general pathology (denf 2701) fall, 2005 topic: hemodynamic disorders, thrombosis, shock fall, 2005;...

General Pathology (DENF 2701)General Pathology (DENF 2701)Fall, 2005Fall, 2005

Topic: Hemodynamic Disorders, Thrombosis, ShockTopic: Hemodynamic Disorders, Thrombosis, Shock

Fall, 2005; Mondays & Wednesdays, 11:00-11:50 am; Room 132Fall, 2005; Mondays & Wednesdays, 11:00-11:50 am; Room 132Course Director: Dr. Jerry BouquotCourse Director: Dr. Jerry Bouquot

Room 3.094B; 713-500-4420; 713-745-2330 (cell)Room 3.094B; 713-500-4420; 713-745-2330 (cell)

Blood Flow ProblemsBlood Flow Problems HemorrhageHemorrhage (rupture of vessel) (rupture of vessel) EdemaEdema (excess interstitial fluid) (excess interstitial fluid) HemophiliaHemophilia (diminished clotting capacity) (diminished clotting capacity) ThrombosisThrombosis (vessel blockage from local clot) (vessel blockage from local clot) EmbolismEmbolism (vessel blockage from something upstream) (vessel blockage from something upstream) IschemiaIschemia (diminished local blood flow) (diminished local blood flow) InfarctionInfarction (complete blockage of local blood flow) (complete blockage of local blood flow) ShockShock (generalized lack of tissue perfusion) (generalized lack of tissue perfusion)

HemorrhageHemorrhage

Ruptured vessels, usually from trauma or infection or atherosclerosis

– Can lose 20% of blood volume (more if slow lose) with little effect

on health

– Great blood loss >> hypovolemic shock (hemorrhagic shock)

Hemorrhagic diathesis: tendency to bleed with minor injury

Hematoma: localized pool of blood outside vessels (e.g. bruise)

– If severe: death from blood loss (e.g. dissecting aortic aneurysm)

Hemorrhage (Haemorrhage) Hemorrhage (Haemorrhage) Rupture of Blood VesselsRupture of Blood Vessels

TermTerm DescriptionDescription Main Cause(s)Main Cause(s)

HematomaHematoma Blood in tissuesBlood in tissues Trauma, vessel diseaseTrauma, vessel disease

HemopericardiumHemopericardium Blood in pericardiumBlood in pericardium Rupture of aorta, heartRupture of aorta, heart

HemothoraxHemothorax Blood in pleural Blood in pleural cavitycavity Trauma, aortic ruptureTrauma, aortic rupture

HemoperitoneumHemoperitoneum Blood in peritoneal Blood in peritoneal cavitycavity Rupture of aorta, spleen, liverRupture of aorta, spleen, liver

HemarthrosisHemarthrosis Blood in joint spaceBlood in joint space Bleeding disorder, traumaBleeding disorder, trauma

ExsanguinationExsanguinationExtravasationExtravasation

Post-Anesthetic HematomaPost-Anesthetic Hematoma HemopericardiumHemopericardium

Hemorrhage (Haemorrhage) Hemorrhage (Haemorrhage) Rupture of Blood VesselsRupture of Blood Vessels

TermTerm DescriptionDescription Main Cause(s)Main Cause(s)

PurpuraPurpura(2-10mm)(2-10mm)

Focal hemorrhage Focal hemorrhage (submucosal, etc.)(submucosal, etc.) Vessel fragilityVessel fragility

PetechiaePetechiae(1-2 mm)(1-2 mm)

Focal hemorrhageFocal hemorrhage

(submucosal, etc.)(submucosal, etc.)

Increased pressure, small Increased pressure, small vessel disease, abnormal vessel disease, abnormal clotting diseaseclotting disease

EcchymosisEcchymosis Widespread surface Widespread surface petechiaepetechiae Same as aboveSame as above

PurpuraPurpuraColonic PetechiaeColonic Petechiae

Telangiectasia(Blood in Vessels)

ThrombocytopeniaThrombocytopeniaIdiopathic Thrombocytopenic PurpuraIdiopathic Thrombocytopenic Purpura


Petechiae: 1-2 mm bleeds in skin, mucous membranes or serosal surfaces

– Usually from increased intravascular pressure, low platelet counts

(thrombocytopenia), defective platelet function, clotting factor

deficiencies Purpuras: 3-5 mm bleeds beneath surfaces

– Same causes as petechiae, but also trauma, vessel inflammation

(vasculitis), increased vascular fragility Ecchymosis: 1-2 cm subcutaneous or submucosal hemorrhages

(bruise)

– Color change: red/blue (hemoglobin) >> blue/green (bilirubin) >>

golden brown (hemosiderin) Hemothorax (chest), hemopericardium (heart), hemoperitoneum

(gut), hemarthrosis (joints) Problems: jaundice; iron deficiency anemia

Hematoma/Ecchymosis/Petechiae/PurpuraHematoma/Ecchymosis/Petechiae/PurpuraSubmucosal Hemorrhage; Extravasation of ErythrocytesSubmucosal Hemorrhage; Extravasation of Erythrocytes

© Photos: Dr. Jerry Bouquot, The Maxillofacial Center, Morgantown, West Virginia

Acute trauma from bite/HematomaAcute trauma from bite/Hematoma Cough (viral) hematomaCough (viral) hematoma

Fellatio trauma/PetechiaeFellatio trauma/PetechiaePost-anesthetic hematomaPost-anesthetic hematoma

Hereditary Hereditary Hemorrhagic Hemorrhagic

TelangiectasiaTelangiectasiaOsler-Weber-Rendu SyndromeOsler-Weber-Rendu Syndrome

Autosomal dominant HHT1: mutation, endoglin gene, chromosome 9 HHT2: mutation, ALK-1 (activin receptor-like kinase-1), chromosome 9 Prevalence: 10/100,000 population Poor protein production for endothelium Numerous vascular 1-2 mm hamartomas, especially in mouth (lips, tongue, buccal) Clinical: epistaxis; blanching of telangiectasias GI bleeds, urinary, ocular vessels Clinical: brain lesions tend to abscess; thromboemboli CREST syndrome (Acrosclerosis): Calcinosis cutis, Raynaud’s phenomenon, Esophageal dysfunction, Sclerodactyly, Telangiectasia


Ruptured vessels, usually from trauma or infection or atherosclerosis

– Can lose 20% of blood volume (more if slow lose) with little effect

on health

– Great blood loss >> hypovolemic shock (hemorrhagic shock)

Hemorrhagic diathesis: tendency to bleed with minor injury

Hematoma: localized pool of blood outside vessels (e.g. bruise)

– If severe: death from blood loss (e.g. dissecting aortic aneurysm)

Fluid Balance Across Capillary WallsFluid Balance Across Capillary WallsFactors InvolvedFactors Involved

Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7 th ed., Saunders, Philadelphia, 2003.

Edema (Oedema):

accumulation of excess fluid in

tissues

Interstitial Fluid

How? Hydrostatic pressure up: -- venous obstruction -- heart failure Osmotic pressure down: -- hypoproteinemia Vascular permeability up: -- allergy (histamine) -- acute inflammation

Two major types of edema: Pulmonary edema -- Left sided heart failure Subcutaneous edema -- Right sided heart failure

EdemaEdemaIncreased Fluid in Interstitial SpacesIncreased Fluid in Interstitial Spaces

60% of body weight is water: 1/3 = extracellular (interstitial fluid); 5% = blood plasma

With hemodynamic problems: transudate (protein-poor; specific gravity below 1.012)

With inflammation: exudate (protein-rich; specific gravity above 1.020)

Clinical subtypes: – Hydrothorax (chest dropsy) – Hydropericardium – Hydroperitoneum (Ascites) – Anasarca (severe, generalized edema with subcutaneous swelling)

GingivitisGingivitis


Increased hydrostatic pressure:

– Impaired venous return

– Congestive heart failure (poor right ventricular function)

– Constrictive pericarditis

– Ascites (peritoneal dropsy; e.g. from liver cirrhosis)

– Venous obstruction or compression (thrombosis, external pressure,

dependency of lower limbs)

Arteriolar dilation (heat; neurohumoral dysregulation)

Reduced plasma osmotic pressure (hypoproteinemia)

– Nephrotic syndrome (protein-losing glomerulopathies)

– Liver cirrhosis (ascites)

– Malnutrition

– Protein-losing gastroenteropathy


Lymphatic obstruction

– Interstitial fluids are removed via lymphatic drainage, to thoracic duct

and left subclavian vein

– Inflammation, neoplasm, surgery, irradiation

Sodium retention (water follows sodium)

– Excess salt intake with renal insufficiency

– Increased tubular reabsorption of sodium (renal hypertension;

increased renin-angiotensin-aldosterone secretion) Inflammation (acute, chronic, angiogenesis)

Ludwig’s AnginaLudwig’s AnginaCellulitisCellulitis

Congestive Heart FailureCongestive Heart Failure

Right ventricular malfunction >> Reduced cardiac output >> Reduced renal perfusion >> Renin-angiotensin-aldosterone axis triggered >> Sodium/water retention by kidneys (secondary aldosteronism) >> Increased intravascular volume >> Attempted increase in cardiac output, but heart can’t do it >> Increased venous pressure >> Edema Help: salt restriction, diuretics, aldosterone antagonists

Right or left sideRight or left sideUsually from hypertensionUsually from hypertension

Events Leading to Systemic EdemaEvents Leading to Systemic EdemaSecondary to Primary Heart FailureSecondary to Primary Heart Failure


Lymphatic ObstructionLymphatic ObstructionCauses EdemaCauses Edema

Lymphedema (from inflammation or neoplasm, usually)

Filariasis (parasite infection) >> massive edema/fibrosis of genitals and legs (elephantiasis)

Resected axillary nodes (breast cancer) >> massive edema of arm and peau d-orange (orange peel stippling, depressions at site of hair follicles)

Reduced Plasma Osmotic PressureReduced Plasma Osmotic PressureCauses EdemaCauses Edema

Albumin = the protein most responsible for colloid osmotic pressure Reduced albumin in blood >> Decreased osmotic pressure >> Not as much fluid reabsorbed across endothelium >> More fluid outside vessels (edema) and less inside vessels >> Less plasma volume >> Renal hypoperfusion >> secondary aldosteronism, etc.

Albumin loss from leaky glomerular capillary walls: nephrotic syndrome Reduced albumin synthesis: liver diseases (e.g. cirrhosis); malnutrition Problem: salt and water retention don’t help; salt isn’t large molecule -- It exacerbates the edema

Extra Credit QuestionExtra Credit Question

Ascites refers to severe edema of:

A. Brain

B. Pericardium

C. Peritoneum

D. Lungs

E. Lower extremities

Edema: Clinical ProblemsEdema: Clinical Problems

Subcutaneous edema: mostly a annoyance, but points to underlying cardiac failure (right sided) or renal failure – Dependent edema (pitting edema): gravity draws fluids downward Impaired wound healing or clearance of infection Brain edema: Swollen brain is painful, may be fatal, may force brain substance out through foramina (herniated) -- May compress vascular supply in brain stem -- Trauma, brain abscess, viral infections, etc. Pulmonary edema: fluid fills lungs >> less oxygen diffusion, maybe infection; can be fatal – Especially in left ventricular heart failure – Also: pneumonia, hypersensitivity reactions, adult respiratory distress syndrome (ARDS)

Pulmonary EdemaPulmonary Edema

Excess BloodExcess Blood

Hyperemia: Local increase in blood volume from active process

– E.g.: arterial dilation during exercise, etc. Tissue is more red than normal (excess oxygenated blood;

erythema)

Congestion: Local increase in blood volume from passive process

– E.g.: cardiac failure, venous obstruction Tissue is blue-red (poorly oxygenated blood; cyanosis) Congestion of capillary beds >> edema Chronic passive congestion: long-standing stasis and hypoxia; may

rupture vessel walls (hemorrhage and hemosiderin deposits)

Organ CongestionOrgan Congestion

Lungs: Acute pulmonary congestion: engorged alveolar capillaries and

pulmonary edema Chronic pulmonary congestion: fibrotic, thick septa

-- Heart failure cells (macrophages filled with hemosiderin)

Liver: Acute hepatic congestion: distended central vein and sinusoids;

peripheral cells better oxygenated

– Chronic passive hepatic congestion: Central regions of lobules are

red/brown and less cellular, perhaps necrotic (nutmeg liver)

– Can also be from shock

Congested Liver (Passive) = Nutmeg LiverCongested Liver (Passive) = Nutmeg LiverRight Heart FailureRight Heart Failure

Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.; Kumar, Cotran, Robbins. Robbins Basic pathology, 7th ed., Saunders, Philadelphia, 2003.

Types of ShockTypes of ShockGeneralized Failure of Tissue PerfusionGeneralized Failure of Tissue Perfusion

From profound hypotension (low blood pressure) Cardiogenic shock -- failure of heart to pump Hypovolemic shock -- lack of blood to pump (hemorrhage, fluid loss) Septicemic/Septic/Endotoxic shock -- bacterial infections (dilated veins, no blood return) Obstructive shock -- blockage of major artery Anaphylactic shock -- allergic reaction (dilated veins, no blood return) Neurogenic shock -- dilated veins, no blood return

Persistence of shock: Systemic acidosis >> dilation of previously constricted vessels >> hypotension Blood diverted from gut and kidneys to maintain perfusion of heart & brain Kidney damage; urine output falls Gut stasis, then necrosis

ShockShock

TissueTissue Early ChangeEarly Change Late ChangeLate Change

SkinSkin Pale, coldPale, cold CyanosisCyanosis

KidneysKidneys Low urine outputLow urine output Necrosis of tubular epitheliumNecrosis of tubular epithelium

GutGut Bowel stasisBowel stasis Necrosis of lining epitheliumNecrosis of lining epithelium

LungsLungs TachypnoeaTachypnoea Necrosis of alveolar epitheliumNecrosis of alveolar epithelium

LiverLiver Fatty changeFatty change Necrosis of neuronsNecrosis of neurons

BrainBrain Reduced consciousnessReduced consciousness Necrosis of neurons, comaNecrosis of neurons, coma

HeartHeart TachycardiaTachycardia Myocardial necrosisMyocardial necrosis

Effects of Effects of LipopolysaccharideLipopolysaccharide

LPS = lipopolysaccharide

TNF = tumor necrosis factor

IL = interleukin

NO = nitric oxide

PAF = platelet-activating factor

Protection from ShockProtection from Shock

Renin-angiotensin-aldosterone system -- retention of sodium, fluids; expanded blood volume Increased catecholamines from adrenals Increased sympathetic activity -- tachycardia -- vasoconstriction Increased ADH -- increased sodium and water retention

ThrombosisThrombosisThree Primary InfluencesThree Primary Influences

Endothelial injury (the dominant influence); does not need to be

physically disrupted to do this

Abnormal blood flow (turbulence; stasis)

– Platelets contact endothelium and each other

– Less flow: less dilution of clotting factors

– Less flow: less ingress of clotting inhibitors

– Activates endothelium

Hypercoagulability (hypercoagulation state)

– Primary (genetic)

– Secondary (acquired)

Predisposition to ThrombosisPredisposition to Thrombosis

Site Predisposition to Thrombosis

ArteryArteryAtheromaAtheroma

AneurysmAneurysm

Heart valveHeart valve Inflammation caused by infectionInflammation caused by infection

VentricleVentricleInflammation following infarctionInflammation following infarction

Ventricular aneurysmVentricular aneurysm

AtriumAtriumAtrial fibrillation (leads to stasis)Atrial fibrillation (leads to stasis)

Mitral valve stenosisMitral valve stenosis

VeinVeinSlow flow; stagnationSlow flow; stagnation

Hypercoagulation stateHypercoagulation state

Cerebral venous sinusCerebral venous sinusInflammation following infectionInflammation following infection

Hypercoagulability stateHypercoagulability state

Thrombosis RiskThrombosis RiskGenetic and AcquiredGenetic and Acquired

Factor V Leiden mutation Prothrombin mutation Antithrombin III deficiency Protein C deficiency Protein S deficiency Prolonged bed rest; immobilization Myocardial infarction Tissue damage Cancer Prosthetic cardiac valves Disseminated intravascular coagulation (DIC) Lupus anticoagulant (anticardiolipin antibody) Corticosteroid use Congenitally elevated levels of homocysteine Atrial fibrillation/Cardiomyopathy Nephrotic sydnrome Hyperestrogenic states/Oral contraceptive use Sickle cell anemia Smoking

Factor V Leiden mutationThe most common of the hypercoagulation mutations – 2-15% of population – 60% of patients with deep vein thrombosis – 75% of patients with ischemic osteonecrosis

Mutant factor Va: in the 3' untranslated region of prothrombin gene (G20210A mutation)

Mutation cannot be inactivated by protein C >> less antithrombotic activity

Effects of Vascular InjuryEffects of Vascular Injury

Photos: Kumar, Cotran, Robbins. Robbins Basic pathology, 7 th ed., Saunders, Philadelphia, 2003.

Coagulation CascadeCoagulation Cascade

Factor X > Factor Xa > Factor II ConversionFactor X > Factor Xa > Factor II Conversion


Normal Platelet Thrombus InhibitionNormal Platelet Thrombus Inhibition

Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995; Kumar, Cotran, Robbins. Robbins Basic pathology, 7th ed., Saunders, Philadelphia, 2003.

Thrombus FormationThrombus Formation

Photos: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995; Kumar, Cotran, Robbins. Robbins Basic pathology, 7th ed., Saunders, Philadelphia, 2003 ☺☺

Virchow Virchow Triad in Triad in

ThrombosisThrombosis

Coagulation Activity of Endothelial CellsCoagulation Activity of Endothelial Cells


Fibrinolytic SystemFibrinolytic System


ThrombusThrombusLaminated Pattern of Platelets and Fibrin RBCsLaminated Pattern of Platelets and Fibrin RBCs

Photo: Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.

Elements from activated coagulation cascade

Aggregated platelets

Insoluble fibrin -- from soluble plasma fibrinogen

Entrapped erythrocytes (RBCs)

Tiger stripes (RBCs layered between platelets, heart)

Mural ThrombiMural ThrombiIn Ventricles (Left) and Aortic Aneurysm (Right)In Ventricles (Left) and Aortic Aneurysm (Right)


Embolization (Embolus)Embolization (Embolus)Thromboembolism of Pulmonary ArteryThromboembolism of Pulmonary Artery

Photo: Kumar, Cotran, Robbins. Robbins Basic pathology, 7 th ed., Saunders, Philadelphia, 2003; . Stevens A, Lowe J. Slide atlas of pathology. Mosby, London, 1995.

Thrombotic VegetationsThrombotic VegetationsMitral ValveMitral Valve


Fate of the ThrombusFate of the Thrombus

Propagation (obstruction) Embolization (dislodged and transported elsewhere) Dissolution Organization

Venous ThrombosisVenous ThrombosisOutcomesOutcomes


Bone Marrow EmbolusBone Marrow EmbolusIn Pulmonary VesselIn Pulmonary Vessel


Infarction (Infarct)Infarction (Infarct)Lung (Left); Spleen (Right)Lung (Left); Spleen (Right)


Intracerebral HemorrhageIntracerebral Hemorrhage


Myocardial InfarctionMyocardial InfarctionRegional Full-Thickness (Left); Circumferential Subendocardial (Right)Regional Full-Thickness (Left); Circumferential Subendocardial (Right)


Left VentricleLeft Ventricle

Myocardial InfarctionMyocardial InfarctionChronological AppearanceChronological Appearance


Mural ThrombusMural ThrombusOver Myocardial InfarctionOver Myocardial Infarction


Kidney InfarctionKidney InfarctionReplaced by Fibrotic Scar (Left)Replaced by Fibrotic Scar (Left)


Myocardial InfarctionMyocardial InfarctionRuptureRupture


VentricleVentricle

Myocardial InfarctionMyocardial InfarctionChronological AppearanceChronological Appearance


general pathology (denf 2701) fall, 2005 topic: hemodynamic disorders, thrombosis, shock fall, 2005;...

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