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The Obstetrician & Gynaecologist 10.1576/toag.13.4.225.27687 http://onlinetog.org 2011;13:225–230 Review

Review Heritable thrombophilias:

implications for pregnancy and
current evidence for treatment
Authors Bethan Myers / Sue Pavord
Key content:
• All the major heritable thrombophilias have been found to be significantly associated
with increased risk of venous thromboembolism, but the absolute risk remains low.
• The association of heritable thrombophilias with adverse pregnancy outcomes
remains controversial.
• Testing for thrombophilias should only be performed when this may affect management.
• Ideally, testing should be performed some time after the acute event, when the
woman is not receiving anticoagulation and is not pregnant.
Learning objectives:
• To understand the relationship of thrombophilias with risk for venous
thromboembolism.
• To understand the difficulties in determining possible associations of pregnancy
complications with hereditary thrombophilias.
• To learn who and when to test for hereditary thrombophilias.
Ethical issues:
• Thrombophilia testing should be performed in an expert centre where it can be
supported by effective counselling and explanation of the implications of both
positive and negative results. This is particularly the case when testing because of a
family rather than a personal history.
• Detailed and sensitive discussion regarding adverse outcomes and hereditary
thrombophilias is important, as well as giving an honest summary of the current
knowledge and a clear explanation of results in terms that can be understood.
Keywords fetal growth restriction / pre-eclampsia / pregnancy complications /
pregnancy loss / venous thromboembolism
Please cite this article as: Myers B, Pavord S. Heritable thrombophilias: implications for pregnancy and current evidence for treatment. The Obstetrician & Gynaecologist 2011;13:225–230.

Author details
Bethan Myers MA DTM&H FRCP FRCPath
Consultant Haematologist and Haemophilia
Director
Department of Haematology, Lincoln County
Hospital, Greetwell Road, Lincoln, Lincolnshire
LN2 5QY, UK; and
Obstetric Haematologist
Department of Haematology, Nottingham
University Hospitals, City Hospital Campus,
Hucknall Road, Nottingham NG5 1PB, UK
Email: bethan.myers@btinternet.com
(corresponding author)
Sue Pavord FRCP FRCPath Senior Lecturer in Medical Education
Consultant Haematologist, Haemophilia University Hospitals of Leicester, Leicester, UK
Director and Obstetric Haematologist
Department of Haematology, Leicester Royal
Infirmary, Infirmary Square, Leicester
LE1 5WW, UK; and

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Introduction
In 1990 the British Committee for Standards in
Haematology (BCSH) defined thrombophilias as
familial or acquired disorders of the haemostatic
mechanism which are likely to predispose to
thrombosis.1 However, the term is often used
loosely to describe all conditions predisposing to
thrombosis. This review concentrates on the
heritable thrombophilias, pregnancy and
treatment.
Heritable thrombophilias
These can be due to deficiencies of the naturally
occurring anticoagulants, such as antithrombin,
protein C and protein S, or to abnormalities of
coagulant factors, such as factor V Leiden and
prothrombin G20210A gene mutation (PTM),
resulting in gain of procoagulant function.
Approximately 11% of the normal population have
one of these inherited thrombophilias, which can
be readily detected by laboratory tests. There are
other known thrombophilias for which tests are not
routinely available, such as thrombomodulin
deficiency, tissue factor pathway inhibitor
deficiency,2 defects of the fibrinolytic pathway3 and
others that have not yet been described. Other risk
factors have been proposed, including high
concentrations of procoagulant factors such as
VIII,4 IX,5 XI6 and fibrinogen.7 Among them, high
levels of factor VIII have subsequently been
confirmed by other investigators8 as being, at least
in part, genetically determined, as shown by
familial clustering.9 However, the value of
measuring these weaker factors in assessing risk of
venous thrombosis has not been confirmed.
Homozygosity for methylenetetrahydrofolate
reductase (MTHFR) C677T can cause
hyperhomocysteinaemia, which has been
associated with increased risk of vascular events,
but a recent review10 calculated no significant
increased risk in pregnant women homozygous for
MTHFR C677T.
Heritable thrombophilias
and risk of venous
thromboembolism
All the major heritable thrombophilias have been
found to be significantly associated with increased
risk of venous thromboembolism in and out of
Table 1 Thrombophilia Prevalence in normal
Major heritable thrombophilias and population (%)
relative risk for venous
thromboembolism in pregnancy10
FactorV Leiden heterozygosity
FactorV Leiden homozygosity
2–7
Prothrombin mutation heterozygosity
Prothrombin mutation homozygosity
2 6.8
Protein S deficiency 0.03–0.13
Protein C deficiency
Antithrombin deficiency
0.20–0.33
0.25–0.55
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The Obstetrician & Gynaecologist
pregnancy (Table 1). However, despite the increase
in relative risk, the absolute risk of venous
thromboembolism remains low. The most
prothrombotic condition is antithrombin
deficiency, where the absolute risk for pregnancy-
related venous thromboembolism is 31% if no
anticoagulation prophylaxis is administered,
increasing to 49% in women with previous venous
thromboembolism.11 Risk is higher with the rarer
type I antithrombin deficiency than with the milder
but more common type II deficiencies.
Heritable thrombophilias can act in synergy with
acquired risk factors such as obesity, immobility
and medical conditions, to give a resulting risk
which is greater than would be expected for the sum
of the individual factors.12
Laboratory investigations
Detection of thrombophilia does not affect the
initial management of venous thrombosis but may
affect decisions regarding duration of
anticoagulation. Detection may be beneficial for
first-degree family members who are carriers of the
defect but who are still asymptomatic. Relatives
identified with the same condition may be accorded
a lower threshold for primary preventative
strategies than those without. Testing may also help
to identify those individuals with combined or
homozygous defects who are at higher risk of
venous thromboembolism13–15 or more likely to
develop it earlier in life.16
Who to test for thrombophilia
In general, laboratory testing should be performed
whenever the results may influence decisions on
therapy or prevention. The clinical circumstances
surrounding the thrombotic event are far more
important in determining duration of
anticoagulation than the presence of thrombophilia.
For example, a deep vein thrombosis occurring
during plaster immobilisation of the lower leg
following fracture will only require a short course
of treatment as opposed to an unprovoked
spontaneous pulmonary embolus, which may
necessitate long-term therapy. Laboratory testing
should be selective and considered as only one
factor in the assessment of risk of recurrence.
Testing may need to be extended to first-degree
family members of the proband as it may influence
decisions regarding primary prevention measures.
Guidelines from the Royal College of Obstetricians
and Gynaecologists17 and the British Committee for
Standards in Haematology18 suggest testing women
Relative in the presence of:
risk
9.32
34.4 • history of unprovoked venous thrombosis
26.4
• thrombosis in association with pregnancy or the
3.19
combined contraceptive pill
4.76
4.69
• a previous event due to a minor provoking factor,
such as travel
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• first-degree family history of idiopathic venous
thrombosis; or venous thromboembolism
related to pregnancy, use of the combined
contraceptive pill or a minor risk factor. If the
family member has a known thrombophilia, tests
can be selective.
In the first two groups of women, testing does not
influence the need for antenatal prophylaxis, but may
affect decisions about dosage/duration of treatment
and is beneficial for first-degree relatives.Where
testing is performed on an asymptomatic person as
part of family studies, the risks, benefits and
limitations of the tests should be carefully explained
and considered. Testing is not indicated for:
• arterial thrombosis
• assisted conception or ovarian hyperstimulation
syndrome, in the absence of venous
thromboembolism
• significant provoking factors to a thrombotic event
• family history of provoked thrombosis.
When to test
Factor V Leiden and prothrombin mutations are
detected by genetic analysis and tests can, therefore,
be performed at any time. Plasma levels of protein
C, protein S and antithrombin should be tested at
least 4 weeks after the acute event, because of the
initial consumption of factors during the
thrombotic process. Free (biologically active)
protein S levels fall in pregnancy because of the rise
in protein S-binding globulin and, therefore, testing
should be carried out at approximately 3 months
postpartum. Rarely, protein C and antithrombin
can be affected in pregnancy and clarification of
baseline levels may be necessary in the nonpregnant
state. Most of the tests are not reliable during
anticoagulation, as heparin reduces levels of
antithrombin and warfarin affects proteins C and S,
which are both vitamin K-dependent factors. It is,
therefore, preferable to postpone laboratory testing
until 4 weeks after discontinuation of treatment. In
summary, testing should be performed:
• away from the acute event
• when anticoagulation is discontinued
• when the woman is not pregnant or on the
combined contraceptive pill.
Venous thromboembolism
prevention strategies
All women should be assessed for risk of
thrombosis, either in early pregnancy or before
pregnancy, and this should be repeated if
circumstances change or if hospital admission is
required.17 Pregnant women should be advised
about general antithrombotic measures such as
weight control, good hydration, leg care and
mobility. Women with previous deep vein
thrombosis should also be advised to wear
© 2011 Royal College of Obstetricians and Gynaecologists
2011;13:225–230 Review
antiembolic stockings, or class II compression
stockings if still within 2 years of the thrombotic
event. Women with known thrombophilia will
require antenatal low molecular weight heparin if
they have a personal history of thrombosis. For
women with thrombophilia and no history of
thrombosis, the need for antenatal low molecular
weight heparin will depend on the nature of their
thrombophilia, their family history and the
presence of additional acquired factors such as
obesity. With antithrombin deficiency, the high risk
of venous thrombosis in pregnancy justifies
prophylaxis even in previously asymptomatic cases
with no additional factors.
During labour and delivery, attention should be
given to hydration, use of antiembolic stockings
and early mobilisation. Women with
thrombophilia will need low molecular weight
heparin in the postpartum period for at least 7 days.
This will need to be extended to 6 weeks for those
with a positive family history or other risk factors.
Those previously receiving long-term warfarin will
need to return to this regimen in the postpartum
period, overlapping with low molecular weight
heparin for the first few days and until the
international normalised ratio (prothrombin time)
is within normal limits. Both warfarin and heparin
are safe during breastfeeding.
Heritable thrombophilias and
pregnancy complications
The possible causal relationship between heritable
thrombophilias and adverse pregnancy outcome
has remained a controversial issue for the last two
decades.
Placental development and the theoretical basis
for association
From 9 to 12 weeks of gestation there is uterine
spiral artery remodelling caused by the invasion of
trophoblast cells into the uterine lining. Thus
maternal blood is flowing over fetal tissue and
hypercoaguable maternal blood could potentially
contribute to placental pathology.
Thrombin plays a central role in normal placental
development and the latter appears to be strongly
coupled with maternal haemostasis. In animal
experiments, knockout mice that do not express
thrombomodulin on the trophoblast cells have
inadequate placentation and there is early
embryonic death. This early lethality is dependent
on tissue factor expression and thrombin
generation19 but, at least in animal experiments, is
not dependent on fibrinogen and heparin does not
ameliorate the lethal effect. The thrombomodulin
deficiency does not appear to lead to fibrin
deposition and placental thrombosis and, therefore,
there must be alternative mechanisms causing the
early embryonic demise.20 Microthrombi are a
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Table 2 Outcome Factor V Leiden OR
Results of three meta-analyses of (95% CI)
23 10
pregnancy loss and thrombophilia Rey Robertson
Recurrent first- 2.01 1.91
trimester loss (1.13–3.58) (1.01–3.61)
Late pregnancy 3.26 2.06
loss (1.82–5.83) (1.1–3.86)
CI = confidence interval; OR = odds ratio.
common finding in the placental vasculature of
women with pregnancy loss and placental
thrombosis has been described in association with
individual thrombophilic defects. However, this is
not a consistent finding and similar findings are
described in women without thrombophilic defects.
Thus, individual maternal haemostatic and
trophoblastic cell characteristics form a complex
combination of factors that affect placental
development and of that maternal thrombophilia
may be one component.
Pregnancy complications: confounding factors
Large numbers of studies examining the relationship
between adverse pregnancy outcomes and the
presence of a laboratory-detectable thrombophilia
have produced conflicting and inconsistent results.
There are a number of reasons for this:
• Pregnancy complications, such as pregnancy loss,
pre-eclampsia and placental abruption, are
distressing experiences which often have
extremely traumatic outcomes. Women who have
gone through these experiences are often highly
motivated to try any treatment, even if unproven,
in the hope of a better outcome in subsequent
pregnancies. This, together with the fact that in
most cases the outcome of the next pregnancy is
likely to be good, has made it difficult to conduct
large randomised prospective studies.
• Different definitions, for example, for pregnancy
loss, are used in different studies, which hinders
the comparison or combination of studies.
• Women with pregnancy complications are a
heterogeneous group and underlying factors for
early and late complications are likely to differ.
Thrombophilia is only one of several factors that
can affect pregnancy outcome.
• Both thrombophilias and pregnancy
complications are common, increasing the
chances of finding incidental associations.
Furthermore, the prevalence of thrombophilias
varies among different ethnic groups,
contributing to differing study results.
• Rodger21 recently summarised the overall
difficulty: to detect an odds ratio of ≥2, with a
risk factor that has a prevalence of <5%, a sample
size >1000 is required in the 1:1 case control
studies. Although there are many studies, most
have sample sizes smaller than this.
• Finally, many of the earlier studies have been
criticised for methodological flaws.
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The Obstetrician & Gynaecologist
Prothrombin G20210A OR Protein S deficiency OR
(95% CI) (95% CI)
24 23 10 23 10
Rodger Rey Robertson Rey Robertson
2 2.56 2.7 14.7
(1.13–3.38) (1.04–6.29) (1.37–5.34) (0.99–2.18)
Pooled results of early 2.3 2.66 7.39 20.09
and late losses (1.09–4.87) (1.28–5.53) (1.28–42.6) (3.7–109.15)
Pregnancy loss and
thrombophilia
Up to 50% of conceptuses fail before implantation
and 15% of recognised pregnancies end in
miscarriage. Most studies do not differentiate
between very early loss (<10 weeks) and later losses
in the first trimester. Interestingly, when embryonic
loss has been studied, presence of a thrombophilia
appears to have a protective effect.22
Table 2 summarises the results of three meta-
analyses, by Rey,23 Robertson10 and Rodger.24 It
should be noted that the studies included by Rodger
differed from the other two in that they were
restricted to prospective studies and, in general, this
set of studies shows weaker associations.
Similar results were found for all three meta-
analyses for pregnancy loss and factor V Leiden.
Robertson and Rodger noted heterogeneity in the
analysis: factor V Leiden had a stronger association
with late rather than early losses. Comparable
results were found with PTM: Rey and Robertson
reported a strong association of late fetal loss with
protein S deficiency and Robertson noted an
association between hyperhomocysteinaemia and
early pregnancy loss.
A recent prospective study25 evaluated pregnancy
outcomes in 1700 asymptomatic nulliparous women
who underwent genotyping before 22 weeks of
gestation for factor V Leiden, PTM, MTHFR and
thrombomodulin polymorphisms. The women had
no family or personal histories of thromboembolism
or thrombophilia. The primary composite outcome
was the development of severe pre-eclampsia, fetal
growth restriction, placental abruption, stillbirth or
neonatal death. Results were similar in carriers and
noncarriers. Women with PTM had increased risk of
a composite outcome (odds ratio [OR] 3.58, 95%
confidence interval [CI] 1.20–10.61) and, conversely,
homozygosity for the MTHFR polymorphism had a
protective effect (OR 0.26, CI 0.08–0.86).
The conclusion from this and the other studies is
that the absolute risks are low and that screening is
not indicated.
Pre-eclampsia and
thrombophilia
Results from studies are, again, variable.
Robertson10 included 25 studies (11 183 women),
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reporting significant associations with factor V
Leiden (OR 2.19, CI 1.46–3.27), PTM (OR 2.54, CI
1.52–4.23) and hyperhomocysteinaemia (OR 3.49,
CI 1.21–10.11). However, Rodger’s data24 from
12 401 women showed no association with factor V
Leiden (OR 1.22, CI 0.89–1.66) or PTM (OR 1.24,
CI 0.72–2.12) and no evidence of statistical
heterogeneity. Any association, if present at all,
appears to be slight.
Fetal growth restriction, small
for gestational age and
thrombophilia
Robertson10 analysed data on fetal growth
restriction in five studies (195 women) and did not
demonstrate an association with hereditary
thrombophilias. Rodger24 analysed 20 654 cases
involving small-for-gestational-age babies and,
similarly, found no association with factor V Leiden
(OR 1.0, 95% CI 0.80–1.25) or pooled PTM
heterozygotes and homozygotes (OR 1.25, 95%
CI 0.92–1.70).
Placental abruption and
thrombophilia
Robertson10 evaluated seven studies (922 women)
regarding placental abruption and found
significant associations only with factor V Leiden
(OR 4.7, CI 1.13–19.59) and PTM (OR 7.71,
CI 3.01–19.76). Rodger24 analysed 12 401 cases and
found a more modest association with factor V
Leiden (OR 2.28, CI 0.92–5.67). Pooled relative risk
for PTM and placental abruption in 5672 cases was
2.63 (CI 0.15–44.6) and significant heterogeneity
was noted.
Conception and
thrombophilia
Some authors have suggested associations between
infertility and thrombophilia. Bellver et al.26
evaluated markers for thrombophilia and thyroid
autoimmunity in women with recurrent pregnancy
loss, recurrent implantation failure and
unexplained infertility. They found at least one
thrombophilia marker in as many as 50% of
participants in all groups, including controls; there
was no significant difference in the presence of
hereditary thrombophilias among the study group.
Although the authors suggest that thrombophilia
could be an aetiological factor in infertility, the
results do not support this conclusion.
Outcomes for prophylaxis and
thrombophilias
Clinicians are increasingly using anticoagulants for
women with previous adverse pregnancy
outcomes. This is partly from extrapolation of
results of studies of the acquired thrombophilia
© 2011 Royal College of Obstetricians and Gynaecologists
2011;13:225–230 Review
• Unselected testing in pregnancy is not recommended. Box 1
Positive tests have a poor positive predictive value. Recommendations for women with
thrombophilia and adverse
• Current national and international guidelines advocate
testing only for antiphospholipid syndrome antibodies and
pregnancy outcomes
not for hereditary thrombophilias in women with pregnancy
complications, in view of the weak associations of most
pregnancy outcomes with thrombophilia.
• As some adverse outcomes have been associated with
hyperhomocysteinaemia (such as pre-eclampsia), a
pragmatic approach may be to advise women with relevant
clinical histories to take folic acid, 5 mg daily, for the duration
of the pregnancy.
antiphospholipid syndrome27 and partly from the
intuitive conclusion that antithrombotic therapy is
likely to improve outcome in those with a
prothrombotic diathesis. The pathophysiology of
antiphospholipid syndrome, however, has been
shown to be complex and the anticoagulant
treatment in this case involves other processes in
addition to antithrombotic activity; it is, therefore,
not directly comparable. Even in antiphospholipid
syndrome, it is disputed whether a heparin and
aspirin combination is superior to aspirin alone in
recent meta-analyses.28,29
A prospective study by Vossen et al.30 evaluated 131
women with thrombophilia and 60 controls, all in
their first pregnancies. The risk of fetal loss
appeared slightly increased in those without
thromboprophylaxis: 7/83 in the treatment group
(8%) versus 10/48 in the control group (21%),
relative risk 0.3 (95% CI 0.1–1.0). The authors
commented that, per type of defect, the relative risk
varied only minimally from 1.4 for factor V Leiden
to 1.6 for antithrombin deficiency compared with
control women and that prophylactic
anticoagulation differed greatly in type, dose and
duration, precluding solid conclusions on the effect
of thromboprophylaxis on fetal loss.
The results of the ALIFE31 and SPIN32 studies,
examining the effect of antithrombotic treatment
on the pregnancies of women with at least two
miscarriages, were published in 2010. Neither
demonstrated benefit from low molecular weight
heparins and, although not powered specifically to
examine thrombophilias, this subgroup showed no
benefit in either study.
For recommendations for women with
thrombophilia and adverse pregnancy outcomes
see Box 1.
Conclusion
Of paramount importance for the management of
thrombophilias in pregnancy is careful selection of
women to be investigated, the timing of testing and
the tests to be carried out. This enables effective
strategies to prevent future events among women
who carry genetic defects but are still asymptomatic
and to reduce the risk of recurrent thrombosis
among those with previous events.
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References
1 British Committee for Standards in Haematology. Guidelines on the
investigation and management of thrombophilia. J Clin Pathol
1990;43:703–9. doi:10.1136/jcp.43.9.703
2 Ariëns RA, Alberio G, Moia M, Mannucci PM. Low levels of heparin-
releasable tissue factor pathway inhibitor in young patients with
thrombosis. Thromb Haemost 1999;81:203–7.
3 Van Tilburg NH, Rosendaal FR, Bertina RM. Thrombin activatable
fibrinolysis inhibitor and the risk of deep vein thrombosis. Blood
2000;95:2855–9.
4 KosterT, Blann AD, Briët E, Vandenbroucke JP, Rosendaal FR. Role
of clotting factorVIII in effect of von Willebrand factor on occurrence of
deep-vein thrombosis. Lancet 1995;345:152–5. doi:10.1016/S0140-
6736(95)90166-3
5 van Hylckama Vlieg A, van der Linden IK, Bertina RM, Rosendaal FR. High
levels of factor FIX increase the risk of venous thrombosis. Blood
2000;95:3678–82.
6 Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM, Rosendaal FR. High
levels of coagulation factor FXI as a risk factor for venous thrombosis. N
Engl J Med 2000;342:696–701. doi:10.1056/NEJM200003093421004
7 KosterT, Rosendaal FR, Reitsma PH, van derVelden PA, Briët E,
Vandenbroucke JP. FactorVII and fibrinogen levels as risk factors for
venous thrombosis. A case control study of plasma levels and DNA
polymorphism. The Leiden Thrombophilia Study (LETS). Thromb
Haemost 1994;71:719–22.
8 O’Donnell J, Tuddenham EG, Manning R, Kemball-Cook G, Johnson D,
Laffan M. High prevalence of elevated factorVIII levels in patients referred
for thrombophilia screening: role of increased synthesis and relationship
to the acute phase reaction. Thromb Haemost 1997;77:825–8.
9 Kamphuisen PW, Lensen R, Houwing-Duistermaat JJ, Eikenboom JC,
Harvey M, Bertina RM, Rosendaal FR. Heritability of elevated factorVIII
antigen levels in factorV Leiden families with thrombophilia. Br J
Haematol 2000;109:519–22. doi:10.1046/j.1365-2141.2000.02091.x
10 Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GD, et al;
Thrombosis: Risk and Economic Assessment of Thrombophilia Screening
(TREATS) Study. Thrombophilia in pregnancy: a systemic review. Br J
Haematol 2006;132:171–96. doi:10.1111/j.1365-2141.2005.05847.x
11 Vicente V, Rodríguez C, Soto I, Fernández M, Moraleda JM. Risk of
thrombosis during pregnancy and post-partum in hereditary thrombophilia.
Am J Hematol 1994;46:151–2. doi:10.1002/ajh.2830460218
12 Pomp ER, le Cessie S, Rosendaal FR, Doggen CJ. Risk of venous
thrombosis: obesity and its joint effect with oral contraceptive use and
prothrombotic mutations. Br J Haematol 2007;139:289–96. doi:10.1111/j.
1365-2141.2007.06780.x
13 Gerhardt A, Sharf RE, Zotz RB. Effect of hemostatic risk factors on the
individual probability of thrombosis during pregnancy and the
puerperium. Thromb Haemost 2003;90:77–85.
14 Koeleman BP, Reitsma PH, Allaart CF, Bertina RM. Activated protein C
resistance as an additional risk factor for thrombosis in protein C deficient
families. Blood 1994;84:1031–5.
15 Zöller B, Berntsdotter A, García de Frutos P, Dahlbäck B. Resistance to
activated protein C as an additional genetic risk factor in hereditary
deficiency of protein S. Blood 1995;85:3518–23.
16 van Boven HH, Reitsma PH, Rosendaal FR, Bayston TA, Chowdhury V,
Bauer KA, et al. FactorV Leiden (FVR506Q) in families with inherited
antithrombin deficiency. Thromb Haemost 1996;75:417–21.
17 Royal College of Obstetricians and Gynaecologists. Reducing the Risk of
Thrombosis and Embolism During Pregnancy and the Puerperium.
Green-top Guideline No. 37a. London: RCOG Press; 2009
[www.rcog.org.uk/files/rcog-corp/GTG37aReducingRiskThrombosis.pdf.]
230
The Obstetrician & Gynaecologist
18 Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S, et al. Clinical
guidelines for testing for heritable thrombophilia. Br J Haematol
2010:149;209–220. doi:10.1111/j.1365-2141.2009.08022.x
[www.bcshguidelines.com/documents/Heritable_thrombophilia_bjh_
07_2010.pdf].
19 Isermann B, Sood R, Pawlinski R, Zogg M, Kalloway S, Degen JL, et al.
The thrombomodulin-protein C system is essential for the maintenance
of pregnancy. Nat Med 2003:9;331–7. doi:10.1038/nm825
20 Weiler-Guettler H, Christie PD, Beeler DL, Healy AM, Hancock WW,
Rayburn H, et al. A targeted point mutation in thrombomodulin generates
viable mice with a prethrombotic state. J Clin Invest 1998;101:1983–91.
doi:10.1172/JCI2006
21 Rodger M. Thrombophilia and placenta-mediated complications: from
bench to bedside to policy. Thromb Res 2009;123 Suppl 2:S100–4.
doi:10.1016/S0049-3848(09)70021-0
22 Roqué H, Paidas MJ, Funai EF, Kuczynski E, Lockwood CJ. Maternal
thrombophilias are not associated with early pregnancy loss. Thromb
Haemost 2004;91:290–5.
23 Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss:
a meta-analysis. Lancet 2003;361:901–8. doi:10.1016/S0140-6736
(03)12771-7
24 Rodger MA, Betancourt MT, Clark P, Lindqvist PG, Dizon-Townson D, Said
J, et al. The association of factorV Leiden and prothrombin gene mutation
and placenta mediated pregnancy complications: A systematic review
and meta-analysis of prospective cohort studies. PLoS Med
2010;7:e1000292. doi:10.1371/journal.pmed.1000292
25 Said JM, Higgins JR, Moses EK, Walker SP, Borg AJ, Monagle PT, et al.
Inherited thrombophilia polymorphisms and pregnancy outcomes in
nulliparous women. Obstet Gynecol 2010;115:5–13.
doi:10.1097/AOG.0b013e3181c68907
26 Bellver J, Soares SR, Alvarez C, Muñoz E, Ramírez A, Rubio C, et al. The
role of thrombophilia and thyroid autoimmunity in unexplained infertility,
implantation failure and recurrent spontaneous abortion. Hum Reprod
2008;23:278–84. doi:10.1093/humrep/dem383
27 Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin
and aspirin plus heparin in pregnant women with recurrent miscarriage
associated with phospholipid antibodies. BMJ 1997;314:253–7.
28 Laskin CA, Spitzer KA, Clark CA, Crowther MR, Ginsberg JS, Hawker GA,
et al. Low molecular weight heparin and aspirin for recurrent pregnancy
loss: Results from the randomised, controlled HepASA trial. J Rheumatol
2009;36:279–87. doi:10.3899/jrheum.080763
29 Mak A, Cheung WL, Cheak AA, Ho RC. Combination of aspirin and
heparin is superior to aspirin alone in enhancing live births in patients
with recurrent pregnancy loss and positive antiphospholipid antibodies: a
meta-analysis of randomised controlled trials and meta-regression.
Rheumatology 2009;49:281–8. doi:10.1093/rheumatology/kep373
30 Vossen CY, Preston FE, Conard J, Fontcuberta J, Makris M, van der Meer
FJ, et al. Hereditary thrombophilia and fetal loss: a prospective follow-up
study. J Thromb Haemost 2004;2:592–6. doi:10.1111/j.1538-7836.2004.
00662.x
31 Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR,
Hamulyák K, et al. Aspirin plus heparin or aspirin alone in women with
recurrent miscarriage. N Engl J Med 2010;362:1586–96. doi:10.1056/
NEJMoa1000641
32 Clark P, Walker ID, Langhorne P, Crichton L, Thomson A, Greaves M, et al;
Scottish Pregnancy Intervention Study (SPIN) collaborators. SPIN: the
Scottish Pregnancy Intervention Study: a multicentre randomised
controlled trial of low molecular weight heparin and low dose aspirin in
women with recurrent miscarriage. Blood 2010;115:4162–7.
doi:10.1182/blood-2010-01-267252
© 2011 Royal College of Obstetricians and Gynaecologists