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.

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[email protected]
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-

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

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

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

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

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

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

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

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

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:

) 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

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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