Women with bleeding disorders: Clinical and psychological issues

Inherited bleeding disorders show wide variation in severity and prevalence but are described in all populations. Some are related to defects in primary haemostasis such as platelet function disorders or von Willebrand disease and others such as haemophilia A and B, and factor XI deficiency are due to defects in secondary haemostasis. Inherited bleeding disorders affect both men and women but this review article aims to discuss the impact of bleeding disorders in women. While it has been recognized that women are affected by bleeding disorders such as von Willebrand disease (VWD) and other rare bleeding disorders, arguably until recently, the dominant clinical and research focus in the field of bleeding disorders has focused predominantly on management of males with haemophilia A and B. Exciting advances in care for people with haemophilia should not overshadow the increasing attention that has been given to the impact of bleeding disorders on women. It is well recognized that autosomal dominant or recessive bleeding disorders such VWD and FXI, FXIII deficiency affect both males and females but that females with the gene for haemophilia A or B also manifest bleeding symptoms is under recognized. A significant number of these females have clotting factor levels that would classify them as having mild, moderate and even severe haemophilia. This review will discuss the impact of bleeding disorders on women summarizing important genetic aspects of disorders that impact on the severity of women's symptoms, outline approach to management of bleeding issues specific to women such as heavy menstrual bleeding and care in pregnancy and childbirth, and also discuss some of the psychological impacts for women with bleeding disorders. It may be almost said that the females hand down the disease, while the males are the victims of it. The Lancet, Sept 18, 1886.2 The definition of a carrier in relation to genetics is an “individual who is heterozygous for a recessive gene and thus does not express the recessive phenotype but can transmit it to offspring.” Until recently, all women with the haemophilia gene were described as “carriers” and those with bleeding symptoms were known as “symptomatic carriers.” It has long been recognized many women with the haemophilia gene have bleeding symptoms and that the severity of prevalence of symptoms is related to the clotting factor level and that even female carriers with clotting factors between 40%-60% reported more bleeding symptoms than non-carriers in families.3 In 2012, the World Federation of Haemophilia (WFH) updated its definitions of haemophilia stating that haemophilia occurs in males or females as with severity related to the clotting factor level: mild haemophilia is someone who has clotting factor levels of 5%-40% of the normal amount, moderate haemophilia someone with levels 1%-5% normal and severe haemophilia someone with levels <1% normal. It recommends the use of the term “symptomatic carrier” to be a woman with factor levels of 40%-60%.4 The normal number of chromosomes in humans is 46: males and females have 22 paired chromosomes and a set of sex chromosomes: two X chromosomes in genetic females and an X and a Y chromosome in genetic males. The genes that code for factor VIII (8) and IX (9) clotting proteins that are deficient in haemophilia A and B, respectively, are found on the X chromosome. Haemophilia is caused by inheritance of either a faulty factor 8 (F8) or 9 (F9) gene resulting in reduced production of that clotting factor. Males inherit a single X chromosome so a faulty gene that makes <1% of the normal amount of the clotting factor will result in severe haemophilia. A female who inherits the same faulty F8 or F9 gene usually has a normal gene on the other X chromosome so most females who carry a single abnormal gene will make clotting factor on the other gene. The amount of clotting factor found in females with the haemophilia gene varies from normal levels to very low levels due to a process called lyonization or X chromosome inactivation that occurs early in embryonic development, Figure 1.5 While it might be anticipated that the normal gene would always become dominant, this is not the case. The severity of the haemophilia will depend on the abnormal gene's production of clotting factor and how “extreme” the lyonization is i.e how inactivated the production of the normal gene is. It is important for females in families with haemophilia and the clinicians caring for them to be aware that a female can complete inactivation of the normal F8 or F9 and have severe haemophilia. The most recent Annual Global Survey from the WFH reports a total of 295, 866 people with bleeding disorders have been identified in 113 countries worldwide6 with almost 185 000 people with haemophilia A or B. It has been estimated that for every 100 males with haemophilia there will be 277 female family members—mothers, aunts, sisters, or daughters who may have the haemophilia gene and require counselling and testing, although only 156 will be true somatic carriers.7 This translates to almost 500 000 women globally who should be assessed regarding their haemophilia status. Females with bleeding disorders will require the same management as males when faced with hemostatic challenges such as surgery, epistaxis, joint and muscle bleeds. Menstruation, pregnancy and childbirth are bleeding challenges that are unique to women with bleeding disorders. Heavy menstrual bleeding (HMB) previously known as menorrhagia or dysfunctional uterine bleeding is a condition that affects many women worldwide. Previous definitions related to the volume of blood lost each menstrual cycle but a more qualitative definition has been developed (FIGO definition) where heavy menstrual blood loss is that which interferes with a woman's physical, social, emotional and/or material quality of life.8 Heavy menstrual bleeding is 2-3 times more common in women with BD with the majority of women with VWD and other bleeding disorders reporting HMB.9 The duration of menstruation is also prolonged with one in four women with BD reporting bleeding for more than 8 days compared to one on 25 women without BD. In addition, heavy menstrual bleeding is reported throughout menstruation in women with BD women whereas women with HMB without BD tend to have the heaviest bleeding in the first 3 days.10 Heavy menstrual bleeding is a cause of iron deficiency and iron deficiency anaemia. It also has a major impact on women's quality of life that demands equal attention. A qualitative study where women with HMB were interviewed about its impact identified irritation and inconvenience, pain associated with bleeding, feeling self-consciousness about odour, and experiencing social embarrassment.11 Women described frustration at how HMB impacted their lives and related their irritation with having to prepare for their menstrual cycle, avoiding activities such as exercising and socializing, having to make special plans to organize their work schedule, buy extra sanitary products. They described having suffered social embarrassment as a result of bleeding staining their clothes or furniture and commented on much they worried about events like this occurring. Most women developed complex strategies to prevent such events occurring and many reported that they avoided going out, even to work, when they were menstruating. Up to 90% of women with BD have heavy menstrual bleeding.12 Haematologists and clinicians caring for women with BD should remain vigilant to this problem and ensure that they ask appropriate questions. Relevant clinical questions to ask are whether women soak through a pad or tampon within 1 hour or soak through bedclothes or have ever needed treatment for iron or iron deficiency anaemia.13 Questions should also explore the impact of menstrual bleeding on women's quality of life. Quality of life issues is also important to explore in clinical studies assessing the impact on interventions in treatment of HMB. Only four of 10 women who perceive that they have excessive menstrual blood loss will consult their doctor about it.14 Social taboos related to menstruation exist across all cultures and the majority of the world's religions, which may explain why women have a reluctance to discuss issues relating to menstruation with clinicians, especially male clinicians. Menstrual taboos frequently call for the exclusion of women from religious activities and social activities, such as work, cooking, bathing, and also from sexual intercourse while they are menstruating and some religions this isolation continues after completion the menstrual cycle.15, 16 A common theme is that menstrual blood is “polluting” and women are “impure” while they are menstruating and women are required to ritually cleanse themselves after their menstrual cycle is complete. One argument is that these cultural and religious practices have been developed as a way of oppressing women but some anthropological researchers suggest this explanation alone is too simplistic 17 and cannot be applied across all cultural groups without understanding the specific cultural reasons underlying such practices. Open discussion of social and religious taboos related to menstruation may make it easier for all women to seek help when they have heavy blood loss and this may be of particular women with IBD who tend to have heavier blood loss and bleed for longer than other women. As in all women with HMB, it is important to take a careful history and examination to exclude other underlying causes of HMB such as polyps, uterine fibroids or malignancy.18 Assuming no other cause of bleeding is found that requires intervention one of the major decisions in management relates to whether a woman wishes to preserve her fertility and also if she requires contraception as these decisions will impact treatment choices. While limited numbers of studies have been carried out assessing the efficiency of treatment methods for HMB in specific populations of women with BD, there is general agreement that in general management approaches can be used as for women without BD, although non-steroidal anti-inflammatory drugs should be avoided as they may impact platelet function.19 Antifibrinolytic agents such as tranexamic acid and ε-aminocaproic acid stabilize the fibrin clots by making it resistant to breakdown by the plasmin in the fibrinolytic pathway. Placebo-controlled trials have demonstrated to reduce blood loss by up to 50% in women with heavy menstrual bleeding as well as showing improvements in the impact of HMB on social, leisure and work activities.20 Desmopressin (DDAVP) works by releasing VWF from storage bodies in the endothelial cells and can be used for treating HMB in women with type 1 VWD, women with the gene for haemophilia A who have low levels of FVIII, and also in women with inherited platelet function disorders. It is unlikely to be fully effective for women with type 2 VWD and does not work in women with type 3 VWD. It is most likely to be useful in conjunction with other therapies.19 Women with factor deficiencies who have severe bleeding may require clotting factor replacement, the use of which should follow standard clinical practice guidelines with doses titrated to severity of bleeding and the clotting factor level. Hormonal methods are an option for women who wish to preserve their fertility but are not planning pregnancy.19 They include progesterone only pills, combined oestrogen and progesterone pills, and medroxyprogesterone injections. Methods of long-acting reversible contraceptives (LARC) are being increasingly used and the levonorgestrel intrauterine system (LNG-IUS) is the method that has been studied the most in women with HMB.20 The progesterone only pill and the combined oral contraceptive (COC) pill have both been used to control HMB. Combined oral contraceptive pills are recommended in preference to progesterone only pill for control of HMB.20 Initially COC was recommended to be taken as 21 active days then seven placebo days so that bleeding could occur during those days. Increasingly the COC were used in a continuous cycle so that the placebo pills were not taken and the active pills continued. Not only does this provide effective contraception with no increase the risk of endometrial abnormalities but it also leads to amenorrhoea or reduced menstrual bleeding in up to three-quarters of women. Some women do experience troublesome break-though bleeding. Importantly, the vast majority of women resume normal menses after discontinuation of continuous cycle COC with no impact on fertility rates.21 The levenorgestrel intrauterine system (LNG-IUS) is a long-acting reversible contraceptives that provide effective contraception for 5 years with very low failure rates of <0.1%, which is similar to rates reported with permanent contraception. Irregular bleeding is reported in the first 6 months after insertion of LNG-IUS but after 2 years 75% of women report amenorrhoea or very light periods. After 5 years it can be replaced if contraception or control of menstrual bleeding is still required. Once discontinued there is a rapid return to fertility and it can also be introduced in the immediate postpartum period and is safe during breastfeeding.22 Studies in women with heavy menstrual bleeding have show that LNG-IUS is more effective than other methods at reducing menstrual blood loss and is recommended over combined oral contraceptives for this indication. Both the combined oral contraceptive pill and the LNG-IUS have shown improvements in quality of life in women with HMB.20 Progesterone-containing rod implants such as Nexplanon® and Jadelle provide effective contraceptive cover but their efficacy is reducing bleeding in women with HMB has not been studied. However, it is possible that the progestogen-only implants would not be as effective at controlling bleeding in women with HMB as the LNG-IUS as the unpredictable menstrual bleeding patterns or “spotting” experienced with the implants that tend to persist long-term and is often cited a reason women choose to discontinue using this form of contraception. Global endometrial ablation (GEA) uses high temperature or electrical (radiofrequency) energy to ablate the endometrium. Second generation techniques such as Thermachoice® or Novasure® can be carried out under local anaesthetic usually as a day procedure. Amenorrhoea is achieved in around 50% of women following GEA and rates may be higher with radiofrequency ablation techniques such as Novasure®. As many as one in three women will require retreatment or hysterectomy within about 5 years.23 Studies suggest that GEA is effective in women with coagulation disorders.24 Importantly GEA does not provide contraception and if pregnancy does occur the outcomes are poor with ectopic pregnancy and placenta accreta reported. Other treatable causes of abnormal uterine bleeding must be excluded before GEA is carried out. Hysterectomy provides definitive treatment for HMB but it is a major operation and it is more expensive and there is a higher rate of complications than with medical therapy. Hysterectomy is more expensive than LNG-IUS and provides equivalent improvements in health-related quality of life but a significant proportion of women initially treated with LNG-IUS go on to have a hysterectomy within 10 years.25 There are barriers to equity of access to options for treatment for HMB across the globe. This will in part be due to access to and delivery of health care in countries with more limited financial resources but in addition, there are barriers to and of agents for many of which are also be important for in such as the of have taken decisions that are likely to women's access to contraceptive agents by the of the for health to cover contraception that will make them more expensive for This may have an impact on women's to contraceptive agents for treatment of HMB and barriers to equity in health a unique to all women. estimated women will experience bleeding during pregnancy or after the of their each with most bleeding occurring in the postpartum Women with inherited bleeding disorders are more likely to have a postpartum only after the of the and delivery of the placenta but also in the postpartum days and is a with in many of the blood clotting factors such as FVIII, Other clotting factors such as are the clotting factor of women with IBD during pregnancy and impacts on management of these women during at the of childbirth, and in the The inheritance of IBD dominant, impacts on the of the the from either or both and this must be taken when plans for In when a for care for these women the following questions should be management of the of of an and for delivery of the is recommended in all women with IBD to reduce the risk of primary experienced clinical should provide care for the woman during pregnancy and at delivery and should an and/or with appropriate to ensure all appropriate issues relating to and the period have been risk factors for should be assessed before delivery and women should have access during Women should be at a with a blood with tranexamic acid is recommended for women for days postpartum to reduce the risk of secondary VIII and VWF are the clotting factors that increase during pregnancy to an that often a woman's bleeding phenotype of Women with mild type 1 VWD in the amount but not the function of and women who are carriers of haemophilia A or have mild haemophilia A are very likely to increase the and VWF levels to levels of by the of pregnancy so that no specific intervention is required at the of to ensure haemostasis. The and VWF levels will to levels in the first postpartum days so secondary or can Women with type 2 VWD will have an increase in VWF but will make more abnormal VWF so the bleeding phenotype is unlikely to be Women with type 3 VWD will not be to a significant increase in women are likely to require VWF at the of and in the postpartum period to reduce the risk of IX levels do not during pregnancy so women who have the gene for haemophilia B who have low levels of are likely to require at the of and in the postpartum period to reduce the risk of other disorders, the level is not of the bleeding risk in with deficiency and who have been to a tend to and that this will the for coagulation factor bleeding phenotype will have been by the of XI levels do not during in haemophilia care over recent have the life and quality of life for people with haemophilia who in countries with access to in care and clinical outcomes have been not only with advances in methods of but also in to decisions about out for haemophilia. genetic and are the methods of to for is common and is more often carried out to help with psychological than to help provide to help a about the pregnancy if the was affected by severe One of the most issues in pregnancy care relates to the recommended of in women who may be having an with a severe bleeding is the first in an with a BD and of to and clinicians is the risk of and bleeding. can result in long-term or especially bleeding the can be rapid and life and can occur after in with normal haemostasis with reported in around 1 in and in 1 by delivery and 1 by with rates in in by by i.e or are at risk of A review of bleeding reported at in with haemophilia reported that there is increase in the rate of and an rate of and to by by were over four times more likely to have a was associated with a risk of occurring in of by or The risk of is in to women haemophilia gene is This is as around of with haemophilia have no family history and one in three are due to a in female carrier so all with haemophilia is not is recommended by many for all women with likely to be affected by severe bleeding disorders to the risk of but this is not a Women have a higher risk of bleeding following and after two or more there is significant increase in the risk of placenta In some of the especially where women have is the of and is more and more for families for number of However, or with and especially or should be avoided in to have bleeding disorders as the risk of and is and blood during should be avoided in to have severe inherited BD. blood or blood should be taken to the clotting of the should be with blood and to haemophilia treatment or of until bleeding with severe IBD should be given four doses of oral for inherited disorders can be carried out in with applied after until is some to exclude in all with severe with bleeding symptoms or clinical symptoms of should have a In to with clinical of bleeding in women with IBD an important of care is and the psychological Women a of or or for having a genetic disease that they might on to their recessive disease, such as it is that males and females both are for the faulty gene from one generation to the However, females who inherit the from their tend to have or no bleeding symptoms whereas than males who inherit the from their more severe bleeding symptoms on the clotting factor level. This may explain why with disorders like haemophilia more and are more likely to than with Women with disorders were more likely to themselves for their disease than women with autosomal recessive disorders. is for women with if may be when women with haemophilia gene that they can have a with of and when a is Women may it to discuss carrier with their and family especially where there is a of understanding about the and its Women also feeling of of medical and can when become in treating their bleeding disorders and may have to with clinicians who have about the than they the aspects of care is to clinicians and families work using and provide care for people with bleeding disorders and their should be to take to discuss women's and help to attention has been given in recent years to the impact bleeding disorders on women from a clinical of and also In times of in the care of people with bleeding disorders, especially in the treatment of it is to these important and at haemophilia treatment should be of and to specific women's