Impact of restrictive platelet transfusion strategies on transfusion rates: A cohort study in very preterm infants.

BACKGROUND: Evidence supports a restrictive platelet transfusion threshold in preterm neonates. We aimed to describe the effect of implementing this threshold on transfusion rates. STUDY DESIGN AND METHODS: This retrospective observational cohort study included all very preterm infants (born <32 weeks' gestation) admitted to a neonatal intensive care unit between 2004 and 2022, divided into three epochs. Platelet transfusion thresholds changed from 30 × 109/L for stable neonates and 50 × 109/L for unstable neonates (January 2004 to December 2009) to 20 × 109/L for stable neonates and 50 × 109/L for unstable neonates (January 2010 to June 2019) to 25 × 109/L for non-bleeding neonates and 50 × 109/L for neonates with major bleeding (July 2019 to July 2022). The primary outcome was the percentage of transfused neonates in each epoch. Secondary outcomes included the median number of transfusions per neonate, the percentage of transfusions given above 25 or 50 × 109/L, and major bleeding and mortality rates. RESULTS: The percentage of neonates transfused was 12.2% (115/939), 5.8% (96/1660), and 4.8% (25/525) in Epoch I, II, and III, respectively (p < .001), a relative reduction of 61%. The median number of transfusions per transfused neonate was 2.0 (interquartile range [IQR]: 1.0-3.0) in Epoch I, and 1.0 (IQR: 1.0-2.0) in subsequent Epochs (p = .04). The percentage of infants receiving at least one transfusion above 50 × 109/L in Epoch I, II, and III was 51.3% (59/115), 17.7% (17/96), and 20.0% (5/25; p < .001). Mortality and bleeding rates did not significantly differ between epochs. DISCUSSION: Implementation of restrictive platelet guidelines led to reduction of the rate and number of platelet transfusions.

Severe postpartum hemorrhage and the risk of adverse maternal outcome: A comparative analysis of two population-based studies in France and the Netherlands.

Objectives: Among women with severe PPH (sPPH) in France and the Netherlands, we compared incidence of adverse maternal outcome (major obstetric hemorrhage (≥2.5L blood loss) and/or hysterectomy and/or mortality) by mode of delivery. Second, we compared use and timing of resuscitation and transfusion management, second-line uterotonics and uterine-sparing interventions (intra-uterine tamponade, compression sutures, vascular ligation, arterial embolization) by mode of delivery. Methods:  Secondary analysis of two population-based studies of women with sPPH in France and the Netherlands. Women were selected by a harmonized definition for sPPH: (total blood loss ≥ 1500 ml) AND (blood transfusion of ≥ 4 units packed red blood cells and/or multicomponent blood transfusion). Findings: Incidence of adverse maternal outcome after vaginal birth was 793/1002, 9.1 % in the Netherlands versus 88/214, 41.1 % in France and 259/342, 76.2% versus 160/270, 59.3% after cesarean. Hemostatic agents such as fibrinogen were administered less frequently (p < 0.001) in the Netherlands (vaginal birth: 83/1002, 8.3% versus 105/2014, 49.5% in France; cesarean: 47/342, 13.7% and 152/270, 55.6%). Second-line uterotonics were started significantly later after PPH-onset in the Netherlands than France (vaginal birth: 46 versus 25 min; cesarean: 45 versus 18 min). Uterine-sparing interventions were less frequently (p < 0.001) applied in the Netherlands after vaginal birth (394/1002,39.3 %, 134/214, 62.6%) and cesarean (133/342, 38.9 % and 155/270, 57.4%), all initiated later after onset of refractory PPH in the Netherlands. Interpretation: Incidence of adverse maternal outcome was higher among women with sPPH in the Netherlands than France regardless mode of birth. Possible explanatory mechanisms are earlier and more frequent use of second-line uterotonics and uterine-sparing interventions in France compared to the Netherlands.

Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders.

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).

Back to base pairs: What is the genetic risk for red bloodcell alloimmunization?

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.

Evening aspirin intake results in higher levels of platelet inhibition and a reduction in reticulated platelets - a window of opportunity for patients with cardiovascular disease?

Cardiovascular events occur most frequently in the early morning. Similarly, the release of reticulated platelets (RP) by megakaryocytes has a peak in the late night and early morning. Which aspirin regimen most effectively inhibits platelets during these critical hours is unknown. Hence, the primary objective of this trial was to assess platelet function and RP levels at 8.00 AM, in stable cardiovascular (CVD) patients, during three different aspirin regimens. In this open-label randomized cross-over study subjects were allocated to three sequential aspirin regimens: once-daily (OD) 80 mg morning; OD-evening, and twice-daily (BID) 40 mg. Platelet function was measured at 8.00 AM & 8.00 PM by serum Thromboxane B2 (sTxB2) levels, the Platelet Function Analyzer (PFA)-200® Closure Time (CT), Aspirin Reaction Units (ARU, VerifyNow®), and RP levels. In total, 22 patients were included. At 8.00 AM, sTxB2 levels were the lowest after OD-evening in comparison with OD-morning (p = <0.01), but not in comparison with BID. Furthermore, RP levels were similar at 8.00 AM, but statistically significantly reduced at 8.00 PM after OD-evening (p = .01) and BID (p = .02) in comparison with OD-morning. OD-evening aspirin intake results in higher levels of platelet inhibition during early morning hours and results in a reduction of RP levels in the evening. These findings may, if confirmed by larger studies, be relevant to large groups of patients taking aspirin to reduce cardiovascular risk.

Serum fatty acid chain length associates with prevalent symptomatic end-stage osteoarthritis, independent of BMI.

Higher body mass index (BMI) is associated with osteoarthritis (OA) in both weight-bearing and non-weight-bearing joints, suggesting a link between OA and poor metabolic health beyond mechanical loading. This risk may be influenced by systemic factors accompanying BMI. Fluctuations in concentrations of metabolites may mark or even contribute to development of OA. This study explores the association of metabolites with radiographic knee/hip OA prevalence and progression. A 1H-NMR-metabolomics assay was performed on plasma samples of 1564 cases for prevalent OA and 2,125 controls collected from the Rotterdam Study, CHECK, GARP/NORREF and LUMC-arthroplasty cohorts. OA prevalence and 5 to 10 year progression was assessed by means of Kellgren-Lawrence (KL) score and the OARSI-atlas. End-stage knee/hip OA (TJA) was defined as indication for arthroplasty surgery. Controls did not have OA at baseline or follow-up. Principal component analysis of 227 metabolites demonstrated 23 factors, of which 19 remained interpretable after quality-control. Associations of factor scores with OA definitions were investigated with logistic regression. Fatty acids chain length (FALen), which was included in two factors which associated with TJA, was individually associated with both overall OA as well as TJA. Increased Fatty Acid chain Length is associated with OA.

Prevalence and Incidence of Non-neutralizing Antibodies in Congenital Hemophilia A- A Systematic Review and Meta-Analysis.

Objectives: In hemophilia A the presence of non-neutralizing antibodies (NNAs) against Factor VIII (FVIII) may predict the development of neutralizing antibodies (inhibitors) and accelerate the clearance of administrated FVIII concentrates. This systematic review aimed to assess: (1) the prevalence and incidence of NNAs in patients with congenital hemophilia without inhibitors and (2) the association between NNAs and patient and treatment characteristics. Methods: We conducted a search in MEDLINE, Embase, Web of Science and the Cochrane database. We included cross-sectional and longitudinal studies reporting on NNAs in patients with hemophilia A and B, who were inhibitor-negative at the start of the observation period. Data were extracted on: hemophilia type and severity, patient and treatment characteristics, NNA prevalence and incidence, NNA assays and inhibitor development. Two independent reviewers performed study selection, data extraction and risk of bias assessment, using adapted criteria of the Joanna Briggs Institute. Studies were classified as high-quality when ≥5/9 criteria were met. NNA assays were classified as high-quality when both quality criteria were met: (1) use of positive controls and (2) competition with FVIII to establish FVIII-specificity. We reported NNA prevalence and incidence for each study. The pooled NNA prevalence was assessed for well-designed studies in previously treated patients, employing high-quality NNA assays. Results: We included data from 2,723 inhibitor-negative patients with hemophilia A, derived from 28 studies. Most studies were cross-sectional (19/28) and none reported on NNAs in hemophilia B. Study design was of high quality in 16/28 studies and the NNA assay quality was high in 9/28 studies. Various NNA assays were used, predominantly ELISA (18/28) with different cut-off values. We found a large variety in NNA prevalence (Range, 0-100%). The pooled NNA prevalence in high-quality studies was 25% (95% CI, 16-38%). The incidence of new NNA development was reported in one study (0.01 NNA per person-exposure day). Conclusion: This systematic review identified studies that were heterogeneous in study design, patient population and NNA assay type, with NNA prevalence ranging from 0 to 100% in inhibitor-negative patients with hemophilia A. The pooled NNA prevalence was 25% in high-quality studies including only previously treated patients and performing high-quality NNA assays.

Variation in red cell transfusion practice in the intensive care unit - An international survey.

PURPOSE: Unclear recommendations in transfusion guidelines may possibly lead to inconsistency in treatment of patients admitted to the intensive care unit. This study aimed to uncover variation in red blood cell (RBC) transfusion decisions in the ICU worldwide. METHODS: Members of the European Society of Intensive Care Medicine (ESICM) were requested to complete an online questionnaire which included four different hypothetical clinical scenarios. The scenarios represented patients with acute myocardial infarction (AMI), abdominal sepsis, traumatic brain injury (TBI) and post-surgical complications. Hemoglobin level was 7∙3 g/dL in all scenarios. The questionnaire explored the physicians' transfusion decision in each clinical scenario and identified patient characteristics that were most influential in the transfusion decision. RESULTS: In total 211 members participated in the study, of whom 142 (67%) completed the entire survey. Most variation was observed in the clinical scenario of sepsis, in which 49% decided to transfuse and 51% decided not to. In the clinical scenarios of AMI, TBI and post-surgical complications this was respectively; 75/25%, 35/65% and 66/34%. CONCLUSIONS: Critical care physicians differed in outcome of RBC transfusion decisions and weighed patient characteristics differently. These findings indicate that variation in transfusion practice amongst critical care physicians exists.

Are thrombocytopenia and platelet transfusions associated with major bleeding in preterm neonates? A systematic review.

Over 75% of severely thrombocytopenic preterm neonates receive platelet transfusions to prevent bleeding, but transfusion guidelines are based mainly on expert opinion. The aim of this review was to investigate whether platelet counts, platelet transfusions or platelet indices are associated with major bleeding in preterm neonates. We performed a systematic search of the EMBASE and MEDLINE databases until December 2017. We included randomized trials, cohort and case control studies. (Prospero: CRD42015013399). We screened 8734 abstracts and 1225 fulltexts, identifying 36 eligible studies. In 30, timing of the platelet counts or transfusions in relation to the bleeding was unclear. Of the remaining six studies, two showed that thrombocytopenia was associated with increased risk of bleeding, two showed no such assocation, and three showed lack of an association between platelet transfusions and bleeding risk. No studies assessing platelet indices were found. The study results suggest that prophylactic platelet transfusions may not reduce bleeding risk in preterm neonates.

Clinically relevant differences between assays for von Willebrand factor activity.

Essentials It is unclear whether there are differences between von Willebrand factor (VWF) activity assays. We compared the four most used VWF activity assays in 661 von Willebrand disease (VWD) patients. All assays correlated excellently, but a discrepant classification was seen in 20% of patients. Differences between VWF activity assays have a large impact on the classification of VWD. SUMMARY: Background Measuring the ability of von Willebrand factor (VWF) to bind to platelets is crucial for the diagnosis and classification of von Willebrand disease (VWD). Several assays that measure this VWF activity using different principles are available, but the clinical relevance of different assay principles is unclear. Objective To compare the four most widely used VWF activity assays in a large VWD patient population. Methods We measured VWF:RCo (ristocetin to activate VWF + whole platelets), VWF:GPIbR (ristocetin + platelet glycoprotein Ib receptor [GPIb] fragments), VWF:GPIbM (gain-of-function GPIb fragments that bind VWF spontaneously without ristocetin) and VWF:Ab (monoclonal antibody directed against the GPIb binding epitope of VWF to mimic platelets) in 661 VWD patients from the nationwide 'Willebrand in the Netherlands' (WiN) Study. Results All assays correlated excellently (Pearson r > 0.9), but discrepant results led to a different classification for up to one-fifth of VWD patients. VWF:RCo was not sensitive enough to classify 18% of patients and misclassified half of genotypic 2B VWD patients, especially those with p.Arg1306Trp. VWF:GPIbR was more sensitive, accurately classified the vast majority of patients, and was unaffected by the p.Asp1472His variant that causes artificially low VWF:RCo. VWF:GPIbM was the most precise assay but misclassified over a quarter of genotypic 2A, 2B and 3 patients. VWF:Ab, often not considered an actual VWF activity assay, performed at least equally to the other assays with regard to accurate VWD classification. Conclusion Although the different VWF activity assays are often considered similar, differences between assays have a large impact on the classification of VWD.

Prospective validation of the EuroSCORE II risk model in a single Dutch cardiac surgery centre.

OBJECTIVE: The EuroSCORE I was one of the most frequently used pre-operative risk models in cardiac surgery. In 2011 it was replaced by its successor the EuroSCORE II. This study aims to validate the EuroSCORE II and to compare its performance with the EuroSCORE I in a Dutch hospital. METHODS: The EuroSCORE II was prospectively validated in 2,296 consecutive cardiac surgery patients between 1 April 2012 and 1 January 2014. Receiver operating characteristic curves on in-hospital mortality were plotted for EuroSCORE I and EuroSCORE II, and the area under the curve was calculated to assess discriminative power. Calibration was assessed by comparing observed versus expected mortality. Additionally, analyses were performed in which we stratified for type of surgery and for elective versus emergency surgery. RESULTS: The observed mortality was 2.4% (55 patients). The discriminative power of the EuroSCORE II surpassed that of the EuroSCORE I (area under the curve EuroSCORE II 0.871, 95% confidence interval (CI) 0.832-0.911; area under the curve additive EuroSCORE I 0.840, CI 0.798-0.882; area under the curve logistic EuroSCORE I 0.761, CI 0.695-0.828). Both the additive and the logistic EuroSCORE I overestimated mortality (predictive mortality additive EuroSCORE I median 5.0%, inter-quartile range 3.0-8.0%; logistic EuroSCORE I 10.7%, inter-quartile range 5.8-13.9), while the EuroSCORE II underestimated mortality (median 1.6%, inter-quartile range 1.0-3.5). In most stratified analyses the EuroSCORE II performed better. CONCLUSION: Our results show that the EuroSCORE II produces a valid risk prediction and outperforms the EuroSCORE I in elective cardiac surgery patients.

Management of postpartum hemorrhage: how to improve maternal outcomes?

Postpartum hemorrhage is the leading cause of maternal mortality and severe morbidity. Despite efforts to improve maternal outcomes, management of postpartum hemorrhage still faces at least four challenges, discussed in this review. First, current definitions for severe postpartum hemorrhage hamper early identification of women with a high risk of adverse outcomes. Adaptations to the definitions and the use of clinical tools such as shock index and early warning systems may facilitate this early identification. Second, surgical and radiological interventions to prevent hysterectomy are not always successful. More knowledge on the influence of patient and bleeding characteristics on the success rates of these interventions is necessary. Scarce data suggest that early timing of intrauterine balloon tamponade may improve maternal outcomes, whereas early timing of arterial embolization seems to be unrelated to maternal outcomes. Third, fluid resuscitation with crystalloids and colloids is unavoidable in the early phases of postpartum hemorrhage but may result in dilutional coagulopathy. Effects of different volumes of clear fluids on the occurrence of dilutional coagulopathy and maternal outcomes is unknown. Fourth, a better understanding of diagnosis and correction of coagulopathy during postpartum hemorrhage is needed. Low plasma fibrinogen levels at the start of postpartum hemorrhage predict progression to severe hemorrhage, but standard coagulation screens are time consuming. A solution may be point-of-care coagulation testing; however, clinical usefulness during postpartum hemorrhage has not been demonstrated. To date, early administration of tranexamic acid is the only hemostatic intervention that was proven to improve outcomes in women with postpartum hemorrhage.

Factor VIII products and inhibitor development in previously treated patients with severe or moderately severe hemophilia A: a systematic review.

Essentials Data on product-related immunogenicity in previously treated haemophilia A patients is scarce. A systematic review and meta-analysis of all currently available evidence was conducted. The overall incidence rate was 2.06 per 1000 person-years (95% confidence interval: 1.06-4.01). Some recombinant factor VIII products were associated with increased immunogenicity. SUMMARY: Background Patients with severe hemophilia A who have been treated extensively with factor VIII products have a low but potentially serious risk of inhibitor development. It is unknown why these patients develop inhibitors, and data on product-related immunogenicity are scarce. Aims To summarize the currently available evidence on the relationship between inhibitor development and recombinant FVIII product type in previously treated patients (PTPs) with severe hemophilia A. Methods Longitudinal studies were included that reported on de novo inhibitor formation in patients with baseline FVIII activity levels of < 0.02 IU mL-1 who had been treated with FVIII for at least 50 days. Pooled incidence rates of inhibitor development according to product types were calculated with a random intercept Poisson regression model. Results Forty-one independent cohorts were included; 39 patients developed de novo inhibitors during 19 157 person-years of observation. The overall incidence rate was 2.06 per 1000 person-years, with a 95% confidence interval (CI) of 1.06-4.01. According to product type, the pooled incidence rates were 0.99 (95% CI 0.37-2.70) per 1000 person-years for patients treated with Advate, 5.86 (95% CI 0.25-134.92) per 1000 person-years for those treated with Kogenate/Helixate, 1.35 (95% CI 0.66-2.77) per 1000 person-years for those treated with Kogenate FS/Helixate NexGen, 12.05 (95% CI 1.53-94.78) per 1000 person-years for those treated with Refacto, and 4.64 (95% CI 0.82-26.43) per 1000 person-years for those treated with Refacto AF. Conclusion These results suggest that some products may be associated with increased immunogenicity. However, the low incidence of inhibitors in PTPs and the differences in study design may cause significant variation in estimates of risk.

Variation in red cell transfusion decisions in the intensive care unit - a nationwide survey in the Netherlands.

BACKGROUND AND OBJECTIVES: Most guidelines recommend a restrictive transfusion trigger of 7 g/dl. It is unclear whether this resulted in more uniform transfusion practices. The primary objective was to uncover the extent of variation in transfusion decisions within four scenarios of critically ill patients among critical care physicians in the Netherlands. MATERIALS AND METHODS: An online survey comprising four different hypothetical clinical scenarios was sent to all members of the Dutch Society of Intensive Care. The scenarios represented patients with acute myocardial infarction (Hb 8·5 g/dl), abdominal sepsis (Hb 7·1 g/dl), traumatic brain injury (TBI) (Hb 7·9 g/dl) and post-surgical complications (Hb 7·3 g/dl). The questions explored the decision whether or not to transfuse and a ranking of clinical characteristics playing the most important role in the transfusion decision. RESULTS: A total of 224 members (22%) participated in the study of whom 188 (84%) completed all questions. The percentages of respondents that decided to transfuse ranged from 25·9% in the scenario with TBI to 81·6% in the scenario with post-surgical complications. Most controversy was seen in the scenario with sepsis for which 43·2% decided to transfuse, whereas 56·8% decided not to. Haemoglobin level, diagnosis and haemodynamics were most important for the transfusion decision in all scenarios. CONCLUSIONS: Physicians decided differently on red-blood-cell transfusion given the clinical scenarios and weighed clinical characteristics differently in their transfusion decisions. These findings suggest there still is substantial variation in critical care transfusion practice.

Chronic use of low-dose aspirin is not associated with lower bone mineral density in the general population.

BACKGROUND: Low-dose aspirin is the cornerstone of secondary prevention of cardiovascular disease. Previous studies suggested that the use of aspirin is associated with an increased fracture risk. However, there is uncertainty whether this is due to an effect of aspirin on bone mineral density (BMD). METHODS: Between 2008 and 2012, information on medication use and dual X-ray absorptiometry measured vertebral and femoral BMD of 916 participants was collected in the Netherland Epidemiology of Obesity study. The cross-sectional association between chronic low-dose aspirin use and BMD was estimated using linear regression, controlling for demography, body composition, comorbidity and other medication use which could affect BMD. A subgroup analysis in postmenopausal women (n=329) was conducted. RESULTS: After full adjustment, there was no difference between aspirin users and non-users for vertebral BMD (adjusted mean difference: 0.036 (95% CI -0.027 to 0.100) g/cm2) and femoral BMD (adjusted mean difference: 0.001 (-0.067 to 0.069) g/cm2). Also in the subgroup of postmenopausal women, aspirin use was not associated with lower vertebral (adjusted mean difference: 0.069 (-0.046 to 0.184) g/cm2) or femoral BMD (adjusted mean difference: -0.055 (-0.139;0.029) g/cm2). CONCLUSION: Chronic use of low-dose aspirin is not associated with lower BMD in the general population. The increased risk of fractures observed in aspirin users in previous studies is therefore more likely to be the result of common causes of aspirin use and fractures, but not of direct effects of aspirin on BMD.

Comparison of haemostatic function of PAS-C-platelets vs. plasma-platelets in reconstituted whole blood using impedance aggregometry and thromboelastography.

BACKGROUND AND OBJECTIVES: There are concerns about the haemostatic function of platelets stored in platelet additive solution (PAS). Aim of this study was to compare the haemostatic function of PAS-C-platelets to plasma-platelets in reconstituted whole blood. MATERIALS AND METHODS: In our experiment, whole blood was reconstituted with red blood cells, solvent-detergent (SD) plasma and either PAS-C-platelets or plasma-platelets (n = 7) in a physiological ratio. On storage days 2, 5, 8 and 13, the agonist-induced aggregation (multiple electrode aggregometry), clot formation (thromboelastography) and agonist-induced CD62P responsiveness (flow cytometry) were measured. RESULTS: Samples with PAS-C-platelets showed significantly lower aggregation than plasma-platelets when induced with adenosine diphosphate, -6 U (95% confidence interval: -8; -4) or thrombin receptor-activating protein, -15 U (-19; -10). Also when activated with collagen and ristocetin, the PAS-C-platelets showed less aggregation, although not statistically significant. All samples with PAS-C-platelets showed significantly lower agonist-induced CD62P responsiveness than samples with plasma-platelets. However, there was no difference regarding all TEG parameters. CONCLUSION: Our findings demonstrate that the function - aggregation and CD62P responsiveness - of PAS-C-platelets in reconstituted whole blood is inferior to that of plasma-platelets, which may have implications in the setting of massive transfusions.

Intensity of factor VIII treatment and the development of inhibitors in non-severe hemophilia A patients: results of the INSIGHT case-control study.

Essentials Research suggests that intensive treatment episodes may increase the risk to develop inhibitors. We performed an international nested case-control study with 298 non-severe hemophilia A patients. Surgery and a high dose of factor VIII concentrate were associated with increased inhibitor risk. Physicians need to review arguments for factor VIII dose and elective surgery extra critically. SUMMARY: Background Inhibitor development is a major complication of treatment with factor VIII concentrates in hemophilia. Findings from studies among severe hemophilia A patients suggest that intensive treatment episodes increase the risk of developing inhibitors. Objectives We set out to assess whether intensive treatment is also associated with an increased risk of inhibitor development among non-severe hemophilia A patients. Patients/Methods We performed a nested case-control study. A total of 75 inhibitor patients (cases) and 223 control patients were selected from 2709 non-severe hemophilia A patients (FVIII:C, 2-40%) of the INSIGHT cohort study. Cases and controls were matched for date of birth and cumulative number of exposure days (EDs) to FVIII concentrates. Conditional logistic regression was used to calculate both unadjusted and adjusted odds ratios (aOR); the latter were adjusted for a priori specified confounders. Results Peak treatment of 5 or 10 consecutive EDs did not increase inhibitor risk (aOR, 1.0; 95% confidence interval (CI), 0.4-2.5; and aOR, 1.8; CI, 0.6-5.5, respectively). Both surgical intervention (aOR, 4.2; CI, 1.7-10.3) and a high mean dose (> 45 IU kg-1 /ED) of FVIII concentrate (aOR, 7.5; CI, 1.6-35.6) were associated with an increased inhibitor risk. Conclusions Our findings suggest that high-dose FVIII treatment and surgery increase the risk of inhibitor development in non-severe hemophilia A. Together with the notion that non-severe hemophilia A patients are at a lifelong risk of inhibitor development, we suggest that in the future physicians will review the arguments for the FVIII dose and elective surgery extra critically.