How to teach thrombosis and infarction

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How to teach thrombosis and infarction

• Dr. Udaya Kumar.M. MD.,
• Professor
• Department of pathology
• Sri Devaraj Urs Medical College
• Tamaka. Kolar.
• karnataka.

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Plan of teaching

• Vessels and their histology
• Normal hemostasis
• Thrombosis
• infarction

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• Cardiovascular system
• Heart and blood vessels

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Hemostasis and Thrombosis
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Components of Blood

• Plasma proteins, electrolytes and water
• Cells RBCs, WBCs PLTs

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Normal hemostasis is the result of a set of
well-regulated processes that accomplish two
important functions (1) They maintain blood in
a fluid, clot-free state in normal vessels
(2) They are
poised to induce a rapid and localized hemostatic
plug at a site of vascular injury.
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NORMAL HEMOSTASIS

• The general sequence of events in hemostasis at
  the site of vascular injury
•     There is a brief period of arteriolar
  vasoconstriction,
• reflex neurogenic mechanisms
  and
• local secretion of factors
  such as endothelin
•     Primary hemostasis Exposure of
  subendothelial extracellular matrix (ECM)
• platelets to adhere gt activated gt release
  secretory granules gt aggregation gt Hemostatic
  plug
•     Secondary hemostasis Tissue factor
  secreted platelet factors gt activate the
  coagulation cascade gt activation of thrombin
• fibrin clot, resulting in local
  fibrin deposition.
• further platelet recruitment
  and granule release
•    Activation of counterregulatory mechanisms,
  t-PA are set into motion to limit the hemostatic
  plug to the site of injury

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Diagrammatic representation of the normal
hemostatic process A, transient
vasoconstriction B, Platelets adhere to exposed
extracellular matrix (ECM) via von Willebrand
factor (vWF) and are activated, undergoing a
shape change and granule release released
adenosine diphosphate (ADP) and thromboxane A2
(TxA2) lead to further platelet aggregation to
form the primary hemostatic plug. C, Local
activation of the coagulation cascade (involving
tissue factor and platelet phospholipids) results
in fibrin polymerization, "cementing" the
platelets into a definitive secondary hemostatic
plug. D, Counter-regulatory mechanisms, such as
release of tissue type plasminogen activator
(t-PA) (fibrinolytic) and thrombomodulin
(interfering with the coagulation cascade), limit
the hemostatic process to the site of injury.
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Hemostasis Adhesion and Recruitment
Diagram from Robbins Pathologic Basis of Diseases
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Hemostasis Thrombin activation
Diagram from Robbins Pathologic Basis of Diseases
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Hemostasis - Plug
Diagram from Robbins Pathologic Basis of Diseases
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Endothelium

• Antithrombotic properties
• Antiplatelet effects
• Anticoagulatn effects
• Fibrinolytic effects
• Prothrombotic propertities
• Platelets effects
• Procoagulant effects
• Antifibrinolytic effects

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Antithrombotic effects

• Antiplatelet effect
• Intact endothelium,PGI 2,NO,ADP ase.
• Anticoagulant effect
• Membrane _at_ heparin like molecule
• Thrombomodulin
• Tissue factor pathway inhibitor
• Fibrinolytic effects
• t -PA

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Prothrombotic property

• Platelet effect
• v WF,product of normal endothelium
• Procoagulant effect
• Tissue factor- activation of extrinsic cascade
• Antifibrinolytic effects
• Secreting inhibitors of palsminogen inhibitors,
  which depress fibrinolysis.

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Endothelium
Antithrombotic Properties Antiplatelet,
anticoagulant fibrinolytic effects Prothrombotic
Properties vWF, TNF, IL1, Antifibrinolytic
effects
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Platelets
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Platelet granules

• Alpha granules
• Express P selectin
• Fibrinogen
• Fibronectin
• Factor V
• Factor VIII
• Platelet factor
• PDGF
• TGF beeta

• Dense bodies
• ADP
• ATP
• Ionized calcium
• Histamine
• Serotonin
• Epinephrine

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Extracellular matrix

• Collagen
• Proteoglycans
• Fibronectin
• Adhesive glycoproteins

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Platelet reaction- general

• Adhesion and shape change
• Secretion (release reaction)
• Aggregation

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Platelet adhesion

• Platelet surface receptor vWF-collagen
• vWF gpIb _at_ can withstand shear force of flowing
  blood.

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Platelet secretion

• Paltelet activation- phospholipid complex
  expression-activation of intrinsic pathway.

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Platelet aggregation

• ADP TX A2- autocatalytic reaction- builds up
  enlarging platelet aggregate.-Reversible
• Thrombin generation-platelet contraction-viscous
  metamorphosis- irreversible.
• Secondary hemostastic plug
• Fibrinogen to fibrin- cementing platelets

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Coagulation cascade
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Coagulation cascade

• Has Two pathways converging onto a Common
  pathway Intrinsic Extrinsic.
• Each reaction has an
• -Enzyme Activated Coagulation factor.
• -Substrate Proenzyme form of factor
• -Cofactor Reaction accelerator
• -Product Activated Factor.

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Clotting regulated by 3 natural anticoagulants

• Antithrombin
• - Inhibit activity of thrombin and serine
  proteases- IXa Xa,XIa,XIIa,
• -Acts by binding to heparin like molecules
• Protein C and protein S
• Vitamin K dependent proteins
• Tissue factor pathway inhibitor

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The fibrinolytic system
The fibrinolytic system, illustrating the
plasminogen activators and inhibitors
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Fibrinolytic cascadelimits the size of the clot

• Generation of plasmin
• Derived from plasminogen
• Tissue type PA
• Urokinase type of PA
• Plasmin breaks down fibrin and interferes with
  polymerization
• FDP,s are weak anticoagulants

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Thrombosis
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Definition

• Thrombus a blood clot.
• Thrombosis a pathological process whereby there
  is formation of a blood clot in uninjured
  vasculature or after relatively minor injury.

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The Hemostatic Balance
Procoagulant Factors
Anticoagulant Factors
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Definition

• Embolus
• A detached intravascular solid, liquid or
  gaseous mass that is carried by the blood to a
  site distant from its point of origin.

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Abnormal Blood Flow
Abnormal Vessel Wall
Abnormal Blood

• The Hypercoagulable State
• Primary (genetic)
• Secondary (acquired)

Dr. Rudolph Virchow 1821-1902
Virchows triad
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ENDOTHELIAL INJURY
THROMBOSIS
ABNORMAL BLOOD FLOW
HYPERCOAGULABILITY
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Endothelial Injury

• Dominant factor
• Sufficient as the sole factor
• Examples include
• Myocardial infarction
• Ulcerated atheromatous plaques
• Hemodynamic injury such as hypertension,
  turbulent flow over heart valves
• Endotoxins, inflammation, etc

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Endothelial injury

• Physical loss of endothelium
• Exposure of subendothelium
• Dysfunctional endothelium
• Release of procoagulant factors
• Less synthesis of anticoagulants
• Subtle influences
• Homocystinuria,hypercholesterolemia,
• radiation,cigarette smoke

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Endothelial injury

• Thrombus in cardiac chambers
• Over atherosclerotic plaques
• Sites of trauma
• Vasculitis

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Atherosclerosis involving aorta
Normal aorta for comparison
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Arterial Thrombosis
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Polyarteritis nodosa (PAN)
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Polyarteritis nodosa (PAN)
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Giant cell arteritis
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Acquired/Environmental Thrombotic Factors
Immobility Blood stasis Surgery Cancer Pregna
ncy Oral Contraception Hormone Replacement
Therapy
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Abnormal Blood Flow

• Turbulence in arterial flow as a result of
  changes in the diameter of the vessel leading to
  non-laminar flow, resulting in
• Platelet coming into contact with endothelium.
• Prevent dilution by fresh flowing blood of
  activated clotting factors.
• Retard inflow of clotting factor inhibitors.
• Promote endothelial cell activation predisposing
  to local thrombosis.

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Hemodynamic DisordersVascular Rheology Laminar
Flow
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Hemodynamic DisordersVascular Rheology - Stenosis
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Hemodynamic DisordersVascular Rheology -
Turbulence
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Clinical settingsturbulence and stasis -
thrombosis

• Ulcerated atheromatous plaque
• Aneurysms
• Myocardial infarction
• Mitral valve stenosis
• Hyperviscosisty syndromes
• Sickle cell anemia

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Thrombosis
Venous Deep Vein Thrombosis Pulmonary
Embolism Arterial Myocardial
Infarction Stroke
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Hypercoagulability

• Defined as
• any alteration of the coagulation pathways
  that predispose to thrombosis

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Hypercoagulability

• Alteration of the coagulation pathway that
  predisposes to thrombosis
• Higher viscosity of blood changing the flow
  dynamics of blood

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Leiden mutation

• Substitution of G for A _at_ 506
• Resistance to inactivation by protein C
• Va gets unchecked coagulation

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Homocysteine

• Arterial and venous thrombosis
• Inhibition of antithrombin III endothelial
  thrombomodulin
• Acquired / inherited
• Homozygosity for C677T mutation in
  methyltetrahydrofolate reductase gene

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Polymorphism in coagulant genes

• impart increased risk of venous thrombosis

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Loss of Function Mutations
Natural Anticoagulant Proteins Antithrombin Prot
ein C Protein S
0.02 0.2 of General Population 1-3 prevalence
in Thrombosis Population Stronger Risk Factors
For VTE 10 to 25-fold
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Genetic Associations and Hemostasis
Hemophilia Single Gene Mutation
Thrombosis Multigenic
Environmental Factors
Single Gene Disorder
Genetic diagnosis available
Genetic pathogenesis still under investigation
Genetic therapy feasible
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XII XIIa
XI XIa
IX IXa
VIIIaCaPl
X Xa
VaCaPl
II IIa
Fibrinogen Fibrin
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State - - Mechanism

• Pregnancy-/OC use
• Disseminated cancer
• Advanced age
• Smokign obesity

• Increased synthesis of coagulation factors
  reduced synthesis of antithrombin III
• Heterozygosity for Factor V Leiden
• Release of procoagulant factors
• Increased susceptibility to platelet aggregation
• Reduced PGI2 secretion by endothelium
• Unknown mechanisms

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Heparin induced thromobocytopenia

• On administration of unfractionated heparin used
  for Rx
• Induces antibodies that bind to complexes on
  platelet and endothelial surfaces
• Results in platelet activation, endothelial
  injury,prothrombotic state
• Low molecular wt heparin are used instead

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Antiphospholipid antibody syndrome

• Multiple thrombosis
• High titers of antibodies against anionic
  phospholipids. ex. prothrombin.
• in vivo- hypercoagulable state
• In vitro interfere with assembly of phospholipid
  complexes that inhibit coagulation

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Antiphospholipid antibody syndrome

• Two categories
• Well defined _at_ with autoimmune disease
• Ex .SLE
• 2.Primary antiphospolipid syndrome

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APL Ab syndrome? Hypercoagulable state

• Not clear mechanism
• Direct platelet activation
• Inhibition of PGI2 production by endothelial
  cells
• Interference with protein C synthesis/ activity

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Antiphospholipid antibody syndrome clinical
features

• Recurrent venous arterial thrombi
• Repeated miscarriages cardiac valvular
  vegetations
• Thromocytopenia
• Renal microangiopathy
• Renovascular HTN
• Pulmonary embolism
• Deep leg, hepatic, rtinal veins- venous thrombosis

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Morphology of thrombus

• Thrombi may develop anywhere in the
  cardiovascular system within the cardiac
  chambers on valve cusps or in arteries, veins,
  or capillaries.
• They are of variable size and shape
• Arterial or cardiac thrombi usually begin at a
  site of endothelial injury (e.g., atherosclerotic
  plaque) or turbulence (vessel bifurcation)
• Venous thrombi characteristically occur in sites
  of stasis.
• Characteristic of all thromboses firmly
  attached at the point of origin
• Growth of thrombi Arterial thrombi grow in a
  retrograde direction
• Venous
  thrombi - grow in the direction of blood flow
• Complication Embolus.

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• Lines of Zahn
• Mural thrombi
• Arterial thrombi
• Venous thrombosis, or phlebothrombosis
• Vegetations

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Aortic aneurysm with thrombus formation note
the Lines of Zahn
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Lines of Zahn"
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Vegetations in Infective endocarditis involving
the aortic valve
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Infected prosthetic valve with vegetations
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Libman-Sacks endocarditis
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Venous thrombi Vs PM clots

• Postmortem clots are gelatinous
• A dark red dependent portion where red cells have
  settled by gravity and a yellow chicken fat
  supernatant resembling melted and clotted chicken
  fat
• They are usually not attached to the underlying
  wall
• In contrast, red thrombi are firmer, almost
  always have a point of attachment, and on
  transection reveal vague strands of pale gray
  fibrin.

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Venous thrombi Vs PM clots
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Fate of a Thrombus

• Four events in the ensuing days to weeks
• The thrombus may propagate
• The thrombus may become organised and recanalised
• The thrombus may become organised and
  incorporated into the wall of the vessel
• The thrombus may be dissolved completely
• The thrombus may dislodge and become an embolus
  or emboli

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Fate of a Thrombus
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Propagation of Thrombus
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Cerebral Embolism Formation
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Classification of Thrombi

• Anatomical
• Cardiac
• Arterial
• Venous
• Capillary

• Morphological
• Pale (platelet thrombus)
• Red (RBC thrombus)
• Mixed (intermittent layers)

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Thrombosis of the descending aorta extending from
the origins of the renal arteries down to the
iliac vessels
Renal Artery
Thrombus
Iliac Artery
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A mixed thrombus
Pale thrombus
Red thrombus
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Venous Thrombosis

• Two distinct types
• Phlebothrombosis predisposes to thromboemboli
  to lungs
• Thrombophlebitis unusual to have associated
  pulmonary thromboemboli
• Migratory thrombophlebitis or Trousseau syndrome

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DISSEMINATED INTRAVASCULAR COAGULATION (DIC)

• DIC is not a primary disease but rather a
  potential complication of any condition
  associated with widespread activation of thrombin
  
• Its a thrombohemorrhagic disorder
• Thrombin formation is the main mechanism
• Both platelets and coagulation factors are
  depleted
• Lab findings Low PLT count, gtaPTT, gtPT,
  fragmented RBCs in the smear

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Effects of Thrombosis

• Dependent on location and degree of vascular
  occlusion.
• Effects also dependent on the availability of
  collateral blood supply and susceptibility of
  area of supply to interruption of blood supply.

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A mixed thrombus
Pale thrombus
Red thrombus
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INFARCTION

• Dr.Udaya Kumar. M.D.

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Common clinical examples of infarction

• Myocardial infarction
• Cerebral infarction
• Pulmonary infarction
• Gangrene of limbs

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Atrial fibrillation with mural thrombi
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INFARCTION

• Def An infarct is an area of ischemic necrosis
  caused by occlusion of either the arterial supply
  or the venous drainage in a particular tissue

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Basis of infarction

• Vascular compromise
• Obstruction to arterial supply
• Impeded venous drainage

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Common causes

• Arterial occlusion
• 99 result from arterial occlusion (thrombotic or
  embolic events)
• Other causes
• local vasospasm
• expansion of an atheroma (hemorrhage within a
  plaque)
• extrinsic compression of a vessel (e.g., by
  tumor)
• twisting of the vessels (e.g., in testicular
  torsion or bowel volvulus)
• compression of the blood supply by edema or by
  entrapment in a hernia sac
• traumatic rupture of the blood supply
• Venous occlusion (organs with single venous out
  flow)
• Thrombosis

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Hemodynamic Disorders Infarcts - Pathology
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Hemodynamic Disorders Infarcts - Pathology
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Classification

• Based on the colour presence or absence of
  infection

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Classification of Infarction(basis of colour or
infection)

• Red Infarct
• (haemorrhagic)
• venous occlusions
• loose CT that allows blood to collect in
  infarcted zone (e.g. lungs)
• tissues with dual circulation permit flow of
  blood into necrotic tissue (not enough perfusion
  to prevent infarction)
• previously congested tissues (sluggish venous
  flow)
• When flow re-established to previous area of
  arterial occlusion necrosis

• White Infarct
• (anaemic)
• arterial occlusions
• solid organs (e.g. spleen heart kidney)

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Development of an Infarct

• ischaemia
• ?
• accumulation of deO2 blood from anoxic
  capillaries
• (venous infartcs usually intensely haemorrhagic)
• ?
• 1224 hours
• ?
• ischaemic necrosis
• ?
• typically show coagulative necrosis
• (swelling of cells ? pale ? nuclei disappear ?
  ghost architecture)
• ?
• surrounding inflammatory change (vital reaction)
• ?
• PMN followed by mononuclear phagocytes
• ?
• phagocytosis of breakdown material
• ?
• pale yellow area of infarction surrounded by red
  inflammatory zone

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Reaction of Body

• Fever
• ?ESR
• ?WCC
• Enzymes released by dead dying cells

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Morphology

• Red (hemorrhagic) infarcts occur
• with venous occlusions (such as in ovarian
  torsion)
• in loose tissues (such as lung), which allow
  blood to collect in the infarcted zone
• in tissues with dual circulations (e.g., lung and
  small intestine), permitting flow of blood from
  the unobstructed vessel into the necrotic zone
  (obviously such perfusion is not sufficient to
  rescue the ischemic tissues)
• in tissues that were previously congested because
  of sluggish venous outflow and
• when flow is re-established to a site of previous
  arterial occlusion and necrosis (e.g., following
  fragmentation of an occlusive embolus or
  angioplasty of a thrombotic lesion) 

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Morphology

• White (anemic) infarcts occur
• with arterial occlusions in solid organs with
  end-arterial circulation (such as heart, spleen,
  and kidney), where the solidity of the tissue
  limits the amount of hemorrhage that can seep
  into the area of ischemic necrosis from adjoining
  capillary beds

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Most of the infarcts are wedge shaped

• with the occluded vessel at the apex and the
  periphery of the organ forming the base
• when the base is a serosal surface, there is
  often an overlying fibrinous exudate.
• The lateral margins may be irregular, reflecting
  the pattern of vascular supply from adjacent
  vessels.

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Margins become hyperemic

• Initially all infarcts are poorly defined and
  slightly hemorrhagic
• Later margins tend to become better defined by a
  narrow rim of hyperemia attributable to
  inflammation at the edge of the lesion.

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Examples of infarcts A, Hemorrhagic, roughly
wedge-shaped pulmonary infarct. B, Sharply
demarcated white infarct in the spleen.
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Pulmonary infarction
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Splenic infarction
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Histology of infarction

• Change depends on time
• Ischemic coagulative necrosis
• Inflammation
• Liquifactive necrosis
• Abscess formation
• Scar tissue

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Remote kidney infarct, now replaced by a large
fibrotic cortical scar.
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Factors That Influence Development of an Infarct

• The major determinants include
• the nature of the vascular supply
• the rate of development of the occlusion
• the vulnerability of a given tissue to hypoxia
  and
• the blood oxygen content.

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Factors That Influence Development of an Infarct

• The major determinants
• Nature of the vascular supply
• (double or single blood supply)
• The availability of an alternative blood supply
• Lungs, dual pulmonary and bronchial artery blood
  supply
• Liver, Hepatic artery and portal vein
• Hand and forearm, radial and ulnar arterial
  supply,
• Relatively insensitive to infarction.
• In contrast, renal and splenic circulations are
  end-arterial, and obstruction of such vessels
  generally causes infarction.

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Factors That Influence Development of an Infarct

• The major determinants
• Rate of development of occlusion.
• Slowly developing occlusions are less likely to
  cause infarction because they provide time for
  the development of alternative perfusion
  pathways.
• For ex
• , small interarteriolar anastomoses normally
  with minimal functional flowinterconnect the
  three major coronary arteries in the heart.
• If one of the coronaries is only slowly occluded
  ,
• flow within this collateral circulation
  may increase sufficiently to prevent infarction,
  even though the major coronary artery is
  eventually occluded.

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Factors That Influence Development of an Infarct

• The major determinants
• (3) Vulnerability to hypoxia.
• The susceptibility of a tissue to hypoxia
  influences the likelihood of infarction.
• Neurons undergo irreversible damage for only 3 to
  4 minutes.
• Myocardial cells, die after only 20 to 30
  minutes of ischemia.
• Fibroblasts within myocardium viable even after
  many hours of ischemia

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Factors That Influence Development of an Infarct

• The major determinants
• (4) Oxygen content of blood.
• The partial pressure of oxygen in blood also
  determines the outcome of vascular occlusion.
• Partial flow obstruction of a small vessel in an
  anemic or cyanotic patient might lead to tissue
  infarction, whereas it would be without effect
  under conditions of normal oxygen tension.
• In this way, congestive heart failure, with
  compromised flow and ventilation, could cause
  infarction in the setting of an otherwise
  inconsequential blockage.

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Factors That Influence Development of an Infarct

• The major determinants
• (4) Oxygen content of blood.
• What is the critical value for HGB ?

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Infarction

• Examples
• cerebral infarction
• myocardial infarction
• pulmonary infarction
• bowel infarction
• ischaemic necrosis of extremeties (gangrene)

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Infarcts of Particular Tissue

• Myocardial infarction (MI)
• atheroma formation with thrombus ? CAD
• localised infarction
• LV ? pale ? coagulative necrosis ? fibrous scar
• full thickness of wall ?pericarditis
  endocardial infarction
• circumferential subendocardial infarct
• inner 1/3 LV wall
• d.t. additional strain on heart with comprimised
  blood supply
• Infarction of the brain (Stroke)
• atheroma thrombus formation ? cerebral artery
• liquefactive necrosis ? tissue soft ?
  phagocytosis/washed away ? cystic space ? gliosis
• Pulmonary infarction
• pulmonay embolism common post mortem finding ?
  not a major cause of pulmonary infarction
• circulatory defects are required ? e.g. CHF

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Infarcts of Particular Tissue

• Infarction of the kidney
• usually due to emboli ? branch of renal artery
• wedge shaped pale capsule not usually involved
• fibrosis
• Intestinal infarction
• arterial or venous obstruction vovulus
  compression
• loose tissue appears red
• gangrene ? putrifactive organisms from gut
• Splenic infarction
• Post embolic ? pale areas coagulative necrosis
• Fibrinous peritonitis ? pain

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Compartment syndrome
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Compartment syndrome
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Inguinal hernia
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Inguinal hernia
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Strangulated hernia
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Umbilical hernia
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Umbilical Hernia
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Umbilical hernia
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Volvulus
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Volvulus
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Volvulus involving caecum
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Torsion - ovary
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Torsion - ovary
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Torsion - ovary
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Torsion Fallopian tube
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Torsion testis torsion of hydatid
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Torsion - testis
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Hemodynamic Disorders Watershed Infarcts - Brain
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Hemodynamic Disorders Watershed Infarcts
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Hemodynamic Disorders Watershed Infarcts
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Gangrene of the fingers
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Thank you for your attention
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