Efficacy and Safety Analyses of Recombinant Factor VIIa in Severe Post-Partum Hemorrhage.

Background: Despite a range of available treatments, it is still sometimes challenging to treat patients with severe post-partum hemorrhage (sPPH). Objective: This study evaluated the efficacy and safety of recombinant activated factor VIIa (rFVIIa) in sPPH management. Methods: An open-label, multi-center, randomized controlled trial (RCT; NCT00370877) and four observational studies (OS; OS-1 (NCT04723979), OS-2, OS-3, and OS-4) were analyzed regarding efficacy (need for subsequent invasive procedures, including uterine compression sutures, uterine or iliac artery ligations, arterial embolization, or hysterectomy) and safety (incidence of thromboembolic events (TE) and maternal mortality) of rFVIIa for sPPH. The RCT, and OS-1 and OS-2, included a control group of women who did not receive rFVIIa (with propensity score-matching used in OS-1 and OS-2), whereas OS-3 and OS-4 provided descriptive data for rFVIIa-exposed women only. Results: A total of 446 women exposed to rFVIIa and 1717 non-exposed controls were included. In the RCT, fewer rFVIIa-exposed women (50% [21/42]) had an invasive procedure versus non-exposed women (91% [38/42]; odds ratio: 0.11; 95% confidence interval: 0.03-0.35). In OS-1, more rFVIIa-exposed women (58% [22/38]) had an invasive procedure versus non-exposed women (35% [13.3/38]; odds ratio: 2.46; 95% confidence interval: 1.06-5.99). In OS-2, 17% (3/18) of rFVIIa-exposed women and 32% (5.6/17.8) of non-exposed women had an invasive procedure (odds ratio: 0.33; 95% confidence interval: 0.03-1.75). Across all included women, TEs occurred in 1.5% (0.2% arterial and 1.2% venous) of rFVIIa-exposed women and 1.6% (0.2% arterial and 1.4% venous) of non-exposed women with available data. Conclusions: The positive treatment effect of rFVIIa on the RCT was not confirmed in the OS. However, the safety analysis did not show any increased incidence of TEs with rFVIIa treatment.

Laboratory approach for vaccine-induced thrombotic thrombocytopenia diagnosis in the Netherlands.

BACKGROUND AND OBJECTIVES: Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare adverse effect characterized by thrombocytopenia and thrombosis occurring after COVID-19 vaccination. VITT pathophysiology is not fully unravelled but shows similarities to heparin-induced thrombocytopenia (HIT). HIT is characterized by the presence of antibodies against platelet factor 4 (PF4)/heparin complex, which can activate platelets in an FcγRIIa-dependent manner, whereas IgG-antibodies directed against PF4 play an important role in VITT. MATERIALS AND METHODS: We characterized all clinically suspected VITT cases in the Netherlands from a diagnostic perspective and hypothesized that patients who developed both thrombocytopenia and thrombosis display underlying mechanisms similar to those in HIT. We conducted an anti-PF4 ELISA and a functional PF4-induced platelet activation assay (PIPAA) with and without blocking the platelet-FcγRIIa and found positivity in both tests, suggesting VITT with mechanisms similar to those in VITT. RESULTS: We identified 65 patients with both thrombocytopenia and thrombosis among 275 clinically suspected VITT cases. Of these 65 patients, 14 (22%) tested positive for anti-PF4 and PF4-dependent platelet activation. The essential role of platelet-FcγRIIa in VITT with mechanisms similar to those in HIT was evident, as platelet activation was inhibited by an FcγRIIa-blocking antibody in all 14 patients. CONCLUSION: Our study shows that only a small proportion of clinically suspected VITT patients with thrombocytopenia and thrombosis have anti-PF4-inducing, FcɣRIIa-dependent platelet activation, suggesting an HIT-like pathophysiology. This leaves the possibility for the presence of another type of pathophysiology ('non-HIT like') leading to VITT. More research on pathophysiology is warranted to improve the diagnostic algorithm and to identify novel therapeutic and preventive strategies.

Umbilical Cord Blood as an Alternative to Neonatal Blood for Complete Blood Count: A Comparison Study.

OBJECTIVE: To assess concordance between umbilical cord blood (UCB) and neonatal blood (NB) laboratory test results at birth. STUDY DESIGN: This retrospective study considered very preterm neonates (<32 weeks' gestational age) admitted to a tertiary neonatal intensive care unit from 2012 to 2023. Inclusion criteria required neonates with a complete blood count measured in both UCB and NB drawn within 2 hours after birth. Median hemoglobin (Hb) and hematocrit (Hct) concentrations were compared between UCB (venous samples) and NB (venous, arterial, or capillary samples). RESULTS: A total of 432 neonates with paired UCB and NB values were included in the study. Hb concentration in UCB was 14.7 g/dL (IQR 13.5-16.1 g/dL) compared with 14.8 g/dL (IQR 12.6-19.3 g/dL) in venous NB samples, 13.9 g/dL (IQR 12.9-15.3 g/dL) in arterial NB and 18.7 g/dL (IQR 16.6-20.8 g/dL) in capillary NB. The regression equation showed a correction factor of 1.08 for converting Hb values from UCB to venous NB. Median Hct concentration in UCB was 0.45 L/L (IQR: 0.41-0.49 L/L) compared with 0.48 L/L (IQR 0.43-0.54 L/L) in venous NB, 0.42 L/L (IQR 0.38-0.45 L/L) in arterial NB and 0.57 L/L, (IQR 0.51-0.63 L/L) in capillary NB. CONCLUSIONS: Hb and Hct concentrations measured in UCB are similar to those measured in venous blood in very preterm infants and are valid alternatives for NB tests at birth. Hb and Hct concentrations in arterial and capillary NB are respectively lower and higher compared with UCB measurements.

The spectrum of neutralizing and non-neutralizing anti-FVIII antibodies in a nationwide cohort of 788 persons with hemophilia A.

Objectives: Anti-factor VIII (FVIII) antibodies have been reported to exhibit both neutralizing and non-neutralizing characteristics. This is the first study investigating the full spectrum of FVIII-specific antibodies, including non-neutralizing antibodies, very-low titer inhibitors, and inhibitors, in a large nationwide population of persons with hemophilia A of all severities. Methods: All persons with hemophilia A (mild (FVIII > 5-40 IU/dL)/moderate [FVIII 1-5 IU/dL)/severe (FVIII < 1 IU/dL)] with an available plasma sample who participated in the sixth Hemophilia in the Netherlands study between 2018 and 2019 were included. The presence of anti-FVIII antibodies of the immunoglobulin A, M, and G isotypes and IgG subclasses, along with antibody titer levels, were assessed using direct-binding ELISAs. FVIII specificity was assessed using a competition-based ELISA approach. The inhibitor status was determined using the Nijmegen ultra-sensitive Bethesda assay (NusBA) and the Nijmegen Bethesda assay (NBA). Results: In total, 788 persons with hemophilia A (336 (42.6%) mild, 123 (15.6%) moderate, 329 (41.8%) severe hemophilia) were included. The median age was 45 years (IQR 24-60), and the majority (50.9%) had over 150 exposure days to FVIII concentrates. Within our population, 144 (18.3%) individuals had non-neutralizing FVIII-specific antibodies, 10 (1.3%) had very low-titer inhibitors (NusBA positive; NBA negative), and 13 (1.6%) had inhibitors (both NusBA and NBA positive). IgG1 was the most abundant FVIII-specific antibody subclass, and the highest titer levels were found for IgG4. In individuals without a reported history of inhibitor development, no clear differences were observed in antibody patterns between those who were minimally or highly exposed to FVIII concentrates. IgG4 subclass antibodies were only observed in persons with a reported history of FVIII inhibitor or in those with a currently detected (very low-titer) inhibitor. Conclusion: In this cross-sectional study, we identified non-neutralizing antibodies in a relatively large proportion of persons with hemophilia A. In contrast, in our population, consisting of persons highly exposed to FVIII concentrates, (very low-titer) inhibitors were detected only in a small proportion of persons, reflecting a well-tolerized population. Hence, our findings suggest that only a small subpopulation of non-neutralizing FVIII-specific antibodies is associated with clinically relevant inhibitors.

Challenging the dogma: Red blood cell-directed autoimmunity as risk factor for red blood cell alloimmunisation after blood transfusion.

Red blood cell autoimmunity and alloimmunity are potentially linked. Quantification of this association can tailor extensively matched red blood cell transfusions in patients with autoimmunity. Using an incident new-user cohort comprising 47 285 previously non-transfused, non-alloimmunised patients, we compared transfusion-induced red blood cell alloimmunisation incidences in direct antiglobulin test (DAT)-positive and control patients. Additionally, we performed case-control analyses to handle potential confounding by clinical immunomodulators. Among (IgG and/or C3d) DAT-positive patients (N = 380), cumulative red blood cell alloimmunisation incidences after 10 units transfused reached 4.5% (95% confidence interval [CI] 2.5-8.2) versus 4.2% (CI 3.9-4.5, p = 0.88) in controls. In case-control analyses, alloimmunisation relative risks among DAT-positive patients increased to 1.7 (CI 1.1-2.8). Additional adjustments for pre-DAT transfusion exposure or the extent of Rh/K mismatching did not impact results. In conclusion, while patients with DAT positivity show an intrinsically increased alloimmune red blood cell response, their absolute risk is comparable to control patients due to counteracting co-existing immunosuppressive conditions. Consequently, isolated DAT positivity in patients lacking overt haemolysis or complicated alloantibody testing does not seem to warrant extended matching strategies.

Transfusion of ever-pregnant donor red blood cells and mortality of male patients.

Previous studies found exposure to red blood cell transfusions from female donors who have been pregnant reduces survival in male patients compared to exposure to male donor products, but evidence is not consistent. We postulate the previously observed association is modified by offspring sex, with an expected increased mortality risk for male patients receiving units from female donors with sons. Here, marginal structural models were used to assess the association between exposure to units from ever-pregnant donors, ever-pregnant donors with sons and ever-pregnant donors with daughters, and mortality. Clinical data were collected on first-ever transfusion recipients in the Netherlands and donor data were supplemented with information about offspring sex and date of birth. In this analysis, 56,825 patients were included, of whom 8,288 died during follow-up. Exposure to red blood cell units from everpregnant donors with sons was not associated with increased all-cause mortality risk among male transfusion recipients (hazard ratio [HR] 0.91, 95% confidence interval 0.83-1.01). Exposure to ever-pregnant donors, irrespective of offspring sex, was associated with mortality in male patients aged between 18 and 50 years (ever-pregnant donors: HR 1.81, 95% CI 1.31-2.51) compared to male donor units, but was protective in female patients. This study suggests that the observed increased mortality risk for exposure to red blood cell units from parous female donors does not depend on offspring sex. The increased risk of mortality seen in younger adult male patients is consistent with previous observations, but the underlying biological mechanism could not be identified in this study.

Donor pregnancies and transfusion recipient mortality: A role for red blood cell storage?

BACKGROUND AND OBJECTIVES: Donor characteristics have been implicated in transfusion-related adverse events. Uncertainty remains about whether sex, and specifically pregnancy history of the blood donor, could affect patient outcomes. Whether storage duration of the blood product could be important for patient outcomes has also been investigated, and a small detrimental effect of fresh products remains a possibility. Here, we hypothesize that fresh red blood cell products donated by ever-pregnant donors are associated with mortality in male patients. MATERIALS AND METHODS: We used data from a cohort study of adult patients receiving a first transfusion between 2005 and 2015 in the Netherlands. The risk of death after receiving a transfusion from one of five exposure categories (female never-pregnant stored ≤10 days, female never-pregnant stored >10 days, female ever-pregnant stored ≤10 days, female ever-pregnant stored >10 days and male stored for ≤10 days), compared to receiving a unit donated by a male donor, which was stored for >10 days (reference), was calculated using a Cox proportional hazards model. RESULTS: The study included 42,456 patients who contributed 88,538 person-years in total, of whom 13,948 died during the follow-up of the study (33%). Fresh units (stored for ≤10 days) from ever-pregnant donors were associated with mortality in male patients, but the association was not statistically significant (hazard ratio 1.39, 95% confidence interval 0.97-1.99). Sensitivity analyses did not corroborate this finding. CONCLUSION: These findings do not consistently support the notion that the observed association between ever-pregnant donor units and mortality is mediated by blood product storage.

Type 1 VWD classification revisited: novel insights from combined analysis of the LoVIC and WiN studies.

ABSTRACT: There is significant ongoing debate regarding type 1 von Willebrand disease (VWD) defintion. Previous guidelines recommended patients with von Willebrand factor (VWF) levels <30 IU/dL be diagnosed type 1 VWD, whereas patients with significant bleeding and VWF levels from 30 to 50 IU/dL be diagnosed with low VWF. To elucidate the relationship between type 1 VWD and low VWF in the context of age-induced increases in VWF levels, we combined data sets from 2 national cohort studies: 162 patients with low VWF from the Low VWF in Ireland Cohort (LoVIC) and 403 patients with type 1 VWD from the Willebrand in The Netherlands (WiN) studies. In 47% of type 1 VWD participants, VWF levels remained <30 IU/dL despite increasing age. Conversely, VWF levels increased to the low VWF range (30-50 IU/dL) in 30% and normalized (>50 IU/dL) in 23% of type 1 VWD cases. Crucially, absolute VWF antigen (VWF:Ag) levels and increase of VWF:Ag per year overlapped between low VWF and normalized type 1 VWD participants. Moreover, multiple regression analysis demonstrated that VWF:Ag levels in low VWF and normalized type 1 VWD patients would not have been different had they been diagnosed at the same age (ß = 0.00; 95% confidence interval, -0.03 to 0.04). Consistently, no difference was found in the prevalence of VWF sequence variants; factor VIII activity/VWF:Ag or VWF propeptide/VWF:Ag ratios; or desmopressin responses between low VWF and normalized type 1 VWD patients. In conclusion, our findings demonstrate that low VWF does not constitute a discrete clinical or pathological entity. Rather, it is part of an age-dependent type 1 VWD evolving phenotype. Collectively, these data have important implications for future VWD classification criteria.

Darbepoetin alfa to reduce transfusion episodes in infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions in the Netherlands: an open-label, single-centre, phase 2, randomised, controlled trial.

BACKGROUND: Up to 88% of infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions require erythrocyte transfusions after birth. We aimed to investigate the effect of darbepoetin alfa on the prevention of postnatal anaemia in infants with haemolytic disease of the fetus and newborn. METHODS: We conducted an open-label, single-centre, phase 2 randomised controlled trial to evaluate the effect of darbepoetin alfa on the number of erythrocyte transfusions in infants with haemolytic disease of the fetus and newborn. All infants who were treated with intrauterine transfusion and born at 35 weeks of gestation or later at the Leiden University Medical Center, Leiden, Netherlands, were eligible for inclusion. Included infants were randomised by computer at birth to treatment with 10 µg/kg darbepoetin alfa subcutaneously once a week for 8 weeks or standard care (1:1 allocation, in varying blocks of four and six, with no stratification). Treating physicians and parents were not masked to treatment allocation, but the research team, data manager, and statistician were masked to treatment allocation during the process of data collection. The primary outcome was the number of erythrocyte transfusion episodes per infant from birth up to 3 months of life in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03104426) and has been completed. FINDINGS: Between Oct 31, 2017, and April 31, 2022, we recruited 76 infants, of whom 44 (58%) were randomly assigned to a treatment group (20 [45%] were allocated to receive darbepoetin alfa and 24 [55%] were allocated to receive standard care). Follow-up lasted 3 months and one infant dropped out of the trial before commencement of treatment. A significant reduction in erythrocyte transfusion episodes was identified with darbepoetin alfa treatment compared with standard care (median 1·0 [IQR 1·0-2·0] transfusion episodes vs 2·0 [1·3-3·0] transfusion episodes; p=0·0082). No adverse events were reported and no infants died during the study. INTERPRETATION: Darbepoetin alfa reduced the transfusion episodes after intrauterine transfusion treatment for haemolytic disease of the fetus and newborn. Treatment with darbepoetin alfa or other types of erythropoietin should be considered as part of the postnatal treatment of severe haemolytic disease of the fetus and newborn. FUNDING: Sanquin Blood Supply. TRANSLATION: For the Dutch translation of the abstract see Supplementary Materials section.

Prophylactic radiologic interventions to reduce postpartum hemorrhage in women with risk factors for placenta accreta spectrum disorder: a nationwide cohort study.

OBJECTIVE: To quantify the association between prophylactic radiologic interventions and perioperative blood loss in women with risk factors for placenta accreta spectrum disorder (PAS). METHODS: We conducted a retrospective nationwide cohort study of women with risk factors for placenta accreta spectrum disorder who underwent planned cesarean section in 69 Dutch hospitals between 2008 and 2013. All women had two risk factors for PAS: placenta previa/anterior low-lying placenta and a history of cesarean section(s). Women with and without ultrasonographic signs of PAS were studied as two separate groups. We compared the total blood loss of women with prophylactic radiologic interventions, defined as preoperative placement of balloon catheters or sheaths in the internal iliac or uterine arteries, with that of a control group consisting of women without prophylactic radiologic interventions using multivariable regression. We evaluated maternal morbidity by the number of red blood cell (RBC) units transfused within 24 h following childbirth (categories: 0, 1-3, >4), duration of hospital admission, and need for intensive care unit (ICU) admission. RESULTS: A total of 350 women with placenta previa/anterior low-lying placenta and history of cesarean section(s) were included: 289 with normal ultrasonography, of whom 21 received prophylactic radiologic intervention, and 61 had abnormal ultrasonography, of whom 22 received prophylactic intervention. Among women with normal ultrasonography without prophylactic intervention (n = 268), the median blood loss was 725 mL (interquartile range (IQR) 500-1500) vs. 1000 mL (IQR 550-1750) in women with intervention (n = 21); the adjusted difference in blood loss was 9 mL (95% confidence interval (CI) -315-513), p = .97). Among women with abnormal ultrasonography, those without prophylactic intervention (n = 39) had a median blood loss of 2500 mL (IQR 1200-5000) vs. 1750 mL (IQR 775-4000) in women with intervention (n = 22); the adjusted difference in blood loss was -1141 mL (95% CI -1694- -219, p = .02). Results of outcomes on maternal morbidity were comparable among women with and without prophylactic intervention. CONCLUSION: These findings suggest that prophylactic radiologic interventions prior to planned cesarean section may help to limit perioperative blood loss in women with clear signs of placenta accreta spectrum disorder on ultrasonography, but there was no evidence of a difference within the subgroup without such ultrasonographic signs. The use of these interventions should be discussed in a multidisciplinary shared decision-making process, including discussions of potential benefits and possible complications. TRIAL REGISTRATION: Netherlands Trial Registry, https://onderzoekmetmensen.nl/en/trial/28238, identifier NL4210 (NTR4363).

Desmopressin in nonsevere hemophilia A: patient perspectives on use and efficacy.

Background: Desmopressin increases plasma factor VIII and von Willebrand factor levels in persons with nonsevere hemophilia A. Patients' perspectives on desmopressin are relevant to increase and optimize its suboptimal use. However, patients' views on desmopressin are not reported. Objectives: To evaluate the perspectives of persons with nonsevere hemophilia A on desmopressin use, barriers for its use, side effects, and their knowledge about desmopressin's efficacy and side effects. Methods: Persons with nonsevere hemophilia A were included in a cross-sectional, national, multicenter study. Questionnaires were filled out by adult patients and children aged ≥12 years themselves. Caretakers filled out questionnaires for children aged <12 years. Results: In total, 706 persons with nonsevere hemophilia A were included (544 mild, 162 moderate, [age range, 0-88 years]). Of 508 patients, 234 (50%) patients reported previous desmopressin use. Desmopressin was considered as at least moderately effective in 171 of 187 (90%) patients. Intranasal administration was the modality of choice for 138 of 182 (76%) patients. Flushing was the most reported side effect in 54 of 206 (26%) adults and 7 of 22 (32%) children. The most frequently reported advantage and disadvantage were the convenience of intranasal, out-of-hospital administration by 56% (126/227) and side effects in 18% (41/227), respectively. Patients' self-perceived knowledge was unsatisfactory or unknown in 28% (63/225). Conclusion: Overall, desmopressin was most often used intranasally and considered effective, with flushing as the most common side effect. The most mentioned advantage was the convenience of intranasal administration and disadvantage was side effects. More information and education on desmopressin could answer unmet needs in patients with current or future desmopressin treatment.

Transition readiness among adolescents and young adults with haemophilia in the Netherlands: Nationwide questionnaire study.

INTRODUCTION: Care for adolescents with haemophilia is transferred from paediatric to adult care around the age of 18 years. Transition programs help to prepare adolescents for this transfer and prevent declining treatment adherence. Evaluating transition readiness may identify areas for improvement. OBJECTIVE: Assess transition readiness among Dutch adolescents and young adults with haemophilia, determine factors associated with transition readiness, and identify areas of improvement in transition programs. METHODS: All Dutch adolescents and young adults aged 12-25 years with haemophilia were invited to participate in a nationwide questionnaire study. Transition readiness was assessed using multiple-choice questions and was defined as being ready or almost ready for transition. Potential factors associated with transition readiness were investigated, including: socio-demographic and disease-related factors, treatment adherence, health-related quality of life, and self-efficacy. RESULTS: Data of 45 adolescents and 84 young adults with haemophilia (47% with severe haemophilia) were analyzed. Transition readiness increased with age, from 39% in 12-14 year-olds to 63% in 15-17 year-olds. Nearly all post-transition young adults (92%, 77/84) reported they were ready for transition. Transition readiness was associated with treatment adherence, as median VERITAS-Pro treatment adherence scores were worse in patients who were not ready (17, IQR 9-29), compared to those ready for transition (11, IQR 9-16). Potential improvements were identified: getting better acquainted with the adult treatment team prior to transition and information on managing healthcare costs. CONCLUSIONS: Nearly all post-transition young adults reported they were ready for transition. Improvements were identified regarding team acquaintance and preparation for managing healthcare costs.

Patients' and health care providers' perspectives on quality of hemophilia care in the Netherlands: a questionnaire and interview study.

Background: Hemophilia care has improved greatly because of advances in treatment options and comprehensive care. In-depth insight into the perspectives of persons with hemophilia and health care providers on their care may provide targets for further improvements. Objectives: To assess satisfaction of the hemophilia population with their care, to explore factors determining care satisfaction, and to identify areas for potential health care improvements, including digital health tools. Methods: First, to assess care satisfaction and factors determining satisfaction and health care improvements, data from a nationwide, cross-sectional questionnaire among 867 adult and pediatric Dutch persons with hemophilia A or B were analyzed. This included the Hemophilia Patient Satisfaction Scale questionnaire, Canadian Hemophilia Outcomes Kids' Life Assessment Tool satisfaction questions, a visual analog scale satisfaction score, and open questions. Second, to further explore factors determining satisfaction and health care improvements, semistructured interviews were conducted with 19 persons with hemophilia or their parents and 18 health care providers. Results: High care satisfaction was found, with an overall median Hemophilia Patient Satisfaction Scale score of 12 (IQR, 6-21). Participants in the interviews reported that patient-professional interactions, availability of care, and coordination of care were major factors determining satisfaction. Suggested health care improvements included improved information provision and coordination of care, especially shared care with professionals not working within comprehensive care centers. Participants suggested that digital health tools could aid in this. Conclusion: Satisfaction with hemophilia care is high among persons with hemophilia in the Netherlands, although several potential improvements have been identified. Accentuating these is especially relevant in the current era of treatment innovations, in which we might focus less on other aspects of care.

In patients with hemophilia, a decreased thrombin generation profile is associated with a severe bleeding phenotype.

Background: Heterogeneity in clinical bleeding phenotype has been observed in hemophilia patients with similar FVIII or FIX activity levels. Thrombin generation and plasmin generation, as a global hemostasis assay, may contribute to a better prediction of which patients are at an increased risk of bleeding. Objectives: The objective of this study was to describe the association between clinical bleeding phenotype and thrombin generation and plasmin generation profiles in patients with hemophilia. Methods: The Nijmegen Hemostasis Assay, which simultaneously measures thrombin and plasmin generation, was performed in plasma samples of patients with hemophilia participating in the sixth Hemophilia in the Netherlands study (HiN6). Patients receiving prophylaxis underwent a washout period. A severe clinical bleeding phenotype was defined as a self-reported annual bleeding rate of ≥5, a self-reported annual joint bleeding rate of ≥3, or the use of secondary/tertiary prophylaxis. Results: In total, 446 patients, with a median age of 44 years, were included in this substudy. Thrombin generation and plasmin generation parameters differed between patients with hemophilia and healthy individuals. The median thrombin peak height was 1.0 nM, 25.9 nM, 47.1 nM, and 143.9 nM in patients with severe, moderate, and mild hemophilia and healthy individuals, respectively. A severe bleeding phenotype was observed in patients with a thrombin peak height of <49% and a thrombin potential of <72% compared to healthy individuals, and was independent of the hemophilia severity. The median thrombin peak height was 0.70% in patients with a severe clinical bleeding phenotype and 30.3% in patients with a mild clinical bleeding phenotype. The median thrombin potentials for these patients were 0.06% and 59.3%, respectively. Conclusion: A decreased thrombin generation profile is associated with a severe clinical bleeding phenotype in patients with hemophilia. Thrombin generation in combination with bleeding severity may be a better tool to personalize prophylactic replacement therapy irrespective of hemophilia severity.

Colorectal cancer screening in patients with inherited bleeding disorders: high cancer detection rate in hemophilia patients.

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 <.001, respectively). In patients with hemophilia, the detection rate of CRC/AA was significantly higher than that in the general male population (4.5% vs. 1.8%, p = .02), and the positive predictive value of FIT for CRC/AA was comparable (32.3% vs. 39.7%, n.s.). In patients with VWD, the detection rate was similar to that of the general population (0.8% vs. 1.4%, n.s.), whereas the positive predictive value was significantly lower than that in the general population (6.3% vs. 36.8%, p = .02). CONCLUSION: This study indicates that despite a high false-positive rate of FIT in patients with inherited bleeding disorders, the detection rate of CRC and/or AA in hemophilia patients is high. FIT performs different in patients with hemophilia or VWD compared with the general population.

Natural history of human platelet antigen 1a-alloimmunised pregnancies: a prospective observational cohort study.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare disease that untreated can lead to intracranial haemorrhage or death. The natural history of FNAIT is still unclear; therefore, the benefits of screening cannot be estimated and no routine screening is yet in place. We aimed to assess the incidence of clinically detectable FNAIT among pregnancies in human platelet antigen-1a (HPA-1a)-immunised women. METHODS: We did a prospective observational cohort study of pregnant women negative for rhesus D (RhD) and rhesus c (Rhc) antigens, without age limits, who underwent routine antenatal screening for red cell antibodies at 27 weeks' gestation and were typed for HPA-1a between March 1, 2017, and May 1, 2020. HPA-1a-negative women were tested for HPA alloantibodies. Health-care professionals were masked to all test results. The main outcome was the proportion of neonates with severe, clinically detectable FNAIT, defined as having an intracranial bleed, organ bleed, or bleeding-related death observed during pregnancy or within the first week of life. Cases of clinically detectable FNAIT not categorised as severe were categorised as mild. This study is registered with ClinicalTrials.gov (NCT04067375). FINDINGS: Of 153 106 women typed for HPA-1a, 3722 (2·4%) were negative for HPA-1a. 913 HPA-1a-negative women gave informed consent, underwent HPA-1a antibody screening, and were included in the study. Anti-HPA-1a antibodies were detected in 85 HPA-1a-negative participants, among whom three with HPA-1a-negative fetuses and one with a previous child with FNAIT were excluded. As controls, 820 HPA-1a-negative, non-immunised pregnancies and 2704 randomly selected pregnancies of women negative for RhD and Rhc who were typed HPA-1a positive were included. Of 81 fetuses included, one (1·2%) was diagnosed with severe HPA-1a-mediated intracranial haemorrhage and three (3·7%) had mild FNAIT. Gravidity and parity did not seem to be risk factors for HPA-1a immunisation. 73 (90·1%) of 81 HPA-1a-immunised women were positive for HLA-DRB3*01:01. INTERPRETATION: Our data suggest that, without intervention, the incidence of major clinically detectable bleeding in FNAIT is estimated as 11 (95% CI 0-32) per 10 000 HPA-1a-negative pregnancies. These findings imply that severe bleeding is a rare event that potentially could be prevented by a screening programme. FUNDING: Landsteiner Foundation for Blood Transfusion Research and Sanquin.

Socioeconomic participation of persons with hemophilia: Results from the sixth hemophilia in the Netherlands study.

Background and objectives: Treatment availability and comprehensive care have resulted in improved clinical outcomes for persons with hemophilia. Recent data on socioeconomic participation in the Netherlands are lacking. This study assessed participation in education, in the labor market, and social participation for persons with hemophilia compared with the general male population. Methods: Dutch adults and children (5-75 years) of all hemophilia severities (n = 1009) participated in a questionnaire study that included sociodemographic, occupational, and educational variables. Clinical characteristics were extracted from electronic medical records. General population data were extracted from Statistics Netherlands. Social participation was assessed with the PROMIS Ability to Participate in Social Roles and Activities short form, with a minimal important difference set at 1.0. Results: Data from 906 adults and children were analyzed. Participation in education of 20 to 24 year olds was 68% (general male population: 53%). Educational attainment was higher compared with Dutch males, especially for severe hemophilia. Absenteeism from school was more common than in the general population. The employment-to-population ratio and occupational disability were worse for severe hemophilia than in the general population (64.3% vs. 73.2% and 14.7% vs. 4.8%, respectively), but similar for nonsevere hemophilia. Unemployment was 5.4% (general male population: 3.4%). Absenteeism from work was less common (38% vs. 45.2%). Mean PROMIS score was similar to or higher than in the general population (54.2; SD 8.9 vs. 50; SD 10). Conclusion: Socioeconomic participation of persons with nonsevere hemophilia was similar to the general male population. Some participation outcomes for persons with severe hemophilia were reduced.

Prediction of Inhospital Mortality in Critically Ill Patients With Sepsis: Confirmation of the Added Value of 24-Hour Lactate to Acute Physiology and Chronic Health Evaluation IV.

We previously reported the added value of 24-hour lactate concentration alone and in combination with 24-hour lactate clearance and lactate concentration at admission for the prediction of inhospital mortality in critically ill patients with sepsis. We aimed to validate this finding. DERIVATION COHORT: The derivation cohort from Leiden, The Netherlands, consisted of 451 critically ill patients with sepsis. VALIDATION COHORT: The validation cohort consisted of 4,440 critically ill adult patients with sepsis from the Medical Information Mart for Intensive Care cohort admitted to the ICU of Beth Israel Deaconness Medical Center, Boston, MA, between January 2006 and 2018. PREDICTION MODEL: Predictors of mortality were: age, chronic comorbidities, length of stay pre-ICU, Glasgow Coma Scale, and Acute Physiology Score. Lactate concentration at 24-hour alone, in combination with 24-hour lactate clearance and in combination with lactate concentration at admission, was added to assess improvement of the prediction model. The outcome was inhospital mortality. RESULTS: Inhospital mortality occurred in 160 patients (36%) in the derivation cohort and in 2,347 patients (53%) in the validation cohort. The Acute Physiology and Chronic Health Evaluation (APACHE) IV model had a moderate discriminative performance (recalibrated C-statistic, 0.62; 95% CI, 0.60-0.63). Addition of 24-hour lactate concentration increased the recalibrated C-statistic to 0.64 (95% CI, 0.62-0.66). The model with 24-hour lactate concentration and lactate concentration at admission showed the best fit as depicted by the smallest Akaike Information Criterion in both the derivation and validation data. CONCLUSION: The 24-hour lactate concentration and lactate concentration at admission contribute modestly to prediction of inhospital mortality in critically ill patients with sepsis. Future updates and possible modification of APACHE IV should consider the incorporation of lactate concentration at baseline and at 24 hours.

Postnatal treatment for children with fetal and neonatal alloimmune thrombocytopenia: a multicentre, retrospective, cohort study.

BACKGROUND: Children affected by fetal and neonatal alloimmune thrombocytopenia (FNAIT) are at risk of severe intracranial haemorrhage. Management in the postnatal period is based on sparse evidence. We aimed to describe the contemporary management and outcomes of patients with FNAIT in high-income countries. METHODS: In this multicentre, retrospective, cohort study, we set up a web-based registry for the collection of deidentified data on the management and course of neonates with FNAIT. Eight centres from seven countries (Australia, Norway, Slovenia, Spain, Sweden, the Netherlands, and the USA) participated. Eligibility criteria comprised neonates with FNAIT being liveborn between Jan 1, 2010, and Jan 1, 2020; anti-human platelet antigen (HPA) alloantibodies in maternal serum; confirmed maternal and fetal HPA incompatibility; and bleeding detected at antenatal ultrasound, neonatal thrombocytopenia (<150 × 109 platelets per L), or both in the current or previous pregnancy. Clinical data were retrieved from local medical records of the first neonatal admission and entered in the registry. The key outcome was the type of postnatal treatment given to neonates with FNAIT. Other outcomes were daily median platelet counts in the first week of life, median platelet count increment after first unmatched versus first matched transfusions, and the proportion of neonates with mild or severe bleeding. FINDINGS: 408 liveborn neonates with FNAIT were entered into the FNAIT registry, of whom 389 from Australia (n=74), Norway (n=56), Slovenia (n=19), Spain (n=55), Sweden (n=31), the Netherlands (n=138), and the USA (n=16) were included in our analyses. The median follow-up was 5 days (IQR 2-9). More neonates were male (241 [64%] of 379) than female (138 [36%]). Severe thrombocytopenia (platelet count <50 × 109 platelets per L) was reported in 283 (74%) of 380 neonates, and extreme thrombocytopenia (<10 × 109 platelets per L) was reported in 92 (24%) neonates. Postnatal platelet count nadir was higher in the no-treatment group than in all other groups. 163 (42%) of 389 neonates with FNAIT received no postnatal treatment. 207 (53%) neonates received platelet transfusions, which were either HPA-unmatched (88 [43%] of 207), HPA-matched (84 [41%]), or a combination of both (35 [17%]). The proportion of neonates who received HPA-matched platelet transfusions varied between countries, ranging from 0% (Slovenia) to 63% (35 of 56 neonates; Norway). Postnatal intravenous immunoglobulin treatment was given to 110 (28%) of 389 neonates (alone [n=19] or in combination with platelet transfusions [n=91]), with the proportion receiving it ranging from 12% (17 of 138 neonates; the Netherlands) to 63% (ten of 16 neonates; the USA) across countries. The median platelet increment was 59 × 109 platelets per L (IQR 35-94) after HPA-unmatched platelet transfusions and 98 × 109 platelets per L (67-134) after HPA-matched platelet transfusions (p<0·0001). Severe bleeding was diagnosed in 23 (6%) of 389 liveborn neonates, with one having a severe pulmonary haemorrhage and 22 having severe intracranial haemorrhages. Mild bleeding was diagnosed in 186 (48%) neonates. INTERPRETATION: Postnatal management of FNAIT varies greatly between international centres, highlighting the absence of consensus on optimal treatments. Our data suggest that HPA-matched transfusions lead to a larger median platelet count increment than HPA-unmatched transfusions, but whether HPA matching is also associated with a reduced risk of bleeding remains unknown. FUNDING: Sanquin.

Platelet degranulation and bleeding phenotype in a large cohort of Von Willebrand disease patients.

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.