Thromboembolic events in severe postpartum hemorrhage treated with recombinant activated factor VII: a systematic literature review and meta-analysis.

Postpartum hemorrhage (PPH) is an obstetric complication with high associated morbidity. Recombinant activated factor VII (rFVIIa) is used to treat severe PPH when uterotonics fail to stop bleeding. However, data on the safety of rFVIIa treatment of severe PPH from adequately powered trials are lacking. We systematically reviewed published data on the incidence of thromboembolic events (TEs) in women with PPH treated or not treated with rFVIIa (PROSPERO CRD42022360736). Databases (Embase, MEDLINE, BIOSIS, Current Contents, and the Cochrane Library) were searched for peer-reviewed publications published between January 1996 and August 2022 and conference abstracts published between January 2017 and August 2022 using search terms related to thromboembolism or infarction and PPH. Data were extracted from all publications reporting on a general population of women with PPH with information on TEs. Descriptive summary statistics and the estimated proportion of TEs were analyzed using a generalized linear mixed model based on the binomial distribution. Quality assessments were based on the checklist by Downs and Black. From 1637 potentially eligible studies, 55 publications were included reporting on 611 women treated and 32,488 women not treated with rFVIIa. The global estimated proportion of TEs was 1.82% (prediction interval [PI], 0.30-10.23) and 0.72% (PI, 0.03-16.47) in women with severe PPH treated and those not treated with rFVIIa, respectively. The estimated proportions of TEs were similarly small, with wide and largely overlapping PIs. Additional well-designed trials are needed to improve understanding of TE incidence in PPH.

Red Blood Cell Transfusion in European Neonatal Intensive Care Units, 2022 to 2023.

Importance: Red blood cell (RBC) transfusions are frequently administered to preterm infants born before 32 weeks of gestation in the neonatal intensive care unit (NICU). Two randomized clinical trials (Effects of Transfusion Thresholds on Neurocognitive Outcomes of Extremely Low-Birth-Weight Infants [ETTNO] and Transfusion of Prematures [TOP]) found that liberal RBC transfusion thresholds are nonsuperior to restrictive thresholds, but the extent to which these results have been integrated into clinical practice since publication in 2020 is unknown. Objective: To describe neonatal RBC transfusion practice in Europe. Design, Setting, and Participants: This international prospective observational cohort study collected data between September 1, 2022, and August 31, 2023, with a 6-week observation period per center, from 64 NICUs in 22 European countries. Participants included 1143 preterm infants born before 32 weeks of gestation. Exposure: Admission to the NICU. Main Outcomes and Measures: Study outcome measures included RBC transfusion prevalence rates, cumulative incidence, indications, pretransfusion hemoglobin (Hb) levels, volumes, and transfusion rates, Hb increment, and adverse effects of RBC transfusion. Results: A total of 1143 preterm infants were included (641 male [56.1%]; median gestational age at birth, 28 weeks plus 2 days [IQR, 26 weeks plus 2 days to 30 weeks plus 2 days]; median birth weight, 1030 [IQR, 780-1350] g), of whom 396 received 1 or more RBC transfusions, totaling 903 transfusions. Overall RBC transfusion prevalence rate during postnatal days 1 to 28 was 3.4 transfusion days per 100 admission days, with considerable variation across countries, only partly explained by patient mix. By day 28, 36.5% (95% CI, 31.6%-41.5%) of infants had received at least 1 transfusion. Most transfusions were given based on a defined Hb threshold (748 [82.8%]). Hemoglobin levels before transfusions indicated for threshold were below the restrictive thresholds set by ETTNO in 324 of 729 transfusions (44.4%) and TOP in 265 of 729 (36.4%). Conversely, they were between restrictive and liberal thresholds in 352 (48.3%) and 409 (56.1%) transfusions, respectively, and above liberal thresholds in 53 (7.3%) and 55 (7.5%) transfusions, respectively. Most transfusions given based on threshold had volumes of 15 mL/kg (470 of 738 [63.7%]) and were administered over 3 hours (400 of 738 [54.2%]), but there was substantial variation in dose and duration. Conclusions and Relevance: In this cohort study of very preterm infants, most transfusions indicated for threshold were given for pretransfusion Hb levels above restrictive transfusion thresholds evaluated in recent trials. These results underline the need to optimize practices and for implementation research to support uptake of evidence.

Toward Personalized Care and Patient Empowerment and Perspectives on a Personal Health Record in Hemophilia Care: Qualitative Interview Study.

BACKGROUND: To enable personalized treatment and shared decision-making in chronic care, relevant health information is collected. However, health information is often fragmented across hospital information systems, digital health apps, and questionnaire portals. This also pertains to hemophilia care, in which scattered information hampers integrated care. We intend to co-design a nationwide digital personal health record (PHR) for patients to help manage their health information. For this, user perspectives are crucial. OBJECTIVE: This study aims to assess patients' and health care providers' perspectives regarding the use of a PHR in hemophilia care in the Netherlands, required functionalities, and expectations and concerns. METHODS: In this semistructured interview study, 19 pediatric and adult persons with hemophilia, parents, and women with other inherited bleeding disorders, as well as 18 health care providers working within and outside of hemophilia treatment centers, participated. Perspectives of patients and providers were explored separately. To explore requirements, participants were asked to prioritize functionalities. RESULTS: Participants expected a PHR would increase the transparency of health information, improve patients' understanding of their illness, and help the coordination of care between health care providers and institutions. Prioritized functionalities included the integration of relevant health information and patient-entered data. Formulated expectations and concerns focused on 4 themes: usability, safety, inclusiveness, and implementation. While patients expressed worries over medicalization (ie, more confrontational reminders of their illness), providers were concerned about an increased workload. CONCLUSIONS: People with hemophilia, their parents, and health care providers welcomed the development of a PHR, as they expected it would result in better coordinated care. Formulated expectations and concerns will contribute to the successful development of a PHR for persons with hemophilia, and ultimately, for all persons with a chronic condition.

Large deletions and small insertions and deletions in the factor VIII gene predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors.

INTRODUCTION: Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome. MATERIAL AND METHODS: We included people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing. RESULTS: We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59-71.30) and 4.25 times higher (95 % CI, 1.53-12.3) among carriers of F8 large deletions and small insertions and deletions, respectively. CONCLUSION: F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure.

Prophylactic Radiologic Interventions for Postpartum Hemorrhage Control in Women With Placenta Accreta Spectrum Disorder: A Systematic Review and Meta-analysis.

OBJECTIVE: To quantify the association between prophylactic radiologic interventions and perioperative blood loss during cesarean delivery in women with placenta accreta spectrum disorder through a systematic review and network meta-analysis. DATA SOURCES: On January 3, 2023, a literature search was conducted in PubMed, EMBASE, Cochrane Library, and Web of Science. We also checked ClinicalTrials.gov retrospectively. Prophylactic radiologic interventions to reduce bleeding during cesarean delivery involved preoperative placement of balloon catheters, distal (internal or common iliac arteries) or proximal (abdominal aorta), or sheaths (uterine arteries). The primary outcome was volume of blood loss; secondary outcomes were the number of red blood cell units transfused and adverse events. Studies including women who received an emergency cesarean delivery were excluded. METHODS OF STUDY SELECTION: Two authors independently screened citations for relevance, extracted data, and assessed the risk of bias of individual studies with the Cochrane Risk of Bias in Non-randomized Studies of Interventions tool. TABULTATION, INTEGRATION, AND RESULTS: From a total of 1,332 screened studies, 50 were included in the final analysis, comprising 5,962 women. These studies consisted of two randomized controlled trials and 48 observational studies. Thirty studies compared distal balloon occlusion with a control group, with a mean difference in blood loss of -406 mL (95% CI, -645 to -167). Fourteen studies compared proximal balloon occlusion with a control group, with a mean difference of -1,041 mL (95% CI, -1,371 to -710). Sensitivity analysis excluding studies with serious or critical risk of bias provided similar results. Five studies compared uterine artery embolization with a control group, all with serious or critical risk of bias; the mean difference was -936 mL (95% CI, -1,522 to -350). Reported information on adverse events was limited. CONCLUSION: Although the predominance of observational studies in the included literature warrants caution in interpreting the findings of this meta-analysis, our findings suggest that prophylactic placement of balloon catheters or sheaths before planned cesarean delivery in women with placenta accreta spectrum disorder may, in some cases, substantially reduce perioperative blood loss. Further study is required to quantify the efficacy according to various severities of placenta accreta spectrum disorder and the associated safety of these radiologic interventions. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42022320922.

Most major bleeds in preterm infants occur in the absence of severe thrombocytopenia: an observational cohort study.

OBJECTIVE: To describe the incidence of major bleeds according to different platelet counts in very preterm infants, and to explore whether this association is influenced by other risk factors for bleeding. DESIGN: Observational cohort study. SETTING: A Dutch tertiary care neonatal intensive care unit. PATIENTS: All consecutive infants with a gestational age at birth <32 weeks admitted between January 2004 and July 2022. EXPOSURE: Infants were stratified into nine groups based on their nadir platelet count (×109/L) during admission (<10, 10-24, 25-49, 50-99, 100-149, 150-199, 200-249, 250-299 and ≥300), measured before the diagnosis of a major bleed and before any platelet transfusion was administered. MAIN OUTCOME MEASURE: Incidence of major bleeds during admission. Logistic regression analysis was used to quantify the relationship between nadir platelet count and incidence of major bleeds. RESULTS: Among 2772 included infants, 224 (8%) developed a major bleed. Of the infants with a major bleed, 92% (206/224) had a nadir platelet count ≥50×109/L. The incidence of major bleeds was 8% among infants with and without severe thrombocytopenia (platelet count <50×109/L), 18/231 (95% CI 5 to 12) and 206/2541 (95% CI 7 to 9), respectively. Similarly, after adjustment for measured confounders, there was no notable association between nadir platelet counts below versus above 50×109/L and the occurrence of major bleeds (OR 1.09, 95% CI 0.61 to 1.94). CONCLUSION: In very preterm infants, the vast majority of major bleeds occur in infants without severe thrombocytopenia.

Description of mitochondrial oxygen tension and its variability in healthy volunteers.

OBJECTIVES: Describing mitochondrial oxygenation (mitoPO2) and its within- and between-subject variability over time after 5-aminolevulinic acid (ALA) plaster application in healthy volunteers. DESIGN: Prospective cohort study. SETTING: Measurements were performed in Leiden University Medical Center, the Netherlands. PARTICIPANTS: Healthy volunteers enrolled from July to September 2020. INTERVENTIONS: Two ALA plasters were placed parasternal left and right, with a 3-hour time interval, to examine the influence of the calendar time on the value of mitoPO2. We measured mitoPO2 at 4, 5, 7, 10, 28, and 31 hours after ALA plaster 1 application, and at 4, 5, 7, 25, and 28 hours after ALA plaster 2 application. PRIMARY AND SECONDARY OUTCOME MEASURES: At each time point, five mitoPO2 measurements were performed. Within-subject variability was defined as the standard deviation (SD) of the mean of five measurements per timepoint of a study participant. The between-subject variability was the SD of the mean mitoPO2 value of the study population per timepoint. RESULTS: In 16 completed inclusions, median mitoPO2 values and within-subject variability were relatively similar over time at all time points for both plasters. An increase in overall between-subject variability was seen after 25 hours ALA plaster time (19.6 mm Hg vs 23.9 mm Hg after respectively 10 and 25 hours ALA plaster time). CONCLUSIONS: The mitoPO2 values and within-subject variability remained relatively stable over time in healthy volunteers. An increase in between-subject variability was seen after 25 hours ALA plaster time warranting replacement of the ALA plaster one day after its application. TRIAL REGISTRATION: ClinicalTrials.gov with trial number NCT04626661.

Disease severity in subsequent pregnancies with RhD immunization: A nationwide cohort.

BACKGROUND AND OBJECTIVES: To evaluate the severity of haemolytic disease of the foetus and newborn (HDFN) in subsequent pregnancies with RhD immunization and to identify predictive factors for severe disease. MATERIALS AND METHODS: Nationwide prospective cohort study, including all pregnant women with RhD antibodies. All women with at least two pregnancies with RhD antibodies and RhD-positive foetuses were selected. The main outcome measure was the severity of HDFN in the first and subsequent pregnancy at risk. A subgroup analysis was performed for the group of women where RhD antibodies developed after giving birth to an RhD-positive child and thus after receiving anti-D at least twice (group A) or during the first pregnancy at risk for immunization (group B). RESULTS: Sixty-two RhD immunized women with a total of 150 RhD-positive children were included. The severity of HDFN increased for the whole group significantly in the subsequent pregnancy (p < 0.001), although it remained equal or even decreased in 44% of women. When antibodies were already detected at first trimester screening in the first immunized pregnancy, after giving birth to an RhD-positive child (group A), severe HDFN in the next pregnancy was uncommon (22%). Especially when no therapy or only non-intensive phototherapy was indicated during the first immunized pregnancy (6%) or if the antibody-dependent cell-mediated cytotoxicity result remained <10%. Contrarily, women with a negative first trimester screening and RhD antibodies detected later during the first pregnancy of an RhD-positive child (group B), often before they had ever received anti-D prophylaxis, were most prone for severe disease in a subsequent pregnancy (48%). CONCLUSION: RhD-mediated HDFN in a subsequent pregnancy is generally more severe than in the first pregnancy at risk and can be estimated using moment of antibody detection and severity in the first immunized pregnancy. Women developing antibodies in their first pregnancy of an RhD-positive child are at highest risk of severe disease in the next pregnancy.

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.

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.

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.

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 ever-pregnant donors with sons was not associated with increased all-cause mortality risk among male transfusion recipients (hazard ratio [HR]=0.91, 95% confidence interval [CI]: 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.