failure due to hypoperfusion

2nd Year Pathology 2010 Multiorgan Failure Multiple organ damage due to ischaemia secondary to hypoperfusion brain: ischaemic encephalopathy heart: subendocardial infarcts kidney: acute tubular necrosis GIT: haemorrhagic enteropathy / ischaemia liver: fatty change / centrilobular haemorrhagic necrosis ARDS in lungs commonly present concurrently Due to microvascular injury, not ischaemia

2nd Year Pathology 2010 Stages of Shock  Nonprogressive phase  Reflex compensatory mechanisms maintain perfusion of vital organs  Tachycardia, peripheral vasoconstriction (pale cold clammy skin), renal conservation of fluid (anuria )  Progressive phase  Tissue hypoperfusion & metabolic imbalance  Development of acidosis  Due to anaerobic glycolysis and renal failure  Causes arteriolar dilatation and peripheral pooling of blood  Worsens hypotension and exacerbates tissue ischaemia  Irreversible phase  Irreversible cellular and tissue injury  No response even if haemodynamic defects corrected

2nd Year Pathology 2010 Consequences of Shock Pink hyaline membranes lining alveolar spaces in ARDS

2nd Year Pathology 2010 Consequences of Shock Normal glomerulus and tubules ATN – swollen, sloughed and flattened regenerating tubular epithelium, normal glomerulus

2nd Year Pathology 2010 Consequences of Shock Prognosis varies with cause and duration  If circulatory disturbance corrected during nonprogressive phase  full recovery  If progress to irreversible phase  high mortality Hypovolaemic shock  > 80 – 90% survival in young healthy adults ( % mortality) Cardiogenic shock due to MI / Septic shock  up to 75% mortality even with appropriate management

2nd Year Pathology 2010 Summary Infarction  Definition  Infarct Types  Timing of Infarcts  Reperfusion injury Shock  Types of shock and aetiology  Stages of shock  Consequences