Debra Pollard

Pregnancy in women with von Willebrand's disease or factor XI deficiency

Objective To assess the obstetric outcome in women with von Willebrands disease or factor XI deficiency.

The obstetric and gynaecological management of women with inherited bleeding disorders – review with guidelines produced by a taskforce of UK Haemophilia Centre Doctors’ Organization

Summary.  The gynaecological and obstetric management of women with inherited coagulation disorders requires close collaboration between obstetrician/gynaecologists and haematologists. Ideally these women should be managed in a joint disciplinary clinic where expertise and facilities are available to provide comprehensive assessment of the bleeding disorder and a combined plan of management. The haematologist should arrange and interpret laboratory tests and make provision for appropriate replacement therapy. These guidelines have been provided for healthcare professionals for information and guidance and it is also intended that they are readily available for women with bleeding disorders.

Quality of life during menstruation in patients with inherited bleeding disorders

Menorrhagia is a common and major problem for patients with inherited bleeding disorders, especially vWD. Quality of life during menstruation was assessed in 99 patients with inherited bleeding disorders including vWD (n = 57), carriers of haemophilia A (n = 17), carriers of haemophilia B (n = 7) and FXI deficiency (n = 18), and comparison was performed with an age‐matched control group (n = 69). A questionnaire was used that included four main sections: (i) general health, (ii) health and daily activities, (iii) dysmenorrhea and (iv) quality of life during the menstrual period. Although patients with inherited bleeding disorders felt that their health (in general) was very good, they had significantly poorer quality of life on all the scales used than controls. Thirty‐nine per cent reported having cut down on the amount of time spent on work and other activities as a result of their menstruation; 47% felt that they accomplished less than they would like during this period, 38% felt that they were limited in the kind of work and other activities that they could do, and 40% found that it took extra effort to perform their work. Fifty‐one per cent experienced moderate, severe or very severe dysmenorrhoea. Quality of life was statistically poorer in patients with vWD, menstrual scores> 100 according to the pictorial blood assessment chart (PBAC), those who had periods ≥8 days and those who experienced flooding or passage of clots. In conclusion, menstruation has a negative effect on the quality of life in patients with inherited bleeding disorders especially in those with objectively confirmed menorrhagia.

Pregnancy in carriers of haemophilia

Summary.  The aim of the study was to review the complications, management and outcome of pregnancy in carriers of haemophilia over a 10‐year period following the introduction of a multidisciplinary management guideline. Comparison was made to a 10‐year cohort prior to implementation of the guidelines. A retrospective review of case notes of carriers of haemophilia (41 haemophilia A, 12 haemophilia B) who had received obstetric care at the Royal Free Hospital between 1995 and 2005 was conducted. There were 90 pregnancies (65 live births, 13 miscarriages, 12 terminations). Prenatal testing was taken up in 97% (63/65) of pregnancies where the mother was known to be a carrier of haemophilia. The majority (71%; 46/65) chose only to have non‐invasive fetal sex determination. Seventeen (26%) had invasive testing (13 primarily for haemophilia and four primarily for chromosomal abnormalities). Termination of pregnancy was opted for in 67% (6/9) of pregnancies affected with haemophilia. Pregnancy was accompanied by a marked rise in factor VIII levels compared to only a small rise in factor IX levels. Invasive intrapartum monitoring techniques and instrumental deliveries were avoided in all pregnancies known to be at risk of haemophilia. Regional block was performed in 25 pregnancies for labour/delivery with no complications. The caesarean section rate was 47%. The incidence of primary and secondary postpartum haemorrhage was 19% and 2%, respectively. There were two neonatal head bleeding complications associated with prolonged labour or instrumental delivery. Availability of management guideline and care provided in a multidisciplinary approach can help to minimize bleeding complications in carriers of haemophilia and their newborns.

Menorrhagia in Adolescents with Inherited Bleeding Disorders

STUDY OBJECTIVES We reviewed the management and treatment outcomes of menorrhagia in adolescents with inherited bleeding disorders and assessed the impact of menorrhagia on their quality of life. DESIGN Retrospective review of case notes and a questionnaire study. SETTING Comprehensive-care hemophilia treatment center. PARTICIPANTS Adolescents with inherited bleeding disorders who had registered at the center and were attending the multidisciplinary hemophilia and gynecology clinic for management of menorrhagia. INTERVENTIONS Review of medical records and assessment of menstrual blood loss using the pictorial blood assessment chart and quality of life measurements during menstruation using a questionnaire. MAIN OUTCOME MEASURES Scores on pictorial blood assessment charts and quality of life measurements before and after treatment. RESULTS Of 153 girls aged 12 to 19 years who had registered at the center and had an inherited bleeding disorder, 42 (27%) attended the multidisciplinary clinic for management of menorrhagia. The majority (38/42; 90%) had experienced menorrhagia since menarche. Of the group, 5 (12%) required hospital admission for acute menorrhagia and severe anemia. Treatment options for menorrhagia included tranexamic acid, desmopressin, combined oral contraceptive pills, clotting factor concentrate, and the levonorgestrel intrauterine system. These treatment modalities, alone or in combination, were associated with a reduction in menstrual blood loss (median pre- and posttreatment pictorial blood assessment chart scores were 215 and 88, respectively) and improvement in quality of life scores (median pre- and posttreatment were 26 and 44, respectively). CONCLUSIONS Menorrhagia is a common symptom in adolescents with inherited bleeding disorders. It can present acutely, and it adversely affects quality of life. Treatment options include hemostatic and/or hormonal therapies and can improve the quality of life of affected girls.

Pregnancy complications and obstetric care in women with inherited bleeding disorders

Women with inherited bleeding disorders (IBD) require the input of a multidisciplinary team to improve outcomes of pregnancy. The role of the haemophilia nurse within the multidisciplinary team is to provide educational and emotional support to the women and to facilitate and co‐ordinate patient‐centred care. Prenatal diagnosis in cases of haemophilia is an integral part of the management of early pregnancy with a recent drive towards non‐invasive prenatal diagnostic techniques. There is a current lack of data on the risk of miscarriage and bleeding complications during pregnancy. A clear association has only been established in women with fibrinogen and factor XIII deficiency. In the affected neonate with severe bleeding disorders such as haemophilia, the risk of head bleeding is significant, and appropriate management of labour and delivery has an important impact on reducing the risk. Women with IBD are at risk of both primary and secondary postpartum haemorrhage. Appropriate risk assessment and advance planning for haemostatic cover can reduce the bleeding risk.

Monitoring low dose recombinant factor VIIa therapy in patients with severe factor XI deficiency undergoing surgery

Although factor XI (FXI) concentrate is an effective replacement therapy in severe FXI deficiency without inhibitors, some patients are unwilling to receive it because it is plasma-derived. We report on the use and monitoring of low dose, recombinant factor VIIa (rFVIIa, NovoSeven®), to cover surgery (caesarean section, cholecystectomy and abdominoplasty) in four female patients (FXI:C 2-4 IU/dl, aged 32-51 years) who wished to avoid exposure to plasma. None of our patients had inhibitors to FXI. Our aim was to find the optimal dose of rFVIIa by in vitro spiking of patient samples and to correlate this with the response to rFVIIa in vivo . Prior to surgery, venous blood was collected into sodium citrate with corn trypsin inhibitor and spiked with 0.25-1.0 μg/ml rFVIIa in vitro , equivalent to a 15-70 μg/kg dose of rFVIIa in vivo . Analysis using thromboelastometry and thrombin generation assays, triggered with tissue factor, showed that the thrombin generation assay was insufficiently sensitive to the haemostatic defect in these patients. A concentration of 0.5 μg/ml was as effective as 1.0 μg/ml FVIIa in normalising thromboelastometry in vitro in all four patients. Therefore, patients received 15-30 μg/kg rFVIIa at 2-4 hourly intervals with tranexamic acid 1g every six hours. Post treatment samples were taken at 10-240 minutes and showed initial normalisation of thromboelastometry with gradual return to baseline after 2-4 hours. In conclusion, low-dose rFVIIa therapy was successfully used in four patients with severe FXI deficiency undergoing surgery to prevent bleeding and can be monitored using thromboelastometry.

The experience of girls and young women with inherited bleeding disorders.

Haemophilia carriers and women with inherited bleeding disorders (IBD) experience menorrhagia, bleed following dentistry, surgery, injury or childbirth. Symptoms are easily treated leading to full and active lives. Nevertheless, some girls and women suffer with abnormal bleeding for many years before diagnosis. We explored the experiences of girls and young women (aged 9–34 years) with IBD by means of focus groups which consisted of moderated discussion addressing specific aspects of bleeding, management and coping strategies. Subsequently, these issues were explored further though a paper‐based questionnaire distributed via five specialist haemophilia centres in the UK. The study suggested that young women with IBD who are managed at haemophilia centres receive appropriate care and feel well supported. Although the clinic‐based literature available to these women is “fit for purpose”, it does not fully address the perceived needs specifically regarding sex, menorrhagia, conception and childbirth, the Pill, tattoos/piercings and so on, leading many to turn to other information sources. Most of those who responded to our survey are confident in their lives, able to manage their IBD and take pragmatic views towards the inherited nature of their condition. But there is a substantial subgroup of women who experience stigmatization, isolation and bullying and express concerns relating to fertility and conception. Overall, this cohort would benefit from opportunities for mutual support. This could be via Internet‐based social networking and may be of particular value to those who are unable to seek help from traditional medical services due to religious or other cultural barriers.

Prophylaxis in severe prothrombin deficiency.

Severe prothrombin (Factor II, FII) deficiency is an extremely rare autosomal recessive condition with an estimated incidence of 1:2 million and an increased prevalence in populations where consanguineous partnerships are more common. International registry data indicate that patients with a FII of <10 iu/dl have a significant risk of severe spontaneous bleeding including haemarthrosis and intracerebral haemorrhage. To our knowledge there is only one published case report of the use of prophylactic FII infusions in an individual with severe prothrombin deficiency. We describe the case of a boy with severe prothrombin deficiency who was treated with on demand prothrombin complex concentrate up to the age of 6 years, but in response to an increasing number of spontaneous bleeding episodes and increased levels of exercise was started on regular prophylaxis. Our patient was born by an induced vaginal delivery at term to Caucasian parents at that time residing overseas. He was given intramuscular vitamin K at birth with no adverse effects. At 4 d of age, he bled significantly from the umbilical stump requiring two attempts at suturing to control bleeding. No coagulation screen or factor assays were performed at this time. At 1 month he was investigated for fresh rectal bleeding which required a blood transfusion. At 4 months he was diagnosed with severe prothrombin deficiency when his FII level was found to be between 1–3 iu/dl. His parents were found to have FII levels of 68 and 54 iu/dl and further enquiry revealed that his maternal grandmother and his paternal grandfather were first cousins. Baseline thromboelastometry measurements were insensitive to his prothrombin deficiency but thrombin generation assay of platelet poor plasma was reduced. His family predominantly lived overseas until he was 6 years old and throughout this time he required on-demand treatment with prothrombin complex concentrate (Prothrombinex, Defix and Octaplex) for trauma-induced bleeding episodes. These tended to be soft-tissue and muscle bleeds although there were at least two haemarthroses when he was 5 years old. The family settled back in the UK when he was 6 years old and about to attend school. At this point he was having a number of soft tissue bleeding episodes with no clear traumatic trigger, so for this reason, and in order that his activities at school need not be circumscribed, he was started on prophylactic prothrombin complex concentrate (Octaplex, Octapharma) 40 iu/kg by Factor IX (FIX) content, administered once a week. He was initially treated at home by one of our haemophilia Clinical Nurse Specialists who then taught his mother to treat him. Aside from occasional gum bleeding associated with erupting adult teeth, which is managed with tranexamic acid mouth wash, he had no spontaneous or trauma-related bleeding episodes for 18 months whilst on prophylaxis. Within the last few weeks he has had one severe spontaneous knee bleed 6 d after treatment and, given that his FII level was 8 iu/dl at 5 d, it is reasonable to conclude that a level below this will not prevent bleeding episodes. We plan to increase the frequency of his prophylaxis to every 5 d to prevent further breakthrough bleeds. He is involved in football, athletics, tennis, cricket and swimming at school. He is now 9 years old and is likely to be able to treat himself within the next 12 months. Table I and Fig 1 show his FII, FIX and Factor X levels and Thrombogram parameters pre-infusion, and 1 and 4 h post-infusion.

Review of a multidisciplinary clinic for women with inherited bleeding disorders

Dear Editor, Women with inherited bleeding disorders are particularly at risk of bleeding complications from the regular haemostatic challenges during menstruation and child birth. During the last decade, there has been an international research interest in women with inherited bleeding disorders and this has led to considerable progress in the identification of obstetric and gynaecological problems in these women, as well as raising the clinical awareness among their care providers. Menorrhagia is the commonest bleeding symptom in women with inherited bleeding disorders and could be the first or only presenting symptom. Child birth presents a haemostatic challenge. Thus these women require specialized and individualized care during pregnancy to include preconceptual counselling, prenatal diagnosis, and antenatal, intrapartum and postnatal care. A multidisciplinary approach has been recommended [1]. A multidisciplinary clinic was set up at the Katharine Dormandy Haemophilia Centre and Haemostasis Unit in 2002. A review of this clinic incorporating a quality of care survey was conducted covering the years 2002–2005. (This has previously been published in abstract form [2].) The healthcare professionals included a consultant haematologist (C.A. Lee), a consultant obstetrician and gynaecologist (R.A. Kadir), a haemophilia nurse specialist (D. Pollard), and a family therapist (N. Dunn). Between October 2002 and September 2005, 178 patients were seen at the clinic with 312 appointments. The most common diagnoses were carrier of haemophilia, 50 (28%), von Willebrand disease (VWD), 44 (24%), and factor XI (FXI) deficiency, 28 (16%). North London has a large population of Ashkenazi Jewish people in whom the carriage rate for FXI deficiency is 8% [3]. The most common management issues at the appointments were menorrhagia, 137 (44%), and pregnancy, 112 (36%). There were 72 women who experienced menorrhagia and after being fully assessed various treatments were offered and prescribed – in descending order of use, tranexamic acid, combined oral contraceptive pill, levonorgestrel-releasing intrauterine system [4], desmopressin, progestogens (oral cyclical or injectable), clotting factor concentrate and gonadotrophinreleasing hormone analogue with add back therapy. Uterine artery embolization, endometrial ablation, hysterectomy, and myomectomy were the surgical options offered/performed when appropriate. There were 13 women who attended preconceptual counselling, five carriers of haemophilia A; one carrier of haemophilia B; one doubtful bleeding state; three FXI deficiency, one partner with a bleeding disorder, one thrombotic disorder, and one carrier of haemophilia A with VWD. Of the 112 women seen for management of pregnancy there were 28 who wanted to discuss prenatal diagnosis, 27 who were carriers of haemophilia and one who had FXI deficiency. The options that were offered included second-trimester ultrasound scanning; analysis of free fetal DNA (ffDNA) in maternal blood [5] and first-trimester ultrasound scanning; chorion villus sampling (CVS); and amniocentesis. The majority opted for non-invasive prenatal diagnosis – eight had second-trimester ultrasound scanning and 16 ffDNA with first-trimester ultrasound scan. A CVS was performed for five women, four of whom had shown a male fetus on ffDNA. It was possible to send a quality of care survey to 111 women who attended the clinic and there was a 61% response rate – 88% valued the presence of the haematology and gynaecology professionals in the same consultation; 90% considered this model of care to be beneficial or quite beneficial; 92% felt included in the decision-making about their care; and Correspondence: Rezan A. Kadir, Haemophilia Centre and Haemostasis Unit, Royal Free Hospital, Pond Street, London, NW3 2QG. Tel.: 0207 794 0500; fax: 0207 4726759; e-mail: rezan.abdul-kadir@royalfree.nhs.uk