The considerable proportion of women with menorrhagia 20%, who are comprehen-sively tested for haemostatic abnormalities, are found to have underlying bleeding disorders such as von Will
Trang 1INVITED REVIEW
Gynecological and obstetrical manifestations of inherited
bleeding disorders in women
F P E Y V A N D I , I G A R A G I O L A and M M E N E G A T T I
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 tendency to significant episodes Women
with inherited bleeding disorders are particularly disadvantaged
since, in addition to suffering from general bleeding symptoms,
they are also at risk of 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 their
reproductive life These latter problems include excessive
menstrual bleeding or menorrhagia, miscarriage, bleeding
complications during pregnancy and after delivery and their
related complications such as acute or chronic anaemia The
management of these women is difficult because of considerable
inter-individual variation Moreover, reliable information on
clinical management is scarce, only a few available long term
prospective studies of large cohorts provide evidence-based
guideline about diagnosis and treatment
Keywords: haemophilia, management, platelet disorders, rare
bleeding disorders, von Willebrand disease, women
Introduction
Women are more likely to manifest a bleeding disorder as they
have more opportunities to experience bleeding challenges in
their lifetime due to the natural cycle of menses and
reproduction Menstruation and ovulation may be associated
with significant bleeding leading to the limitation in
conduct-ing daily activities, changes in social functionconduct-ing and adverse
effect on quality of life At least 5–10% of women at
reproductive age will seek medical attention for menorrhagia
[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 responsible for menorrhagia; however, an underlying aetiology is identified in only 50% of cases [3] Organic causes include infections of any genitourinary origin and bleeding disorders as well as organic dysfunction as hepatic or renal failure Chronic liver disease impairs production of clotting factors and reduces hormone metabolism (e.g oestrogen) Any of these problems may lead to heavy uterine bleeding The most common endocrinologic cause of heavy menstrual bleeding in adolescent girls is anovulatory dysfunctional uterine bleeding owing to the immaturity of the hypotha-lamic–pituitary–ovarian axis Anatomic aetiologies for men-orrhagia include uterine fibroids, endometrial polyps and hyperplasia Intra Uterine Device (IUD) placement, steroid hormones, chemotherapy agents, hypothalamic depressants, phenytoin and anticoagulants, which could also cause increased menstrual bleeding [4] The considerable proportion
of women with menorrhagia (20%), who are comprehen-sively tested for haemostatic abnormalities, are found to have underlying bleeding disorders such as von Willebrand disease (VWD), platelets function alteration or rare bleeding disorders (RBDs: deficiencies of coagulation factors such as fibrinogen, factor (F)II, FV, FV + FVIII, FVII, FX, 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 other problems that 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 challenge in women with inherited bleeding disorders, since information about these issues are really scarce and limited to few case reports An 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: flora.peyvandi@unimi.it
Trang 2menstruation During menstruation higher levels of
prosta-glandin E2 and prostaprosta-glandin F2a in menstrual fluid are found
in menorrhagic women when compared with those with
normal menses [5,6] Furthermore, the release of prostaglandin
E2, prostaglandin F2a and prostacyclin by the endometrium
and myometrium during menstruation are increased in tissues
obtained from menorrhagic women [7,8]; and increased
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 based on the aberrant formation of a platelet plug that is a
crucial first step in the regulation of blood flow [13] Thus, it is
not surprising that platelet dysfunction and VWD have
both been associated with menorrhagia, sometimes of a severe
nature, and that menorrhagia is a common presenting symptom
among female patients with VWD From a historical
perspec-tive, it is interesting to note that the first patient identified with
this disorder by Erik von Willebrand in 1926 eventually died of
uncontrollable menstrual bleeding at age 13 years
Menorrhagia
History and definition
The term ƠmenorrhagiaÕ 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): ƠDisputatio medica,
inauguralis, de menstruorum profluvio immodicoÕ [14] The
term ƠmenorrhagiaÕ was regularly used 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
ƠMenstruation 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 cycle
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 80 mL per
menstrual cycle [17]
Differential diagnosis in women with menorrhagia
It is important for the 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 the first clinical manifestation that women with bleeding disorders encounter, often at menarche; therefore, many affected patients initially attend their gynaecologist Recently, a consensus on diagnosis
in women with menorrhagia was published by an international experts panel and recommendations were provided only if consensus could be reached [18] Experts agreed that an underlying bleeding disorder should be considered if any of the following indicators are present: menorrhagia since menarche; family history of a bleeding disorder; personal history of bleeding such as epistaxis, notable 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 to conventional management of menorrhagia [18] However, only a relatively small proportion of these patients will have a true underlying disorder of haemostasis Conse-quently, the discriminatory power of various bleeding symp-toms in predicting an underlying disorder of haemostasis has been incorporated into a scoring system (Ơbleeding score assessmentÕ) through the International Society of Haemostasis and Thrombosis network [19,20] On the other hand, as measuring actual menstrual 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 to 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 ƠpositiveÕ bleeding history need 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 levels 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
Trang 3affected with VWD and FXI deficiency were shown to have
significantly higher menstrual scores [24] The reported
prev-alence of menorrhagia in carriers of haemophilia was estimated
to be about 10–57% [25]
In women with VWD, menorrhagia was determined to be a
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 in women with GlanzmannÕs
thrombasthenia are contrasting since two studies report
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] and 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 herein 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 compared to 114 controls, reported that PBAC was significantly higher in affected 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 evidence-based, because of the small number of women who were analysed
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 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
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
Bernard-Soulier syndrome (9) Case reports 60 GlanzmannÕs thrombasthenia (16) Case reports 31
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
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
Trang 460% of them undergo hysterectomy or 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 with 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 with menorrhagia and an
underlying haemostatic defect should be beneficial in terms of
allowing for the use of specific haemostatic measures in the
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, to anticipate the possibility of an acute
menorrhagia [43] Haemostatic therapy includes
antifibrin-olytic (tranexamic acid and aminocaproic acid) and
DDAVP or desmopressin (1-desamino-8-D-arginine
vaso-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 approach for early 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 uncertain thrombotic risk reported in some studies [48–50]
Miscarriage Miscarriage is relatively common in the general population, with 12–13.5% of recognised pregnancies resulting in sponta-neous abortion, while there are case reports and case series 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 miscarriage 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
Trang 5play 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 adheres the surface epithelium 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 hypofidysfi-brinogenemia, 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 foetus at the equivalent
gestational stage seen in humans The fibrinogen deficiency
does not alter embryonic development, but formation of the
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 gives 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 to confirm 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 coagulation disorders, since information 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 FXIII are relatively unchanged
[59] All of these changes contribute to the hypercoagulable
state of pregnancy, and, in women with bleeding disorders,
contribute to improved haemostasis
The risk of bleeding in early pregnancy is unknown in carriers of haemophilia, but there is evidence that the risk after
24 weeksÕ gestation is not increased [28]
A case-control study reports the experience of 86 women with VWD and 70 controls with bleeding problem during pregnancy This report evidences that 1.3% of women with 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 and immediate postpartum period; pregnancy and delivery appeared uncomplicated in women with 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 deaths, in the last two 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 and > 1000 mL for caesarean sections within 24 h of delivery [65,66] PPH is classified as primary when occurs within the first 24 h postpartum or secondary, occurring between 24 h and up to 6 weeks of postpartum The median 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, there 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 recent data documenting and comparing the incidence of PPH in women with VWD and controls come from US discharge database, reporting that 6%
Trang 6of 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 resulted 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 deficiency [75] and in severe 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 These 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 with subnormal factor levels, despite
the pregnancy-related rise of FVIII, intravenous 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)1before any
invasive procedure and delivery The mainstays of therapy are
desmopressin (DDAVP) and plasma concentrates that contain
VWF DDAVP may be used in women with 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 documeasure-ment treatmeasure-ment 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 subset of women with type 2 VWD
respond to desmopressin Identification of those individuals
requires a test dose of DDAVP and subsequent measurement
of VWF:RCo 1 and 4 h after the dose If the VWF: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 type 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 and 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 of 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 and 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 and family history
of bleeding and thrombosis [82] No specific treatment is required in asymptomatic women
A significant rise 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 FX deficiency and a history of adverse pregnancy outcome may benefit from replacement therapy during pregnancy [79], and to cover labour and delivery to minimise the risk of bleeding complications [84] In FXIII deficiency a therapy should be commenced as early as possible in pregnancy to prevent foetal loss [85] and the treatment should 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,
Trang 7Table 2 Available recommendation for treatment in women with inherited bleeding disorders for menorrhagia (A) and during/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)1is 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 lg kg)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.
Trang 8especially 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 on very limited available data, it
is difficult to make recommendation for the obstetric
manage-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 heterozygosity in two partners of
families affected 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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