Venous thromboembolism in Gynaecology

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Venous thromboembolism in Gynaecology

• Dr Edward Sang,
• Fellow, Gynaecologic Oncology
• University of Pretoria

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Outline

• Introduction
• The coagulation cascade
• Contraception
• HRT
• Pathogenesis of VTE
• Risk factors
• Diagnosis of VTE
• Prevention of VTE
• Treatment of VTE

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Introduction

• Venous thrombosis and its major complication PE
  are major causes of morbidity and mortality in
  hospitalized patients
• The diagnosis of acute VTE in outpatients is now
  being made more frequently because of increased
  diagnostic suspicion and the availabilty of
  reliable, noninvasive diagnostic tests

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Introduction

• VTE is associated with significant morbidity
• Largely preventable
• Although venous thrombosis can occur in any vein,
  it most commonly occurs in the legs
• Superficial venous thrombosis occurs most
  frequently in varicosities and is usually benign
  and self-limiting but if extensive can be
  associated with DVT which is more serious

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Introduction

• Thrombi localized in the calf veins are often
  smaller and therefore less commonly associated
  with long-term disability or clinically important
  PE
• By contrast proximal DVT involving the popliteal,
  femoral or iliac venous system can be complicated
  by PE
• Also, extensive damage to venous valves by the
  clot often leads to Postphlebitic syndrome

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In Gynaecology

• 40 of all deaths following gynaecologic surgery
  can be directly attributed to PE
• PE is also the 2nd leading cause of death in
  women who undergo induced abortion
• Most frequent cause of postop death in patients
  with uterine or cervical carcinoma

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Contraception (RCOG)

• Relative risk of VTE increases in the first few
  months after initiating combined hormonal
  contraception. The risk reduces with increasing
  duration of use but it remains above the
  background risk until the combined hormonal
  contraceptive is stopped
• Not advised in women gt35 years who smoke, have
  BMI gt35 kg/m2 or gt 45 years with family h/o VTE
  in first degree relative
• Should be stopped 4 weeks before major surgery
  where immobilization is expected
• Progesterone-only methods of contraception do not
  appear to be associated with an increased
  incidence of VTE
• 
  
  Green-top guideline no. 40, July 2010

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HRT and VTE

• The WHI study in the USA confirmed an increase in
  risk of PE in women using HRT
• The mechanism is unclear
• Produces reduction in Fibrinogen and FVII
  activation, enhances fibrinolysis and is
  associated with increased resistance to activated
  protein C
• Although many of these effects are opposing, the
  net effect appears to be an increase in thrombin
  generation.
• Should be avoided in women with previous VTE and
  should be stopped should a woman develop VTE
  while on HRT
• The Writing Group for the Womens Health
  Initiative Investigators. Risks and benefits of
  estrogen plus progestin in healthy postmenopausal
  women principal results from the Womens Health
  Initiative randomized controlled trial. JAMA
  2002 288 32133.

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Pathogenesis of VTE

• Venous thrombi are composed predominantly of
  fibrin and red cells
• Pathologic or physiologic venous thrombosis
  occurs when activation of blood coagulation
  exceeds the ability of natural anticoagulant
  mechanisms and the fibrinolytic system to prevent
  clot formation

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Virchows triad

• Pathogenesis of VTE first outlined by Prof
  Rudolph Virchow in 1858
• He proposed that thrombotic disorders were
  associated with the triad of
• Stasis
• Vascular injury
• Hypercoagulability

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Pathogenesis

• Vessel wall injury activates coagulation and
  tissue damage can impair fibrinolysis by reducing
  synthesis of tissue plasminogen activator (t-PA)
  and increasing endothelial cell production of
  plasminogen activator inhibitor-1 (PAI-1), the
  major inhibitor of the fibrinolytic pathway

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Pathogenesis

• Normally, activated coagulation factors are
  diluted in the flowing blood and are neutralized
  by inhibitors on the surface of endothelial cells
  or by circulating antiproteinase
• Activated clotting factors that escape regulation
  as a result of reduced levels of inhibitors or
  sudden generation of overwhelming amounts of
  these factors, trigger the coagulation system,
  leading to fibrin formation

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Pathogenesis

• Homeostatic mechanisms are immediately invoked to
  reduce the likelihood of pathologic thrombus
  formation thus, when thrombus forms, the
  fibrinolytic system is immediately activated as a
  result of the release of t-PA and urokinase from
  monocytes and leukocytes which are attracted to
  the thrombus by released fibrinopeptides and
  platelet products

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Activation of blood coagulation

• Coagulation proteins circulate as inactive
  precursors or zymogens (except small amounts of
  FVII)
• Each zymogen is converted into an active enzyme
  that then activates the next zymogen in the
  coagulation pathway
• In vivo, coagulation is initiated exclusively by
  the TF pathway

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TF pathway

• A proportion of circulating activated FVII
  (FVIIa) binds to TF at sites of vascular injury
• The TF-FVIIa complex then activates both FIX and
  FX

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• Levels of FVIIa can be increased by FXa but this
  reaction is downregulated by tissue factor
  pathway inhibitor (TFPI)
• TFPI renders FXa inactive by complexing with it
  the TFPI-FXa complex then binds the FVIIa-TF
  complex and prevents further activation of FX

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Common pathway

• FXa completes the coagulation cascade by
  converting prothrombin to thrombin in the
  presence of activated FV, phospholipid and
  calcium
• Thrombin then converts fibrinogen to fibrin,
  activates platelets and activates FXIII which in
  the presence of calcium cross-links the fibrin
  stabilizing the clot
• To ensure continuous generation of thrombin,
  thrombin and FXa activate FVIII and FV, markedly
  accelerating the coagulation reactions involving
  these 2 cofactors and thrombin activates FXI
  which in turn activates additional FIX
  establishing a positive feedback loop

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Coagulation intrinsic pathway

• Coagulation may be activated by contact of FXII
  with collagen on exposed subendothelium of
  damaged vessels or by contact with prosthetic
  surfaces

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• Coagulation may also be initiated by the exposure
  of blood to TF available locally as a result of
  vascular wall damage, by activation of
  endothelial cells by cytokines and by activated
  monocytes that migrate to areas of vascular
  injury

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Coagulation

• FX can be activated directly by extracts of
  malignant cells that contain a cysteine protease,
  which may be one of the mechanisms by which
  thrombosis is induced in patients with malignant
  disease
• A factor elaborated by hypoxic endothelial cells
  can also directly activate FX, potentially
  leading to thrombosis in patients with severe
  venous stasis

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Clinical risk factors

• Malignancy
• Extensive surgery
• Trauma
• Burns
• MI
• Local hypoxia produced by venous stasis

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Venous stasis

• Venous return from the legs is enhanced by venous
  valves which prevent blood from pooling in the
  lower legs and by contraction of the calf muscles
  which propel blood up from the extremities
• Venous stasis may contribute to thrombogenesis by
  allowing stagnation of the blood with associated
  local hypoxia which stimulates endothelial cell
  release of an activator of FX
• Venous thrombosis is produced by immobility,
  venous obstruction, increased venous pressure,
  venous dilatation and increased blood viscosity

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Vessel wall damage

• Normal endothelium is nonthrombogenic but damage
  or injury can trigger the activation of platelets
  and coagulation
• Thus vascular injury leads to the expression of
  TF
• Damage is by direct trauma or exposure to
  endotoxin, inflammatory cytokines (e.g. IL-1 and
  TNF), thrombin or low oxygen tension
• Damaged endothelial cells synthesize TF and PAI-1
  and internalize thrombomodulin-changes that
  promote thrombogenesis. Damaged cells also
  produce less t-PA, the main activator of
  fibrinolysis

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Endothelial protective mechanisms

• Normal endothelium is nonthrombogenic to flowing
  blood
• Endothelial cell-surface glycosaminoglycans and
  thrombomodulin are potent inhibitors of
  coagulation
• Vessel wall generation of prostacyclin and nitric
  oxide and synthesis of plasminogen activators
  limit platelet aggregation and fibrin deposition

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Endothelial protective mechanisms

• Thrombomodulin and heparan sulfate present on the
  luminal surface of endothelial cells are
  important modulators of thrombin activity
• Heparan sulfate, a glycosaminoglycan similar to
  heparin, catalyzes the inhibition of thrombin and
  FXa by antithrombin
• Thrombomodulin serves as a surface-bound receptor
  for thrombin
• Once thrombomodulin complexes with thrombin,
  thrombin is no longer capable of activating
  platelets, converting fibrinogen to fibrin or
  activating Fs V, VIII and XIII
• Instead complexed thrombin acquires enhanced
  ability to activate protein C which inactivates
  Fs Va and VIIIa. This reaction requires protein S
  as a cofactor (i.e. a potent anticoagulant
  pathway)

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Endothelial protective mechanisms

• Generation of plasminogen activators by vascular
  wall cells limits fibrin deposition and platelet
  aggregation is inhibited by release of
  prostacyclin (PGI2) and endothelium-derived
  nitric oxide
• Endothelial cell affinity for t-PA, plasminogen
  and activated protein C and protein S may
  contribute to the thromboresistance of the vessel
  wall
• Plasminogen binds to the cell surface where it
  can be activated to plasmin by t-PA promoting
  local fibrinolytic activity
• Bound activated protein C and S have a potent
  anticoagulant function

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Inhibitors of blood coagulation

• Activated coagulation factors are serine
  proteases and their activity is modulated by
  several naturally occuring plasma inhibitors
• Important inhibitors of blood coagulation are
• Antithrombin
• Protein C
• Protein S
• Others
• Factor V Leiden
• Prothrombin G 20210A mutations
• Hyperhomocysteinaemia
• Antiphospholipid antibodies

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DVT

• Pain
• Oedema
• Erythema
• Prominent superficial veins
• Non-specific 50-80 of patients with these signs
  and symptoms will not have DVT
• 80 of patients with symptomatic PE will not have
  signs and symptoms of DVT

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Pulmonary embolism

• Has few definite symptoms
• But onset of respiratory distress with
  hypotension, chest pain and cardiac arrhythmias
  may be harbingers of impending death
• Can convert a successful operation into a
  postoperative fatality

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Prevention of VTE

• Small doses of SC heparin (most widely used and
  studied)
• Unfractionated heparin
• LMWH
• Graduated compression stockings (2nd in use after
  heparin)
• Simple, absence of major side effects
• Avoid tourniquet
• May not fit perfectly due to variation in anatomy
• Intermittent pneumatic compression stockings
• Should be used for at least 5 days postop
• Pneumatically inflated sleeves placed around
  calf/leg
• Various designs some as effective as heparin

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Diagnosis of VTE

• Venography
• Impedence plethysmography
• Doppler ultrasound
• MRI/MRI Venography

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Venography

• Is the reference standard for the diagnosis of
  DVT
• However
• is uncomfortable, invasive
• Requires injection of contrast which may cause an
  allergic reaction or renal inury
• 5 risk of phlebitis
• Therefore not routinely used

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I125 labeled Fibrinogen scanning

• Involves IV injection of isotope-labeled
  fibrinogen which is expected to be incorporated
  into the evolving thrombus and can be imaged by a
  scintillation scanner
• High correlation to venography
• Not used much as is cumbersome

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Impedence plethysmography

• Based on the principal of electrical resistance
  in specific areas of the body
• When there is resistance to blood flow due to
  thrombus, there is marked reduction in the
  electrical resistance over that vessel
• Most useful in proximal DVT but relatively poor
  in visualizing thrombi below the knee due small
  size and slow flow rates in soleal sinuses

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Doppler ultrasound

• Most widely used imaging technique for diagnosis
  of VTE
• Measures flow velocity in blood vessels
• A reflected sound signal is converted to both an
  audible form and visual image on a computer
  screen
• A thrombus causes a decrease in the reflected
  signal that can be heard or visualized
• Most machines now use color enhancement to
  identify arteries (red) and veins (blue)

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Duplex Doppler ultrasound

• Combines real-time and doppler ultrasound
• Allows a radiologist to visualize a vessel and
  identify any thrombus in it

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Light Reflection Rheography

• Uses infrared light directed at the skin
• The backscattered rays are quantitated, which
  allows an estimation of blood volume
• Low-cost and sensitive tool for DVT detection
• Not accurate in the diagnosis of DVT in pregnancy

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Indirect CT Venography

• Uses IV contrast medium injection followed by CT
  scanning of the limbs or chest
• Detects more VTE than CT pulmonary angiography

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MRI/MRI Venography

• Use differences in signal intensities to
  distinguish flowing blood from stagnant blood
  (clot)
• Does not need contrast so can be used in pregnant
  women
• MRI still in its infancy in VTE diagnosis

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Nonimaging methods

• Automated quantitative D-dimer assay
• 95 NPV
• No proven consistent correlation between a
  positive D-dimer assay and venous thrombosis

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Others

• Real-time ultrasound
• Radioisotope imaging

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Diagnosis of PE Pulmonary angiogram

• Reference standard in diagnosis of PE
• A negative result excludes PE but tertiary
  pulmonary arteries must be visualized
• Problems of allergy and patients allergic to
  radio-opaque dye should not undergo pulmonary
  angio

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Ventilation-perfusion lung scan

• The lung scan consists of a perfusion and
  ventilation component
• Perfusion particles of isotopically labeled
  microaggregates of human albumin are injected IV
  after which they become trapped in the pulmonary
  capillary bed. Their distribution reflects lung
  blood flow and is recorded with an external
  photoscanner
• A normal perfusion scan excludes PE but an
  abnormal one is none-specific
• Ventilation uses radioactive gases or aerosols
  inhaled or exhaled by the patient while a gamma
  camera records the distribution of radioactivity
  in the alveolae
• The ventilation imaging improves the specificity
  of perfusion scanning

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Prevention of VTE

• Unfractionated heparin
• LMWH
• Graduated compression stockings
• Intermittent pneumatic compression stockings

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Treatment of VTE

• UFH bolus dose (5000-10,000 IU or 80 IU/kg) then
  IV infusion (30-40,000 IU/day or 18 IU/kg)
• Monitored using APTT
• LMWH e.g. Clexane (Enoxaparin) 1.5mg/kg daily
• Monotored using anti-Xa activity (target is 0.5-1
  U/ml)
• Warfarin started and heparin continued until INR
  is 2-3

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Heparin

• Acts as an anticoagulant by activating
  antithrombin and accelerates the rate at which
  antithrombin inhibits clotting enzymes esp.
  thrombin and FXa
• Heparin also enhances the inhibition of FIXa,
  FXIa and FVIIa bound to TF by antithrombin

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Warfarin

• A vitamin K antagonist
• Interferes with synthesis of Vit K-dependent
  clotting factors prothrombin, Fs VII, IX and X

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LMWH

• MW of 5000 (1/3 that f UFH)
• Compared to UFH
• More effective
• Less haemorrhagic risk
• Lower mortality