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Contains fulltext : 292432.pdf (Publisher’s version ) (Open Access) BACKGROUND: The population-based colorectal cancer (CRC) screening program in individuals aged 55 to 75 years in the Netherlands uses fecal immunochemical testing (FIT), to detect hemoglobin in feces, followed by colonoscopy in individuals with a positive FIT. OBJECTIVES: The objectives of this study are to assess the false-positive rate, detection rate, and positive predictive value of FIT for CRC and advanced adenoma (AA) in patients with Von Willebrand disease (VWD) or hemophilia. METHODS: We performed a multicenter, nationwide cross-sectional study embedded in 2 nationwide studies on VWD and hemophilia in the Netherlands. RESULTS: In total, 493 patients with hemophilia (n = 329) or VWD (n = 164) were included, of whom 351 patients participated in the CRC screening program (71.2%). FIT positivity and false-positive rate in patients with hemophilia and VWD were significantly higher than those in the general population (14.8% vs. 4.3%, p < .001 and 10.3% vs. 2.3%, p

Contains fulltext : 208376.pdf (Publisher’s version ) (Open Access)

We describe the pattern of change in coagulation parameters during the course of severe postpartum hemorrhage in a retrospective cohort study among 1312 women experiencing severe postpartum hemorrhage necessitating blood transfusion. Levels of hemoglobin, hematocrit, platelet count, fibrinogen, activated partial thromboplastin time (aPTT) and prothrombin time (PT) per categorized volume of blood loss during severe postpartum hemorrhage were described and compared between women with and without the composite adverse outcome. Need for surgical intervention, severe acute maternal morbidity, and maternal mortality were jointly considered the composite adverse outcome. Of the 1312 women, 463 (35%) developed the composite adverse outcome. The incidence of a fibrinogen level < 2 g/L was 26% (342 per 1312). Low fibrinogen and prolonged aPTT during the first 2 L of hemorrhage were associated with a subsequent composite adverse outcome; median fibrinogen and aPTT among women with and without the composite end point after 1.5 to 2 L of hemorrhage were 1.5 g/L (interquartile range [IQR], 1.0-1.9) vs 2.7 g/L (IQR, 1.9-3.4) and 39 s (IQR, 30-47) vs 32 s (IQR, 28-36), respectively. PT and platelet count as assessed during the first 2 L of hemorrhage were not associated with morbidity or mortality. Our results suggest that detection of low levels of fibrinogen and elevated aPTT levels during early postpartum hemorrhage can contribute to the identification of women that may benefit from targeted hemostatic treatment. Essential in this identification process is the moment of reaching a level of fibrinogen of

BACKGROUND: Storage time of platelet (PLT) concentrates has been negatively associated with clinical efficacy outcomes. The aim of this study was to quantify the association between storage time of PLT concentrates and interval to the next PLT transfusion for different types of PLT components, stored for up to 7 days and transfused to transfusion-dependent hematooncology patients with thrombocytopenia. STUDY DESIGN AND METHODS: From a cohort of patients from 10 major Dutch hospitals, patients were selected whose transfusion patterns were compatible with PLT transfusion dependency due to hematooncologic disease. Mean time to the next transfusion and mean differences in time to the next transfusion for different storage time categories (i.e., fresh, 5 days) were estimated, per component type, using multilevel mixed-effects linear models. RESULTS: Among a cohort of 29,761 patients who received 140,896 PLT transfusions we selected 4441 hematooncology patients who had received 12,724 PLT transfusions during periods of PLT transfusion dependency. Transfusion of fresh, compared to old, buffy coat–derived PLTs in plasma was associated with a delay to the next transfusion of 6.2 hours (95% confidence interval [CI], 4.5-8.0 hr). For buffy coat–derived PLTs in PAS-B and -C this difference was 7.7 hours (95% CI, 2.2-13.3 hr) and 3.9 hours (95% CI, –2.1 to 9.9 hr) while for apheresis PLTs in plasma it was only 1.8 hours (95% CI, –3.5 to 7.1 hr). CONCLUSION: Our results indicate that the time to the next transfusion shortens with increasing age of transfused buffy coat–derived PLT concentrates. This association was not observed for apheresis PLTs.

BACKGROUND: Concern of transfusion-transmitted bacterial infections has been the major hurdle to extend shelf life of platelet (PLT) concentrates. We aimed to investigate the association between storage time and risk of positive blood cultures at different times after transfusion.STUDY DESIGN AND METHODS: We performed a nationwide cohort study among PLT transfusion recipients in Denmark between 2010 and 2012, as recorded in the Scandinavian Donations and Transfusions (SCANDAT2) database. Linking with a nationwide database on blood cultures (MiBa), we compared the incidence of a positive blood culture among recipients of PLTs stored 6 to 7 days (old) to those receiving fresh PLTs (1-5 days), using Poisson regression models. We considered cumulative exposures in windows of 1, 3, 5, and 7 days.RESULTS: A total of 9776 patients received 66,101 PLT transfusions. The incidence rate ratio (IRR) of a positive blood culture the day after transfusion of at least one old PLT concentrate was 0.77 (95% confidence interval [CI], 0.54-1.09) compared to transfusion of fresh PLT concentrates. The incidence rate of a positive blood culture was lower the day after receiving one old compared to one fresh PLT concentrate (IRR, 0.57; 95% CI, 0.37-0.87). Three, 5, or 7 days after transfusion, storage time was not associated with the risk of a positive blood culture.CONCLUSION: Storage of buffy coat-derived PLT concentrates in PAS-C up to 7 days seems safe regarding the risk of a positive blood culture. If anything, transfusion of a single old PLT concentrate may decrease this risk the following day.

BACKGROUND: Extension of storage time of platelet (PLT) concentrates may result in an increased risk of bacteremia, directly via transfusion of contaminated products or indirectly via transfusion-related immunomodulation. We aimed to quantify the association of storage time of PLT concentrates and all-cause bacteremia in hematologic patients. STUDY DESIGN AND METHODS: We established a cohort of hematologic patients who received a PLT transfusion between 2005 and 2015. Cases were defined as patients with a bacteremia the day after transfusion and matched to as many controls as possible. A conditional logistic regression was performed, stratified by storage medium. RESULTS: Among 3514 patients receiving 36,032 PLT concentrates stored in plasma, 613 cases of bacteremia were found. The relative risk of all-cause bacteremia the day after transfusion was 0.80 (95% confidence interval [CI], 0.58-1.12) for PLT concentrates stored 3 to 4 days and 0.67 (95% CI, 0.49-0.92) for at least 5 days, compared to no more than 2 days. Among 1527 patients receiving 11,822 PLT concentrates stored in PLT additive solution, 182 cases of bacteremia were found. The relative risk of all-cause bacteremia was 1.14 (95% CI, 0.70-1.84) for PLT concentrates stored for 3 to 4 days and 1.19 (95% CI, 0.70-2.01) for at least 5 days, compared to not more than 2 days. CONCLUSION: Storage time of PLT concentrates was not associated with increased occurrence of all-cause bacteremia the day after transfusion. If anything, fewer cases of bacteremia occurred with increasing storage time of PLT concentrates in plasma. These bacteremias are not directly caused by transfusion of a contaminated product and the underlying mechanism warrants further research.

Patients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified joint bleeds were matched for age, sex and Factor VIII level or von Willebrand Factor activity in a nested case-control study within the Willebrand in the Netherlands study. Assessments included the Hemophilia Joint Health Score (0-124), Pettersson score (0-13 per joint X-ray), Hemophilia Activity List score (0-100), joint pain (Visual Analog Scale 0-10), and the Impact on Participation and Autonomy questionnaire (0-20). Arthropathy was defined as a Hemophilia Joint Health Score of 10 or higher, or a Pettersson score over 3 of at least one joint. We included 48 patients with verified joint bleeds (cases) and 48 controls: 60% males, mean age 46 years (range 18-80), median von Willebrand Factor activity 5 versus 8 IU/dL and Factor VIII 24 versus 36 IU/dL. Arthropathy occurred in 40% of the cases versus 10% of the controls (P3: 13 of 19 vs. 3 of 28, P

Background: Ovarian insufficiency (OI) and infertility are common and devastating late effects of cancer treatment and hematopoietic stem cell transplantation (HSCT). In children, gonadal insufficiency may subsequently lead to abnormal pubertal development. The aim of this study was to assess the cumulative incidence of OI and the need for hormonal induction of pubertal development after HSCT in childhood. We additionally assessed HSCT-related risk factors for OI. Procedures: A single center cohort study was undertaken of female patients transplanted during childhood, surviving at least 2 years post-HSCT and who were at least 10 years old at initiation of the study. Of 141 eligible patients, 109 were included and hormone levels and clinical data of these patients during follow-up were collected. Risk factors for OI were analyzed by multivariate Cox regression analysis. Results: Cumulative incidence of OI was 56% at a median follow-up of 7.2 years. Eight patients, initially diagnosed with OI, showed recovery of ovarian function over time. Hormonal induction of puberty was necessary in 44% of females who were pre-pubertal or pubertal at HSCT. In multivariate analysis, more advanced pubertal stage at HSCT was associated with OI. We found a trend for an association of busulfan with OI in patients conditioned with chemotherapy only. Conclusions: The incidence of OI after HSCT was high and associated with more advanced pubertal stage at HSCT. Almost half of the females who were pre-pubertal or pubertal at HSCT required hormonal induction of pubertal development.

Introduction and Objectives: Inhibitor development in nonsevere haemophilia A patients (FVIII:C, 2-40 IU/dL) has a heterogeneous clinical phenotype, ranging from irrelevant transient inhibitors to high titre neutralizing antibodies with severe bleeding complications. Data on inhibitor presentation are scarce and selected, favouring those with severe complications. The aim of current study was to describe the presenting symptoms of inhibitors in a large unselected cohort of nonsevere haemophilia patients. Materials and Methods: Clinical data were collected of 107 inhibitor patients derived from a source population of 2,709 nonsevere haemophilia A patients that were treated between 1980 and 2011 in 34 European and Australian centers (the INSIGHT consortium). Patients were subdivided according to age and calendar period at time of inhibitor development (10-year groups), aiming to search for age-related trends and trends over time. Results: Age at inhibitor detection varied widely between 1 and 85 years with a median age of 38 years (IQR, 15-61). Most inhibitors developed in the period of 2000-2010 (n = 64, 60%). Inhibitors developed after a median of 28 exposure days (IQR, 14-66), which was comparable between all age groups. Fifty-seven patients (56%) had high titre inhibitors (>5 BU/mL). About half of the high titre inhibitors developed in patients older than 40 years (n = 30, 53%) and 60% after the year 2000 (n = 34). In 13 (12%) inhibitor patients the inhibitor was detected during routine laboratory screening and no clinical signs of the inhibitor were present. More than half of the patients (n = 61) had an increased bleeding tendency at presentation with inhibitor. In 80 patients (80%) endogenous FVIII:C was decreased to below 5 IU/dL (including 33/44 patients with low titer inhibitors), of whom FVIII:C fell below ≤ 0.01 IU/mL in 49 patients (46%). Conclusion: Half of the patients with nonsevere haemophilia A and inhibitors developed high titre inhibitors; these were more common in the last decennium. More than half of the patients presented with bleeding complications and 46% had changed to a severe phenotype. These results stress the importance of close follow-up after exposure to therapeutic factor VIII concentrates in nonsevere haemophilia A patients.

Introduction and Objectives: Non-severe hemophilia A (baseline FVIII:C, 2-40 IU/dL) is caused by a mutation in the F8 gene. There is limited knowledge on the factors determining the variation in baseline FVIII:C. The aim is to identify the determinants of baseline FVIII:C in non-severe hemophilia A patients. Materials and Methods: We analyzed clinical data for non-severe hemophilia A patients, treated between 1980-2013, in European Haemophilia Treatment Centers (HTCs) participating in the INSIGHT/RISE project. We performed analyses on mutations that were present in ≥10 patients. Age (at FVIII:C measurement), F8 gene mutation, VWF:Ag, VWF:Act and HTC were analyzed as potential determinants by multivariate regression analyses. Results: We identified nine missense mutations present in ≥10 patients in 321 individuals, median age 23 years (IQR 7-47). From these individuals we had data on 667 FVIII:C measurements in 5 HTCs. Median baseline FVIII:C, VWF:Ag and VWF: Act were 17 IU/dL (IQR 11-22), 98 IU/dL (IQR 78-128) and 91 IU/dL (70-115) respectively. Baseline FVIII:C, VWF:Ag and VWF:Act all increased with age, both in the total population and within the two largest mutation groups (Asn618Ser, 113 patients; Arg593Cys, 107 patients). VWF:Ag, age and F8 mutation were significant predictors of baseline FVIII:C (p

Introduction and Objectives: Large inter-individual variation in DDAVP response is observed in non-severe hemophilia A patients. Prediction of the response to DDAVP may support its optimal clinical use. The aim is to analyze the predictive value of known determinants of the DDAVP response. Materials and Methods: We included non-severe hemophilia A patients (FVIII:C, 2- 40 IU/dL) from 34 hemophilia treatment centres in Europe, Australia and North America that participate in the RISE project. Data on the following potential determinants were analyzed: age at DDAVP test, blood group, F8 gene mutation, baseline FVIII:C, body mass index (BMI), VWF:Ag and VWF:Act. Main outcome, the response 1 h after DDAVP administration, is classified as complete (CR; FVIII: C > 50 IU/dL) or not complete (FVIII:C ≤ 50 IU/dL). Data were first analyzed by binary logistic regression analysis. Next, the predictive value of the combined determinants for a CR was used to construct a receiver operator curve (ROC). The area under the ROC curve (AUC) reflects the predictive value of the combined determinants as it represents the proportion of patients with correctly predicted CRs. AUC >80% is considered good, 70-80% fair, and 60-70% poor. Results: We included 850 non-severe hemophilia A patients; median age at time of DDAVP administration was 20 years (IQR 8-40), median baseline FVIII:C, VWF:Ag and VWF:Act levels were 17 IU/dL (IQR 10-25), 95 IU/dL (IQR 72-118), and 86 IU/ dL (IQR 67-111), respectively. A CR was present in 64% of the patients. In the total population, the predictive value for CR was 74% (fair). F8 genotype was known in 508 patients (60%), displaying 136 different missense mutations. Most prevalent were Asn618Ser (n = 105, CR in 84%), Arg593Cys (n = 91, CR in 62%), and Arg2150His (n = 17, CR in 59%). The predictive value of the combined determinants for a CR in the Arg593Cys group was 76% (fair), but was poor in the Asn618Ser group and the Arg2150His group (AUC = 62%, and 67%, respectively). Conclusions: The predictive value of the known determinants of DDAVP response is fair in the complete study group. However, it varies among different mutation groups between fair and poor. This suggests yet unidentified determinants of the response to DDAVP.

Introduction and Objectives: Neutralizing antibodies (inhibitors) directed against the FVIII protein may increase the bleeding frequency and compromise the management of bleeding episodes in nonsevere haemophilia A patients. The median annual bleeding frequency in patients without inhibitors is described to be 0 (IQR 0-3) for mild haemophilia and 1 (IQR 0-13) for moderate haemophilia. The aim of this study was to evaluate the burden of bleeding and to describe the treatment strategies that are used for bleeding episodes in a large group of unselected inhibitor patients with nonsevere haemophilia A. Materials and Methods: We included all inhibitor patients from the INSIGHT study, an international multicentre cohort study including all 2709 nonsevere HA patients (FVIII:C 2-4 IU/dL) that received at least 1 exposure to FVIII concentrate between 1980-2011. Data of the 1st inhibitor period were analyzed. Results: We included 107 nonsevere HA inhibitor patients (median baseline FVIII:C 9 IU/dL (IQR 6-16); median age of 38 years (IQR 15-61)). A high titre inhibitor (> 5 BU/mL) was present in 57 (53%) patients. In 30 (28%) patients the FVIII:C level was decreased ≤1 IU/dL. Eighty-nine patients (83%) received treatment for bleeding episodes. Most patients had spontaneous bleeds (n = 49, 46%); a higher proportion of high titre patients had spontaneous bleeds compared to low titre patients (83% vs. 53%, relative risk (RR) 2.7, 95% confidence interval (CI) 1.3-5.8). The median number of bleeding episodes per inhibitor year was 2 (IQR 1-5); this did not differ between patients with FVIII:C ≤ 1 IU/dL and those with measurable FVIII levels (p = 0.5), patients with low titre and high titre inhibitors (p = 0.5) and patients receiving eradication treatment or not (p = 0.7). In order to treat bleedings, FVIII concentrate was used in 59 patients (55%), FVIII bypassing agents in 50 (47%) and desmopressin in 18 patients (17%). Desmopressin was used more often in patients with remaining circulating FVIII:C levels compared to patients with a FVIII:C ≤ 1 IU/dL and in patients without eradication treatment compared to patients with eradication treatment (25% vs. 3%; RR 7.4, CI 1.0-53.5 and 25% vs. 0%; RR 14.0, CI 0.9 - 224.6, respectively). Conclusion: Inhibitor development in nonsevere HA patients aggravates the burden of bleeding with the majority (83%) of the patients needing treatment for bleeding episodes, at a median of 2 bleeding episodes per year.

BACKGROUND: Donor white blood cell (WBC) antibodies are thought to increase the risk of transfusion-related acute lung injury (TRALI). WBC antibodies can be present in blood products from donors who have been alloexposed. Alloexposed donors are increasingly excluded from donating plasma, but can still donate plasma-poor products. We aimed to quantify the contribution of alloexposed donors to the occurrence of TRALI for different blood product types. STUDY DESIGN AND METHODS: We performed a case-referent study including all reported TRALI patients and all Dutch blood donors. Data on alloexposure status of donors of all TRALI cases reported between January 2004 and October 2008, in the Netherlands, were compared to information on the total donor population. RESULTS: Alloexposure status of all 223 involved donors was compared to the expected status. The overall percentage of TRALI cases that could have been prevented by the deferral of all alloexposed donors (i.e., population-attributable risk [PAR]) was 51% (95% confidence interval [CI], 14%-88%). In 19 recipients of exclusively plasma-poor products (mostly red blood cells [RBCs]), alloexposure of the donors was not associated with TRALI, while in 28 recipients of both plasma-poor and plasma-rich products (>200 mL plasma), the PAR was 94% (95% CI, 34%-100%). CONCLUSIONS: Alloexposed donors conferred an increased risk of TRALI in recipients of plasma-rich products, but not in recipients of plasma-poor products. Although WBC antibodies are an important risk factor for TRALI, among RBC recipients another risk factor must be more important.

BACKGROUND: Transfusion-related acute lung injury (TRALI) is one of the most serious complications of blood transfusion. It can be caused by incompatible white blood cell antibodies in transfused plasma. The objective of this study was to quantify the reduction of TRALI after introduction of male-only plasma for transfusion as a preventive measure, which took effect in 2007. STUDY DESIGN AND METHODS: In the Netherlands all cases of TRALI are reported to the national hemovigilance office. All reported cases of TRALI from 2002 to November 2009 were considered for inclusion. Those meeting the Canadian consensus clinical definition were included and subdivided according to whether or not the patient had received quarantine fresh-frozen plasma (Q-FFP) in the 6-hour period before the reaction. The numbers of TRALI cases involving plasma donated before the measure and of those involving plasma donated after the measure were compared to TRALI cases that did not involve Q-FFP to adjust for reporting bias. RESULTS: A total of 110 cases were included in the analysis. Of 68 cases before the measure, 36 involved Q-FFP. Thirty-one cases occurred after the measure of which eight involved Q-FFP. Eleven occurred in the transitional period, of which four involved Q-FFP. The population-attributable risk of premeasure plasma among TRALI cases occurring before the measure was 0.33 (95% confidence interval, 0.09-0.51). CONCLUSIONS: In the Netherlands the male-only Q-FFP measure was associated with a 33% reduction of TRALI cases.

Background and Objectives. Patients with severe hemophilia A have considerably different factor VIII half-lives. Whether this is associated with their clinical characteristics has not been reported. The aim of this study was to describe the association of factor VIII half-lives with treatment and clinical characteristics of patients with severe hemophilia A, who have been treated with individually tailored prophylaxis. Design and Methods. Patients were selected from a single-center cohort of 214 patients with severe hemophilia, born between 1944 and 1995. To improve efficiency we measured factor VIII half-life in 42 patients selected from the extremes of the distribution of phenotypes of severe hemophilia. We assessed information on life-long joint bleeds and clotting factor consumption. Orthopedic outcome was assessed by the Pettersson score. Results. Among these patients with severe hemophilia, factor VIII half-life ranged from 7.4-20.4 hours (median 11.8 hours). A one-hour increase in factor VIII half-life was associated with 96 (95% confidence interval (Cl) 2-190) IU less clotting factor use per kg per year. Age was an important determinant of factor VIII half-life, and explained a large part of the association between factor VIII half-life and clotting factor consumption. The median number of joint bleeds per year and arthropathy were similar for patients with different half-lives. Interpretations and Conclusions. Among patients with severe hemophilia, treated prophylactically with clotting factor, those with a shorter factor VIII half-life required slightly more clotting factor to prevent joint bleeds and subsequent arthropathy than similar patients with a longer factor VIII half-life.

Background and Objectives. Since venous access in small children can be difficult to obtain, implantable venous access devices (IVAD) are used to administer clotting factor in such patients with severe hemophilia. The aim of our study was to evaluate how many children in our center needed an IVAD in order to be able to start early prophylaxis, what the differences were between children who needed an IVAD and those who did not and what the complications of the IVAD were. Design and Methods. All 70 patients with severe hemophilia born between January 1987 and October 2000 treated at our center before they were 6 years old were studied. Results. An IVAD was placed in 23 children (33%). Children with an IVAD started prophylactic treatment at a mean age of 2 years (SD 1.3), those without at a mean age of 3.6 years (SD 1.6) (p< 0.001). Home treatment was feasible at a mean age of 2.8 years (SD 1.3) in children with an IVAD and at 4.5 years in those without an IVAD (SD 1.8) (p = 0.001). Infection was the most frequent complication; the mean number of infections per IVAD was 0.61. Thrombosis was more common than initially thought (15%). The infection rate in children with inhibitory antibodies was 3.1 per 1000 patient-days; in children without an inhibitor it was 0.72 per 1000 patient-days. Interpretation and Conclusions. In 33% of the children in our cohort an IVAD was needed in order to start early prophylaxis. IVAD are needed more frequently when prophylaxis is started at an early age, but have the advantage that home treatment is feasible earlier. Infection is the most common complication, particularly in children with inhibitors.

Background and Objectives. Since venous access in small children can be difficult to obtain, implantable venous access devices (IVAD) are used to administer clotting factor in such patients with severe hemophilia. The aim of our study was to evaluate how many children in our center needed an IVAD in order to be able to start early prophylaxis, what the differences were between children who needed an IVAD and those who did not and what the complications of the IVAD were. Design and Methods. All 70 patients with severe hemophilia born between January 1987 and October 2000 treated at our center before they were 6 years old were studied. Results. An IVAD was placed in 23 children (33%). Children with an IVAD started prophylactic treatment at a mean age of 2 years (SD 1.3), those without at a mean age of 3.6 years (SD 1.6) (p< 0.001). Home treatment was feasible at a mean age of 2.8 years (SD 1.3) in children with an IVAD and at 4.5 years in those without an IVAD (SD 1.8) (p = 0.001). Infection was the most frequent complication; the mean number of infections per IVAD was 0.61. Thrombosis was more common than initially thought (15%). The infection rate in children with inhibitory antibodies was 3.1 per 1000 patient-days; in children without an inhibitor it was 0.72 per 1000 patient-days. Interpretation and Conclusions. In 33% of the children in our cohort an IVAD was needed in order to start early prophylaxis. IVAD are needed more frequently when prophylaxis is started at an early age, but have the advantage that home treatment is feasible earlier. Infection is the most common complication, particularly in children with inhibitors.