Gynaecological and obstetrical

bleeding problems in women with

inherited bleeding disorders

Danijela Mikovic, S. M. Siboni, M. Benedik-Dolnicar,

C. Bidlingmaier, T. Celkan, R. Gilmore, H. Pergantou,
P. Giangrande, F.Peyvandi

16th International Meeting DLTH, Timisoara, Romania, 19-21 May 2011

 Female physiology
and inherited bleeding disorders

Menstruation,pregnancy,
Menstruation,pregnancy, delivery
delivery
Women with inherited bleeding disorders are particularly at risk of bleeding as
a result of regular haemostatic chalenge
Gynaecologists and obstetricians
may be the first clinicans
to encounter these women.

Menorrhagia or obstetric haemorrhage

could be the first presenting symptom.
 Who
Who are
are the
the women
women with
with
inherited
inherited bleeding
bleeding disorders
disorders

 Von Willebrand Disease

 Carriers of hemophilia
 Rare coagulation disorders
- Afibrinogenemia, FVII, FX, combined
F V +VIII, XI and XIII deficiency
 Platelet disorders
- Bernard-Soulier syndrome and Glanzmann
thrombasthenia
 Bleeding manifestations in women are an important public health
problem.

5-10% of women during the reproductive age, experiences

menorrhagia and represents half of women who experience
hysterectomy

Vessey et al, 1992; Kadir et al, 1998, Carlson et al, 1993

According to estimates, up to 20% of women with menorrhagia

have an underlying bleeding disorder

Kadir R. et al. Lancet 1998;351:485-489

 Natural history in women with inherited
bleeding disorders

Menarche Pregnancy
Menstruation Delivery

Menorrhagia Bleeding
Other problems:
 Anaemia  During pregnancy
 Dysmenorrhea  Postpartum
 Haemorrhagic ovarian cyst  After abortion
 Increase of endometriosis,
polyps and fibroids?

Quality of life:
 Significantly reduced
 Effects on social life, work,
and education
 Menorrhagia

Defined as menstrual loss of Lancet 1998

≥ 80 mL per cycle or, less commonly,

heavy
menses exceeding 7 days
 Menorrhagia occurs in
approximately half of women with
inherited
bleeding disorders
HJÖRDIS

The first described patient

with von Willebrand disease

passed away at the age of 13

as a result of excessive bleeding
during her 4th menstrual cycle
 up to 20% of women with idiopathic
menorrhagia have an underlying bleeding
disorder

James A. et al, Haemophilia 2010;16(5): 160-167

 Haemostasis testing should be considered

 menorrhagia from menarche

 idiopathic menorrhagia in reproductive age
 before surgical intervention for menorrhagia

- especially if there is a bleeding history

Lee CA et al, Haemophilia, 12:301-36, 2006.

Pregnancy and Post-
partum
Hemostasis during pregnancy
 Postpartum
Postpartum
haemorrhage
haemorrhage

Despite
Despitethe
thecritical
criticalrole
roleof
of
uterine
uterinecontractility
contractility
in
incontroling
controlingpostpartum
postpartumbleeding
bleeding

increased risk of postpartum haemorrhage

- especially high prevalence of delayed PPH
- 10-25 times more common
Causes of maternal death
 RISK OF
MISCARRIAGE

Increased risk was documented:

- fibrinogen deficiency
- FXIII deficiency

whether there is an increased risk of miscarriage in women with other bleeding

disorders is not clear
 FEMALES WITH VON WILLEBRAND DISEASE:
72 YEARS AS THE SILENT MAJORITY
Kouides PA, Haemophilia 4:465-76 (1998)

Diagnosis
Diagnosis isis difficult
difficult

Women may consider their symptoms "normal“, and they come to attention only
after serious bleeding events

Education & Diagnosis

 Treatment
Treatment possibilities
possibilities
Levonorgestrel IUD
Oral contraceptive

Endometrial
ablation

Intranasal
DDAVP
(Stimate® )

VWF/FVIII Antifibrinolytic Hysterectomy

concentrate therapy
Management
Management is
is difficult
difficult

Considerable
Considerableinter-individual
inter-individualvariations
variations
 Few
Fewavailable
availablelong
longterm
termprospective
prospectivestudies
studies
of
oflarge
largecohorts
cohortsoo patients
patients
 Reliable
Reliableinformation
informationon
onclinical
clinicalmanagement
management
isis often
oftenscarce
scarce
 To
Toprovide
provideevidence-based
evidence-basedguidelines
guidelinesonon
diagnosis
diagnosisand
andtreatment
treatmentisisreally
reallydifficult
difficult

Lee et al. Haemophilia 2006: 12: 3101-336

 Rare
Rare Bleeding
Bleeding Disorders
Disorders

Afibrinogenemia, FII, FV, FVII, FXI, FXIII and combined deficiencies

• 3-5% of inherited coagulation deficiencies

• prevalence 1:500 000 to 1: 2 000 000

Information are limited to case reports and
small case series
Study Sample size Type of study Prevalence
and population
Mauser Bunschoten et al [1988] 102 obligate carriers of haemophilia A Case series 31%

Mauser Bunschoten et al [1988] 19 obligate carriers of haemophilia B Case series 10%

Greer et al [1991] 18 obligate carriers of haemophilia A Case series 22%

Greer et al [1991] 5 obligate carriers of haemophilia B Case series 40%

Kadir et al [19999] 30 haemophilia carriers Prospective cohort 57%

Yang and Ragni [2004] 5 Amish women with haemophilia B Case series 20%

Lak et al [1999] 20 women with afibrinogenaemia Case series 70%

Kadir et al [1999] 20 women with factor XI deficiency Prospective cohort 59%

Burrows et al [2000] 11 women with factor XIII deficiency Summary of case reports 64%

Lak et al [2003] 20 women with factor XIII deficiency Case series 35%

Shetty et al [2000] 5 females aged 13–33 with combined Case series 60%
factor V and factor VIII deficiency

Lopez et al [1998] 35 women with Bernard-Soulier Summary of case reports 51%

syndrome

George et al [1990] 55 women with Glanzmann’s thrombasthaenia Summary of case reports 98%

James, Haemophilia, 2005

European Network of Rare
Bleeding Disorders
Funded in 2007 by the European Community
action programme for public health (PHEA-DG
SANCO)

AIMS:
• To develop a network of EU Centres
• To harmonise data on RBDs in Europe through a common on-line
database
• To make the network accessible to all centres in Europe and
internationally
• To produce guidelines
• To support the pharmaceutical industry in the development of new
products
Records:
• data on 592 patients entered in EN-RBD 40%
33%

30%
24%

20% 17%
16%
11%
10%

22 0%
0-10 11-20 21-40 41-60 >60

Ag e (ye a rs)
54 100%

80%
64 146
20 60%
49%
51%

40%

20%

12 0%

Ma le Fe m a le

21
9

160 30

54
Spontaneous bleeding episodes in 172
women (post-menarche)
 Laboratory severity definition based on
coagulant activity level

Coagulant activity
Severe Moderate Mild
FII, FV, FV+VIII, FVII, FX, FXI <1% 1%-10% >10%
FXIII <5% 5%-10% >10%
Fibrinogen <10mg/dl 10-50mg/dl >50mg/dl
 Menorrhagia
SEVERE PHENOTYPE (32 women) MODERATE PHENOTYPE (31 women)
100% 100%
88% 88%

80% 80%

60% 60% 56%

43%
40% 33% 40%

20%
20% 20%

0% 0% 0%
0% 0%

Fib rin o g e n FV FVII FXI FXIII FV FVII FX FXI

MILD PHENOTYPE (109 women)

100%

80%

60%

40%
33%

20% 20% 21%

20% 14%
9%
2%
0%

Fib rin o g e n FV FV+FVIII FVII FX FXI FXIII

 Bleeding during pregnancy
SEVERE PHENOTYPE: 30 pregnancies
and
MODERATE PHENOTYPE: 41 pregnancies

Data only on
FV, FVII and FXI
deficiencies:

MILD PHENOTYPE (132 pregnancies)

NO patients had bleeding during pregnancies 100%

80%

60%

40%

20%

7%
4% 3%
0% 0% 0% 0%
0%

Fib rin o g e n FV FV+FVIII FVII FX FXI FXIII

 Spontaneous abortion
SEVERE PHENOTYPE (30 pregnancies) MODERATE PHENOTYPE (41 pregnancies)
100% 100%

80% 80%

60% 60%

40% 40%

18% 18%
20% 14% 20% 14%

0% 0%
0% 0%

FV FVII FXI FV FVII FXI

MILD PHENOTYPE (132 pregnancies)

100%

80%

60%

43%
40% 37%

27%

20% 15%
13%

0% 0%
0%

Fib rin o g e n FV FV+FVIII FVII FX FXI FXIII

 Vaginal delivery on prophylaxis ( ) or w/o prophylaxis ( )
SEVERE PHENOTYPE (23 deliveries) MODERATE PHENOTYPE (43 deliveries)
100%
100%
100%

80% 80%

60% 60%

40% 40%
29%
20%
20% 14% 20%
10% 8%
no no no
del 0% del 0% 0% del
0% 0%

FV FVII FXI FV FVII FXI

MILD PHENOTYPE (142 deliveries)

100%

80%

60%
60%

37%
40%

25% 25%
20%
20%
17%

no n o 6% no
del del 0% 0% d e l 0% 0%
0%

Fib rin o g e n FV FV+FVIII FVII FX FXI FXIII

 Heterozygous women
(coagulant activity >30%)

n° women in reproductive age = 79

n° pregnancies = 127
n° deliveries = 93
 Spontaneous menorrhagia Bleeding during pregnancy
100% 100%

80% 80%

60% 60%
50%

40% 40%

25%
19%
20% 20%
7%
5%
3%
0% 0% 0% 0%
0% 0%
FV FVII FX FXI FXIII FV FVII FX FXI FXIII

Abortion Delivery on prophylaxis ( ) or w/o ( )

100% 100%

80% 80%

60%
60% 60%

43%
39%
40% 40% 34%
30% 30%

20% 20%
20% 20%

no 8%
0% del 0% 0%
0% 0%

FV FVII FX FXI FXIII FV FVII FXI FXIII

 Conclusion

• Prolonged and heavy menstrual bleeding is quite prevalent in the general population,
but it is more common among individuals with a hemostatic defect
• Menorrhagia is a symptom cross-affecting all type of deficiencies with any degree of
severity (Lee CA, 2006; EN-RBD data)
• The prevalence of spontaneous abortions is about 18% in all deficiencies, even if
recurrent miscarriages have been reported only in afibrinogenemia and severe FXIII
deficient women (De Moerloose P, 2009; Karimi M, 2009; EN-RBD data)
• Bleeding during pregnancy seemed to be rare in all type of deficiencies with any
degree of severity (EN-RBD data)
• Post-partum bleeding often occurs if replacement therapy is not administered for at
least two or three days after delivery (James AH, 2005)
• Further prospective study is needed to compare women with RBDs to a similar
normal population in order to understand the putative causes of the reported
symptoms
 Acknowledgments

• European Centres involved in the project:

– M. Benedik-Dolnicar and L. Kitanovski, National Haemophilia Center, University Children’s Hospital, Ljubljana, Slovenia;
– C. Bidlingmaier, Pediatric Hemophilia and Thrombosis Centre, Children‘s University Hospital, Munich, Germany;
– T. Celkan and N. Özdemir, Cerrahpasa Medical Faculty of Istanbul University, Istanbul, Turkey;
– A. Gadisseur, Antwerp University Hospital UZA, Edegem, Belgium;
– P. Giangrande, Oxford Haemophilia & Thrombosis Centre, University of Oxford, Oxford, United Kingdom;
– M. Giansily Blaizot and J.F. Schved, Hopital Saint Eloi, Montpellier, France
– R. Gilmore, National Centre for Hereditary Coagulation Disorders, St James's Hospital, Dublin, Ireland;
– S. Halimeh and B. Fraeser, MVZ Labor Duisburg GmbH - Duisburg, Germany;
– J. Ingerslev, Centre for Hemophilia and Thrombosis, University Hospital Skejbi, Aarhus, Denmark;
– D. Mikovic, Blood Transfusion Institute of Serbia, Belgrade, Serbia;
– K. Peerlink, Hemofilie Centrum Leuven, Katholieke Universiteit, Leuven, Belgium;
– H. Pergantou, Haemophillia Center, Haemostasis Unit, Agia Sofia Children’s Hospital, Athens, Greece;
– F. Peyvandi, M. Menegatti, R. Palla and S.M. Siboni, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Università
degli Studi di Milano, Milan, Italy.
• We also thank P. Lanzi for his precious work as database manager and S. Malosio for her valuable assistance in
the management of this project.
Hradec Kralove, Check Republic - May 2013
17th International Meeting
Danubean League against Thrombosis and Haemorrhagic Disorders