Dr. Paul Giangrande Oxford Haemophilia & Thrombosis Centre and Nuffield Department of Clinical Medicine University

1. Bleeding disorders in women Dr. Paul Giangrande Oxford Haemophilia & Thrombosis Centre and Nuffield Department of Clinical Medicine University of Oxford paul.giangrande@ndm.ox.ac.uk

2. 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?

3. Frequency of bleeding disorders in women with heavy menstrual bleeding:Kadir 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.”

4. 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

5. 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.

7. 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

8. 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

9. Rare bleeding disorders in the UK:UKHCDO 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)

10. Clinical manifestations of rare bleeding disorders:Mannucci PM Blood 104 1243-1252 (2004) = haemophilia = rare bleeding disorders

11. 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

12. 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

13. Normal range in our laboratory: 26-36 seconds, using Triniclot reagent

14. Normal range in our laboratory: 26-36 seconds, using Triniclot reagent

15. 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

16. Blood 69: 1691-1987 (1987)

17. 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

18. Von Willebrand’s disease (VWD): …..or would either “deficiency” or “disorder” be better?

19. 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)

20. Book published by Royal College of Obstetricians and Gynaecologists in UK: specifically aimed at trainees preparing for their specialist examinations

21. Importance of history taking: • Easy bruising • Nose bleeds (epistaxis) • Heavy menstrual periods (menorrhagia) • Bleeding after: • operations • dental extractions • giving birth • Family history

22. 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.”

23. Objective criteria include: • Anaemia (low haemoglobin level) • Need for blood transfusion after surgery • Prolonged bleeding from trivial wounds lasting > 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

24. 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)

25. Very rigorous with good sensitivity but far too long to use in routine clinical work

27. 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.

28. 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)

35. 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

36. 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.

37. 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.