Low vitamin C status and hypermobility-related disorders in patients with bleeding disorder of unknown cause.

INTRODUCTION: Bleeding disorder of unknown cause (BDUC) is a challenging diagnosis that predominantly affects women. Previous investigations into connective tissue disorders (CTD) and vitamin C have not been conducted. AIM: To examine the association between hypermobility-related disorders, vitamin C status and BDUC. METHODS: Patients were selected following laboratory and genetic screening that yielded negative results for known hemostasis disorders. Sixty patients with BDUC and an ISTH BAT score ≥ 10 underwent clinically examination for skin hyperextensibility and for hypermobility assessed by Beighton score. Vitamin C was analyzed by high-performance liquid chromatography. Genetic screening for causal variants in 42 CTD genes was performed. RESULTS: The majority of patients were female (56/60). Median ISTH BAT score was 13 (range 10-23). Beighton score was positive in 29/60 patients compared to 1/20 healthy controls (HC) (p < .001). Hyperextensive skin was observed in (18/60) patients, and none (0/20) of the HC (p = .0041). Ten patients met the clinical diagnostic criteria for hypermobile Ehlers-Danlos syndrome (hEDS), and one patient was diagnosed with Noonan syndrome. Genetic screening excluded various subtypes of EDS with known genetic backgrounds. Average vitamin C level was adequate, but lower than in HC (55.9 vs. 70.4 µmol/L; p = .001). Suboptimal, or low vitamin C were identified in 19/60 compared to 1/20 HC (p = .018). CONCLUSION: Our study demonstrates that BDUC is frequently associated with hypermobility disorders and low vitamin C status. Our results could pave the way for a randomized study of vitamin C supplementation in patients with BDUC.

Adherence and Quality of Life in Adult Patients With Haemophilia A, Haemophilia B and Von Willebrand Disease: A National Cross-Sectional Survey.

BACKGROUND: New treatments for patients with bleeding disorders (PWB) have emerged, including products with extended half-life and subcutaneous administration. These less frequent treatments can potentially enhance quality of life (QoL), but adherence becomes critically important. AIM: To investigate adherence and QoL among PWB and explore the correlation between treatment adherence and QoL in adult patients with haemophilia A (HA), haemophilia B (HB) and Von Willebrand disease (vWD) in Denmark. METHOD: This survey used disease-specific patient-reported questionnaires: Veritas-PRO and Veritas-PRN to measure adherence, and Haemo-A-QoL and VWD-QoL to assess QoL. RESULTS: Responses were obtained from 149 patients with HA, 32 with HB and 118 with vWD. Adherence was reported by 87.1% of patients on prophylaxis and 71.2% of patients treated on demand, according to Veritas-PRO and Veritas-PRN cut-off scores. High QoL was generally reported, decreasing with age in HA and HB, but not in vWD. CONCLUSION: Danish patients with HA, HB and vWD reported high QoL and high adherence to prescribed treatments. There was no correlation between treatment adherence and QoL among the different patient groups. These findings highlight the need for further research to better understand adherence behaviours and identify opportunities to further improve QoL in PWB.

Acquired Haemophilia A in four north European countries: survey of 181 patients.

Acquired haemophilia A (AHA) is a rare bleeding disorder caused by acquired antibodies against coagulation factor VIII. In the Nordic countries, treatment and outcomes have not been studied in recent times. To collect retrospective data on patients diagnosed with AHA in the Nordic countries between 2006 and 2018 and compare demographic data and clinical outcomes with previously published reports, data were collected by six haemophilia centres: three Swedish, one Finnish, one Danish and one Estonian. The study included 181 patients. Median age at diagnosis was 76 (range 5-99) years, with even gender distribution. Type and severity of bleeding was comparable to that in the large European Acquired Haemophilia Registry study (EACH2). Bleedings were primarily treated with activated prothrombin complex concentrate (aPCC) with a high success rate (91%). For immunosuppressive therapy, corticosteroid monotherapy was used most frequently and this may be the cause of the overall lower clinical remission rate compared to the EACH2 study (57% vs. 72%). Survey data on 181 patients collected from four north European countries showed similar demographic and clinical features as in previous studies on AHA. aPCC was used more frequently than in the EACH2 study and the overall remission rate was lower.

Health and quality of life of patients with haemophilia: A national study of 124 Danish men.

PURPOSE: In the past decades, haemophilia treatment has greatly improved the health of persons with haemophilia (PWH). This study compares PWH to the general population on social conditions and health. METHODS: In December 2021, all Danes with moderate or severe haemophilia A or B, or von Willebrands disease type 3 were invited to participate in an online self-report survey concerning sociodemographic factors, self-rated health, teeth status, chronic health conditions, symptoms and loneliness. This study compares responses from the 124 adult male PWH with responses from a male general population sample (N = 4849). Analyses used logistic regression, controlling for age and highest completed education. RESULTS: Fewer PWH were in the oldest age group (65-84 years). Controlling for age, no significant differences were found regarding cohabitation status or education. Fewer PWH were employed (OR = .48, [.33-.71])-particularly in the 45-64 age group. PWH were less likely to report good health (OR = .49, [.31-.77]). The odds of joint disease was much higher (OR = 13.00, [8.37-20.28]). Also, hypertension (OR = 2.25, [1.13-5.65]) and previous stroke (OR = 2.51, [1.44-3.50]) were more frequent. PWH were more likely to report pain in the arms/hands/legs/hips (OR = 2.94, [1.92-4.52]), but less likely to report pain in the head/neck/shoulder (OR = .66, [.45-.96]). CONCLUSION: The disease burden of haemophilia has improved so PWH resembles the general population in areas such as marriage and education. However, even for young PWH, the disease still imposes a significant burden from hemophilia arthropathy and pain in extremities and joints. Middle-aged PWH also have poorer levels of employment than same-aged peers.

No difference in quality of life between persons with severe haemophilia A and B.

INTRODUCTION: Good health-related quality of life (HRQoL) is an important goal in the treatment of persons with haemophilia B (PwHB). Studies focusing on this population are limited, however, and data are insufficient. AIM: To assess the HRQoL in PwHB and to compare this to data on persons with haemophilia A (PwHA), as well as to evaluate the impact of joint health on HRQoL and to identify areas of insufficient care. METHODS: The B-NORD study enrolled persons with severe haemophilia B and matched controls with haemophilia A. HRQoL was assessed using the EQ-5D-3L questionnaire and joint health using Haemophilia Joint Health Score 2.1 (HJHS). RESULTS: The EQ-5D-3L was completed by 63 PwHB and 63 PwHA. Mobility problems were reported by 46% of PwHB and 44% of PwHA, pain/discomfort by 62% and 56%, and anxiety/depression by 33% and 17%, respectively. No significant difference was observed between PwHA and PwHB in EQ-5D profiles, level sum score, EQ-5D index (PwHB mean .80, PwHA mean .83, p = .24), or EQ VAS score (PwHB: mean 70, PwHA: mean 77, p = .061). Linear regression adjusted for age demonstrated that an increase in HJHS score was associated with a significant decrease in both EQ-5D index (B -.003, R2 .22) and EQ VAS score (B -.37, R2 .17). CONCLUSION: Despite the majority of patients being treated with prophylaxis, impaired HRQoL was reported in both PwHB and PwHA. No differences in HRQoL were found between the two groups. Impaired joint health had a significant negative impact on HRQoL.

Pain, depression and anxiety in people with haemophilia from three Nordic countries: Cross-sectional survey data from the MIND study.

INTRODUCTION: People with haemophilia (PwH) may experience symptoms of haemophilia-related pain, depression or anxiety, which can negatively impact health-related quality of life. AIM: To obtain the perspective of PwH and treaters from Sweden, Finland and Denmark on the management of haemophilia-related pain, depression and anxiety using cross-sectional survey data from the MIND study (NCT03276130). METHODS: PwH or their caregivers completed a survey about experiences of pain, depression and anxiety related to haemophilia, and the standard EQ-5D-5L instrument. Five investigators at haemophilia treatment centres (HTC) were sent a complementary survey containing questions about the management of pain and depression/anxiety. RESULTS: There were 343 PwH (mild: 103; moderate: 53; severe: 180; seven lacking severity information) and 71 caregiver responses. Experience of pain in the last 6 months was reported by 50% of PwH respondents and 46% of caregiver respondents. Anxiety/depression was reported by 28% of PwH respondents. Reporting of pain and anxiety/depression was associated with disease severity. Whilst 62% of PwH who had experienced pain at any time point (n = 242) felt this was adequately addressed and treated at their HTC, only 24% of those who had experienced depression/anxiety (n = 127) felt this was adequately addressed. Disease severity was negatively associated with EQ-5D-5L utility value (p < .001). In the HTC survey, 4/5 and 2/5 agreed that pain and depression/anxiety, respectively, are adequately addressed. CONCLUSIONS: Pain and depression/anxiety occur more frequently with increasing haemophilia severity, with negative impacts on health-related quality of life. PwH with depression/anxiety or unaddressed pain could benefit from improved management strategies.

Quality of life in a large multinational haemophilia B cohort (The B-Natural study) - Unmet needs remain.

INTRODUCTION: The B-Natural study is a multicentre, multinational, observational study of haemophilia B (HB) designed to increase understanding of clinical manifestations, treatment and quality of life (QoL). AIM: To characterise and compare QoL in HB across disease severity groups and individuals with inhibitors to identify gaps in treatment. METHODS: A total of 224 individuals from 107 families were enrolled from a total of 24 centres in North America (n = 16), Europe (n = 7) and Asia (n = 1). Of these, 68 (30.4%) subjects had severe (<1 IU/dL), median age 15.6 years, 114 (50.9%) moderate (1-5 IU/dL), age 13.3 years, and 42 (18.8%) mild (>5-< 40 IU/dL), age 12.1 years, disease. Twenty-nine participants had inhibitors or a history of inhibitors. Three versions of the EQ-5D instrument were used as a measure of QoL: proxy (ages 4-7), youth (ages 8-15) and self (age 16+). Each instrument included a visual analogue scale ranging from 100 (best health) to 0 (worst health) to assess current day's health (EQ VAS). Range-of-motion (ROM) for elbows, knees and ankles was assessed using a four-point scale, from which a composite score was calculated. RESULTS: In all severity groups, a proportion of subjects showed less than optimal QoL. The majority of the mild and moderate severe participants reported a normal EQ-5D health profile (79% and 72%, respectively), whereas about half (47%) of the severe participants and only 13% of the inhibitor participants reported this profile. CONCLUSION: The B-Natural study reveals impacted QoL in all disease severities of HB including those with inhibitors. Unmet needs remain and include nonsevere HB.

Treatment outcomes in persons with severe haemophilia B in the Nordic region: The B-NORD study.

INTRODUCTION: Data on outcome in persons with haemophilia B (PwHB) are limited and mainly extrapolated from studies of haemophilia A (HA). AIM: To characterize treatment outcomes in persons with severe HB in the Nordic region, with a focus on joint health, compared with matched controls with HA. METHODS: PwHB attending haemophilia centres in Denmark, Finland, Norway and Sweden were enrolled and matched with controls with HA. Joint assessment using Haemophilia Joint Health Score (HJHS) and ultrasound according to Haemophilia Early Arthropathy Detection protocol (HEAD-US) was conducted. Adherence was evaluated using the Validated Haemophilia Regimen Treatment Adherence Scale (VERITAS). RESULTS: Seventy-nine males with HB, with median age of 30 years (range 1-75), were enrolled. Eleven patients (14%) had a history of or current inhibitor. Twenty-nine PwHB (37%) reported joint bleeds during the prior year, and 35% had previously undergone joint surgery. Ninety-five per cent were on prophylaxis, and 70% used recombinant concentrates, with a median factor consumption of 3,900 IU/kg/year for standard half-life products. Only two patients had a VERITAS score corresponding to 'non-adherence'. Joint health, assessed with HJHS, showed a significant lower score among PwHB compared with HA controls, explained by a difference in the 18-49 age group, without observed differences in older or younger subgroups. The HEAD-US scores were overall low. CONCLUSION: The Nordic cohort of PwHB is well treated by prophylaxis, but the goal of zero bleeds for all is not reached. Our findings suggest that patients with severe HB suffer from a milder arthropathy than patients with severe HA.

The B-Natural study-The outcome of immune tolerance induction therapy in patients with severe haemophilia B.

INTRODUCTION: Inhibitors develop less frequently in haemophilia B (HB) than haemophilia A (HA). However, when present, the success of tolerization by immune tolerance induction (ITI) therapy is lower and the risk of complications higher. AIM: To evaluate the use and outcome of ITI in patients with HB and inhibitors. METHODS: Subjects include singletons or siblings with a current/history of inhibitors enrolled in B-Natural-an observational study designed to increase understanding of clinical management of patients with HB. Patients were followed for 6 months and information on demographics, medical and social history, and treatment were recorded. RESULTS: Twenty-nine patients with severe HB and inhibitors were enrolled in 24 centres. Twenty-two underwent one or more courses of ITI with or without immune suppression. Eight patients (36.4%) were successfully tolerized after the first course of ITI. One of these successes (12.5%) experienced allergic manifestations, whereas the corresponding number for the 10 treatment failures was five (50%). One of seven (14.2%) patients with large deletions and three of eight (37.5%) with nonsense mutations were tolerized at the first attempt, and all patients experiencing nephrosis either failed or were on-going. At study end, 11 (50%) were considered successfully tolerized after one or more ITI courses, three were unsuccessful, and eight were still undergoing treatment. CONCLUSION: Our data underscore the possibilities and difficulties of achieving tolerization in patients with HB with inhibitors. The type of mutation and complications appear to correlate with ITI outcome, but more accurate definitions of successful ITI are warranted.

Natural history study of factor IX deficiency with focus on treatment and complications (B-Natural).

INTRODUCTION: Haemophilia B (HB) is less well studied than haemophilia A (HA); despite similarities between the two inherited bleeding disorders, important differences remain that require further research. AIM: B-Natural is a multi-centre, prospective, observational study of HB, designed to increase understanding of clinical manifestations, treatment, quality-of-life (QoL), inhibitor development, immune tolerance induction (ITI) outcome, renal function and create a biorepository for future investigations. METHODS: Participants include sibling pairs/groups without a current/history of inhibitors and singletons or siblings with a current/history of inhibitors followed for six months. Demographics, medical, social history and treatment were recorded. A physical examination including joint range of motion (ROM) was performed; QoL was assessed. Samples were collected for F9 gene mutation, HLA typing, non-inhibitory antibodies and renal function testing. RESULTS: Twenty-four centres enrolled 224 individuals from 107 families including 29 with current/history of inhibitors. Of these, 68, 30.4%, had severe (<1% FIX level of normal); 114, 50.9%, moderate (1%-5%); and 42, 18.8%, mild (>5-<40%) disease. At enrolment, 53.1% had 50 + exposure days to exogenous FIX. Comparison of joint scores showed significant (P < .05) differences between those with severe (with/without inhibitors), and those with moderate/mild disease. The majority with severe disease, 80.0% with current/history of inhibitors and 64.3% of those without, were treated with prophylaxis. CONCLUSION: B-Natural provides data supporting an increased understanding of HB and its impact throughout life. The need for optimal disease control to normalize physical and psychosocial outcomes is underscored, and further analyses will contribute to an increased understanding of critical issues in HB.

Coagulation factor VIII is vital for increasing global coagulation after physical exercise.

BACKGROUND: In a previous smaller study, we found evidence of a diminished global coagulation capacity after maximal exercise in patients with severe haemophilia A (HA). AIM: To validate these results, we repeated the study in a larger cohort. We also examined if the exercise-induced increased levels of von Willebrand factor (VWF) might prolong the effect of factor concentrate administered just before exercise. METHODS: We studied individual and global coagulation parameters after maximal physical exercise in 10 persons with severe HA and 10 healthy matched control subjects. Blood samples were taken before, 10 minutes, 60 minutes and 4 hours after exercise. RESULTS: Rotational thromboelastometry (ROTEM) and thrombin generation assay-calibrated automated thrombogram (TGA-CAT) showed significantly increased coagulation capacity after maximal exercise in healthy controls but not in patients with severe HA. VWF antigen and activity levels increased significantly in both groups, whereas FVIII:C only showed a significant increase in the control group. No statistically significant differences were seen between FVIII pharmacokinetic results obtained with and without exercise. CONCLUSION: Our findings do not support the presence of a FVIII-independent mechanism that increases global coagulation, but rather underscores the importance of FVIII in mediating the increased coagulation capacity seen after exercise. Our results could not support the hypothesis that exercise-induced increased levels of VWF for patients with severe HA lead to a prolonged effect of factor concentrate administered just before exercise.

"Development in well-being and social function among Danish hemophilia patients with HIV: a three-wave panel study spanning 24 years".

BACKGROUND: Between 1975 and 1985 a total of 91 Danish patients with moderate and severe hemophilia (PWH) was infected with HIV constituting a major scandal in the Danish health care system. This study describes the burden of HIV infection among Danish PWH by evaluating changes from 1988 to 2012 in well-being, social function, experiencing stigma and openness about disease among Danish HIV+ PWH. METHODS: Three anonymous surveys were conducted in 1988, 2001 and 2012 targeting all Danish patients with moderate to severe hemophilia. Survey responses were received from 53, 21 and 18 HIV+ PWH respectively. A matched comparison sample of HIV- PWH was identified for each survey-year, using propensity score matching. Differences for each survey-year and trends over time were analyzed using ordinal logistic regression. RESULTS: In 1988, HIV+ PWH had more psychosomatic symptoms than HIV- PWH, but in 2001 life satisfaction was higher among HIV+ PWH than among HIV- PWH. Tests of differences in trend over time showed larger improvements in life satisfaction among HIV+ PWH than HIV- PWH, while HIV- PWH showed an increase in educational level compared to HIV+ PWH. Analysis restricted to HIV+ PWH showed an increase in perceived stigmatization. CONCLUSIONS: Differences between Danish HIV+ and HIV- PWH regarding well-being and psychosomatic symptoms seem to have evened out between 1988 and 2012. However, results suggest that HIV+ PWH still experience stigmatization and lower levels of education.

Joint Mobility and Physical Function of Danish Hemophilia Patients: A Three-Wave Panel Study Spanning 24 Years.

BACKGROUND: The positive effects of factor treatment of hemophilia are well established, but the long-term outcomes are not well documented. This panel study evaluated changes in bleeding frequency, joint mobility, physical function, and symptoms in Danish patients with moderate to severe hemophilia A or B over 24 years. METHODS: Three anonymous surveys were conducted in 1988, 2001, and 2012 targeting Danish patients with moderate to severe hemophilia, and the study participants, respectively, were 128, 156, and 164 male patients with hemophilia (PWH). The number of bleeding episodes, the use of factor concentrate, comorbidities, joint mobility, physical function, and symptoms were evaluated by means of self-reporting. Trends over time were analyzed using ordinal and multinomial logistic-regression models controlling for age group. RESULTS: The proportion of PWH in the oldest age group (55-88 years) increased from 4% in 1988 to 18% in 2012. In 1988, a high risk of bleeding episodes was primarily found in the age group of 16-34 years. In 2012, a high risk was primarily found in the age group of 35-54 years. Joint mobility and physical function increased significantly from 1988 to 2012 but showed a noticeable decrement in the older age groups, even in 2012. Pain in the extremities, anxiety, and depression decreased significantly, but back pain increased. No significant changes were found for 7 other symptoms. CONCLUSIONS: Significant improvements in joint mobility and physical function have occurred over the last 24 years, but PWH > 35 years still experience a decline in these areas with age. This decline underscores the importance of life-long treatment and continuous rehabilitation of PWH.

Impact of Training in Serious Illness Communication and Work Life Balance on Physicians' Self-Efficacy, Clinical Practice and Perception of Roles.

Purpose: Serious illness communication is a core task in hemato-oncology that require advanced communication skills and can be emotionally demanding. A 2-day course was implemented as a mandatory part of the 5-year hematology specialist training program in Denmark in 2021. The aim of this study was to assess the quantitative and qualitative effect of course participation on self-efficacy in serious illness communication and measure the prevalence of burnout among physicians in hematology specialist training. Methods: For quantitative assessment course participants answered three questionnaires: Self-efficacy Advance care planning (ACP), Self-efficacy Existential communication (EC) and the Copenhagen Burnout Inventory at baseline, 4 and 12 weeks after the course. The control group answered the questionnaires once. Qualitative assessment was performed as structured group interviews with course participants 4 weeks after the course, transcribed, coded, and transformed into themes. Results: All self-efficacy EC scores and 12 out of 17 self-efficacy ACP scores improved after the course, though mostly non-significant. Course participants reported altered clinical practice and perception of role as a physician. The physicians' confidence that they could find the time to discuss ACP were low and remained low. The prevalence of burnout was high. Burnout levels were non-significantly lower after the course. Conclusion: A mandatory course of formal training can increase physician self-efficacy in serious illness communication and alter clinical practice and perception of roles. The high level of burnout among physicians in hemato-oncology calls for institutional interventions in addition to training.

High use of pain, depression, and anxiety drugs in hemophilia: more than 3000 people with hemophilia in an 11-year Nordic registry study.

Background: Pain is a common feature of hemophilia, but prevalence of depression and anxiety is less studied. Registry data on prescription drugs can provide an objective measure of the magnitude of these complications. Objectives: To identify treatment patterns of prescribed pain, antidepressant, and antianxiety medications compared with those of matched controls in 4 Nordic countries. Methods: The MIND study (NCT03276130) analyzed longitudinal individual-level national data during 2007-2017. People with hemophilia (PwH) were identified from National Health Data Registers by diagnosis or factor replacement treatment and compared with population controls. Three subgroups were defined by the use of factor concentrates and sex (moderate-to-high factor consumption (factor VIII [FVIII] use of ≥40 IU/kg/week or FIX use of ≥10 IU/kg/week), low factor consumption, and women including carriers). Results: Data of 3246 PwH, representing 30,184 person-years, were analyzed. PwH (including children and adults) used more pain, depression, and anxiety medications compared with controls. This was most accentuated in the moderate-to-high factor consumption group and notably also observed in men with low factor consumption and women including carriers, usually representing a milder phenotype. A higher opioid use was observed across all age groups: 4- to 6-fold higher in the moderate-to-high factor consumption group and 2- to 4-fold higher in the low factor consumption group. Conclusion: The consistent higher use of pain, depression, and anxiety medications among PwH compared with population controls, regardless of age, sex, or factor consumption, in broad national data suggests a need for improved bleed protection and hemophilia care for all severities including mild hemophilia.

Real-World Effectiveness of rFIXFc Prophylaxis in Patients with Haemophilia B Switched from Standard Half-Life Therapy in Three European Countries.

INTRODUCTION: The current study describes real-world clinical outcomes and factor usage among patients with haemophilia B switching from standard half-life factor IX (SHL FIX) treatment to recombinant factor IX Fc fusion protein (rFIXFc) prophylaxis in European treatment centres. METHODS: This non-interventional, retrospective, multicentre chart review evaluated medical records from adult and paediatric patients with haemophilia B in Denmark, Germany and the UK. Patients had documented SHL FIX treatment, on-demand or prophylaxis, for ≥ 6 months before starting rFIXFc prophylaxis, and subsequent data for ≥ 6 months afterwards (up to 24 months). Primary endpoints included annualised bleeding rates (ABRs), prophylactic factor consumption and injection frequency. RESULTS: Data from 30 patients (24/30 [80.0%] with severe disease) showed overall mean (standard deviation, SD) ABRs of 4.7 (6.3) on SHL FIX treatment and 1.7 (2.3) after switching to rFIXFc prophylaxis. The reduction in mean (SD) ABRs was greater when switching from SHL FIX on-demand treatment (n = 6), with a decrease from 10.5 (9.9) to 2.6 (4.5), than when switching from SHL FIX prophylaxis (n = 24), with a decrease from 3.3 (4.3) to 1.5 (1.4). Among prior SHL FIX prophylaxis patients, switching to rFIXFc prophylaxis increased the proportion of those with zero bleeds from 21.7% to 45.8% during the 6 months before and after switching, respectively. In the total population, five of six target joints (83.3%) present when patients started rFIXFc prophylaxis subsequently resolved. In patients switching from SHL FIX prophylaxis to rFIXFc prophylaxis, mean (SD) weekly injection frequency was reduced by 1.0 (0.7) and mean (SD) factor consumption was reduced by 27.7 (49.6) IU/kg/week. CONCLUSION: This study demonstrates the effectiveness of rFIXFc prophylaxis in real-world clinical practice. Improvements in both clinical effectiveness and factor usage associated with rFIXFc prophylaxis may potentially reduce patient burden and improve quality of life.

Factor IX antibodies and tolerance in hemophilia B in the Nordic countries - The impact of F9 variants and complications.

INTRODUCTION: The development of inhibitory antibodies (inhibitors) in persons with hemophilia B (PwHB) causes significant morbidity. Data on the impact of the F9 variant and immune tolerance induction (ITI) outcome are limited. The aim of this study was to investigate the presence of neutralizing and non-neutralizing antibodies (NNA) in severe hemophilia B (HB) and to evaluate ITI outcome and complications in relation to the pathogenic F9 variant. MATERIALS AND METHODS: Persons with severe HB in the Nordic countries were enrolled and information on F9 variants, inhibitors, ITI and complications were collected. Analyses of anti-FIX antibodies with a fluorescence-immunoassay (xFLI) and an ELISA method were conducted. RESULTS: Seventy-nine PwHB were enrolled. Null variants were seen in 33 (42 %) PwHB and 12 (15 %) had a current or former inhibitor. Eleven (92 %) of the inhibitor patients had experienced allergic manifestations and three (25 %) nephrotic syndrome. Of 10 PwHB with at least one ITI attempt, eight (80 %) were considered tolerant at enrolment. Immunosuppression was included in seven of eight successful or partially successful attempts. Five PwHB had at least one ITI failure before a successful or partially successful ITI. No NNA could be identified. CONCLUSION: A high proportion of severe F9 gene defects among persons with severe HB in the Nordic countries may explain the observed relatively high prevalence of inhibitors. ITI success was independent of the F9 variant and attained despite allergic manifestations and previous ITI failures. Inclusion of immunosuppression tentatively enhances the chances of ITI success. No NNA were observed.

[Diagnosing von Willebrand disease].

Von Willebrand disease (VWD) is an inherited bleeding disorder with abnormal primary haemostasis due to defects in, or decreased concentration of the glycoprotein von Willebrand factor. In Denmark, the estimated prevalence of VWD is 1% corresponding to approximately 50,000 patients, but only a few hundred have been diagnosed, mostly due to prolonged bleeding after a trauma or during surgery. Thus, VWD is underdiagnosed in the general population. Improved anamnestic screening for bleeding disorders such as VWD in certain high-risk groups can facilitate institution of prophylactic treatment.

Factor VII-activating protease in patients with acute deep venous thrombosis.

Factor VII-activating protease (FSAP) is involved in haemostasis and inflammation. FSAP cleaves single chain urokinase-type plasminogen activator (scu-PA). The 1601GA genotype of the 1601G/A polymorphism in the FSAP gene leads to the expression of a FSAP variant with reduced ability to activate scu-PA, without affecting the ability to activate coagulation Factor VII (FVII). Previous studies have investigated the association of the 1601GA genotype with incidence and progression of carotid stenosis and deep venous thrombosis (DVT). The present study is the first to evaluate the potential association between the FSAP phenotype and DVT. We studied the association between the 1601G/A polymorphism, FSAP activity, FSAP antigen, Factor VIIa (FVIIa), prothrombin fragment 1+2 (F1+2), and C-reactive protein (CRP) in plasmas of 170 patients suspected for DVT. FSAP genotypes were equally distributed in patients with (n=64) and without DVT (n=106), (P=0.94). The 1601GA genotype was associated with significant reduction of FSAP activity (P<0.001) and FSAP antigen levels (P=0.04). Patients with DVT showed significantly higher FSAP activity (P=0.008), FSAP antigen (P=0.003), and F1+2 levels (P<0.001) than patients without DVT. The association between the FSAP measures and DVT disappeared when adjusted for CRP levels. F1+2 correlated positively to FSAP antigen (P=0.01), while FVIIa-levels were comparable in patients with and without DVT. We conclude that even though FSAP measures are significantly increased in patients with acute DVT, alterations in the scu-PA activating properties of FSAP are presumably not markedly involved in the development of acute DVT, and that the association between FSAP and DVT disappears after adjustment for CRP.