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Thrombophilia and adverse pregnancy outcomes

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Title: Thrombophilia and adverse pregnancy outcomes


1
Thrombophilia and adverse pregnancy outcomes
  • Dr. Mohammed Abdalla
  • Egypt, Domiat General Hospital

2
Thrombophilia
  • the tendency to thrombosis

3
  • 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

4
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
5
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 .

6
placental vasculopathy
  • villous infarcts.
  • multiple infarcts.
  • fibrinoid necrosis of decidual vessels.
  • fetal stem vessel thrombosis.
  • placental hypoplasia.
  • spiral artery thrombosis .

7
antiphospholipid syndrome
8
antiphospholipid syndrome
  • In the antiphospholipid antibody syndrome the
    body recognizes phospholipids (part of a cell's
    membrane) as foreign and produces antibodies
    against them.

9
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.

10
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.

11
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
12
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.

13
PRINCIPAL PATHOGENIC MECHANISMS MEDIATED BY APL

14
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.

15
OBSTETRICAL AND FETAL MANIFESTATIONS IN THE
COHORT OF 1,000 APS PATIENTS ENROLLED BY THE
EUROPEAN APL FORUM

16
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

17
Inherited Thrombophilia
18
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.

19
  • 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

20
  • higher prevalence of FV Leiden mutation in women
    with severe preeclampsia compared to controls.
  • Nagy et al Clin genet 1998

21
  • 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

22
  • 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

23
  • 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

24
  • 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,

25
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

26
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.

27
prothrombin (G20210A) mutation
  • A change of G to A at position 20210 in
    prothrombin (prothrombin 20210A) elevates
    baseline prothrombin levels and thrombin
    formation.

28
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.

29
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.

30
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.

31
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.

32
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.

33
MANAGEMENT OF THROMBOPHILIC PREGNANT WOMEN
34
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
35
  • 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
36
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.
37
  • 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

38
  • 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)

39
  • 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 .

40
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