Pediatric Hematology and Oncology, 31:467–474, 2014 C Informa Healthcare USA, Inc. Copyright ISSN: 0888-0018 print / 1521-0669 online DOI: 10.3109/08880018.2014.886316
ORIGINAL ARTICLE Hemostastis and Thrombosis
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The Frequency of Menorrhagia and Bleeding Disorders in University Students Turkiz Gursel,1 Aydan Biri,2 Zuhre Kaya,1 Selda Sivaslıoglu,1 and Meryem Albayrak1 1
Department of Pediatrics, Medical School of Gazi University, Ankara, Turkey; 2 Department of Obstetrics and Gynecology, Medical School of Gazi University, Ankara, Turkey
Study Objective: Menorrhagia is an important health problem in women of reproductive age. The aims of this study were to assess the prevalence of menorrhagia and hemostatic abnormalities associated with menorrhagia in university students. Methods: The pictorial blood assessment chart (PBAC) was used to identify students with menorrhagia. Those with a PBAC score > 100 were examined by pelvic ultrasound and laboratory tests including complete blood count, levels of clotting factors, von Willebrand factor antigen, and ristocetin cofactor activity and Platelet Function Analyser-100 (PFA-100). Platelet aggregation was studied in students with prolonged PFA-100 closure time. Results: Menorrhagia was identified in 82 (21.8%) of 376 students. Six of 82 students who had pelvic pathologies were excluded. Eleven (14.5%) of the remaining 76 students were found to have bleeding disorders, including von Willebrand disease in five (6.5%), platelet function disorder in four (5.2%), and clotting factor deficiencies in two (2.6%). Conclusions: Menorrhagia is a common but mostly unrecognized and untreated problem among university students. Underlying bleeding disorders are not rare and require comprehensive hemostatic evaluation for identification. Keywords bleeding disorders, menorrhagia, university students
INTRODUCTION Menorrhagia, defined as more than 80 mL blood loss per cycle is a common problem causing significant morbidity and impairment of life quality in women of reproductive age [1–3]. It may be caused by pelvic or systemic pathologies, but the etiology remains unexplained in approximately 50% of women [1]. Recent investigations indicate that bleeding disorders, particularly von Willebrand disease (VWD) and platelet function disorders (PFD), are common in unexplained menorrhagia. The overall prevalence of bleeding disorders range from 5% to 20%, depending on the study population and methodology [4–10]. In a systematic review of 11 studies, the overall prevalence of VWD is 13% ranging from 5% to 26% [11]. Platelet function disorders have been identified in 1%–47% and clotting factor deficiencies in 1%–8% of women with unexplained menorrhagia [12]. In adolescent girls, menorrhagia primarily results from anovulatory cycles due to immaturity of hypothalamic–pituitary axis. Bleeding disorders are the second most Received 1 December 2013; accepted 19 January 2014. Address correspondence to Dr. Turkiz ¨ Gursel, ¨ Department of Pediatrics, Gazi University Medical School, 06500 Bes¸evler, Ankara, Turkey. E-mail: [email protected]
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T. Gursel et al.
common cause of menorrhagia in this age group [13–19]. In a recent systematic review of eight published studies by Ahuja et al., the prevalence of VWD, PFD, and clotting factor deficiencies in adolescents girls with menorrhagia range between 5%–36%, 2%–44%, and 8%–9%, respectively [20]. These studies mostly involve retrospective chart reviews of inpatients with acute menorrhagia or referrals to hemophilia treatment centers. Data on the frequency and etiology of menorrhagia in university students are scarce, despite gynecological complaints are common in this age group [21–23]. The pictorial blood-loss assessment chart (PBAC) is a practical and objective method that has a high sensitivity and specificity when >100 score is accepted to define menorrhagia [24, 25]. The aims of this study were to assess the prevalence of menorrhagia and hemostatic abnormalities associated with menorrhagia in university students. METHODS Subjects Students living in a large university residence for female undergraduates were invited to participate in this study by a letter explaining the purpose of the study, along with an informed consent form and a PBAC with written instructions. Of the 650 students who received the PBAC, 376 returned it being completed satisfactorily and consented to participate in the study. Menstrual blood loss was estimated by PBAC using scoring system of Higham et al. [26]. Menorrhagia was defined as a PBAC score of >100, which is considered as being equivalent to >80 mL blood loss in a cycle [3]. Students with menorrhagia were invited to our institution for further evaluation with detailed personal and family history of bleedings and pelvic examination by ultrasound and laboratory investigations. Bleeding history included the following questions: (1) easy bruising, (2) epistaxis lasting >10 minutes or requiring intervention, (3) gum bleeding after tooth brushing, (4) bleeding after tooth extraction, surgery or an injury, (5) menses > 7 days, and (6) family history of bleeding symptoms. Pelvic ultrasonography was performed by an experienced gynecologist. Students with pelvic anatomic pathologies, known bleeding disorders, and oral contraceptive use were excluded. The study was approved by the Institutional Review Board of the Medical School of Gazi University. Laboratory Investigations Complete blood count was determined by a Beckman/Coulter, Model LH 750 Hematology Analyser. Venous blood for coagulation tests was collected into Vacutainer tubes (Beckton Dickinson, Plymouth, UK) containing 0.105 M sodium citrate, plasma was separated and prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen level and PFA-100 analyses were performed within 3 hours of blood collection. Aliquots of plasma samples were kept at −80◦ C until assayed for VWF:Ag, VWF:RCo, and clotting factors II, V, VII, VIII, IX, X and XI. Coagulation assays were performed at a Sysmex CA 7000 Coagulation analyser using kits and calibrators from Siemens Healthcare Diagnostics (Marburg, Germany). Diagnosis of VWD based on a VWF:Ag and or VWF:RCo level of less than 45 IU/dL for persons with blood type O and < 50 IU/dL for those with non-O blood types according to our laboratory’s reference values. PFA-100 Analyser closure time was determined using both PFA-100 Collagen/EPI (CEP˙I) and PFA-100 collagen/ADP (CADP) cartridges (Siemens Healthcare Diagnostics, Marburg, Germany). Platelet aggregation was measured in plateletrich plasma using final concentrations of 2.5 mM/mL ADP, 2 mg/mL collagen, and 1.2 mg/ml ristocetin in a Chrono-Log Lumi-Aggregometer (Hovertown, PA). The results of platelet aggregation were expressed as percent aggregation, i.e., change in light Pediatric Hematology and Oncology
Menorrhagia and Bleeding Disorders in Students
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transmission and values below the 2SD lower limit of normal range were defined as decreased aggregation response. Blood collection for aggregation studies was deferred for 10 days in students who had ingested drugs affecting platelet functions, particularly nonsteroidal anti-inflammatory agents within the previous week. Statistical Analysis The statistical analysis was performed using a software package SPSS 15.0 version. Demographic data were defined by descriptive statistics. Categorical variables were compared with χ 2 -test. Age and PBAC scores were compared with Mann–Whitney U-test. The levels of significance are indicated by P-values 0.6) consistent with type-1 VWD in all of these five students. PFA-100 closure time was prolonged with CEPI and /or CADP in 9 (11.8%) of the 76 students with menorrhagia. Four of them (5.2% of study population) had decreased platelet aggregation in response to ADP and/or collagen and normal VWF:Ag and VWF:RCo levels and were defined as having PFD. Of the remaining five students with prolonged PFA-100 closure time, four had VWD, while one had no other abnormal hemostatic test. Two (2.6%) of the 76 students had clotting factor deficiencies, one with mild (43 IU/dL) factor XI (FXI) deficiency and one with mild (45 IU/dL) F VII deficiency. The levels of other clotting factors were normal in all students, except for cases with VWD. Platelet count and PT/aPTT tests were normal in all of the 76 students with menorrhagia. Anemia (hemoglobin level < 12.0 g/dL) was detected in five (45.5%) of the 11 TABLE 1
Clinical and Laboratory Characteristics of the Study Group With bleeding disorders
Number (%) Age (year) (mean ±SD) ∗ PBAC score (mean ±SD) Easy bruisability Epistaxis Gum bleeding Post traumatic bleeding ∗ Menses > 7 days Family history of bleeding Hb < 12g/dL
11 (14.5%) 19.7 ± 4.8 271.7 ± 72.1 6 (26.0%) 3 (13.0%) 5 (21.8%) 2 (8.7%) 5 (21.8%) 2 (8.7%) 5 (45.5%)
PBAC: pictorial blood-loss assessment chart. ∗ P < .05. C Informa Healthcare USA, Inc. Copyright
Without bleeding disorders 65 (85.5%) 21.2 ± 5.4 263 ± 180.4 31 (36.0%) 17 (19.7%) 11 (12.7%) 9 (10.4%) 5 (5.8%) 13 (15.4%) 10 (15.3%)
vWD vWD vWD vWD vWD FXI deficiency FVII deficiency PFD PFD PFD PFD
Diagnosis
19 23 20 23 17 15 19 18 22 21 17
Age (year)
214 375 249 155 235 400 285 237 227 306 310
PBAC (scor) 13.5 14.0 14.0 12.7 13.0 14.5 15.4 11.3 13.2 13.0 13.2
PT (s) 27.3 29.6 39.0 27.5 25.0 32.4 30.1 23.5 30.5 28.0 32.2
APTT (s) 48 37 27 50 50 52 84 89 130 140 81
vWfAg (%) 36 30 17 33 48 61 83 66 133 120 86
vWf: Rco(%) 56 39 36 52 43 101 67 86 78 106 110
FVIII (%) 118 78 92 66 64 77 45 77 110 63 88
FVII (%)
Clinical and Laboratory Characteristics of University Students with Bleeding Disorders
87 130 96 83 60 43 83 93 111 55 55
FXI (%) 132 92 132 117 71 108 58 119 122 103 139
CT-CADP (s) 162 158 186 207 134 156 109 163 237 196 200
CT-EP˙I (s)
PFA-100
64 72 58 66 50 — — 43 20 38 39
AggrADP (%)
52 56 68 54 61 — — 45 29 40 8
Aggr (%)
58 50 40 78 60 — — 48 41 56 66
Rist. (%)
Platelet aggregation
PFA: platelet function analyser; vWd: von Willebrand disease; PFD: platelet function disorder; normal range of blood parameters: PT (prothrombin time) : 10–12 s, aPTT(activated partial thromboplastin time): 22–36 s, CT-ADP: 65–125 s, CT epinephrin: 85–157 s, vWfAg: 50%–200%, and other factors level: 50%–200%.
1 2 3 4 5 6 7 8 9 10 11
Patients (P)
TABLE 2
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B O O A AB O O 0 A O A
Blood Type
Menorrhagia and Bleeding Disorders in Students
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students with bleeding disorders and in 10 (15.4%) of the remaining 65 students with normal hemostatic test results. The overall prevalence of anemia was 19.7% (15/76) in students with menorrhagia. None of them had received treatment for anemia. Only nine (11.8%) of the 76 students were aware that their menses were heavy, but only five (6.5%) had sought medical care for this reason. The mean level of PBAC score and the patient number with menstrual bleeding above 7 days were significantly higher in patients with bleeding disorder than those of without bleeding disorder (P < .05) (Table 1). DISCUSSION Menorrhagia has been reported to affect approximately 20% of menstruating women [1, 27]. Its prevalence in adolescent girls under age 18 years range between 8.6% and 37.5% in questionnaire-based population surveys from different countries [28–30]. However, few data are available on the frequency of menorrhagia in young women beyond the age of 18 years in whom menses are no longer anovulatory. In a crosssectional population survey, the prevalence of self-reported menorrhagia is 46.7%, with a cumulative incidence of 25.1% among 18–24 years of age British women [31]. In the present study, we have found the prevalence of menorrhagia to be 21.8% in university students aged between 17 and 25 years. It should be noted that frequency of self-reported menorrhagia tends to be higher than that assessed by objective methods such as PBAC or acide hematin [32]. Of note, only a small proportion (11.8%) of the students in our study was aware that their menses were heavy and even fewer (6.5%) had sought medical care before. These data demonstrate that menorrhagia is a common but largely unrecognized and untreated problem among young women in Turkey. In a previous report from this country, only 0.4% of female university students sought medical care for their menstrual problems [33]. There is wide variability in the frequency of underlying bleeding disorders in women with menorrhagia, due to the differences in the definitions of menorrhagia, selection of study population (outpatients vs. inpatients or referrals to hemophilia centers or hematology clinics), and diagnostic tests and criteria [11, 12, 20]. Our study population is a representative of the young women with menorrhagia in general population. They were screened by a comprehensive test panel, able to detect VWD, clotting factor deficiencies, and moderate to severe platelet function defects. The overall prevalence of bleeding disorders in our study group is (14.5%) comparable with several studies performed in fertile age women with menorrhagia. The most common bleeding disorder in our study group is VWD occurring in 6.5%, followed by platelet function disorders in 5.2% and clotting factor deficiencies in 2.6%. In a systemic review by Shankar et al., the prevalence of VWD range between 6.0% and 20.9% in women with menorrhagia [11]. However, the frequency of VWD were 6.0% and 8.0% in two previous studies which used PBAC score >100 for diagnosis of menorrhagia and measured the levels of VWF:Ag, VWF:RCo, and FVIII as part of the initial screening [7, 34]. Despite menorrhagia is the most common symptom of PFD, few studies examined platelet functions in women with menorrhagia. Several investigators used PFA100 as a screening test, since studying platelet aggregation and release reaction are time consuming, expensive, and often not readily available for routine clinical practice. The frequency of PFD range between 3.2% and 7.0% in these studies [5, 6, 8, 35]. It was 5.2% in our study group. Although studies performing comprehensive platelet function analysis as part of the initial evaluation have shown decreased platelet aggregation and/or release reaction in 29.9%, 47.3%, and 56.0% of women with menorrhagia, clinical relevance of these subtle platelet abnormalities has not been substantiated yet [7, 10, 34]. C Informa Healthcare USA, Inc. Copyright
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Clotting factor deficiency is the least common of bleeding disorders seen in women with menorrhagia. Two students in our study had a clotting factor deficiency, one with mild FXI deficiency and the other with mild FVII deficiency. FXI deficiency is the most frequent clotting factor deficiency, occurring in 1.0%–11.9% in women with menorrhagia [6, 8, 10, 34]. It can cause significant uterine bleeding during miscarriage or childbirth, even in women with mild deficiency [36]. Because aPTT test is usually normal in mild FXI deficiency, measurement of FXI level should be considered during investigation of bleeding disorders in menorrhagia. One limitation of the present study is the lack of a second hemostatic testing to confirm the diagnosis of bleeding disorders in students with menorrhagia. This is an important issue, particularly for cases presenting with only one bleeding symptom such as menorrhagia or epistaxis which are common in general population. In the present study, frequency of bleeding symptoms were not significantly different between students with and without an underlying bleeding disorder, except for menses >7 days which was more frequent in those with bleeding disorders (Table 1). Evaluating bleeding symptoms by a standardized bleeding questionnaire could be useful to predict the presence of a bleeding disorder, before performing extensive hemostatic investigations, which are expensive and requires technical expertise are to be performed [37]. Menorrhagia is a public health concern for several reasons: first, it is the most common cause of anemia in menstruating women. Our results confirm that anemia is more common in women with menorrhagia (19.7%) as compared to that (9.7%) found in general population in Turkey [38]. More importantly, it was twice common in students with menorrhagia who had an underlying bleeding disorder (36.1%) than those (15.2%) without it. Anemia went unrecognized and untreated, as for menorrhagia, highlighting the need for screening programmes aiming identification of menorrhagia in young population. Second, menorrhagia adversely affects quality of life, school attendance, and academic performance in students [2]. Finally, early recognition of underlying bleeding disorders in young women can prevent future risks of excessive bleedings during childbirth, abortion, or diagnostic /therapeutic curettage.
CONCLUSIONS Our study shows that menorrhagia is a common but mostly unrecognized and untreated problem among university students. Underlying bleeding disorders are not rare and often mild in degree requiring comprehensive hemostatic evaluation for identification. Limited access to health care providers indicate the need for public education and screening programmes to prevent health problems related with menorrhagia in young female population.
Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This study was partly supported by a grant (No: BAP 121/2002) from Scientific Research Fund of Gazi University, Ankara, Turkey.
REFERENCES [1] Oehler MK, Rees MC. Menorrhagia: an update. Acta Obstet Gynecol Scand. 2003;82:405–422. [2] Kadir RA, Edlund M, Von Mackensen S. The impact of menstrual disorders on quality of life in women with inherited bleeding disorders. Haemophilia. 2010;16:832–839. Pediatric Hematology and Oncology
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Menorrhagia and Bleeding Disorders in Students [3] Reid PC, Coker A, Coltart R. Assesment of menstrual blood loss using a pictorial chart: a validation study. BJOG. 2000;107:320–322. [4] Edlund M, Blomb¨ack M, von Schoultz B, Andersson O. On the value of menorrhagia as a predictor for coagulation disorders. Am J Hematol. 1996;53:234–238. [5] Kadir RA, Economides DL, Sabin CA, et al. Frequency of inherited bleeding disorders in women with menorrhagia. Lancet. 1998;351:485–489. [6] Dilley A, Drews C, Miller C, et al. von Willebrand disease and other inherited bleeding disorders in women with diagnosed menorrhagia. Obstet Gynecol. 2001;97:630–636. [7] Philipp CS, Dilley A, Miller CH, et al. Platelet functional defects in women with unexplained menorrhagia. J Thromb Haemost. 2003;1:477–484. [8] Veyradier A, Gervaise A, Boyer-Neumann C, et al. Screening for bleeding disorders in women with menorhaggia using a platelet function analyser. J Thromb Haemost. 2006;4:483–485. [9] Acharya S, Barraclough J, Ibrahim M, et al. The usefulness of the platelet function analyser (PFA100) in screening for underlying bleeding disorders in women with menorrhagia. J Obstet Gynaecol. 2008;28:310–314. [10] Akay OM, Mutlu F, Gulbas Z. Platelet dysfunction and other hemostatic disorders in women with menorrhagia: the utility of whole blood lumi-aggregometer. Intern Emerg Med. 2008;3:191–193. [11] Shankar M, Lee CA, Sabin CA, et al. von Willebrand disease in women with menorrhagia: a systematic review. BJOG. 2004;111:734–740. [12] James AH, Ragni MV, Picozzi VJ. Bleeding disorders in premenopausal women: (another) public health crisis for hematology? Hematology Am Soc Hematol Educ Program. 2006:474–485. [13] Claessens EA, Cowell CA. Acute adolescent menorrhagia. Am J Obstet Gynecol. 1981;139:277–280. [14] Smith YR, Quint EH, Hertzberg RB. Menorrhagia in adolescents requiring hospitalization. J Pediatr Adolesc Gynecol. 1998;11:13–15. [15] Bevan JA, Maloney KW, Hillery CA, et al. Bleeding disorders: a common cause of menorrhagia in adolescents. J Pediatr. 2001;138:856–361. [16] Oral E, Ca˘gdas¸ A, Gezer A, et al. Hematological abnormalities in adolescent menorrhagia. Arch Gynecol Obstet. 2002;266:72–74. [17] Jayasinghe Y, Moore P, Donath S, et al. Bleeding disorders in teenagers presenting with menorrhagia. Aust N Z J Obstet Gynaecol. 2005;45:439–443. [18] Mikhail S, Varadarajan R, Kouides P. The prevalence of disorders of haemostasis in adolescents with menorrhagia referred to a haemophilia treatment centre. Haemophilia. 2007;13:627–632. [19] Kulp L, Mwangi CN, Loveless M. Screening for coagulation disorders in adolescents with abnormal uterine bleeding. J Pediatr Adolesc Gynecol. 2008;21:27–30. [20] Ahuja SP, Hertweck SP. Overview of bleeding disorders in adolescent females with menorrhagia. J Pediatr Adolesc Gynecol. 2010;23:S15–S21. [21] Adams Hillard PJ, Deitch HR. Menstrual disorders in the college age female. Pediatr Clin North Am. 2005;52:179–197. [22] Cakir M, Mungan I, Karakas T, et al. Menstrual pattern and common menstrual disorders among university students in Turkey. Pediatr Int. 2007;49:938–942. [23] Kılıc¸ SC ¸ , Sarper N, Zengin E, Gelen SA. Screening bleeding disorders in adolescents and young women with menorrhagia. Turk J Hematol 2013;30:168. [24] Wyatt KM, Dimmock PW, Walker TJ, O’Brien PM. Determination of total menstrual blood loss. Fertil Steril. 2001;76:125–131. [25] Zakherah MS, Sayed GH, El-Nashar SA, Shaaban MM. Pictorial blood loss assessment chart in the evaluation of heavy menstrual bleeding: diagnostic accuracy compared to alkaline hematin. Gynecol Obstet Invest. 2011;71:281–284. [26] Higham JM, O’Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol. 1990;97:734–739. [27] Vessey MP, Villard Mackintosh L, McPherson K, et al. The epidemiology of hysterectomy: findings in a large cohort study. Br J Obstet Gynaecol. 1992;99:402–407. [28] Houston AM, Abraham A, Huang Z, D’Angelo LJ. Knowledge, attitudes, and consequences of menstrual health in urban adolescent females. J Pediatr Adolesc Gynecol. 2006;19:271–275. [29] Revel-Vilk S, Paltiel O, Lipschuetz M, et al. Underdiagnosed menorrhagia in adolescents is associated with underdiagnosed anemia. J Pediatr. 2012;160:468–472. [30] Friberg B, Orn¨o AK, Lindgren A, Lethagen S. Bleeding disorders among young women: a populationbased prevalence study. Acta Obstet Gynecol Scand.2006; 85: 200-206. [31] Shapley M, Jordan K, Croft PR. An epidemiological survey of symptoms of menstrual loss in the community. Br J Gen Pract. 2004;54:359–363. [32] Warner PE, Critchley HO, Lumsden MA, et al. Menorrhagia I: measured blood loss, clinical features, and outcome in women with heavy periods: a survey with follow-up data. Am J Obstet Gynecol. 2004;190:1216–1223. C Informa Healthcare USA, Inc. Copyright
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[33] Vicdan K, Kukner ¨ S, Dabakolu T, et al. Demographic and epidemiologic features of female adolescents in Turkey. J Adolesc Health. 1996;18:54–58. [34] Miller CH, Philipp CS, Stein SF, et al. The spectrum of haemostatic characteristics of women with unexplained menorrhagia. Haemophilia. 2011;17:e223–229. [35] Philipp CS, Miller CH, Faiz A, et al. Screening women with menorrhagia for underlying bleeding disorders: the utility of the platelet function analyser and bleeding time. Haemophilia. 2005;11:497–503. [36] Bolton-Maggs PH. Factor XI deficiency-resolving the enigma? Hematol Am Soc Hematol Educ Program. 2009:97–105. [37] Philipp CS, Faiz A, Dowling NF, et al. Development of a screening tool for identifying women with menorrhagia for hemostatic evaluation. Am J Obstet Gynecol. 2008;198:163.e1–163.e8. [38] Kara B, C ¸ al S, Aydogan A, Sarper N. The prevalence of anemia in adolescents: a study from Turkey. J Pediatr Hematol Oncol. 2006;28:316–321.
Pediatric Hematology and Oncology
ORIGINAL ARTICLE Hemostastis and Thrombosis
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The Frequency of Menorrhagia and Bleeding Disorders in University Students Turkiz Gursel,1 Aydan Biri,2 Zuhre Kaya,1 Selda Sivaslıoglu,1 and Meryem Albayrak1 1
Department of Pediatrics, Medical School of Gazi University, Ankara, Turkey; 2 Department of Obstetrics and Gynecology, Medical School of Gazi University, Ankara, Turkey
Study Objective: Menorrhagia is an important health problem in women of reproductive age. The aims of this study were to assess the prevalence of menorrhagia and hemostatic abnormalities associated with menorrhagia in university students. Methods: The pictorial blood assessment chart (PBAC) was used to identify students with menorrhagia. Those with a PBAC score > 100 were examined by pelvic ultrasound and laboratory tests including complete blood count, levels of clotting factors, von Willebrand factor antigen, and ristocetin cofactor activity and Platelet Function Analyser-100 (PFA-100). Platelet aggregation was studied in students with prolonged PFA-100 closure time. Results: Menorrhagia was identified in 82 (21.8%) of 376 students. Six of 82 students who had pelvic pathologies were excluded. Eleven (14.5%) of the remaining 76 students were found to have bleeding disorders, including von Willebrand disease in five (6.5%), platelet function disorder in four (5.2%), and clotting factor deficiencies in two (2.6%). Conclusions: Menorrhagia is a common but mostly unrecognized and untreated problem among university students. Underlying bleeding disorders are not rare and require comprehensive hemostatic evaluation for identification. Keywords bleeding disorders, menorrhagia, university students
INTRODUCTION Menorrhagia, defined as more than 80 mL blood loss per cycle is a common problem causing significant morbidity and impairment of life quality in women of reproductive age [1–3]. It may be caused by pelvic or systemic pathologies, but the etiology remains unexplained in approximately 50% of women [1]. Recent investigations indicate that bleeding disorders, particularly von Willebrand disease (VWD) and platelet function disorders (PFD), are common in unexplained menorrhagia. The overall prevalence of bleeding disorders range from 5% to 20%, depending on the study population and methodology [4–10]. In a systematic review of 11 studies, the overall prevalence of VWD is 13% ranging from 5% to 26% [11]. Platelet function disorders have been identified in 1%–47% and clotting factor deficiencies in 1%–8% of women with unexplained menorrhagia [12]. In adolescent girls, menorrhagia primarily results from anovulatory cycles due to immaturity of hypothalamic–pituitary axis. Bleeding disorders are the second most Received 1 December 2013; accepted 19 January 2014. Address correspondence to Dr. Turkiz ¨ Gursel, ¨ Department of Pediatrics, Gazi University Medical School, 06500 Bes¸evler, Ankara, Turkey. E-mail: [email protected]
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T. Gursel et al.
common cause of menorrhagia in this age group [13–19]. In a recent systematic review of eight published studies by Ahuja et al., the prevalence of VWD, PFD, and clotting factor deficiencies in adolescents girls with menorrhagia range between 5%–36%, 2%–44%, and 8%–9%, respectively [20]. These studies mostly involve retrospective chart reviews of inpatients with acute menorrhagia or referrals to hemophilia treatment centers. Data on the frequency and etiology of menorrhagia in university students are scarce, despite gynecological complaints are common in this age group [21–23]. The pictorial blood-loss assessment chart (PBAC) is a practical and objective method that has a high sensitivity and specificity when >100 score is accepted to define menorrhagia [24, 25]. The aims of this study were to assess the prevalence of menorrhagia and hemostatic abnormalities associated with menorrhagia in university students. METHODS Subjects Students living in a large university residence for female undergraduates were invited to participate in this study by a letter explaining the purpose of the study, along with an informed consent form and a PBAC with written instructions. Of the 650 students who received the PBAC, 376 returned it being completed satisfactorily and consented to participate in the study. Menstrual blood loss was estimated by PBAC using scoring system of Higham et al. [26]. Menorrhagia was defined as a PBAC score of >100, which is considered as being equivalent to >80 mL blood loss in a cycle [3]. Students with menorrhagia were invited to our institution for further evaluation with detailed personal and family history of bleedings and pelvic examination by ultrasound and laboratory investigations. Bleeding history included the following questions: (1) easy bruising, (2) epistaxis lasting >10 minutes or requiring intervention, (3) gum bleeding after tooth brushing, (4) bleeding after tooth extraction, surgery or an injury, (5) menses > 7 days, and (6) family history of bleeding symptoms. Pelvic ultrasonography was performed by an experienced gynecologist. Students with pelvic anatomic pathologies, known bleeding disorders, and oral contraceptive use were excluded. The study was approved by the Institutional Review Board of the Medical School of Gazi University. Laboratory Investigations Complete blood count was determined by a Beckman/Coulter, Model LH 750 Hematology Analyser. Venous blood for coagulation tests was collected into Vacutainer tubes (Beckton Dickinson, Plymouth, UK) containing 0.105 M sodium citrate, plasma was separated and prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen level and PFA-100 analyses were performed within 3 hours of blood collection. Aliquots of plasma samples were kept at −80◦ C until assayed for VWF:Ag, VWF:RCo, and clotting factors II, V, VII, VIII, IX, X and XI. Coagulation assays were performed at a Sysmex CA 7000 Coagulation analyser using kits and calibrators from Siemens Healthcare Diagnostics (Marburg, Germany). Diagnosis of VWD based on a VWF:Ag and or VWF:RCo level of less than 45 IU/dL for persons with blood type O and < 50 IU/dL for those with non-O blood types according to our laboratory’s reference values. PFA-100 Analyser closure time was determined using both PFA-100 Collagen/EPI (CEP˙I) and PFA-100 collagen/ADP (CADP) cartridges (Siemens Healthcare Diagnostics, Marburg, Germany). Platelet aggregation was measured in plateletrich plasma using final concentrations of 2.5 mM/mL ADP, 2 mg/mL collagen, and 1.2 mg/ml ristocetin in a Chrono-Log Lumi-Aggregometer (Hovertown, PA). The results of platelet aggregation were expressed as percent aggregation, i.e., change in light Pediatric Hematology and Oncology
Menorrhagia and Bleeding Disorders in Students
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transmission and values below the 2SD lower limit of normal range were defined as decreased aggregation response. Blood collection for aggregation studies was deferred for 10 days in students who had ingested drugs affecting platelet functions, particularly nonsteroidal anti-inflammatory agents within the previous week. Statistical Analysis The statistical analysis was performed using a software package SPSS 15.0 version. Demographic data were defined by descriptive statistics. Categorical variables were compared with χ 2 -test. Age and PBAC scores were compared with Mann–Whitney U-test. The levels of significance are indicated by P-values 0.6) consistent with type-1 VWD in all of these five students. PFA-100 closure time was prolonged with CEPI and /or CADP in 9 (11.8%) of the 76 students with menorrhagia. Four of them (5.2% of study population) had decreased platelet aggregation in response to ADP and/or collagen and normal VWF:Ag and VWF:RCo levels and were defined as having PFD. Of the remaining five students with prolonged PFA-100 closure time, four had VWD, while one had no other abnormal hemostatic test. Two (2.6%) of the 76 students had clotting factor deficiencies, one with mild (43 IU/dL) factor XI (FXI) deficiency and one with mild (45 IU/dL) F VII deficiency. The levels of other clotting factors were normal in all students, except for cases with VWD. Platelet count and PT/aPTT tests were normal in all of the 76 students with menorrhagia. Anemia (hemoglobin level < 12.0 g/dL) was detected in five (45.5%) of the 11 TABLE 1
Clinical and Laboratory Characteristics of the Study Group With bleeding disorders
Number (%) Age (year) (mean ±SD) ∗ PBAC score (mean ±SD) Easy bruisability Epistaxis Gum bleeding Post traumatic bleeding ∗ Menses > 7 days Family history of bleeding Hb < 12g/dL
11 (14.5%) 19.7 ± 4.8 271.7 ± 72.1 6 (26.0%) 3 (13.0%) 5 (21.8%) 2 (8.7%) 5 (21.8%) 2 (8.7%) 5 (45.5%)
PBAC: pictorial blood-loss assessment chart. ∗ P < .05. C Informa Healthcare USA, Inc. Copyright
Without bleeding disorders 65 (85.5%) 21.2 ± 5.4 263 ± 180.4 31 (36.0%) 17 (19.7%) 11 (12.7%) 9 (10.4%) 5 (5.8%) 13 (15.4%) 10 (15.3%)
vWD vWD vWD vWD vWD FXI deficiency FVII deficiency PFD PFD PFD PFD
Diagnosis
19 23 20 23 17 15 19 18 22 21 17
Age (year)
214 375 249 155 235 400 285 237 227 306 310
PBAC (scor) 13.5 14.0 14.0 12.7 13.0 14.5 15.4 11.3 13.2 13.0 13.2
PT (s) 27.3 29.6 39.0 27.5 25.0 32.4 30.1 23.5 30.5 28.0 32.2
APTT (s) 48 37 27 50 50 52 84 89 130 140 81
vWfAg (%) 36 30 17 33 48 61 83 66 133 120 86
vWf: Rco(%) 56 39 36 52 43 101 67 86 78 106 110
FVIII (%) 118 78 92 66 64 77 45 77 110 63 88
FVII (%)
Clinical and Laboratory Characteristics of University Students with Bleeding Disorders
87 130 96 83 60 43 83 93 111 55 55
FXI (%) 132 92 132 117 71 108 58 119 122 103 139
CT-CADP (s) 162 158 186 207 134 156 109 163 237 196 200
CT-EP˙I (s)
PFA-100
64 72 58 66 50 — — 43 20 38 39
AggrADP (%)
52 56 68 54 61 — — 45 29 40 8
Aggr (%)
58 50 40 78 60 — — 48 41 56 66
Rist. (%)
Platelet aggregation
PFA: platelet function analyser; vWd: von Willebrand disease; PFD: platelet function disorder; normal range of blood parameters: PT (prothrombin time) : 10–12 s, aPTT(activated partial thromboplastin time): 22–36 s, CT-ADP: 65–125 s, CT epinephrin: 85–157 s, vWfAg: 50%–200%, and other factors level: 50%–200%.
1 2 3 4 5 6 7 8 9 10 11
Patients (P)
TABLE 2
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B O O A AB O O 0 A O A
Blood Type
Menorrhagia and Bleeding Disorders in Students
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students with bleeding disorders and in 10 (15.4%) of the remaining 65 students with normal hemostatic test results. The overall prevalence of anemia was 19.7% (15/76) in students with menorrhagia. None of them had received treatment for anemia. Only nine (11.8%) of the 76 students were aware that their menses were heavy, but only five (6.5%) had sought medical care for this reason. The mean level of PBAC score and the patient number with menstrual bleeding above 7 days were significantly higher in patients with bleeding disorder than those of without bleeding disorder (P < .05) (Table 1). DISCUSSION Menorrhagia has been reported to affect approximately 20% of menstruating women [1, 27]. Its prevalence in adolescent girls under age 18 years range between 8.6% and 37.5% in questionnaire-based population surveys from different countries [28–30]. However, few data are available on the frequency of menorrhagia in young women beyond the age of 18 years in whom menses are no longer anovulatory. In a crosssectional population survey, the prevalence of self-reported menorrhagia is 46.7%, with a cumulative incidence of 25.1% among 18–24 years of age British women [31]. In the present study, we have found the prevalence of menorrhagia to be 21.8% in university students aged between 17 and 25 years. It should be noted that frequency of self-reported menorrhagia tends to be higher than that assessed by objective methods such as PBAC or acide hematin [32]. Of note, only a small proportion (11.8%) of the students in our study was aware that their menses were heavy and even fewer (6.5%) had sought medical care before. These data demonstrate that menorrhagia is a common but largely unrecognized and untreated problem among young women in Turkey. In a previous report from this country, only 0.4% of female university students sought medical care for their menstrual problems [33]. There is wide variability in the frequency of underlying bleeding disorders in women with menorrhagia, due to the differences in the definitions of menorrhagia, selection of study population (outpatients vs. inpatients or referrals to hemophilia centers or hematology clinics), and diagnostic tests and criteria [11, 12, 20]. Our study population is a representative of the young women with menorrhagia in general population. They were screened by a comprehensive test panel, able to detect VWD, clotting factor deficiencies, and moderate to severe platelet function defects. The overall prevalence of bleeding disorders in our study group is (14.5%) comparable with several studies performed in fertile age women with menorrhagia. The most common bleeding disorder in our study group is VWD occurring in 6.5%, followed by platelet function disorders in 5.2% and clotting factor deficiencies in 2.6%. In a systemic review by Shankar et al., the prevalence of VWD range between 6.0% and 20.9% in women with menorrhagia [11]. However, the frequency of VWD were 6.0% and 8.0% in two previous studies which used PBAC score >100 for diagnosis of menorrhagia and measured the levels of VWF:Ag, VWF:RCo, and FVIII as part of the initial screening [7, 34]. Despite menorrhagia is the most common symptom of PFD, few studies examined platelet functions in women with menorrhagia. Several investigators used PFA100 as a screening test, since studying platelet aggregation and release reaction are time consuming, expensive, and often not readily available for routine clinical practice. The frequency of PFD range between 3.2% and 7.0% in these studies [5, 6, 8, 35]. It was 5.2% in our study group. Although studies performing comprehensive platelet function analysis as part of the initial evaluation have shown decreased platelet aggregation and/or release reaction in 29.9%, 47.3%, and 56.0% of women with menorrhagia, clinical relevance of these subtle platelet abnormalities has not been substantiated yet [7, 10, 34]. C Informa Healthcare USA, Inc. Copyright
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T. Gursel et al.
Clotting factor deficiency is the least common of bleeding disorders seen in women with menorrhagia. Two students in our study had a clotting factor deficiency, one with mild FXI deficiency and the other with mild FVII deficiency. FXI deficiency is the most frequent clotting factor deficiency, occurring in 1.0%–11.9% in women with menorrhagia [6, 8, 10, 34]. It can cause significant uterine bleeding during miscarriage or childbirth, even in women with mild deficiency [36]. Because aPTT test is usually normal in mild FXI deficiency, measurement of FXI level should be considered during investigation of bleeding disorders in menorrhagia. One limitation of the present study is the lack of a second hemostatic testing to confirm the diagnosis of bleeding disorders in students with menorrhagia. This is an important issue, particularly for cases presenting with only one bleeding symptom such as menorrhagia or epistaxis which are common in general population. In the present study, frequency of bleeding symptoms were not significantly different between students with and without an underlying bleeding disorder, except for menses >7 days which was more frequent in those with bleeding disorders (Table 1). Evaluating bleeding symptoms by a standardized bleeding questionnaire could be useful to predict the presence of a bleeding disorder, before performing extensive hemostatic investigations, which are expensive and requires technical expertise are to be performed [37]. Menorrhagia is a public health concern for several reasons: first, it is the most common cause of anemia in menstruating women. Our results confirm that anemia is more common in women with menorrhagia (19.7%) as compared to that (9.7%) found in general population in Turkey [38]. More importantly, it was twice common in students with menorrhagia who had an underlying bleeding disorder (36.1%) than those (15.2%) without it. Anemia went unrecognized and untreated, as for menorrhagia, highlighting the need for screening programmes aiming identification of menorrhagia in young population. Second, menorrhagia adversely affects quality of life, school attendance, and academic performance in students [2]. Finally, early recognition of underlying bleeding disorders in young women can prevent future risks of excessive bleedings during childbirth, abortion, or diagnostic /therapeutic curettage.
CONCLUSIONS Our study shows that menorrhagia is a common but mostly unrecognized and untreated problem among university students. Underlying bleeding disorders are not rare and often mild in degree requiring comprehensive hemostatic evaluation for identification. Limited access to health care providers indicate the need for public education and screening programmes to prevent health problems related with menorrhagia in young female population.
Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. This study was partly supported by a grant (No: BAP 121/2002) from Scientific Research Fund of Gazi University, Ankara, Turkey.
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