Women and VWD
All women’s aspects related to VWD need to be evaluated, diagnosed, and managed together with hematologists and gynecologists, and pediatric doctors in case of planning a delivery (Figure 1). Women/girls represent majority of population with VWD (61%), as reported by a 1092 patient-study from the Netherlands, and accordingly women/girls are referred to special centers more often than men/boys [1]. The mean age of the first bleed, was 8.9 years in boys and 10.6 in girls. The time delay from the first bleed to the diagnosis was 7.7 years for boys but 11.6 years for girls, illustrating the need for improvement.
Menorrhagia and its management
In women, menorrhagia is the most typical symptom of bleeding disorders affecting primary hemostasis. Platelet disorders and VWD are the most frequent underlying conditions. Almost all women with VWD (89-99%) suffer from menorrhagia [2,3]. It is typical that menstruation is heavy and lasts for several days. This usually leads to iron deficiency anemia (IDA), which further enhances the bleeding tendency. Thus, prevention and management of iron deficiency is critical to improve hemostasis and overall quality of life of women with VWD. The same applies to repetitive gastrointestinal bleeds.
Despite this knowledge, the self-reported outcome studies imply that 40% of VWD patients do not receive attention to heavy menstrual bleeds (HMB). Accordingly, almost half of the patients had also suffered from the often-neglected IDA [4]. After the laboratory diagnosis of iron deficiency confirms the etiology of anemia, oral or intravenous iron should be commenced. If there is an urgent need to improve erythropoiesis and/or oral iron is not tolerated or insufficient, iron should be administered intravenously.
Combined hormonal contraception with estrogen or other hormonal treatment (such as intrauterine device, IUD with progesterone) offers a suitable means to simultaneously manage heavy menstrual bleeds and contraception.
Menstrual blood loss is diminished with estrogen containing oral contraceptive pills and progesterone IUD in women with VWD, even in type 3 patients. Estrogens increase the plasma level of VWF, except in patients with type 3 VWD. However, the response is variable and unpredictable. The mechanism of action is partly dependent on the increased level of VWF and partly on the local effect on the endometrium. Gonadotropin-releasing hormone may be of further help, if recommended by the gynecologist.
Massive uterine bleeds need to be managed with interventional radiologists, or angiologists, who may use embolization techniques to stop the bleeds.
Either DDAVP (patients with VWD type 1 and some patients with VWD type 2 according to a desmopressin test and other functional tests) or VWF replacement therapy is indicated temporarily on the days of heavy bleeds, unless VWF is not in prophylactic use. Tranexamic acid is useful for all types of VWD, if tolerated. Tranexamic acid at repeated doses loads to the tissues and is having a prolonged pharmacodynamic action together with the other treatment modalities.
Menstrual pain has been advised to be controlled with non-steroidal anti-inflammatory drugs. However, COX2-inhibitors, coxibs, are best for the hemostatic purpose since the prostaglandin and arachidonic acid metabolites are directed towards some platelet activation, rather than their inhibition.
Menopausal bleeds
Fibroid formation and menopause can cause problematic bleeds not only in general, but especially if the primary hemostasis is compromised. This needs to be discussed with the patient and the gynecologist in advance to have a management plan in place. Again, the role of managing anemia and hormonal regimens as well as local interventional management tools, such as hysterectomy or thermal balloon endometrial abrasion, are important.
Abortion and miscarriage
Deliberate abortion needs replacement support aiming at factor (VWF and FVIII) above 50% and tranexamic acid to control fibrinolysis. Oral hormonal contraception or local hormonal intrauterine device (IUD) is recommended as alternatives if pregnancy is not planned near-term.
Insemination and early organogenesis may be influenced by VWD, but the literature is conflicting regarding patient outcome. Increased miscarriages rates have been reported by a patient-reported outcome study [5], but not in a single center pilot study from Canada although the numbers of miscarriages were 25% in 20/80 pregnancies in VWD patients versus 16% in 50 control pregnancies (p-value 0.28). A case-control study did not either show increased risk of placental abruption, preterm delivery, fetal growth restriction or stillbirth [6]. Later larger studies have supported these data, both in type 1 or type 3 VWD [7].
Pregnancy
In case of pregnancy, a written follow-up plan on the laboratory assays, their timing, replacement therapy, interventions and concomitant medications is useful and needed to secure the safety of the patient and the next steps, also covering the emergency hours.
Deliveries should be managed by a team, which is familiar to the plans, and the pediatric doctor should be involved as early as possible when a child with VWD or a bleeding disorder of unknown origin will be or is born.
Follow-up during pregnancy is important, but there is no consensus on how often this should be done. In some centers, both clinical and laboratory testing is carried out in each trimester, while other centers only perform a planned examination in the last trimester. A clinical and laboratory examination is necessary if an increased bleeding tendency is noted. It is important to follow the complete blood count, including platelet counts, which sometimes decrease related to pregnancy itself. Thrombocytopenia should be noted in association with VWD and especially with type 2B, and low platelet count may bring new challenges to the management. Moreover, it can be valuable to screen the coagulation factors, including fibrinogen, D-dimer (disproportionate fibrinolysis) and FXIII in selected cases. If the pregnant woman in addition to VWD has thrombotic propensity, thrombophilia, family history or significant obesity or fatty liver, the balancing with hemostatic and possible anticoagulation are relevant.
If bleeding episodes occur, this needs interim attention including the clinical and laboratory assessment and possibly VWF prophylaxis, if the VWF values do not rise or are rapidly eliminated, which typically occurs along pregnancy in severe VWD type 1 and in some forms of type 2. However, in some cases of type 1 the half-life of VWF is low and should be observed by evaluating the trough values at 4-6 hours after VWF administration.
Another issue is normal cationic calcium and magnesium levels since they are hemostatic relevant players. Calcium is needed in all steps of hemostasis and platelet functions. Especially, magnesium is involved in FIX activation and platelet-collagen interactions and should be in balance and under normal references with calcium [8,9].
Delivery
Mode of delivery should follow the obstetrical decision-making together with the pregnant woman and the hematologist. Vaginal delivery is to be preferred, and the indications for caesarean section are mainly obstetrical, considering both the mother and the baby.
It is important to have a written plan in patient files regarding the approaching delivery, latest at the week 36. The management of pain relief is an essential part of the preparations.
Epidural/spinal anesthesia (neuraxial anesthesia)
It is difficult to evaluate the hemostatic thresholds in VWD for neuraxial anesthesia, since the evidence is based on small, retrospective studies and case reports [10]. As a general rule, women with VWD type 1 can have epidural/spinal anesthesia if their VWF activity and FVIII level are more than 50 IU/dL, e.g., within normal reference values. VWF activity levels should be maintained at least at 50 IU/dL while the epidural is in place and for at least 6 hours after its removal. For type 2 and type 3 VWD an individual assessment is necessary, depending on the actual factor levels of VWF activity, FVIII, and red cell and platelet count and prophylactic VWF administration plans and their responses. The risk for procedure-associated bleeding needs to be related to other risks, for instance with general anesthesia.
Replacement therapy
On individual basis, as VWF and FVIII tend to rise physiologically during pregnancy, the VWF dose and type of concentrate should be evaluated. Note that a pure VWF replacement therapy would not add to endogenous FVIII levels unless given at least 6 hours ahead of the delivery. A pure VWF concentrate is a valuable alternative to manage the patient, especially if thrombotic risk factors are present. Women with type 3 VWD typically do not show any increase of FVIII and VWF during pregnancies because endothelial VWF stores are lacking. Thus, VWF/FVIII concentrates are required to manage delivery to keep the levels above 40 IU/dL for vaginal delivery and above 50 IU/dL for cesarian section [11]. Replacement therapy should be prolonged up to 5–7 days to maintain FVIII and VWF activity levels > 50 U/dL, but usually not above 150-190 IU/dl.
Postpartum hemorrhages (PPH)
The days after delivery, the VWF and FVIII:C activities are falling whereby bleeding may be an issue. Postpartum hemorrhage may also occur due to uterine injury, its retention or extra-uterine tissue injuries. In addition, wound healing is impaired in VWD, since not only plasma, but also tissue and platelet VWF is reduced. Hemostatic support is therefore necessary according to laboratory analysis at each obstetric unit. A preparatory plan should be in place for a case of PPH [12]. Rapid bedside estimation of coagulation or needs for transfusion by thrombelastometry (ROTEM or TEG) is of value, however, it does not detect the contribution of VWF, whereby actual plasma samples and traditional laboratory analysis are needed. Iron deficiency anemia should be recognized and well managed not only antepartum, but also postpartum, and especially after PPH.