Bleeding history. Testing for VWD and other bleeding disorders in all women with menorrhagia is neither practical nor necessary. The first step in investigating for an underlying bleeding disorder in these women is to take a focused personal and family history of bleeding symptoms. This can be used to identify women with significant additional bleeding symptoms suggestive of an underlying bleeding disorder . The frequency of bleeding symptoms has been showed to be significantly higher in patients with VWD than in women without a bleeding disorder . Significantly more women with VWD had menorrhagia since menarche (65%), compared with women without a bleeding disorder (9%). Bleeding after tooth extraction, and postpartum and postoperative bleeding were also more common among women with VWD .
Bleeding history should include :
Excessive menstrual bleeding since menarche;
History of PPH, surgery-related bleeding or bleeding associated with dental work;
History of bruising >5 cm one to two times per month, epistaxis one to two times per month, frequent gum bleeding, family history of bleeding symptoms. [A ‘positive screen’ entails any one from 1 or 2, or two or more from 3.]
Initial investigation for an underlying bleeding disorder in women with menorrhagia should consist of a focused personal and family history of bleeding symptoms (grade C, level IV).
1. Full blood count and ferritin.
The initial laboratory evaluation for an underlying bleeding disorder should consist of full blood count (FBC) and serum ferritin, which will exclude thrombocytopenia and assess the degree of anaemia. If the detailed history identified a ‘positive screen’ and the platelet count is normal, then a stepwise sequence of testing for various bleeding disorders should be carried out. This also applies to women who are considering major surgical intervention, regardless of the presence of a positive screen . It is essential for these testing to be undertaken in settings where necessary expertise and resources are available on-site to ensure appropriate and accurate diagnosis.
PT and activated PTT (APTT) are standard tests of haemostasis, which are carried out as part of the initial evaluation. However, they have poor sensitivity, specificity and both positive and negative predictive values for an underlying bleeding disorder . Normal PT and APTT do not exclude an underlying bleeding disorder, but they should be adequate for screening for the severe rare clotting factor deficiencies . A mixing study should be performed in cases of prolonged APTT to distinguish between a deficiency state and an inhibitor.
3. von Willebrand screen.
This includes VWF:Ag, VWF:AC and FVIII levels (FVIII:C). FVIII level can be reduced in VWD as VWF protects FVIII from proteolytic cleavage . Comprehensive guidelines on the diagnosis of VWD have been produced by the UKHCDO .
Difficulties in diagnosing type 1 VWD because of its variable expression influenced by genetic and environmental factors are well established [136,137]. These factors include women's race, ABO blood group, phase of the menstrual cycle and the use of oral contraceptives.
At present, there is a lack of consensus in the literature supporting a true variation of VWF levels during the menstrual cycle. Initial studies have suggested a decrease in VWF and FVIII levels during menstruation [138–140]. A longitudinal study of 39 healthy Caucasian women sampled on days 2, 8, 15 and 21 showed a strong cyclic variation with a decrease in VWF values in the early follicular phase and peak values in the luteal phase . However, another longitudinal study of 95 healthy women sampled serially at days 4–7, 11–15 and 21–28, did not found this variation . A recent cross-sectional study of 90 controls and 85 women with menorrhagia, assigned into groups that were more finely divided in the sampling time during the menstrual cycle, found the lowest VWF levels on days 1–4 and the highest on days 9–10 . Due to the inconsistencies in these results, recommendations for testing exclusively during menses cannot be made. However, the time of testing in relation to the menstrual cycle should be noted, and if the results from the initial testing were borderline or just below the normal range, repeat testing during days 1–4 of the menstrual cycle would be advisable.
It is currently not clear whether the concurrent use of COC would obscure the diagnosis of VWD. It has been observed that oestrogen increases VWF levels . There has been report of COC use masking the diagnosis of VWD . A review of the literature on the effect of COCs on coagulation factors reveals large variations of study designs and results . The majority of the studies demonstrated an increase in fibrinogen, prothrombin, FVII, FVIII and VWF whilst other factors, such as FV, FIX and FXIII, did not seem to be affected. The effect appears to be related to oestrogen, dose dependent, and appreciable above a dose of 50 μg of ethynylestradiol. The effect of smaller doses of oestrogen, which are commonly used today, is less and may not be significant. In a study of 20 non-pill users and 20 women on low-dose COC (≤30 μg), no significant difference between the mean values of APTT, fibrinogen, FVIII:C, VWF:Ag, VWF:AC and FXI were found . Due to lack of evidence presently demonstrating a definite effect of COC on VWF levels, a practical approach would be to still test women when on COC, especially if they are still experiencing menorrhagia. Repeat testing off COC should however be considered if results are borderline or in the lower half of the normal range.
Patients with blood type O have 25% lower VWF levels compared with other blood types . This means if VWD testing is adjusted for the ABO blood type, a lower VWF level would be required as a cut off for the diagnosis of VWD for blood type O patients. Consequently, this would exclude blood type O patients with subnormal level defined as two standard deviations below the mean of the total population (i.e. <50 IU dL−1), but a level within the normal range for blood type O patients (i.e. >35 IU dl−1). However, type O patients with VWF levels between 35 and 50 IU dL−1 were found to have similar bleeding symptoms as non-O patients in that range . Therefore, the use of ABO adjusted ranges for VWF levels may not be necessary because bleeding symptoms seem to depend on the VWF level regardless of the blood type.
4. Platelet function analysis.
Neither BT nor platelet function analyser (PFA-100) are effective screening tests for mild VWD and platelet function disorders [148–150]. However, they can be performed concurrently with VWF testing as a baseline and used for monitoring postintervention to ensure adequate haemostasis.
If all initial haemostasis testing and complete gynaecological evaluation are normal, platelet aggregation and release studies should be considered. A relatively high prevalence of platelet function abnormalities was recently reported in women with menorrhagia [117,127]. Amongst 74 women with unexplained menorrhagia, platelet aggregation and platelet ATP release were decreased with one or more agonist in 35 (47.3%) and 43 (58.1%) women respectively. The prevalence odds of platelet aggregation abnormalities was found to be 4.2-fold higher among women with menorrhagia than control women .
5. Other clotting factor levels.
If the VWD (including FVIII) screen and platelet function analysis are both normal, depending on the degree and severity of additional personal bleeding symptoms and the family history, testing for additional coagulation deficiencies (FV, FVII, FIX, FXI and FXIII) should be considered.
6. Non-haematological tests.
There is some evidence linking hypothyroidism with menorrhagia [151–153]. Thyroid function tests should be considered if the patient is symptomatic.
Laboratory testing for an inherited bleeding disorder should be carried out if the woman presenting with menorrhagia has a positive bleeding history or if surgical intervention is planned (grade C, level IV).
Laboratory testing should only be undertaken in settings where necessary expertise and resources are available on-site to ensure appropriate and accurate diagnosis (grade C, level IV).
Laboratory testing should be carried out in the following stepwise sequence (grade C, level IV):
FBC and ferritin;
PT and APTT;
von Willebrand screen (VWF:Ag, VWF:RCo and FVIII:C) Testing exclusively during menstruation, off COC or adjusted for blood type is not necessary at the initial evaluation. However, these details should be documented and repeat testing should be considered if the results are borderline.
Platelet function analysis (platelet aggregation and release studies);
Other clotting factor levels;
Thyroid function tests if symptomatic.
Menorrhagia in women with inherited bleeding disorders Menorrhagia has been well recognized as a common symptom in women with inherited bleeding disorders including VWD, other clotting factor deficiencies and platelet disorders [27,99,154–156]. In a review of the obstetric and gynaecological manifestations of bleeding disorders, menorrhagia was reported in 32–100% of women with type I VWD and in 10–70% of women with other bleeding disorders . In a study of 38 females with type I VWD, menorrhagia was the most common bleeding symptoms, occurring in 93% of adult women . Using the PBAC to assess menstrual blood loss, menorrhagia (PBAC score >100) was confirmed in 74%, 59% and 57% of women with VWD, FXI deficiency and who were carriers of haemophilia respectively . The duration of menstruation was also found to be significantly longer and episodes of flooding more common in women with inherited bleeding disorders compared with the control group (P = 0.001).
Menstruation has a major influence on women's lifestyle and employment. Menorrhagia has been found to have a negative effect on the quality of life in women with inherited bleeding disorders . In the same study, 39% of these women had to cut down on the time they spent on their work or other activities, 47% felt they had accomplished less than they would like during this period, and 38% felt they were limited in the kind of work they could do . The impact of menstruation on young women in terms of restrictions in sport activity, travel, work, studies and sex is also substantial . Although these comments were made in regard to the impact of menses in general, this effect is likely to be even greater in women with an inherited bleeding disorder and excessive menstrual bleeding. Early recognition, accurate diagnosis and appropriate management will help to improve not only the quality of care for these women but also their quality of life.
Menorrhagia is one of the most common bleeding manifestations in women with inherited bleeding disorders and has a negative effect on their quality of life (grade B, level III).
Management of menorrhagia in women with inherited bleeding disorders. A multidisciplinary clinic, including both haematologist and gynaecologist, set up within the network of haemophilia treatment centres (HTCs) is ideal for providing comprehensive care for the management of menorrhagia in women with inherited bleeding disorders. This ensures appropriate and accurate on-site haemostasis testing; avoids communication problems between professionals; allows clear management plans to be made (and competent completion of desmopressin test dose); and can address the psychosocial aspects related to bleeding disorders.
In a survey by the Centers for Disease Control and Prevention in the USA, 95% (71 of 75) of women receiving care in HTCs reported a strong positive opinion and satisfaction . Similar positive findings were found among patients of the multidisciplinary clinic at the Katharine Dormandy Haemophilia Centre of the Royal Free Hospital in London .
Menorrhagia in women with an underlying bleeding disorder is likely, but not exclusively, to be due to a defect in haemostasis. The cause of menorrhagia may be multifactorial in these women. In a survey of women with VWD, half of the women undergoing hysterectomy for menorrhagia had additional uterine pathology such as fibroids or endometriosis . Therefore, a thorough gynaecological evaluation should be performed to exclude pelvic pathology, especially the possibility of malignancy in older women.
The Royal College of Obstetricians and Gynaecologists has produced management guidelines of menorrhagia in general [102,107]. Most of these have not been assessed in menorrhagia related to an underlying bleeding disorder, but for best clinical practice, the results for general menorrhagia patients can be extrapolated.
Management of bleeding disorder-related menorrhagia involves consideration of the patient's age, childbearing status and preference in terms of perceived efficacy and side-effect profile. Therapeutic options for the control of menorrhagia in women with underlying bleeding disorders include medical treatments [such as anti-fibrinolytics (tranexamic acid), intranasal and subcutaneous DDAVP, oral contraceptives, levonorgestrel (LNG) intrauterine device and clotting factor replacement] and surgical treatments (such as endometrial ablation and hysterectomy). They are similar to the treatment options for menorrhagia in general with the exception of DDAVP and clotting factor replacement. However, management of women with inherited bleeding disorders requires additional monitoring of the haemostatic parameters and awareness of the increased risk of bleeding with any surgical interventions.
Management of menorrhagia in women with inherited bleeding disorders should be provided by a multidisciplinary team including a haematologist and gynaecologist (grade C, level IV).