WOMEN AND

INHERITED BLEEDING DISORDERS

Danijela Mikovic
Blood Transfusion Institute of Serbia, Belgrade
20th International Meeting of the DLTH
13-16 May 2019, Antalya, Turkey
 Kouides PA, Haemophilia 4:465-76 (1998)

Women may consider their

symptoms "normal“

They come to attention only after serious bleeding

events or anaemia.
Lack of awareness and literature data

- repeated bleeding episodes

- many years of reduced quality of life
- unnecessary surgical interventions

Kadir R et al. Haemophilia 2011;7(Suppl.1);1-2.

FIRST EDITION, January 2009 SECOND EDITION, November 2018
https://www.ehc.eu/events/conference-on-women-and-bleeding-disorders/
Inherited bleeding disorders - Inheritance
Inheritance

Von Willebrand disease Haemophilia

Rare bleeding disorders

Autosomal Recessive, X-linked

Affected males and

females Affected males

Bleeding manifestation are more Women carriers with low

frequent in women FVIII/FIX – bleeding tendency
DISTRIBUTION
DISTRIBUTION BY
BY GENDER
GENDER

World Federation of Hemophilia, 2009

 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 chalenges!
 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 occurs in approximately
Postpartum haemorrhage
half of
occurs in approximately
women with inherited bleeding
one third of women with
disorders
inherited bleeding disorders

James A. Obstet Gynecol Surv 2006;61(2):136-45

Peyvandi F et al. J Thromb Haemost 2011.
 Due to the lack of timely
diagnosis many young women undergoing
hysterectomy
to stop uterine bleeding!

James A. Obstet Gynecol Surv 2006;61(2):136-45; Peyvandi F et al. J Thromb Haemost 2011.
Gynaecologists and obstetricians
may be the first clinicans
to encounter these women.

Menorrhagia or obstetric haemorrhage

can be the first presenting symptom.
 Insufficient information !!!

Gynaecologists/Obstetricians in Great Britain and United States:

 underestimate prevalence of VWD in menorrhagia and

postpartum haemorrhage

 often not familiar with bleeding disorders and specific

haemostatic therapy

 average of 16 years from onset of symptoms to diagnosis

Kirtava A . et al, Haemophilia 2004; 10: 158–61.

Chi et al. Haemophilia 2006; 12: 405– 12.
Diagnosis is often difficult:

 Physician may not suspect diagnosis

 Approriate haematological input may be unavailable

 Specialized laboratories are often not available

 Laboratory methods are not standardized

Kadir R et al. Haemophilia 2011;7(Suppl.1);1-2.

VON WILLEBRAND DISEASE

Precise diagnosis is still challenging!

• heterogeniety of the disease

• additional factors influencing
laboratory and clinical presentation
• limitations of the tests
REGISTERED PATIENTS WITH VWD - VARIABILITY

NUMBER OF
NUMBER OF
POPULATION PATIENTS
PATIENTS
(per million inhabitants)

SERBIA 7 022 268 300 43

SLOVENIA 2 066 748 186 90

DENMARK 10 067 744 200 53

NORWAY 5 282 223 596 112

USA 325 719 178 11 336 35

UK 66 022 273 10 842 164

World federation of haemophilia, Annual Global Survey 2017

VWD Type 1 versus ′Low VWF level′

When investigating a patient with mucocutaneous bleeding

(Guidelines: NIH 2008; UKHCDO 2014):

• diagnosis of type 1 VWD

- VWF activity <30 U/dL

• designation of ′low VWF level′

- VWF activity 30-50 U/dL

Laffan MA et al. Br J Haemat . 2014;167,453-465

RARE BLEEDING DISORDERS

Significant challenge for diagnosis!

• Rarity
• Variable clinical presentation
• Limitations of laboratory assays
 Rare Bleeding Disorders Databases

RBDD, from 2004 EN-RBD, 2007-2010 PRO-RBDD, from 2012

www.eu.rbdd.org/

IRCCS Maggiore Hospital, Mangiagalli and Regina Elena Foundation and University of Milan
NUMBER OF REPORTED PATIENTS INCREASED

Annual Global Surveys, WFH

Number 2007 2016

Countries 105 117
Haemophilia 126.402 181.469
VWD 51.367 74.318
Rare coagulopathies
11.557 24.204

Platelet disorders 3.973 3.275

Unknown bleeding 3.774 17.711
disorders

Total 197.073 300.977

CARRIERS OF HAEMOPHILIA

• wide range of FVIII/FIX values (5-219 IU/dl)

• inreased bleeding tendency with low levels
• ~80% have factor level within normal range
Plug I et al. Blood 2006;108:52-6.

Carriers with clotting factor levels of 40-60% of normal

may have an increased bleeding tendency !
CARRIERS OF HAEMOPHILIA

Increased bleeding tendency was observed despite having

only one out of 44 carriers with FVIII <40%.
Paroskie A et al. Br J Haematol 2015;170:223–8.
How many
carriers are there?

Casper CK, Lin JC. Haemophilia (2010);16:840–842.

For every 100 men with haemophilia:

• 277 women potential carriers

- all need counselliing, factor level and genetic testing

• 156 women obligate carriers

Casper CK, Lin JC. Haemophilia (2010)

• 30-100 carriers with low FVIII /FIX (< 40 IJ/dL)

Hermans C, Kulkarni R, Haemophilia (2018)
HAEMOPHILIA CARRIERS
with low FVIII/FIX are infrequently included in
national registries

REGISTRED FEMALE CARRIERS

FRANCE SERBIA

Haemophilia A 258 Haemophilia A 8

Haemophilia B 97 Haemophilia B 2

4.8% (355/7346) 1.8% (10/545)

of all registered patients of all registered patients
with haemophilia with haemophilia

https://www.francecoag.org/SiteWebPublic/html/accueil. Nacionalni Registar Srbije 2018

html. 2018.
CARRIER SCREENING IS
SUBOPTIMAL
- in developed countries
prevalence of screening 41-49%

PROMOTION OF SCREENING IS
IMPORTANT

Women are often unaware

of their status, even when
they are obligate carriers!

Dunn NF et al. Haemophilia 2008

Gillham A et al. J Genetic Couns, 2015.
Treatment decision

UK Haemophilia Centre Doctors Organization

The obstetric and gynaecological management

of women with inherited bleeding disorders
– review with guidelines -
Haemophilia 2006
Guideline for the diagnosis and management
of the rare coagulation disorders
Br J Haematol 2014
MENORRHAGIA
MENORRHAGIA - TREATMENT POSSIBILITIES
Levonorgestrel IUD
Oral contraceptive

Endometrial
ablation

Intranasal
DDAVP
(Stimate® )

Clotting factor
concentrates Antifibrinolytic
therapy Hysterectomy
TREATMENT OF MENORRHAGIA

MEDICAL SURGICAL
HORMONAL
- Levonorgestrel IUS  Endometrial ablation
- Combined contraceptives  Hysterectomy

HAEMOSTATIC
- Tranexamic acid
- DDAVP
- Clotting factor replacement

Davies J, Kadir RA. Thromb Res. 2017;151 Suppl 1:S70-S77.

ALGORITHM FOR MANAGEMENT

James A et al. AJOG 2009;201(1):12.e1-8.

 COMBINED HORMONAL
LEVONORGESTREL IUS CONTRACEPTIVES

• Release 20 mg of progestins • Decrease blood loss, supress

per day to the endomethrium ovulation, increase FVIII/VWF

• Reduce blood loss by 74-97% • Reduce blood loss by 50%

• Contraindication : VTE, migraine
• Contraindication: unexplained
with aura, malignancy
vaginal bleeding, uterine sepsis

Davies J, Kadir RA. Thromb Res. 2017;151 Suppl 1:S70-S77.

Bradley LD, Gueye NA. Am J Obstet Gynecol. 2016 Jan;214(1):31-44. .
TRANEXAMIC ACID DESMOPRESSIN

• Reversibly block lysine • Endogenous release of

binding sytes VWF and FVIII
• Women with & without IBDs • VWD type 1 & HA carriers
• Usage • Usage
- 1gr/6-8h -150-300 µg nasal; 0,3 µg/kg sc/iv
- for 3-4 days during cycle - for 2-3 days during cycle
- decrease blood loss by 50% - decrease blood loss by 34-59%

• Concern: thrombosis • Concern: hyponatremia

Wellington K et al. Drugs 2003. . Rodeghiero F. Haemophilia 2008.

CLOTTING FACTOR REPLACEMENT

Inefficiency or intolerance of drug treatment!

• SEVERE FORM OF THE DISEASE

Prophylaxis for several days during menstruation or throughout the whole cycle to
prevent ovulation bleeding

• ACUTE BLEEDING
Adolescents suffer from menorraghia, often with episodes of acute menorrhagia and
requiring blood transfusion

Davies J, Kadir RA. Thromb Res. 2017;151(Suppl 1):S70-S77.

SURGICAL TREATMENT

Inefficiency or intolerance of medical treatment!

ENDOMETRIAL ABLATION
- Conservative surgery

HYSTERECTOMY
- Definite treatment option

Should be carried out by experienced professional and

perioperavite bleeding prophylaxis is necessary!
HISTERECTOMY
IN WOMEN WITH VWD vs. WITHOUT VWD

Histerectomy for nonmalignant conditions

Complication With Without P Histerectomy With Without P

VWD VWD VWD VWD
Periop. bleeding 2,75% 0,89% <0.00 Frequency 26% 9% <0.00
1 1
Transfusion 7,34% 2,13% <0,001 Mean age 33 yrs 38 yrs 0.17

James A et al. Haemophilia 2009. Kirtava A et al. Haemophilia 2003.

Of particular concern for women with IBD is EARLY HYSTERECTOMY,

HYSTERECTOMY
specially if they are undiagnosed for many years with 'unexplained’ menorrhagia!
Pregnancy, Delivery and
Postpartum
HAEMOSTATIC CHANGES IN PREGNANCY
Gradually rise in various coagulation factors reaching
highest levels in the third trimester.

VWF 3-fold, FVIII 2-fold, FIX minimal increase!

Kadir R. Haemophilia 2009;15(5):990-1005.
WOMEN WITH
INHERITED BLEEDING DISORDERS

• Do not achieve the same level of deficient

clotting factor as other women
• Haemostatic abnormality may persist throughout
pregnancy, especially if the defect is severe

• Due to persistent low factor level and/or rapid

fall after delivery
- increased risk of antenatal bleeding
- particularly high risk of early and delayed PPH
James AH et al.Haemophilia 2015;21(1):81-7.
 Antenatal and peripartum
care is mandatory!
RECOMMENDATION FOR ANTENATAL CARE

MULTIDISCIPLINARY Combined expertise in obstetric and haemostasis

APPROACH

Obstetric risk factors

ANTENATAL Bleeding risk factors
RISK ASSESMENT • type and severity of disoder
• pregnancy induced changes of factor level

COAGULATION In the third trimester

• preferably at 32 to 34 weeks
FACTOR CHECK

Delivery
ADVANCED • place, mode
Haemostatic coverage
INDIVIDUALIZED PLAN • type, dose, duration

Abdul-Kadir R et al. Transfusion 2014;54(7):1756-68.

PREGNANCY – BLEEDING RISK
CLOSE OBSERVATION
•asymptomatic women

BLEEDING PROPHYLAXIS
•Invasive diagnostic and therapeutic procedures
- CVS, amniocenthesis, cordocentesis
- Cervical cerclaige
•Pregnancy terminations
- Spontaneous
- Intentional

Factor level should be measured to assess the need for haemostatic

treatment!
Huq FY, Kadir RA. Haemophilia 2011;17(Suppl 1):20-30.
PREGNANCY – ANTENATAL COMPLICATIONS
• Miscarriage,
• Antepartum haemorrhage
• Foetal loss

- Fibrinogen deficiency
- FXIII deficiency

Risk of pregnancy loss in severe cases without prophylaxis is 60-90%.

Kadir R et al. Haemophilia 2009;15(5):990-1005.

PREVENTION OF PREGNANCY LOSS

Regular clotting factor replacement

initial dose frequency trough level
FXIII 20-40 IU/kg 1 time/week >10-20%
Fibrinogen 50-100 mg/kg 1 time/month >1-1.5 g/L

• Should be commenced as early as possible in pregnancy

• Should be continued during delivery and for at least 3 days postpartum

Asahina T et al. Obstet Gynecol Surv 2007;62:255-60.

Peyvandi F. Thromb Res 2012;130 (Suppl. 2):S7-S11.
DELIVERY

INCREASED RISK OF BLEEDING

Despite the critical role of uterine

contractility in controling postpartum
blood loss.
RISK OF POSTPARTUM HAEMORRHAGE

GENERAL BLEEDING
POPULATION DISORDERS
EARLY PPH 4-6% 16-29%
- within 24 hrs of delivery

LATE PPH <1% 20-29%

- 24 hrs to 6 weeks
postpartum

Greer LA et al. 1991; Kadir RA et al. 1998; Ramsahoye BH et al .1995

DELIVERY - MANAGEMENT

PLACE
− Unit with available laboratory and replacement therapy
− High risk patients should be referred to a specialized centre

MODE
VAGINAL DELIVERY
− small risk of maternal&foetal bleeding
− active management of the 3rd stage
− avoid prolonged labor and instrumental delivery
CESAREAN SECTION
− in those circumstances is considered less traumatic

UKHCDO Guidelines Br J Haematol 2014; BJOG 2017.

DELIVERY – HAEMOSTATIC COVER

BLEEDING PROPHYLAXIS
VAGINAL DELIVERY
− mild form of the disease without significant bleeding history
often can be managed by observation and concentrate
infusion only if bleeding occurs
− if the disease is severe and/or strong personal or family history
of bleeding prophylaxis is necessary

CESAREAN SECTION
− is likely to require concentrate infusion as for other sugrical
procedures

UKHCDO Guidelines Br J Haematol 2014; BJOG 2017.

POSTPARTUM HAEMORRHAGE - PROPHYLAXIS

Generally, all women with inherited bleeding disorders

have to be considered potentially at risk for developing PPH!

TO MINIMIZE THE RISK

•SHOULD BE MONITORED during childbirth and immediate

postpartum
•MAY REQUIRE PROPHYLAXIS
- 3–4 days for vaginal delivery
- 5–7 days for caesarean section
- it can be prolonged up to 2 weeks or longer
•MAY REQUIRE CLOSE OBSERVATION for several weeks
THE CHOICE OF PRODUCTS
Specific factor concentrates are treatment
of choice; FFP and cryo if no suitable
alternative available! DDAVP and
antifybrinolitics in mild deficiencies.

Huq FY, Kadir RA. Haemophilia 2011;17(Suppl. 1):20–30.

DOSAGE
The aim is to raise deficient factor
above suggested haemostatic level.
Frequency of administration according
to plasma half life.

Kadir RA, Davies J. J Throm Haemost 2013;11(Suppl. 1):170–9.

PROPHYLAXIS – VWD, HAEMOPHILIA CARRIERS

Prophylaxis in women with factor level <50 IU/dl

the aim is to raise deficient factor level
above 50 IU/dl for vaginal delivery or
Cesarean section

Kadir RA and Davies J. J Throm Haemost 2013; 11 (Suppl. 1): 170–179

 Guideline for the diagnosis and management
of the RARE COAGULATION DISORDERS

Laboratory criteria for disease severity are as proposed by

European Network of Rare Bleeding Disorders

Mumford AD et al. UKCDO guideline on behalf of BCSH. BJH 2014;167: 304-26.

PROPHYLAXIS – RARE BLEEDING DISORDERS

• SMALL NUMBER OF CONCENTRATES

• LIMITED EXPERIENCE OF THEIR USE
• NO FII AND FV CONCENTRATES

• SEVERE FXIII AND FIBRINOGEN DEFICIENCIES

- should be continued during labour and
delivery
• SEVERE FVII AND FX DEFICIENCIENCIES
- recommended
• FXI DEFICIENCY
- should be considered on individual basis
• FII, FV AND COMBINED FV+FVIII DEFICIENCIES
- difficult to make recommendation