Women and bleeding disorders

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Bleeding disorders in women
Dr. Paul Giangrande Oxford Haemophilia
Thrombosis Centre and Nuffield Department of
Clinical Medicine University of Oxford
paul.giangrande_at_ndm.ox.ac.uk
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How to secure early diagnosis and appropriate
treatment?

• What are the commonest disorders?
• What are the obstacles to diagnosis?
• What can be done to facilitate diagnosis and
  treatment?

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Frequency of bleeding disorders in women with
heavy menstrual bleedingKadir RA et al Lancet
351 485-489 (1998)

• 150 women with heavy menstrual bleeding but no
  pelvic abnormality screened
• Inherited bleeding disorder in 26 (17)
• Commonest disorders von Willebrand disease,
  platelet disorders, factor XI deficiency.
• Inherited bleeding disorders are found in a
  substantial proportion of women with menorrhagia
  and a normal pelvis.

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Congenital bleeding disorders

• Rare conditions
• Few doctors ever see a case
• Low public awareness
• Patients often only mildly affected
• Few, if any, problems in day-to day life
• Frequently diagnosed in middle age
• Often no apparent family history
• Diagnostic tests are complex, expensive and not
  readily available

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Normal platelet count 150-400 x 109/l
Megakaryocyte in bone marrow platelets bud off
from the cytoplasm of these polyploid cells. Life
span of platelets is around 10 days.
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Von Willebrand disease

• Common but usually mild bleeding disorder
• Up to 1 of population affected as defined by
  reduced plasma level of VWF, although only
• 125 / million have significant bleeding disorder
• Sadler JE Thromb. Haemostasis 84
  160-174 (2000)
• Autosomal dominant inheritance (gene on
  chromosome 12p) females also affected
• Autosomal dominant inheritance women affected as
  frequently as men
• Typical features include
• Easy bruising
• Prolonged bleeding from cuts and scratches
• Nose bleeds (epistaxis)
• Heavy menstrual periods (menorrhagia)
• Joint bleeding not a typical feature

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Rare bleeding disorders

• Women affected just as much as men
• Usually parental consanguinity
• More common in certain ethnic groups
• More common in certain parts of the world
• (e.g. S.E Asia, Middle East)
• Orphan diseases, hitherto neglected by
• patient advocacy groups
• drug manufacturers
• Specific factor concentrates often not available
• even if they are, usually not licensed by
  regulators
• little or no brand choice
• not necessarily recombinant

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Rare bleeding disorders in the UKUKHCDO 2009

• Factor XIII 56 (46 treated)
• Factor XI 1883 (75 treated)
• Factor X 180 (32 treated)
• Factor VII 641 (47 treated)
• Factor V 130 (8 treated)
• Fibrinogen 172 (17 treated)
• Factor VIII 5346 (2863 treated)
• Factor IX 1125 (618 treated)

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Clinical manifestations of rare bleeding
disordersMannucci PM Blood 104 1243-1252 (2004)
haemophilia
rare bleeding disorders
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Obstacles to diagnosis (1)

• Lack of awareness of problem by women themselves
  what is normal?
• Long-term problem of menorrhagia may be regarded
  as normal, and positive family history may
  ironically reinforce this idea
• Failure of health care professionals to think of
  the possibility of underlying bleeding disorder
• Tendency to look for physical conditions such as
  fibroids in women with menorrhagia
• Full medical history not elicited
• Referrers discouraged after run of negative cases

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Obstacles to diagnosis (2)

• Poor sensitivity of laboratory tests
• Common misconception that normal screening test
  results (PT, APTT and platelet count) completely
  excludes possibility of underlying bleeding
  problem
• Specialist interpretation of tests often
  required
• No single test suffices
• Specialist tests like platelet function tests and
  factor assays may not be available in local
  hospital
• Overdiagnosis of bleeding disorders such as VWD
  is also a significant problem

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Factor XI Ceph Actin FS Actin FSL Triniclot Pathromtin
11 46.1 52.6 42.6 45.8 65.8
30 36.6 38.8 34.7 36.9 52.5
50 32.7 33.8 31.2 33.8 46.8
69 30.4 31.7 29.0 31.5 43.6
89 28.7 29.7 26.9 30.1 41.5
Normal range in our laboratory 26-36 seconds,
using Triniclot reagent
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Factor IX Ceph Actin FS Actin FSL Triniclot Pathromtin
12 38.7 42.4 38.2 40.7 53.8
39 32.9 35.4 32.3 33.8 44.9
69 30.9 32.4 29.7 31.6 42.2
95 29.0 30.4 28.4 30.8 41.0
121 28.8 29.4 27.6 29.5 40.2
Normal range in our laboratory 26-36 seconds,
using Triniclot reagent
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Factors which influence VWF level

• ABO group
• Secretor status
• Age
• Race
• Difficult venepuncture
• Physical exertion
• Mental stress
• Oestrogen therapy
• Menstrual cycle

• Pregnancy
• Systemic disease
• Malignancy
• Infection
• Inflammation
• Pre-eclampsia
• Postoperative state
• Hypothyroidism
• Diabetes mellitus

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Blood 69 1691-1987 (1987)
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A diagnosis of bleeding disorder can have
significant adverse social consequences

• Self-esteem
• School
• Employment
• Participation in sports
• Life insurance
• Credit rating (e.g mortgage)
• Travel insurance
• Marriage prospects

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Von Willebrands disease (VWD)
..or would either deficiency or disorder
be better?
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How to promote awarenessamong health care
professionals

• Publications and presentations aimed at health
  care professionals (e.g. gynaecologists, ENT
  surgeons)
• Use of bleeding scores to better identify
  patients requiring more detailed evaluation
• Professional guidelines (recipes describing
  work up of patients)
• NGOs and not-for-profit organizations expanding
  their mandates (e.g. WFH, EHC)

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Book published by Royal College of Obstetricians
and Gynaecologists in UK specifically aimed at
trainees preparing for their specialist
examinations
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Importance of history taking

• Easy bruising
• Nose bleeds (epistaxis)
• Heavy menstrual periods (menorrhagia)
• Bleeding after
• operations
• dental extractions
• giving birth
• Family history

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Guidelines on the management of menorrhagia in
secondary careRoyal College of Obstetricians
Gynaecologists, UK (1998)
This . emphasises the importance of a careful
history specifically with regard to a long
history of menorrhagia since menarche, and a
history of bleeding after tooth extraction,
operations and childbirth. If these factors are
present, testing for bleeding disorders should
be carried out. This should be arranged in
conjunction with the local haematology department
as many of the necessary tests are not routine.
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Objective criteria include

• Anaemia (low haemoglobin level)
• Need for blood transfusion after surgery
• Prolonged bleeding from trivial wounds lasting gt
  15 minutes and requiring medical attention
• Haematoma at site of injections (e.g
  vaccination), bleeding from umbilical stump
• Oral cavity bleeding associated with tooth
  eruption, bites to lips and tongue
• Excessive menstrual blood loss

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Useful tool, but not specific for bleeding
disorders
Assessment of menstrual blood loss using a
pictorial chart. Higham JM et al. Brit. J. Obs.
Gynae. 97 734-739 (1990)
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Very rigorous with good sensitivity but far too
long to use in routine clinical work
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Philipp C et al. Am. J. Obs. Gyne. 204 209.e1-7
(2011)
Simple to use in daily practice. Sensitivity of
89 for haemostatic defects.
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How to promote awarenessamong women

• Be proactive and identify potential affected
  women from analysis of family trees of people
  already diagnosed with inherited bleeding
  disorders
• Commission articles in general press and leisure
  magazines
• Internet websites (online social groups)

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On line social groups

• Advantages
• Convenient anonymous
• Cost-effective, no time restrictions
• No geographical barriers (disability, pain)
• distance/ transport to face-to-face support
  groups
• No interference with family/work/commitments
• More time to reflect on content of disclosure
• Expressive writing paradigm Writing cure
  written disclosure of about stressful or
  traumatic experiences yields significant
  improvements in physical and psychological
  health.
• Support is exchanged among patients - not only
  sought but also provided to others
• Expert patients website visitors
• Disadvantage
• Requires access to a home computer with internet
  connection and associated skills
• Bypass doctors opinion
• Flaming aggressive /abusive/malicious
  messages
• False information
• Although can be corrected by referee or site
  moderator

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Conclusions

• Von Willebrand disease is by far the commonest
  congenital bleeding disorder
• Normal basic clotting tests results do not
  exclude the possibility of a underlying bleeding
  disorder
• Objective assessment tools may be used to
  identify subjects requesting more detailed
  investigation
• Assessment of platelet function is desirable
• Patient organisations already focussing on
  conditions other than haemophilia
• Awareness in the wider community can only be
  achieved by using media such as radio and
  leisure magazines.

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Acknowledgement I would like to express my
thanks to Ms Georgie Robinson, Services Manager
with the UK Haemophilia Society, for helpful
discussions and providing material for this talk.