Thromboembolism Panel

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Thromboembolism Panel

• Dr Hommam
• Dr Jalilian
• Dr Moosavi
• Dr Torkestani
• Dr Vafaei

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Significance of VTE

• Highest risk during pregnancy and peurperium
• Incidence 1/10000 ( nonpregnant) .1/1600 (
  pregnant)
• 6 - 22 X
• Antepartum postpartum
• DVT ..Antepartum ( 74)
• PEPostpartum (60.5)
• Cesarean section 30.3 RR for PE
• 50 due to thrombophilia
• Responsible for 20 of pregnancy- related deaths

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Aims of this panel

• Oral presentation
• Who needs thromboprophylaxy?
• Who needs screening for thrombophilia?
• Review of guideline for thromboprophylaxy
• Thromboprophylaxy in cases with previous history
  of VTE
• Thromboprophylaxy in cases with thrombophilia.
• Thromboprophylaxy in cases with ART
• Peripartum thromboprophylaxy
• Early diagnosis of VTE
• Treatment of VTE

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Risk Factors
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Pregnancy as a prothrombotic state

• Virchow triad stasis, local trauma to the vessel
  wall, and hypercoagulability
• Increased level of factor I, VII, VIII, IX, X ,
  XIII , VWB ( 20-1000)
• Decreased activity of Pr S ( 39)
• Decreased level of Pr S after cesarean section
  and infection
• Venous statsis due to compression
• Increased in deep vein capacitance ( prog.,
  Prostacycline and nitric oxide)

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Risk factors
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Risk factors
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Risk factors

• Obstetrics

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Thrombophilia

• Reduction in inhibitory proteins for coagulation
• 15 white people
• 50 TE events in pregnancy ((Lockwood, 2002
  Pierangeli, 2011)
• Inherited
• Acquired

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Inherited thrombophilia

• Family history
• VTE before 45 y/o
• VTE without risk factor
• VTE with minimal provocation ( long flight,
  estrogen)
• Family history of sudden dead due to PE
• History of multiple family members requiring
  long-term anticoagulation therapy because of
  recurrent thrombosis (Anderson, 2011)

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Inherited thrombophilia

• Antithrombin Deficiency
• Type I
• Type II
• Autosomal Dominant
• Most thrombogenic of the heritable coagulopathies
• Homozygous antithrombin deficiency is lethal

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Inherited thrombophilia

• Protein C Deficiency
• gt100 different AD mutations
• prevalence 2 to 3 per 1000, but many of these
  individuals do not have a thrombosis history
  because the phenotypic expression is highly
  variable (Anderson, 2011).

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Inherited thrombophilia

• Protein S Deficiency
• Decreased in pregnancy ( 30-24)
• Decreased after cesarean and infection

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Inherited thrombophilia

• Factor V Leiden Mutation
• Most prevalent of the known thrombophilia
• Heterozygous inheritance for factor V Leiden is
  the most common 3 to 15 percent of selected
  European populations and 3 percent of African
  Americans, but it is virtually absent in African
  blacks and Asians (Lockwood, 2012).
• Diagnosis during pregnancy DNA analysis for
  the mutant factor V gene. This is because
  bioassay is confounded by the fact that
  resistance is normally
• increased after early pregnancy because of
  alterations in other coagulation proteins

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Factor V Leiden Mutation

• Universal prenatal screening for the Leiden
  mutation and prophylaxis for carriers without a
  prior venous thromboembolism is not indicated

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Inherited thrombophilia

• Prothrombin G20210A Mutation
• Excessive accumulation of prothrombin

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Inherited thrombophilia

• Hyperhomocysteinemia
• Most common cause C667T thermolabile mutation
  of the enzyme 5, 10-methylene-tetrahydrofolate
  reductase (MTHFR)
• Deficiency of several enzymes involved in
  methionine metabolism ( correctible nutritional
  deficiencies of folic acid, vitamin B6, or
  vitamin B12)
• Autosomal recessive
• Decreased in normal pregnancy
• fasting threshold of gt 12 µmol/L

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Hyperhomocysteinemia

• Elevated homocysteine level is actually a weak
• risk factor (ACOG, 2013).
• The ACOG (2013) has concluded that there is
  insufficient evidence to support assessment of
• MTHFR polymorphisms or measurement of fasting
  homocysteine levels in the evaluation for venous
  thromboembolism.

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Other Inherited thrombophilia

• Protein Z
• plasminogen activator inhibitor type 1 (PAI-1)
• a paternal thrombophilia could increase the
  risk of a maternal thromboembolism. (Galanaud
  (2010).
• Paternal thrombophiliathe PROCR 6936G
  alleleaffects the endothelial protein C
  receptor. This receptor is expressed by villous
  trophoblast and thus is exposed to maternal blood.

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Acquired thrombophilia

• Anticardiolipin
• Lupus anticoagulant
• ß2-glycoprotein I
• In addition to vascular thromboses, these
  include
• (1) at least one otherwise unexplained fetal
  death at or beyond 10 weeks
• (2) at least one preterm birth before 34 weeks
  because of eclampsia, severe preeclampsia, or
  placental insufficiency or
• (3) at least three unexplained consecutive
  spontaneous abortions before 10 weeks.

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Acquired thrombophilia

• Arterial
• Venous
• Unusual sites

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Thrombophilias and Pregnancy Complications
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• ACOG(2013) Definitive causal link cannot be
  made between inherited thrombophilias and adverse
  pregnancy outcomes.
• In contrast, the association between
  antiphospholipid syndrome and adverse pregnancy
  outcomesincluding fetal loss, recurrent
  pregnancy loss, and
• preeclampsiais much stronger.

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Thrombophilia Screening

• Given the high incidence of thrombophilia in the
• population and the low incidence of venous
• thromboembolism, universal screening during
• pregnancy is not cost effective
• If thrombophilia testing is performed, it is
  done before anticoagulation because heparin
  induces a decline in antithrombin levels, and
  warfarin decreases protein C and S concentrations
  (Lockwood, 2002).

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Thrombophilia Screening

• SELECTIVE SCREENING
• (1) a personal history of venous thromboembolism
  that was associated with a non recurrent risk
  factor such as fractures, surgery, and/or
  prolonged immobilization
• (2) a first-degree relative (parent or sibling)
  with a history of high-risk thrombophilia or
  venous thromboembolism before age 50 years in the
  absence of other risk factors.

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Do we need to test IT in cases with adverse
pregnancy outcome?

• ACOG(2013) Testing for inherited thrombophilias
  in women who have experienced recurrent fetal
  loss or placental abruption is not recommended
  because there is insufficient clinical evidence
  that antepartum heparin prophylaxis prevents
  recurrence. Similarly, testing is not recommended
  for women with a history of fetal-growth
  restriction or preeclampsia
• Screening for antiphospholipid antibodies may be
  appropriate in women who have experienced a fetal
  loss.

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Screening Tests

• Should be performed at least 6 weeks after the
  thrombotic event, while the patient is not
  pregnant, and when she is not receiving
  anticoagulation or hormonal therapy.
• Lack of association between methylenetetrahydrofol
  ate reductase (MTHFR)
• gene mutationsthe most common cause of
  hyperhomocysteinemiaand adverse pregnancy
  outcomes, screening with fasting homocysteine
  levels or MTHFR mutation analyses is not
  recommended (ACOG 2013).

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Screening Tests
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Thromboprophylaxis
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Thromboprophylaxis

• There is a lack of overall agreement about which
  groups of women should be offered
  thromboprophylaxis during or after pregnancy or
  offered testing for thrombophilias
• All women should undergo a documented assessment
  of risk factors for VTE in early pregnancy or
  before pregnancy.

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Basic rules in thromboprophylaxy
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Basic rules in thromboprophylaxy
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Basic rules in thromboprophylaxy
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Post NVD prophylaxy
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Post C/S thromboprophylaxy
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Thromboprophylaxy in lactation
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Thromboprophylaxy in ART
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Venous Thrombo -Embli
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Early diagnosis of VTE

• 70 iliofemoral veins in pregnancy
• Left sided ( 90- 97) compression of the left
  iliac vein by the right iliac and ovarian artery,
  both of which cross the vein only on the left
  side
• Abrupt in onset, Pain, edema
• Reflex arterial spasm causes a pale, cool
  extremity with diminished pulsations.
• Calf pain, either spontaneous or in response to
  squeezing or to Achilles tendon stretchingHomans
  sign
• 30 - 60 percent may be asymptomatic PE

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Diagnosis of DVT
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• Compression US Noninvasive technique is
  currently the most-used first-line test
  noncompressibility and
• typical echoarchitecture of a thrombosed vein.
• MRI Excellent delineation of anatomical detail
  above the inguinal ligament, The venous system
  can also be reconstructed using MR Venography
• D-Dimer Screening Tests increases in nl
  pregnancy, multifetal, cesarean , abruption, PET,
  sepsis
• Negative D-dimer test should be
  considered
• reassuring (Lockwood, 2012 Marik,
  2008).

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• Normal findings with venous ultrasonography
• results do not always exclude a pulmonary
  embolism. This is because the thrombosis may have
  already embolized or because it arose from iliac
  or other deep-pelvic veins, which are less
  accessible to ultrasound evaluation

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• Venography The gold standard to exclude lower
  extremity deep-vein thrombosis, NPV 98
• Fetal radiation exposure without shielding is
  approximately 3 mGy (Nijkeuter, 2006).
• venography is associated with significant
  complications, including thrombosis, and it is
  time consuming and cumbersome

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Treatment of VTE

• Bed Rest ( 60 chance of PE reduced to 5 with
  Rx)
• LMWH/ UFH
• ACCP Recommend LMWH
• Better bioavailability,
• Longer plasma half-life,
• More predictable dose response,
• Reduced risks of osteoporosis and
  thrombocytopenia,
• Less frequent dosing (Bates, 2012).
• Safe in pregnancy and lactation
• Increased risk of hematoma ( lt 2 hr of cesarean)

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Treatment of VTE

• After symptoms have abated ( almost 7 days),
  graded ambulation should be started.
• Elastic stockings are fitted
• Graduated compression stockings should be
  continued for 2 years after the diagnosis to
  reduce the incidence of postthrombotic syndrome.
  This syndrome can include chronic leg
  paresthesias or pain, intractable edema, skin
  changes, and leg ulcers.
• Duration of RX 20 weeks therapeutic and then
  prophylaxis if still pregnant
• DVT postpartum 6 months

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Unfractionated Heparin

• Initial treatment of thromboembolism
• Delivery
• Surgery
• Thrombolysis may be necessary (ACOG 2011).
• (1) Initial intravenous therapy followed by
  adjusted-dose subcutaneous UFH given every 12
  hours
• (2) Twice-daily, adjusted dose subcutaneous UFH
  with doses adjusted to prolong the activated
  partial thromboplastin time (aPTT) into the
  therapeutic range 6 hours postinjection (Bates,
  2012)

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• Bolus intravenous dose of 70 to 100 U/kg( 5000
  to 10,000 U) followed by
• continuous intravenous infusions beginning at
  1000 U/hr or 15 to 20 U/kg/hr, titrated to
• achieve an aPTT of 1.5 to 2.5 times control
  values (Brown, 2010).
• Intravenous anticoagulation should be maintained
  for at least 5 to 7 days, after which treatment
  is converted to subcutaneous heparin to maintain
  the aPTT to at
• least 1.5 to 2.5 times control throughout the
  dosing interval.
• APS aPTT does not accurately assess heparin
  anticoagulation, and thus anti-factor Xa levels
  are
• preferred.

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Low-Molecular-Weight Heparin

• 4000 to 5000 daltons
• unfractionated heparin has equivalent activity
  against factor Xa and thrombin, but LMWH have
  greater activity against factor Xa than thrombin
• More predictable anticoagulant response
• Fewer bleeding complications (because of their
  better bioavailability, longer half-life,
  dose-independent clearance, and decreased
  interference with platelets (Tapson, 2008).
• cleared by the kidneys

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LMWH (enoxaparin, tinzaparin, anddalteparin.

• 1 mg/kg ( wt of early pregnancy)
• Target therapeutic level peak anti-factor Xa
  activity 3 hours post- injection, with a target
  therapeutic range of 0.41.0 U/mL.
• Assay measurement accuracy and reliability are
  uncertain correlations with bleeding and
  recurrence risks are lacking and assay costs are
  high.
• So ACCP
• Routine monitoring with anti-Xa levels is
  difficult to justify.

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Labor and Delivery

• Therapeutic or prophylactic anticoagulation
  should be converted from LMWH to the shorter
  half-life UFH in the last month of pregnancy or
  sooner if delivery appears imminent
• ACOG (2013) Twice-daily adjusted-dose
  subcutaneous UFH or LMWH discontinue their
  heparin 24-36 hours before labor induction or
  cesarean delivery.
• Patients receiving once-daily LMWH should take
  only 50 percent of their normal dose on the
  morning of the day before delivery (Bates, 2012).

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Labor and Delivery

• The American Society of Regional Anesthesia and
• Pain Medicine advises withholding neuraxial
  blockade for 10 to 12 hours after the last
  prophylactic dose of LMWH or 24 hours after the
  last therapeutic dose (Horlocker, 2010).

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Anticoagulation with Warfarin Compounds

• Warfarin derivatives are generally
  contraindicated because they readily cross the
  placenta and may cause fetal death and
  malformations from hemorrhages (. 12 wks)
• Warfarin lt12 weeks nasal hypolasia, Stippled
  epiphyses,ACC, Dandy walker, cerebral atrophy,
  optic atrophy
• To avoid paradoxical thrombosis and skin necrosis
  from the early anti-protein C effect of warfarin,
  these
• women are maintained on therapeutic doses of
  UFH or LMWH for 5 days and until the INR is in a
  therapeutic range (2.03.0) for 2 consecutive
  days (ACOG 2013 Stewart, 2010).

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Thromboprophylaxy in mechanical heart Valve
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Complications of Anticoagulation

• Heparin-Induced Thrombocytopenia
• Nonimmune Benign, reversible , within the
  first few days of therapy and resolves in
  approximately 5 days without therapy cessation.
• Immune reaction paradoxically causes
  thrombosis monitoring every 2 or 3 days from
  day 4 until day 14
• Replace by danaparoid,

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Complications of Anticoagulation

• Heparin-Induced Osteoporosis
• Long term users 6 mo or gt
• Bleeding

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SUPERFICIAL VENOUS THROMBOPHLEBITIS

• Analgesia
• Elastic support
• Heat
• Rest

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Pulmonary Embolism
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PULMONARY EMBOLISM

• Dyspnea 82 percent,
• Chest pain 49 percent,
• Cough 20 percent,
• Syncope 14 percent,
• Hemoptysis 7 percent
• Tachypnea, apprehension, and tachycardia
• Massive Pulmonary Embolism hemodynamic
  instability

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Nonspecific diagnostic tests

• CXR Normal, atelectasis , effusion
• ECG S1Q3T3, Right axis deviation, p pulmonale ,
  and T-wave inversion in the anterior chest leads
  may be evident on the ECG ( mimic nl physiologic
  changes in Preg.)
• ABG normal, hypoxic
• Echocardiograpy (TEE)

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Specific diagnostic tests

• V/Q scan preferred to CTPA in pregnancy (
  avoiding breast irradiation), normal V/Q
  scan findings do not exclude pulmonary embolism
• a fourth of V/Q scans in pregnant women were
  nondiagnostic
• CTPA first line in nonpregnant, more accurate
• MRA ( gadolinium) Relatively contraindicated,
  high sensitivity for detection of central
  pulmonary emboli, the sensitivity for detection
  of subsegmental emboli is less precise
• Pulmonary angiography

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Treatment of PE Vena Caval Filters

• The woman who has very recently suffered a
  pulmonary embolism and who must undergo cesarean
  delivery presents a particularly serious problem
• Heparin therapy fails to prevent recurrent
  pulmonary embolism from the pelvis or legs, or
• when embolism develops from these sites despite
  heparin treatment

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Treatment of PE

• Thrombolysis risk of recurrence or death was
  significantly lower in patients given
  thrombolytic agents and heparin compared with
  those given heparin alone
• Embolectomy
• Anticoagulant

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Many thanks for your attention
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Many thanks to panelist
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Previous VTE
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Previous gt 1 VTE
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No prior VTE
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Antiphospholipid antibody
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Antiphospholipid antibody