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Prevalence and Treatment of Von Willebrand Disease Related


									                     JOURNAL OF COAGULATION DISORDERS                                                              REVIEW ARTICLE

Prevalence and Treatment of Von Willebrand Disease-
Related Menorrhagia in Adolescents: A Review
Sameh Mikhail1 and Peter Kouides2
Affiliations: 1Lombardi Cancer Center, Georgetown University Hospital, Washington, DC, USA and 2Mary M Gooley Hemophilia Center of Rochester, Rochester
General Hospital, Rochester, NY, USA

                                                              A B S T R A C T

  Heavy menstrual bleeding is a fairly common problem among women of reproductive age and a frequent complaint among adolescents.
The pathophysiological mechanisms that cause menorrhagia in adolescents are different than those that cause menorrhagia in older women.
Compared with the adult menorrhagia population, there have been far fewer studies about the prevalence of bleeding disorders and the
efficacy of different treatment strategies in adolescents with menorrhagia. Excessive menstrual bleeding caused by bleeding disorders results
in hospitalizations, administration of blood products, time lost from school and other activities, and decreased quality of life. Moreover,
managing menorrhagia in patients with undiagnosed disorders of hemostasis may be associated with unwanted risks and complications. The
studies evaluating the prevalence of Von Willebrand disease (VWD) in adolescents with menorrhagia identified over 500 patients with a
prevalence range from 3% to 36%, depending on the clinical setting studied. The highest prevalence is seen in adolescents referred to an
outpatient hemophilia center, whereas the lowest is seen in the acute hospital setting. Treatment of VWD is often complex, requiring a
combination of therapies. Furthermore, different subtypes of VWD respond differently to treatment. There are three main hemostatic agents
used to stop and/or prevent bleeding at the time of hemostatic challenges, including: (1) the non-transfusional agent desmopressin; (2)
antifibrinolytic therapy; and (3) purified blood products that contain factor VIII and Von Willebrand factor concentrated from plasma.
Additional treatment modalities include estrogen–progesterone preparations that are frequently adjunctive and can be an alternative to the
main lines of treatment.

  Keywords: Adolescents, menorrhagia, von Willebrand disease

  Correspondence: Peter Kouides, Mary M Gooley Hemophilia Center, Rochester General Hospital, 1415 Portland Avenue, Suite 425,
Rochester, NY 14621, USA. Tel: (1)-585-922-4020; Fax: (1)-585-563-1832; e-mail:

INTRODUCTION                                                                     Compared with the adult menorrhagia population, there
                                                                               have been far fewer studies about the prevalence of bleeding
  Heavy menstrual bleeding is a fairly common problem
                                                                               disorders and the efficacy of the different treatment strategies
among women of reproductive age [1]. It is also a frequent
                                                                               in this population. In 2008, Pawar et al [9] studied QOL in
complaint in adolescent girls [2]. In a population-based study
                                                                               adolescents with menorrhagia. Their survey revealed that a
by Friberg et al [3], 37% of 1019 of schoolgirls surveyed
                                                                               pictorial blood assessment chart (PBAC) score of .100 was
admitted to having heavy menstrual periods. Menorrhagia in
                                                                               associated with poorer QOL, adversely affected social
adolescent girls, however, most likely has different patho-
                                                                               activities and travel plans, and resulted in greater school
physiological mechanisms from those occurring in older
                                                                               absenteeism. Instituting effective treatment for VWD-induced
women [4]. While anatomic causes are commonly the cause
                                                                               menorrhagia may alleviate many of these unwanted complica-
of menorrhagia in women in their fourth and fifth decades
                                                                               tions. Intuitively, earlier identification of patients with
[4], in adolescents, anovulatory cycles are often the cause of
                                                                               bleeding disorders should eliminate unnecessary diagnostic
excessive blood loss due to the immaturity of the hypotha-
                                                                               procedures and allow the institution of appropriate precau-
lamic–pituitary–ovarian axis [5].
                                                                               tions before surgical interventions [10]. Moreover, the
  Recent studies indicate that bleeding disorders, particularly                presence of a bleeding disorder considerably increases the
von Willebrand disease (VWD) and platelet function (PFD)                       risk of postoperative hemorrhage [11].
disorders, are more prevalent than previously thought in women
with menorrhagia [6, 7]. The prevalence of VWD in the general                  PREVALENCE STUDIES OF HEMOSTATIC
population is estimated to be approximately 1%. In women with
menorrhagia, however, studies have reported a prevalence
                                                                               DISORDERS IN ADOLESCENTS WITH
ranging from 10% to 20% in Caucasian women [8], and from                       MENORRHAGIA
1% to 2% in black women. Recent literature has suggested that                   Several studies have examined the prevalence of VWD in
menorrhagia caused by bleeding disorders results in hospitali-                 adolescents with menorrhagia in the past three decades [12–
zations, administration of blood products, time lost from school               20] (Table 1). Older studies reported a relatively low
and other activities, and decreased quality of life (QOL).                     prevalence of VWD. Claessens and Cowell [13] studied

JCD 2009; 000:(000). Month 2009                                            1                                    
Journal of Coagulation Disorders

Table 1. Comparison of Published Prevalence Studies in Adolescents with               and outpatient gynecology tertiary care setting. Between 2001
Menorrhagia                                                                           and 2003, they evaluated 106 patients with heavy periods and
                                                                     % Platelet       diagnosed 11 of them with a bleeding disorder. Five percent of
                                                            % VWF function            patients had VWD, while 4% had a PFD. We recently studied
    Study                   n                Setting       deficiency disorder        the prevalence of VWD and PFD in adolescents referred to our
    Mikhail et al (2006)   61    Outpatient hematology        36          7           hemophilia treatment center between 2001 and 2004 for heavy
                                                                                      menstrual periods [17]. The prevalence of VWD in our referral
    Jayasinghe et al (2005) 106 Inpatient and outpatient       5          4           population was 22/61 (36%) (95% confidence interval (CI) 24–
    Philipp et al (2004)   25 Outpatient primary care          4        44            49%). The proportion of patients with platelet aggregation
                                clinic                                                abnormalities by platelet-rich plasma (PRP) aggregation
                                                                                      without release was 4/61 (7%) (95% CI 2–16%). In 2008,
    Kanbur et al (2002)    46 Inpatient                        4        NA
                                                                                      Shaw et al [23] evaluated 48 patients referred for abnormal
    Bevan et al (2001)     71    Emergency department,         3          8           preprocedural coagulation studies. Five patients (10%) had
                                   urgent care, and
                                                                                      low VWF levels, two patients (4%) had possible type I VWD,
                                                                                      and two (4%) patients had PFD. In all patients, personal and
    Oral et al (2001)      25 Inpatient                        8        NA            family history of bleeding symptoms had a positive predictive
    Smith et al (1998)     46 Inpatient                        5        NA            value of 45% for hemostatic disorders. Although not designed
    Falcone et al (1995)   61    Inpatient                     0a
                                                                                      to evaluate the prevalence of menorrhagia in the study
                                                                                      population, this study confirms that VWF deficiency is
    Claessens et al (1981) 59 Inpatient                        5          2           prevalent in adolescents presenting with a bleeding disorder.
    Total                  509                                 8                      PFD may also be a common underlying hemostatic disorder
                                                                                      with the prevalence in the above studies varying widely based
    The study did not test for VWF deficiency.                                        on the method of platelet function testing, where aggregation
                                                                                      with release [12, 19] is likely to be more sensitive than
adolescents admitted for acute menorrhagia, as did Smith et al                        aggregation alone.
[20] and Oral et al [18]. In the study by Claessens and Cowell                          In summary, the studies evaluating the prevalence of VWD
[13], 20% of 59 patients had a primary coagulation disorder,                          in menorrhagia have included over 500 patients with a
of whom 5% had von Willebrand factor (VWF) deficiency and                             prevalence range from 3% to 36% depending on the clinical
2% had a PFD. Smith et al [20] retrospectively reviewed the                           setting studied, with the highest prevalence seen in adoles-
charts of 37 adolescents ,20 years of age admitted from 1979                          cents referred to an outpatient hemophilia center [17],
to1995 with excessive uterine blood loss. Eleven percent of                           whereas the lowest prevalence was seen in the acute hospital
admissions were secondary to VWD. Oral et al [18] evaluated                           setting [12].
25 adolescents hospitalized with acute menorrhagia. Seven
patients were diagnosed with a bleeding disorder, which
                                                                                      TREATMENT OF ADOLESCENTS WITH VWD
included two (8%) with VWD. Kanbur et al [16] also
conducted a retrospective chart review of adolescents                                   Treatment of VWD is often complex because a combination
admitted for menorrhagia between 1999 and 2002. A primary                             of therapies is often required [7]. Furthermore, VWD
coagulation disorder was found in 6% of patients, and VWD                             subtypes respond differently to treatment [24]. Therefore,
was diagnosed in 4% of patients. In 1994, however, the study                          adolescents with menorrhagia caused by a bleeding disorder
by Falcone et al [14] did not report any cases of VWD in 61                           should be managed by a hematologist with expertise in
adolescents admitted for menorrhagia. Two patients were                               treating VWD. There are four main agents used to stop and/or
diagnosed with hematological disorders, but specific testing                          prevent excessive bleeding for VWD-related menorrhagia:
for VWF deficiency was not performed in their evaluation. In                          1. The non-transfusional agent desmopressin (DDAVP)
2001, Bevan et al [12] retrospectively reviewed the records of                              [25–27];
71 adolescent females with menorrhagia presenting to the                              2. Antifibrinolytic therapy with either tranexamic acid
emergency department, urgent care, or who were admitted to                                  (Cyclokapron TM ) or epsilon aminocaproic acid
the medical wards. VWD was found in 3% of patients, while a                                 (AmicarTM);
PFD identified by platelet aggregation and release was present                        3. Hormonal preparations;
in 8% of patients. However, the authors acknowledged that                             4. Purified blood products that contain factor VIII and VWF
their study might have underestimated the prevalence of VWD                                 [28] concentrated from plasma.
because many of the levels were drawn in the emergency                                  Unfortunately, there is scant literature on the treatment of
department at the time of initial evaluation. Stress and                              menorrhagia in adolescents with bleeding disorders. Most of
subsequent catecholamine release have been shown to elevate                           the investigations have been conducted in adult patients.
the levels of VWF [21, 22].
  Phillip et al [19] evaluated 25 adolescent women presenting                         Desmopressin
in the primary care setting with the diagnosis of menorrhagia.                          DDAVP increases factor VIII and VWF transiently by
VWD was found in 4% of patients and PFD in 44%.                                       stimulating their release from storage sites into plasma
Jayasinghe et al [15] studied 106 adolescents in an inpatient                         [29]. This action is mediated by binding to vasopressin V2

JCD 2009; 000:(000). Month 2009                                                   2                              
                                                                                   Von Willebrand disease in adolescent menorrhagia

receptors, resulting in activation of cyclic adenosine mono-           Table 2. Indication for Desmopressin in Different Types of Von Willebrand
phosphate-mediated signaling in vascular endothelial cells             Disease [24]
[30]. Additionally, DDAVP appears to improve platelet                   VWD type                                       Response
function, which results in increased platelet adhesion and                 1                                   Usually effective
aggregation [31–33].The aim of DDAVP is to avoid the use of
                                                                           2A                                  Usually ineffective
plasma-derived products in patients with VWD who undergo
hemostatic challenges [34]. DDAVP is available in intrave-                 2B                                  May be contraindicated
nous, subcutaneous, and intranasal forms. An intravenous                   2M                                  Predicted to be ineffective
dose of 0.3 mg/kg is expected to increase plasma factor VIII
                                                                           2N                                  Rarely effective
and VWF levels three to five times above the baseline levels
within 30 min [34–36]. The subcutaneous and intranasal                     3                                   Ineffective
routes are convenient for home treatment in adolescents with
menorrhagia [29]. Intranasal DDAVP is given at a dose of
                                                                       showed that it increased QOL and improved social activities,
150 mg (one intranasal spray) for patients weighing ,50 kg
                                                                       work performance, and subjective well-being. Their study
and 300 mg (two 150-mg intranasal sprays; one in each nostril)
                                                                       included adolescents, but did not specifically investigate the
in patients weighing .50 kg [25]. Table 2 shows the                    treatment effects in this age group.
indication of DDAVP in the different types of menorrhagia.
DDAVP is safe and associated mostly with mild to moderate                The relative efficacy of the above hemostatic agents was
adverse effects, primarily headache, facial flushing, and              recently studied in a multicenter trial of females aged 18–
weight gain [25, 27, 37]. The main limitation to the use of            50 years with abnormal laboratory hemostasis (including
DDAVP is the development of tachyphylaxis, resulting in                VWD). The study compared intranasal (in) DDAVP and
progressive reduction in responsiveness after repeated                 tranexamic acid (TA) using a crossover design and comparing
administrations [38]. DDAVP was well studied in adults                 PBAC for assessment of menstrual blood loss (MBL) and four
[25–27, 29, 35, 36, 39], but experience is limited in                  previously validated QOL measures. Both medications
adolescents. Some studies evaluating the effect of DDVAP               reduced menstrual flow and improved QOL among females
in females with menorrhagia included adolescents [25], but             with menorrhagia and abnormal laboratory hemostasis. TA,
its effect in this age group was not systematically examined.          however, proved to be more effective than in-DDAVP in the
                                                                       reduction of PBAC and in improvement of four QOL
  In 2005, Amesse et al [40] studied the effectiveness of DDAVP        measures. There is a new sustained release formulation
in adolescents with VWD-associated menorrhagia. Intranasal             (XP12B) of tranexamic acid, permitting two or three times a
DDAVP alleviated symptoms, determined by improvement in                day dosing currently under study in the United States [43].
PBAC scores, in 77% (17/22) of patients. Twenty-three percent
(5/22) of the patients treated with DDAVP experienced mild             Hormonal preparations
adverse events secondary to their treatment. The adverse events
                                                                         Estrogen–progesterone preparations are adjunctive and a
were mild to moderate headaches (2/22), facial flushing (2/22),
                                                                       promising alternative to the main lines of treatment,
and one patient reported both facial flushing and moderate
                                                                       particularly if contraception is an additional goal or if the
headaches. The minor side-effects resolved without interven-
                                                                       bleeding pattern is anovulatory. Hormonal preparations are
tion, but occasionally led to discontinuation of treatment.
                                                                       thought to exert their effect in patients with VWD-associated
Serious adverse events (hyponatremia and/or seizures) were
                                                                       menorrhagia by inducing changes in the endometrium that
not encountered in the study population.
                                                                       make it less likely to bleed profusely at the time of
                                                                       menstruation [24]. Oral contraceptives (OC) do not signifi-
Antifibrinolytic amino acids (tranexamic acid and
                                                                       cantly change the levels of factor VIII and VWF. However, they
epsilon aminocaproic acid)                                             are used commonly in reducing the severity of menorrhagia in
  Antifibrinolytic therapy can be useful alone or as an adjunct        patients with VWD, even in those with severe type 3 VWD [24,
to other VWD therapies for the prevention and treatment of             44].The study by Amesse et al [40] evaluating the use of OC in
mucosal tract bleeding characterized by rich fibrinolytic              adolescents with type 1 VWD revealed that OC alleviated
activity, such as the nasopharynx, gastrointestinal, and               menstrual blood loss, as determined by the PBAC score, in 86%
genitourinary tract [41]. It can be given orally, intravenously,       (12/14) of patients. Moreover, the study compared the
or topically. Epsilon aminocaproic acid (50–60 mg/kg every             effectiveness of DDAVP intranasal spray and OC therapy, as
4–6 h) and tranexamic acid (20–25 mg/kg every 8–12 h)                  assessed by improvement in PBAC score, and showed no
interfere with the lysis of newly formed clots by saturating the       statistically significant difference between the two treatment
binding sites on plasminogen, consequently preventing its              modalities (RR51.109; P5–0.6810; 95% CI50.8122–1.515). It
attachment to fibrin and rendering plasminogen unavailable             is worth noting that the majority of adolescents (81%) treated
to activation within the developing blood clot [24, 41]. To our        with DDAVP or OC experienced alleviation of menorrhagia
knowledge, the use of antifibrinolytic agents in the treatment         symptoms, determined by improvement in PBAC scores.
of menorrhagia in adolescents with VWD has never been                  Another hormonal option in women with VWD-related
systematically studied. Winkler [42] surveyed 849 patients             menorrhagia that appears promising in older women is the
treated with tranexamic acid for heavy menstrual bleeding and          levonorgestrel intrauterine system (LNG IUS) (MIRENATM). In                                             3                                     JCD 2009; 000:(000). Month 2009
Journal of Coagulation Disorders

a study from the Royal Free Hospital in London [45], LNG IUS              strategy of escalated prophylaxis, an international prophylaxis
was assessed in 16 women (13 with type1 VWD, two with FXI                 study was initiated last year [55] in women with type 2 or 3
deficiency, and one with platelet storage disorder) with                  VWD-related menorrhagia with dosing initially at 50 units/kg
bleeding disorders. As in women with normal coagulation,                  weekly. In non-responders, defined as PBAC remaining .100,
irregular spotting was seen in all of the women. The length of            this dose is escalated to twice a week, then thrice a week.
the spotting ranged from 30 to 90 days (median 42 days).
Eleven of the women did not think that the irregular bleeding             Von Willebrand factor concentrates devoid of FVIII
affected their life, while the remaining five were only slightly            In Europe, a highly purified VWF concentrate (WilfactinH)
affected. At 9 months of follow-up, nine women became                     has been developed to avoid excessive post-infusion FVIII:C
amenorrheic, and the PBAC score ranged from 24 to 75                      levels in patients with VWD, as these patients typically have
(median 47; P50.0001) in the remaining seven. The hemoglo-                intact endogenous production of FVIII. However, as FVIII
bin concentrations also increased significantly. Prior to                 levels rise slowly, reaching a peak between 6 and 8 h after a
insertion of the LNG-IUS, all the women had at least 1 day a              VWF transfusion, co-administration of FVIII is usually
month on which their life was severely affected by bleeding,              necessary to maintain hemostasis in patients with baseline
and 37.5% had at least three affected days per month. Nine
                                                                          FVIII levels of 30 IU/dL or lower [56–58]. Purified VWF
months after insertion of the LNG-IUS, none of them had any
                                                                          concentrates controlled bleeding in patients with severe VWD,
days severely affected by menstruation. Long-term follow-up at
                                                                          and hemostasis was rated as excellent or good in 89% of the
a median of 53 months has shown persistent benefit [46]. All
                                                                          50 patients studied [58]. A potential indication for VWF
of the women in this study had mild to moderate factor
                                                                          concentrates devoid of FVIII is cases in which repeated
deficiencies. It would be interesting to note whether this
                                                                          infusions are anticipated in patients who are at high risk for
treatment is as effective in those with severe factor deficiencies.
                                                                          thrombosis [56]. A recombinant VWF concentrate is presently
Subsequent studies of the levonorgestrel intrauterine device
                                                                          undergoing phase I/II study by the Baxter Corporation [59].
(IUD) have been positive, including a relatively large study of 28
women with a broad range of hemostatic disorders (68%
                                                                          Platelet transfusion
efficacy), although 4/28 (14%) of those women had it removed
due to treatment failure or spotting [47]. Whether the                      Platelet transfusions are rarely used, but can potentially be
underlying bleeding disorder promotes prolonged spotting,                 effective in the uncommon situation where bleeding is not
as recently reported in one case [48], deserves further study as          controlled with large doses of VWF/FVIII concentrates [56].
persistent spotting is an indication for removal. At this point,          For example, in patients with type 3VWD, platelets lack VWF
the LNG IUS is usually considered in medically refractory cases           completely, and subsequently there is no uptake of VWF from
of adolescent VWD-related menorrhagia, as evidence is                     plasma after VWF infusions [60, 61].
accruing for its safety and efficacy in adolescents with
menorrhagia [49]. LNG IUS is a promising treatment modality               Experimental therapy
that will potentially move to the first line as there is emerging           Gene therapy has been attempted to correct VWD [62].
evidence that it is safe in adolescents [50, 51]. Paterson et al          However, it is not as attractive as gene therapy for hemophilia
[49] demonstrated that LNG IUS is widely used by gynecol-                 as VWD is typically a mild disorder with effective treatment
ogists in adolescents with menorrhagia.                                   options [56]. Interleukin-11 is presently undergoing study for
                                                                          mild VWD, as preliminary data have shown that it can elevate
VON WILLEBRAND FACTOR REPLACEMENT                                         VWF levels 1.5- to threefold when given daily for 7 days
                                                                          without tachyphylaxis ensuing [63].
Von Willebrand factor/factor VIII concentrates
                                                                            In summary, recent studies have showed that VWD is
  Approximately 10–15% of women with VWD will not
                                                                          prevalent in adolescents with menorrhagia. Several effective
respond to DDAVP because they have either severe type 1
                                                                          treatment options are available for the treatment of VWD-
VWD or type 2 or 3 VWD. In those patients, for severe
                                                                          associated menorrhagia. These treatment modalities are
intractable menorrhagia refractory to antifibrinolytic therapy
                                                                          relatively well studied in adults. However, studies are lacking
and/or hormonal therapy or for prophylaxis before surgery, a
                                                                          in adolescents with heavy menstrual bleeding. Further
plasma-derived von Willebrand factor containing FVIII
                                                                          systematic studies in this age group are needed to determine
concentrate can be administered [52, 53]. Presently licensed
                                                                          the most efficacious treatment for VWD-related menorrhagia.
brands in the United States are Humate-P (CSL Behring, King
of Prussia, PA, USA) and Alphanate-SD (Grifols, Los Angeles,                   Disclosure: The authors declare no conflict of interest.
CA, USA). Both products undergo viral inactivation. The
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