Factor VIII mutation and desmopressin-responsiveness in 62 patients with mild haemophilia A.

Utilization of the synthetic vasopressin analogue (1-deamino-8-D-arginine-vasopressin, DDAVP) in treatment of mild haemophilia A (MHA, specific clotting factor VIII activity level 0.05-0.4 IU mL(-1) ) is convenient and effective for many but not all patients. Genetic testing for patients with MHA is increasingly recognized as providing valuable information for patient care beyond informing reproductive decisions, and as more patients are genotyped, mutation data can be utilized to individualize treatment decisions. To determine if genetic information informs response to DDAVP, a retrospective chart review was performed under Institutional Review Board approval to extract patient data with MHA, genetic mutation results, and response to DDAVP challenge. 62 patients met inclusion criteria. Complete responses (C) presented in mean value IU mL(-1) (range), were recorded for 32 of 62(52%) subjects: pre 0.19(0.04-0.45) and post 0.78(0.5-1.95); partial responses (P) were recorded for 15 of 62(24%) subjects: pre 0.1(0.06-0.15) and post 0.4(0.3-0.47); responses that were not clinically significant (N) were recorded for 15 of 62(24%) subjects: pre 0.17(0.02-0.34) and post 0.25(0.03-0.44). Subjects (related and unrelated) with the same mutation showed a trend towards a similar response to DDAVP. Eight genotypes were common to two or more subjects (n = 26). Two genotypes were concordant in all subjects [p.Ser2192Ile n = 3(C), p.Ala2220Pro n = 2(P)]. Of mutations in the C1 or C2 domains, 13 of 15(87%) subjects responded to DDAVP [C = 9(60%); P = 4(27%); n = 2(13%)]. Baseline FVIII:C did not predict magnitude of response to DDAVP. Genetic mutation results can assist with predicting DDAVP responsiveness, but baseline FVIII:C may not.

Screening for fall risk in patients with haemophilia.

Many risk factors for falls identified in the general population are found in patients with haemophilia. Furthermore, fall risk increases with age and patients with haemophilia are increasingly entering the over 65 age group. After a fall occurs, there are often behavioural changes that have significant health consequences and further increase fall risk. Fall risk can be quickly assessed in the clinical setting with specific questions in the medical history and by a variety of performance-based screening tools. Identification of fall risk enables early intervention, thereby preventing injury and fear of physical activity, both of which have been associated with falling and may carry an increased risk in patients with haemophilia. Review of the existing literature on assessment of fall risk reveals the importance of screening in the clinical setting, which is commonly done via a fall history and performance-based assessment tools. Selecting appropriate fall risk screening tools is an important step in identifying and providing optimal interventions for those at risk. Assessments of fall history, fear of falling, gait velocity, gait variability and vestibular dysfunction are suggested as screening tools for patients with haemophilia. Additional research is needed to determine the optimal screening, evaluation and treatment techniques for these patients. The longitudinal physical therapy care provided by Haemophilia Treatment Centres presents a unique opportunity for instituting measures that will reduce the incidence of falling in patients with haemophilia.

Survey of current prophylaxis practices and bleeding characteristics of children with severe haemophilia A in US haemophilia treatment centres.

Every other day (qod) factor VIII prophylaxis prevents joint bleeds in children with severe haemophilia A. Although three times weekly or qod prophylaxis is recommended by the National Hemophilia Foundation (NHF), how widely these practices have been adopted is not known. We sought to define current prophylaxis practices at US haemophilia treatment centres (HTCs). An email survey was distributed to US HTCs, utilizing web-based membership rosters of the Centers for Disease Control (CDC) and the Hemostasis Thrombosis Research Society (HTRS). Of 62 HTCs responding, prophylaxis is initiated on a three times weekly schedule in 29 (46.8%), twice weekly in 13 HTCs (21.0%) and once weekly in 20 HTCs (32.2%). Central venous catheters are used to infuse factor prophylactically at 55 HTCs (88.7%), including in 100% of children initiating prophylaxis at 19 HTCs (30.6%) and in 50% of those at 41 HTCs (66.1%), but avoided altogether at seven HTCs (11.3%). Prophylaxis is initiated after one or more bleeds in 56 HTCs (90.3%), but after the first bleed in only 28 HTCs (25.2%). Among 226 newborns with severe haemophilia A in 62 HTCs, 1.82 births/HTC/year, the median age at first bleed, excluding circumcision, is 7 months. Of the 113 (53.5%) newborns who underwent circumcision, 62 (54.9%) bled. Despite a recommended standard of three times weekly prophylaxis, over half of surveyed HTCs do not follow these guidelines, and nearly one-third begin prophylaxis on a once weekly schedule to delay or avoid the need for central venous access.

Factor X deficiency and pregnancy: preconception counselling and therapeutic options.

Women with factor X deficiency (FXD) who want to become pregnant face uncertain risks to themselves and to an unborn infant from haemorrhagic complications during pregnancy and at parturition. Women with FXD may also experience difficulty achieving pregnancy secondary to haemorrhagic symptoms of the reproductive organs. Case reports describe differences in bleeding phenotypes and pregnancy outcomes that are not easily correlated with prepregnancy bleeding symptoms or factor X levels. The aim of this article is to identify factors for consideration and information to assist the physician in counselling women with FXD who want to become pregnant, and to offer guidelines for management where appropriate. We identified cases of pregnancy among women with FXD and their outcomes from the literature; 15 women with 24 pregnancies were identified and 18 were successful. The women in this small cohort did not have an increased rate of spontaneous abortion, (8.3% vs. 13.5% in the general US population) but did have a 2.5-fold increased risk of preterm labour (37.5% vs. 12.2% in the general US population). The role of prophylaxis to control reproductive haemorrhagic symptoms, including haemorrhagic complications of pregnancy has not yet been defined, but use of prophylaxis may allow more women to be able to attempt pregnancy. Women who had access to a tertiary care centre with a multidisciplinary team including an obstetrician with high-risk obstetric training, a haematologist, a perinatologist, and access to a reference laboratory and blood bank were able in most cases to successfully deliver healthy, term infants.

Gene transfer into murine hematopoietic stem cells with helper-free foamy virus vectors.

Gene transfer into hematopoietic stem cells (HSCs) is an ideal treatment strategy for many genetic and hematologic diseases. However, progress has been limited by the low HSC transduction rates obtained with retroviral vectors based on murine leukemia viruses. This study examined the potential of vectors derived from the nonpathogenic human foamy virus (HFV) to transduce human CD34(+) cells and murine HSCs. More than 80% of human hematopoietic progenitors present in CD34(+) cell preparations derived from cord blood were transduced by a single overnight exposure to HFV vector stocks. Mice that received transduced bone marrow cells expressed the vector-encoded transgene long term in all major hematopoietic cell lineages and in over 50% of cells in some animals. Secondary bone marrow transplants and integration site analysis confirmed that gene transfer occurred at the stem cell level. Transgene silencing was not observed. Thus vectors based on foamy viruses represent a promising approach for HSC gene therapy. (Blood. 2001;98:604-609)

Transduction of feline hematopoietic cells by oncoretroviral vectors pseudotyped with the subgroup A feline leukemia virus (FeLV-A).

The domestic cat is an outbred species with many identified analogues of human genetic diseases. Therefore, it has the potential to serve as a large animal model for evaluating the feasibility of hematopoietic stem cell gene therapy. This study compared gene transfer rates into feline hematopoietic progenitors by oncoretroviral vectors pseudotyped with the subgroup A feline leukemia virus (FeLV-A), the gibbon ape leukemia virus (GALV), and the murine amphotropic virus. Gene transfer rates were superior with the FeLV-A pseudotypes, which were then tested for their ability to transduce a cat hematopoietic repopulating cell. At more than 1 year posttransplantation, persistent marking was seen in both lymphoid and myeloid lineages of a myeloablated domestic cat that had received autologous marrow cells transduced with an FeLV-A pseudotyped vector.