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Haemodynamic disorders , thromboembolism and shock by Dr Nadeem (RMC)

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lecture slides on Haemodynamic changes

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Haemodynamic disorders , thromboembolism and shock by Dr Nadeem (RMC)

  1. 1. HAEMODYNAMICHAEMODYNAMIC DISORDERS,DISORDERS, THROMBOEMBOLISMTHROMBOEMBOLISM ANDAND SHOCKSHOCK
  2. 2. HAEMODYNAMICHAEMODYNAMIC CHANGESCHANGES •• The health and well- being of cells and tissues dependsThe health and well- being of cells and tissues depends upon:upon: 1. An intact blood circulation to deliver oxygen1. An intact blood circulation to deliver oxygen 2. Normal fluid homeostasis2. Normal fluid homeostasis ••The abnormalities in blood supply or fluid balance leads toThe abnormalities in blood supply or fluid balance leads to different disorders like:different disorders like: (i) Edema(i) Edema (ii) Vascular Congestion(ii) Vascular Congestion (iii) Hemorrhage(iii) Hemorrhage (iv) Thrombosis(iv) Thrombosis (v) Embolism(v) Embolism (vi) Infarction(vi) Infarction (vii) Shock(vii) Shock
  3. 3. • Thrombosis, embolism and InfarctionThrombosis, embolism and Infarction underlie three most impotent causes ofunderlie three most impotent causes of morbidity and mortality in Western societymorbidity and mortality in Western society • For example:For example: -Myocardial Infarction-Myocardial Infarction - Cerbrovascular accident- Cerbrovascular accident - Stroke- Stroke
  4. 4. HYPEREMIAHYPEREMIA ANDAND CONGESTIONCONGESTION
  5. 5. HYPEREMIA ANDHYPEREMIA AND CONGESTIONCONGESTION The term hyperemia and congestion indicate aThe term hyperemia and congestion indicate a locallocal increased volume of blood in a particularincreased volume of blood in a particular tissuetissue HYPEREMIAHYPEREMIA It is anIt is an Active ProcessActive Process resulting fromresulting from increased tissue inflow because of arteriolar dilation, asincreased tissue inflow because of arteriolar dilation, as in skeletal muscle during exercise, or at sites inin skeletal muscle during exercise, or at sites in inflammation.inflammation. The effected tissue is redder because of theThe effected tissue is redder because of the engorgement with oxygenated bloodengorgement with oxygenated blood
  6. 6. CONGESTIONCONGESTION It is aIt is a Passive ProcessPassive Process resulting from impairedresulting from impaired outflow from a tissue. It may occur systemically oroutflow from a tissue. It may occur systemically or locally.locally. •• Systemic Congestion:Systemic Congestion: As in cardiac failureAs in cardiac failure •• Local Congestion:Local Congestion: As in isolated venous obstructionAs in isolated venous obstruction In congestion tissue has a blue red colourIn congestion tissue has a blue red colour ((CyanosisCyanosis)) particularly as worsening congestion leads toparticularly as worsening congestion leads to accumulation of deoxygenated hemoglobin in theaccumulation of deoxygenated hemoglobin in the affected tissues.affected tissues. Congestion of capillary beds is closely related to theCongestion of capillary beds is closely related to the development of edema, so that congestion and edemadevelopment of edema, so that congestion and edema commonly occur togethercommonly occur together
  7. 7. HYPEREMIAHYPEREMIA CONGESTIONCONGESTION Active processActive process Passive processPassive process Results from increasedResults from increased tissue in- flow due totissue in- flow due to arteriolar dilatationarteriolar dilatation Results from impaired outResults from impaired out flow from a tissueflow from a tissue Effected tissue is redEffected tissue is red because of the engorgementbecause of the engorgement with oxygenated bloodwith oxygenated blood Effected tissue is bluish –Effected tissue is bluish – red due to accumulation ofred due to accumulation of deoxygenated blood.deoxygenated blood. Will lead to Erythema Will lead to Cyanosis Examples: (i) In skeletal muscle during exercise ; (ii) At sites of inflammation Example: (i) Systemic: As in congestive cardiac failure ; (ii) Local: As in isolated venous obstruction Hyperemia Vs CongestionHyperemia Vs Congestion
  8. 8. Hyperemia Vs Congestion In both cases there is an increased volume and pressure of blood in a given tissue with associated capillary dilation and a potential for fluid extravasation. In Hyperemia: increased inflow leads to engorgement with oxygenated blood, resulting in erythema In Congestion: diminished outflow leads to a capillary swollen with deoxygenated venous blood and resulting in cyanosis
  9. 9. MORPHOLOGIC CHANGES IN HYPEREMIAMORPHOLOGIC CHANGES IN HYPEREMIA AND CONGESTIONAND CONGESTION GROSS EXAMINATIONGROSS EXAMINATION:: Cut surface of hyperemic or congestedCut surface of hyperemic or congested tissue area haemorrhagic and wet.tissue area haemorrhagic and wet. MICROSCOPIC EXAMIANTIONMICROSCOPIC EXAMIANTION:: a)a) Pulmonary CongestionPulmonary Congestion:: (i)(i) Acute Pulmonary CongestionAcute Pulmonary Congestion: Alveolar capillaries are: Alveolar capillaries are engorged with blood. There may be associated alveolar septalengorged with blood. There may be associated alveolar septal edema or focal intra alveolar hemorrhage.edema or focal intra alveolar hemorrhage. (ii)(ii) Chronic Pulmonary CongestionChronic Pulmonary Congestion: The septa have become: The septa have become thickened and fibrotic. The alveolar spaces may containthickened and fibrotic. The alveolar spaces may contain numerous hemosidrin laden macrophagesnumerous hemosidrin laden macrophages ((Heart FailureHeart Failure Cells)Cells) b)b) Congestion of LiverCongestion of Liver:: The central regions of the hepatic lobulesThe central regions of the hepatic lobules are grossly red brown and slightly depressed due to loss of cellsare grossly red brown and slightly depressed due to loss of cells and are accentuated against the surrounding zones ofand are accentuated against the surrounding zones of uncongested liveruncongested liver( nutmeg liver)( nutmeg liver) .(.(so called because itso called because it resembles the alternating pattern of light and dark seen when aresembles the alternating pattern of light and dark seen when a whole nutmeg is cut) In long standing congestion due to cardiacwhole nutmeg is cut) In long standing congestion due to cardiac failure there can be hepatic fibrosisfailure there can be hepatic fibrosis ((Cardiac CirrhosisCardiac Cirrhosis))
  10. 10. Heart Failure CellsHeart Failure Cells Haemosidrin laden macrophages seen in alveolarHaemosidrin laden macrophages seen in alveolar spaces, in pulmonary congestionspaces, in pulmonary congestion Nutmeg liverNutmeg liver Alternating pattern of lightAlternating pattern of light and dark areas seen inand dark areas seen in congestion of liver (resemblescongestion of liver (resembles alternating dark and light when a whole nutmegalternating dark and light when a whole nutmeg is cut)is cut) CCardiac Cirrhosisardiac Cirrhosis Hepatic fibrosis seen in chronic heart failureHepatic fibrosis seen in chronic heart failure
  11. 11. Liver with Chronic Passive Congestion and Haemorrhagic Necrosis A: Central areas are red and slightly depressed compared with the surrounding tan viable parenchyma, forming a “nutmeg liver” pattern (so called because it resembles the alternating pattern of light and dark seen when a whole nutmeg is cut B: Centrilobular necrosis with degenerating hepatocytes and haemorrhage
  12. 12.  Left-sided heart failureLeft-sided heart failure  chronic congestion of lungchronic congestion of lung  lung edema, haemorrhage:lung edema, haemorrhage: weightweight increased, sogginess subcrepitant, sectioningincreased, sogginess subcrepitant, sectioning permits the free escape of a frothy hemorrhagicpermits the free escape of a frothy hemorrhagic fluid,fluid,  Microscope showed alveolar walls are dilated andMicroscope showed alveolar walls are dilated and alveolar space edema,full with red cells and canalveolar space edema,full with red cells and can findfind ““heart failure cell”” brown induration of the lungbrown induration of the lung
  13. 13.  ““HHeart failure cell”eart failure cell” macrophagesmacrophages phagocytose red cellphagocytose red cell then the red cell break downthen the red cell break down intointo hemosiderin granuleshemosiderin granules
  14. 14. Acute congestion of the lung with pulmonary edema. Chronic congestion with heart failure cells
  15. 15. Right-Sided Heart FailureRight-Sided Heart Failure Nutmeg liverNutmeg liver:Liver congestion in centrilobular:Liver congestion in centrilobular areas surrounded by fatty degenerationareas surrounded by fatty degeneration peripheral regionsperipheral regions cardiac sclerosiscardiac sclerosis persistence
  16. 16. Nnutmeg liver (photo is offered by ) Histologic appearance of atrophy and necrosis of cells in the central part of the liver lobule in chronic congestion
  17. 17. Chronic venous congestion ( nutmeg liver)
  18. 18. Chronic venous congestion ( nutmeg liver) with recent infarction
  19. 19. Slide 5 Section in the lung shows Thickened alveolar wall with congested dilated alveolar capillaries. The alveolar spaces contain intact and haemolysed red blood cells, brown haemosidren granules, heart failure cells and homogenous pink transudate. The heart failure cells are large, rounded phagocytic cells engulfing brown haemosidren granules and red blood cells. Diagnosis Chronic venous congestion,
  20. 20. Chronic venous congestion, lung
  21. 21. Chronic venous congestion liver Atrophic liver cells Dilated sinusoids Central vein
  22. 22. EDEMAEDEMA
  23. 23. EDEMAEDEMA ““Edema is the increased fluid in the interstitialEdema is the increased fluid in the interstitial tissue spaces and or body cavities”tissue spaces and or body cavities” Approximately 60% of lean body weight isApproximately 60% of lean body weight is water, two thirds of which is intracellular, withwater, two thirds of which is intracellular, with the reminder in the extra cellular compartments,the reminder in the extra cellular compartments, mostly as interstitial fluid (only about 5% ofmostly as interstitial fluid (only about 5% of total body water is in blood plasma). The termtotal body water is in blood plasma). The term edema signifies increased fluid in the interstitialedema signifies increased fluid in the interstitial tissue spaces.tissue spaces.
  24. 24. The interstitial tissue is in equilibrium with plasma on one hand and parenchymal cell cytoplasm on the other.  Movement of water and electrolytes among plasma , interstitium, cells and lymphatics is shown by arrows Components of Interstitial tissue: A. Water ; Electrolytes; Hydrogen ions; Glucose ; Lipids B. Ground substance; Glycoprotein; Hyaluronic acid; Fibronectins C. Fibrillar proteins ; Collagen( Osteoid in bone and chondroid in cartilage); Elastin ; D. Interstitial cells; Fibroblasts; Macrophages ; lymphocytes; Mast cells; Adipocytes (fat cells)
  25. 25. NORMAL TISSUE FLUID CIRCULATIONNORMAL TISSUE FLUID CIRCULATION Hydrostatic blood pressure forces water out of capillaries at the arterial end, but the plasma oncotic pressure attributable to albumin sucks water back into capillary beds at the venous end . A small amount of water drains from the tissues through lymphatic channels
  26. 26. Variables Affecting Fluid Transit Across capillary Walls Capillary hydrostatic and osmotic forces are normally balanced so that there is no net loss or gain of fluid across the capillary bed. However increased hydrostatic pressure or diminished plasma osmotic pressure leads to a net accumulation of extravascular fluid(edema). As the interstitial fluid pressure increases, tissue lypmhatics remove much of the excess volume via thoracic duct. If the ability of the lypmhatics to drain fluid is exceeded, persistent tissue edema results
  27. 27. PATHOPHYSIOLOGIC CATEGORIES OF EDEMAPATHOPHYSIOLOGIC CATEGORIES OF EDEMA I.I. Increased Hydrostatic Pressure:Increased Hydrostatic Pressure: a.a. Impaired venous returnImpaired venous return Congestive heart failureCongestive heart failure Constrictive pericarditisConstrictive pericarditis Ascities (Liver Cirrhosis)Ascities (Liver Cirrhosis) Venous obstruction or compression , e.g., ThrombosisVenous obstruction or compression , e.g., Thrombosis b.b. Arteriolar dilatationArteriolar dilatation HeatHeat Neurohumoral dysregulationNeurohumoral dysregulation II.II. Reduced Plasma Osmotic PressureReduced Plasma Osmotic Pressure (Hypoprotenemia)(Hypoprotenemia) Protein losing Glomerulonephritis (Nephrotic Syndrome)Protein losing Glomerulonephritis (Nephrotic Syndrome) Liver Cirrhosis (Ascities)Liver Cirrhosis (Ascities) MalnutritionMalnutrition Protein – losing GastroenterophathyProtein – losing Gastroenterophathy
  28. 28. III.III. Lymphatic Obstruction:Lymphatic Obstruction: InflammatoryInflammatory NeoplasiaNeoplasia Post surgicalPost surgical Post irradiationPost irradiation Parasitic ( Filaraisis)Parasitic ( Filaraisis) IV.IV. InflammationInflammation ( increased capillary permeability)( increased capillary permeability) Acute inflammationAcute inflammation Chronic inflammationChronic inflammation AngiogenesisAngiogenesis V.V. Sodium RetentionSodium Retention Excessive salt intake with renal insufficiencyExcessive salt intake with renal insufficiency Increased tubular reabsorption of sodiumIncreased tubular reabsorption of sodium Renal HypoperfusionRenal Hypoperfusion Increased renin- angiotensin – aldosterone secretionIncreased renin- angiotensin – aldosterone secretion
  29. 29. Arterial EndArterial End Venous EndVenous End Hydrostatic pressure is moreHydrostatic pressure is more than osmotic pressurethan osmotic pressure Osmotic pressure is moreOsmotic pressure is more than hydrostatic pressurethan hydrostatic pressure
  30. 30. I.I. INCREASED HDROSTATIC PRESSUREINCREASED HDROSTATIC PRESSURE Normal Hydrostatic pressure at the arteriolar end of capillaries is mm of Hg and at the venular end of capillaries it is about 15 mm of Hg eased venous pressure exceeds that of plasma oncotic pressure and water remains in the tissues. al increase in Hydrostatic Pressure: It result from impaired venous out flow. example, deep venous thrombosis in the lower extremities leads to ma which is restricted to lower limbs eralized Increase in Venous Pressure: Generalized increase in venous ssure, with resulting systemic edema, occur most commonly in con- stive Heart Failure affecting left ventricle
  31. 31. Congestive heart failure is associated with reduced cardiac output and therefore reduced renal perfusion. Renal hypo perfusion, then triggers the Rennin- Angiotensin – Aldosterone Axis, inducing sodium and water retention by kidneys . This process is putatively designed to increase intravascular volume and thereby improve cardiac out put ( via Frank- Starling Law) , with restoration of normal renal perfusion . If the failing heart can not increase cardiac out put , however , the extra fluid load results only in increased venous pressure and eventually Edema
  32. 32. Pathways leading to systemic edema due to primary heart failure, primary renal failure, or reduced plasma oncotic pressure (e.g., from malnutrition, diminished hepatic synthesis, or protein loss due to the nephrotic syndrome)
  33. 33. II.II.REDUCED PLASMA ONCOTIC PRESSUREREDUCED PLASMA ONCOTIC PRESSURE (Hypoalbuminaemic oedema)(Hypoalbuminaemic oedema) The normal colloid osmotic pressure is about 20 mm of Hg. It is an pposing force to the hydrostatic pressure . Normally at arterial end ltration of tissue fluids occur because the hydrostatic pressure is igher than the osmotic pressure. At the venous end the osmotic ressure is higher than the hydrostatic pressure resulting in the ithdrawal of the tissue fluid. Therefore fall in the osmotic pressure due to hypoprotenemia) results in oedema ow plasma albumin concentration reduces the plasma oncotic essure so that water can not be sucked back into the capillary bed t the venous end.
  34. 34. Causes of hypoalbuminemia are: (i) Protein malnutrition (as in Kwashiorkor) (ii) Liver failure (reduced albumin synthesis) (iii) Nephrotic syndrome (excessive albumin loss in urine) (iv) Protein – losing enteropathy (a variety of diseases are responsible) Hypoalbuminemia as the cause of oedema can be verified easily by measuring the albumin concentration in serum
  35. 35. III.III. LYMPHATIC OBSTRUCTIONLYMPHATIC OBSTRUCTION (Lymphatic Oedema)(Lymphatic Oedema) Lymphatic obstruction prevents drainage of water from tissues Important causes of lymphatic obstruction are: (i) Parasitic infection Filariasis often causes impairment in lymphatic drainage and cause massive lymph edema in inguinal region (Elephantiasis) (ii) Surgical removal of axillary lymph nodes in carcinoma breast can lead to lymph edema of arms.
  36. 36. Lymphatic ObstructionLymphatic Obstruction  FilariasisFilariasis ––  A parasitic infectionA parasitic infection affecting inguinalaffecting inguinal lymphatics resulting inlymphatics resulting in elephantiasiselephantiasis
  37. 37. Lymphatic Obstruction NeoplasticLymphatic Obstruction Neoplastic  Resection and/or radiation to axillary lymphaticsResection and/or radiation to axillary lymphatics inin breast cancer patients can lead to --breast cancer patients can lead to -- arm edemaarm edema  Carcinoma of breastCarcinoma of breast withwith obstructioobstruction of superficialn of superficial lymphaticslymphatics can lead to edema of breast skin -- --withcan lead to edema of breast skin -- --with an unusual appearance:an unusual appearance: “peau d’orange” (orange“peau d’orange” (orange peel)peel)
  38. 38. IV.IV.INFLAMMATORY OEDEMAINFLAMMATORY OEDEMA It is a feature of acute inflammation. In acutely inflamed tissues there is increased vascular (mainly venular ) permeability due to separation of endothelial cells under the influence of chemical mediators. Fluid with high protein content leaks out of the permeable vessels into the inflam- ed tissue causing it to swell. There is increased lymphatic drainage, but this cannot cope with all the water released into tissues and edema results
  39. 39. V.V.SODIUM AND WATER RETNETIONSODIUM AND WATER RETNETION  Salt retention may occur with any acute reduction ofSalt retention may occur with any acute reduction of renal functionrenal function  Sodium and Water retention is clearly contributorySodium and Water retention is clearly contributory factors in several forms of edemafactors in several forms of edema  Increased salt, with obligate accompanying water ,Increased salt, with obligate accompanying water , causes bothcauses both (i) increased hydrostatic pressure( due to expansion(i) increased hydrostatic pressure( due to expansion of the intravascular fluid volume)of the intravascular fluid volume) andand (ii) Diminished vascular colloid osmotic pressure.(ii) Diminished vascular colloid osmotic pressure.
  40. 40. Pathophysiology of Localized EdemaPathophysiology of Localized Edema Factors influencing accumulation in the interstitial spaceFactors influencing accumulation in the interstitial space PathologicPathologic conditioncondition VascularVascular permeabilitypermeability CapillaryCapillary HydrostaticHydrostatic PressurePressure InterstitialInterstitial TissueTissue OsmoticOsmotic PressurePressure LymphaticLymphatic FlowFlow AcuteAcute InflammatoryInflammatory EdemaEdema IncreasedIncreased IncreasedIncreased Normal OrNormal Or IncreasedIncreased IncreasedIncreased AllergicAllergic EdemaEdema IncreasedIncreased IncreasedIncreased Normal OrNormal Or IncreasedIncreased IncreasedIncreased Edema ofEdema of VenousVenous ObstructionObstruction NormalNormal IncreasedIncreased NormalNormal IncreasedIncreased Edema ofEdema of LymphaticLymphatic ObstructionObstruction NormalNormal NormalNormal Normal OrNormal Or IncreasedIncreased DecreasedDecreased
  41. 41. MORPHOLOGY OF OEDEMAMORPHOLOGY OF OEDEMA Gross FeaturesGross Features :: Oedema causes swelling, heaviness andOedema causes swelling, heaviness and pallor of the affected tissue . The cut surface of anpallor of the affected tissue . The cut surface of an oedematous organ, as lung, oozes fluidoedematous organ, as lung, oozes fluid Microscopic Features:Microscopic Features: Oedema appears asOedema appears as homogenoushomogenous pale eosinophilic substancepale eosinophilic substance . Eosinophilic staining is. Eosinophilic staining is due to its protein content . Pale staining is due to fluiddue to its protein content . Pale staining is due to fluid dilution.dilution. Microscopically oedema fluid generally manifests as cellMicroscopically oedema fluid generally manifests as cell swelling with clearing and separation of extra cellularswelling with clearing and separation of extra cellular matrix elements.matrix elements.
  42. 42. TYPES OF OEDEMATYPES OF OEDEMA I.I. Localized Or GeneralizedLocalized Or Generalized II.II. Pitting Or Non- pittingPitting Or Non- pitting III.III. Transudate Or ExudateTransudate Or Exudate
  43. 43. I.I. Localized Or GeneralizedLocalized Or Generalized Localized:Localized: a. Inflammatory Oedemaa. Inflammatory Oedema b. Lymphatic oedema due to lymphatic obstructionb. Lymphatic oedema due to lymphatic obstruction c. Oedema due to localized venous congestionc. Oedema due to localized venous congestion d. Pulmonary oedemad. Pulmonary oedema Generalized:Generalized: a. Cardiac Oedema: Seen in right sided heart failure.a. Cardiac Oedema: Seen in right sided heart failure. b. Nutritional Oedema: Due to hypoprotenemia seen in:b. Nutritional Oedema: Due to hypoprotenemia seen in: - Malnutrition- Malnutrition - Malabsorption- Malabsorption - Chronic liver disease ( decreased protein synthesis)- Chronic liver disease ( decreased protein synthesis) c. Renal Oedema: It particularly starts around the eye lidsc. Renal Oedema: It particularly starts around the eye lids then becomes generalized.then becomes generalized.
  44. 44. II.II.Pitting Or Non- Pitting OedemaPitting Or Non- Pitting Oedema Pitting Oedema:Pitting Oedema: Pitting oedema occurs when venousPitting oedema occurs when venous pressurepressure is increased ( e.g., right sided heart failure) or osmoticis increased ( e.g., right sided heart failure) or osmotic pressurepressure is decreased ( e.g., hypoprotenemia)is decreased ( e.g., hypoprotenemia) It is more marked in theIt is more marked in the dependent partsdependent parts ( feet in an( feet in an ambulantambulant patient and the sacrum in a bed ridden patient)patient and the sacrum in a bed ridden patient) If the edematous part is pressed by the thumb , aIf the edematous part is pressed by the thumb , a pitpit isis formed which refills slowly after the thumb is removed.formed which refills slowly after the thumb is removed. Dorsum of theDorsum of the foot ,ankle, shin and sacrum are the usual sites to look forfoot ,ankle, shin and sacrum are the usual sites to look for pittingpitting edema.edema. Non – Pitting Oedema:Non – Pitting Oedema: When thumb is pressed no pittingWhen thumb is pressed no pitting takes place.takes place. Non- pitting oedema takes place in different sites.Non- pitting oedema takes place in different sites. 1. In cases of lymphatic oedema, e.g., Filaraisis.1. In cases of lymphatic oedema, e.g., Filaraisis.
  45. 45. IIIIII.. TRANSUDATE Or EXUDATETRANSUDATE Or EXUDATE The edema fluid occurring in hydrodynamicThe edema fluid occurring in hydrodynamic derangements is typicallyderangements is typically protein – poorprotein – poor Transudate,Transudate, .. Conversely, because of increasedConversely, because of increased vascular permeability , inflammatory edema isvascular permeability , inflammatory edema is protein rich - Exudate.protein rich - Exudate.
  46. 46. TRANSUDATE EXUDATE PROTEIN Less than 3.o g/dl More than 3.0 gram/dl COLOUR : .Clear Or Straw Turbid or Purulent SPECIFIC GRAVITY Less than 1.012 More than 1.012 CELL COUNT Less than 100/cmm More than 100/cmm TYPE OF CELL: Lymphocytes & mesothelial Lmphocytes & Neutrophils RED BLOOD CELLS: Absent Often present CLOT FORMATION None Usual TOTAL PROTEIN: Less than 3.0 g/dl More than 3.0 g/dl RIVOLTA TEST Negative Positive GLUCOSE As in plasma Reduced LDH Less than 550 Units More than 550 units Transudate VS ExudateTransudate VS Exudate
  47. 47. TRANSUDATE EXUDATE CAUSES (i) Congestive Cardiac Failure (ii) Cirrhosis (i) Bacterial Infection (ii) Malignancies (iii) Tuberculosis PROTEIN SOURCE Mainly Albumin Mainly Fibrinogen NATURE Normal tissue fluid but in amounts exceeding the normal Inflammatory Fluid Transudate VS ExudateTransudate VS Exudate
  48. 48. CLINICAL CORRELATIONSCLINICAL CORRELATIONS HYDROTHORAX:HYDROTHORAX: Accumulation of fluid in pleural cavityAccumulation of fluid in pleural cavity HYDROPERICARDIUM:HYDROPERICARDIUM: Accumulation of fluid inAccumulation of fluid in pericardiumpericardium ASCITIES:ASCITIES: Accumulation of fluid in peritoneal cavityAccumulation of fluid in peritoneal cavity ANASARCA:ANASARCA: Severe and generalized edema withSevere and generalized edema with profound subcutaneous tissue swellingprofound subcutaneous tissue swelling
  49. 49. Edema -Edema - MorphologyMorphology  Dependent EdemaDependent Edema is a prominentis a prominent feature of Congestive Heartfeature of Congestive Heart FailureFailure  Facial EdemaFacial Edema is often the initialis often the initial manifestation of Nephrotic Syndromemanifestation of Nephrotic Syndrome Subcutaneous EdemaSubcutaneous Edema  Edema of the subcutaneous tissue is most easily detectedEdema of the subcutaneous tissue is most easily detected GrosslyGrossly (not(not microscopically)microscopically)  Push your finger into itPush your finger into it  and a depression remainsand a depression remains
  50. 50. Non –pitting EdemaNon –pitting Edema
  51. 51. Periorbital edema in Nephrotic SyndromePeriorbital edema in Nephrotic Syndrome
  52. 52. EdemaEdema Clinical Correlation:Clinical Correlation: Subcutaneous EdemaSubcutaneous Edema  Annoying but Points to Underlying DiseaseAnnoying but Points to Underlying Disease  However, it can impair wound healing orHowever, it can impair wound healing or clearance of Infectionclearance of Infection
  53. 53. Edema-Edema- MorphologyMorphology Pulmonary EdemaPulmonary Edema is most frequently seen in Congestive Heartis most frequently seen in Congestive Heart FailureFailure  May also be present in renal failure, adultMay also be present in renal failure, adult respiratory distress syndrome (ARDS),respiratory distress syndrome (ARDS), pulmonary infections and hypersensitivitypulmonary infections and hypersensitivity
  54. 54. Pulmonary Edema-Gross:Pulmonary Edema-Gross:  The Lungs are typically 2-3 times the normal weightThe Lungs are typically 2-3 times the normal weight  Cross sectioning causes an outpouring of frothy,Cross sectioning causes an outpouring of frothy, sometimes blood-tinged fluidsometimes blood-tinged fluid
  55. 55. Pulmonary Edema Normal
  56. 56. EDEMA -EDEMA - SummarySummary INCREASED HYDROSTATIC PRESSURE Congestive Heart Failure Ascites Venous Obstruction DECREASED ONCOTIC PRESSURE Nephrotic Syndrome Cirrhosis Protein Malnutrition INCREASED PERMEABILITY Inflammation LYMPHATIC OBSTRUCTION Inflammatory Neoplastic  HEARTHEART  LIVERLIVER  KIDNEYKIDNEY
  57. 57. GENERALIZED EDEMAGENERALIZED EDEMA  HEARTHEART  LIVERLIVER  KIDNEYKIDNEY
  58. 58. HAEMORRHAGEHAEMORRHAGE
  59. 59. HAEMORRHAGEHAEMORRHAGE  ““Extravasations of blood from vessels”Extravasations of blood from vessels”  Occurs in variety of settingsOccurs in variety of settings  Risk of haemorrhage (often after a seemingly insignificantRisk of haemorrhage (often after a seemingly insignificant injury) is increased in a wide variety of clinical disordersinjury) is increased in a wide variety of clinical disorders collectively calledcollectively called Haemorrhagic DiathesisHaemorrhagic Diathesis  Trauma, atherosclerosis, or inflammatory or neoplasticTrauma, atherosclerosis, or inflammatory or neoplastic erosion of a vessel wall also may lead to haemorrhage,erosion of a vessel wall also may lead to haemorrhage, which may be extensivewhich may be extensive
  60. 60. HAEMORRHAGE …. ManifestationsHAEMORRHAGE …. Manifestations Haemorrhage may be manifested by different appearances andHaemorrhage may be manifested by different appearances and clinical consequencesclinical consequences 1.1. Haematoma :Haematoma : Haemorrhage may be external or accumulateHaemorrhage may be external or accumulate within a tissue as a Haematoma ; which ranges inwithin a tissue as a Haematoma ; which ranges in significance from trivial (e.g., asignificance from trivial (e.g., a bruisebruise) to fatal 9e.g.,) to fatal 9e.g., Massive Rretroperitoneal Haematoma resulting fromMassive Rretroperitoneal Haematoma resulting from RRupture of a Dissecitng Aortic Aneurysmupture of a Dissecitng Aortic Aneurysm )) 2.2. HemothoraxHemothorax 33. Hemoperitonium. Hemoperitonium 4.4.HemopericardiumHemopericardium 5.5. HemarthrosisHemarthrosis 6.6. Petichiae:Petichiae: Minute (1 to 2 mm in diameter) hemorrhage intoMinute (1 to 2 mm in diameter) hemorrhage into skin, mucous membranes or serosal surfaces.skin, mucous membranes or serosal surfaces. Causes include:Causes include: (i)(i) ThrombocytopniaThrombocytopnia (ii)(ii) Platelet function defectsPlatelet function defects (iii)(iii) Loss of vascular wall support (Vitamin C deficiency)Loss of vascular wall support (Vitamin C deficiency)
  61. 61. HAEMORRHAGEHAEMORRHAGE 7.7. PurpuraPurpura:: Slightly larger (3 to 5 mm) haemorrhages. CanSlightly larger (3 to 5 mm) haemorrhages. Can result form the same disorders that cause petechiae, as wellresult form the same disorders that cause petechiae, as well as trauma ,vascular inflammation (vasculitis and increasedas trauma ,vascular inflammation (vasculitis and increased vascular fragilityvascular fragility 8.8. EcchmosesEcchmoses :: Are larger (1 to 2 cm) subcutaneousAre larger (1 to 2 cm) subcutaneous hamatomas (colloquially calledhamatomas (colloquially called BruisesBruises ))
  62. 62. HAEMORRHAGEHAEMORRHAGE  Clinical significance of any particular haemorrhage dependsClinical significance of any particular haemorrhage depends on the volume of blood lost and the rate of bleedingon the volume of blood lost and the rate of bleeding  Greater loss can lead toGreater loss can lead to Hypovolemic ShockHypovolemic Shock  Site of haemorrhage is also importantSite of haemorrhage is also important  Chronic or recurrent external blood loss (e.g., due to pepticChronic or recurrent external blood loss (e.g., due to peptic ulcer or menstrual bleeding) frequently culminates in ironulcer or menstrual bleeding) frequently culminates in iron deficiency as a consequence of loss of iron indeficiency as a consequence of loss of iron in haemoglobinhaemoglobin
  63. 63. THROMBOSISTHROMBOSIS
  64. 64. THROMBOSISTHROMBOSIS  The formation of a clotted mass of bloodThe formation of a clotted mass of blood within the non interrupted cardiovascularwithin the non interrupted cardiovascular system is termed thrombosis,system is termed thrombosis, and the mass itselfand the mass itself ThrombusThrombus  Thrombosis is the formation of a solid mass from theThrombosis is the formation of a solid mass from the constituents of blood (platelets, fibrin and entrapped redconstituents of blood (platelets, fibrin and entrapped red and white cells) within the heart or vascular system in aand white cells) within the heart or vascular system in a living organismliving organism
  65. 65. THROMBOSISTHROMBOSIS Normal HemstasisNormal Hemstasis is the result of a set of well regulatedis the result of a set of well regulated processes that accomplish two important functions:processes that accomplish two important functions: (i) It maintain(i) It maintain blood in a fluid, clot free stateblood in a fluid, clot free state in normalin normal vessels.vessels. (ii) It produces a localized(ii) It produces a localized Haemostatic PlugHaemostatic Plug at the siteat the site of vascular injury.of vascular injury. The pathologic opposite to hemostasis isThe pathologic opposite to hemostasis is ThrombosisThrombosis Both Hemostasis and Thrombosis depend on threeBoth Hemostasis and Thrombosis depend on three components:components: (i) The Vascular Wall(i) The Vascular Wall (ii) Platelets(ii) Platelets (iii) Coagulation Cascade(iii) Coagulation Cascade
  66. 66. INVOLVEMENT OF BLOOD VESSELS, PLATELETSINVOLVEMENT OF BLOOD VESSELS, PLATELETS AND BLOOD COAGULATION IN HAEMOSTASISAND BLOOD COAGULATION IN HAEMOSTASIS
  67. 67. Mechanism of normal Haemostasis A: In normal uninjured blood vessels sub endothelial connective tissue, especially collagen and elastin, is not exposed to the circulating blood. B: In the first few seconds after injury, exposure of sub endothelial tissue attracts platelets, which adhere at the site of injury. Endothelial injury also activates Hageman factor (factor XII) , which in turn activates the intrinsic pathway of coagulation cascade. Release of tissue thromboplastin activates the extrinsic pathway. C: Haemostasis is achieved in minutes. Platelet degranulation stimulates further platelet aggregation . Fibrin formed by activation of the coagulation cascade combines with the mass of aggregated platelets to form the definitive haemostatic plug that seals the injury . Plasmin (fibrinolysin) formed by the activation of fibrinolytic pathway prevents excessive fibrin formation. D: During healing (hours to days), the thrombus retracts , and organization and fibrosis of the thrombus occurs. Reendotheliazation of the vessels is the final step
  68. 68. Primary Haemostasis: Endothelial injury exposes highly thrombogenic sub-endothelial extracellular matrix , facilitating platelet adherence ,activation and aggregation .The formation of the initial platelet plug is called primary haemostasis Secondary Haemostasis: Activated thrombin promotes the formation of an insoluble fibrin clot by cleaving fibrinogen ; thrombin also is a potent activator of additional platelets, which serve to reinforce the haemostatic plug . This sequence termed secondary haemostasis , results in the formation of a stable clot capable of preventing further haemorrhage Primary And Secondary haemostaticPrimary And Secondary haemostatic HaemostasisHaemostasis
  69. 69. ROLE OF ENDOTHELIUM IN HAEMOSTASISROLE OF ENDOTHELIUM IN HAEMOSTASIS Intact endothelium cells serve primarily to inhibit platelet adherence and blood clotting. While injury or activation of endothelial cell result in procoagulant effect that augments local clot formation Anti platelet substances in Endothelium: (i) Prostacyclin (ii) Nitric Oxide (iii) Adenosine diphosphate Anticoagulant substances in Endothelium: (i) Antithrombin III (ii) Thrombomodulin (iii) Protein C (iv) Protein S
  70. 70. Endothelial cells and Coagulation- Summary Intact normal endothelial cell help to maintain blood flow by inhibiting the activation of platelets and coagulation factors Endothelial cells stimulated by injury or inflammatory cytokines up-regulate expression of pro-cogulant factors (e.g., tissue factor) that promotes clotting and down regulate expression of anticoagulant factors Loss of endothelial integrity exposes sub-endothelial vWF and basement membrane collagen, stimulating platelet adhesion , platelet activation and clot formation
  71. 71. ROLE OF PLATELETS IN HAEMOSTASISROLE OF PLATELETS IN HAEMOSTASIS Platelets Adhesion and Aggregation: Von Willebrand’s Factor functions as a bridge between sub endothelial collagen and the Gp Ib platelet receptor. Aggregation involves linking platelets via fibrinogen bridges bound to the platelet GpIIb- IIIa receptors
  72. 72. ROLE OF PLATELETS IN HAEMOSTASISROLE OF PLATELETS IN HAEMOSTASIS Platelets Adhesion Platelet Activation Shape Change Release Reaction Platelet Aggregation
  73. 73. ROLE OF PLATELETS IN HAEMOSTASISROLE OF PLATELETS IN HAEMOSTASIS n
  74. 74. ROLE OF PLATELETS IN HAEMOSTASISROLE OF PLATELETS IN HAEMOSTASIS (I)Platelets Adhesion Defects: -Von Willebrand Disease:Congenital Deficiency/Absence of von Willebrand Factor leads to inherited bleeding disorder- von Willebrand Disease -Beranrd Soulier Disease: Absence of Gp1b- Leads to inherited bleeding disorder Bernard Soulier Disease (II) Platelets Aggregation Defects: Absence of GpIIb/IIIa- leads to inherited bleeding disorder- Glanzmann thormobasthenia
  75. 75. ROLE OF PLATELETS IN HAEMOSTASISROLE OF PLATELETS IN HAEMOSTASIS Platelet Adhesion, Activation and Aggregation- Summary Endothelial injury exposes the underlying basement membrane ECM; platelets adhere to the ECM primarily through binding of platelet GpIb receptor to vWF Adhesion leads to platelet activation , an event associated with secretion of platelet granule contents, including calcium ( a cofactor for several coagulation proteins) and ADP ( a mediator of further platelet activation) ; dramatic changes in shape and membrane composition; and activation of GpIIb/IIIa receptors The GpIIb/IIIa receptors on activated platelets form bridging cross links with fibrinogen ,leading to platelet aggregation Concomitant activation of thrombin promotes fibrin deposition, cementing the platelet plug in place
  76. 76. ROLE OF COAGULATION SYSTEM IN HAEMOSTASISROLE OF COAGULATION SYSTEM IN HAEMOSTASIS INTRINSIC PATHWAY EXTRINSIC PATHWAY kalikrein Kallikrein VII VIIa XIII XIIa HMWK XI XIa IX IXa Ca++ X Xa VIIICa++ ; Pl Prothrombin (II) Thrombin ( IIa ) Ca++ ; Pl Fibrinogen(I) Fibrin (Ia) XIII XIIIa COMMON PATHWAY Tissue Factor Ca++ ; Pl
  77. 77. CAOGULATION SYSTEMCAOGULATION SYSTEM Coagulation System comprises of several proteinsCoagulation System comprises of several proteins which are normally present in the blood in an inactive form.which are normally present in the blood in an inactive form. When there is injury to the blood vessels, the coagulationWhen there is injury to the blood vessels, the coagulation system becomes activated and results in the formation of asystem becomes activated and results in the formation of a fibrin clot. Fibrin enmeshes the platelet aggregate at thefibrin clot. Fibrin enmeshes the platelet aggregate at the site of vascular injury and converts the instable primarysite of vascular injury and converts the instable primary platelet plug to firm , definitive and stable haemostaticplatelet plug to firm , definitive and stable haemostatic plug.plug. In the coagulation cascade first there is initiation ofIn the coagulation cascade first there is initiation of Intrinsic and Extrinsic Pathways. Both of these thenIntrinsic and Extrinsic Pathways. Both of these then converge onto the activation of Common Pathway. Theconverge onto the activation of Common Pathway. The Common Pathway then at the end leads to the formation ofCommon Pathway then at the end leads to the formation of a stable haemostatic pluga stable haemostatic plug EXTRINSIC PATHWAY:EXTRINSIC PATHWAY: In the Extrinsic pathway, the factors released fromIn the Extrinsic pathway, the factors released from damaged tissues activate factor VII which in turn in thedamaged tissues activate factor VII which in turn in the presence of Tissue Factor, activates factor X.presence of Tissue Factor, activates factor X.
  78. 78. INTRNISIC PATHWAY:INTRNISIC PATHWAY: In this pathway initially factor XII is activated, when itIn this pathway initially factor XII is activated, when it comes in contact with sub endothelial elements of the bloodcomes in contact with sub endothelial elements of the blood vessels including collagen, High Molecular Weigh Kininogenvessels including collagen, High Molecular Weigh Kininogen (HMWK) and Kalikrein . The activated factor XIIa then(HMWK) and Kalikrein . The activated factor XIIa then converts factor XI into its activated form XIa. The next stepconverts factor XI into its activated form XIa. The next step is the conversion of IX into IXa by factor XIa. Factor IXa inis the conversion of IX into IXa by factor XIa. Factor IXa in the presence of calcium, platelets and factor VIII thenthe presence of calcium, platelets and factor VIII then converts X to Xa.converts X to Xa. COMMON PATHWAY:COMMON PATHWAY: The common pathway is initiated by the conversion of factorThe common pathway is initiated by the conversion of factor X in into Xa. Activated Factor X (Xa) then convertsX in into Xa. Activated Factor X (Xa) then converts Prothrombin (II) into Thrombin (IIa), and for this Factor V,Prothrombin (II) into Thrombin (IIa), and for this Factor V, Calcium ions and Platelets are required. Thrombin thenCalcium ions and Platelets are required. Thrombin then converts fibrinogen (I) into fibrin monomers (IIa). The fibrinconverts fibrinogen (I) into fibrin monomers (IIa). The fibrin monomers form cross linking meshwork under the influencemonomers form cross linking meshwork under the influence of activated factor XIII . In this meshwork blood cells getof activated factor XIII . In this meshwork blood cells get entangled to form a clot.entangled to form a clot.
  79. 79. SEQUENCE OF HAEMOSTATIC EVENTS ATSEQUENCE OF HAEMOSTATIC EVENTS AT THE SITE OF VASCULAR INJURYTHE SITE OF VASCULAR INJURY The general sequence of events in haemostasis atThe general sequence of events in haemostasis at the site of vascular injury are:the site of vascular injury are: First Phase : Blood Vessel Wall Response:First Phase : Blood Vessel Wall Response: After injury,After injury, there is a brief period of arteriolarthere is a brief period of arteriolar VasoconstrictionVasoconstriction ,, largely attributable to reflex neurogenic mechanismslargely attributable to reflex neurogenic mechanisms and augmented by the local secretion of factors such asand augmented by the local secretion of factors such as endothelium derived vasoconstrictors. The effect isendothelium derived vasoconstrictors. The effect is transient and bleeding will resume if platelets andtransient and bleeding will resume if platelets and coagulation system are not activated.coagulation system are not activated. Second Phase: Platelets Adhesion, Activation, ShapeSecond Phase: Platelets Adhesion, Activation, Shape change, Release Reaction and Aggregation:change, Release Reaction and Aggregation: EndothelialEndothelial injury exposes highly thrombogenic subendothelialinjury exposes highly thrombogenic subendothelial matrix, which allows platelets to adhere and becomematrix, which allows platelets to adhere and become activated that is, to undergo a shape change and releaseactivated that is, to undergo a shape change and release secretary granules. Within minutes the secretedsecretary granules. Within minutes the secreted products have recruited additional platelets to form aproducts have recruited additional platelets to form a haemostatic plughaemostatic plug ((Primary Haemostatic Plug)Primary Haemostatic Plug)
  80. 80. Third Phase: Activation of Intrinsic and Extrinsic PathwaysThird Phase: Activation of Intrinsic and Extrinsic Pathways of Coagulation:of Coagulation: Tissue FactorTissue Factor a membrane bound procagulant factor,a membrane bound procagulant factor, synthesized by endothelium, is also exposed at the sitesynthesized by endothelium, is also exposed at the site of injury. It acts in conjunction with the secreted plateletof injury. It acts in conjunction with the secreted platelet factors to activate the coagulation cascade, culminatingfactors to activate the coagulation cascade, culminating in the activation ofin the activation of ThrombinThrombin . In turn, thrombin converts. In turn, thrombin converts circulating soluble fibrinogen to insoluble fibrin resultingcirculating soluble fibrinogen to insoluble fibrin resulting in local fibrin deposition. Thrombin also induces furtherin local fibrin deposition. Thrombin also induces further platelet recruitment and granule release. Whole thisplatelet recruitment and granule release. Whole this sequence is calledsequence is called Secondary Haemostasis.Secondary Haemostasis. Polymerized fibrin and platelets aggregates form aPolymerized fibrin and platelets aggregates form a solid,solid, permanent plugpermanent plug to prevent any furtherto prevent any further haemorrhage.haemorrhage. Dissolution of ClotDissolution of Clot :: Once the clot is formed counterOnce the clot is formed counter regulatory mechanisms, likeregulatory mechanisms, like Fibrinolytic SystemFibrinolytic System are setare set into action to restrict the haemostatic plug to the site ofinto action to restrict the haemostatic plug to the site of injuryinjury
  81. 81. The involvement of blood vessels, platelets and blood coagulation in hemostasis
  82. 82. Screening TestsScreening Tests ForFor BloodBlood CoagulationCoagulation
  83. 83. Screening Tests of BloodScreening Tests of Blood CoagulationCoagulation Screening tests provide an assessment of the ‘extrinsic’ and ‘intrinsic’Screening tests provide an assessment of the ‘extrinsic’ and ‘intrinsic’ systems of blood coagulation and also the central conversion ofsystems of blood coagulation and also the central conversion of fibrinogen into fibrinfibrinogen into fibrin.. Prothrombin Time (PT) :Prothrombin Time (PT) :Measures factors VII, X, V, prothrombin andMeasures factors VII, X, V, prothrombin and fibrinogen. Tissue thrombopolastin (a brain extract) and calcium arefibrinogen. Tissue thrombopolastin (a brain extract) and calcium are added to citrated plasma. The normal time for clotting is 10-14 seconds.added to citrated plasma. The normal time for clotting is 10-14 seconds. (measures extrinsic & common pathway).(measures extrinsic & common pathway). Activated Partial Thromboplastin Time (APTT):Activated Partial Thromboplastin Time (APTT):Measures factorsMeasures factors VIII, IX, XI and XII in addition to factor, X, V, prothrombin andVIII, IX, XI and XII in addition to factor, X, V, prothrombin and fibrinogen. Three substances, phospholipids, a surface activator (e.g.fibrinogen. Three substances, phospholipids, a surface activator (e.g. kaolin) and calcium- are added to citrated plasma. The normal time forkaolin) and calcium- are added to citrated plasma. The normal time for clotting is about 30-40 seconds. (Measures intrinsic & commonclotting is about 30-40 seconds. (Measures intrinsic & common pathway).pathway). Thrombin Time (TT):Thrombin Time (TT): is sensitive to a deficiency of fibrinogen.is sensitive to a deficiency of fibrinogen. Diluted bovine thrombin is added to citrated plasma at a concentrationDiluted bovine thrombin is added to citrated plasma at a concentration giving a clotting time of 14-16 seconds with normal subjectgiving a clotting time of 14-16 seconds with normal subject..
  84. 84. Screening Tests of Blood Coagulation-InterpretationScreening Tests of Blood Coagulation-Interpretation Prothrombin Time: (PT)Prothrombin Time: (PT) Abnormalities indicated by prolongation: Deficiency or inhibition of oneAbnormalities indicated by prolongation: Deficiency or inhibition of one or more of the following coagulation factors: VII, X, V, IV, fibrinogen.or more of the following coagulation factors: VII, X, V, IV, fibrinogen. Most common cause of prolonged PT:Most common cause of prolonged PT: 1.1. Liver diseaseLiver disease 3.3. D.I.CD.I.C 2.2. Warfarin therapyWarfarin therapy 4.4. Heparin therapyHeparin therapy    Activated Partial Thromboplastin Time (APTT)Activated Partial Thromboplastin Time (APTT) Abnormalities indicated by prolongation: Deficiency or inhibition of oneAbnormalities indicated by prolongation: Deficiency or inhibition of one oror more of the following coagulation factors: XII, XI, IX (Christmas diseasemore of the following coagulation factors: XII, XI, IX (Christmas disease oror Haemophilia B) VIII (haemphilia A) X, V, II, fibrinogen.Haemophilia B) VIII (haemphilia A) X, V, II, fibrinogen. Most common causes of prolonged APTT:Most common causes of prolonged APTT: 1.1. HemophiliaHemophilia 3.3. D.I.C.D.I.C. 2.2. Christmas diseaseChristmas disease 4.4. Heparin therapyHeparin therapy III)Thrombin Time (TT)III)Thrombin Time (TT) Abnormalities indicated by prolongation: Deficiency or abnormality ofAbnormalities indicated by prolongation: Deficiency or abnormality of
  85. 85. Anticoagulant Therapy- MonitoringAnticoagulant Therapy- Monitoring Oral Anticoagulant Parental Anticoagulant -Prothrombin Time (PT) -INR -Activated Partial Thromboplastin TIME (APTT)
  86. 86. Anti-clotting MechanismsAnti-clotting Mechanisms One of the major functions of homeostasis is to keep the blood in fluidOne of the major functions of homeostasis is to keep the blood in fluid state. When a clot forms repair mechanisms start which close the gap instate. When a clot forms repair mechanisms start which close the gap in the blood vessel permanently and at the same time the clot which isthe blood vessel permanently and at the same time the clot which is formed is gradually broken down so that the circulation may be re-formed is gradually broken down so that the circulation may be re- established. Besides this, clotting should also be limited to the requiredestablished. Besides this, clotting should also be limited to the required site. This is achieved by anticlotting mechanisms.site. This is achieved by anticlotting mechanisms. The substances which normally keep the blood in the fluid state are:The substances which normally keep the blood in the fluid state are:   (i)(i)Anti thrombin IIIAnti thrombin III   (ii)(ii) Protein CProtein C   (iii)(iii) Protein SProtein S (iv)(iv) Tissue factor Pathway InhibitorTissue factor Pathway Inhibitor    Once the clot is formed then its lysis takes places byOnce the clot is formed then its lysis takes places by fibrinolyticfibrinolytic systemsystem..
  87. 87. Coagulation Factors- Summary -Coagulation occurs via sequential enzymatic conversion of a cascade of circulating and locally synthesized proteins -Tissue factor elaborated at sites of injury is the most important initiator of the coagulation cascade in vivo -At the final stage of coagulation , thrombin converts fibrinogen into insoluble fibrin that contributes to formation of the definitive haemostatic plug -Coagulation normally is restricted to sites of vascular injury by: - Limiting enzymatic activation to phospholipid surfaces provided by activate platelets or endothelium - natural anticoagulants elaborated at sites of endothelial injury or during activation of coagulation cascade - Expression of thrombomodulin on normal endothelial cells, which binds thrombin and converts it into and anticoagulant - Activation of fibrinolytic system ( e.g., by association of tissue palsminogen activator with fibrin_
  88. 88. THROMBOSISTHROMBOSIS The formation of a clotted mass of blood within the nonThe formation of a clotted mass of blood within the non interrupted cardiovascular system is termed thrombosis,interrupted cardiovascular system is termed thrombosis, and the mass itself Thrombusand the mass itself Thrombus Thrombosis is the formation of a solid mass from theThrombosis is the formation of a solid mass from the constituents of blood (platelets, fibrin and entrapped red and whiteconstituents of blood (platelets, fibrin and entrapped red and white cells) within the heart or vascular system in a living organism.cells) within the heart or vascular system in a living organism. Thrombosis Vs Blood ClotThrombosis Vs Blood Clot:: TheThe thrombosis is usuallythrombosis is usually distinguished fromdistinguished from Blood ClotBlood Clot although the distinction isalthough the distinction is somewhat arbitrary and both invoke the coagulation cascade.somewhat arbitrary and both invoke the coagulation cascade. Clotting occurs in tissues when blood escapes from an injuredClotting occurs in tissues when blood escapes from an injured vessel (hematoma formation) . It also occurs in vessels after deathvessel (hematoma formation) . It also occurs in vessels after death (postmortem clotting of blood) and in vitro ( in a test tube outside(postmortem clotting of blood) and in vitro ( in a test tube outside the body) . A thrombus is generally attached to the endothelium andthe body) . A thrombus is generally attached to the endothelium and is composed of layers of aggregated platelets and fibrin ,is composed of layers of aggregated platelets and fibrin , whereas a blood clot contains randomly oriented fibrin withwhereas a blood clot contains randomly oriented fibrin with entrapped platelets and red cellsentrapped platelets and red cells Clearly the development of a blood clot is life saving when aClearly the development of a blood clot is life saving when a large vessel ruptures or severed. However, when a thrombuslarge vessel ruptures or severed. However, when a thrombus develops in the unruptured cardiovascular system, it may be lifedevelops in the unruptured cardiovascular system, it may be life threateningthreatening
  89. 89. SUMMARY OF THROMBOGENESISSUMMARY OF THROMBOGENESIS 1.Endothelial injury releases tissue factor and exposes sub endothelial connective tissues 2. Platelet adherence and plasma clotting system are triggered. 3. Granule release and prostaglandin generation begins 4. Platelet aggregation induced by released ADP and vasoconstriction (5HT, Thromboxane) result in primary (temporary) haemostatic plug. 5. Thrombin, thromboxanes, and endoperoxiedes promote releases reaction and irreversible aggregation. Platelet mass and trapped red cells are enmeshed in fibrin to form definitive (permanent) haemostatic plug. 6. Endothelial plasmnogen activator and plasma antithrombin check rapid clotting
  90. 90. PATHOGENESIS OF THROMBOSISPATHOGENESIS OF THROMBOSIS Three primary influences predispose to thrombus formation, theThree primary influences predispose to thrombus formation, the so calledso called Virchow’s Triad:Virchow’s Triad: (i) Endothelial Injury(i) Endothelial Injury (ii) Stasis or turbulence of blood flow(ii) Stasis or turbulence of blood flow (iii) Blood Hypercoagubality(iii) Blood Hypercoagubality Virchow’s Triad in Thrombosis: Endothelial injury is the single most important factor. Note that injury to endothelial cells can affect local blood flow and/or coagulability. Abnormal blood flow (stasis or turbulence) in turn, cause endothelial injury.The factors may act independently or may combine to cause thrombus formation
  91. 91. I.I.ENDOTHELIAL INJURYENDOTHELIAL INJURY Endothelial damage stimulates both plateletEndothelial damage stimulates both platelet adhesion and activation of the coagulation cascade.adhesion and activation of the coagulation cascade. Endothelial injury is frequently an initiating factor whenEndothelial injury is frequently an initiating factor when thrombus occurs in the arterial circulation. Whenthrombus occurs in the arterial circulation. When thrombosis occurs in veins and in microcirculation thenthrombosis occurs in veins and in microcirculation then endothelial injury is less conspicuous.endothelial injury is less conspicuous. Common causes of endothelial injury are:Common causes of endothelial injury are: (i) In heart and arterial circulation the endothelial injury(i) In heart and arterial circulation the endothelial injury is seen in myocardial infarction and valvulitis.is seen in myocardial infarction and valvulitis. (ii) Toxins from inflammatory processes(ii) Toxins from inflammatory processes (iii) local compression of vessels (e.g., during operation)(iii) local compression of vessels (e.g., during operation)
  92. 92. II.II.ALTERATIONS IN BLOOD FLOWALTERATIONS IN BLOOD FLOW The two factors which contributes to formation of thrombosisThe two factors which contributes to formation of thrombosis by altering the normal blood flow are:by altering the normal blood flow are: (i)(i) Turbulence in Blood Flow:Turbulence in Blood Flow: Turbulence means deviation ofTurbulence means deviation of the blood stream which become distorted and abnormally hitsthe blood stream which become distorted and abnormally hits the vascular and cardiac lining ; thus not only deviating thethe vascular and cardiac lining ; thus not only deviating the platelets towards the endothelium, but also lead to endothelialplatelets towards the endothelium, but also lead to endothelial damage. It contributes todamage. It contributes to arterial and cardiac thrombosisarterial and cardiac thrombosis (ii)(ii) Stasis in Blood Flow:Stasis in Blood Flow: It is the major factor in theIt is the major factor in the development ofdevelopment of venous thrombosisvenous thrombosis The normal blood flow isThe normal blood flow is LAMINARLAMINAR. In laminar blood flow. In laminar blood flow the cellular elements flow centrally in the vessel lumen,the cellular elements flow centrally in the vessel lumen, separated from endothelium by a slower moving clear zone ofseparated from endothelium by a slower moving clear zone of plasma. Stasis and turbulence then leads to thrombosis inplasma. Stasis and turbulence then leads to thrombosis in following manner:following manner: a. They disrupt laminar blood flow and bring platelets ina. They disrupt laminar blood flow and bring platelets in contact with the endothelium.contact with the endothelium. b. They prevent dilution of activated clotting factors byb. They prevent dilution of activated clotting factors by freshfresh flowing blood.flowing blood. c. They retard the inflow of clotting factor inhibitors andc. They retard the inflow of clotting factor inhibitors and permit the build up of thrombi.permit the build up of thrombi. d. Promote endothelial cell activation, predisposing to locald. Promote endothelial cell activation, predisposing to local thrombosis.thrombosis.
  93. 93. III.III.HYPERCOAGULABILITYHYPERCOAGULABILITY Hypercoagulability contributes less frequently to thrmobotic states but it is anHypercoagulability contributes less frequently to thrmobotic states but it is an important component in thrombosis. It is defined asimportant component in thrombosis. It is defined as any alteration in theany alteration in the coagulation pathway that predisposes to thrombosiscoagulation pathway that predisposes to thrombosis It can be divided into primary (genetic) and secondary (acquired) disordersIt can be divided into primary (genetic) and secondary (acquired) disorders PRIMARY (Genetic) HYPERCOAGULABLE STATES:PRIMARY (Genetic) HYPERCOAGULABLE STATES:  Mutations in Factor V (Factor V Leiden)Mutations in Factor V (Factor V Leiden)  Antithrombin III deficiencyAntithrombin III deficiency  Protein C or S deficiencyProtein C or S deficiency  HomocystenemiaHomocystenemia  Allelic variation in Prothrombin levelAllelic variation in Prothrombin level SECONDARY (Acquired) HYPERCOAGULABLE STATES:SECONDARY (Acquired) HYPERCOAGULABLE STATES:  Prolonged bed rest or immobilizationProlonged bed rest or immobilization  Myocardial infarctionMyocardial infarction  Tissue damage( Surgery, fracture, burn)Tissue damage( Surgery, fracture, burn)  CancerCancer  Antiphospholipid Antibody syndrome (Lupus Anticoagulant)Antiphospholipid Antibody syndrome (Lupus Anticoagulant)  Oral ContraceptivesOral Contraceptives  SmokingSmoking  Heparin Induced Thrombocytpenia with Thrombosis (HITT)Heparin Induced Thrombocytpenia with Thrombosis (HITT)
  94. 94. 9898 InheritedInherited TThrombophiliahrombophilia -- Factor V Leiden mutationFactor V Leiden mutation (Resistance to activated protein C)(Resistance to activated protein C) - Prothrombin gene mutation- Prothrombin gene mutation ((Hyperprothrombinemia -Hyperprothrombinemia - prothrombin variant G20210Aprothrombin variant G20210A)) - Protein S deficiency- Protein S deficiency - Protein C deficiency- Protein C deficiency - Antithrombin (AT) deficiency- Antithrombin (AT) deficiency - Dysfibrinogenemia- Dysfibrinogenemia - Hyperhomocysteinemia- Hyperhomocysteinemia
  95. 95. 9999 AcquiredAcquired Hypercoagulable DHypercoagulable Disordersisorders  MalignancyMalignancy  Presence of a central venousPresence of a central venous cathetercatheter  Surgery, especially orthopedicSurgery, especially orthopedic  TraumaTrauma  ImmobilizationImmobilization  Congestive failureCongestive failure  PregnancyPregnancy  Oral contraceptivesOral contraceptives  Hormone replacement therapyHormone replacement therapy  Antiphospholipid antibodyAntiphospholipid antibody syndromesyndrome  Myeloproliferative disordersMyeloproliferative disorders  Polycythemia veraPolycythemia vera  Essential thrombocythemiaEssential thrombocythemia  Paroxysmal nocturnalParoxysmal nocturnal hemoglobinuriahemoglobinuria  Tamoxifen, Thalidomide,Tamoxifen, Thalidomide, LenalidomideLenalidomide  Inflammatory bowel diseaseInflammatory bowel disease  Nephrotic syndromeNephrotic syndrome
  96. 96. Mutations in Factor V Laiden:Mutations in Factor V Laiden:  There is a substutitution for the normal argenine residue atThere is a substutitution for the normal argenine residue at position 506 of factor V.position 506 of factor V. Due to this mutation factor VDue to this mutation factor V cannot be inactivated by cleavage at the usual argininecannot be inactivated by cleavage at the usual arginine residue and is therefore resistant to anticoagulantresidue and is therefore resistant to anticoagulant effect of activated protein C.effect of activated protein C.  The patients with this mutation usually present with recurrentThe patients with this mutation usually present with recurrent thrombosis and recurrent abortionsthrombosis and recurrent abortions Primary (Genetic) Hypercoagulable StatesPrimary (Genetic) Hypercoagulable States
  97. 97. Antithrombin III, Protein C and S DeficiencyAntithrombin III, Protein C and S Deficiency::  Patients with this deficiency usually present withPatients with this deficiency usually present with deep venous thrombosis and recurrentdeep venous thrombosis and recurrent thromboembolism in adolescence or early adult life.thromboembolism in adolescence or early adult life. Primary (Genetic) Hypercoagulable StatesPrimary (Genetic) Hypercoagulable States
  98. 98. Antithrombin III, Protein C and S DeficiencyAntithrombin III, Protein C and S Deficiency::  Patients with this deficiency usually present withPatients with this deficiency usually present with deep venous thrombosis and recurrentdeep venous thrombosis and recurrent thromboembolism in adolescence or early adult life.thromboembolism in adolescence or early adult life. Primary (Genetic) Hypercoagulable StatesPrimary (Genetic) Hypercoagulable States
  99. 99. 103103 Prothrombin Gene MutationProthrombin Gene Mutation  A single –nucleotide substitution (G to A) in the 3 ‘ –untranslatedA single –nucleotide substitution (G to A) in the 3 ‘ –untranslated region of the prothrombin gene is a fairly common alleleregion of the prothrombin gene is a fairly common allele  This variant results in increased prothrombin transcription and isThis variant results in increased prothrombin transcription and is associated with a nearly three fold increased risk for venousassociated with a nearly three fold increased risk for venous thormbosesthormboses  Prothrombin (factor II) is the precursor of thrombin, the end-Prothrombin (factor II) is the precursor of thrombin, the end- product of the coagulation cascadeproduct of the coagulation cascade  Heterozygous carriers have 30Heterozygous carriers have 30%% higher plasma prothrombin levelshigher plasma prothrombin levels than normalsthan normals  Heterozygous carriers haveHeterozygous carriers have an increased risk of deep vein andan increased risk of deep vein and cerebral vein thrombosiscerebral vein thrombosis Primary (Genetic) Hypercoagulable StatesPrimary (Genetic) Hypercoagulable States
  100. 100. 104104 Hereditary thrombophiliaHereditary thrombophilia  Characteristics:Characteristics: - thrombosis without any predisposing conditionthrombosis without any predisposing condition - thrombosis at young agethrombosis at young age - thrombosis in unusual sitesthrombosis in unusual sites (upper extremities, mesenteric vessels, hepatic or portal veins)(upper extremities, mesenteric vessels, hepatic or portal veins) - family history of thrombosisfamily history of thrombosis Neonatal purpura fulminans (homozygous PC or PS deficiency)Neonatal purpura fulminans (homozygous PC or PS deficiency)
  101. 101. Antiphospohlipid Antibody SyndromeAntiphospohlipid Antibody Syndrome:: Anti-phospohlipid antibodies are directed againstAnti-phospohlipid antibodies are directed against epitopes on the surface of plasma proteins. Theseepitopes on the surface of plasma proteins. These antibodies produce hyper-coagulable state by directantibodies produce hyper-coagulable state by direct platelet activation, inhibition of prostacyclin, andplatelet activation, inhibition of prostacyclin, and interference in Protein C synthesis. The patients withinterference in Protein C synthesis. The patients with these antibodies usually present with recurrentthese antibodies usually present with recurrent thrombosis and repeated miscarriagesthrombosis and repeated miscarriages Acquired (Secondary ) Hypercoagulable StatesAcquired (Secondary ) Hypercoagulable States
  102. 102. Oral Contraceptives Use and Pregnancy:Oral Contraceptives Use and Pregnancy:  In these conditions there is increased hepatic synthesisIn these conditions there is increased hepatic synthesis of many coagulant factors and reduced synthesis ofof many coagulant factors and reduced synthesis of antithronbin IIIantithronbin III Acquired (Secondary ) Hypercoagulable StatesAcquired (Secondary ) Hypercoagulable States
  103. 103. Heparin Induced Thrombocytopenia with ThrombosisHeparin Induced Thrombocytopenia with Thrombosis (HITT)(HITT)  Occurs in 5% patients treated with unfracftionatedOccurs in 5% patients treated with unfracftionated heparin (for therapeutic anticoagulation)heparin (for therapeutic anticoagulation)  Antibodies are formed against heprin and plateletAntibodies are formed against heprin and platelet membrane protein (platelet factor 4)membrane protein (platelet factor 4)  These antibodies may also bind similar complexesThese antibodies may also bind similar complexes present on platelet and endothelial surfaces , resultingpresent on platelet and endothelial surfaces , resulting in platelet activation, aggregation and consumptionin platelet activation, aggregation and consumption (hence Thrombocytopenia), as well as causing(hence Thrombocytopenia), as well as causing endothelial injuryendothelial injury  Overall result is aOverall result is a pro-thrombotic state, evenpro-thrombotic state, even in the face of heparin administration andin the face of heparin administration and low platelet countlow platelet count Acquired (Secondary ) Hypercoagulable StatesAcquired (Secondary ) Hypercoagulable States
  104. 104. TYPES OF THROMBITYPES OF THROMBI A thrombus is easily recognized as a solid mass in the lumen of aA thrombus is easily recognized as a solid mass in the lumen of a blood vessel that is often attached to the vessel wall.blood vessel that is often attached to the vessel wall. PALE THORMBIPALE THORMBI RED THROMBIRED THROMBI Thrombi in the fastThrombi in the fast flowingflowing arterialarterial circulationcirculation areare composed predominantlycomposed predominantly of fibrin and platelets,of fibrin and platelets, with few entrappedwith few entrapped erythrocytes – hence theerythrocytes – hence the term Pale Thrombusterm Pale Thrombus Typically occurs inTypically occurs in venous circulationvenous circulation ,, where the slowerwhere the slower blood flow encouragesblood flow encourages entrapment of redentrapment of red cells. They arecells. They are composed of platelets,composed of platelets, fibrin and largefibrin and large numbers ofnumbers of erythrocytes trappederythrocytes trapped in the fibrin mesh.in the fibrin mesh.
  105. 105. SITES OF THROMBOSISSITES OF THROMBOSIS I.I. ARTERIAL THROMBOSIS:ARTERIAL THROMBOSIS: Arterial thrombosis is common and typically occurs afterArterial thrombosis is common and typically occurs after endothelial damage and local turbulence has been caused byendothelial damage and local turbulence has been caused by atheroscleorsis.Large and medium sized arteries such as the aorta,atheroscleorsis.Large and medium sized arteries such as the aorta, carotid arteries, arteries of circle of Willis, coronary arteries, andcarotid arteries, arteries of circle of Willis, coronary arteries, and arteries of the intestine and limbs are mainly affectedarteries of the intestine and limbs are mainly affected Mural Thrombi:Mural Thrombi: When arterial thrombi arise in heart chambers or inWhen arterial thrombi arise in heart chambers or in aortic lumen, they are usually adherent to the wall of underlyingaortic lumen, they are usually adherent to the wall of underlying structure and are termed Mural Thrombi.structure and are termed Mural Thrombi. Lines of Zahn: When arterial thrombus is formed in the heart or aorta, thrombi may have grossly (and microscopically) apparent laminations called lines of Zahn; these are produced by alternating pale layers of platelets admixed with some fibrin and darker layers containing more red blood cells
  106. 106. II.II.VENOUS THROMBOSISVENOUS THROMBOSIS 1.1. PHLEBOTHROMBOSISPHLEBOTHROMBOSIS :: It denotes venous thrombosis occurring inIt denotes venous thrombosis occurring in the absence of obvious inflammation. Phlebothrombosis occursthe absence of obvious inflammation. Phlebothrombosis occurs mostlymostly in deep veins of the legin deep veins of the leg ((Deep Venous Thrombosis ; DVT)Deep Venous Thrombosis ; DVT) Deep venous thrombosis is common and has important medical implications because the large thrombi that form in these veins are often easily detached. They travel in the circulation to the heart and lung and lodge in the pulmonary arteries (Pulmonary Embolism) Venous Thrombus in Femoral Vein: Femoral vein opened to reveal a thrombus
  107. 107. 2.2. THROMBOPHELIBITISTHROMBOPHELIBITIS :: It denotes venous thrombosisIt denotes venous thrombosis occurring secondary to acute inflammation .occurring secondary to acute inflammation . Thrombophelibitis is a common phenomenon in infectedThrombophelibitis is a common phenomenon in infected wounds or ulcers and characteristically involves thewounds or ulcers and characteristically involves the superficial veins and the extremities . The effected veinsuperficial veins and the extremities . The effected vein is firm and cord like and shows signs of acuteis firm and cord like and shows signs of acute inflammation (pain, redness, warmth, swelling). This typeinflammation (pain, redness, warmth, swelling). This type of thrombus is firmly attached to the vessel wall and theyof thrombus is firmly attached to the vessel wall and they rarely embolize.rarely embolize.
  108. 108. III.III. CARDIAC THROMBOSISCARDIAC THROMBOSIS In Different circumstances Thrombi are formed inIn Different circumstances Thrombi are formed in different locations inside the heart:different locations inside the heart: 1.1. Thrombi may occur in ventricles after MyocardialThrombi may occur in ventricles after Myocardial InfarctionInfarction 2.2. Thrombi may occur in Atria in Atrial FibrillationThrombi may occur in Atria in Atrial Fibrillation 3.3. Thrombi may be formed in Heart Valves in RheumaticThrombi may be formed in Heart Valves in Rheumatic Endocarditic or in Infective EndocarditicEndocarditic or in Infective Endocarditic
  109. 109. FATE OF THROMBOSISFATE OF THROMBOSIS If a patient survives the immediate effects of a thromboticIf a patient survives the immediate effects of a thrombotic vascular obstruction, thrombi undergo some combination of thevascular obstruction, thrombi undergo some combination of the following five events in the ensuing days or weeksfollowing five events in the ensuing days or weeks
  110. 110. Thrombus- FateThrombus- Fate •PropagationPropagation •EmbolizationEmbolization •DissolutionDissolution •Organization and RecanalizationOrganization and Recanalization
  111. 111. 1. Lysis of the thrombosis and complete resolution of normal structure usually can occur only when the thrombus is relatively small and is dependent upon the activity of Fibrinolytic System 2. Organization : The thrombus may be replaced by scar tissue which contracts and obliterates the lumen; the blood bypasses the occluded vessel through collateral circulation 3. Dystrophic Calcification 4. Recanalization: Occasionally some of the capillaries dilate and allow the passage of blood through the thrombus or the fibrosed thrombus shrinks from the vascular wall leaving a space which gets lined by endothelium. 5.Propagation: The thrombus may accumulate more platelets and fibrin and eventually leads to vessel obstruction
  112. 112. 5. Emoblization: Emboli can result from fragmentation of the thrombus and can result in infarction at a distant site
  113. 113. THROMBUSTHROMBUS CLOTCLOT Occurs inside cardiovascularOccurs inside cardiovascular systemsystem Occurs inside or outside theOccurs inside or outside the cardiovascular systemcardiovascular system Occurs during life in circulatingOccurs during life in circulating bloodblood Occurs during life or after deathOccurs during life or after death in stagnant bloodin stagnant blood Contains platelets ( e.g., lines ofContains platelets ( e.g., lines of Zhan)Zhan) No plateletsNo platelets FirmFirm SoftSoft Firmly adherent to theFirmly adherent to the cardiovascular sitecardiovascular site Loosely adherentLoosely adherent Pale, red or mixedPale, red or mixed Red or yellowRed or yellow
  114. 114. Thrombosis – Summary A thrombus is a solid mass of blood constituents formed within the vascular system in life. Predisposing factors (Virchow’s triad) :abnormalities of the vessel wall; abnormalities of blood flow; abnormalities of the blood constituents. Arterial thrombosis is most commonly superimposed on athermoa Venous thrombosis is most commonly due to stasis Clinical consequences include: arterial thrombosis (tissue infarction distally); venous thrombosis (oedema, due to impaired venous drainage); and embolism
  115. 115. EMBOLISMEMBOLISM ••““An Embolus is a detached intravascular solid,An Embolus is a detached intravascular solid, liquid or gaseous mass that is carried by the bloodliquid or gaseous mass that is carried by the blood to a site distant from its point of origin”to a site distant from its point of origin” ••Virtually 99% of the emboli represent some part of aVirtually 99% of the emboli represent some part of a dislodged thrombus, hence the commonly used termdislodged thrombus, hence the commonly used term ThromboembolismThromboembolism.. ••Inevitably, emboli lodge in vessels too small to permitInevitably, emboli lodge in vessels too small to permit further passage, resulting in partial or complete vascularfurther passage, resulting in partial or complete vascular occlusion. The potential consequences of suchocclusion. The potential consequences of such thromboembolic events is the ischemic necrosis of distalthromboembolic events is the ischemic necrosis of distal tissue known astissue known as InfarctionInfarction
  116. 116. ThrombosisThrombosis EmbolismEmbolism Emboli lodge in vessels too smallEmboli lodge in vessels too small to permit further passageto permit further passage Partial or complete vascular occlusionPartial or complete vascular occlusion InfarctionInfarction
  117. 117. TYPES OF EMBOLITYPES OF EMBOLI 1.1. ThromboembolismThromboembolism (i) Pulmonary Thromboembolism(i) Pulmonary Thromboembolism (ii) Systemic Thromboembolism(ii) Systemic Thromboembolism 2.2. Fat EmbolismFat Embolism 33. Air Embolism. Air Embolism 4.4. Amniotic Fluid EmbolismAmniotic Fluid Embolism 5.5. Nitrogen Gas Embolism (Decompression Sickness)Nitrogen Gas Embolism (Decompression Sickness)
  118. 118. I.I. PULMONARY THROMBOEMBOLISMPULMONARY THROMBOEMBOLISM Cause and Incidence:Cause and Incidence: The most serious form ofThe most serious form of thrombembolism is pulmonary embolism, which maythrombembolism is pulmonary embolism, which may cause sudden death. It has an incidence of 20 to 25 percause sudden death. It has an incidence of 20 to 25 per 100,000 hospitalized patients100,000 hospitalized patients Over 90% of Pulmonary Emboli originate in the deep veinsOver 90% of Pulmonary Emboli originate in the deep veins of the leg (phelebothrombosis)of the leg (phelebothrombosis) .. More rarely, thrombi inMore rarely, thrombi in pelvic venous plexus are the source.pelvic venous plexus are the source. Pulmonary embolism is common in the following conditionsPulmonary embolism is common in the following conditions that predispose to the development of phlebothrombosis:that predispose to the development of phlebothrombosis: (i)(i) Immediate post operative periodImmediate post operative period (ii)(ii) Immediate post partum periodImmediate post partum period (iii)(iii) Lengthy immobilization in bedLengthy immobilization in bed (iv)(iv) Cardiac FailureCardiac Failure (v)(v) use of Oral Contraceptivesuse of Oral Contraceptives
  119. 119. CLINICAL EFFECTS OF PULMONARY EMBOLISMCLINICAL EFFECTS OF PULMONARY EMBOLISM The size of the embolus is the factor most influencing theThe size of the embolus is the factor most influencing the clinical effects of pulmonary embolismclinical effects of pulmonary embolism 1.1. Massive Emboli:Massive Emboli: Large emboli (several centimeter long)Large emboli (several centimeter long) maymay lodge in the outflow tract of the right ventricle or inlodge in the outflow tract of the right ventricle or in the main pulmonary artery,the main pulmonary artery, where they cause circulatorywhere they cause circulatory obstruction andobstruction and Sudden DeathSudden Death .. 2.2. Medium Sized Emboli:Medium Sized Emboli: obstruction of medium sizedobstruction of medium sized arteriesarteries may causemay cause Pulmonary InfarctPulmonary Infarct 3.3. Small Emboli:Small Emboli: Small emboli lodge in minor branches ofSmall emboli lodge in minor branches of pulmonary artery with no immediate effects. In manypulmonary artery with no immediate effects. In many instances, the emboli either fragment soon afterinstances, the emboli either fragment soon after lodgment of dissolve during fibrinolysis, in which caselodgment of dissolve during fibrinolysis, in which case clinical effects are minimal. If numerous small emboliclinical effects are minimal. If numerous small emboli occur over a long period, however, the pulmonaryoccur over a long period, however, the pulmonary microcirculation may be so severely compromised thatmicrocirculation may be so severely compromised that Pulmonary Hypertension resultsPulmonary Hypertension results
  120. 120. II.II.SYSTEMIC THROMBOEMBOLISMSYSTEMIC THROMBOEMBOLISM Causes:Causes:Thromboembolism occurs in systemic arteries whenThromboembolism occurs in systemic arteries when the detached thrombus originates in the left side of thethe detached thrombus originates in the left side of the heart or a large artery.heart or a large artery. Systemic arterial thromboembolism commonly occurs:Systemic arterial thromboembolism commonly occurs: 1.1. In patients who have infective endocarditic withIn patients who have infective endocarditic with vegetations on the mitral and aortic valves.vegetations on the mitral and aortic valves. 2.2. In patients who have suffered myocardial infarction inIn patients who have suffered myocardial infarction in which mural thrombus has occurred.which mural thrombus has occurred. 3.3. In patients with mitral stenosis and arterial thrombosis.In patients with mitral stenosis and arterial thrombosis. 4.4. In patients with aortic and ventricular aneurysms, whichIn patients with aortic and ventricular aneurysms, which contain mural thrombicontain mural thrombi
  121. 121. Clinical Effects of Systemic Thromboembolism:Clinical Effects of Systemic Thromboembolism: In contrast to venous emboli,which tend to lodgeIn contrast to venous emboli,which tend to lodge primarily in one vascular bed (the lung), arterial emboliprimarily in one vascular bed (the lung), arterial emboli can travel to a wide variety of sites . The site of arrestcan travel to a wide variety of sites . The site of arrest depends on the point of origin of the thromboembolismdepends on the point of origin of the thromboembolism and the volume of blood flow through the down streamand the volume of blood flow through the down stream tissues. The major sites for arterial embolization are thetissues. The major sites for arterial embolization are the lower extremities (75%) and the brain (10%)., withlower extremities (75%) and the brain (10%)., with intestines, kidneys, spleen and upper extremitiesintestines, kidneys, spleen and upper extremities involved to a lesser extent.involved to a lesser extent. The consequences of systemic emboli depend onThe consequences of systemic emboli depend on any collateral vascular supply in the affected tissue, theany collateral vascular supply in the affected tissue, the tissue vulnerability to ischemia, and the caliber of thetissue vulnerability to ischemia, and the caliber of the vessel occluded. In general, however, arterial embolivessel occluded. In general, however, arterial emboli cause infarction of tissues in the distributution of thecause infarction of tissues in the distributution of the obstructed vessel.obstructed vessel.
  122. 122. III.III.FAT EMBOLISMFAT EMBOLISM Causes:Causes: Fat Embolism occurs when globules of fat enter theFat Embolism occurs when globules of fat enter the bloodstream, typicallybloodstream, typically after fractures of large bones(eg,after fractures of large bones(eg, femur) have exposed the fatty bone marrowfemur) have exposed the fatty bone marrow .. Although fatAlthough fat globules can be found in the circulation in as many asglobules can be found in the circulation in as many as 90% of patients who have sustained serious fractures,90% of patients who have sustained serious fractures, few patients demonstrate clinically significant signs of fatfew patients demonstrate clinically significant signs of fat embolism.embolism. Clinical Effects of Fat Embolism:Clinical Effects of Fat Embolism: Fat embolism syndromeFat embolism syndrome typically begins 1 to 3 days after injury, with suddentypically begins 1 to 3 days after injury, with sudden onset of tachypnea, dyspnea and tachycardia . Besidesonset of tachypnea, dyspnea and tachycardia . Besides pulmonary insufficiency, the syndrome is characterized bypulmonary insufficiency, the syndrome is characterized by neurological symptoms,including irritability andneurological symptoms,including irritability and restlessness, which can prgress to delirium or coma. Arestlessness, which can prgress to delirium or coma. A diffuse petechial rash in non dependent areas occurringdiffuse petechial rash in non dependent areas occurring in the absence of thrombocytopenia is seen in 20 to 30%in the absence of thrombocytopenia is seen in 20 to 30% of cases and is useful in establishing a diagnosis.of cases and is useful in establishing a diagnosis. The typical clinical features of fat embolism include aThe typical clinical features of fat embolism include a Haemorrhagic skin rash, dyspnea, tachycardia,Haemorrhagic skin rash, dyspnea, tachycardia, tachypnea, irritability and restlessness.tachypnea, irritability and restlessness.
  123. 123. IV.IV.AIR EMBOLISMAIR EMBOLISM CAUSESCAUSES:: a.a. Surgery of or Trauma to internal Jugular vein:Surgery of or Trauma to internal Jugular vein: In injuriesIn injuries to the internal jugular vein, the negative pressure in theto the internal jugular vein, the negative pressure in the thorax tends to suck air into the jugular vein. Thisthorax tends to suck air into the jugular vein. This phenomenon does not occur in injuries to other systemicphenomenon does not occur in injuries to other systemic veins because they are separated by valves from theveins because they are separated by valves from the negative pressure in the chestnegative pressure in the chest b.b. Child birth or Abortion:Child birth or Abortion: Air embolism may occur duringAir embolism may occur during childbirth or abortion, when air may be forced intochildbirth or abortion, when air may be forced into ruptured placental venous sinuses by forcefulruptured placental venous sinuses by forceful contractions of uterus.contractions of uterus. c.c. Blood Transfusion:Blood Transfusion: Air embolism during blood transfusionAir embolism during blood transfusion occurs only if positive pressure is used to transfuse theoccurs only if positive pressure is used to transfuse the blood and only if the transfusion is not discontinued atblood and only if the transfusion is not discontinued at its completion.its completion. Clinical Effects of Air Embolism:Clinical Effects of Air Embolism: When air enters the bloodWhen air enters the blood stream, it passes into the right ventricle, creating a frothystream, it passes into the right ventricle, creating a frothy mixture that effectively obstructs the circulation andmixture that effectively obstructs the circulation and causes death.causes death.
  124. 124. V.V.NITROGEN GAS EMBOLISMNITROGEN GAS EMBOLISM (DECOMPRESSION SICKNESS)(DECOMPRESSION SICKNESS) CAUSE:CAUSE: Decompression sickness is a form of embolism thatDecompression sickness is a form of embolism that occurs in Caisson workers and undersea divers if theyoccurs in Caisson workers and undersea divers if they ascend too rapidly after being submerged for longascend too rapidly after being submerged for long periods. This disorder is also called theperiods. This disorder is also called the BendsBends oror Caisson DiseaseCaisson Disease .. (Caissons are high pressure underwater chambers used for(Caissons are high pressure underwater chambers used for deep water construction work)deep water construction work) When air is breathed under high underwaterWhen air is breathed under high underwater pressure, an increased volume of air, mainly oxygen andpressure, an increased volume of air, mainly oxygen and nitrogen, goes into solution in the blood and equilibratesnitrogen, goes into solution in the blood and equilibrates with the tissues . If decompression to sea level is toowith the tissues . If decompression to sea level is too rapid, the gases that equilibrated in the tissues come outrapid, the gases that equilibrated in the tissues come out of solution. Oxygen is rapidly absorbed into the blood,of solution. Oxygen is rapidly absorbed into the blood, but nitrogen gas coming out of solution can not bebut nitrogen gas coming out of solution can not be absorbed rapidly enough and forms bubbles in theabsorbed rapidly enough and forms bubbles in the tissues and blood stream that acts as emboli.tissues and blood stream that acts as emboli.
  125. 125. Clinical Effects of Nitrogen Gas EmbolismClinical Effects of Nitrogen Gas Embolism Platelets adhere to nitrogen gas bubbles in thePlatelets adhere to nitrogen gas bubbles in the circulation an activate coagulation cascade. The resultingcirculation an activate coagulation cascade. The resulting disseminated intravascular coagulation aggravates thedisseminated intravascular coagulation aggravates the ischemic state caused by impaction of gas bubbles inischemic state caused by impaction of gas bubbles in capillaries. Involvement of brain in severe cases maycapillaries. Involvement of brain in severe cases may cause extensive necrosis and death. In less severecause extensive necrosis and death. In less severe cases, nerve and muscle involvement causescases, nerve and muscle involvement causes severesevere muscle contractions with intense pain (the bends)muscle contractions with intense pain (the bends) .. Nitrogen gas emboli in lungs causeNitrogen gas emboli in lungs cause Severe difficulty inSevere difficulty in breathing (the chokes)breathing (the chokes) that is associated with alveolarthat is associated with alveolar edema and haemorrhageedema and haemorrhage
  126. 126. VI.VI. AMNIOTIC FLUID EMBOLISMAMNIOTIC FLUID EMBOLISM Cause:Cause: The underlying cause is infusion of amniotic fluidThe underlying cause is infusion of amniotic fluid into the maternal circulation via a tear in the placentalinto the maternal circulation via a tear in the placental membranes and rupture of uterine veins.membranes and rupture of uterine veins. Clinical Effects:Clinical Effects: Amniotic Fluid Embolism is a grave butAmniotic Fluid Embolism is a grave but uncommon complication of labour and the immediateuncommon complication of labour and the immediate postpartum period. It has a mortality of over 80%.Withpostpartum period. It has a mortality of over 80%.With the vastly increased pressures in the uterus duringthe vastly increased pressures in the uterus during labour, amniotic fluid may be forced into the maternallabour, amniotic fluid may be forced into the maternal uterine veins. These amniotic fluid emboli travel in theuterine veins. These amniotic fluid emboli travel in the circulation and lodge in the lungs, causing respiratorycirculation and lodge in the lungs, causing respiratory distress. The onset is characterized by sudden severedistress. The onset is characterized by sudden severe dyspnea, cyanosis, and hypotensive shock, followed bydyspnea, cyanosis, and hypotensive shock, followed by seizures and coma.seizures and coma.
  127. 127. AMNIOTIC FLUID EMBOLISM Two small pulmonary arterioles are packed with laminated swirls of foetal squamous cells. There is marked edema and congestion and elsewhere in the lung tissue there are small orgainzing thrombi , consistent with disseminated intravascular coagulation.
  128. 128. SummarySummary •• An Embolus is a mass of material in the vascularAn Embolus is a mass of material in the vascular system able to become lodged within a vessel andsystem able to become lodged within a vessel and block its lumen.block its lumen. •• Most Emboli are derived from Thrombi.Most Emboli are derived from Thrombi. ••Other types of embolic material include: AtheromatousOther types of embolic material include: Atheromatous plaque material, Vegetations on heart valves(infectiveplaque material, Vegetations on heart valves(infective endocarditic), Amniotic Fluid , Gas and Fat.endocarditic), Amniotic Fluid , Gas and Fat. ••Most common occurrence is Pulmonary Embolism fromMost common occurrence is Pulmonary Embolism from deep leg vein thrombosisdeep leg vein thrombosis
  129. 129. INFARCTIONINFARCTION Definition:Definition: An Infarct is an area of ischemicAn Infarct is an area of ischemic necrosis caused by occlusion of either thenecrosis caused by occlusion of either the arterial supply or venous drainage in aarterial supply or venous drainage in a particular tissueparticular tissue Nearly 99% of all infarcts result from thrombosis orNearly 99% of all infarcts result from thrombosis or embolic events and almost all result from arterialembolic events and almost all result from arterial occlusion. More rarely, obstruction of venous drainageocclusion. More rarely, obstruction of venous drainage results in infarction.results in infarction. Tissue infarction is a common and extremelyTissue infarction is a common and extremely important cause of clinical illness. Important clinicalimportant cause of clinical illness. Important clinical entities which are attributable to infarction are:entities which are attributable to infarction are: 1.1. Myocardial InfarctionMyocardial Infarction 2.2. Cerebral InfarctionCerebral Infarction 3.3. Pulmonary InfarctionPulmonary Infarction 4.4. Intestinal InfarctionIntestinal Infarction
  130. 130. CLASSIFICATION OF TYPES OF INFARCTCLASSIFICATION OF TYPES OF INFARCT The appearance of infarcts varies with the site .The appearance of infarcts varies with the site . Various classification schemes are usedVarious classification schemes are used A.A. PALE Versus RED INFARCTPALE Versus RED INFARCT B.B. SOLID Versus LIQUIFIED INFARCTSOLID Versus LIQUIFIED INFARCT C.C. STERILE Versus SEPTIC INFARCTSTERILE Versus SEPTIC INFARCT
  131. 131. A.A. PALE Versus RED INFARCTPALE Versus RED INFARCT Pale Infarct:Pale Infarct: Occur as a result of arterial obstruction in solidOccur as a result of arterial obstruction in solid organs such as heart, kidney, spleen and brain. Theseorgans such as heart, kidney, spleen and brain. These organs lack significant collateral circulation, and theorgans lack significant collateral circulation, and the solidity of the tissue limits the amount of haemorrhagesolidity of the tissue limits the amount of haemorrhage that can seep into the area of ischemic necrosis fromthat can seep into the area of ischemic necrosis from adjoining capillary bedsadjoining capillary beds Red or Haemorrhagic Infarct:Red or Haemorrhagic Infarct: (i) In tissues that have a double blood supply , e.g., lung,(i) In tissues that have a double blood supply , e.g., lung, intestines and liver permitting some continued flow intointestines and liver permitting some continued flow into the area although the amount is not sufficient to preventthe area although the amount is not sufficient to prevent infarction . The infarct is red because of extravasation ofinfarction . The infarct is red because of extravasation of blood in the infarcted area from necrotic small vessels.blood in the infarcted area from necrotic small vessels. (ii) With venous occlusion (such as in ovarian torsion)(ii) With venous occlusion (such as in ovarian torsion) (iii) In loose tissues (such as lung), which allow blood to(iii) In loose tissues (such as lung), which allow blood to collect in the infarcted zone.collect in the infarcted zone. (iv) In tissues that were previously congested because of(iv) In tissues that were previously congested because of sluggish venous outflowsluggish venous outflow (v) When flow is reestablished to a site of previous arterial(v) When flow is reestablished to a site of previous arterial occlusionocclusion
  132. 132. B .B . SOLID Versus LIQUEFIED INFARCTSOLID Versus LIQUEFIED INFARCT In all tissues other than brain, infarction usuallyIn all tissues other than brain, infarction usually produces coagulative necrosis of cells, leading to solidproduces coagulative necrosis of cells, leading to solid infarct. In brain, on the other hand, liquefactive necrosisinfarct. In brain, on the other hand, liquefactive necrosis of cells leads to the formation of a fluid mass in the areaof cells leads to the formation of a fluid mass in the area of infarction. The end result is a cystic cavityof infarction. The end result is a cystic cavity C.C. STERILE Versus SEPTIC INFARCTSTERILE Versus SEPTIC INFARCT Most infarcts are sterile. Septic infarcts areMost infarcts are sterile. Septic infarcts are characterized by secondary bacterial infection of thecharacterized by secondary bacterial infection of the necrotic tissue. Septic infarcts are characterized by acutenecrotic tissue. Septic infarcts are characterized by acute inflammation that frequently converts the infarcts to aninflammation that frequently converts the infarcts to an abscess. Secondary bacterial infection of an infarct mayabscess. Secondary bacterial infection of an infarct may also result in gangrene (e.g., intestine).also result in gangrene (e.g., intestine). Septic infarcts occur:Septic infarcts occur: 1. Due to presence of microorganisms, as in lesions of1. Due to presence of microorganisms, as in lesions of infective endocarditisinfective endocarditis 2. When infarction occurs in a tissue that normally contain2. When infarction occurs in a tissue that normally contain bacteria , e.g., intestinebacteria , e.g., intestine
  133. 133. Pale infarct : Spleen
  134. 134. Infarct brain
  135. 135. MORPHOLOGY OF INFARCTSMORPHOLOGY OF INFARCTS ●●Infarction occurs in tissue supplied by anInfarction occurs in tissue supplied by an artery that, when occluded leaves anartery that, when occluded leaves an insufficient collateral blood supply. Infarctsinsufficient collateral blood supply. Infarcts in kidney, spleen and lungs arein kidney, spleen and lungs are WedgeWedge ShapedShaped ,, with the occluded artery situatedwith the occluded artery situated near the apex of the wedge and the base ofnear the apex of the wedge and the base of the infarct located on the surface of thethe infarct located on the surface of the organorgan . The characteristic shape of infarcts. The characteristic shape of infarcts in these organs is due to symmetricin these organs is due to symmetric dichotomous branching pattern of thedichotomous branching pattern of the arteries supplying them.arteries supplying them. ●The cerebral and myocardial infarcts are irregular shaped and determined by the distribution of the occluded artery and the limits of collateral arterial supply.
  136. 136. Infarct of Intestine: Infarction may follow thrombosis of or embolization to the mesenteric arteries. The sequence of changes usually seen in solid organs is altered by the effects of anastomosis and, in later stages by Bacterial Invasion Infarct of Heart (Myocardial Infarction) Evolution of Myocardial Infarction: Changes are not evident in the initial hours. The dead tissue elicits an inflammatory reaction, characterized first by neutrophils then by macrophages. If no complications take place then the infarct heals by fibrosis and scar is formed
  137. 137. Infarct of Brain: These are usually due to thrombosis of diseased vessels or due to embolism from the left heart. The usual changes of infarction takes place, but the necrosis is liquefactive- cerebral softening.
  138. 138. EVOLUTION OF INFARCTEVOLUTION OF INFARCT ThrombosisThrombosis EmbolismEmbolism Occlusion of Blood Supply (Ischemia)Occlusion of Blood Supply (Ischemia) Necrosis of Parenchymal cells and Connective Tissue frame workNecrosis of Parenchymal cells and Connective Tissue frame work ( INFARCTION)( INFARCTION) Inflammatory responseInflammatory response Superadded BacterialSuperadded Bacterial InfarctionInfarction Releases of Lysosomal EnzymesReleases of Lysosomal Enzymes GangreneGangrene Heterolysis or AutolysisHeterolysis or Autolysis Macrophages Phagocytose liquefied debrisMacrophages Phagocytose liquefied debris In growth of granulation TissueIn growth of granulation Tissue Scar FormationScar Formation

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