von Willebrand's disease: an Important cause of dysfunctional uterine bleeding

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1 Blood Cfhl.,f!,ul...amn dnd Ft'b1UWl.v.)is 2::02. 13:S9-'JJ von Willebrand's disease: an Important cause of dysfunctional uterine bleeding Y. L. Woo, B. White, R. Corbally, M. Byrne, N. O'Connell, E. O'Shea, B. L. Sheppard, J. Bonnar and O. P. Smith (Received 30 May 2001; revised 2 October 2001; accepted 11 October 2001) We assessed the prevalence of von Wille brand's disease (VWD) in patients with objectively confirmed dysfunctional uterine bleeding. A case-control study was designed to include 38 patients with objectively confirmed dysfunctional uterine bleeding and 38 age-matched controls with normal menstrual blood loss (MBL). Menorrhagia was defined as a mean MBL of greater than 80 ml on three consecutive menses as measured by the alkali haematin method. von Willebrand factor antigen, von Willebrand factor activity (VWF:Ac) and factor VIII:C were measured on three serial venous blood samples 1 week apart. VWD was diagnosed in five of 38 (13%) patients with menorrhagia and one of 38 (2.6%) patients with normal menstrual blood loss. The mean VWF:Ac value was significantly reduced in patients with menorrhagia (mean:!: standard deviation, 84.5 :!: 26.7 IU/dl versus 103.9:!: 34.5 IU/dl; P < 0.01) and this effect persisted after exclusion of patients diagnosed with VWD. Failure to investigate patients for VWD will limit the potential benefits of medical therapies such as tranexamic acid or nasal desmopressin [1-desamino-8-0-arginine vasopressin, (DDA VP)J and, in addition, will lead to an increased risk associated with surgical intervention in patients with undiagnosed VWD. Blood Coagul Fibrinolysis 13: Lippincott Williams & Wilkins. Keywords: von Willebrand's disease, von Willebrand factor, menorrhagia, dysfunctional uterine bleeding Introduction von Willebrand's disease (VWD) is caused by a qualitative or quantitative defect in von Willebrand factor (VWF) resulting in impaired primary haemostasis [1]. This condition is associated with increased bleeding from mucosal surfaces of the nose and mouth, and with excessive menstrual blood loss (MBL). It is the most common inherited bleeding disorder, with a prevalence in the general population of 1 in 100 [2,3]' Menorrhagia is defined objectively as > 80 ml MBL [4]. The pathological mechanisms responsible for this condition vary and include polyps, fibroids and endometriosis; however, in 50% of cases, no pathology is detectable and such women are diagnosed as having dysfunctional uterine bleeding [4]. Despite the high prevalence of VWD in the general population, women who are referred for investigation of menorrhagia are not routinely screened for this coagulation disorder. A recent single-centre study identified a high prevalence of 'v'wd (13%) and factor XI (FXI) deficiency (4%) in patients with menorrhagia [5]. FXI deficiency is most commonly seen in the Ashkenazi Jewish population, and the prevalence of FXI deficiency in this study may reflected the high prevalence of Jewish patients in the catchment area of this centre [6,7]. On the contrary, VWD is commonly seen in all patient populations, suggesting that a similar percentage of patients with menorrhagia will have VWD regardless of their ethnic origin [2]. We compared the prevalence of vwd in patients who had excessive MBL with an age-matched cohort of patients with normal MBL. The duthors are with the Ndtiondl Centre for Inherited Coagulation disorders,md Trmity College Dep,mment of Obstetrics,wd Gynaecology, St f,.,mes's Hospital, Dublin, Ireland. Address correspondence to Dr 0. Smith, Consultant P,u:diatric H"em,ltologist, National Centre for Inherited CoagulatIOn Disorders, Department of H.tematology. St j.lmes's Hr)spit,z/. j,pnes's Street, Dublin.9, Irel,md. Te!: (+353) , ext 2953!20J.l.; /:l.':: (+353) ; osmith@stj",nes.le 0957~ 5135! 2\]01 Lippim:otr \Villi,lll1s & \'\+ilkins Blood Coagulatiun and Fibrinolvsis 2002, Vol 13, :--Ie) 2 89

2 y. L. \Voo et al. Methods We previously assessed MEL in women who were referred to a gynaecology outpatient clinic with symptoms of menorrhagia [8]. MEL was measured by the alkali haematin analysis of sanitary towels on three consecutive menses. Menorrhagia was defined as a mean value of greater than 80 ml measured over three consecutive menstrual periods. The exclusion criteria included previous thromboembolic disease or known bleeding disorders. All patients had a normal gynaecological evaluation that included hys~ teroscopy, endometrial biopsy and cervical smear 3-12 months before measurement of MEL. These patients satisfied the diagnostic criteria for dysfunc~ tional uterine bleeding, as no explanation was evident for the excessive menstrual bleeding. Five years after the completion of the initial study, 38 patients with objectively confirmed menorrhagia and 38 controls with objectively confirmed normal MEL were enrolled in a follow-up study. The controls were women from the initial study who complained of menorrhagia but whose MEL was < 80 ml on each of three consecutive menstrual periods. One interviewer recorded the number of bleeding symptoms, including easy bruising, epistaxis, postoperative bleeding, bleeding post dental extraction and a family history of bleeding. Fifteen millilitres of venous whole blood were collected on three occasions 1 week apart into molll sodium citrate tubes (Sarstedt Monovette 9NC/3, Numbrecht, Germany). Plasma was separated by centrifugation at 2000 X g for 20 min at 4 C. Factor VIlI:C (FVIII:C) was measured by one-stage clotting assay on the ACL3000 coagulometer (Instrumentation Laboratory, Warrington, Cheshire, UK) using factor VIII (FVIII)-deficient plasma (Sigma Diagnostics, St Louis, Missouri, USA). von Willebrand factor antigen (VWF:Ag) and von Willebrand activity (VWF:Ac) were assayed by enzyme-linked immunosorbent assay (Asserchrom; Diagnostica Stago, Asnieres, France, and Shield Diagnostics, Dundee, UK respectively). In addition, a full blood count and blood group were taken on the initial visit. Statistical analysis was performed using the Mann-Whitney test using StatView 4.5 (Abacus Concepts, California, USA). Results Thirty-eight patients with menorrhagia (mean age ± standard deviation, 49.3 ± 6.1) and 38 agematched controls (age, ) with normal menstrual blood loss were enrolled in the study. VWD was diagnosed in five out of 38 (13%) patients with menorrhagia as compared with one out of 38 (2.5 %) patients with normal MEL (Table 1). Four of the five patients with VWD and menorrhagia underwent a hysterectomy (two vaginal and two abdominal). The mean VWF:Ag, VWF:Ac and FVIII:C were calculated for each patient, and the means of these values were then calculated for both patient groups. VWF:Ac was significantly lower in patients with menorrhagia (84.5 ± 26.7 IU/dl versus ± 34.5 IU/dl; P < 0.01), and this persisted after exclusion those patients diagnosed with VWD (90 24IU/dl versus IU/dl; P = 0.04) (see Tables 1 and 2). VWF:Ag and FVIII:C were lower in patients with menorrhagia but this failed to achieve statistical significance (see Tables 1 and 2). There was no significant difference in the prevalence Table 1. von WiIlebrand profile in patients with dysfunctional uterine bleeding Menorrhagia Normal MBL (n 38) (n 38) P value Age 49,28 ± 6, ,1 NS VWD 5/38 (13%) 1138 (2.5%) NS Bleeding history 20/38 (52.6%) 17/38 (44.7%) NS Mean VWF:Ac ± SD (IUldl) 84.5 ± ± 34.5 < om :Viean VWF:Ag ± (IUldl) 88.9 ± ± Mean FVIII:C SD (IUldl) ± 39 NS PLT count (X 10"/1) Sa ± 61 NS Blood group 0 27/38 (71%) (55%) NS HRT 12/38 (31.6%) 7/38 (18.4%) NS MBL, Menstrual blood loss; VWD, von Willebrand's disease; VWF:Ac, von Willebrand factor activity; VWF:Ag, von Willebrand factor antigen; FVIII:C, factor VIII;C; PL T, platelet: HRT, hormone replacement therapy; SD, standard deviation; NS, not significant, P > Blood Coagulation,md Fibrinolysis 20a2, Vol 13, No 2 J'"

3 VMD and dysfunctional uterine bleeding of blood group 0 in patients with menorrhagia (27/ 38 versus 21138; P> 0.05). There were 12 patients in the menorrhagia group and seven in the normal MBL group who were receiving hormone replacement therapy (HRT). The exclusion of patients receiving HRT did not effect the overall findings of the study (see Table 3). Discussion Vessel injury results in a primary haemostatic response, which includes vasoconstriction, platelet adhesion and platelet aggregation. VWF binds to the glycoprotein Ib and lib/ilia receptor on platelets and to the subendothelial matrix, and thereby plays a pivotal role in facilitating platelet adhesion and subsequent aggregation [9]. In addition, \lwf circulates bound to FVIII:C preventing enzymatic degradation and localizing FVIII to the sites of vessel injury. Therefore, a qualitative or quantitative defect in VWF results in impaired primary haemostasis (platelet adhesion and aggregation) and, in addition, may be associated with a decrease in circulating FVIII:C [10J. The diagnosis of VW'D requires laboratory and clinical assessment. The measurement of the VWF profile (VWF:Ag, VWF:Ac and FVIII:C) is the primary laboratory investigation for diagnosing VWD [1J. The diagnosis of VWD is complicated by the fluctuations in the baseline VWF profile under the influence of hormonal changes that accompany the menstrual cycle, with lowest values occurring on days 7-14 of the [11,12J. The diagnosis of VWD has important implications for the management of the patient and their family members. Treatment options include desmopressin infusions, intermediate factor concentrate that contains high concentrations of 'VWF, antifibrinolytic therapy and, more recently, nasal DDAVP [8,13]. Home treatment with nasal DDAVP, at the time of menstruation, has been associated with a reduction in MBL in patients with VWD [14]. The subjective diagnosis of menorrhagia has long been recognized as unreliable and the need for more accurate measurement of menstrual blood loss is well documented [15-17]. The gold standard assessment requires the measurement of menstrual blood by laboratory-based techniques such as the alkali haematin method [18,19]. Due to the difficulties involved in laboratory-based measurements of menstrual loss, it has been necessary to use less accurate objective measurements, such as pictorial charts, to assess the contribution of inherited bleeding disorders to menorrhagia [5, 19]. To our knowledge, this study represents the first reported data determining the role of VWF in patients and controls in whom MBL was defined by an objective laboratory measurement. Patients who were commenced on HRT in the interval between measurement of MBL and the subsequent laboratory investigations for VWD were not excluded from the study. HRT may have influenced VWF and FVIlI:C levels, resulting in an underestimate of the prevalence of VWD. However, the major findings of the study, namely that VWD:Ac is lower and VWD more common in patients with menorrhagia than the general population, is unaffected after the exclusion of patients who were receiving HRT (Table 3). The time interval between the measurement of MBL and subsequent assessment of VWF profile is unlikely to effect the difference in VWF:Ac between the two groups as both sets of patients were age matched and exposed to a similar time interval. VWD was diagnosed in 13% of patients with objectively confirmed menorrhagia, which is similar to the previously published study [5,20]. The combined data suggests that there is a true elevation in the prevalence of VWD in women with menorrhagia compared with the general population, and the Table 2. von Willebrand profile excluding those patients diagnosed with von Willebrand's disease Menorrhagia Normal MEL (n = 33) (11 37) P value (years) 47.7 ± ± 6.1 NS Mean VWF:Ac ± SD (IUldl) ge ± ± Mean VWF:Ag ± SD (IUldl) 92.7 ± ± 37.7 NS Mean FVIlI:C ± SD (IU/dl) le3.7 ± 2e.3 lis 38 NS Blood group 0 22/33 (66%) le/37 (5+%) NS MBL, Menstru.ll blood loss; VWF:Ac, von Willebrand factor activity; VWF:Ag, Willebrand factor antigen; FVII1:C, factor VIII:C; SD, standmd deviation; NS, P 0,05. von not Blood C,),lgui.ltion.md 2002, Vol 13, No l 91

4 y. L. Woo e[ al. Table 3. von Willehrand profile excluding those patients receiving hormone replacement therapy Menorrhagia Normal :VlBL (n 26) (n 31 ) P value Mean age ± sd (years) 47.7 ± ± 6.1 NS VW'D 4/26 (15.4%) Ii31 (3.2%) NS Mean vwf:ac SD (lv/dl) 83.8 ::t: ± vlean vwf:ag ± SD (IU/dl) 90.9 ::t: ± 40 NS Mean FVHI:C ± SD (IG/dl) ± 42 NS Blood group 0 18/26 (69%) 18/31 (58%) NS MBL, Menstrual blood loss; VWD, von Willebrand's disease; VWF:Ac, von Wille brand factor activity; VWF:Ag, von Willebrand factor antigen; FVIII:C, factor VIII:C; sd, standard deviation; NS, not significant, P > Table 4. Details of five patients with menorrhagia who were diagnosed with von Willebrand's disease Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Age (years) Hormone replacement therapy No No Yes :\fo No Hysterectomy Yes Yes Yes Yes No Bleeding history Family history (for bleeding) Yes Yes Yes Yes Yes Easy bruising Yes No Yes Yes No Epistaxis No Yes Yes Yes No Postpartum No Yes Yes No Yes Post dental extraction No Yes No Yes No Laboratory data Mean MBL (ml) VWF:Ac (IG/dl) VWF:Ac (IV/dl) 'v'wf:ac (IUldl) VWF:Ag (lv/dl) VWF:Ag (IU/dl) VWF:Ag (IUldl) FVIII:C (IUdl) FVIII:C (IUldl) FVIII:C (IUldl) Blood group RIPA (low dose) Neg Neg Neg Neg Neg Platelet COUnt (X J0 9 II) MBL, Menstrual blood loss; VWF:Ac, von Willebrand factor actlvity; VWF:Ag, von Willebrand facror antigen; FVIII:C, factor VIII:C; RIPA (low dose), platelet aggregation in presence of low dose ristocetin (0.5 mg/ml). failure to achieve statistical significance in the current study is likely to reflect the small sample size. In addition, the functional VWF assay, which is the most sensitive marker of VWD [10,i1,22], was significantly lower in patients with menorrhagia even after exclusion of those patients with VWD. This may have clinical relevance for women with menorrhagia who have VWF in the lower range of normal. It is possible that such women may benefit from nasal DDAVP or tranexamic acid. The high prevalence of VWD in the general population and its frequent association with menorrhagia indicates that the investigation of patients with dysfunctional uterine bleeding should include a haemostatic assessment. At the very least, a detailed family and personal history of bleeding history should be obtained from each patient and investigations for VWD performed if there is a family history of VWD, a positive bleeding history such as postpartum haemorrhage or if the patient is due to 92 Blood Coagulation Jnd Fibrinolysis 2002, Vol 13, No :2

5 VMD and dysfunctional uterine bleedmg undergo surgical a procedure. The financial implications of this approach may be minimized by limiting investigations to patients with objectively confirmed MBL. A positive bleeding history may only become apparent after a significant haemostatic challenge such as dental extraction, surgery or childbirth, and this should be considered in the assessment of patients who have not been exposed to such prior haemostatic challenges. Conclusion The measurement of the laboratory investigations for VWF should be incorporated into the diagnostic evaluation of patients referred to gynaecological clinics with dysfunctional uterine bleeding. Failure to identify patients with VWD will limit medical therapeutic options such as nasal DDAVP and tranexamic acid, and in addition will increase the risk of haemorrhagic complications associated with surgical intervention. References 1. Sadler JE. A revised classification of von Willebrand disease. For the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 1994; 71; Werner EJ, Broxson EH, Tucker EL, Giroux DS, Shults J, Abshire TC Prevalence of yon Willebrand disease in children: a multiethnic study. ] Pediatr 1993; 123: Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood 1987; 69: Rees M. Menorrhagia. Br kfed ] (Gin Res Ed) 1987; 294: Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. Frequency of inherited bleeding disorders in women with menorrhagia. Lancet 1998; 351: Seligsohn lj. High gene frequency of factor XI (PTA) deficiency in Ashkenazi Jews. Blood 1978; 51: Seliasohn U, Modan M. Definition of the population at risk of bleeding due to factor XI deficiency in Ashkenazic Jews and the value of activated partial thromboplastin time in its detection. Isr ] I'vled Sci 1981; 17: Bonnar J, Sheppard BL. Treatment of menorrhagia during menstruation: randomised controlled trial of ethamsylate, mefenamic acid, and tranexamic acid [see comments]. BM] 1996; 3B: Ruggeri ZM. Mechanisms initiating platelet thrombus formation [see comments]. Thromb Haemost 1997; 78: [published erratum appears in Thromb Haemost 1997; 78(4):1304]. 10. Werner EJ, Abshire TC, Giroux DS, Tucker EL, Broxson EH. Relative value of diagnostic studies for von Willebrand disease. J Pediatr 1992; 121: Kadir RA, Economides DL, Sabin CA, Owens D, Lee CA. Variations in coagulation factors in women: effects of age, ethnicity, menstrual cycle and combined oral contraceptive. Thromb Haemost 1999; 82: Abildgaard CF, Suzuki Z, Harrison J, Jefcoat K, Zimmerman TS. Serial studies in von Willebrand's disease: variability versus 'variants'. Blood 1980; 56: Lethagen S, Harris AS, Nilsson IM. Intranasal desmopressin (DDAVP) by spray in mild hemophilia A and von Wi!lebrand's disease type 1. Blut 1990; 60: Lethagen S, Ragnarson TG. Self-treatment with desmopressin intranasal spray in patients with bleeding disorders: effect on bleeding symptoms and socioeconomic factors. Ann Hematol1993; 66: Fraser IS, McCarron G, Markham R. A preliminary study of factors influencing perception of menstrual blood loss volume. Am J Obstet Gynecol 1984; 149: Haynes PJ, Hodgson H, Anderson AB, Turnbull AC. Measurement of menstrual blood loss in patients complaining of menorrhagia. Br ] Obstet Gynaecol 1977; 84: Hallberg L, Hogdahl AM, Nilsson L, Rybo G. Menstrual blood loss - a population study. Variation at different ages and attempts to define normality. Acta Obstet Gynecol Scand 1966; 45: Hallberg L, Nilsson IM. Determination of menstrual blood loss. Scand] Clin Invest 1964; 16: Higham JM, O'Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br ] Obstet Gynaecol1990; 97: Dilley A, Drews C, Miller C, Lally C, Austin H, Ram~swamy D, et al. von Willebr~nd disease and other inherited bleeding disorders in women with diagnosed menorrhagia. Obstet Gynecol 2001; 97: Rodeghiero F, Castaman G, Tosetto A. von Willebrand factor antigen is less sensitive than ristocetin cofactor for the diagnosis of type I von Wille brand disease results based on an epidemiological investigation. Thromb Haemost 1990; 64: Murdock PJ, Woodhams BJ, Matthews KB, Pasi KJ, Goodall AH. von Willebrand factor activity detected in a monoclonal antibody-based ELISA: an ~lternative to the ristocetin cofactor platelet agglutination assay for diagnostic use. Thromb Haemost 1997; 78: Blood Coagulation.lnd Fibrinolvsis 2002, Vol \3, No 2 93