Inhibition of tissue factor pathway inhibitor by the aptamer BAX499 improves clotting of hemophilic blood and plasma.

BACKGROUND: Tissue factor pathway inhibitor (TFPI) is the major inhibitor of tissue factor-initiated coagulation, making it an interesting and novel therapeutic target in hemophilia treatment. The aptamer BAX499 (formerly ARC19499) is designed to improve hemostasis by specifically inhibiting TFPI. OBJECTIVES: The aim of the study was to examine the concentration-dependent augmentation of clotting by BAX499. METHODS: Whole blood clot formation was quantified by rotational thromboelastometry and thromboelastography, and thrombin generation in platelet-poor plasma was assessed with the calibrated automated thrombogram, in samples from patients with congenital hemophilia A (N=55) and B (N=11), patients with acquired hemophilia A (N=1), and healthy controls (N=37). RESULTS: BAX499 significantly improved clotting of samples from hemophilic patients in a concentration-dependent manner, resulting in clotting profiles in samples from patients with severe hemophilia that were similar to those of healthy controls. CONCLUSION: BAX499 improved ex vivo clotting parameters in blood and plasma from patients with hemophilia A and B with different severity of disease, and also in a patient with acquired hemophilia. These results further support the contention that anti TFPI strategies may be an effective treatment for hemophilic patients.

Postoperative paraneoplastic factor VIII auto-antibodies in patients with solid tumours.

Paraneoplastic FVIII antibodies may occur concurrent with the diagnosis or at various times after diagnosis and treatment of cancer. Between 2002 and 2009, we observed two patients with acquired haemophilia A due to an FVIII auto-antibody, which appeared 4 and 5 months after uncomplicated cancer surgery. We aimed to evaluate if such an association of cancer surgery and FVIII antibody formation has been observed previously. We retrieved all published case reports of cancer-associated FVIII auto-antibodies from PubMed for the period 1950-2010. The search in the literature revealed 13 patients in whom a FVIII inhibitor developed after uncomplicated surgery for cancer and a bleeding-free time interval of up to 6 months; 11/15 patients had abdominal cancers (five colon cancer, four pancreatic cancer, gastric cancer and choledochus carcinoma one each). The median time period between surgery and antibody detection was 3 months (1 week-6 months). In most cases, the antibody titre was low (median: 14 BU mL⁻¹, range: 1.7-64 BU mL⁻¹). Immunosuppressive treatment was successful in most of the cases - nine of the treated patients reached a sustained CR of the antibody after a median time of 3 months. Postoperative paraneoplastic FVIII inhibitors may be regarded as a special, not yet recognized subgroup of acquired FVIII antibodies. They share some characteristics with postpartum FVIII inhibitors with regard to the latency period between the triggering event and the appearance of the antibody, and between the usually low antibody titres and their good response to immunosuppressive treatment.

[Austrian haemophilia registry: up-date 2008 ]. / Osterreichisches Hämophilie Register: Update 2008.

The treatment of haemophilia requires continuous development of knowledge related to various aspects of diagnosis and therapy. It is, therefore, essential to collect valid and representative data, which are comparable on an international level. The Austrian Haemophilia Registry was set up by the Scientific Advisory Panel of the Austrian Haemophilia Society and by the patient organisation. For the design, it was decided to divide the registry into three sections, two concerning quality control and a third concerning scientific questions, the latter requiring written informed consent. A web-based software is used to collect data. Transfer and storage of data are secured and the server is situated in a computer center with video and access control. Data entry was initiated early 2008. Currently, only preliminary data are available. Our further focus is on continued data entry, which will further enable us to provide information concerning the characteristics of the haemophilia patient population in Austria and the actual treatment modalities used.

Survival in a cohort of patients with haemophilia at the haemophilia care center in Vienna, Austria, from 1983 to 2006.

Survival of patients with haemophilia is still a relevant issue of great interest. A survival analysis was conducted among 226 patients with haemophilia A and B (128 severe haemophiliacs), who were treated at the haemophilia care centre in Vienna. Information on mortality in our patient cohort was obtained from the Austrian Central Death Register. Overall, 96 of a total of 226 patients (42.5%) died between 1983 and 2006; 37 patients (38.5%) died due to HIV-infection, 15 due to HCV infection, 15 due to bleeding (15.6%, respectively) and 29 (30.2%) due to various other causes. The mortality of HIV-positive patients was 74.3% (n = 55) and that of HCV-positive patients was 40.4% (n = 55) in the analysed period. The patient mortality rates were compared with those of the general Austrian male population following adjustment for age and calendar period. We found that the cumulative relative survival of all patients was 0.694 (95% CI 0.614-0.767). The cumulative relative survival of patients with severe haemophilia (FVIII or IX level < or =1%) was 0.489 (0.394-0.579), but was normal (0.986; 95% CI 0.858-1.082) for patients with mild or moderate haemophilia (FVIII or IX level 2-50%). The survival rate was lowest in HIV-positive patients (0.287; 95% CI 0.186-0.398), but was also decreased to 0.874 (0.776-0.951) in HIV-negative patients. It can, therefore, be concluded that the survival of patients with severe haemophilia is still decreased compared to those with non-severe haemophilia and the general male population, regardless of HIV-infection.

The impact of severe haemophilia on the social status and quality of life among Austrian haemophiliacs.

Although many studies of the impact of haemophilia on the quality of life were conducted, there is hardly any data on the social status of haemophiliacs. It was the aim of our study to obtain data on the social status of Austrian haemophiliacs and to compare these with an age- and sex-matched reference population. Furthermore, we collected data on the quality of life of haemophilia patients. We conducted a case-control study in two Austrian haemophilia centres with 53 patients (mean age 36.7 +/- 10.6 years) and 104 male controls (mean age 36.7 +/- 11.1 years). Socio-demographic data were collected using a standardized questionnaire and quality-of-life data using the SF-36. More patients (56.6%) than controls (37.5%) were married (P = 0.023), whereas more controls (17.3%) than patients (3.8%) had a partner with whom they were not married (P = 0.016). The percentage having children was equivalent in both groups (47% and 41% respectively), but controls had more children (mean number 1.5 in patients and 2.1 in controls, P < 0.007). A greater number of patients was unemployed (34% of patients, 9% of controls, P < 0.001) as well as retired (23% and 4% respectively; P < 0.001). Patients had worse scores regarding physical functioning, role-physical, bodily pain and general health (P < 0.001), whereas vitality, social functioning, role-emotional and mental health were similar in both groups. Despite their disability, most of the Austrian haemophiliacs share a sound family environment. This suggests that they are highly capable of coping with their chronic disease and is indicated by good scores for role-emotional and mental health.

Adult-type hypolactasia and calcium availability: decreased calcium intake or impaired calcium absorption?

UNLABELLED: Adult-type hypolactasia, as mediated by a widespread genetic predisposition, not only reduces calcium intake but also calcium absorption in the presence of high amounts of lactose and may, therefore, promote osteoporosis. A lactose-reduced diet and lactose-free calcium supplements may reverse this imbalance. INTRODUCTION AND HYPOTHESIS: Adult-type hypolactasia (HL) defined by the LCT(-13910) polymorphism may reduce calcium intake by reducing dairy consumption and, therefore, promote osteoporosis. This study aimed to evaluate whether lactose also decreases intestinal calcium absorption in subjects with HL and whether lactose-reduced diet and lactose-free calcium supplementation as recommended could maintain bone mineral density (BMD). METHODS: Based on LCT genotyping, 73 postmenopausal women with and without HL underwent a conventional H(2) breath test with a concomitant oral strontium absorption test lasting 150 minutes, which closely reflects intestinal calcium absorption. In addition, we compared bone-specific laboratory parameters, lumbar and femoral BMD, and spinal radiographs to a similar bone assessment 5 years earlier. RESULTS: LCT genotyping and functional lactose malabsorption tests were highly correlated. Dairy product consumption was reduced by 80% in HL individuals. During concomitant lactose application, mean strontium absorption was blunted by 54% in HL subjects after 150 minutes (1272 +/- 629 microg/L vs. 2020 +/- 1130 microg/L in lactose tolerant subjects, p=0.001). Nevertheless, BMD in HL subjects remained stable with lactose-free calcium supplements during the observation period. CONCLUSION: Both decreased calcium intake as well as lactose-associated impaired calcium absorption may predispose subjects with HL to osteoporosis. Lactose-free calcium supplementation may help to maintain BMD in HL subjects.