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Contains fulltext : 282506.pdf (Publisher’s version ) (Open Access) Patients with type 1 and type 2 von Willebrand disease (VWD) can be treated with desmopressin. Although a previous study has shown that the location of the causative VWF gene variant is associated with desmopressin response in type 1 VWD, the association between variants in the VWF gene and desmopressin response is not yet fully understood. Our primary aim was to compare desmopressin response in type 1 VWD patients with and without a VWF gene variant. Secondly, we investigated whether desmopressin response depends on specific VWF gene variants in type 1 and type 2 VWD. We included 250 patients from the Willebrand in the Netherlands study: 72 type 1 without a VWF gene variant, 108 type 1 with a variant, 45 type 2A, 16 type 2M, and 9 type 2N patients. VWF gene was analyzed with ion semiconductor sequencing and Multiplex Ligation-dependent Probe Amplification. Complete response to desmopressin was observed in all type 1 VWD patients without a variant, 64.3% of type 1 patients with a variant, and 31.3% of type 2 patients (P < .001). Despite a large interindividual variability in desmopressin response, patients with the same variant had comparable desmopressin responses. For instance, in 6 type 1 patients with exon 4 to 5 deletion, mean VWF activity at 1 hour after desmopressin was 0.81 IU/mL, with a coefficient of variation of 22.9%. In conclusion, all type 1 VWD patients without a VWF gene variant respond to desmopressin. In type 1 and type 2 VWD patients with a VWF variant, desmopressin response highly depends on the VWF gene variants.

Genotyping is not routinely performed at diagnosis of von Willebrand disease (VWD). Therefore, the association between genetic variants and pathogenic mechanism or the clinical and laboratory phenotype is unknown in most patients, especially in type 1 VWD. To investigate whether genotyping adds to a better understanding of the pathogenic mechanisms and variability in phenotype, we analyzed the VWF gene in 390 well-defined VWD patients, included in the WiN study. A VWF gene variant was found in 155 patients (61.5%) with type 1, 122 patients (98.4%) with type 2, and 14 patients (100%) with type 3 VWD. Forty-eight variants were novel. For each VWF gene variant, the pathogenic mechanisms associated with reduced VWF levels was investigated using the FVIII:C/VWF:Ag and VWFpp/VWF:Ag ratios. In type 1 VWD, reduced synthesis or secretion of VWF was most frequently found in patients with nonsense variants, frameshift variants, and deletions, whereas rapid clearance of VWF was mainly found in patients with missense variants. Furthermore, type 1 VWD patients with and without a VWF gene variant were clearly distinct in their clinical features such as age of diagnosis, laboratory phenotype, and bleeding phenotype. In type 2 VWD, 81% of variants were associated with an increased clearance of VWF. To conclude, we identified the pathogenic mechanisms associated with various VWF gene variants in type 1, 2, and 3 VWD patients. Additionally, major differences in the phenotype of type 1 VWD patients with and without a variant were observed, which may be of importance for clinical management.

BACKGROUND: In patients with non-severe hemophilia A, we lack detailed knowledge on the timing of treatment with factor VIII (FVIII) concentrates. This knowledge could provide information about the expected treatment timing in patients with severe hemophilia A treated with non-replacement therapies. OBJECTIVE: To assess the FVIII treatment history in patients with non-severe hemophilia A. METHODS: Patients with non-severe hemophilia (baseline FVIII activity [FVIII:C] 2-40 IU/dL) were included from the INSIGHT study. The primary outcome was median age at first FVIII exposure (ED1). In a subgroup of patients for whom more detailed information was available, we analyzed the secondary outcomes: median age at first 20 EDs, annualized bleeding rate for all bleeds (ABR), joint bleeds (AJBR), and major spontaneous bleeds (ASmBR). RESULTS: In the total cohort (n = 1013), median baseline FVIII activity was 8 IU/dL (interquartile range [IQR] 4-15) and the median age at ED1 was 3.7 years (IQR 1.4-7.7). Median age at ED1 rose from 2.5 years (IQR 1.2-5.7) in patients with FVIII:C 2-5 IU/dL to 9.7 years (IQR 4.8-16.0) in patients with FVIII:C 25-40 IU/dL. In the subgroup (n = 104), median age at ED1, ED5, ED10, and ED20 was 4.0 years (IQR 1.4-7.6), 5.6 years (IQR 2.9-9.3), 7.5 years (IQR 4.4-11.3), and 10.2 years (IQR 6.5-14.2), respectively. Median ABR, AJBR, and ASmBR were 1.1 (IQR 0.5-2.6), 0.3 (IQR 0.1-0.7), and 0 (IQR 0-0), respectively. CONCLUSION: This study demonstrates that in non-severe hemophilia A, the age at first FVIII exposure increases with baseline FVIII:C and that major spontaneous bleeds rarely occur. ispartof: JOURNAL OF THROMBOSIS AND HAEMOSTASIS vol:18 issue:12 pages:3203-3210 ispartof: location:England status: published

Contains fulltext : 282574.pdf (Publisher’s version ) (Open Access) Von Willebrand disease (VWD) is a bleeding disorder caused by quantitative (type 1 or 3) or qualitative (type 2A/2B/2M/2N) defects of circulating von Willebrand factor (VWF). Circulating VWF levels not always fully explain bleeding phenotypes, suggesting a role for alternative factors, like platelets. Here, we investigated platelet factor 4 (PF4) in a large cohort of patients with VWD. PF4 levels were lower in type 2B and current bleeding phenotype was significantly associated with higher PF4 levels, particularly in type 1 VWD. Based on our findings we speculate that platelet degranulation and cargo release may play a role across VWD subtypes.

Contains fulltext : 248809.pdf (Publisher’s version ) (Open Access) INTRODUCTION: The negative impact of haemophilia on social participation is well established in previous studies, however, the impact of Von Willebrand disease (VWD) on social participation has not been studied. AIM: To compare the social participation of a large cohort of VWD patients in the Netherlands with the general Dutch population. In addition, to identify factors associated with social participation in VWD. METHODS: Patients participating in the "Willebrand in the Netherlands" study completed an extensive questionnaire on educational level, absenteeism from school or work, and occupational disabilities. RESULTS: Seven-hundred and eighty-eight VWD patients were included (mean age 38.9 years, 59.5% females), of whom 136 children

Background Dosing of replacement therapy with factor VIII concentrate in patients with haemophilia A in the perioperative setting is challenging. Underdosing and overdosing of factor VIII concentrate should be avoided to minimise risk of perioperative bleeding and treatment costs. We hypothesised that dosing of factor VIII concentrate on the basis of a patient's pharmacokinetic profile instead of bodyweight, which is standard treatment, would reduce factor VIII consumption and improve the accuracy of attained factor VIII levels.Methods In this open-label, multicentre, randomised, controlled trial (OPTI-CLOT), patients were recruited from nine centres in Rotterdam, Groningen, Utrecht, Nijmegen, The Hague, Leiden, Amsterdam, Eindhoven, and Maastricht in The Netherlands. Eligible patients were aged 12 years or older with severe or moderate haemophilia A (severe haemophilia was defined as factor VIII concentrations of

Red blood cell (RBC) alloimmunization is a serious complication of blood transfusions, challenging selection of compatible units for future transfusions. Genetic characteristics may be associated with the risk of RBC alloimmunization and may therefore serve to identify high-risk patients. The aim of this systematic review was to summarize the available evidence on genetic risk factors for RBC alloimmunization. Electronic databases were searched up to April 2020 for studies (Search terms included transfusion, alloimmunization and genetic). A total of 2581 alloimmunized cases and 26,558 controls were derived from 24 studies. The alleles that were most frequently studied and that demonstrated significant associations in a meta-analysis with alloimmunization to the Duffya antigen were HLA-DRB1*04 (Odds Ratio 7.80 (95%CI 4.57-13.33)), HLA-DRB1*15 (OR 3.76 (95%CI 2.14-6.59)), and HLA-DRB1*03 (OR 0.12 (95%CI 0.05-0.29)). Furthermore, significant associations with anti-K formation was found for the alleles HLA-DRB1*10 (OR 2.64 (95%CI 1.41-4.95)), HLA*DRB1*11 (OR 2.11, (95% CI 1.34-3.32)), and HLA-DRB1*13 (OR 1.71 (95%CI 1.26-2.33)). Overall, the available evidence was of moderate to low quality, hampering interpretation of reported results. There is an urgent need for high quality evidence on genetic risk factors for RBC alloimmunization.

Introduction: Incidence of massive transfusion after birth was high in the Netherlands between 2004 and 2006 compared with other high-income countries. This study investigated incidence, causes, management and outcome of women receiving massive transfusion due to postpartum hemorrhage in the Netherlands in more recent years.Material and Methods: Data for all pregnant women who received eight or more units of packed red blood cells from a gestational age of 20 weeks and within the first 24 hours after childbirth, during 2011 and 2012, were obtained from a nationwide retrospective cohort study, including 61 hospitals with a maternity unit in the Netherlands.Results: Incidence of massive transfusion due to postpartum hemorrhage decreased to 65 per 100 000 births (95% CI 56-75) between 2011 and 2012, from 91 per 100 000 births (95% CI 81-101) between 2004 and 2006, while median blood loss increased from 4500 mL (interquartile range 3250-6000) to 6000 mL (interquartile range 4500-8000). Uterine atony remained the leading cause of hemorrhage. Thirty percent (53/176) underwent peripartum hysterectomy between 2011 and 2012, compared with 25% (83/327) between 2004 and 2006. Case fatality rate for women who received massive transfusion due to postpartum hemorrhage was 2.3% (4/176) between 2011 and 2012, compared with 0.9% (3/327) between 2004 and 2006.Conclusions: The incidence of postpartum hemorrhage with massive transfusion decreased in the Netherlands between both time frames, but remained an important cause of maternal mortality and morbidity, including peripartum hysterectomy. National surveillance of maternal morbidity and mortality due to postpartum hemorrhage through an improved and continuous registration with confidential enquiries may lead to the identification of clear improvements of maternal care.

Background In recent years, more awareness is raised about sex-specific dilemmas in inherited bleeding disorders. However, no large studies have been performed to assess differences in diagnosis, bleeding phenotype and management of men and women with bleeding disorders. Therefore, we investigated sex differences in a large cohort of well-defined patients with autosomal inherited bleeding disorders (von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs)). Methods We included patients from three nationwide cross-sectional studies on VWD, RBDs and CPDs in the Netherlands, respectively the WiN, RBiN and TiN study. In all studies a bleeding score (BS) was obtained, and patients filled in an extensive questionnaire on the management and burden of their disorder. Findings We included 1092 patients (834 VWD; 196 RBD; 62 CPD), of whom 665 (60.9%) were women. Women were more often referred because of a bleeding diathesis than men (47.9% vs 36.6%, p = 0.002). Age of first bleeding was similar between men and women, respectively 8.9 ± 13.6 (mean ±sd) years and 10.6 ± 11.3 years (p = 0.075). However, the diagnostic delay, which was defined as time from first bleeding to diagnosis, was longer in women (11.6 ± 16.4 years) than men (7.7 ± 16.6 years, p = 0.002). Similar results were found when patients referred for bleeding were analyzed separately. Of women aging 12 years or older, 469 (77.1%) had received treatment because of sex-specific bleeding. Interpretation Women with autosomal inherited bleeding disorders are more often referred for bleeding, have a longer diagnostic delay, and often require treatment because of sex-specific bleeding. Funding The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda), and CSL Behring (unrestricted grant).

Inhibitor development is a major complication of treatment with factor VIII concentrates in nonsevere haemophilia A. It has been suggested that plasma-derived factor VIII (FVIII) concentrates elicit fewer inhibitors than recombinant FVIII concentrates, but studies in severe haemophilia A patients have shown conflicting results. We designed a case-control study to investigate the clinical and genetic risk factors for inhibitor development in nonsevere haemophilia A patients. We investigated whether the type of FVIII concentrate was associated with inhibitor development in nonsevere haemophilia A patients. This nested case-control study includes 75 inhibitor patients and 223 controls, from a source population of the INSIGHT study, including all nonsevere haemophilia A patients (FVIII:C 2-40%) that were treated with FVIII concentrates in 33 European and one Australian centre. Cases and controls were matched for date of birth and cumulative number of exposure days (CED) to FVIII concentrate. A conditional logistic regression model was used to calculate unadjusted and adjusted odds ratios. No increased risk for inhibitor development was found for any type of FVIII concentrate; either when comparing recombinant FVIII concentrates to plasma-derived FVIII concentrates (adjusted odds ratio 0 center dot 96, 95% confidence interval (CI) 0 center dot 36-2 center dot 52) or for specific types of FVIII concentrates.

Introduction Patients with bleeding disorders may experience limitations in sports participation and physical activity. Several studies on sports participation have been performed in haemophilia patients, but studies in patients with von Willebrand disease (VWD) are lacking. Aim We assessed the sports participation and physical activity of a large cohort of VWD patients. Methods Patients were included from the "WiN study." All patients completed a questionnaire on sports participation, physical activity, quality of life and bleeding symptoms (Tosetto bleeding score). Results From the 798 included patients, 474 had type 1, 301 type 2 and 23 type 3 VWD. The mean age was 39 +/- 20 (standard deviation) years. Five hundred and fifty-two patients (69.3%) participated in various types of sports. Type 3 VWD patients more often did not participate in sports due to fear of bleeding and physical impairment, respectively, OR = 13.24 (95% CI: 2.45-71.53) and OR = 5.90 (95% CI: 1.77-19.72). Patients who did not participate in sports due to physical impairment had a higher bleeding score item for joint bleeds 1.0 (+/- 1.6) vs 0.5 (+/- 1.1) (P = 0.036). Patients with type 3 VWD and patients with a higher bleeding score frequently had severe limitations during daily activities, respectively, OR = 9.84 (95% CI: 2.83-34.24) and OR = 1.08 (95% CI: 1.04-1.12). Conclusion The majority of VWD patients participated in sports. Patients with type 3 VWD, a history of joint bleeds and a more severe bleeding phenotype frequently experienced limitations in sports participation and physical activities during daily life.

Desmopressin increases endogenous factor VIII levels in hemophilia A. Large inter-individual variation in the response to desmopressin is observed. Patients with a lower baseline factor VIII activity tend to show a reduced response, therefore, desmopressin is less frequently used in moderate hemophilia A patients (baseline factor VIII activity 1-5 international units/deciliter), even though factor VIII levels may rise substantially in some of them. We aim to describe the response to desmopressin in moderate hemophilia A patients and to identify predictors. We selected data on 169 patients with moderate hemophilia from the multicenter Response to DDAVP In non-severe hemophilia A patients: in Search for dEterminants (RISE) cohort study. Adequate response to desmopressin was defined as a peak factor VIII level ≥ 30, and excellent response as ≥ 50 international units/deciliter after desmopressin administration. We used univariate and multiple linear regression techniques to analyze predictors of the peak factor VIII level. Response was considered adequate in 68 patients (40%), of whom 25 showed excellent response (15%). Intravenous administration, age, pre-desmopressin factor VIII activity and von Willebrand factor antigen, peak von Willebrand factor activity and desmopressin-induced rise in von Willebrand factor antigen were significant predictors of peak factor VIII level and explained 65% of the inter-individual variation. In 40% of moderate hemophilia A patients, desmopressin response was adequate, thus it is important not to with-hold this group of patients from desmopressin responsiveness. Among the six predictors that we identified for desmopressin-induced factor VIII rise, factor VIII activity and desmopressin-induced rise in von Willebrand factor antigen had the strongest effect.

Item does not contain fulltext 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

Introduction: To compare the outcomes of women who were initially managed by intrauterine balloon tamponade or uterine artery embolization because of persistent postpartum hemorrhage demanding an immediate intervention to control bleeding.Material and Methods: Propensity score-matched cohort study including women who had intrauterine balloon tamponade or uterine artery embolization as initial management strategy to control persistent postpartum hemorrhage, that is, refractory to first-line therapy combined with at least one uterotonic agent. The primary outcome measure was a composite of peripartum hysterectomy and/or maternal mortality. Secondary outcomes measures were total volume of blood loss and total number of packed red blood cells transfused.Results: Our 1:1 propensity score-matched cohort comprised of 50 women who had intrauterine balloon tamponade and 50 women who underwent uterine artery embolization at a blood loss between 1000 and 7000 mL. There was no statistically significant difference in the hysterectomy risk between the two groups (n = 6 in each group, odds ratio [OR] 1.00, 95% confidence interval [CI] .30-3.34), in total volume of blood loss (median 4500 mL, interquartile range [IQR] 3600-5400) for balloon vs 4000 mL (IQR 3250-5000) for embolization, P = 0.382) or in total units of packed red blood cells transfused (median 7 (IQR 5-10) for balloon vs 6 [IQR 4-9] for embolization, P = 0.319). Fifteen women (30%) who were initially managed by an intrauterine balloon still underwent uterine artery embolization, of whom one had an embolization-related thrombo-embolic event. Maternal mortality occurred in neither of the intervention groups.Conclusions: No difference in the risk of peripartum hysterectomy and/or maternal death was observed between women who had intrauterine balloon tamponade and women who underwent uterine artery embolization as an initial management for persistent postpartum hemorrhage. Although this study was underpowered to demonstrate equivalence, our study design provides a framework for future research in which intrauterine balloon tamponade may prove to be a suitable intervention of first choice in the management of persistent postpartum hemorrhage.

This cohort study examines the association of timing of receipt of plasma transfusions among women experiencing persistent postpartum hemorrhage with adverse maternal outcomes., Key Points Question Is plasma transfusion within the first 60 minutes of persistent postpartum hemorrhage (PPH) associated with incidence of maternal adverse outcomes? Findings In this cohort study of 114 propensity score–matched women with persistent PPH, plasma transfusion within the first 60 minutes of persistent PPH was not associated with incidence of maternal adverse outcomes compared with no or later plasma transfusion, independent of severity of PPH at the time of plasma transfusion. Meaning These findings do not support the theory that early plasma transfusion in women with persistent PPH is better than no or later plasma transfusion., Importance Early plasma transfusion for women with severe postpartum hemorrhage (PPH) is recommended to prevent coagulopathy. However, there is no comparative, quantitative evidence on the association of early plasma transfusion with maternal outcomes. Objective To compare the incidence of adverse maternal outcomes among women who received plasma during the first 60 minutes of persistent PPH vs women who did not receive plasma for similarly severe persistent PPH. Design, Setting, and Participants This multicenter cohort study used a consecutive sample of women with persistent PPH, defined as PPH refractory to first-line measures to control bleeding, between January 1, 2011, and January 1, 2013. Time-dependent propensity score matching was used to select women who received plasma during the first 60 minutes of persistent PPH and match each of them with a woman who had shown the same severity and received the same treatment of PPH but who had not received plasma at the moment of matching. Transfusions were not guided by coagulation tests. Statistical analysis was performed from June 2018 to June 2019. Exposures Transfusion of plasma during the first 60 minutes of persistent PPH vs no or later plasma transfusion. Main Outcomes and Measures Incidence of adverse maternal outcomes, defined as a composite of death, hysterectomy, or arterial embolization. Results This study included 1216 women (mean [SD] age, 31.6 [5.0] years) with persistent PPH, of whom 932 (76.6%) delivered vaginally and 780 (64.1%) had PPH caused by uterine atony. Seven women (0.6%) died because of PPH, 62 women (5.1%) had a hysterectomy, and 159 women (13.1%) had arterial embolizations. Among women who received plasma during the first 60 minutes of persistent PPH, 114 women could be matched with a comparable woman who had not received plasma at the moment of matching. The incidence of adverse maternal outcomes was similar between the women, with adverse outcomes recorded in 24 women (21.2%) who received early plasma transfusion and 23 women (19.9%) who did not receive early plasma transfusion (odds ratio, 1.09; 95% CI, 0.57-2.09). Results of sensitivity analyses were comparable to the primary results. Conclusions and Relevance In this cohort study, initiation of plasma transfusion during the first 60 minutes of persistent PPH was not associated with adverse maternal outcomes compared with no or later plasma transfusion, independent of severity of PPH.

Background The absence of a uniform and clinically relevant definition of severe postpartum haemorrhage hampers comparative studies and optimization of clinical management. The concept of persistent postpartum haemorrhage, based on refractoriness to initial first-line treatment, was proposed as an alternative to common definitions that are either based on estimations of blood loss or transfused units of packed red blood cells (RBC). We compared characteristics and outcomes of women with severe postpartum haemorrhage captured by these three types of definitions. Methods In this large retrospective cohort study in 61 hospitals in the Netherlands we included 1391 consecutive women with postpartum haemorrhage who received either ≥4 units of RBC or a multicomponent transfusion. Clinical characteristics and outcomes of women with severe postpartum haemorrhage defined as persistent postpartum haemorrhage were compared to definitions based on estimated blood loss or transfused units of RBC within 24 h following birth. Adverse maternal outcome was a composite of maternal mortality, hysterectomy, arterial embolisation and intensive care unit admission. Results One thousand two hundred sixty out of 1391 women (90.6%) with postpartum haemorrhage fulfilled the definition of persistent postpartum haemorrhage. The majority, 820/1260 (65.1%), fulfilled this definition within 1 h following birth, compared to 819/1391 (58.7%) applying the definition of ≥1 L blood loss and 37/845 (4.4%) applying the definition of ≥4 units of RBC. The definition persistent postpartum haemorrhage captured 430/471 adverse maternal outcomes (91.3%), compared to 471/471 (100%) for ≥1 L blood loss and 383/471 (81.3%) for ≥4 units of RBC. Persistent postpartum haemorrhage did not capture all adverse outcomes because of missing data on timing of initial, first-line treatment. Conclusion The definition persistent postpartum haemorrhage identified women with severe postpartum haemorrhage at an early stage of haemorrhage, unlike definitions based on blood transfusion. It also captured a large majority of adverse maternal outcomes, almost as large as the definition of ≥1 L blood loss, which is commonly applied as a definition of postpartum haemorrhage rather than severe haemorrhage.

Objective: To determine the association between increasing volumes of crystalloids and colloids administered before transfusion of packed red blood cells in women with persistent postpartum haemorrhage and adverse maternal outcomes. Study design: Retrospective cohort study in the Netherlands. Women with persistent postpartum haemorrhage and known clear fluids volume for resuscitation were included. Women who received ≤2 L of clear fluids were the reference group. We determined the effect of every additional litre of clear fluids on total blood loss, severe maternal morbidity and mortality. Results were adjusted for patient and bleeding characteristics. Results: Of the 883 included women, 199 received ≤2 L of clear fluids. Median blood loss for the reference group was 2.9 L (interquartile range 2.2–3.4). Adjusted mean difference in blood loss compared with the reference group was 0.2 L (95% confidence interval −0.1 to 0.5) for women in the >2 to ≤3 L, 0.4 L (0.1–0.7) for the >3 to ≤4 L category, 0.6 L (0.5–0.7) for the >4 to ≤5 L category, and 1.9 L (1.5–2.3) for the >5 to ≤7 L category. Adjusted odds ratios for adverse maternal outcomes were 1.0 (0.7–1.6), 1.2 (0.8–1.9), 1.8 (1.1–3.1) and 4.4 (2.6–7.5) for women in the 2 to ≤3 L category, >3 to ≤4 L, >4 to ≤5 L, and >5 to ≤7 L volume categories respectively. Results were similar in strata of different severities of bleeding. Conclusion: Clear fluids volume >4 L was independently associated with adverse maternal outcome in women with persistent postpartum haemorrhage.

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SummaryThe development of an inhibitory antibody in non-severe haemophilia A patients may aggravate the bleeding phenotype considerably. Effective treatment of bleeding episodes may be challenging, with ensuing severe complications. At present, evidence is scarce for optimal treatment of bleeding episodes in this patient group. The aim of this study was to describe the incidence and the treatment of bleeding episodes in inhibitor patients in a population-based unselected cohort of non-severe haemophilia A patients with clinically relevant inhibitors. Data were available for 100 of the 107 non-severe haemophilia A patients (factor VIII (FVIII) baseline, 2–40 lU/dl) from 29 centres in Europe and one centre in Australia who had developed a clinically relevant inhibitor between 1980 and 2011. The majority (89 %) of the patients were treated during the inhibitor period for bleeding episodes or a surgical intervention: 66 % needed treatment for bleeding episodes, at a median annual bleeding rate (ABR) of 1.1 (interquartile range (IQR) 0.1–2.5) and a median total of 2 (IQR 1–6) bleeding episodes. Compared to the median ABR before inhibitor development of 0.095 bleeds per year (IQR 0.02–0.42), the increase in ABR is more than a 10-fold. More than 90 % of the bleeding episodes were treated with only one type of product, most frequently (51 %) FVIII concentrates. This study provides the incidence of bleeding episodes and treatment choices in non-severe haemophilia A patients with inhibitors. The 10-fold increase to a median ABR of 1.1 episodes per year emphasizes the impact of inhibitor development for non-severe haemophilia A patients.

Item does not contain fulltext Granulocyte colony-stimulating factor (G-CSF) mobilized peripheral haematopoietic progenitor cells collected by apheresis (HPC-A) are the most common source used for allogeneic hematopoietic stem cell transplantation (HSCT). Retrospective short and long-term donor follow-up studies show very low risks of serious complications and do not report compelling evidence of increased cancer occurrence. Some studies reported a prolonged period of leucopenia without an obvious association with infectious complications. However, beyond the first few weeks after the procedure a relationship between events is elusive. We therefore evaluated medical service utilization by prospectively recruited HPC-A donors and first-time platelet apheresis donors for comparison for 1 year after donation. Data were prospectively collected using questionnaires and by medical record review. A total of 215 HPC-A donors (111 unrelated donors and 104 related donors) and 96 first-time platelet donors consented to participation in the study. Follow-up was available for 202 (96%): questionnaires were returned by 74% and records from nonstudy contacts were available for 94% of donors. During the 1-year follow-up, 94 of the donors who returned questionnaires sought medical attention for diagnostic evaluation and/or treatment: 41% of HPC-A donors and 40% of platelet donors. Medical service utilization the first year after HPC-A donation is similar to that after first-time platelet donation. The occurrence of serious medical conditions in both related and unrelated HPC-A donors underscores the importance of participation in long-term follow-up in large cohorts. The findings in this relatively small cohort contribute to evidence on the safety of G-CSF mobilization and HPC-A. J. Clin. Apheresis 31:523-528, 2016. (c) 2015 Wiley Periodicals, Inc.

Item does not contain fulltext 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.

Contains fulltext : 177213.pdf (Publisher’s version ) (Open Access) 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

Introduction Patients with chemotherapy-induced thrombocytopaenia frequently experience minor and sometimes severe bleeding complications. Unrestrictive availability of safe and effective blood products is presumed by treating physicians as well as patients. Pathogen reduction technology potentially offers the opportunity to enhance safety by reducing bacterial and viral contamination of platelet products along with a potential reduction of alloimmunisation in patients receiving multiple platelet transfusions. Methods and analysis To test efficacy, a randomised, single-blinded, multicentre controlled trial was designed to evaluate clinical non-inferiority of pathogen-reduced platelet concentrates treated by the Mirasol system, compared with standard plasma-stored platelet concentrates using the percentage of patients with WHO grade ≥2 bleeding complications as the primary endpoint. The upper limit of the 95% CI of the non-inferiority margin was chosen to be a ≤12.5% increase in this percentage. Bleeding symptoms are actively monitored on a daily basis. The adjudication of the bleeding grade is performed by 3 adjudicators, blinded to the platelet product randomisation as well as by an automated computer algorithm. Interim analyses evaluating bleeding complications as well as serious adverse events are performed after each batch of 60 patients. The study started in 2010 and patients will be enrolled up to a maximum of 618 patients, depending on the results of consecutive interim analyses. A flexible stopping rule was designed allowing stopping for non-inferiority or futility. Besides analysing effects of pathogen reduction on clinical efficacy, the Pathogen Reduction Evaluation and Predictive Analytical Rating Score (PREPAReS) is designed to answer several other pending questions and translational issues related to bleeding and alloimmunisation, formulated as secondary and tertiary endpoints. Ethics and dissemination Ethics approval was obtained in all 3 participating countries. Results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal. Trial registration number NTR2106; Pre-results.