Thrombophilia and adverse pregnancy outcomes

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Thrombophilia and adverse pregnancy outcomes

• Dr. Mohammed Abdalla
• Egypt, Domiat General Hospital

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Thrombophilia

• the tendency to thrombosis

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• The contact between placenta and maternal
  circulation is crucial for the success of
  pregnancy. Pro-thrombotic changes and thrombosis
  may interfere with these processes leading to
  adverse pregnancy outcomes at any gestational age

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Thrombophilia
Inherited

• hyperhomocysteinemia (C677T) mutation ).
• FV Leiden mutation (A506G) mutation ).
• mutation in prothrombin (G 20210 A) .
• The prothrombin II (PTII) mutation.
• protein S deficiency.
• Protein C deficiency.

Acquired
lupus anticoagulant antibodies
The antiphospholipid syndrome.
anticardiolipin antibodies
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placental vasculopathy

• Placental pathologists use the term placental
  vasculopathy to describe pathological placental
  changes were found to be associated with some
  clinical conditions such as preeclampsia, IUGR,
  placental abruption and some cases of fetal loss
  and preterm labor .

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placental vasculopathy

• villous infarcts.
• multiple infarcts.
• fibrinoid necrosis of decidual vessels.
• fetal stem vessel thrombosis.
• placental hypoplasia.
• spiral artery thrombosis .

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antiphospholipid syndrome
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antiphospholipid syndrome

• In the antiphospholipid antibody syndrome the
  body recognizes phospholipids (part of a cell's
  membrane) as foreign and produces antibodies
  against them.

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antiphospholipid syndrome

• APA syndrome is an acquired autoimmune
  thrombophilia in which vascular thrombosis and/or
  recurrent pregnancy losses occur in patients
  having laboratory evidence for antibodies against
  phospholipids or phospholipid-binding protein
  cofactors in their blood.

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antiphospholipid syndrome

• Antiphospholipid antibodies are a family of
  approximately 20 antibodies directed against
  negatively charged phospholipid binding proteins.
• only the lupus anticoagulant and anticardiolipin
  antibodies (IgG and IgM subclass, but not IgA)
  have been shown to be of clinical significance.

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antiphospholipid syndrome

• primary APS (PAPS) (53)
• secondary APS (47) .
• (37) Secondary APS (SAPS) associated with SLE or
  SLE-like syndrome.
• Females are more frequently affected than males.
  It mainly affects the second and third decades of
  life.

"Euro-Phospholipid Project Group". in a cohort of
1000 patients. Arthritis Rheum 2002
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antiphospholipid syndrome

• The mechanism of aPL-associated pregnancy loss is
  related to the adverse effect of these
  antibodies on embryonic implantation, trophoblast
  function and differentiation. and placental
  vasculopathy.

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PRINCIPAL PATHOGENIC MECHANISMS MEDIATED BY APL

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Sapporo criteria

• An International Consensus Conference held in
  Sapporo in 1998 stated that recurrent arterial
  and/or venous thrombosis and/or miscarriages in
  the persistent presence of a positive
  anti-phospholipid test are formal classification
  criteria for APS
• clinical criteria
• thrombosis, one or more confirmed episodes of
  venous, arterial, or small vessels disease .
• pregnancy criteria

• one or more unexplained fetal deaths after ten
  weeks of pregnancy.
• one or more preeclampsia or placental
  insufficiencies occurring before 34 weeks .
• three or more unexplained consecutive
  spontaneous abortions less than 10 weeks.

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OBSTETRICAL AND FETAL MANIFESTATIONS IN THE
COHORT OF 1,000 APS PATIENTS ENROLLED BY THE
EUROPEAN APL FORUM

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Sapporo criteria

• laboratory criteria
• The laboratory criteria are medium or high titer,
  not low titer, IgG or IgM anticardiolipin
  antibody, and/or a lupus anticoagulant on two or
  more occasions at least six weeks apart.
• When the aPTT is prolonged and not "correctable"
  by mixture with normal plasma, the presence of an
  "anticoagulant" or "inhibitor" should be suspected

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Inherited Thrombophilia
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Inherited Thrombophilia

• three important inherited thrombophilias
• mutation in factor V causing Resistance to
  activated protein C (responsible of 2030 of
  venous thromboembolism events.)
• mutation in prothrombin (guanine 20210 adenine )
• mutation in methylenetetrahydrofolate reductase
  (MTHFR) (cytosine 677 thymine (C677T) ) The
  mutation is responsible for reduced MTHFR
  activity and is the most frequent cause of mild
  hyperhomocysteinemia and can be found in 515 of
  the population.

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• A high rate of protein S deficiency, APCR,
  hyperhomocysteinemia and aCL IgG or IgM was found
  in women with severe preeclampsia .
• Dekker et al Am J Obstet Gynecol 1995

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• higher prevalence of FV Leiden mutation in women
  with severe preeclampsia compared to controls.
• Nagy et al Clin genet 1998

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• 120 women with severe preeclampsia, (72
  nulliparous) and 101 healthy matched for age and
  parity. 18.3 of preeclamptic women were carriers
  of the FV Leiden mutation compared to 3 in
  controls .
• Rigo et al Hypertens Pregnancy 2000

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• 110 healthy women who had during pregnancy severe
  preeclampsia, IUGR , severe abruptio placentae
  and stillbirth were enrolled in the study. The
  control group comprised 110 healthy matched women
  with normal pregnancies. All 220 patients were
  tested for all known thrombophilias at least 2
  months after delivery.
• The total prevalence of all thrombophilias
  detected in the 110 women with complications was
  65 compared to 18 in controls.
• Kupferminc et al N Eng J Med 1999

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• in USA tested the genetic thrombophilic mutations
  in 110 women with severe preeclampsia and 97
  controls. Most women were nulliparous and 60 of
  them were African Americans. No difference was
  found in the prevalence of thrombophilias between
  the women with severe preeclampsia and control
  women groups, or in fetal genetic thrombophilias.
• Livingstone et al Am J Obstet Gynecol 2001

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• tested 113 nulliparous women with preeclampsia
  100 with severe disease, 13 with mild disease and
  103 controls for the C677T polymorphism of the
  MTHFR gene. No difference in homozygosity for
  MTHFR was found between the 2 groups
  (preeclampsia 3 vs controls 6)
• Laivuori et al in Finland Obstet Gynecol 2000,

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factor V Leiden(A506G) mutation

• adenine 506 guanine (A506G) mutation in factor V
  (factor V Leiden) (a substitution of glutamine
  for arginine at amino acid 506 of factor V)
  Factor V Leiden (FVL) is a mutation in the factor
  V molecule, rendering it resistant to cleavage by
  activated protein C. Factor V remains a
  procoagulant and thus predisposes the carrier to
  clot formation.
• It has been linked with an increased risk for
  venous thromboembolism due to Resistance to
  activated protein C and is responsible of 2030
  of venous thromboembolism events

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factor V Leiden(A506G) mutation

• The Factor V Leiden (FVL) mutation, present in
  3-8 of the general population, leads to less
  than normal anticoagulant response to activated
  protein C resulting in an increased risk for
  venous thrombosis.
• Individuals with one copy of the FVL gene
  mutation (heterozygotes) have a seven fold
  increased risk for thrombosis compared to the
  general population whereas homozygotes have an
  eighty fold increase.

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prothrombin (G20210A) mutation

• A change of G to A at position 20210 in
  prothrombin (prothrombin 20210A) elevates
  baseline prothrombin levels and thrombin
  formation.

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MTHFR (C677T) mutation

• cytosine 677 thymine (C677T) mutation (a C to T
  change at position 677 of MTHFR) is responsible
  for reduced MTHFR activity results in decreased
  synthesis of 5-methyltetrahydrofolate, the
  primary methyl donor in the conversion of
  homocysteine to methionine and the resulting
  increase in plasma homocysteine concentrations
• ( Hyperhomocysteinemia ) is a risk factor for
  thrombosis
• Dietary restriction of folate and vitamin B12
  remains the most common cause.

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MTHFR (C677T) mutation

• A homozygous methylenetetrahydrofolate reductase
  (MTHFR) mutation, present in 1-4 of the general
  population, is associated with a three fold
  increased risk for DVT or PE, as well as
  preeclampsia and placental abruption.

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Protein S deficiency

• Protein S deficiency (PSD), present in up to 2
  of the general population, is found in
  approximately 15 of individuals with a DVT or PE
  and 6 of women with obstetrical complications
  including a relatively high risk for stillbirth.

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Protein C deficiency

• Protein C deficiency (PCD), present in about 1.5
  of the general population, is associated with a
  lower risk for obstetrical complications than PSD
  and is found in 3-5 of individuals with a DVT or
  PE.
• Furthermore, PCD combined with a FVL mutation is
  a relatively common cause of DVTs and show a
  higher risk for thrombosis compared to FVL alone.

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Antithrombin III deficiency

• Antithrombin III deficiency (ATIII), present in
  less than 0.5 of the general population, as
  with PSD and PCD, may rarely result from
  mutational events
• Because of its relative rarity, actual risks for
  thrombotic events are difficult to estimate, but
  without question this entity contributes to
  thrombotic risks during pregnancy.

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MANAGEMENT OF THROMBOPHILIC PREGNANT WOMEN
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Obstetric management

• The gold standard therapy to prevent miscarriages
  and obstetrical complications is represented by
  the association of low-dose aspirin and heparin
  (unfractionated or low molecular weight heparin).
• Intravenous immunoglobulin has been used in
  pregnant women with APS, but a recent controlled
  study found no benefit in comparison to the
  aspirin-heparin treatment .

The Pregnancy Loss Study Group. Am J Obstet
Gynecol 2000 182 122-7
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• Recently, the Cochrane Collaboration reported a
  15 reduction in the risk of preeclampsia (32
  trials with 29,331 women) and a 14 reduction in
  fetal and/or neonatal death (30 trials with
  30,093 women). This reduction in death was the
  greatest amongst high-risk women (4134 women).
• The combination of aspirin and heparin or low
  molecular weight (LMW) heparin is effective in
  recurrent fetal loss in APS syndrome and could be
  considered for women with inherited
  thrombophilias and history of severe
  preeclampsia, IUGR, abruptio placentae or fetal
  loss, although no controlled studies on the
  subject are currently available

Antiplatelet drugs for prevention of
pre-eclampsia and its consequences Systematic
review.BMJ 2001
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Recurrent pre-eclampsia and/ or embryonic loss
without history of thrombotic events 1)
Standard heparin 5,000 - 7,500 U every 12 hours
in the first trimester 5,000 - 10,000 U every 12
hours in the second and third trimesters. 2)
Low molecular weight heparin 1) Enoxaparin 40
mg/day or dalteparin 5,000 U/day or 2)
Enoxaparin 30 mg every 12 hours or dalteparin
5,000 U every 12 hours.
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• Fetal death or severe early pre-eclampsia or
  severe placental insufficiency, without history
  of thrombotic events
• 1) Standard heparin 7,500 - 10,000 U every 12
  hours in the first trimester 10,000 U every 12
  hours in the second and third trimesters.
• 2) Low molecular weight heparin
• 1) Enoxaparin 40 mg/day daily or dalteparin
  5,000 U/day, or
• 2) Enoxaparin 30 mg every 12 hours or dalteparin
  5,000 U every 12 hours

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• Anticoagulation treatment in women with previous
  thrombotic events
• 1) Standard heparin 7,500 U every 8-12 hours
  adjusted to maintain the mid-interval heparin
  levels in the therapeutic range.
• 2) Low molecular weight heparin
• 1) Weight-adjusted (e.g., enoxaparin 1 mg/kg
  every 12 hours or dalteparin 200 U/kg every 12
  hours), or
• 2) Intermediate dosage (e.g., enoxaparin 40
  mg/day or dalteparin 5,000 U/day until 16 weeks'
  gestation and every 12 hours from 16 weeks'
  gestation onwards)

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• Treatment should be prolonged for life if aPL
  positivity persists .
• Whether or not APS patients can be safely
  treated with intermediate-intensity warfarin
  treatment (INR range from 2.0 to 2.9) or with a
  high-intensity treatment (INR 3.0), is still a
  matter for debate due to the report of severe
  hemorrhagic complications associated with
  high-intensity anticoagulation therapy .

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Thank you