Thrombosis, Embolism and Infarction

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Thrombosis, Embolism and Infarction

• Dr. Raid Jastania

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Hemostasis and Thrombosis

• Hemostasis is the physiological process of
  maintaining blood in fluid state and formation of
  hemostatic plug at site of vessel injury.
• Thrombosis is the pathological process of blood
  clotting in uninjured vessel or exagurated
  response to minimal injury.
• Components
• Vessel wall
• Platelets
• Coagulation pathways

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Normal Hemostasis

• Vessel injury - brief period of arteriolar
  vasoconstriction (neurogenic reflex ,endothelin)
• Endothelial injury exposes ECM (highly
  thrombogenic material).
• Platelets adhere to endothelial cells and ECM,
  and are activated. They release their secretory
  granules. Platelet aggregation occurs forming
  hemostatic plug (Primary hemostasis)
• Tissue factor (produced by endothelium) activates
  coagulation - formation of thrombin which act of
  finbrinogen to form fibrin (secondary Hemostsis)

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Normal Hemostasis

• The process continues to form the permanent plug
  formed by polymerized fibrin and platelet
  aggregates.
• At the same time tissue plasminogen activator
  (t-PA) is formed and it limits hemostatic plug.
• Fibrinolysis is also activated to limit heostatic
  plug to the site of injury.

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Thrombosis

• Thrombosis is the pathological process of blood
  clotting in uninjured vessel or an exaggerated
  blood clotting response to minimal injury.
• Virchow Triad (factors predisposing thrombosis)
• Endothelial injury
• Blood stasis or turbulence of blood flow
• Blood hypercoagulability

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Endothelial Injury

• An important factor in arterial thrombosis.
• Occurs in myocardial infarction, ulcerated
  atherosclerosis, trauma, and inflammatory disease
  of vessels.
• Endothelial dysfunction is also a predisposing
  factor for thrombosis. Eg. Hypertension,
  bacterial endotoxins, hypercholestrolemia,
  radiation, cigarette smoking.
• Loss of endothelium will expose the ECM and hence
  activation of platelets and thrombosis.

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Blood Stasis and Turbulence of Flow

• Turbulence enhances endothelial injury.
• Stasis enhances venous thrombosis.
• Both result in
• Bringing platelets close to endothelium
• Accumulation of clotting factors
• Prevent clotting factors inhibitors
• Endothelial activation
• Example aortic aneurysm, MI, valve stenosis,
  rheumatic heart disease, hyperviscosity, sickle
  cell disease.

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Hypercoagulability

• It is an alteration in coagulation leading to
  thrombosis.
• Primary (genetic)
• Factor V mutation
• Antithrombin III deficiency
• Secondary
• Prolonged immobilization
• Cancer
• Lupus anticoagulant
• Nephrotic syndrome
• Contraceptive pills
• Smoking

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Hypercoagulability

• Heparin-induced Thrombocytopenia
• When heparin is administered it induces the
  formation of antibodies that bind platelets and
  activate them.
• Antiphospholipid syndrome (Lupus anticoagulant)
• Antibodies to phospholipid (eg. Cardiolipin)
• In-vitro it inhibits coagulation
• In-vivo it induces coagulation

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Thrombosis

• May develop in the heart, arteries, veins and
  capillaries.
• Arterial thrombi and cardiac thrombi occur at
  site of endothelial injury or turbulence of flow.
• Venous thrombi occur in areas of blood stasis.
• Thrombi usually are attached to the underlying
  vessel wall (mural thrombi)
• Arterial thrombi grow back to the heart.
• Venous thrombi grow toward the heart.

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Thrombosis

• Arterial thrombi are firmly attached to the wall
  and show lines of Zahn (layers of fibrin and
  platelets alternate with layers of RBC and WBC.
• Venous thrombi do no show clear lamination.
• In the heart common causes MI, dilated
  cardiomyopathy, arrhythmia, myocarditis, or
  valvular disease.

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Thrombosis

• In arteries common causes atherosclerosis, and
  aneurysm.
• Arterial thrombi usually occlude the lumen,
  common in coronary, cerebral, and femoral
  arteries.
• Venous thrombi (phlebothrombosis) are almost
  always occlusive, Red thrombi, 90 occur in lower
  extremities.

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Fate of thrombus

• Propagation (progression)
• Embolization
• Lysis
• 4.Organization and recanalization (inflammation
  and fibrosis)

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Venous Thrombosis

• Superficial eg. Saphenous vein
• Local congesion, edema, swelling, pain,
  tenderness, ischemia, risk of infection
• Rarely embolize
• Deep Vein Thrombosis eg. Popliteal, femoral,
  iliac veins.
• Can embolize
• There is a lot of collaterals so the congestion
  and edema are not prominent.
• 50 are asymptomatic.

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Venous Thrombosis

• Blood stasis is common predisposing factor for
  venous thrombosis. Eg. Heart failure, surgery,
  trauma, burn, pregnancy, cancer (Trousseau
  syndrome)

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Cardiac and arterial thrombi

• MI, valve disease, arrhythmia, atherosclerosis
• Possible embolism to brain, kidneys, spleen.

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Disseminated Intravascular Coagulation

• Sudden widespread fibrin thrombi in the
  microcirculation
• Occurs in pregnancy, and with malignancy.
• Leading to circulatory insufficiency brain ,
  lung, heart, kidneys
• Leading to consumption of platelets and clotting
  factors and risk of bleeding.

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Embolism

• Detached intravascular solid, liquid or gaseous
  mass carried by blood to a distant site.
• Types Thrombus 90, fat, air, cholesterol,
  tumor, bone marrow, foreign body
• Occlusion of vessels and ischemia/infarction

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Pulmonary Thromboembolism

• 20-25/ 100,000 of hospital patients
• 95 coming from DVT (above knee)
• may occlude main pulmonary artery (Saddle
  embolus)
• or in small branches of vessels (multiple)
• Paradoxical embolus cardiac embolus passing to
  the right side through septal defect.

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Pulmonary Thromboembolism

• 20-25/ 100,000 of hospital patients
• 95 coming from DVT (above knee)
• may occlude main pulmonary artery (Saddle
  embolus)
• or in small branches of vessels (multiple)
• Paradoxical embolus cardiac embolus passing to
  the right side through septal defect.

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Pulmonary Thromboembolism

• 60-80 are asymptomatic
• most organize
• can lead to cor pulmonale, sudden death.
• Result in hemorrhage, and rarely infarction
• Obstruction of small vessels lead to small
  infarctions
• Multiple emboli may lead to pulmonary
  hypertension

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Fat EmbolismAir EmbolismAmniotic Fluid Embolism
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Infarction

• Ischemic necrosis caused by occlusion of arterial
  or venous vessles.
• Example MI, cerebral infarction, pulmonary
  infarct, bowel infract, gangrene
• 99 due to thrombosis, mostly arterial
• Can be
• Vasospasm
• External pressure
• Trauma
• Twisting of organs eg. Testicular torsion
• Edema

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Infarction

• Venous infarct occurs in organs with single
  venous outflow. Eg. Testis, ovary
• Types Red infarct, white infarct, septic infarct
• Red infarct
• Due to venous occlusion
• In loose tissue eg. Lung
• Organs with dual circulation
• In tissues that have be previously congested
• White infarct
• Arterial occlusion of solid organs, eg. Heart,
  kidneys, spleen

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Infarction

• Infarction is usually wedge shape surrounded by
  rim of hyperemia
• Hemosiderin pigment may accumulate following
  hemorrhage
• Necrosis is of coagulative type (except brain
  liquifactive)
• Inflammation within few hours
• Repair process

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Factors influencing development of Infarct

• Nature of the blood supply
• Dual lung, liver, hands
• End-arterial spleen, kidneys
• Rate of occlusion
• Eg. Atherosclerosis of coronary arteries is
  gradual slow process

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Factors influencing development of Infarct

• 3. Vulnerability to hypoxia
• Neuron 3-4 minutes
• Heart 20-30 minutes
• Fibrous tissue hours
• 4. Oxygen content of the blood
• Eg. Heart failure patient have low oxygen
  concentration in blood

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Normal Endothelium

• Endothelial cells are activated by injury,
  infection, plasma mediators and cytokines. They
  have pro-thrombotic and anti-thrombotic functions.

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• Anti-thrombotic properties
• Anti-platelet effect
• Non activated platelets do not adhere to
  endothelium.
• PGI2, and NO (produced by endothelium) prevent
  platelet adhesion
• Anticoagulant properties
• Heparin-like molecule activate anti-thrombin III
• Thrombomodulin binds thrombin which activate
  protein C (anticoagulant)
• Fibrinolytic properties
• Endothelium synthesize t-PA (fibrinolysis)

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• Pro-thrombotic properties
• Von Willebrand factor
• It enhances binding of platelets to ECM.
• Tissue factor
• Produced by endothelium, it activates extrinsic
  clotting pathway
• Plasminogen activator inhibitors (PAI)

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Normal Platelets

• Platelets contain
• Alpha-granules P-selectin, fibrinogen,
  fibronectin, factor V, factor VIII,
  PDGF,TGF-alpha.
• Delta-granules ATP, ADP, Ca, histamine,
  epinephrine

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Normal Platelets

• On encountering ECM
• 1. Platelets adhere to ECM (collagen) mediated by
  vWF.
• 2. Secrete their granules
• 3.Platelets aggregate forming the primary
  hemostatic plug which is reversible. With the
  action of thrombin, platelet contraction occur
  and the plug becomes irreversible (secondary
  hemostatic plug)

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Normal Platelets

• PGI2 inhibits platelet aggregation
• Thromboxane A2 (TXA2) enhances platelet
  aggregation
• Aspirin inhibits the synthesis of TXA2

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Normal coagulation Cascade

• It is series of enzymatic conversions turning
  inactive proenzymes to active forms.
• They lead to formation of thrombin
• Thrombin converts fibrinogen to fibrin.
• Each reaction needs enzyme, substrate, cofactor,
  phospholipid complex, Ca ions
• Two pathways extrinsic and intrinsic both lead
  to activation of factor X.

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• Intrinsic pathway is activated by activation of
  Hageman factor (factor XII).
• Extrinsic pathway is activated by tissue factor.
• The process is controlled by anticoagulants
• Antithrombins (eg. Antithrombin III). It is
  activated by binding to Heparin-like molecule on
  endothelium.
• Protein C and S (vit K dependent) they inactivate
  factors Va and VIIIa.

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• Fibrinolytic cascade
• While coagulation occurs
• Factor XII or tissue plasminogen activator (t-PA)
  act on plasminogen to form plasmin.
• Plasmin start the process of fibrin lysis an the
  production of fibrin degradation produces.
• The function of plasmin is controlled (opposed)
  by plasminogen activator inhibitor (PAI) and
  alph2-antiplasmin.