Tài liệu Gynecological and obstetrical manifestations of inherited bleeding disorders in women docx

INVITED REVIEW
Gynecological and obstetrical manifestations of inherited
bleeding disorders in women
F. PEYVANDI, I. GARAGIOLA and M. MENEGATTI
U.O.S. Dipartimentale per la Diagnosi e la Terapia delle Coagulopatie, A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS
Ca
`
Granda Ospedale Maggiore Policlinico, Universita
`
degli Studi di Milano, Luigi Villa Foundation, Milan, Italy
To cite this article: Peyvandi F, Garagiola I, Menegatti M. Gynecological and obstetrical manifestations of inherited bleeding disorders in women.
J Thromb Haemost 2011; 9 (Suppl. 1): 236–245.
Summary. Patients affected by bleeding disorders present a
wide spectrum of clinical symptoms that vary from a mild or
moderate bleeding t endency to s ignificant e pisodes. Women
with inherited bleeding disorders are particularly disadvantaged
since, in addition to suffering from general bleeding symptoms,
they are also a t risk o f bleeding complications from regular
haemostatic challenges during menstruation, pregnancy and
childbirth. Moreover, such disorders pose important problems
for affected women due to their reduced quality of life caused by
limitations in activities and work, and alteration of t heir
reproductive life. These latter problems include excessive
menstrual bleeding or menorrhagia, miscarriage, bleeding
complications during p regnancy and after delivery a nd their
related complications such as acute or chronic anaemia. T he
management of these women is difficult because of considerable
inter-individual variation. Moreover, reliab le information on
clinical management is scarce, only a few available long term
prospective s tudies of large cohorts provide evidence-based
guideline a bout diagnosis and treatment.

Keywords: haemophilia, management, platelet disorders, rare
bleeding disorders, von Willebrand d isease, w omen.
Introduction
Women are more likely to manifest a bleeding disorder as they
have more opportuni ties to experience bl eeding cha llenges in
their lifetime due to the natural cycle of menses and
reproduction. Menstruation and o vulation may be a sso ciated
with sig nifican t bleeding leading to the li mitation in conduct-
ing daily activities, changes in social f u nctioning a nd adverse
effect on quality o f life. At least 5–10% of women at
reproductive ag e wi ll seek medical attention fo r men orrhagia
[1]. The World Health Organisation (WHO) estimates that 18
million women worldwide are afflicted [ 2]. A variety of
organic, endocrine, gynaecologic or other systemic causes may
be respon sible for m enorrh agia; however, an underlying
aetiology is identified in only 50% of cases [3]. Organic causes
include infections of any g en itourin ary origin and bleeding
disorders a s well as organic dysfunction as hepatic or renal
failure. Chroni c liver d isease impairs production of clotting
factors and reduces hormone metabolism (e.g. oestrogen).
Any of these problems may lead to heavy uterine b leeding.
The most common endocrinologic cause of heavy menstrual
bleeding in adolescent girls is anovulatory d ysfunctional
uterine bleeding owing to the immaturity of the hypotha-
lamic–pituitary–ovarian axis. Anatomic aetiologies for men-
orrhagia include uterin e fibroi ds, en dometrial po lyps and
hyperplasia. Intra Uterine Device (IUD) placement, steroid
hormones, chemotherapy agents, hypothalamic depressants,
phenytoin and anticoagulants, which could al so cau se
increased menstrual bleeding [4]. The considerable proportion

ofwomenwithmenorrhagia(20%), who are comp rehen-
sively tested for h aemostatic abnormalities, are f o und to have
underlying bleeding dis orders such as von Willebran d disease
(VWD), platelets function alteration or rare bleeding disorders
(RBDs: deficiencies of c oagula tion factors s uch as fi b rinogen,
factor (F)II, FV , FV + FVIII, F VII, F X, FXI and FXIII).
Menorrhagia is only one of the gynaecological problems that
women with bleeding disorders are more likely to experience,
being at risk of o ther problems t hat may present with increased
bleeding in conditions such as haemorrhagic ovarian cysts,
endometriosis, hyperplasia, polyps, fibroids, pregnancy and
childbirth. Pregnancy and childbirth, two important stages in
the life of a woman, pose a special clinical ch allenge i n w omen
with inherited bleeding disorders, since information about these
issues are really scarce and limited to few c ase reports. A n
accurate counselling for women affected with bleeding disor-
ders is therefore recommended.
Pathophysiology of abnormal uterine bleeding
(menorrhagia)
In the presence of ovulatory cycles, withdrawal of progester-
one triggers a cascade of molecular and cellular events within
the endometrium, initiating its breakdown and culminating in
Correspondence: Flora Peyvandi, MD, PhD, Angelo Bianchi Bonomi
Haemophilia and Thrombosis Centre, University of Milan, Via Pace, 9
-20122, Milan, Italy.
Tel.: +39 02 55035414; fax: +39 02 54100125.
E-mail: fl
Journal of Thrombosis and Haemostasis, 9 (Suppl. 1): 236–245 DOI: 10.1111/j.1538-7836.2011.04372.x
Ó 2011 International Society on Thrombosis and Haemostasis
menstruation. During menstruation higher levels of prosta-

glandin E2 a nd prostaglandin F2a in menstrual fluid are found
in menorrhagic women when compared with those with
normal menses [ 5,6]. Furthermore, the release of p rostaglandin
E2, prostaglandin F2a and prostacyclin by the endometrium
and myometrium during menstruation are increased in tissues
obtained f rom m enorrhagic w omen [7,8]; and i ncreased
concentrations of prostaglandin E receptors are also found
in myometrium [9]. Recent studies on the function of
prostaglandin receptors in endometrium have shown that
prostanoids promote angiogenesis and may have a role in
aberrant neovascularisation leading to dysfunctional uterine
bleeding [10]. Moreover, local endometrial aberrations are
considered to be the major contributing factor to essential
menorrhagia. Kooy et al. [11] demonstrated that patients with
menorrhagia have high endometrial endothelial cell prolifer-
ation indices, supporting the hypothesis that disturbed angio-
genesis may be a direct cause of excessive menstrual bleeding.
In addition, fibrinolytic activity is significantly elevated in the
endometrium of most women with ovulatory dysfunctional
uterine bleeding [12].
The pathophysiology of abnormal uterine bleeding during
menstruation in women affected by haemostasis defects could
be b ased o n the aberran t for mation o f a platelet pl ug th at is a
crucial fi rst s tep in t he r egulation of bl ood flow [13]. Thus, it is
not surprising that platelet dysfunction and VWD have
both been associated wi th menorrhagia, sometimes of a severe
nature, and that me norrhagia is a common presenting symptom
among f emale p atients with VWD. From a historical pe rspec-
tive, it is i nteresting to note that the first patient identified with
this disorder by Erik von Willebrand in 1926 eventually died of

uncontrollable menstrual b leeding a t a ge 13 years.
Menorrhagia
History and definition
The term ÔmenorrhagiaÕ appeared for the first time in the late
1700s and one of the earliest written uses were it was
mentioned was a treatise in Latin (1775): ÔDisputatio medica,
inauguralis, de menstruorum pro fluvio immodicoÕ [14]. T he
term ÔmenorrhagiaÕ was r egularly u sed in publications
throughout the 19th and 20th centuries, but the establish-
ment of definitions for normal or abnormal menstrual loss
has been difficult [15]. In 2006, the American College of
Obstetricians and Gynecologists and the American Academy
of Pediatrics issued a committee consensus report entitled
ÔMenstruation in Girls and Adolescents: Using the Menstrual
Cycle as a Vital SignÕ [16]. The consensus stated that normal
menstruation begins at 11–14 years of age, the normal c ycle
interval is 21–45 days, and the normal length of menstrual
flow is 7 days or less with product use no more than 3–6
pads or tampons per day. Therefore, menorrhagia can be
defined as heavy menstrual bleeding lasting for more than
7 days or resulting in the loss of more than 8 0 mL per
menstrual cycle [17].
Differential diagnosis in women with menorrhagia
It is important for t he clinician , when encountering women
with menorrhagia, to understand whether bleeding symptoms
represent a manifestation of a gynaecological problem or a
disorder of haemostasis. Menorrhagia is often t he first clinical
manifestation that women with bleeding disorders encounter,
often at menarche; therefore, many affected patients initially
attend their gynaecologist. Recently, a c onsensus o n diagnosis

in women w ith menorrhagia was published by a n international
experts p anel and recommendations were provided only if
consensus could be reached [18]. Experts agreed that an
underlying bleeding d isorder should be considered if any o f the
following indicators are present: menorrhagia since m enarche;
family history of a bleeding disorder; personal history of
bleeding such as epistaxis, notab le bruising without injury,
minor wound bleeding, bleeding of oral cavity or gastrointes-
tinal tract without an obvious anatomic lesion, prolonged or
excessive bleeding after dental extraction, unexpected postsur-
gical bleeding, haemorrhage from ovarian cysts or corpus
luteum, haemorrhage that required blood transfusion, failure
of response t o c onventional management of menorrhagia [18].
However, only a relatively small proportion of these patients
will have a t rue under lying disorder of haemostasis. Conse-
quently, the discriminatory p ower of various bleeding symp-
toms in predicting an underlying disorder of haemostasis has
been incorporated into a scoring system (Ôbleeding score
assessmentÕ) th rough the Intern ational Society of Haemostasis
and Thrombosis network [19,20]. On the other hand, as
measuring actual m enstrual blood loss is not feasible in clinical
practice, Higham and colleagues devised the pictorial blood
assessment chart (PBAC) as an alternative [21], to determine
blood loss by visual self-assessment and scoring of sanitary pad
and tampon saturation. Recently, a study was conducted t o
develop a short, easy to administer screening tool for stratifying
women with unexplained menorrhagia for haemostatic testing
for underlying bleeding disorders. A combination of eight
questions in four categories resulted in a sensitivity of 82%
[95% confidence interval (CI): 75–90%] for bleeding disorders.

Adding a PBAC score > 100 increased the sensitivity of the
screening tool to 95% (95% CI: 91–99%) [22]. Eventually,
women with a ÔpositiveÕ bleeding history n eed to be screened
by coagulation tests including complete blood count (CBC),
prothrombin time (PT), partial thromboplastin time
(PTT), thrombin time (TT), VWD profile (VWF antigen,
RiCof), FVIII levels, platelet function analyses (BT, PFA-100),
FXIII l evels and other specific factors. If PT or PTT are
prolonged, mixing test is necessary to distinguish deficiency of a
coagulation factor from a natural inhibitor. If these tests turn
out normal, studies of platelet function should be planned [23].
Menorrhagia in women with bleeding disorders
In the last 20 years, it has been well-established that menor-
rhagia is more prevalent in women with all bleeding disorders,
however, using the PBAC, carriers of haemophilia and women
Women with inherited bleeding disorders 237
Ó 2011 International Society on Thrombosis and Haemostasis
affected with VWD and FXI deficiency were shown to h ave
significantly higher menstrual scores [24]. The reported prev-
alence of menorrhagia in carriers of haemophilia was estimated
to be about 10–57% [25].
InwomenwithVWD,menorrhagiawasdeterminedtobea
common and a major health problem: published data point out
that in type 1 VWD, it occurs in 79–93% of women [26,27],
whereas, in women with type 2 and type 3 VWD, the
prevalence ranges from 32%–63% and 56–69%, respectively
[28,29].
Menorrhagia in women with severe platelet dysfunction has
been reported to be present in 51% of women with Bernard-
Soulier syndrome [30]; data on i n women with GlanzmannÕs

thrombasthenia are contrasting since two studies repo rt
different frequencies of 13% and 98% [31,32].
In other bleeding disorders the reported prevalence was:
59% in women with FXI deficiency [33]; 35–64% in those
with FXIII deficiency [34] a nd 35–70% in those with other
rare factor deficiencies as reported in a number of case series
[35]. From this reports it can also be inferred that menor-
rhagia seems to be a major bleeding symptoms in women
with rare bleeding disorders, regardless of factor level.
Table 1 summarises populations, sample size and type of
published studies described h erein. Nonetheless several stud-
ies reported the prevalence of menorrhagia in women with
bleeding disorders, only a few compare affected with healthy
control women [26,36,37]. A recent study collecting informa-
tion on prevalence of menorrhagia in 35 women affected
with bleeding disorders comp ared to 114 c ontrols, reported
that PBAC was significantly h igher in a ffected women than
in controls (mean 258 vs. 171, P = 0.01) and menorrhagia
had a prevalence of 71% of women with VWD, 53% in
haemophilia carriers, 52% in women with RBDs and 46%
in controls [38]. However, the prevalence reported in platelet
disorders and in the majority of reports on rare coagulation
disorders are not evid ence-based, because of t he small
number of women who were analys ed.
Complications and treatment of menorrhagia
Women with menorrhagia often undergo unnecessary surgical
interventions to relieve heavy menstrual bleeding, and at least
Table 1 Populations, sample size and type of published studies herein reported
Population (sample size) Type of study Reference
Menorrhagia

Haemophilia carriers (30) Prospective cohort 25
VWD type 1 (29) Case series 26
VWD type 1 (99) Survey 27
VWD type 2 (5) Case series 28
VWD registry on type 1, 2 and 3 Retrospective cohort 29
Bernard-Soulier syndrome (35) Case reports 30
GlanzmannÕs thrombasthenia (55) Case reports 31,32
FXI deficiency (20) Prospective cohort 33
FXIII deficiency (20) Case series 34
VWD (48 types 1, 2 and 3) Case – control 38
Haemophilia carriers (31)
Coagulation deficiencies (35)
Miscarriages
Afibrinogenemia (6 in six reports) Case reports 35
Afibrinogenemia (18) Case serie
Dysfibrinogenemia (1) Case report
FXIII (16) Summary of case reports
FXIII (10 in three reports) Case series
Bleeding during pregnancy and delivery
VWD (86) Case – control 36
Bernard-Soulier syndrome (9) Case reports 60
GlanzmannÕs thrombasthenia (16) Case reports 31
FXI deficiency (21) Case series 61
VWD (48 types 1, 2 and 3) Case – control 38
Haemophilia carriers (31)
Coagulation deficiencies (35)
Post partum hemorrhage
Haemophilia carriers (32) Case series 69
VWD (2843) Database 70
Bernard-Soulier syndrome (7) Case reports 30

GlanzmannÕs thrombasthenia (7) Case reports 71
Hypofibrinogenemia (10) Case reports 72
FV (1), FVII (1) and FX deficiency (1) Case report 73–75
FXI deficiency (62) Case series 76
238 F. Peyvandi et al
Ó 2011 International Society on Thrombosis and Haemostasis
60% of them undergo hysterectomy o r other surgical proce-
dures, including endometrial ablation, dilatation and curettage.
In 1973, Silwer published his experience with 18 women
affected with VWD who underwent hysterectomy compared
with 50 controls. Although there were no statistically significant
differences, the women w ith VWD were more likely to require
transfusion (50% vs. 30% of controls) and were less likely to be
free of any bleeding complications (28% vs. 60% of controls)
[39]. With a proper diagnosis of their condition, many women
with bleeding disorders could avoid these complications and
surgeries, decrease their severity of menstrual bleeding and
improve their quality of life [40].
Recently, Skankar et al. evaluated the quality of life in 187
women with menorrhagia with or without inherited bleeding
disorders (scoring general health, physical, social and mental
functioning, pain, energy) concluding that women with bleed-
ing disorders had a worse quality of life because they had all
scales significantly affected (physical parameters were less
affected in healthy women) [41]. The excessive blood loss can
result in iron deficiency anaemia, which causes tiredness and
fatigue affecting activities of daily living, socialising with friends
or various recreational and sport activities [24]. Thus, menor-
rhagia, which may be a source of inconvenience to women in
general, is significantly more problematic for women affected

with bleeding disorders. However, the average age of the
women identified with an underlying haemostatic defect in
these studies is approximately 35 years [25]. This means that
diagnosis of the underlying haemostatic disorder is a relatively
late one within the average duration of the reproductive
lifespan.
Earlier identification of women w ith menorrhagia and an
underlying haemostatic defect should be beneficial in terms of
allowing for the use o f specific haemostatic measures in t he
management of the menorrhagia [36]. Management of menor-
rhagia in women with bleeding disorders is based on medical
(hormonal or haemostatic therapy) and surgical care with the
primary aim of improving quality of life [42]. Drug therapy,
based on levonorgestrel intrauterine system, combined
hormonal contraceptive methods currently available (pill,
transdermal contraceptive patches, vaginal rings), oral
progestogens and gonadotropin-releasing hormone (GnRH)
analogues, should be the first choice and the only option to
preserve the reproductive function.
In obligate haemophilia carriers, with a positive family
history, clotting factor level should be established before the
onset of menarche, t o anticipate t he possibility o f an a cute
menorrhagia [43]. Haemostatic therapy includes antifibrin-
olytic (tranexamic acid and aminocaproic acid) and
DDAVP or desmopressin (1-desamino-8-
D
-arginine v aso-
pressin), a synthetic vasopressin that stimulates the release
of VWF from endothelial cell, in addition to replacement
treatment with coagulation factors [43]. Surgical options

should include conservative surgery (endometrial resection
and ablation) with hysterectomy performed in cases of
failed medical therapy and/or when fertility is no longer
desired.
In women with VWD, therapy should start on the first or
second day of menses, with the specific therapeutic choice,
dose, duration of therapy, and therapeutic monitoring [44].
In women with platelet dysfunction, intranasal desmopressin
as well as tranexamic acid therapy have been demonstrated to
reduce menstrual blood flow, but in severe disorders such as
GlanzmannÕs thrombasthenia, platelets transfusions may be
needed [45]; however repeated transfusions may result in the
formation of alloimmune antiplatelet antibodies. Such anti-
bodies are antigen-driven and are produced against different
epitopes on the integrin they may block platelet aggregation,
and lead to the rapid removal of transfused platelets by
immune mechanisms. Recombinant FVIIa has been success-
fully used as an alternative a pproach for e arly cessation of
bleeding, often in association with anti-fibrinolytic agents [46].
There are few data on management of acute, severe
menorrhagia, particularly in the adolescent or woman with a
bleeding disorder; however, experts agreed that balloon
tamponade, hormonal therapy (oestrogen) and antifibrinolytic
treatment should be instituted while replacing clotting factor or
platelets as indicated [18]. Tranexamic acid has been shown to
be an effective medical management for menorrhagia in
women with and without bleeding disorders [47]. Antifibrino-
lytic agents are generally well-tolerated despite the unc ertain
thrombotic risk reported in some studies [48–50].
Miscarriage

Miscarriage i s relatively common in the general population,
with 12–13.5% of recognised pregnancies resulting in sponta-
neous a bortion, while there are case reports and case s eries
documenting the increased risk of miscarriage in women with
bleeding disorders [34]. In contrast, the limited number of
reports on women with platelets disorders makes it impossible
to draw any conclusions on the rate of m iscarriage in such
defects [34]. Human GlanzmannÕs thrombasthenia can result
from defects in the genes for either the aIIb or the b3 subunit.
In a study by Hodivala-Dilke et al. [51], a knock-out b3
null-mice model revealing placentation defects that may also
occur in human GlanzmannÕs thrombasthenia patients and
may provide insight into preeclampsia of pregnancy was
proposed. Haemorrhage in a layer of trophoblast, ReichertÕs
membranes, was observed, which was probably due to a
combination of leakage of maternal blood vessels and defective
platelet function. Moreover, a second phenotype was observed
in approximately 20% of b3–null maternally derived placenta
the cell layers within the labyrinth appeared thickened and
occluded sinus volume, thus decreasing efficient blood circu-
lation and exchange of nutrients. This often led to necrosis
within the labyrinth and compromised embryo survival [51].
It is generally believed that women with bleeding disorders
are protected by the hypercoagulable state of pregnancy;
however, an increased risk of miscarriage and placental
abruption resulting in recurrent foetal loss or premature
delivery among women with afibrinogenemia [52–54] or FXIII
deficiency [55] has been reported. Both FXIII and fibrinogen
Women with inherited bleeding disorders 239
Ó 2011 International Society on Thrombosis and Haemostasis

play an important role in placental implantation and mainte-
nance of pregnancy. Homozygous FXIII-A deficient women
are reported to experience recurrent pregnancy losses [55], but
the cause of these losses is still unknown. Usually the
implantation process initiates by the seventh day after ovula-
tion. The blastocyst a dheres the surface e pithelium of endo-
metrium and then giant trophoblasts begin to penetrate it.
After penetration, the blastocyst intrudes into the underlying
decidual stroma and giant trophoblasts expand into masses of
both syncytiotrophoblasts and cytotrophoblasts [56]. When the
cytotrophoblast invade endometrium a complex interaction
involves FXIII-A which cross-links fibrinogen and fibronectin,
both important for the attachment of the placenta to the uterus
[57]. Thus, deficiency of FXIII-A at the site of implantation will
adversely affect fibrin-fibronectin cross-linking, resulting in
detachment of the placenta from the uterus and subsequent
miscarriage [56,57].
Fibrinogen, a major blood glycoprotein, is a dimer of three
polypeptide chains: Aa, Bb and c. The threeoverlapping
hereditary abnormalities of fibrinogen, afibrinogenemia, dysfi-
brinogenemia and hypofibrinogenemia, have been associated
with recurrent pregnancy loss. Hypofibrinogenemic and exper-
imental afibrinogenemic mice exhibited similar features of
bleeding tendency and miscarriage [58]. Pregnant mice homo-
zygous for a deletion of the Fg-cchain, which results in a total
fibrinogen deficiency state, aborted the fo etus at the equivalent
gestational stage seen in humans. The fibrinogen deficiency
does not alter embryonic development, but formation of t he
placenta and yolk sac is significantly compromised. The loss of
embryo in afibrinogenemic mice is because of an abortive

process that is initiated as an exacerbation of the haemorrhage
that normally occurs around sixth day during the critical stage
of maternal and foetal vascular development when the embryo
is invading the maternal deciduas. This event g ives rise to a
robust bleeding that causes extensive placental disruption
resulting in the loss of embryo [58]. In conclusion, on the basis
of the mouse model, the absence or a significant decrease in
maternal fibrinogen is sufficient to cause rupture of the
maternal vasculature affecting embryonic trophoblast infiltra-
tion and leading to haemorrhagic miscarriage. Further studies
are needed t o c onfirm whether inherited bleeding disorders,
other than deficiency of fibrinogen or FXIII are associated with
a higher rate of miscarriage.
Pregnancy and delivery
Pregnancy and delivery also pose a special clinical challenge in
women with c oagulation disord ers, since i nformation about
these issues are really scarce and limited to few case reports.
Normally, pregnancy is accompanied by increased concentra-
tions of fibrinogen, FVII, FVIII, FX and von Willebrand
factor, particularly marked in the third trimester [59]. On the
contrary, FII, FV, FIX and F XIII are r elatively unchanged
[59]. A ll of these c hanges contribute to the hypercoagulable
state of p regnancy, a nd, in women with b leeding disorders,
contribute to improved haemostasis.
The risk of bleeding in early pregnancy is unknown in
carriers of haemophilia, but there is evidence that t he risk after
24 weeksÕ gestation is not increased [28].
A c ase-control study reports the experience of 86 w omen
with VWD and 70 controls with bleeding problem during
pregnancy. This report evidences that 1.3% of women w ith

VWD have heavy bleeding that ended the pregnancy vs. 0.3%
of controls (P = 0.0001) [35]. A review of Kriplani et al. [60]
reported eight previous studies on pregnancy outcome in
women with Bernard-Soulier syndrome. Only one patient had
bleeding in the antenatal period, while most patients became
symptomatic in the intrapartum a nd immediate p ostpartum
period; pregnancy and delivery appeared uncomplicated in
women w ith GlanzmannÕs thrombasthenia, as shown in a case
report that analysed 21 pregnancies in 16 women with this
platelet dysfunction [31].
A recent investigation by Siboni et al. collecting information
on bleeding at the time of menarche, bleeding during pregnancy
and the postpartum period in 35 women affected with different
type of RBDs and 114 controls, recorded that bleeding during
pregnancy was not more frequent in patients than in controls
(21% vs. 6%, P = 0.11) [37]. Nonetheless, excessive bleeding
at delivery was observed in 16% (4/25) of the pregnancies in a
case series including 11 women with FXI deficiency with
different coagulant activity [61].
Post partum haemorrhage
Haemorrhage is the single leading cause of maternal mortality
[62]. According to the World Health Organisation (WHO)
pregnancy-related death s, in the last t wo decades were
approximately 510.000 per year world-wide and 25% of them
were due to severe bleeding occurring in the post-partum
period [63,64].
The conventional definition of post partum haemorrhage
(PPH) is a blood loss of > 500 mL in the first 24 h after
delivery a nd > 1000 mL for caesarean sections within 24 h of
delivery [ 65,66]. PPH is classified as p rimary when occurs

within the first 24 h postpartum or secondary, occurring
between24handupto6weeksofpostpartum.Themedian
duration of bleeding after delivery is 21–27 days [67], but
coagulation factors, elevated during pregnancy, return to
baseline within 14–21 days [68]. Therefore, t here is a period
of time when coagulation factors return to pre-pregnancy
levels, but women could still be at risk of bleeding. Delayed or
secondary PPH is rare in the general population; on the
contrary, women with bleeding disorders are particularly
vulnerable to this type of bleeding.
The prevalence of primary and secondary PPH in haemo-
philia carriers has been reported to be 22% and 9–11%,
respectively [69]. However, two different series of women with
VWD reported a lower prevalence of primary PPH (12.5–
18.5% of deliveries) and a higher prevalence of the secondary
(20–25%) [34]. The most r ecent data documenting and
comparing the incidence of PPH in women with VWD and
controls come from US discharge database, reporting that 6%
240 F. Peyvandi et al
Ó 2011 International Society on Thrombosis and Haemostasis
of pregnancies in such women were complicated by PPH
compared to 4% of controls (OR = 1.5; 95% CI: 1.1–2.0, P-
value < 0.01) [70].
There are limited data of prevalence of PPH in women with
severe platelet dysfunction [34]: among women affected with
the Bernard-Soulier syndrome 3 of 7 (43%) experienced
undefined PPH [30], while the prevalence of primary and
secondary PPH in women with GlanzmannÕs thrombasthenia
was estimated to be 57% and 43%, respectively [71].
In RBDs, PPH was found to be the most common obstetric

complication occurring in 45% of the deliveries in 10 patients
with hypofibrinogenemia [72], and in 76% (13/17) of deliveries
in nine women with FV deficiency [73], who resu lted to be at
higher risk of bleeding, especially if they are affected with the
severe form of the deficiency. Although at a lower rate, PPH
was reported also in a case of severe FVII deficiency [74], a case
of moderate FX deficiency due to an abnormal FX rather than
to a FX d eficiency [75] and in s evere FXI deficiency (levels
< 17 IU dL) [76]. Salomon et al. performed a large study on
62 women affected with FXI deficiency (164 pregnancies)
showing that 69% of women never experienced PPH during 93
deliveries without any prophylactic coverage. T hese authors
therefore argued that prophylactic treatment is not mandatory
for these women, especially with vaginal delivery (however,
excessive bleeding at delivery still did occur on about 20% of
deliveries not covered by FFP). On the contrary, it is well
documented that the risk of delayed PPH is at least 25–30 fold
higher in women with FXI deficiency [34].
Management of pregnancy and delivery
For haemophilia carriers w ith subnormal facto r levels, despite
the pregnancy-related rise of FVIII, in travenous access should
be established and prophylactic treatment given, preferably
using recombinant FVIII and FIX, to cover labour, delivery
and immediate postpartum period, starting at onset of labour.
The use of tranexamic acid has been also suggested to prevent
secondary PPH [42].
Peripartum management of women with VWD at the
beginning requires the laboratory evaluation for VWD that
includes a basic coagulation panel, VWF:Ag assay, VWF:RCo
assay and FVIII levels. The treatment should be instituted if the

levels of VWF:RCo and FVIII are < 50 IU dL
)1
before any
invasive procedure and delivery. The mainstays of therapy are
desmopressin (DDAVP) and plasma concentrates that contain
VWF. DDAVP may be used in women w ith type 1 VWD;
recent data indicate that some individuals have accelerated
clearance of VWF; therefore, even patients with type 1 may
benefit from a test dose of DDAVP and subsequent measure-
ment of VWF:RCo to document treatment efficacy [77]. In
women with type 2, the main problem is that, despite an
increase in secretion of VWF after DDAVP, the VWF secreted
will retain its intrinsic molecular dysfunction. Consequently,
the preferred therapy for type 2 is the use of VWF concentrates
[78]. However, a small s ubset of women with type 2 VWD
respond to desmopressin. Identification of those i ndividuals
requires a test dose of DDAVP and subsequent measurement
ofVWF:RCo1and4hafterthedose.IftheVWF:RCo
corrects after dose, DDAVP is acceptable treatment for those
women. Minor-side effects of DDAVP include flushing,
headache, gastrointestinal complaints, and transient hypo- or
hypertension. Repeated dosing may lead to water retention and
hyponatremia. Desmopressin is safe for the foetus because it
does not cross the placenta in detectable amounts [78].
According to previous reports, women with VWD t ype 3 lack
the physiological rise in VWF during pregnancy. Only few
reports exist about the management of pregnancy and delivery
in women with VWD type 3, hence few data about the clinical
problems and their appropriate management are available.
However, clinical experience suggests that bleeding at delivery

and early postpartum is frequent without replacement therapy.
There are limited data on management of pregnancy a nd
delivery in women with inherited platelet disorders, but
epidural anaesthesia should be avoided and platelet transfusion
before and after delivery ( up to 6 days post partum) have been
reported to reduce the risk of bleeding in women with
GlanzmannÕs thrombasthenia [45]. The use of recombinant
FVIIa has been proposed especially in individuals unresponsive
to platelet transfusion because of isoimmunisation [46]. Reg-
ular replacement therapy throughout pregnancy to maintain a
minimum activity level is recommended in women with
afibrinogenemia and should be commenced as soon as possible
in pregnancy to reduce the probability o f early foetal loss
[79,80]. Management of women with hypofibrinogenemia
should follow similar recommendation depending on the
fibrinogen level, individual bleeding tendency and family
history, as well as previous obstetric history [81]. Thrombotic
events during puerperium have also been reported among
women with afibrinogenemia and hypofibrinogenemia [82], the
potential for thrombosis associated with replacement therapy
must be carefully evaluated a nd balanced against the risk of
bleeding. The management of pregnancy in women with
dysfibrinogenemia needs to be individualised, taking into
account the fibrinogen level and personal a nd family history
of bleeding and thrombosis [82]. No specific treatment is
required in asymptomatic women.
A s ignificant r ise in FVII level is observed during pregnancy in
women with mild/moderate forms of FVII deficiency (hetero-
zygotes) [36], but not in women with severe deficiency [83], who
are more likely to be at risk of PPH, hence, prophylactic

treatment is required for women with low FVII coagulant
activity levels at term and/or significant bleeding history. Also
women with severe F X deficiency and a history of adverse
pregnancy outcome may benefit from replacement therapy
during pregnancy [79], and to cover l abour and delivery to
minimise the risk o f bleeding complications [84]. In FXIII
deficiency a therapy should be c ommenced as early as possible in
pregnancy to prevent foetal loss [85] and t he treatment s hould
also be continued during labour and delivery [86]. On the
contrary treatment is not mandatory for women with FXI
deficiency, especially with vaginal delivery [76]; however, due
to the unpredictable bleeding tendency in FXI deficiency,
Women with inherited bleeding disorders 241
Ó 2011 International Society on Thrombosis and Haemostasis
Table 2 Available recommendation for treatment in women with inherited bleeding disorders for menorrhagia (A) and d uring/after pregnancy (B)
[46,76,87]
(A) Menorrhagia
VWD In women with VWD, therapy should start on the first or second day of menses, with the specific therapeutic
choice, dose, duration of therapy, and therapeutic monitoring. Haemostatic therapy includes antifibrinolytic
(tranexamic acid and aminocaproic acid) and/or DDAVP or desmopressin (1-desamino-8-
D
-arginine vasopressin),
a synthetic vasopressin that stimulates the release of VWF from endothelial cell, in addition to replacement treatment
with coagulation factors.
Platelet disorders In women with platelet dysfunction, intranasal DDAVP as well as tranexamic acid therapy have been demonstrated to
reduce menstrual blood flow, but in severe disorders such as GlanzmannÕs thrombasthenia, platelets transfusions
may be needed.
Rare coagulation
disorders
Therapeutic options for the control of menorrhagia in women with underlying coagulation disorders include:

(1) Medical treatments:
Anti-fibrinolytics
Combined hormonal contraceptives
Intranasal and subcutaneous DDAVP
Oral contraceptives
Levonorgestrel intrauterine device
Clotting factor replacement (expecially in women with severe deficiency and acute bleeding. The role of clotting
factors replacement as prophylaxis in severe bleeders need to be analysed)
(2) Surgical treatments such as endometrial ablation and hysterectomy.
(B) Pregnancy
VWD type 1 DDAVP may be used; recent data indicate that some individuals have accelerated clearance of VWF; therefore, even
patients with type 1 may benefit from a test dose of DDAVP and subsequent measurement of VWF:RCo to document
treatment efficacy
VWD type 2 In women with type 2, the main problem is that, despite an increase in secretion of VWF after DDAVP, the VWF secreted
will retain its intrinsic molecular dysfunction. Consequently, the preferred therapy for type 2 is the use of VWF
concentrates
VWD type 3 Since women with VWD Type 3 lack the physiological rise in VWF during pregnancy, they should receive
prophylaxis at the time of delivery to raise VWF factor levels at least to 50 IU dL
)1
.
Platelet disorders Platelet transfusion before and after delivery (up to 6 days post partum) have been reported to reduce the risk of bleeding
in women with GlanzmannÕs thrombasthenia. The use of rFVIIa has been proposed in cases of isoimmunization.
a- and hypo-
fibrinogenemia
Replacement therapy to maintain a minimum fibrinogen level of 1.5 mg dL
)1
is suggested for the prevention
of PPH in afibrinogenemia. For women with hypofibrinogenaemia, intrapartum replacement is required if
fibrinogen level is below 1.5 mg dL
)1

) and/or the woman has a significant bleeding history. Thrombosis
events were reported during puerpuerium, hence postpartum management, including the use of postpartum
prophylaxis, should take into account any personal and family history of bleeding and thrombosis.
Dysfibrinogenemia Women with dysfibrinogenaemia are also at risk of both postpartum thrombosis and PPH. Postpartum
management of these women should be individualized based on their fibrinogen level as well as personal and
family history of bleeding and thrombosis.
FII Secondary PPH was reported in one pregnancy. Based on this limited data, it is difficult to make
recommendation for the obstetric management. These women are considered potentially at risk of PPH.
Prothrombin complex concentrate to maintain FII level > 20–30 IU Kg
)1
.
FV In women with partial deficiency and no history of bleeding, labour and delivery could be managed expectantly.
Women with FV deficiency especially those with low FV levels appear to be at increased risk of PPH.
Substitution therapy with FFP is recommended to raise FV level to above 15–25%.
FV + VIII There are no enough data in relation to pregnancy in these women, the obstetric experience of women with
FV deficiency and carriers of haemophilia could probably serve as a useful guide in these patients:
FV > 15–25%; FVIII > 50% (combination of DDAVP or FVIII concentrate and virus inactivated FFP).
FVII Women with low FVII levels or positive bleeding history are more likely to be risk of PPH, therefore,
prophylactic treatment is required for women with FVII level of < 10–20%. rFVIIa (15–30 lgkg
)1
)
should be the treatment of choice.
FX Patients with severe FX deficiency (< 1%) tend to be the most seriously affected patients with RBDs,
therefore they may benefit from replacement therapy during pregnancy and to cover labour and delivery
to minimize the risk of bleeding complications. In women with FX level > 10–20% and no significant
bleeding history, a conservative approach could be adopted.
FXI Women with FXI deficiency are at increased risk of both primary and secondary PPH. Prophylactic
treatment with tranexamic acid should be considered post delivery up to 2 weeks, particularly for those
with a bleeding phenotype. The concomitant use of tranexamic acid and FXI concentrates should be avoided.
FXIII The incidence of PPH in women FXIII deficiency is not known. Successful pregnancy in women with

FXIII subunit A deficiency are generally only achieved with replacement therapy throughout pregnancy;
a level > 10–20% during pregnancy should be considered.
242 F. Peyvandi et al
Ó 2011 International Society on Thrombosis and Haemostasis
especially during surgery, the decision for prophylaxis during
labour and delivery needs to be individualised and must take
into consideration FXI level, personal/family bleeding history
and the mode of delivery. Based o n v ery limited available data, it
is difficult to make recommendation for the obstetric man age-
ment of women with prothrombin, FV and FV + FVIII
deficiencies, therefore, careful management of labour and the
immediate postpartum period is necessary. Table 2 reports
available recommendation for the obstetric management of
women with inherited bleeding disorders [46,76,87].
Counselling and prenatal diagnosis
Preconceptual counselling should precede prenatal diagnosis in
known women with inherited bleeding disorders. Genetic
counselling should be carried out before conception to allow
consideration of risk assessment of the potential carrier (in
haemophilia) or state of heteroz ygosity in two partners of
families a ffected with autosomal recessive bleeding disorders.
The counselling should provide adequate information not only
concerning risk of bleeding disorders, but also for suitable
reproductive options and methods of prenatal testing that are
available with the limitation and potential complication. The
ideal management of women with inherited bleeding disorders
is through multidisciplinary clinics with an ideal team including
a laboratory haematologist, an obstetrician-gynaecologist, an
anaesthesiologist, a family physician, a social worker, a
pharmacist, and laboratory technician.

Disclosure of Conflict of Interests
Flora Peyvandi served as a consultant for CSL Behring on the
issue of women with rare bleeding disorders. Isabella Garagiola
and Marzia Menegatti do not have any conflicts of interest to
disclose.
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