Women and inherited bleeding disorders - A review with a focus on key challenges for 2019.

The area of women and inherited bleeding disorders has undergone quick expansion in recent years. More patients are being identified and expertise to diagnose and manage these patients is now essential for practising physicians. Programs to help educate and empower patients and caregivers are now in place. Common inherited bleeding disorders affecting women include von Willebrand disease (VWD), inherited platelet disorders, and rare inherited bleeding disorders such as factor VII (FVII) deficiency and factor XI (FXI) deficiency. Specific clinical tools have been developed to help clinicians and patients screen for the presence of these bleeding disorders in both adult and pediatric populations. Affected women can experience heavy menstrual bleeding and resulting iron deficiency anemia, postpartum hemorrhage, and hemorrhagic ovarian cysts which need to be properly managed. Excessive bleeding can adversely affect quality of life in these women. Front line therapy for bleeding in mild cases focuses on the use of non-specific hemostatic agents such as DDAVP ®, tranexamic acid and hormonal agents but specific factor replacement and/or blood products may be required in more severe cases, in severe bleeding or as second line treatment when bleeding is not responsive to first line agents. Iron status should be optimised in these women especially in pregnancy and use of an electronic app can now help clinicians achieve this. These patients should ideally be managed by a multidisciplinary team whenever possible even remotely. Although clinical research has closed some knowledge gaps regarding the diagnosis and management of these women, there remains significant variation in practise and lack of evidence-based guidelines still exists in many spheres of clinical care in which caregivers must rely on expert opinion. Ongoing efforts in education and research will continue to improve care for these women and restore quality of life for them.

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.

Prophylaxis in severe forms of von Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN).

The bleeding patterns of severe von Willebrand's disease (VWD) adversely affect quality of life, and may be life threatening. There is a presumed role for prophylaxis with VWF-containing concentrates, but data are scarce. The von Willebrand Disease Prophylaxis Network (VWD PN) was formed to investigate the role of prophylaxis in clinically severe VWD that is not responsive to other treatment(s).Using a retrospective design, the effect of prophylaxis was studied. Availability of records to document, or reliably assess, the type and frequency of bleeding episodes prior to, and after, the initiation of prophylaxis was required. Annualized bleeding rates were calculated for the period prior to prophylaxis, during prophylaxis and by primary bleeding indication defined as the site accounting for more than half of all bleeding symptoms. The Wilcoxon signed-rank test of differences in the medians was used. Sixty-one subjects from 20 centres in 10 countries were enrolled. Data for 59 were used in the analysis. The median age at onset of prophylaxis was 22.4 years. Type 3 VWD accounted for the largest number (N = 34, 57.6%). Differences in bleeding rates within individuals during compared with before prophylaxis were significant for the total group (P < 0.0001), and for those with primary bleeding indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding (P = 0.001). The effect of prophylaxis was similar among those age < 18 years and those ≥ 18. One person developed an inhibitor during treatment. We conclude that prophylactic treatment of VWD is efficacious.

A retrospective cohort study of cancer incidence among patients treated with radiosynoviorthesis.

Radiosynoviorthesis (RS) is an intra-articular injection of a radioactive colloid for the treatment of synovitis administered most often to patients with rheumatoid arthritis or haemophilia. Although highly cost-effective in comparison with surgical or arthroscopic synovectomy, the risk of cancer associated with this treatment is not well known. We evaluated the incidence of cancer in a group of patients treated with RS. A cohort of 2412 adult patients with a variety of underlying conditions (mainly rheumatoid arthritis) and treated with at least one RS between January 1976 and December 2001, was recruited from two centres in Montréal. Cancer incidence and mortality data for cohort members over that time period were obtained from regulatory agencies using linkage. Background rates for all and specific types of cancer were obtained for the provincial (Québec) and national (Canada) population according to age, gender and calendar period categories. Category-specific rates in the cohort were compared with rates in similar categories from the general population generating standardized incidence ratios (SIR). The effects of specific isotope doses and of number of RS treatments were analysed using a Cox-regression model. No increase in the risk of cancer was observed (SIR 0.96; 95% confidence interval 0.82-1.12). There was no dose-response relationship with the amount of radioisotope administered or number of RS treatments. The study provides some indication for the safety of the procedure but homogenous diagnostic groups of younger patients (such as haemophilic patients) receiving RS will need more evaluation.

Results of an unrelated transplant search strategy using partially HLA-mismatched cord blood as an immediate alternative to HLA-matched bone marrow.

Cord blood (CB) is an alternative to other sources of stem cells for transplantation. However, the impact of including CB in the initial strategy of unrelated graft search in a cohort of patients has been the object of limited analysis. Here, we report the results of such a strategy in 91 consecutive children. Absence of mismatch was required for adult donors, and up to two mismatches were allowed for CB grafts, with a nucleated cell dose over 2.5 x 10(7) cells/kg. A graft was found for 84 of the 85 children who remained available for a 3-month search. In all, 64 patients were transplanted, 36 with CB and 28 with bone marrow (BM). Primary graft failure, acute grade II-IV and extensive chronic graft-versus-host disease occurred in five, five and zero CB, and in three, one and two BM patients, respectively. The 3-year survival was 59% in CB and 57% in BM patients. Accepting CB as a source of stem cells offers a graft to almost every child in need of an unrelated transplantation, with a probability of survival similar to that of unrelated BM transplantation.

An evaluation of the stability of factor VIII inhibitors in plasma and plasma dried on filter paper discs stored at room temperature.

The transportation of plasma specimens to specialized haemophilia centre laboratories for anti-factor VIII inhibitor titre determination is often necessary. The routine method of transporting frozen specimens on dry ice is limited by its cost and need for special handling. The present study was undertaken to evaluate the effect of storing specimens at room temperature on the FVIII inhibitor titre determinations using the Bethesda assay. Specimens stored both in liquid phase as well as adsorbed onto filter paper discs were studied. The results of the present study demonstrate that plasma specimens stored for up to 2 weeks at room temperature, either in liquid phase or adsorbed onto filter paper, yield equivalent measures of FVIII inhibitor titres using the Bethesda assay to plasma specimens stored frozen at -70 degrees C. Plasma specimens dried on filter paper discs and stored at room temperature offers a reliable, more practical and less expensive alternative to frozen plasma as a means of transport to specialized referral laboratories for analysis of anti-FVIII titres.

Optimization of storage conditions for diluted working solutions of porcine factor VIII and performance of the Bethesda assay for the determination of antiporcine FVIII inhibitor titres.

The use of porcine factor VIII (FVIII) (Hyate:C, Ipsen) has proven to be very successful in treating patients with FVIII inhibitors. The best way to predict the usefulness of porcine FVIII therapy, and/or to estimate the appropriate treatment dose in a given patient, is to measure the patient inhibitor titre against porcine FVIII with the Bethesda assay, using porcine FVIII as the source of FVIII in the assay. The goals of the present study were to (1) find the optimal storage temperature, diluent and concentration for a working solution of porcine FVIII to be used as the source of FVIII for the porcine Bethesda assay, (2) assess the reliability of the labelled FVIII units in the preparation of such working solutions of porcine FVIII and (3) compare the inhibitor titres determined by the Bethesda assay using both porcine and human standard reference curves for measuring residual FVIII. The results of the present study demonstrate that a ready-to-use working solution of 1 U mL(-1) of Hyate:C diluted in human FVIII deficient plasma, either containing or deficient in von Willebrand factor antigen, is stable for up to 12 months, at -20 degrees C. The preparation of the 1 U mL(-1) working solution could be reliably calculated based on the units indicated on the vial label. Finally, using the human standard curve yields similar results to using the porcine standard curve for measuring any titre of allo- or auto-antibody against FVIII in the Bethesda assay, using Hyate:C as the source of FVIII. These findings are of practical value when performing a porcine FVIII-based Bethesda assay.

Quantitative changes of Ricinus communis agglutinin I and Helix pomatia lectin binding sites in the acrosome of rat spermatozoa during epididymal transit.

During passage through the epididymis, spermatozoa undergo a number of changes which result in their acquisition of fertility and motility. Some of the changes that occur include loss of the cytoplasmic droplet and changes in sperm morphology, metabolism and properties of the nucleus and plasma membrane. Changes have also been reported in the acrosomic system of mammalian spermatozoa during their transit through the epididymis. In the present study, the quantitative changes of the glycoconjugate content in the acrosome of rat spermatozoa were examined during their passage through the epididymis using lectin-colloidal gold cytochemistry. Various regions of the epididymis (initial segment, caput, corpus and cauda epididymidis) were fixed by perfusion with 1% or 2% glutaraldehyde buffered in sodium cacodylate (0.1 M), dehydrated in ethanol and embedded without osmication in Lowicryl K4M. Lectin-colloidal gold labeling was performed on thin sections using Ricinus communis agglutinin I (RCA I) or Helix pomatia lectin (HPL) to detect D-galactose- and N-acetyl-D-galactosamine-containing glycoconjugates, respectively. The labeling density over the acrosome of the acrosomic system was evaluated as the number of gold particles per microns 2 of profile area using a Zeiss MOP-3 image analyzer. The overall mean labeling densities over the acrosome of spermatozoa for each lectin was estimated from 4 rats and over the four distinct epididymal regions. The mean labeling density of the acrosome with RCA I and HPL showed a similar pattern along the epididymis, although RCA I revealed approximately twice as many gold particles per epididymal region. In either case, there was a significant decrease in the labeling density of the acrosome of spermatozoa between the initial segment or caput epididymidis and cauda epididymidis (p less than 0.01). A similar decrease was also noted between the initial segment and corpus epididymidis (p less than 0.01). No change was found between the initial segment and caput epididymidis. Controls showed a virtual absence of labeling. These results suggest that in addition to a multitude of changes occurring to spermatozoa during epididymal transit, there are also significant quantitative changes in the glycoconjugate content within the acrosome.