Thrombosis

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Thrombosis

• Thrombosis is the inappropriate activation of
  clotting occurring in uninjured or minimally
  injured vessels.
• There are 3 primary influences on the propensity
  towards thrombosis (Virchows Triad)
• Endothelial injury
• Alteration in flow
• Hypercoagulability

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Fig 4-13 p 131
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Endothelial injury

• This is the dominant influence on initiation of
  coagulation, endothelial injury alone elicits
  coagulation (appropriately so!).
• The endothelium need not be physically disrupted
  to incite thrombosis, anything that perturbs the
  delicate balance of coagulate/dont coagulate
  maintained by the endothelium can elicit
  coagulation.
• Injury may be caused by hemodynamic stresses
  associated with non-laminar flow due to
  dis-kinetic cardiac segments, atherosclerotic
  plaques, etc., abnormal endogenous substances
  (homocysteine, cholesterol) exogenous substances
  (tobacco related substances).
• Thrombosis results from exposed ECM and tissue
  factor, platelet adhesion, depletion of
  anti-coagulant factors.

• Fig 4-7 p 126

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Alteration of Flow

• Normal blood flow is laminar with cellular
  elements located centrally in the vessel lumen
  separated from the endothelial wall by a plasma
  clear zone. Stasis and turbulent flow disrupt
  laminar flow with a number of consequences
• platelets contact endothelium
• dilution of activated clotting factors is
  prevents
• inflow of clot inhibitors is prevented
• Promotion of endothelial activation.
• Stasis elicits thrombosis in the venous system,
  cardiac chambers and aneurysmal dilatations.
• Plaques disrupt laminar flow in addition to
  producing endothelial injury.
• Anything that promotes blood viscosity
  (hyperviscosity syndromes) promotes stasis
  (polycythemia, sickle cell, dehydration, etc.).

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Hypercoagulability

• An alteration of coagulation that predisposes to
  thrombosis, this is the least frequent cause for
  thrombosis but allows the simplest opportunity
  for intervention.
• Heritable Hypercoagulability states
• Tend to present initially in adolescents or young
  women (stroke in the young).
• Characterized by recurrent venous thrombosis and
  thromboembolism
• Lack of Antithrombotic function
• Genetic deficiency in antithrombin III
  (inactivates thrombin, IXa Xa) protein C or
  protein S mutations (normally promote the
  proteolysis of Va VIIIa) that predispose to
  venous thrombosis, although infrequent these
  conditions in concert with acquired states create
  a markedly increased risk of thrombosis.
• Extra Prothrombotic function
• Va resistance A factor V mutation (Leiden
  mutation) 2-15 of Caucasians, alters to cleavage
  site for inactivation of Va by Protein C
• Prothrombin 20210A mutation A point mutation in
  a non-coding region of the prothrombin gene
  resulting in increased levels of prothrombin and
  venous thrombosis
• Methylene tetrahydrofolate reductase mutation
  (MTHFR C677T) A moderate increase in homocyteine
  associated with increased arterial venous
  thrombosis. This can be mitigated by folate, B6
  B12 supplementation. Associated with an
  increased risk of neural tube defects
  neoplasms.
• Constitutively increased factor VIII, IX, XI
  fibrinogen levels

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Hypercoagulable states
Table 4-2 p 132
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Hypercoagulability

• Acquired Hypercoagulability
• Oral contraceptives or hyper-estrogenic states
  (pregnancy) create hypercoagulability by
  increasing the synthesis of coagulation factors
  and deceased production of antithrombin III.
• Certain malignancies and disseminated cancers
  release procoagulant tumor products.
• Advanced age is associated with increased
  platelet aggregation.
• Smoking
• Heparin-induced thrombocytopenia syndrome, 5 of
  the population, most common with unfractionated
  heparin. An antibody forms to heparin-platelet
  factor 4 complex resulting in thrombocytopenia
  (platelet destruction) and thrombosis through
  endothelial activation.
• Antiphospholipid antibody syndrome these
  individuals have antibodies that can activate
  platelets or block protein C activity leading to
  hypercoagulability. Usually discovered due to a
  slightly elevated PTT (? hypocoagulable, antibody
  interferes with intrinsic pathway (lab
  phenomena)). Associated with recurrent arterial
  venous thromboembolism
• Autoimmune disorders may be associated with
  hypercoagulability via a similar antiphospholipid
  antibody (lupus anticoagulant? slightly elevated
  PTT but they are hypercoagulable).

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Hypercoagulable states

• Table 4-2 p 132

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Combination Hyper- Hypocoagulable

• Disseminated Intravascular Coagulation (DIC)
• Diffuse endothelial injury results in systemic
  activation of the coagulation cascade/thrombosis.
  Resulting in
• Microthrombi (occasionally macrothrombi) which
  impair tissue perfusion CNS, heart, renal, lungs
  are particularly at risk.
• Depletion of coagulation factors and production
  of fibrinolytic agents that result in systemic
  hemorrhage.
• What do you do?

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Morphology of Thrombi

• Thrombi may form any where in the vascular
  system, they vary in size and shape depending on
  their site of origin and how firmly they are
  attached at their origin.
• Arterial thrombi
• Found in areas of active flow
• Commonly show layering of platelets fibrin
  (Lines of Zahn)
• Cardiac aortic thrombi tend to be non-occlusive
  (???flow).
• Cardiac mural thrombi based on akinetic/dyskinteic
  wall segments
• Tend to propagate distally often with
  embolization (can propagate retrograde)
• Atherosclerotic plaques, endothelial injury,
  areas of turbulent flow serve as nidus
• Valvular irregularities may be emboli source

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Fig 4-14 p132
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Venous thrombosis

• Characteristically in areas of low/no flow or
  turbulent flow.
• Superficial thrombi usually occur in enlarged
  saphenous veins.
• Deep vein thrombi (DVT) generally occur in veins
  proximal to the knee and due to the abundant
  collateral venous system are asymptomatic in 50
  of instances prior to an embolic event. The
  situations associated with increased risk of DVT
  are legion, anything that involves prolonged
  immobilization (? gt 8 hours, particularly
  associated with dehydration) CHF, trauma
  (including surgical), pregnancy and post-partum
  states and malignancy.
• Often associated with inflammatory changes (
  thrombophlebitis).

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The Fate of the Thrombus

• Once formed the thrombus has a limited number of
  fates
• Propagation with subsequent vessel occlusion,
  depending on the location and type of vessels the
  sequelae may be minor (superficial vein
  thrombosis) or catastrophic (stroke, MI, etc.).
• Embolization to downstream sites (PE)
• Dissolution by fibrinolytic activity (a
  therapeutic intervention)
• Organization recanalization, endothelial cells,
  smooth muscle cells and fibroblasts create
  vascular channels in the thombus.

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Fig 4-15 p 134
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Fig 4-16 p 135
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Organized pulmonary embolus
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Clinical Significance

• Thrombi are important because they
• Cause obstruction of arteries and veins (arterial
  obstruction worse)
• Are possible sources of emboli (worse in venous
  obstruction)

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Embolism

• Embolism refers to any intravascular mass carried
  by blood flow to a site distant from its origin,
  most arise from thrombi other emboli may consist
  of fat, gas bubbles, atherosclerotic debris,
  tumor fragments, bone marrow, foreign bodies,
  particulate matter, etc. Emboli lodge in vessels
  too small to permit further passage, the
  distribution depending on blood flow drown-stream
  from the source.

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Pulmonary Thromboembolism

• PE has a reported incidence of 20-25/100,000
  hospitalized patients, gt95 of PEs originate from
  DVTs. Increased risk with immobilization,
  post-op and CHF (venous stasis).
• Most PEs (60-80) are clinically silent.
• Obstruction of medium sized pulmonary arteries
  may cause pulmonary hemorrhage but pulmonary
  infarction is rare due to the bronchial blood
  supply.
• Obstructon of 60 of the pulmonary circulation
  results in right-heart failure, cardiovascular
  collapse or sudden death. (Saddle embolus).
• Multiple emboli over time may result in pulmonary
  hypertension.

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Fig 4-19 p 138
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• Fig 4-17 p 136

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Systemic Thromboembolism

• Systemic emboli most often arise from
  intracardiac mural thrombi, often associated with
  MI. 25 arise from dilated LA due to valvular
  disease.
• Atherosclerotic plaques are frequently the source
  of non-cardiac emboli.
• The consequences of arterial occlusion depends
  on collateral circulation and tissue sensitivity
  to hypoxia.

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• Common sites of arrest
• ICA branches, especially the MCA
• Mesenteric artery branches
• Renal artery branches (however 75 loss of renal
  function before symptomatic)
• Paradoxical emboli
• Intracardiac (R?L) shunt (patent foramen ovale or
  ASD) of emboli can occur particularly with
  equalization of pressures (? right side with
  pulmonary hypertension, ? left side CHF, MI,
  etc.).

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Fat Embolism

• Fat embolism results form the release of
  microscopic fat globules after long bone
  fracture, fat embolism occurs in 90 of severe
  skeletal trauma but 10 have any clinical signs.
  
• 10 of cases are fatal and present as acute
  pulmonary failure 1-3 days post injury.
• Thrombocytopenia, petechial rash and CNS
  deterioration are frequently seen in severe
  cases.
• Fat emboli produce symptoms due to vessel
  occlusion but also activate platelets and WBCs,
  fatty acid release causes direct endothelial
  injury.

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Fat emboli marrow elements with fat in a vessel
lumen
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Air Embolism

• Gas bubbles in the vasculature can cause
  obstruction resulting in ischemia, room air may
  enter the circulation any time large low pressure
  venous structures are disrupted (thoracic,
  pelvic, obstetric, lower extremity, neck and
  spine procedures), approximately 100 mls of air
  is required to be symptomatic.
• Decompression sickness

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Amniotic fluid embolism

• A rare (1/50,000 deliveries) but catastrophic
  (gt80 mortality) complication of labor, due to
  infusion of amniotic fliud into the maternal
  circulation. The presentation is of acute severe
  dyspnea, cyanosis, DIC, hypotension, shock,
  seizures and coma.

Amniotic fluid embolus, fetal squamous epithelial
cells in a pulmonary arteriole
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30 year old male presented 30 minutes after
being accidently shot with a pneumatic nail gun.
BP 86/60, HR 133. After 20 minutes he
complained of severe left leg pain
Femoral
Profunda
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Conclusions

• Thrombosis is the inappropriate activation of
  hemostasis
• Vircows triad describes the predisposing factors
  for thrombosis
• Endothelial injury/activation
• Alteration in flow
• Hypercoaguability
• Normal endothelial function is a delicate balance
  between pro- and anti-thrombotic influences,
  normally anti-thrombosis predominates.
• Abnormal flow results in
• Stasis
• Loss of dilution of activated factors
• Loss of the influx of clot inhibitors
• Promoting endothelial activation
• Atherosclerotic plaques elicit
• Abnormal flow patterns
• Direct endothelial injury

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Conclusions

• 6. Hypercoagulability
• Inherited
• Acquired
• 7. Hyperestrogenic states, malignancy, age,
  smoking, heparin induced, thrombocytopenia, MI,
  A-fib, prosthetic valves, etc.
• 8. Thrombi may propagate, embolize, dissolve,
  organize and recanalize.
• 9. Venous thromboembolism
• DVT-50 are asymptomatic prior to an embolic
  event
• 10. Arterial thrombosis
• Often results in obstruction with ischemia unless
  a collateral circulatory system is readily
  available
• Embolization to distal vasculature
• 12. DIC causes widespread microthrombi but
  presents as a bleeding diathesis due to systemic
  activation of the fibrinolytic system

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Conclusions

• 13.Anything reaching the intravascular system can
  embolize
• Fat
• Air
• Amniotic fluid
• 14. PE
• 1/2 -3/4ths are silent
• Can cause acute right heart failure and death
• 15. Fat embolism is common (90) is severe
  skeletal trauma, usually is asymptomatic but can
  present as acute pulmonary failure,
  thrombocytopenia and CNS deterioation 1-3 days
  post trauma.

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