Plasma levels of plasminogen activator inhibitor-1 and bleeding phenotype in patients with von Willebrand disease.

INTRODUCTION: von Willebrand disease (VWD) is the most common inherited bleeding disorder. In VWD patients, large variations in bleeding tendency are observed, which cannot be completely explained by the variation in von Willebrand factor levels or activities. Thus, there must be additional factors, for instance, changes in fibrinolysis that have an effect on the variation in bleeding tendency in VWD patients. AIM: To investigate whether plasminogen activator inhibitor-1 (PAI-1) level influences the variation in bleeding tendency in VWD patients. METHODS: PAI-1 antigen levels were measured in the plasma of 633 patients with moderate or severe VWD who participated in the 'Willebrand in the Netherlands' (WiN) study, a nationwide multicentre cross-sectional study. Bleeding severity was assessed using the Tosetto bleeding score. RESULTS: PAI-1 levels increased with age (Spearman's rho: 0.225, P < 0.001) and were higher in men (23 [IQR 12-60] vs. 20 [IQR 10-44] ng mL-1 in women, P = 0.039), whereas the bleeding score was higher in women (11 [IQR 7-17] vs. 9 [IQR 5-14] ng mL-1 in men, P = 0.002). After adjustment for age and sex by stratification, PAI-1 level and bleeding score were negatively correlated (Spearman's rho: -0.170, P = 0.017) in the group of 196 young (age ≤ 45 year) female VWD patients, accounting for 31% of our study population. CONCLUSION: In young female VWD patients, we observed that low PAI-1 levels were associated with a higher bleeding score, which may partly explain the observed variability in bleeding phenotype in VWD patients.

Long-term effects of joint bleeding before starting prophylaxis in severe haemophilia.

INTRODUCTION: Early initiation of prophylaxis in severe haemophilia is critical for effective prevention of arthropathy. However, the optimum time for starting prophylaxis has not been established yet. AIM: This study assessed long-term effects of age at starting prophylaxis and joint bleeding before prophylaxis on haemophilic arthropathy. METHODS: In patients with severe haemophilia (FVIII/IX <0.01 IU mL-1 ), born between 1965 and 2000, haemophilic arthropathy was evaluated on X-rays. Patient groups were compared by multivariable regression analysis, adjusted for bleeding phenotype and lifetime intensity of prophylaxis. RESULTS: One hundred and twenty-four patients were evaluated at a median age of 22 years. When comparing patients according to age at starting prophylaxis, starting before age 6 years was significantly better than starting later (P < 0.01), but no additional benefit of starting before age 3 years was demonstrated. The number of joint bleeds before prophylaxis had a stronger association with arthropathy than age at starting prophylaxis. Starting prophylaxis before the onset of joint bleeding resulted in the best long-term outcome (P ≤ 0.02); starting after one joint bleed appeared to have acceptable long-term outcome. The difference between starting after 0-1 and 2-5 joint bleeds was notable, but statistical significance was not reached (P = 0.15). CONCLUSION: Future research with more patients on early prophylaxis will have to clarify whether starting prophylaxis before joint bleeding is superior.

Evidence for and cost-effectiveness of physiotherapy in haemophilia: a Dutch perspective.

INTRODUCTION: Musculoskeletal impact of haemophilia justifies physiotherapy throughout life. Recently the Dutch Health Care Institute constrained their 'list of chronic conditions', and withdrew financial coverage of physiotherapy for elderly persons with haemophilia (PWH). This decision was based on lack of scientific evidence and not being in accordance with 'state of science and practice'. METHODS: In general, evidence regarding physiotherapy is limited, and especially in rare diseases like haemophilia. 'Evidence based medicine' classifies and recommends evidence based on meta-analyses, systematic reviews and randomized controlled trials, but also means integrating evidence with individual clinical expertise. For the evaluation of physiotherapy - usually individualized treatment - case studies, observational studies and Case Based Reasoning may be more beneficial. RESULTS: Overall annual treatment costs for haemophilia care in the Netherlands are estimated over 100 million Euros, of which 95% is covered by clotting factor concentrates. The cost for physiotherapy assessments in all seven Dutch HTCs (seven centres for adult PWH and seven centres for children) is limited at approximately 500 000 Euros annually. Costs of the actual physiotherapy sessions, carried out in our Dutch first-line care system, will also not exceed 500 000 Euros. Thus, implementation of physiotherapy in haemophilia care the Netherlands in a most optimal way would cost less than 1% of the total budget. AIM: The present paper describes the role of physiotherapy in haemophilia care including available evidence and providing suggestions regarding generation of evidence. Establishing the effectiveness and cost-effectiveness of physiotherapy in haemophilia care is a major topic for the next decennium.

The association of haemophilic arthropathy with Health-Related Quality of Life: a post hoc analysis.

BACKGROUND: The aim of replacement therapy in haemophilia is to improve Health-Related Quality of Life (HRQoL) by preventing bleeding and arthropathy. However, the association of arthropathy with HRQoL is unknown. AIM: To explore the association of haemophilic arthropathy with HRQoL. METHODS: A post hoc analysis on patients with severe/moderate haemophilia with SF36 questionnaire (SF36) and X-rays of ankles, knees and elbows made within 2.5-years. The SF36 scores of 'physical functioning' (SF36-PF, range 0-100, optimum 100) and Utility (SF6D-Utility, range 0-1, optimum 1) and radiological Pettersson scores (PS, range 0-78, optimum 0) were calculated. The association of PS with reduced SF6D-Utility and SF36-PF ( 21 points, the risk of reduced SF6D-Utility was stable (OR 4.16; 95% CI: 2.03-8.51) but SF36-PF continued to decrease: compared to lowest PS, OR for reduced SF36-PF was 5.69 (95% CI: 1.62-20.06) for PS 22-39 and 25.15 (95% CI: 6.53-96.81) for PS 40-78. CONCLUSION: Health-Related Quality of Life only showed a significant deterioration in patients with a Pettersson score of >21 points. This suggests that HRQoL is relatively insensitive to early joint changes.

Joint surgery in von Willebrand disease: a multicentre cross-sectional study.

BACKGROUND: Joint bleeds are reported by 23% of von Willebrand disease (VWD) patients and associated with orthopaedic surgery. Limited data are available on joint surgery in VWD. AIM: To assess the prevalence, indications, management and complications of joint surgery in VWD patients. METHODS: 804 VWD patients with historically lowest von Willebrand factor (VWF) activity ≤30 U dL-1 completed a questionnaire on joint bleeds, joint damage and orthopaedic surgery. We retrieved additional medical file data of patients who underwent surgery on large joints (shoulder, elbow, hip, knee or ankle). RESULTS: 116 out of 804 patients (14%) reported large joint surgery. Compared to VWD patients without previous orthopaedic surgery, these 116 patients reported more frequently a history of joint bleeds and joint damage (41% vs. 20%, P < 0.001 and 61% vs. 20%, P < 0.001). Medical file data on 126 large joint surgeries in 79 VWD patients revealed that this surgery was associated with joint damage due to prior joint bleeds in 24% of the procedures. Preoperative clotting factor correction (CFC) to prevent bleeding was administered in most cases (81%). Documentation on postoperative bleeding was found in 23 surgeries (18%). CONCLUSIONS: Large joint surgery is reported by 14% of VWD patients, related to joint bleeds in 24% and seems associated with bleeding complications frequently despite perioperative CFC.

Joint bleeds in von Willebrand disease patients have significant impact on quality of life and joint integrity: a cross-sectional study.

BACKGROUND: Joint bleeds (JB) are reported in a minority of patients with von Willebrand disease (VWD) but may lead to structural joint damage. Prevalence, severity and impact of JB in VWD are largely unknown. OBJECTIVES: The aim of this study was to assess JB prevalence, onset, treatment and impact on health-related quality of life (HR-QoL) and joint integrity in moderate and severe VWD. METHODS: In the Willebrand in the Netherlands study 804 moderate and severe VWD patients [von Willebrand factor (VWF) activity ≤30U dL(-1)] completed a questionnaire on occurrence, sites and consequences of JB. To analyse JB number, onset, treatment and impact on joint integrity we additionally performed a patient-control study on medical file data comparing patients with JB to age, gender, factor VIII (FVIII)- and VWF activity matched VWD patients without JB. RESULTS: Of all VWD patients 23% (184/804) self-reported JB. These 184 patients reported joint damage more often (54% vs. 18%, P < 0.001) and had lower HR-QoL (SF36, P < 0.05) compared to VWD patients not reporting JB. Of 55 patients with available JB data, 65% had the first JB before age 16. These 55 patients used more clotting factor concentrate (CFC; median dose 43 vs. 0 IE FVIII kg(-1) year(-1) , P < 0.001), more often had X-ray joint damage (44% vs. 11%, P = 0.001] and chronic joint pain (44% vs. 18%, P = 0.008) compared to 55 control VWD patients without JB. CONCLUSION: In conclusion, joint bleeds are reported by 23% of moderate and severe VWD patients, mostly start in childhood, are associated with more CFC use, joint pain, lower HR-QoL and significantly more radiological and self-reported joint damage.

Medical co-morbidities and practice.

All-oral treatments of hepatitis C (HCV) have been trialled in patients with hereditary bleeding disorders and found to be effective. Further refinements of dosing and duration are being established. Importantly for patient acceptability these regimens are interferon-free. Cohort studies in older patients with haemophilia direct the need for attention to weight control, exercice, assessment of cardiovascular risk, especially hypertension and detection of osteoporosis. Where patients live a long way from a comprehensive care centre, telemedicine connections can engage centre experts with the patient and his/her local practitioners in devising and monitoring care plans.

Cardiac catheterization and intervention in haemophilia patients: prospective evaluation of the 2009 institutional guideline.

Ageing haemophilia patients are increasingly confronted with ischaemic heart disease (IHD). Treatment is complex because of the delicate equilibrium between bleeding and thrombosis. In 2009, we developed an institutional guideline on how to treat IHD in this patient population. The aim of this study was to evaluate feasibility and safety of this guideline. Haemophilia patients who underwent coronary angiography or percutaneous coronary intervention between January 2009 and June 2012 were included in the current case series. Nine diagnostic or therapeutic cardiac catheterizations were performed in six haemophilia patients. One patient with moderate haemophilia B was included, whereas the other patients had mild haemophilia A. In six of nine procedures, access to the circulation was gained via the radial artery. Only bare-metal stents were implanted, after which dual antiplatelet treatment was given for at least 4 weeks. During cardiac catheterization/intervention and dual antiplatelet treatment, clotting factor levels were corrected. No thrombotic or clinically relevant bleeding complications occurred. In one patient, a low-titre inhibitor recurred 10 months after catheterization. In-stent restenosis was diagnosed in one patient. This case series indicates that treatment according to the guideline is feasible and safe. Furthermore, based on the case series and developments in new guidelines for non-haemophilic patients with IHD, some adjustments on the 2009 guideline are proposed.

Morbidity and mortality in ageing HIV-infected haemophilia patients.

Over 25 years of follow-up is now available for HIV-infected haemophilia patients. The aim of this study was to retrospectively asses the morbidity and mortality of HIV infection and the effects of HAART in these patients. Data on HIV infection, its treatment and all types of comorbidity were collected from medical records of all 60 HIV-positive haemophilia patients who were treated at the Van Creveldkliniek since 1980 and compared with data from 152 HIV-negative patients with severe haemophilia and the general age-matched male population. AIDS developed in 27 patients (45%), while 31 patients died (52%). Death was solely or partially AIDS-related in 71%. Development of AIDS and AIDS-related deaths declined strongly after the introduction of HAART. Only one major ischaemic cardiovascular event occurred in our study population. Of the 27 patients who were still treated at our clinic in 2010, 25 (93%) were on HAART. They had more often hypertension and diabetes, but less often overweight and obesity and lower cholesterol levels than the general population. The occurrence of spontaneous intracranial bleeding was higher in HIV-positive haemophilia patients on HAART than in HIV-negative patients with severe haemophilia (16.6 vs. 1.2 per 1000 patient years). Since the introduction of HAART, the impact of HIV infection on morbidity and survival has decreased. The increased prevalences of hypertension and diabetes, however, warrant regular screening. HIV-positive haemophilia patients on HAART appear to have an increased risk of spontaneous intracranial bleeding.

Guidelines for the management of hemophilia.

Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence-based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion-transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies.

Risk of inhibitor development in mild haemophilia A increases with age.

Mild haemophilia A is a rare disease with a relatively mild phenotype. Treatment with factor VIII (FVIII) is indicated after trauma or for surgery only. FVIII infusion may result in the development of inhibiting antibodies against FVIII. This study describes the relation between age and other risk factors for inhibitor development in mild haemophilia. A retrospective cohort study was conducted among all patients with mild haemophilia (FVIII 0.05-0.40 IU mL(-1)) registered at the van Creveldkliniek, University Medical Centre Utrecht, The Netherlands. Data on peak treatment with FVIII, gene mutation and history of inhibitor development were obtained from patient files from the period between 1st January 1970 and 31st December 2009. A total of 231 out of 297 (78%) patients had at least one exposure to FVIII, of whom 14 (6.1%) developed an inhibitor to FVIII at a median age of 66 years after a median of 50 exposure days (ED). Age at first exposure, age at peak treatment, number of peak treatments and Arg593Cys mutation were significantly associated with the development of an inhibitor, while continuous infusion with FVIII was not. Although the incidence of inhibitors in mild haemophilia is low, it increases with age and peak treatments. With increasing age patients with mild haemophilia will suffer from co-morbidity more frequently, requiring surgical interventions and exposing them to an increased risk of inhibitor development. Especially patients with a change of arginine in cysteine at 593 are at risk for inhibitor development.

A prospective registry of European haemophilia B patients receiving nonacog alfa, recombinant human factor IX, for usual use.

Nonacog alfa, a recombinant factor IX (FIX) used for the treatment of haemophilia B, was approved in Europe in 1998. In accordance with European Medicines Agency requirements, a registry study was conducted from 2002 to 2009. A reformulated iso-osmotic version was approved for European use in 2007. This study was conducted to evaluate the safety of nonacog alfa in a usual care setting, and provide clinical trial and postmarketing surveillance data support. This open-label, non-interventional, prospective observational cohort study (registry) comprised 52 sites in nine European countries. Patients with haemophilia B receiving nonacog alfa in either formulation for prevention or treatment were followed on a usual care schedule. A total of 218 patients were enrolled, of whom 66 (30.3%) were <18 years of age. Haemophilia severity was evenly distributed, with baseline FIX activity of <1%, 1-5% and >5% in 33.3%, 36.6% and 30.1% of patients, respectively. One hundred thirty-eight patients received the original formulation alone; 80 switched to or received only the new formulation. There was a low incidence of events of special interest (ESIs), with less-than-expected therapeutic effect in five patients (2.2%), inhibitor development in two (0.9%), thrombosis in one (0.5%) and allergic events in eight (3.7%). These accounted for the majority of the 15 serious AEs reported in six patients. Six patients discontinued because of AEs, primarily related to hypersensitivity. Nonacog alfa was shown to be safe for the treatment of haemophilia B, with a low incidence of serious AEs and ESIs.

Prenatal diagnosis for haemophilia: a nationwide survey among female carriers in the Netherlands.

Carriers of haemophilia face difficult choices regarding prenatal diagnosis, but little is known about the determinants that influence their decisions. The aim of this study was to assess the incidence of prenatal diagnosis and potential determinants affecting the choice for prenatal diagnosis. A nationwide survey was performed among all women who underwent carriership testing for haemophilia in the Netherlands between 1992 and 2004. Prenatal diagnosis was assessed in 207 carriers of haemophilia A or B who had been pregnant. Prenatal diagnosis was categorized into early first trimester (Y-PCR testing or chorionic villus sampling) often intended to prevent the birth of a child with haemophilia, and into late prenatal diagnosis (amniocentesis or ultrasound assessment) aimed at obstetrical management. Of 207 carriers 112 (54%) underwent prenatal diagnosis. Forty-eight women underwent early prenatal diagnosis and 64 women underwent late prenatal diagnosis. In 26 pregnancies early prenatal diagnosis was positive for haemophilia, and in 18 of these pregnancies termination was opted for. The choice for early prenatal diagnosis was associated with a liberal view towards termination of pregnancy (relative risk (RR) 12.5; 95% confidence interval (CI) 3.1-51.2), severe haemophilia in the family (RR 20.2; CI 2.7-153.6), absence of a religion (RR 1.9; CI 1.1-3.1) and older age (RR 2.0; CI 1.0-3.9). The choice for late prenatal diagnosis was associated with birth year after 1970 (RR 2.3; CI 1.5-3.5) and a previous child with haemophilia (RR 2.2; CI 1.4-3.4). More than half of all Dutch haemophilia carriers underwent prenatal diagnosis. Several determinants were strongly associated with prenatal diagnosis.

Beneficial effect of successful HCV treatment in patients with inherited bleeding disorders, assessed by liver stiffness measurements.

Hepatitis C infection is a major comorbidity in patients with inherited bleeding disorders. Successful antiviral treatment leads to a reduction in liver fibrosis, as shown by liver biopsies. Liver stiffness measurement (LSM) is a non-invasive method of assessing liver fibrosis. The aim of this cohort study was to evaluate the long-term effect of successful antiviral treatment, using LSM, in HCV-infected patients with inherited bleeding disorders. The LSM were performed in 2005 (LSM 1) and 2009 (LSM 2) in 39 patients who were successfully treated for HCV. The change in liver fibrosis between LSM 1 and 2 was assessed. The median duration of HCV infection was 28.8 years. A total of 22 patients (56%) underwent successful antiviral treatment before LSM 1 (group 1), and 17 patients between LSM 1 and LSM 2 (group 2). The median time since antiviral treatment was 8.8 years in group 1 and 2.5 years in group 2. In group 1, the median results of LSM 1 and 2 were similar (6.0 vs. 5.6 kPa, P-value 0.36), so overall, patients remained stable. In three patients in this group, all treated more than 15 years ago, an increase of liver stiffness was shown. Group 2 showed a significant improvement in median LSM results (10.3 vs. 6.1 kPa, P-value <0.01), with decrease of liver stiffness in 82%. Even after a long HCV infection duration, successful antiviral treatment led to a significant improvement of fibrosis, measured by LSM, mainly in the first few years after completing treatment.

Effect of fibrinolysis on bleeding phenotype in moderate and severe von Willebrand disease.

Patients with von Willebrand disease (VWD), the most common inherited bleeding disorder, display large variation in bleeding tendency, which is not completely related to VWF levels. The cause of variability in clinical expression is largely unknown. The effect of plasma fibrinolytic capacity on bleeding tendency in VWD patients has not been investigated. We hypothesized that enhanced fibrinolysis may result in a more severe bleeding phenotype. Therefore, we measured the fibrinolytic potential in patients with moderate or severe VWD to investigate the contribution of fibrinolysis to the bleeding tendency. Fibrinolytic potential was measured as plasma clot lysis time (CLT) with and without addition of potato carboxypeptidase inhibitor (PCI) in 638 patients with moderate or severe VWD who participated in a nationwide multicentre cross-sectional study. Bleeding severity was measured using the Bleeding Score (BS).The CLTs were significantly longer, indicative of hypofibrinolysis, in men compared to women with VWD [106.2 (IQR 95.7-118.1) vs. 101.9 (IQR 92.8-114.0) min]. The CLTs prolonged with increasing age. No association was found between VWF or FVIII levels and CLT, or between VWF or FVIII levels and CLT(+PCI) . No association was observed for BS in a model with 10log-transformed CLT, adjusted for age, gender, VWF:Act and FVIII [b = 6.5 (95%CI -0.3 to 13.4)]. Our study showed that the plasma fibrinolytic potential does not influence bleeding tendency in VWD patients and therefore does not explain the variability in bleeding phenotype in VWD.

The burden of HCV treatment in patients with inherited bleeding disorders.

Many patients with inherited bleeding disorders are infected with hepatitis C virus (HCV). Antiviral treatment, consisting of pegylated interferon and ribavirin, has many side-effects. The aim of the study was to prospectively assess the occurrence and course of side-effects and changes in health-related quality of life (HRQoL) during antiviral treatment in patients with inherited bleeding disorders and chronic HCV. Forty-seven patients were followed during antiviral treatment. Side-effects of treatment were recorded, and the Beck Depression Inventory and the RAND-36 HRQoL questionnaire were administered at regular intervals. Frequently reported side-effects were fatigue (100%), headache (94%), pruritus and skin rash (94%), concentration problems (89%), decreased appetite (89%), fever, irritability and hair loss (all 85%). Many side-effects disappeared soon after end of treatment, but 4 weeks after cessation fatigue, concentration problems and sleeping problems were still present in more than 30% of patients. Dose reduction was necessary in 21 patients (45%), mostly because of decreasing weight or haemoglobin levels. Two patients stopped treatment prematurely because of side-effects. Depression was present in 28 patients (60%). HRQoL decreased significantly during treatment in all RAND-36 domains, and increased again within 4 weeks after treatment. Major side-effects were similar in patients with successful (n = 31, 66%) and unsuccessful antiviral treatment. In patients with inherited bleeding disorders and chronic HCV, antiviral treatment has many, but mostly transient side-effects and a significant impact on quality of life. Careful follow-up and management of side-effects will ensure optimal compliance and treatment results.

Liver stiffness measurements to assess progression of fibrosis in HCV-infected patients with inherited bleeding disorders.

Hepatitis C is a major co-morbidity in patients with inherited bleeding disorders, leading to progressive liver fibrosis and eventually cirrhosis. Liver stiffness measurement (LSM) is a non-invasive way of assessing the extent of liver fibrosis. This article describes our experience with serial LSM to assess prospectively progression of fibrosis in a cohort of patients with inherited bleeding disorders and chronic hepatitis C. A total of 84 patients underwent serial LSMs, with a median interval of 3.7 years. The change in LSM results over time was assessed. Overall, there was no significant difference between the median results of LSM 1 and LSM 2. The median result of LSM 2 was low (6.6 kPa), after a median duration of infection of 37 years. On the individual level, deterioration of LSM results of more than 2 kPa was seen in 13 patients (16%), 44 patients (52%) remained stable and 27 patients (32%) showed improvement of LSM results of more than 2 kPa. These results are comparable with those of paired liver biopsy studies. LSM appears to be a good alternative for liver biopsies in patients with hepatitis C and inherited bleeding disorders, although the interpretation of the unexpected improvement we found in some of our patients is not straightforward. LSMs will be repeated in our patient population in a few years to be able to better assess the value of serial LSM.

Influence of the type of F8 gene mutation on inhibitor development in a single centre cohort of severe haemophilia A patients.

The development of neutralizing antibodies against factor VIII (FVIII) is a major complication of treatment with FVIII in patients with severe haemophilia A. This study was designed to describe the relationship between the type and location of the factor 8 (F8) gene mutation and the development of clinically relevant inhibitors in patients with severe haemophilia A. We conducted a single centre cohort study among 318 consecutive patients (baseline FVIII activity level <0.01 IU mL(-1)) born between 1934 and 2007 who were treated with FVIII on at least 50 exposure days. The primary outcome was clinically relevant inhibitor development, defined as the occurrence of at least two positive inhibitor titres and a decreased recovery. Clinically relevant inhibitors were diagnosed in 14% (43) of patients (30 high-titre). The cumulative incidence of inhibitor development was 18% (35 of 200) in high-risk gene defects (67% in patients with large deletions, 30% in patients with nonsense mutations, 15% in patients with intron 1 or 22 inversions) and 7% (8 of 118) in low-risk gene defects (7% in patients with small deletions and insertions, 6% in patients with missense mutations, 8% in patients with splice site mutations). In patients with point mutations, the cumulative risk of developing inhibitors was highest in patients with mutations in the A3 and C2 domains (13% and 17% respectively). In conclusion, in agreement with earlier observations, the type and location of the F8 gene mutation were important determinants of inhibitor development in patients with severe haemophilia A.

An ultrapure plasma-derived monoclonal antibody-purified factor IX concentrate (Nonafact®), results of phase III and IV clinical studies.

Nonafact(®), an ultrapure, monoclonal antibody-purified factor IX concentrate (FIX) was developed to minimize risk of thrombotic complications and viral transmission. To investigate the pharmacokinetics, efficacy and safety, phase III/IV studies were performed in the Netherlands and Poland from 1996 to 2007. The mean half-life, in vivo response and recovery of Nonafact(®) were 18.7 (SD 2.0) h, 1.1 (SD 0.2) IU dL(-1) per IU kg(-1) b.w. of FIX infused and 49% (SD 10%), respectively. Eleven surgical procedures were performed in eight patients. During two surgeries, both high-risk, blood loss was observed. No postoperative bleeding occurred. The in vivo recovery of FIX was higher than expected. In the phase III follow-up study, 26 previously treated patients (PTP) were included with a median follow-up of 1130 days. From the 1617 minor bleedings, 80.5% was stopped after a single infusion. In the phase IV study thirteen patients were treated for a median study period of 737 days. In the two follow-up studies the investigators rated the effect of Nonafact(®) as excellent/good in 95% of major bleedings. Surgeries for which Nonafact(®) was given prophylactically were without bleeding problems. In total more than 10 million units of Nonafact(®) were used during almost 120 person-years. Only one minor adverse event was reported. No inhibitors, viral transmissions and thrombogenic events occurred. In conclusion, Nonafact(®) is safe and provides excellent haemostasis in haemophilia B patients treated for spontaneous bleeding or undergoing surgical procedures. Due to the excellent in vivo recovery characteristic, treatment with Nonafact(®) is cost saving compared to other FIX products.