Haemophilia (2014), 20, 238–243
DOI: 10.1111/hae.12335
ORIGINAL ARTICLE von Willebrand disease
An approach to outreach patients with von Willebrand disease in Egypt by targeting women with heavy menstrual bleeding and/or bleeding symptoms N . S H E R I F , * H . G O U B R A N , † A . H A S S A N , ‡ T . B U R N O U F § ¶ and M . E L - E K I A B Y ‡ *Gynecology and Obstetrics Department, Faculty of Medicine Kasr Al Aini University Hospitals- El Manyal, Cairo, Egypt; †Saskatoon Cancer Centre and College of Medicine, University of Saskatchewan, Saskatoon, Canada; ‡Shabrawishi Hospital Blood Bank, Shabrawishi Hospital, Giza, Egypt; §College of Oral Medicine, Institute of Biomedical Materials and Tissue Engineering, Taipei Medical University, Taipei, Taiwan; and ¶Human Protein Process Sciences, Lille, France
Summary. von Willebrand disease (VWD) is frequently ignored as a cause of menorrhagia. We investigated Egyptian women complaining of heavy menstrual bleeding (HMB) and/or other bleeding symptoms to detect potential VWD cases. Seventy-five female patients complaining of HMB and/or bleeding symptoms and 38 age-matched healthy female controls went through a family history questionnaire, a physical examination and were evaluated for bleeding score, pictorial blood assessment chart (PBAC), complete blood count, serum ferritin, blood group, prothrombin time, activated partial thromboplastin time, factor VIII (FVIII) activity, von Willebrand factor (VWF) ristocetin cofactor (RCo) activity, antigen (Ag), and RCo/Ag ratio. Sixty-eight of 75 patients presented with HMB, out of which 46 had no organic pathology and 7 presented other bleeding symptoms. Six patients were diagnosed with VWD, three with HMB, two with other bleeding symptoms and one with family history of
VWD. Two related VWD patients were diagnosed in the control group. There were significant differences in bleeding and PBAC scores, ferritin level, FVIII activity, VWF:RCo and VWF:Ag between VWD patients and controls. This study indicated a high prevalence of VWD among patients with HMB without organic pathology (6.5%) and demonstrated the sensitivity of diagnostic parameters of VWD patients in an outreach campaign. The inexpensive bleeding and PBAC scoring systems are valuable to exclude cases without objective bleeding symptoms. Raising gynaecologists awareness about hereditary bleeding disorders is important to ensure a proper diagnosis and possible referral of these patients. Management of these patients with comprehensive medical care services under a multidisciplinary team would be ideal.
Introduction
[1]. It is a common clinical problem, as approximately 30% of women complain of HMB some time during their childbearing period [2], of whom 10% seek medical advice and require some sort of treatment [3]. The clinical investigation usually focuses on organic pathologies affecting the uterus itself. However, in around 50% of cases, an organic cause cannot be identified [4]. Excessive bleeding accounts for twothirds of all hysterectomies and most endoscopic endometrial destructive surgeries. Still, in approximately 50% of HMB, no pathology is found even after a hysterectomy [4]. Thus, HMB is a critical, often poorly addressed, healthcare problem. However, in the past decade, studies revealed that many women with a normal gynaecological examination complaining of HMB
Heavy menstrual bleeding (HMB) is defined as a complaint of heavy cyclical menstrual bleeding occurring over several consecutive cycles. For an objective assessment, the total menstrual blood loss should be ≥80 mL per menstruation, or the bleeding should have an adverse effect on the daily lifestyle of the woman Correspondence: Thierry Burnouf, Institute of Biomedical Materials and Tissue Engineering, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan. Tel.: +886 2 2 2736 1661; fax: +886 2 2 2737 4113; e-mails: [email protected]; [email protected] Accepted after revision 26 October 2013 238
Keywords: bleeding, menorrhagia, PBAC, von Willebrand factor
© 2013 John Wiley & Sons Ltd
VON WILLEBRAND DISEASE AND MENORRHAGIA IN EGYPT
have an underlying haemostatic disorder [4]. The prevalence of von Willebrand disease (VWD) in such women was reported to be 5–20% of cases [4–6]. Therefore, VWD can be an important underlying cause of HMB. VWD is a congenital bleeding disorder that results from a quantitative deficiency or a qualitative defect in von Willebrand factor (VWF). VWD is considered the commonest among inherited bleeding disorders with autosomal dominant (types 1 and 2) and autosomal recessive patterns (types 3 and 2N). It is usually characterized by mild to moderate bleeding typically with easy bruising or bleeding from mucosal surfaces [7]. Types 1 and 3 VWD are due to variable quantitative deficiencies of VWF and factor VIII (FVIII), with a clinical presentation that is mild to moderate in the first case and severe in the second. Type 2 exhibits different forms of VWF functional abnormalities. As part of a World Federation of Haemophilia (WFH) approach to study different methodologies to identify patients with VWD in developing countries, several projects were set for validation. The projects are running in Egypt, Lebanon and Mexico in cooperation with national haemophilia organizations in these countries and their respective medical centers. Different approaches were followed in the three countries. The three countries mainly targeted increasing awareness about VWD among both health care professionals as well as patients populations and in particular women. They also aimed at improving the tools of diagnosis of VWD and particularly the laboratory diagnosis capacity. In Egypt, the aim was to design a study that included two main steps: (i) increase awareness among health care professionals about VWD and (ii) target two main groups for diagnosis of VWD (women with menorrhagia and relatives of patients with VWD). We then studied the different tools for diagnosis of menorrhagia, bleeding tendency, laboratory work for diagnosis of VWD as well as possible implications of the disease such as iron deficiency and iron deficiency anaemia and comparing them with a group of randomly selected age-matched healthy female controls. This study describes validation of our approach among women with menorrhagia and/or other bleeding symptoms.
Material and methods Patients The study was conducted at the Obstetrics and Gynecology (Ob/Gyn) Department of Cairo University Hospital, and at the haematology department of Shabrawishi Hospital (Giza, Egypt) from September 2011 to May 2012. The ethics committee of the Ob/ Gyn Department approved the study before its commencement. It included 75 women who complained of © 2013 John Wiley & Sons Ltd
239
HMB and/or other bleeding symptoms, and 38 agematched healthy females were used as a control group. The control group was recruited from healthy staff of Shabrawishi Blood transfusion Center as well as healthy female blood donors attending the blood bank. The demographic characteristics of patients and control group are shown in Table 1. Written informed consent was obtained from all women to be included in this study.
Questionnaire Patients from the Ob/Gyn department were first subjected to a thorough family and personal history. They then had a vaginal examination and transvaginal ultrasound. The International Society of Thrombosis and Haemostasis (ISTH) type 1 VWD bleeding score [8] and pictorial blood assessment chart (PBAC) [9] were used to objectively assess the presence of menorrhagia, its severity, and the presence and severity of other bleeding symptoms. A scoring system was used with both questionnaires. Patients with scores supporting the presence of HMB and/or a bleeding tendency were included in the study and underwent haematological workup. Patients of Shabrawishi Hospital had been already referred due to a family history of a bleeding disorder, so they were given a family pedigree questionnaire followed by a haematological workup. The bleeding questionnaire asked about and assessed the amount of bleeding in cases of epistaxis, cutaneous symptoms, bleeding from minor wounds, oral-cavity bleeding, tooth extraction, surgery, HMB, postpartum haemorrhage, gastrointestinal bleeding (GIB), haematoma, haemarthrosis, and central nervous system bleeding [8]. A bleeding score of >5 was used as an indication that the patient had a bleeding tendency. A semi-quantitative assessment of HMB was made using the PBAC. A score of >100 indicates a bleeding in excess of 80 mL and was diagnosed as menorrhagia/HMB [9]. Both questionnaires were administered by a trained female scientist who was able to gain the confidence of patients and thus could openly discuss Table 1. Demographic characteristics of patient and control groups. Cases Age (mean in years) Family history of HBD Negative Positive Blood group A B AB O Menarche (mean in years) Number of deliveries (mean) Number of abortions (mean) Number of pregnancies (mean)
Controls
36.49
31.2
82.9% 17.1%
100% 0%
15 (37.5%) 8 (20%) 5 (12.5%) 12 (30%) 13.5 2.45 0.85 3.28
11 (28.9%) 10 (26.3%) 7 (19.4%) 10 (26.3%) 13.18 1.1 0.2 1.32
HBD, hereditary bleeding disorders.
Haemophilia (2014), 20, 238--243
240
N. SHERIF et al.
menstrual problems with them as a way to overcome social barriers. Patients with PBAC scores suggesting menorrhagia and or bleeding score suggestive of bleeding tendency were referred for haematological assessment, while this assessment was done for the 38 healthy controls to set the normal range of different studied haematological parameters in our laboratory.
Data are presented as the mean standard deviation (SD), median, range, frequencies (number of cases) and percentages when appropriate. Numerical variables between the study groups were compared using the Mann–Whitney U-test for independent samples. To compare categorical data, a chi-squared (v2) test was performed. An exact test was used instead when the expected frequency was 5 and normal PBAC. One patient had normal bleeding and PBAC scores, but was a sister to a known patient with VWD type 3. According to FVIII, VWF:RCo and VWF:Ag levels and the VWF: Rco/Ag ratio, the eight diagnosed cases of VWD were stratified in the following VWD subtypes (Table 2): five with type 1 VWD (VWF:RCo 20–40%, VWF:Ag 22–50%, VWF RCo/Ag ratio >0.6); one with type 2 (reduced VWF:RCo, normal VWF:Ag and VWF:RCo/ Ag ratio
DOI: 10.1111/hae.12335
ORIGINAL ARTICLE von Willebrand disease
An approach to outreach patients with von Willebrand disease in Egypt by targeting women with heavy menstrual bleeding and/or bleeding symptoms N . S H E R I F , * H . G O U B R A N , † A . H A S S A N , ‡ T . B U R N O U F § ¶ and M . E L - E K I A B Y ‡ *Gynecology and Obstetrics Department, Faculty of Medicine Kasr Al Aini University Hospitals- El Manyal, Cairo, Egypt; †Saskatoon Cancer Centre and College of Medicine, University of Saskatchewan, Saskatoon, Canada; ‡Shabrawishi Hospital Blood Bank, Shabrawishi Hospital, Giza, Egypt; §College of Oral Medicine, Institute of Biomedical Materials and Tissue Engineering, Taipei Medical University, Taipei, Taiwan; and ¶Human Protein Process Sciences, Lille, France
Summary. von Willebrand disease (VWD) is frequently ignored as a cause of menorrhagia. We investigated Egyptian women complaining of heavy menstrual bleeding (HMB) and/or other bleeding symptoms to detect potential VWD cases. Seventy-five female patients complaining of HMB and/or bleeding symptoms and 38 age-matched healthy female controls went through a family history questionnaire, a physical examination and were evaluated for bleeding score, pictorial blood assessment chart (PBAC), complete blood count, serum ferritin, blood group, prothrombin time, activated partial thromboplastin time, factor VIII (FVIII) activity, von Willebrand factor (VWF) ristocetin cofactor (RCo) activity, antigen (Ag), and RCo/Ag ratio. Sixty-eight of 75 patients presented with HMB, out of which 46 had no organic pathology and 7 presented other bleeding symptoms. Six patients were diagnosed with VWD, three with HMB, two with other bleeding symptoms and one with family history of
VWD. Two related VWD patients were diagnosed in the control group. There were significant differences in bleeding and PBAC scores, ferritin level, FVIII activity, VWF:RCo and VWF:Ag between VWD patients and controls. This study indicated a high prevalence of VWD among patients with HMB without organic pathology (6.5%) and demonstrated the sensitivity of diagnostic parameters of VWD patients in an outreach campaign. The inexpensive bleeding and PBAC scoring systems are valuable to exclude cases without objective bleeding symptoms. Raising gynaecologists awareness about hereditary bleeding disorders is important to ensure a proper diagnosis and possible referral of these patients. Management of these patients with comprehensive medical care services under a multidisciplinary team would be ideal.
Introduction
[1]. It is a common clinical problem, as approximately 30% of women complain of HMB some time during their childbearing period [2], of whom 10% seek medical advice and require some sort of treatment [3]. The clinical investigation usually focuses on organic pathologies affecting the uterus itself. However, in around 50% of cases, an organic cause cannot be identified [4]. Excessive bleeding accounts for twothirds of all hysterectomies and most endoscopic endometrial destructive surgeries. Still, in approximately 50% of HMB, no pathology is found even after a hysterectomy [4]. Thus, HMB is a critical, often poorly addressed, healthcare problem. However, in the past decade, studies revealed that many women with a normal gynaecological examination complaining of HMB
Heavy menstrual bleeding (HMB) is defined as a complaint of heavy cyclical menstrual bleeding occurring over several consecutive cycles. For an objective assessment, the total menstrual blood loss should be ≥80 mL per menstruation, or the bleeding should have an adverse effect on the daily lifestyle of the woman Correspondence: Thierry Burnouf, Institute of Biomedical Materials and Tissue Engineering, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan. Tel.: +886 2 2 2736 1661; fax: +886 2 2 2737 4113; e-mails: [email protected]; [email protected] Accepted after revision 26 October 2013 238
Keywords: bleeding, menorrhagia, PBAC, von Willebrand factor
© 2013 John Wiley & Sons Ltd
VON WILLEBRAND DISEASE AND MENORRHAGIA IN EGYPT
have an underlying haemostatic disorder [4]. The prevalence of von Willebrand disease (VWD) in such women was reported to be 5–20% of cases [4–6]. Therefore, VWD can be an important underlying cause of HMB. VWD is a congenital bleeding disorder that results from a quantitative deficiency or a qualitative defect in von Willebrand factor (VWF). VWD is considered the commonest among inherited bleeding disorders with autosomal dominant (types 1 and 2) and autosomal recessive patterns (types 3 and 2N). It is usually characterized by mild to moderate bleeding typically with easy bruising or bleeding from mucosal surfaces [7]. Types 1 and 3 VWD are due to variable quantitative deficiencies of VWF and factor VIII (FVIII), with a clinical presentation that is mild to moderate in the first case and severe in the second. Type 2 exhibits different forms of VWF functional abnormalities. As part of a World Federation of Haemophilia (WFH) approach to study different methodologies to identify patients with VWD in developing countries, several projects were set for validation. The projects are running in Egypt, Lebanon and Mexico in cooperation with national haemophilia organizations in these countries and their respective medical centers. Different approaches were followed in the three countries. The three countries mainly targeted increasing awareness about VWD among both health care professionals as well as patients populations and in particular women. They also aimed at improving the tools of diagnosis of VWD and particularly the laboratory diagnosis capacity. In Egypt, the aim was to design a study that included two main steps: (i) increase awareness among health care professionals about VWD and (ii) target two main groups for diagnosis of VWD (women with menorrhagia and relatives of patients with VWD). We then studied the different tools for diagnosis of menorrhagia, bleeding tendency, laboratory work for diagnosis of VWD as well as possible implications of the disease such as iron deficiency and iron deficiency anaemia and comparing them with a group of randomly selected age-matched healthy female controls. This study describes validation of our approach among women with menorrhagia and/or other bleeding symptoms.
Material and methods Patients The study was conducted at the Obstetrics and Gynecology (Ob/Gyn) Department of Cairo University Hospital, and at the haematology department of Shabrawishi Hospital (Giza, Egypt) from September 2011 to May 2012. The ethics committee of the Ob/ Gyn Department approved the study before its commencement. It included 75 women who complained of © 2013 John Wiley & Sons Ltd
239
HMB and/or other bleeding symptoms, and 38 agematched healthy females were used as a control group. The control group was recruited from healthy staff of Shabrawishi Blood transfusion Center as well as healthy female blood donors attending the blood bank. The demographic characteristics of patients and control group are shown in Table 1. Written informed consent was obtained from all women to be included in this study.
Questionnaire Patients from the Ob/Gyn department were first subjected to a thorough family and personal history. They then had a vaginal examination and transvaginal ultrasound. The International Society of Thrombosis and Haemostasis (ISTH) type 1 VWD bleeding score [8] and pictorial blood assessment chart (PBAC) [9] were used to objectively assess the presence of menorrhagia, its severity, and the presence and severity of other bleeding symptoms. A scoring system was used with both questionnaires. Patients with scores supporting the presence of HMB and/or a bleeding tendency were included in the study and underwent haematological workup. Patients of Shabrawishi Hospital had been already referred due to a family history of a bleeding disorder, so they were given a family pedigree questionnaire followed by a haematological workup. The bleeding questionnaire asked about and assessed the amount of bleeding in cases of epistaxis, cutaneous symptoms, bleeding from minor wounds, oral-cavity bleeding, tooth extraction, surgery, HMB, postpartum haemorrhage, gastrointestinal bleeding (GIB), haematoma, haemarthrosis, and central nervous system bleeding [8]. A bleeding score of >5 was used as an indication that the patient had a bleeding tendency. A semi-quantitative assessment of HMB was made using the PBAC. A score of >100 indicates a bleeding in excess of 80 mL and was diagnosed as menorrhagia/HMB [9]. Both questionnaires were administered by a trained female scientist who was able to gain the confidence of patients and thus could openly discuss Table 1. Demographic characteristics of patient and control groups. Cases Age (mean in years) Family history of HBD Negative Positive Blood group A B AB O Menarche (mean in years) Number of deliveries (mean) Number of abortions (mean) Number of pregnancies (mean)
Controls
36.49
31.2
82.9% 17.1%
100% 0%
15 (37.5%) 8 (20%) 5 (12.5%) 12 (30%) 13.5 2.45 0.85 3.28
11 (28.9%) 10 (26.3%) 7 (19.4%) 10 (26.3%) 13.18 1.1 0.2 1.32
HBD, hereditary bleeding disorders.
Haemophilia (2014), 20, 238--243
240
N. SHERIF et al.
menstrual problems with them as a way to overcome social barriers. Patients with PBAC scores suggesting menorrhagia and or bleeding score suggestive of bleeding tendency were referred for haematological assessment, while this assessment was done for the 38 healthy controls to set the normal range of different studied haematological parameters in our laboratory.
Data are presented as the mean standard deviation (SD), median, range, frequencies (number of cases) and percentages when appropriate. Numerical variables between the study groups were compared using the Mann–Whitney U-test for independent samples. To compare categorical data, a chi-squared (v2) test was performed. An exact test was used instead when the expected frequency was 5 and normal PBAC. One patient had normal bleeding and PBAC scores, but was a sister to a known patient with VWD type 3. According to FVIII, VWF:RCo and VWF:Ag levels and the VWF: Rco/Ag ratio, the eight diagnosed cases of VWD were stratified in the following VWD subtypes (Table 2): five with type 1 VWD (VWF:RCo 20–40%, VWF:Ag 22–50%, VWF RCo/Ag ratio >0.6); one with type 2 (reduced VWF:RCo, normal VWF:Ag and VWF:RCo/ Ag ratio
