Pathology

1. HEMODYNAMIC DISORDERS
• EDEMA
• HEAMOSTASIS (BLEEDING)
• THROMBOSIS
• EMBOLISM
• SHOCK

2. Distribution of Body Fluids
• Total body water (TBW) 60% of total body
weight
– Intracellular fluid – inside the cells
– Extracellular fluid – not encased in cells
• Interstitial fluid – found in between cells and tissues
• Intravascular fluid- plasma found in circulatory system
• Lymph, synovial, intestinal, biliary, hepatic, pancreatic,
CSF, sweat, urine, pleural, peritoneal, pericardial, and
intraocular fluids are extracellular

3. Edema

4. • Edema is defined as excess fluid in interstitial
compartment
Interstitial fluid is the balance between
• capillary hydrostatic pressure which tends to
encourage water to enter the interstitium
• plasma oncotic pressure which tends to
encourage water to leave the interstitium
• lymphatic drainage which allows water and
proteins to leave the interstitium

5. 1.Increased Capillary Hydrostatic Pressure
Normal situation
• pressure inside the capillary is greater than
pressure in the interstitial space
• water tends to flow out of the capillary into
the interstitium

6. 1.1.Edema production
• Increased hydrostatic pressure in the capillary
bed leads to increased rate of fluid loss into the
intestitium
• This is most commonly associated with impeded
outflow through venous system (increased
venous back pressure)
• Examples: congestive heart failure, portal
hypertension; localized: venous thrombosis,
varicose veins, pressure from outside (tumours)

7. 2.1`Edema production
• Reduced plasma proteins (especially albumin)
lead to reduced osmotic reabsorption of
interstitial fluid back into capillaries
• Associated with: loss of proteins (nephrotic
syndrome, protein losing enteropathies,
burns) or decreased production of albumin
(liver failure, protein malnutrition)

8. Morphology of edema
Grossly – easily recognizable

9. 3.Lymphatic obstruction
Normal situation
• lymphatic vessels begin as blind ended
capillaries in the interstitium
• they collect excess fluid (about 2ml/min) and
the small amount of protein that accumulate
in the interstitium; this fluid is returned to the
venous circulation via thoracic duct

10. 3.1.Edema production
• obstruction of lymphatics prevents removal of
excess interstitial fluid
• produces localized edema depending upon
which lymphatic drainage is obstructed
• examples: tumors (esp. metastatic to lymph
nodes) surgical removal of lymphatics (radical
mastectomy)
fibrosis and scaring (post-inflammatory or post-
radiation) parasites (filariasis)

12. 4.Sodium Retention
Normal situation
• sodium is the major determinant of the
osmolarity of extracellular fluid
• sodium therefore is a major influence in
extracellular fluid volume
• sodium levels are primarily controlled by
renal excretion,

13. 4.1Edema production
• increased sodium ! increased extracellular
fluid volume; that means
– a proportional increase in interstitial fluid
– increased blood volume ! increased
hydrostatic pressure
• usually occurs on the basis of impaired renal
excretion of sodium (decreased blood flow to
the kidneys,renal disease)

15. 5. Increased Capillary Permeability
• leads to loss of fluid and protein into
interstitium
• usually produces localized edema associated
with inflammation (blisters, hives), burns,
allergic reaction

16. 6.Congestive Heart Failure
• A syndrome that occurs when the heart does
not pump an adequate volume of blood to
meet the needs of the body (decreased
cardiac output).

17. 6.1.Edema production is associated with:
– sodium retention, which leads to increased
blood volume
– increased venous back pressure due to
inability of the heart to effectively pump the
blood that is returned to it

18. 7.Renal disease
• Decreased renal blood flow and some intrinsic
renal diseases lead to sodium retention and thus
production of edema.
8.Nephrotic syndrome
• Massive loss of protein in urine, accompanied by
hypoproteinemia, and generalized edema.
Associated with glomerular damage..

19. 8.1.Mechanism of edema in nephrotic syndrome
1. increased glomerular capillary permeability to proteins
2. loss of protein (especially albumin) in urine
3. hypoalbuminemia
4. decreased colloid osmotic pressure
5. movement of fluid from intravascular space to
interstitium leads to decreased blood volume
6. that leads to activation of renin-angiotensin system
7. results in retention of sodium and water

20. 9.Cirrhosis of the Liver
9.1. Pathogenesis of edema in cirrhosis
1. Scarring and reorganization of liver architecture
obstructs blood flow through the liver; and high
arterial pressure is transmitted into portal system. This
mechanisms lead to increased hydrostatic pressure in
portal system. Ascites is formed.
2. Loss of functioning hepatocytes!decreased production
of albumines and other plasma proteins!decreased
oncotic pressure of the plasma.

21. Hemostasis and thrombosis
• Normal hemostasis – rapid and localized
hemostatic plug formation at a site of vascular
injury.
• Thrombosis
– Pathologic opposite to hemostasis.
– Inappropriate activation of normal hemostatic
process:
• Clot(thrombus) in uninjured vessel
• Thrombotic occlusion of a vessel after minor injury

22. • Both hemostasis and thrombosis depends on
3 components:
– Vascular wall
– Platelet
– Coagulation cascade

23. Normal hemostasis
• Sequence of events at sites of vascular injury:
1. Arteriolar vasoconstriction
2. Primary hemostasis(platelet plug)
3. Secondary hemostasis – fibrin deposition
4. Permanent plug
• Polymerized fibrin and platelet aggregate
5. Counter regulatory response
• Restricts hemostatic plug at site of injury
• Tissue plasminogen activator

25. ENDOTHELIUM
• Antithrombotic and prothrombotic properties.
• The balance b/n antithrombotic and
prothrombotic activities determines whether
thrombus formation, propagation or
dissolution occurs.
• Intact endothelium – antithrombotic
• Injury or activation – prothrombotic
– Hemodynamic factors, cytokines, infectious agents

26. Antithrombotic properties
• Antiplatelet
– Endothelial plasma membrane
– Prostacyclin(PGI2)
– Nitric oxide
– Adenosine diphosphatase
• Anticoagulant
– Membrane associated heparin-like molecules
– Thrombomodulin – thrombin receptor

27. • Fibrinolytic
– Tissue plasminogen activator(t-PA)
– Clear fibrin deposits

28. Prothrombotic properties
• Platelet adhesion
– Exposure of ECM components
– Von willebrand factor(vWF)
• Procoagulant
– Synthesis of tissue factor
– Augmentation of effects of clotting factors
• IXa , Xa
• Antifibrinolytic
– Inhibitors of plasminogen activator(PAIs)

29. PLATELETS
• The interplay of PGI2 and TXA2 constitutes an
exquisitely balanced mechanism for modulating
human platelet function:
– in the normal state, it prevents intravascular platelet
aggregation, but
– after endothelial injury it favors the formation of
hemostatic plugs.
• The clinical use of aspirin (a cyclooxygenase
inhibitor) in patients at risk for coronary
thrombosis is related to its ability to inhibit the
synthesis of TXA2.

30. COAGULATION CASCADE
• 3rd component of hemostatic process.
• Major contributor to thrombosis.
• Once activated the coagulation cascade must
be restricted to the site of vascular injury.

31. • Clotting is regulated by 3 anticoagulants:
1. Antithrombin III
• Activated by heparin-like molecules
• Inhibit thrombin, IXa, Xa, XIa, XIIa,
2. Protein c and s
• Inactivates factors Va and VIIIa.
• Protein c is activated by thrombomodulin
3. Plasmin
• Derived from serum plasminogen
• Inhibit fibrin polymerization
• Degrade fibrin to fibrin degradative products

32. THROMBOSIS
• Definition: The formation of a solid or semisolid mass
from the constituents of the blood within the
vascular system during life.
• PATHOGENESIS:
• Three predisposing factors for thrombus formation (
virchow’s triad)
• Endothelial injury
• Stasis or turbulence of blood flow
• Blood hypercoagulability

34. 1. Endothelial injury
– Most important factor in thrombus formation
– Will expose to the highly thrombogenic sub
endothelial ECM (collagen &tissue
factors)platelet adherence &contact
activation.
– E.g-thrombus in endocardium following
infarction or on ulcerated atheromatous plaques
in artery walls.

35. 2. stasis or turbulence blood flow
• Normal blood flow is laminar.
• Stasis & turbulence
– bring platelets to the surface
– Reduce PGI2 ,
– t-PA
• Stasis- major factor in venous thrombi
• Turbulence –arteries and cardiac thrombosis

36. • E.g- ulcerated plaqueturbulence
• Aneurysms- site of stasis
• myocardial infarction-site of stasismural
thrombus formation
• mitral valve stenosisdilated left atrium-site
of stasis
• polycytemiastasis in small blood vessels.

37. 3. hypercoagulability
• Definition: any alteration of the coagulation
pathway that predisposes to thrombosis
• Can be divided in to:
• Primary(genetic)
• Secondary(acquired)

38. • 1. Primary
• Mutations in factor V(Lieden factor)
• Mutation in prothrombin gene
• Antithrombin III deficiency
• Protein C or S deficiency

39. • 2. Secondary
• Can be categorized into:
a. High risk for hypercoagulability
– Prolonged immobilization
– Myocardial infarction
– Tissue damage(surgery, burns fracture)
– Cancers(release procoagulant tissue products)
– artificial cardiac valves
– DIC

40. • b. low risk factors
• Atrial fibrillation
• Cardiomyopathy
• NS
• Oral contraceptives
• Smoking
• Hyper estrogenic states E.g –pregnancy

41. Morphology
• Can develop anywhere in the cardiovascular system
cardiac chambers ,valve cusps,
arteries, veins,
capillaries
-variable size and shape
-usually have area of attachment to the underlying
vessel

42. Cardiac valve thrombosis/vegitation

44. • The most common site of arterial thrombi In
ascending order
• femoral arteries
• Cerebral arteries
• Coronary arteries

45. Fates of thrombus
• Propagation
• Embolization
• Organization &recanalization
• Dissolution

47. a. Propagation
– Thrombus may accumulate more platelets & fibrin and
propagate to cause vessel obstruction
b. Embolization
– May dislodge &travel to other sites in the
vasculatureEmbolusobstruction of vesselsdeath of
tissues and cells Infarction
E.g- thromboembolismcerebral infarction

48. c. Organization and recanalization
in growth of endothelial cells ,smooth
muscle cells & fibroblastscapillary channels
lumen formationRecanalization
d. Dissolution
• Thrombus may be removed by fibrinolytic
activity

49. • Clinical significance of thrombi
• Thrombi are clinically significant because:
– Causes blood vessel obstruction
– Possible sources of emboli

50. • Clinical effects of arterial &venous thrombi:
• A. Venous thrombosis(phlebothrombosis)
• Affects the lower extremity veins~90%
• Divided in to –superficial and
• -deep venous thrombosis
• 1. Suprficial VT
• Usually occurs in saphenous venous system
• E.g-in varicosities
• Predisposes to infection after slight traumaVaricous Ulcer
• Rarely embolizes
• Causes local edema ,pain ,tenderness(i.e symptomatic

51. • 2. Deep Vein Thrombosis (DVT)
• May embolize, hence serious
• Occurs in deep veins of calf muscles
• May cause pain , edema
• Asymptomatic in ~50%, because of collateral bypass
channels.
• Higher incidence in middle aged &elderly people
,due to increased platelet aggregation& decreased
PGI2 by endothelium

52. • DVT has the following predisposing factors:
• 1. trauma, surgery, burns-result in:-
• Reduced physical activity
• Injury to vessels
• Procoagulant release from tissues
• Reduced t-PA activity(fibrinolysis)

53. • 2. pregnancy &puerperal states
• Increase coagulation factors& decrease
synthesis of antithrombic substances
• 3. myocardial infarction& heart
failurestasis in the left side

54. Embolism
• Definition: Embolus –detached intravascular
solid, liquid or gaseous mass that is carried by
blood to sites distant from its point of origin.

55. • Causes of embolism:
• Embolus can arise from:-
• Thrombus(90% casesthromboembolus)
• Platelet aggregates
• fragment of a tumor
• fat globules
• bubbles of air
• fragment of material from ulcerating atheromatous plaque
• amniotic fluid
• infected foreign material
• bites of bone marrow
• etc…..
• NB: Unless specified embolismthromboembolism

56. • Thromboembolism
• based on the site of origin &impaction-divided
in to:
a. Pulmonary thromboemblism(PTE)
b. Systemic thromboembolism

57. • a. Pulmonary thromboembolism
• Embolus in the pulmonary arteries &their
branches
• Derived from thrombus in the systemic veins
or right side of the heart.
• ~95% arise from deep leg veins
• Follows venous returnpulmonary arteries

58. Pulmonary Thromboembolism
Embolus migrates from deep leg veins through venous system to pulmonary circulation

59. • Depending on size of embolus &state of pulmonary
circulation can have the following effects:
• 1.if large thrombusblock right ventricle out flow or
bifurcation of the main pulmonary trunc(saddle
embolus) or both of its branches sudden
circulatory arrest and Death
• It may result in cor pulmonale or CVA collapse if 60%
of blood volume is obstructed.

60. • 2.very small embolus(60-80% of cases)
• Clinically silent,
• obstruction of medium sized arteries ->
pulmonary haemorrhage but not
infarction,because collaterals from bronchial
circulation.
• but in poor cardioresparatory
condition,medium arteries
obstructionpulmonary infarction.

61. • Small end-arterial vessel obstruction causes
infarction.
• Recurrent thromboembolismpulmonary
hypertension in the long run
• NB: A patient who had one pulmonary
embolus is at high risk of having more.

62. • b. Systemic thromboembolism
• 80% arise from intracardiac mural thrombi
• 2/3 of intramural thrombi associated with left
ventricular wall infarcts &1/4 with dilated left atria 2°
to rheumatic heart diseases.
• 20% emboli arise from aortic aneurysm, thrombi on
ulcerated atherosclerotic plaques, or fragmentation
of valvular vegetation.
• Major sites of embolization: lower extremities(75%),
brain(10%), rest ,intestines, kidneys, spleen.

63. SHOCK
• Definition: is a state /failure of the circulatory system
to maintain adequate cellular perfusion resulting in
widespread reduction in delivery of oxygen &other
nutrients to tissues.
• systemic hypoperfusion -due to
• - co
• -ineffective circulating blood volume
• Hypotension impaired tissue perfusion &cellular
hypoxia

64. Classification of shock
a. hypovolumic shock
b. cardiogenic shock
c. distributive shock-septic shock
-neurogenic shock
-anaphylactic shock
-endocrine shock

65. • A. Hypovolumic shock
• Definition: shock due to reduced blood
volumeCOtissue perfusion
• causes:
• 1. Haemorrhage
• 2. Diarrhea & vomiting
• 3. trauma, burns, etc....
• most common shock in clinical medicine
• loss of >25% of blood volumeshock

66. • B. Cardiogenic shock
• Definition: shock results from sever depression of
cardiac performance.
• primarily-pump failure(myocardial failure)
• hemodynamically-.
• Causes:
1 .myopathic
2. Mechanical

67. 1. myopathic
a. acute MI-if >40% Lt Ventricle &more on Rt ventricle infarction
b. myocarditis
c. cardiomyopaties
d. myocardial depression in septic shock

68. • 2. Mechanical
• Intracardiac
• a. out flow obstruction- E.g-AS
• b. arrhythmia
• c .reduction in forward CO E.g-AR,MR
• Extra cardiac
• Obstructive shock
• a. pericardial tamponade
• b. tension pneumothorax
• c. acute sever PTE (50-60% pulmonary bed involved)
• d. sever pulmonary HTN(10)

69. • C. Distributive shock
• Definition: refers to a group of shock subtypes caused by profound
peripheral vasodilatation despite normal or high cardiac output.
• Causes:
• 1. Septic shock-commonest
• 2. Neurogenic shock-in anesthetic procedure, in spinal cord injury
• -owing to loss of vascular tone &peripheral pooling of blood.
• 3. Anaphylactic shock
• -by generalized Ige mediated hypersensitivity response, associated with
systemic vasodilatation &increased vascular permeability.

70. • 4. Endocrine shock
• -typically occurs in adrenal insufficiency
e.g tubrculous adrenalitis

71. • Aspects of sepsis(terms):
• Bacteremia-presence of viable bacteria in the blood
as evidenced by blood culture.
• Septicemia- presence of microbes or their toxin in
the blood.
• SIRS – two or more of the following conditions
– Fever or hypothermia
– Tachypnea(>24/min)
– Tachycardia(>90/min)
– Leucocytosis or leucopenia

72. • Sepsis – SIRS with proven or suspected
microbial etiology.
• Septic shock – sepsis with hypotension(arterial
blood pressure <90 mmHg systolic, or 40
mmHg less than patient's normal blood
pressure) for at least 1 h despite adequate
fluid resuscitation.

73. SEPTIC SHOCK
• Can be defined as: sepsis+ hypotension+ organ
dysfunction &unresponsive to fluid
administration.
• kind of shock by microbial infection
• by G-ve-most common (endotoxic shock)
• can also occur in G+ve or fungal infections

74. Stages of Shock
• Shock is a progressive disorder that if uncorrected leads to death.
• shock tends to evolve through three stages.
• These stages have been documented most clearly in hypovolemic
shock but are common to other forms as well:
1. An initial nonprogressive stage during which reflex compensatory
mechanisms are activated and perfusion of vital organs is
maintained .
2. A progressive stage characterized by tissue hypoperfusion and
onset of worsening circulatory and metabolic imbalances .
3. An irreversible stage that sets in after the body has incurred
cellular and tissue injury so severe that even if the hemodynamic
defects are corrected, survival is not possible.

75. • In the early nonprogressive phase of shock,
various neurohumoral mechanisms help
maintain cardiac output and blood pressure.
• Neurohumoral mechanisms:
– baroreceptor reflexes,
– release of catecholamines,
– activation of the renin-angiotensin axis,
– antidiuretic hormone release, and
– generalized sympathetic stimulation.

76. • The net effect is tachycardia, peripheral
vasoconstriction, and renal conservation of fluid.
• Cutaneous vasoconstriction is responsible for the
characteristic coolness and pallor of skin in shock
(although septic shock may initially cause cutaneous
vasodilation and thus present with warm, flushed skin).
• Coronary and cerebral vessels are less sensitive to the
sympathetic response and thus maintain relatively
normal caliber, blood flow, and oxygen delivery to their
respective vital organs.

77. • the progressive phase, during which there is
widespread tissue hypoxia.
• In the setting of persistent oxygen deficit,
intracellular aerobic respiration is replaced by
anaerobic glycolysis with excessive production of
lactic acid.
• The resultant metabolic lactic acidosis lowers the
tissue pH and blunts the vasomotor response;
arterioles dilate, and blood begins to pool in the
microcirculation.

78. • Peripheral pooling not only worsens the
cardiac output but also puts endothelial cells
at risk of developing anoxic injury with
subsequent DIC.
• With widespread tissue hypoxia, vital organs
are affected and begin to fail;
• clinically, the patient may become confused,
and the urinary output declines.

79. • an irreversible stage.
– Widespread cell injury is reflected in lysosomal
enzyme leakage, further aggravating the shock state.
– Myocardial contractile function worsens, in part
because of nitric oxide synthesis.
– If ischemic bowel allows intestinal flora to enter the
circulation, endotoxic shock may also be
superimposed.
– At this point, the patient has complete renal
shutdown due to acute tubular necrosis and, despite
heroic measures, the downward clinical spiral almost
inevitably culminates in death.