REVIEW

Bleeding disorders in
pregnancy

gestational thrombocytopenia (GT), 15e20% are due to thrombotic microangiopathies (in particular associated with hypertensive disorders of pregnancy), 3e4% are due to immune
causes, and <1% are due to other rare causes including constitutional thrombocytopenias, infection, and malignancy.

Eleftheria Lefkou
Beverley J Hunt

Gestational thrombocytopenia
The platelet count in pregnancy is generally lower than the nonpregnant state. In 5e8% of all pregnancies, the platelet count at
term is below the normal range (150e400  109/L). In gestational thrombocytopenia (GT) platelet counts are typically >70 
109/L, with about two-thirds just below the normal lower limit,
between 130  109/L and 150  109/L. It is exceptional for the
platelet count to fall below 80  109/L but in rare cases, subsequently confirmed as GT, counts may be as low as 50  109/L.
The cause of GT remains uncertain, but the dilutional effect
on platelet mass of expanded plasma volume in pregnancy and
possibly accelerated destruction of platelets when passing over
trophoblasts contribute to the aetiology.
Characteristically GT is:
 Mild and asymptomatic;
 Not associated with past non-pregnant medical history of
thrombocytopenia in the mother;
 Occurs late in pregnancy (second trimester, more pronounced at labour);
 Not associated with fetal thrombocytopenia;
 Not associated with maternal or neonatal haemorrhage;
 It resolves spontaneously after delivery (within 7 days-6
weeks postpartum);
 Bleeding times are normal, unless platelet count falls
below 80  109/L.
It should be remembered that although fibrinogen is end point
of the coagulation cascade and directly responsible for fibrin
production, it is also the main ligand for platelet aggregation.
Thus the increased fibrinogen levels in pregnancy allow pregnant
women to tolerate lower platelet counts than non-pregnant
women.

Abstract
During pregnancy the physiological changes in the haemostatic system
tend to improve mild inherited bleeding disorders. However, thrombocytopenia and coagulation problems unique to pregnancy may occur. In this review, we discuss and provide recommendations for the management of
bleeding problems seen in pregnancy, such as thrombocytopenia, von Willebrand disease, haemophilias and thrombotic microangiopathies. In the
majority of cases complicated by haematological disease, pregnancy, delivery, and the puerperium should be managed by a multidisciplinary team,
which includes obstetricians, haematologists and obstetric anaesthetists.

Keywords bleeding; haemorrhage; postpartum haemorrhage; thrombocytopenia antepartum

Introduction
Within the circulatory system, blood must flow normally and yet
if vessels are damaged has to form a clot quickly to restrict
excessive bleeding. Due to the competing demands of flow and
haemostasis, the coagulation system is necessarily complex.
Table 1 provides an aetiological division of bleeding disorders.
Pregnancy results in increased levels of fibrinogen, factors VII,
VIII, IX, X and XII, and von Willebrand factor. It also results in
decreased levels of factor XI and protein S. Together, these
changes lead to a prothrombotic state. Thus, most inherited
bleeding disorders tend to improve during pregnancy but worsen
immediately afterwards as the haemostatic system reverts
quickly to the non-pregnant state. An altered fibrinolytic state is
part of a normal physiological response to pregnancy due to an
increase in the fibrinolytic inhibitors PAI-1 and PAI-2 and tissue
plasminogen activator (t-PA).
We review the management of bleeding disorders in pregnancy and the puerperium. Thrombocytopenia is discussed first,
then the thrombotic microangiopathies, and the last part of the
review will deal with the most common inherited bleeding disorders and acquired haemophilia.

Immune thrombocytopenic purpura

Immune thrombocytopenic purpura (ITP) is due to the formation
of autoantibodies, usually IgG, against platelet surface glycoproteins, especially glycoproteins IbeIX and IIbeIIIa, causing
their premature destruction by the reticuloendothelial system.
The incidence of ITP in the general adult population is 6.6 per
100,000, with 1e5 cases per 10,000 pregnancies. ITP is around
100 times less common than GT in pregnancy. ITP is rarely
associated with systemic lupus erythematosus, human immunodeficiency virus (HIV), or drugs.
Due to the increased platelet turnover, the residual platelets
are young and more haemostatically active; therefore, the patients rarely bleed and cerebral haemorrhage occurs in less than
1%. In the last 30 years no maternal deaths have been reported
due to ITP in the UK, and maternal morbidity is minimal if
appropriate therapy is administered during pregnancy and
childbirth.
Usually the clinical problem is differentiating GT from ITP
(Table 3). This has minor clinical importance for the mother, but is
essential for the fetus. Due to the transplacental passage of antibody, ITP may rarely cause thrombocytopenia in the fetus,

Thrombocytopenia in pregnancy
Thrombocytopenia is a common finding in pregnancy, occurring
in 7e10% of pregnancies (Table 2). 75% of cases are due to

Eleftheria Lefkou MD PHD is Consultant Haematologist, Hippokrateion

University Hospital of Thessaloniki, Greece. Conflicts of interest: none
declared.
Beverley J Hunt MB FRCP FRCPath MD is Professor of Thrombosis and
Haemostasis, Kings College, and a Consultant at the Department of
Haematology, Lupus and Pathology, Guys & St Thomas NHS
Foundation Trust, London, UK. Conflicts of interest: none declared.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:11

314

2015 Elsevier Ltd. All rights reserved.

REVIEW

Bleeding disorders
Platelets
Thrombocytopenia
C
Failure of production

C
C

Increased destruction

Pregnancy directly related

C
C
C
C

Dilutional/uncertain

C
C

Platelet dysfunction
C
Hereditary

C
C
C

C
C

Acquired

Vessel wall
C
Drugs (chronic glucocorticoid use,
penicillins, sulphonamides)
C
Vitamin C deficiency
C
Paraproteinaemia
C
nlein purpura and other
HenocheScho
vasculitis
C
Hereditary defects

C
C

Coagulation
C
Acquired causes

C
C
C
C
C

Inherited causes

Decreased megakaryocyte mass e radiation, chemicals, drugs; intrinsic bone marrow

abnormalities (aplastic anaemia, leukaemia, myelofibrosis, myelodysplastic syndrome, etc); replacement of bone marrow with carcinoma cells (plasma cells, etc)
Ineffective thrombopoiesis e megaloblastic anaemias (B12, folic acid deficiency)
Immune mechanisms: autoimmune thrombocytopenic purpura (ITP); autoimmune
diseases (lupus erythematosus)
Splenomegaly (usually secondary to liver disease)
Microangiopathies (PET, HELLP, DIC, TTP)
Acute fatty liver
Gestational thrombocytopenia
HIV
Disorders of platelet adhesion (BernardeSoulier syndrome)
Disorders of platelet aggregation (thromboasthenia, Glanzmann)
Disorders of platelet secretion (a granule deficiency e Grey platelet syndrome, dense
granule deficiency e delta storage pool deficiency, aspirin- like disorders)
Disorders of platelet procoagulant activity (Scott syndrome)
Drugs e aspirin and other NSAIDs; alcohol, antibiotics (carbenicillin, penicillin,
moxalactam, third-generation cephalosporins)
Other e uraemia, liver disease, heart bypass surgery, haematological malignancies,
myeloproliferative disorders, leukaemia, etc)

Hereditary haemorrhagic telangiectasia

EhlerseDanlos syndrome
Vitamin K antagonism/deficiency
Liver disease
Anticoagulation therapy
Disseminated intravascular coagulation
Factor inhibitors
Factor deficiencies (von Willebrand disease, haemophilia A and B, rare e FXI, FVII, FX,
prothrombin deficiency, fibrinogen deficiency/dysfunction

Table 1

coagulopathy or autoimmune disease. Bone marrow examination is

unnecessary unless there is suspicion of leukaemia or lymphoma.
The routine measurement of platelet antibodies is not recommended, because the results are not sufficiently sensitive or
specific.
The aim of management is to maintain a safe platelet count.
Antenatally platelet counts >20e30  109/L do not need treatment
until the third trimester, and during the first two trimesters indications for initiating treatment are no different from a non pregnant patient, unless there is also a defect in platelet function or
abnormal coagulation. Routine platelet counting may underestimate the total count, as most analysers count platelets according to
a size range. However young platelets may be very large and

whereas GT does not. Neonatal thrombocytopenia occurs in up to

14% of pregnancies complicated by ITP: 7.5% have severe
thrombocytopenia with platelet counts <50  109/L. Furthermore,
4% have platelet counts <20  109/L, and are therefore at risk for
haemorrhage at birth. Splenectomy prior to pregnancy is the only
recognized risk factor associated with the development of neonatal
thrombocytopenia. This may be due to the fact that splenectomised
women usually have more severe ITP, and large amounts of
circulating autoantibodies. The main concern for the fetus during
the labour is trauma provoking cerebral haemorrhage.
The British Society of Haematology (BSH) recommends that all
women with platelet counts less than 100  109/L should be
screened for clinical or laboratory evidence of pre-eclampsia,

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:11

315

2015 Elsevier Ltd. All rights reserved.

REVIEW

the use of scalp electrodes for monitoring the labour. Mode of

delivery should be determined by obstetric indications.

Causes of thrombocytopenia in pregnancy

Pregnancy-related

Other

Gestational
(or incidental, 75%)

Spurious (EDTA-induced platelet

aggregation) send a citrate sample
to exclude this
Autoimmune (immune
thrombocytopenic purpura,
drug-induced, systemic lupus
erythematosus, antiphospholipid
syndrome)
Viral, e.g. HIV, EBV, CMV
von Willebrand type IIB disease

Pre-eclampsia (PET)

Haemolysis, elevated liver

enzymes and low platelet
(HELLP syndrome)
Disseminated intravascular
coagulation
Acute fatty liver

Folate deficiency

Specific treatments for ITP

The main treatment options for maternal ITP are corticosteroids or
intravenous immunoglobulin (IVIg). Vinca alkaloids, androgens
and most immunosuppressive drugs should not be used in pregnancy, however azathioprine is safe. In women positive for Helicobacter pylori, its eradication can result in platelet count
improvement.
 Steroids BSH guidelines recommend 1 mg/kg but in our
experience a dosage of 10e20 mg may be effective in
increasing a platelet count of <50 to levels >80 109/L.
 Intravenous immunoglobulin (IVIg) IVIg (usual prescription 0.4 mg/kg/day for 3e5 days) has a similar response
rate as in the non-pregnant woman, however duration of
response is short usually lasting 2e3 weeks and repeated
infusions many be required. Currently there is an international shortage of IVIg.
 Intravenous Anti-D This is given to Rhesus-positive patients in whom red cells coated in antibody block the
reticuloendothelial system, preventing platelet destruction.
It is currently unavailable in the UK and experience in
pregnancy has been limited. Some studies have administered intravenous anti-D daily for 5 days; others a single
dose lasting <5 minutes. In a trial, eight women were
treated in the second and third trimester with one to seven
anti-D infusions. The response rate was 75%, with a fall of
haemoglobin of >20 g/L in one patient. Anti-D crosses the
placenta, but only three of the seven Rhesus-positive babies were Coombs test (antibody present on red cells)
positive, however none of them were anaemic.
 Splenectomy. This is considered acceptable for pregnant
patients with refractory ITP and severe bleeding. Ideally,
this should be performed in the second trimester.
 Rituximab. There is limited data about the use of AntiCD20monoclonal antibody in pregnancy. The manufacturers recommend abstaining from pregnancy during and
for 12 months after its use. Rituximab crosses the placenta
and may cause a delay in neonatal B-lymphocyte maturation, which seems to normalise post-partum.
Life-threatening bleeding in a severe refractory ITP may
respond to high dose intravenous methyl prednisolone and
intravenous IVIg. This needs to be managed by an expert.

Haemolytic uraemic syndrome/

thrombotic thrombocytopenic
purpura
Congenital/marrow disease/
hypersplenism/liver
disease
Drugs (not low molecular
weight heparins)

Table 2

therefore fall outside the counting range. If there is doubt immunologic platelet counts, based on light scatter, should be
considered.
From 35 to 36 weeks gestation it is usual to give treatment to
raise the platelet count to at least 50  109/L in anticipation of
delivery. Concerns over the risk of spinal haematoma formation
and neurological damage have led to recommendations that
spinal or epidural anaesthesia not be performed unless the
platelet count is >80  109/L. This recommendation is based on
consensus rather than evidence. Thromboelastogram (TEG) data
would suggest lower levels of thrombocytopenia might be
tolerated. There is no evidence that the bleeding time predicts the
risk of haemorrhage in this situation.
Current recommendations for the mode of delivery do not
support caesarean section being a safer option for the fetus,
except for obstetric indications. The use of vacuum extraction
and complicated instrumental delivery is contraindicated, as are

Type IIB von Willebrand disease and thrombocytopenia

Type IIB von Willebrand disease should be considered in the
differential diagnosis of thrombocytopenia during pregnancy. The
recognition of this syndrome is important because of the difficult
clinical management problems associated with it (see below).

Distinguishing immune thrombocytopenic purpura (ITP)

from gestational thrombocytopenia (GT)

Time of presentation
Platelet count
Neonatal thrombocytopenia
Resolution after delivery
Platelet size
Antiplatelet
antibodies

GT

ITP

> Second
trimester
>70e80  109
No
Yes
Normal
No/yes

From first
trimester
More severe
Possible
No/yes
Normal/big
Yes/no

Neonatal allo-immune thrombocytopenia

Neonatal allo-immune thrombocytopenia (NAIT) is a disorder
caused by feto-maternal platelet incompatibility, analogous to
that in Rhesus haemolytic disease, with maternal antiplatelet IgG
antibodies crossing the placenta and destroying fetal platelets.
The foreign fetal platelet antigens are inherited from the father.
The majority of cases are caused by antibodies directed against
human platelet antigen-1a (HPA-1a; incidence 80%) and HPA-5b
(15%), but rarer reactions have been reported.

Table 3

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:11

316

2015 Elsevier Ltd. All rights reserved.

REVIEW

A spectrum of thrombotic microangiopathies exists in pregnancy. These commonly are due to the hypertensive disorders of
pregnancy.

The incidence of NAIT is reported to be 1 in 1100 live births,

but it may be under-diagnosed. Mortality is around 10% of
presenting cases, with neurological sequelae, including intracranial haemorrhage (ICH), and subsequent neurodevelopmental
delay in up to 25%.
NAIT should be particularly suspected from the history if
there has been a previously affected sibling or recurrent fetal
loss. Clinical presentation could be with antenatal fetal ICH/hydrocephalus, premature labour, bruising or bleeding in the
neonate, excessive haematoma at injection sites, and postnatal
ICH. Samples of the mothers and newborns blood should be
sent to the Blood Transfusion Laboratory to look for antiplatelet
antibodies. Definitive diagnosis of NAIT depends on testing for
parental platelet antigens.
The risk of a subsequent pregnancy being affected is 100% if
the father is homozygous for the reacting antigen, and 50% if
heterozygous. In general, subsequent pregnancies are at least as
severely affected as the first. It is now also possible to obtain fetal
DNA from maternal blood for platelet antigen typing the fetus
early in pregnancy. Antenatal therapy in subsequent pregnancies
remains contentious, but options include intrauterine platelet
transfusion, maternal immunoglobulin and steroids, all of which
should be done at a specialized fetal medicine centre.
If the newborns platelet count is <30  109/L and the
maternal count is normal, the treatment of choice is urgent
transfusion of 10 ml/kg of matched platelets. If antigen-negative
platelets are not available, IVIg 1 g/kg/day for 2 days may be
effective. There is often a delay in response of 24e48 hours,
leaving a window of risk for ICH.

Pre-eclampsia and HELLP syndrome

Thrombocytopenia occurs in up to 50% of women with preeclampsia (PET), and the severity parallels the severity of PET.
Thrombocytopenia due to PET should be managed according to
the general guidelines for thrombocytopenia described above.
HELLP syndrome is a variant of pre-eclampsia occurring in
the second or third trimester of pregnancy, and presents occasionally postpartum. It complicates between 0.5% and 1% of
pregnancies and 10e20% of those with PET; is associated with
high maternal morbidity and mortality. The pathophysiology is
similar to that of pre-eclampsia with severe liver involvement.
The diagnosis is made by finding red cell fragmentation on a
blood film, together with low platelets and abnormal liver
function tests. DIC may occur in severe cases. Recently, mutations in regulation of the complement genes have been identified
that are associated with HELLP.
HELLP is a progressive condition, but in the majority of
cases women recover completely within 24e48 hours of
delivery. Some women may worsen after delivery or continue
to have symptoms for up to 14 days. HELLP is associated with
a 36% incidence of acute renal failure, 17% placental
abruption and associated risks of intrauterine death and low
birth weight.
Disseminated intravascular coagulation (DIC)
DIC is a clinico-pathological syndrome characterized by uncontrolled systemic activation of coagulation leading to microvascular deposition of fibrin, and thus to consumption of
coagulation factors, platelets and physiological anticoagulants.
This produces a reduction in platelet count and in coagulation
factors, especially fibrinogen, and so prolongation of the APTT
and INR.
Obstetric causes of DIC include amniotic fluid embolism,
placental abruption, eclampsia or pre-eclampsia, retained dead
fetus and septic abortion. Sepsis is one of the major causes of DIC
in pregnancy. In placental abruption, the degree of placental
separation correlates with the extent of DIC. The pathogenic
mechanism of DIC is usually the leakage of tissue factor-like
material into the circulation, with the consequent systemic activation of coagulation.
Management of DIC involves treating the cause and replacing
the missing haemostatic components with blood products.
Rarely, chronic DIC requires low-dose anticoagulation to switch
off the stimulus to DIC, and the advice of an expert in haemostasis should be sought.

Pancytopenia in pregnancy
Pancytopenia in pregnancy is very rare. When observed it can be
due to:
 folate or B12 deficiencies
 aplastic anaemia, paroxysmal nocturnal haemoglobinuria
 Evans syndrome
 B19 parvovirus infection, especially in women with sicklecell, or autoimmune diseases and in immunocompromised
patients or transplant recipients
 pregnancy in bone marrow failure syndromes: Diamond
eBlackfan anaemia and ShwachmaneDiamond syndrome.
Less common causes of acquired anemia in pregnancy are
aplastic anemia, paroxysmal nocturnal hemoglobinuria (PNH)
and autoimmune hemolytic anemia. The diagnosis of aplastic
anemia during pregnancy is made when pancytopenia and a
hypocellular bone marrow is present. Typically the recommendation to terminate the pregnancy is made to women in early
stages of pregnancy. For those in later stages, transfusion support
is given in lieu of immunosuppression or bone marrow transplantation. In many cases the cytopaenias improve after delivery
of the infant. A similar resolution of anemia has been observed
post-delivery amongst cases of autoimmune hemolytic anemia.

Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is an acute, rare
and life-threatening disorder affecting 3$7 persons per million per
annum. TTP is a clinical diagnosis, characterized by the classic
pentad of thrombocytopenia, microangiopathic haemolytic
anaemia, fluctuating neurological signs, renal impairment and
fever, often with insidious onset. Additional complications that
may be seen include gastrointestinal ischaemia (manifest as
abdominal pain) and serous retinal detachment. TTP is usually

Thrombotic microangiopathies
A thrombotic microangiopathy occurs when there is thrombocytopenia and red cell fragments on blood film. The red cell
fragmentation occurs when the red cells pass over fibrin in the
microvasculature. Key investigations are a full blood count,
blood film and coagulation screen.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:11

317

2015 Elsevier Ltd. All rights reserved.

REVIEW

molecular weight vWF multimers in plasma due to their abnormally increased reactivity with platelets. Both types I and II are
inherited as autosomal dominant traits. Type III, the most severe
and the rarest form (<0.01% of the general population and <5%
of vWD cases), is inherited as an autosomal recessive trait.
The typical clinical presentation of women with vWD is easy
bruising, prolonged bleeding from mucous membranes, especially menorrhagia, bleeding after surgery and dental extraction
and a family history. However, many women with mild vWD
remain undiagnosed. Questions about near relatives bleeding
history, especially at the time of surgery, dentistry and childbirth,
are essential in history taking. One of the effects of pregnancy is
to increase levels of vWF, so mothers with type I vWD will not
bleed antenatally. However, levels of vWF fall precipitously
postpartum, resulting in an increased risk of bleeding.
The clinical presentation of type IIB vWD is worsening
thrombocytopenia during pregnancy and after the administration
of desmopressin. Thrombocytopenia in type IIB vWD is thought
to be due to enhanced affinity of the abnormal vWF for the patients platelet vWF receptor, the glycoprotein IbeIX complex.
This leads to subsequent platelet activation, aggregate formation
and clearance by the reticuloendothelial system. A possible
explanation for the presentation of thrombocytopenia during
pregnancy is that in type IIB, women become thrombocytopenic
only during periods of increased production of the abnormal
vWF, brought about by the physiological stimulus of pregnancy.
Diagnosis is made by performing platelet aggregation with low
ristocetin concentration and multimeric analysis will show
absence of high molecular weight forms.
In type III vWF levels show little increment in pregnancy and
these women require vWF concentrates. Desmopressin is of no
value in these patients.
In women with type I vWD, functional and antigenic test for
factor levels (vWF antigen, vWF activity and FVIII:C) should be
checked at booking, 28 and 34 weeks gestation and prior to
invasive procedures. Prophylactic treatment should be given
when factors are <50 IU/dL to cover invasive procedures and
delivery. DDVAP also can be used. Tranexamic acid can also be
used for prevention or control of haemorrhage at delivery. The
combined oral contraceptive pill (COC) increases levels of vWF
and so can be used postpartum.
Women with type I vWD generally do not require prophylactic
treatment for delivery. In women with type II vWD, treatment is
required for operative delivery. In type III vWD all types of delivery require treatment. All women with vWF activity <50 IU/
dL should receive prophylactic treatment prior to the onset of
labour or planned caesarean section. Regional anaesthesia can be
offered when vWF activity is >50 IU/dL. Active management of
the third stage should be recommended.
Post-delivery vWF levels should be monitored and prophylaxis should be given to maintain vWF activity and FVIII levels
>50 IU/dL for at least 3 days (5 days in caesarean section).
Tranexamic acid and the combined oral contraceptive should be
considered in case of postpartum haemorrhage.

due to a deficiency of ADAMTs-13: without this protein, spontaneous platelet aggregates can occur in the microvasculature.
Deficiency can be inherited or acquired, the latter usually due to
an autoantibody. HIV is an increasingly recognised cause. In
pregnancy about a third of cases are due to a late presentation of
previously undiagnosed congenital TTP.
The distinction of TTP from pregnancy-related complications
e pre-eclampsia/, eclampsia and HELLP syndrome e may be
difficult. 12e25% of TTP cases are diagnosed during pregnancy
or postpartum, with 75% of these episodes occurring around the
time of delivery. Routine investigations at presentation should
include full blood count, film, clotting screen, lactate dehydrogenase (LDH), direct antiglobulin test, urea and electrolytes, liver
function tests and urine dipstick for protein.
The management of acute TTP is with immediate plasma
exchange, and general supportive therapy, including red cell
exchange. Immediate treatment is required; delay can result in
death due to platelet aggregates causing myocardial infarction.
Such deaths account for 1% of the UK maternal mortality. The
British Society for Haematology TTP guidelines recommend urgent plasma exchange in any thrombotic microangiopathy that
cannot be explained by a non-TTP pregnancy related cause. The
guidelines state that women with known congenital TTP should
attend specialist centres, receive ADAMTS13 supplementation
during the pregnancy and puerperium, and have serial monitoring of fetal wellbeing.
Haemolytic uraemic syndrome
Haemolytic uraemic syndrome (HUS) is thrombotic microangiopathy characterized by microangiopathic haemolytic
anaemia, thrombocytopenia and renal involvement. Postpartum
HUS is a very rare atypical HUS, usually associated with underlying complement abnormalities. There is poor response to
plasma exchange but eculizumab (a terminal complement inhibitor) appears a promising agent for atypical HUS.

Inherited coagulation factor deficiencies

General management of patients with inherited bleeding disorders involves avoiding intramuscular injections, invasive monitoring techniques, vacuum extraction and rotational/mid-cavity
forceps. A cord blood sample should be sent to assess fetal levels
of the deficient factor. Vitamin K should be given orally to the
newborn and routine immunizations should be given intradermally or subcutaneously.
Von Willebrand disease
von Willebrand disease (vWD) is the most common inherited
bleeding disorder, affecting 1e3% of the general population
and 13% of women with menorrhagia. Von Willebrand factor
(vWF) is a large multimeric glycoprotein, which acts as a ligand
molecule for normal platelet adhesion and aggregation, and
also carries factor VIII, increasing factor VIIIs half-life five-fold.
There are three main types of vWD (types I, II and III) and
within type II there are four subtypes (A, B, M and N). In type I,
the most common (75%), there is a quantitative decrease in vWF
levels. Type II (20e25%) is a qualitative disorder. Type IIB, a
special qualitative variant of vWD, accounts for <5% of all patients with vWD; it is characterized by the selective loss of high

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:11

Haemophilias
Haemophilia A (factor VIII deficiency) and B (factor IX deficiency) are X-linked recessive disorders, and affect approximately 1 in 10,000 male births. At least 30% of newly diagnosed

318

2015 Elsevier Ltd. All rights reserved.

REVIEW

partial deficiency with levels of 15e70 IU/dL (normal range 70

e150 IU/dL).
In FXI deficiency, factor levels do not reflect the severity of
bleeding, bleeding is inconsistent within a family and the clinical
presentation is variable. Haemorrhage tends to occur in sites
prone to fibrinolysis; thus, women with partial or severe deficiency are at risk of excessive uterine bleeding. The unpredictable nature of FXI deficiency requires close monitoring.
Specialized and individualized joint care with a haemophilia
centre during pregnancy and the puerperium is recommended.
Levels of FXI should be checked at booking, 28 and 34 weeks
gestation, and prior to invasive procedures. In general, women
with FXI levels <15 IU/dL have a 16e30% risk of excessive
bleeding during delivery and should receive prophylactic FXI
concentrate at the onset of labour, or prior to planned induction or
caesarean section. Tranexamic acid 1 g 6e8 hourly should be
considered post delivery and for 3 days postpartum, or 5 days
following caesarean section. FXI concentrates carry a thrombotic
risk and so peak levels should not exceed 70 IU/dL. More recently,
recombinant FVIIa has been used successfully in FXI deficiency.

cases of haemophilia occur as a consequence of a new mutation,

so prenatal diagnosis of haemophilia is not possible in all cases.
The UK Haemophilia Centre Doctors Organization recommend that pregnant haemophilia carriers should have their factor
levels checked at booking and at 28 and 34 weeks gestation to
allow appropriate management of labour and delivery and to
assess the need for prophylactic treatment, although supplementation is uncommonly required.
Where a woman is known to be a carrier of haemophilia there
should be adequate provision for genetic screening and counselling, which ideally should be completed pre-pregnancy. Preimplantation genetic diagnosis (PGD) is performed for haemophilia,
or prenatal diagnosis can be made by chorionic villous sampling or
amniocentesis. In a pregnancy where the mother is a confirmed or
suspected carrier of haemophilia A or B, fetal sex should be
determined as this will be helpful in managing pregnancy and
delivery. Fetal sex can be determined either by ultra-sound or by
testing circulating cell-free fetal DNA from maternal blood. For
women wishing to avoid the miscarriage risk associated with first
trimester prenatal diagnosis, but who do want information that
would influence their intrapartum management with a male fetus,
there is an option for third trimester amniocentesis, with a 1% risk
of causing preterm labour.
Regarding the mode of delivery, haemophilia carrier status is
not a contraindication to vaginal delivery. The option of elective
caesarean section in an attempt to reduce the risk of neonatal ICH
may be considered on an individual basis taking into account
knowledge of the fetal haemophilia status and potential maternal
morbidity. Ventouse extraction, rotational and mid-cavity forceps are associated with an increased risk of bleeding and should
be avoided. Invasive monitoring procedures such as placement
of intrapartum scalp electrodes and fetal scalp blood sampling
should be avoided and active management of the third stage
should be practised in carriers of haemophilia. Factor levels
should be monitored post delivery and maintained >50 IU/dL for
at least 3 days (5 days in caesarean section).
During labour, recombinant FVIII and FIX may be required for
pregnant carriers of haemophilia A and B when factor levels are
<50 IU/dL. Desmopressin (DDAVP) increases plasma levels of
von Willebrand factor and FVIII and thus is potentially effective
in carriers of haemophilia A (but not B). The efficacy and safety
of DDVAP in pregnancy has not been systematically studied, but
potential side effects, including placental insufficiency, miscarriage or preterm labour, maternal and/or fetal hyponatraemia,
are rare. Desmopressin does not pass into breast milk in significant amount.
Regional anaesthesia in carriers of haemophilia is not contraindicated if the coagulation screen is normal and the relevant
factor level is above 50 IU dL) (or raised to >50 IU dL by prophylactic treatment). It should be performed by an expert
anaesthetist with the help of a specialized haematologist for
assessment of coagulation status and arrangement of treatment if
required.

Inherited disorders of fibrinogen

Genetic abnormalities of fibrinogen comprise quantitative abnormalities (a- and hypo-fibrinogenaemia) and qualitative abnormalities (dys- and hypodys-fibrinogenaemia).
Afibrinogenaemia is a rare disorder (affecting 1e2 per
million). Fibrinogen levels are <0.1 g/L and bleeding manifestations range from mild to severe. Frequently umbilical cord
haemorrhage is the first presentation. Other bleeding manifestations include epistaxis, oral mucosal bleeding, haemarthrosis,
muscle haematoma, gastrointestinal bleeding, menorrhagia,
postpartum haemorrhage, bleeding after surgery and trauma,
spontaneous splenic rupture and, very rarely, ICH. Recurrent
spontaneous first trimester loss is common because adequate
plasma fibrinogen is vital for implantation.
Patients with hypofibrinogenaemia tend to have mild bleeding
following trauma and surgery. Those with dysfibrinogenaemia
have bleeding (28%) or thrombosis (20%), with some firsttrimester losses, but the majority is asymptomatic (62%).
The management of bleeding episodes in a- or dysfibrinogenaemic patients is with replacement of fibrinogen to a
level of >0.8 g/L, which is usually adequate to maintain haemostasis. Cryoprecipitate has been used as a source of fibrinogen; each bag of cryoprecipitate contains 100e250 mg of
fibrinogen but plasma-derived fibrinogen concentrates are preferable, having had virus inactivation, and are licensed for this
indication. The usual starting dose for adults is 1e2 g intravenously. Recurrent spontaneous first-trimester loss is treated with
regular fibrinogen concentrates to maintain fibrinogen levels
greater than 1 g/L starting early in pregnancy.
To prevent excessive bleeding during surgical procedures,
such as Caesarean section, treatment to raise fibrinogen levels to
1.0e1.5 g/L during the procedure and for 4e14 days following
surgery should be given. Thromboprophylaxis should be
considered, especially in dysfibrinogenaemic patients.

Factor XI deficiency
FXI deficiency is an autosomal disease that affects 1 in 100,000
people, most frequent among the Ashkenazi Jewish population
where there is an incidence of 8%. Homozygotes are severely
affected with FXI levels of <15 IU/dL, while heterozygotes have

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:11

Other inherited bleeding disorders

Rare inherited bleeding disorders such as prothrombin deficiency, FV, FII, FX and FXIII deficiencies, and combined FV and

319

2015 Elsevier Ltd. All rights reserved.

REVIEW

Levi M. Disseminated intravascular coagulation (DIC) in pregnancy and

the peri-partum period. Thromb Res 2009; 123(suppl 2): S63e4.
Loustau V, Debouverie O, Canoui-Poitrine F, et al. Effect of pregnancy on
the course of immune thrombocytopenia: a retrospective study of
118 pregnancies in 82 women. Br J Haematol 2014 Sep; 166:
929e35.
Michel M, Novoa M, Bussel J. Intravenous anti-D as treatment for immune
thrombocytopenic purpura (ITP) during pregnancy. Br J Haematol
2003; 123: 142e6.
Myers B. Diagnosis and management of maternal thrombocytopenia in
pregnancy. Brit J Haematol 2012; 158: 3e15.
Scully M, Hunt BJ, Benjamin S, et al. On behalf of the Brtisih Committee for Standards in Haematology. Guidelines on the diagnosis
and management of thrombotic thrombocytopenic purpura and
other thrombotic microangiopathies. Brit J Haematol 2012; 158:
323e35.
Shin JE, Lee Y, Kim SJ, Shin JC. Association of severe thrombocytopenia
and poor prognosis in pregnancies with aplastic anemia. PLoS One
2014 Jul 24; 9: e103066. http://dx.doi.org/10.1371/journal.pone.
0103066. eCollection 2014.

FVIII deficiency should be managed jointly with the local haemophilia centre.
Acquired haemophilia
Acquired haemophilia is due to the presence of an antibody
(inhibitor), usually against FVIII. Typically this develops 1e4
months postpartum and rarely antepartum. Usually the antibody
disappears spontaneously after a few months. The clinical presentation is with prolonged bleeding, postpartum haemorrhage,
menorrhagia or soft tissue haematomas with a prolonged activated partial thromboplastin time (APTT). In contrast with
inherited haemophilia, acquired haemophilia does not typically
present with haemarthrosis. These patients require management
by a Haemophilia centre.
Thromboprophylaxis in pregnancy and the puerperium
Even in those with an existing bleeding disorder or bleeding
during pregnancy, there is a need for adequate thromboprophylaxis given the high rate of venous thromboembolism associated
with pregnancy and the puerperium.
A
FURTHER READING
Birchall E, Murphy M, Kaplan C, Kroll H, on behalf of the European
FetomaternalAlloimmune Thrombocytopenia Study Group. European
collaborative study of the antenatal management of feto-maternal
alloimmune thrombocytopenia. Br J Haematol 2003; 122: 275.
British Committee for Standards in Haematology General Haematology
Task Force. Guidelines for the investigation and management of
idiopathic thrombocytopenic purpura in adults, children and in pregnancy. Br J Haematol 2003; 120: 574.
Chalmers E, Williams M, Brennand J, Liesner R, Collins P, Richards M,
Paediatric Working Party of United Kingdom Haemophilia Doctors
Organization. Guideline on the management of haemophilia in the
fetus and neonate. Br J Haematol 2011 Jul; 154: 208e15.
Decroocq J, Marcellin L, Le Ray C, Willems L. Rescue therapy with romiplostim for refractory primary immune thrombocytopenia during
pregnancy. Obstet Gynecol 2014 Aug; 124(2 Pt 2 suppl 1): 481e3.
Fakhouri F, Rumeninia L, Provot F, et al. Pregnancy-associated haemolytic
uraemic syndrome revisited in the era of complement gene mutation.
J Am Soc Nephrol 2010; 21: 859e69.
Hunt BJ, Thomas-Dewing RR, Bramham K, Lucas SB. Preventing maternal
deaths due to acquired thrombotic thrombocytopenic purpura.
J Obstet Gynaecol Res 2012 Jun 13; 39: 347e50.
Lee CA, Chi C, Pavord SR, et al. The obstetric and gynaecological management of women with inherited bleeding disorders Haemophilia
Centre Doctors Organization. Haemophilia 2006; 12: 301e36.

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 25:11

Practice points
C

320

Gestational thrombocytopenia does not require treatment in

pregnancy, is not associated with neonatal thrombocytopenia,
and resolves spontaneously after delivery.
Women with immune thrombocytopenic purpura, which is much
rare than gestational thrombocytopaenia, can tolerate lower
platelet levels in pregnancy and intervention is only needed in
preparation for delivery if the platelet counts fall below 50e80 
109/L.
In women with mild von Willebrand disease (vWD) the physiological increase in levels of vWF and FVIII during pregnancy may
mean there is no need for treatment.
Type II B vWD may present with a gradually falling platelet count
during pregnancy, and in such patients enquiry should be made
about a personal and family history of bleeding.
All pregnant women with known inherited bleeding disorders
should be managed jointly with a haemophilia centre.
If obstetric haemorrhage continues longer than expected, and no
bleeding point can be found, then vWD should be considered,
and haematological advice sought urgently.

2015 Elsevier Ltd. All rights reserved.