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Purpose Anaemia is common in patients presenting with aneurysmal subarachnoid (aSAH) and intracerebral haemorrhage (ICH). In surgical patients, anaemia was identified as an idenpendent risk factor for postoperative mortality, prolonged hospital length of stay (LOS) and increased risk of red blood cell (RBC) transfusion. This multicentre cohort observation study describes the incidence and effects of preoperative anaemia in this critical patient collective for a 10-year period. Methods This multicentre observational study included adult in-hospital surgical patients diagnosed with aSAH or ICH of 21 German hospitals (discharged from 1 January 2010 to 30 September 2020). Descriptive, univariate and multivariate analyses were performed to investigate the incidence and association of preoperative anaemia with RBC transfusion, in-hospital mortality and postoperative complications in patients with aSAH and ICH. Results A total of n = 9081 patients were analysed (aSAH n = 5008; ICH n = 4073). Preoperative anaemia was present at 28.3% in aSAH and 40.9% in ICH. RBC transfusion rates were 29.9% in aSAH and 29.3% in ICH. Multivariate analysis revealed that preoperative anaemia is associated with a higher risk for RBC transfusion (OR = 3.25 in aSAH, OR = 4.16 in ICH, p < 0.001), for in-hospital mortality (OR = 1.48 in aSAH, OR = 1.53 in ICH, p < 0.001) and for several postoperative complications. Conclusions Preoperative anaemia is associated with increased RBC transfusion rates, in-hospital mortality and postoperative complications in patients with aSAH and ICH. Trial registration ClinicalTrials.gov, NCT02147795, https://clinicaltrials.gov/ct2/show/NCT02147795

Background Blood transfusions are common medical procedures and every age group requires detailed insights and treatment bundles. The aim of this study was to examine the association of anaemia, co-morbidities, complications, in-hospital mortality, and transfusion according to age groups to identify patient groups who are particularly at risk when undergoing surgery. Methods Data from 21 Hospitals of the Patient Blood Management Network Registry were analysed. Patients were divided into age subgroups. The incidence of preoperative anaemia, co-morbidities, surgical disciplines, hospital length of stay, complications, in-hospital mortality rate, and transfusions were analysed by descriptive and multivariate regression analysis. Results A total of 1 117 919 patients aged 18–108 years were included. With increasing age, the number of co-morbidities and incidence of preoperative anaemia increased. Complications, hospital length of stay, and in-hospital mortality increased with age and were higher in patients with preoperative anaemia. The mean number of transfused red blood cells (RBCs) peaked, whereas the transfusion rate increased continuously. Multivariate regression analysis showed that increasing age, co-morbidities, and preoperative anaemia were independent risk factors for complications, longer hospital length of stay, in-hospital mortality, and the need for RBC transfusion. Conclusion Increasing age, co-morbidities, and preoperative anaemia are independent risk factors for complications, longer hospital length of stay, in-hospital mortality, and the need for RBC transfusion. Anaemia diagnosis and treatment should be established in all patients.

Monoclonal antibodies such as daratumumab that target antigens that are also expressed on red blood cells impede blood group typing. The preferred approach to potential transfusion is to do prior extensive antigen typing of patients' red cells; however, this is not always possible. Ehrend et al describe a technique for absorbing the antibodies from serum to allow accurate red cell typing for transfusion.

Pulmonary embolism (PE) due to deep vein thrombosis is a complication with severe morbidity and mortality rates. Neurocritical care patients constitute an inhomogeneous cohort with often strict contraindications to conventional embolism treatment. The aim of the present study is to identify risk factors for pulmonary embolism for intensified risk stratification in this demanding cohort. In this retrospective analysis, 387 neurocritical care patients received computed tomography for clinical suspicion of PE (304 neurosurgical and 83 neurological patients). Analysed parameters included age, gender, disease pattern, the presence of deep vein thrombosis, resuscitation, in-hospital mortality, present anticoagulation, coronary artery disease, diabetes mellitus, smoking status, hypertension and ABO blood type. Computed tomography confirmed 165 cases of pulmonary embolism among 387 patients with clinical suspicion of pulmonary embolism (42%). Younger age (p p p p p

Background: Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a rare and potentially life-threatening bleeding disorder of the fetus/newborn. Antibodies against human platelet antigen 1a (HPA-1a) are associated with the most frequent FNAIT cases. There are no approved therapies for FNAIT prevention or treatment. RLYB211 is a polyclonal HPA-1a hyperimmune IgG being developed to prevent FNAIT. Objectives: To investigate whether a single dose of anti–HPA-1a (1000 IU) could markedly accelerate the elimination of HPA-1ab platelets transfused into healthy, HPA1a–negative participants as compared with placebo. Methods: This randomized, single-blind, placebo–controlled, single-center, phase 1/2 proof-of-concept study (EudraCT: 2019-003459-12) included HPA-1a– and HLA-A2– negative healthy men. Cohort 1 received intravenous RLYB211 or placebo 1 hour after transfusion of HPA-1ab platelets. Cohort 1B received RLYB211 or placebo, followed by platelet transfusion 1 week later. Primary endpoint was the half-life of transfused platelets in circulation after administration of RLYB211 or placebo, determined by flow cytometry. Proof of concept was ≥90% reduction of half-life relative to placebo. Results: Twelve participants were allocated to cohort 1 or 1B and randomized to receive RLYB211 (n = 9) or placebo (n = 3). RLYB211 markedly accelerated the elimination of HPA-1ab platelets in all participants vs placebo. In cohort 1B, this effect was observed 7 days after RLYB211 administration. Two treatment–emergent adverse events were possibly related to treatment, both in RLYB211–treated participants. No participants developed HPA-1a antibodies at 12 or 24 weeks. Conclusion: These data support the hypothesis that anti–HPA-1a could be used as prophylaxis in women at risk of having an FNAIT–affected pregnancy.

Postoperative thrombotic thrombocytopenic purpura (TTP) shows clinical presentation similar to classical TTP, whereas exact pathophysiological contexts remain unexplained. In this study, we investigated intraoperative and postoperative changes in ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13), von Willebrand factor (VWF), large VWF multimers, and interleukin-6 (IL-6) in vascular surgery patients. The objective was to compare the impact of endovascular, peripheral, and aortic surgery on target parameters which are supposed to play a role in surgery-associated TTP. A total of 93 vascular surgery patients were included and divided into 4 groups according to the specific type of intervention they underwent. Blood samples were taken preoperatively, intraoperatively, and postoperatively on days 2 and 4. The ADAMTS-13 activity decreased significantly in 3 of the 4 groups during surgery (from median 81% to 49%, P < .001, in the group undergoing aortoiliacal interventions), whereas the percentage of large VWF multimers increased in all groups of patients. von Willebrand factor antigen increased significantly in all groups on postoperative day 2 and IL-6 increased significantly in the intraoperative and early postoperative period. There was no significant correlation between the intraoperative decrease in ADAMTS-13 and the increase in VWF or IL-6. No patient in this study showed clinical picture of TTP; the precise cause and clinical significance of moderately reduced ADAMTS-13 activity in the perioperative setting have not yet been definitely determined.

Background The INTERCEPT™ Blood System for Red Blood Cells (RBCs) utilizes amustaline (S-303) and glutathione (GSH) to inactivate pathogens and leukocytes in transfused RBCs. Treatment-emergent low titer non-hemolytic antibodies to amustaline/GSH RBC were detected in clinical trials using a prior version of the process. The amustaline/GSH process was re-formulated to decrease S-303 RBC adduct formation. Study design and methods A standard three-cell antibody screening panel was modified to include reagent red cells (RRC) with high (S-303H) or low (S-303L) S-303 adduct density as assessed by flow cytometry, representative of the original and current amustaline/GSH treatment processes, respectively. General hospital and RBC transfusion-dependent patients never exposed, and clinical trial subjects exposed to amustaline/GSH RBC were screened for antibodies to amustaline/GSH RBC using a standardized agglutination assay. Results Twelve (0.1%) of 10,721 general hospital and 5 (0.5%) of 998 repeatedly-transfused patients not previously exposed to amustaline/GSH RBCs expressed natural, low titer (2-32) IgM and/or IgG (non-IgG1 or IgG3 isotype) antibodies with acridine (a structural element of amustaline) (n = 14) or non-acridine (n = 3) specificity. 11 of 17 sera reacted with S-303L panel RRCs. In clinical studies 81 thalassemia and 25 cardiac surgery patients were transfused with a total of 1085 amustaline/GSH RBCs and no natural or treatment-emergent S-303 antibodies were detected. Conclusion Standardized RRC screening panels are sensitive for the detection of natural and acquired S-303-specific antibodies. Natural low titer antibodies to amustaline/GSH RBC are present in 0.15% of naive patients. The clinical relevance of these antibodies appears minimal but is under further investigation.

Background: Autologous stem cell transplantation is considered a standard of care treatment in eligible patients with multiple myeloma, but puts the patient at high risk for infections and bleeding complications. Acquired von-Willebrand's disease (AVWD) and acquired platelet dysfunction are rare bleeding disorders that are associated with lymphoproliferative disorders such as multiple myeloma. Patients with acquired bleeding disorders who are planned for ASCT to treat the underlying condition are considered at highest risk for bleeding complications, and optimal treatment strategies are not known. Materials and Methods: We summarized the diagnostic and therapeutic approach to a patient affected by AVWD and acquired platelet disorder related to multiple myeloma. The patient who was planned for ASCT presented with moderate to severe bleeding symptoms. Results: Acute bleeding episodes were successfully controlled and prevented during induction and consolidation therapy with immunoglobulins, whereas replacement of plasma-derived VW factor showed no clinical improvement. High-dose melphalan-based consolidation therapy supported with autologous stem-cell transplantation led to an immediate and sustainable rise of von-Willebrand antigen and activity and a subsequent normalization of platelet aggregation activity. After a follow-up of 40 weeks, the patient maintained normalized VW levels and platelet aggregation capacity. There were no further signs or symptoms of bleeding. Conclusion: This case report highlights the necessity for combined supportive and causal treatment in patients with AVWD and paraproteinemic PD. High-dose melphalan with autologous stem cell support may function as a treatment option in patients with myeloma-related AVWD.

Background Nucleic acid-targeted pathogen inactivation technology using amustaline (S-303) and glutathione (GSH) was developed to reduce the risk of transfusion-transmitted infectious disease and transfusion-associated graft-versus-host disease with red blood cell (RBC) transfusion. Study design and methods A randomized, double-blind, controlled study was performed to assess the in vitro characteristics of amustaline-treated RBCs (test) compared with conventional (control) RBCs and to evaluate safety and efficacy of transfusion during and after cardiac surgery. The primary device efficacy endpoint was the postproduction hemoglobin (Hb) content of RBCs. Exploratory clinical outcomes included renal and hepatic failure, the 6-minute walk test (a surrogate for cardiopulmonary function), adverse events (AEs), and the immune response to amustaline-treated RBCs. Results A total of 774 RBC unis were produced. Mean treatment difference in Hb content was -2.27 g/unit (95% confidence interval, -2.61 to -1.92 g/unit), within the prespecified equivalence margins (±5 g/unit) to declare noninferiority. Amustaline-treated RBCs met European guidelines for Hb content, hematocrit, and hemolysis. Fifty-one (25 test and 26 control) patients received study RBCs. There were no significant differences in RBC usage or other clinical outcomes. Observed AEs were within the spectrum expected for patients of similar age undergoing cardiovascular surgery requiring RBCs transfusion. No patients exhibited an immune response specific to amustaline-treated RBCs. Conclusion Amustaline-treated RBCs demonstrated equivalence to control RBCs for Hb content, have appropriate characteristics for transfusion, and were well tolerated when transfused in support of acute anemia. Renal impairment was characterized as a potential efficacy endpoint for pivotal studies of RBC transfusion in cardiac surgery.

Background and objectives A lateral flow assay for simultaneous blood group typing of ABO, RhD, C, E, c, e, Cw and K with stable end-point and without centrifugation is in routine use since several years (MDmulticard® ). The typing of extended phenotype parameters belonging to the Duffy, Kidd, MNSs blood group systems and others, however, has not yet been demonstrated for this technique. Reliable detection of Fyx , a weak Fyb phenotype with a pronounced quantitative reduction of the number of Fyb antigens on the erythrocyte surface, remains a weakness of current serological blood grouping techniques. Material and methods The performance characteristics of the following reagents were evaluated in donor and patient samples in lateral flow technology (MDmulticard® ): Anti-Fya , -Fyb , -Jka , -Jkb , -S, -s, -P1 and -k. The sensitivity to detect Fyx was in addition evaluated with Fyx positive samples, which had been preselected by MALDI-TOF MS-based genotyping. Results All results obtained with the MDmulticard® were in full accordance with those of the CE-certified reference products for all the eight reagent formulations used: Anti-Fya , -Fyb , -Jka , -Jkb , -S, -s, -P1 and -k. Also, all Fyx phenotypes of the selected population of 93 positive samples, originally identified by MALDI-TOF MS-based genotyping, were reliably detected by the lateral flow assay. Conclusion Extended phenotype blood group parameters, including the serologically challenging Fyx phenotype, can be determined simultaneously, rapidly and accurately using the lateral flow (MDmulticard® ) technology, even in cases when IgG class antibodies are the only source of diagnostic antibodies.

Background Biotin-labeled red blood cells (BioRBCs) are used for in vivo kinetic studies. Because BioRBC dosing occasionally induces antibodies, a sensitive and specific anti-BioRBC detection assay is needed. Study design and methods Aims were to 1) develop a gel card assay to evaluate existing, naturally occurring and BioRBC-induced plasma antibodies, 2) compare gel card and tube agglutination detection results, and 3) test for a relationship of antibody induction and BioRBC dose. Reagent BioRBCs were prepared using sulfo-NHS biotin ranging from densities 18 (BioRBC-18) to 1458 (BioRBC-1458) µg/mL RBCs. Results Among BioRBC-exposed subjects, gel card and tube agglutination results were concordant in 21 of 22 adults and all 19 infant plasma samples. Gel card antibody detection sensitivity was more than 10-fold greater than tube agglutination. Twelve to 16 weeks after BioRBC exposure, induced anti-antibodies were detected by gel card in three of 26 adults (12%) at reagent densities BioRBC-256 or less, but in none of 41 infants. Importantly, induced anti-BioRBC antibodies were associated with higher BioRBC dose (p = 0.008); no antibodies were detected in 18 subjects who received BioRBC doses less than or equal to BioRBC-18. For noninduced BioRBC antibodies, six of 1125 naive adults (0.3%) and none of 46 naive infants demonstrated existing anti-BioRBC antibodies using reagent BioRBC-140 or -162. Existing anti-BioRBCs were all neutralized by biotin compounds, while induced antibodies were not. Conclusions The gel card assay is more sensitive than the tube agglutination assay. We recommend reagent BioRBC-256 for identifying anti-BioRBCs. Use of a low total RBC biotin label dose (≤ BioRBC-18) may minimize antibody induction.

Over the past years, next-generation sequencing (NGS) technologies revolutionized the possibilities in a broad range of application areas. Also in the field of forensic genetics, NGS continuously gained in importance and attentiveness. A significant number of sudden cardiac deaths (SCD) in the young is due to heritable arrhythmia syndromes emphasizing the need of examining the genetic basis in these cases also with regard to the identification of relatives and/or patients being at risk. As a result, high-throughput methods became of increasing value in molecular autopsy investigations enabling the analysis of a broad spectrum of genes. Most standard protocols are optimized for high-quality samples and frequently not directly applicable to challenging forensic sample material. In the present study, we intended to examine a comprehensive gene panel associated with SCD and inherited arrhythmogenic disorders. We compared three different hybridization-based library preparation technologies in order to implement a suitable NGS workflow for heterogeneous, forensic as well as diagnostic sample material. The results obtained indicated, that the Illumina technologies Nextera DNA Flex and TruSeq were compatible with samples exhibiting varying levels of degradation. In comparison, the TruSight method also resulted in good sequencing data, but seemed to be more dependent on DNA integrity. The preparation protocols evaluated in our study are not restricted to molecular autopsy investigations and might be helpful for and transferrable to further forensic research applications.

Objective Rupture of an intracranial aneurysm usually presents with an acute onset and requires multidisciplinary intensive care treatment and the overall death and disability rates are high. The ABO blood type is known to play an important role in hemostasis, thrombosis, and vascular NO response. The aspect of ABO blood type in onset, clinical progress, and outcome after subarachnoid hemorrhage (SAH) is largely unexplored. We conducted this study to elucidate the association of ABO blood type with the occurrence and outcome of aneurysmal SAH. Methods In our retrospective study, 470 patients with aneurysmal SAH treated at our institution were included. We performed a χ2 test for comparison between blood types and World Federation of Neurosurgical Societies admission status, cerebral vasospasm, delayed infarction, associated intracerebral hemorrhage and Fisher grade for analysis for their association with SAH. Results No significant difference between blood type and the reviewed variables for SAH outcome were identified: World Federation of Neurosurgical Societies admission status (odds ratio, 1.12; 95% confidence interval [CI], 0.7–1.6; P = 0.56); SAH-associated intracerebral hemorrhage (odds ratio, 0.81; 95% CI, 0.5–1.3; P = 0.36); cerebral vasospasm (odds ratio, 1.08; 95% CI, 0.7–1.6; P = 0.71); DCI (odds ratio, 1.23; 95% CI, 0.8–1.8; P = 0.30); Fisher grade (odds ratio, 1.13; 95% CI, 0.7–1.6; P = 0.19). Conclusions Although a possible relationship between the ABO blood group and the clinical course of patients with SAH was hypothesized, our study showed no significant influence of patient's ABO blood type on cerebral vasospasm onset, SAH-associated intracerebral hemorrhage, or delayed infarction.

To determine whether the implementation of patient blood management (PBM) is effective to decrease the use of red blood cell without impairment of patient's safety.The World Health Organization encouraged all member states to implement PBM programs employing multiple combined strategies to increase and preserve autologous erythrocyte volume to minimize red blood cell transfusions. Data regarding safety issues are not sufficiently available.In this prospective, multicenter study, surgical inpatients from four German University Hospitals were analyzed before (pre-PBM) and after the implementation of PBM. PBM program included multiple measures (ie, preoperative optimization of hemoglobin levels, blood-sparing techniques, and standardization of transfusion practice). Primary aim was to show noninferiority of the PBM cohort with a margin of 0.5%. Secondary endpoints included red blood cell utilization.A total of 129,719 patients discharged between July 2012 and June 2015 with different inclusion periods for pre-PBM (54,513 patients) and PBM (75,206 patients) were analyzed. The primary endpoint was 6.53% in the pre-PBM versus 6.34% in the PBM cohort. The noninferiority aim was achieved (P0.001). Incidence of acute renal failure decreased in the PBM cohort (2.39% vs 1.67%; P0.001, regression model). The mean number of red blood cell transfused per patient was reduced from 1.21 ± 0.05 to 1.00 ± 0.05 (relative change by 17%, P0.001).The data presented show that implementation of PBM with a more conscious handling of transfusion practice can be achieved even in large hospitals without impairment of patient's safety. Further studies should elucidate which PBM measures are most clinically and cost effective.PBM-Study ClinicalTrials.gov, NCT01820949.

Patient Blood Management (PBM) ist ein interdisziplinares Therapiekonzept, welches durch ein umfangreiches praoperatives Anamiemanagement, die Minimierung iatrogener Blutverluste sowie die Ausschopfung der Anamietoleranz zu einer verbesserten Patientenversorgung beitragt. Kostenaspekte von verschiedenen PBM-Masnahmen wurden bislang kaum analysiert. Im Rahmen dieser Arbeit werden die Kosten eines umfassenden PBM-Konzepts und die mit der Einfuhrung assoziierten Projektkosten dargestellt. Es wurden die Sach- und Personalkosten der aus verschiedenen Einzelmasnahmen bestehenden PBM-Saulen sowie der Transfusion von Erythrozytenkonzentraten aus dem Jahr 2013 am Universitatsklinikum Frankfurt analysiert. Zudem wurden die allgemeinen Projektkosten betrachtet. Die patientenbezogenen Mindestkosten einer Erythrozytenkonzentrattransfusion betrugen 147,43 €. Die Kosten von PBM variierten in Abhangigkeit der umgesetzten Einzelmasnahmen. Die Kosten pro Patient betrugen fur die Anamiediagnostik 48,69–123,88 €, Anamietherapie 12,61–127,99 €, Minimierung von Blutverlusten 3,39–1901,81 € und Ausschopfung der Anamietoleranz 28,62 €. Die Projektkosten der Implementierung von PBM beliefen sich auf 24.998,24 €. PBM kombiniert verschiedene Masnahmen, fur deren Realisierung finanzielle Aufwendungen notig sind, wahrend transfusionsassoziierte Kosten durch Ausschopfung der Anamietoleranz gesenkt werden konnen. Im Fokus steht die Optimierung der Patientenversorgung, gleichzeitig spielen gesundheitsokonomische Aspekte eine Rolle, um eine potenzielle Allokation von Ressourcen zu ermoglichen.

Anti-HPA-1a-antibodies are the main cause of fetal and neonatal alloimmune thrombocytopenia (FNAIT) which may result in intracranial hemorrhage (ICH) and death among fetuses and newborns. Advances in understanding the pathogenesis of FNAIT and proof of concept for prophylaxis to prevent immunization suggest that development of hyperimmune anti-HPA-1a IgG aimed at preventing immunization against HPA-1a and FNAIT is feasible. Anti-HPA-1a IgG can be obtained either by isolating immunoglobulin from already-immunized women or by development of monoclonal anti-HPA-1a antibodies. Here we discuss recent advances that may lead to the development of a prenatal and postnatal prophylactic treatment for the prevention of HPA-1a-associated FNAIT and life-threatening FNAIT-induced complications.

Cases of sudden cardiac death (SCD) in young and apparently healthy individuals represent a devastating event in affected families. Hereditary arrhythmia syndromes, which include primary electrical heart disorders as well as cardiomyopathies, are known to contribute to a significant number of these sudden death cases. We performed postmortem genetic analyses in young sudden death cases (aged45years) by means of a defined gene panel using massive parallel sequencing (MPS). The data were evaluated bioinformatically and detected sequence variants were assessed using common databases and applying in silico prediction tools. In this study, we identified variants with likely pathogenic effect in 6 of 9 sudden unexpected death (SUD) cases. Due to the detection of numerous unknown and unclassified variants, interpretation of the results proved to be challenging. However, by means of an appropriate evaluation of the findings, MPS represents an important tool to support the forensic investigation and implies great progress for relatives of young SCD victims facilitating adequate risk stratification and genetic counseling.

Hintergrund Die praoperative Anamie hat in den Industrienationen eine Pravalenz von ungefahr 30 %, ist einer der starksten Pradiktoren fur die perioperative Gabe von Erythrozytenkonzentraten (EK) und zugleich ein eigenstandiger und unabhangiger Risikofaktor fur das Auftreten postoperativer Komplikationen. Im Bereich der Hamotherapie ist weltweit eine breite Variabilitat der Indikationsstellung zum Einsatz von EK auffallend. Vor diesem Hintergrund wird seit 2011 von der Weltgesundheitsorganisation die Implementierung eines Patient-blood-Managements (PBM) gefordert.

Background Patient blood management (PBM) concepts aim to identify patients with anemia and optimize their treatment including use of preoperative iron substitution, blood-sparing techniques and adequate transfusion practice. PBM concepts thus have great potential to increase patient safety and clinical outcome. Nevertheless, up to now, structured PBM programmes have only been implemented in very few hospitals in Germany and safety data regarding clinical outcome parameters is rare. Methods The German PBM network was founded in January 2014 and joined by 24 hospitals different hospitals of varying sizes and levels of patient care. An evidence-based PBM programme will be applied in these hospitals reforming the care of adult patients undergoing surgery, and data will be monitored prospectively. This PBM programme includes the following three main pillars: (1) preoperative optimization of hemoglobin levels in high-risk patients suffering from anemia, (2) standardization of transfusion practice according to evidence-based guidelines and (3) wide implementation of alternatives to transfusion of allogeneic red blood cell (RBC) concentrates including blood-sparing techniques. Primary endpoints are the following composite endpoints: (1) in-hospital myocardial infarction, (2) stroke, (3) acute renal failure, (4) death of any cause, (5) pneumonia and (6) sepsis until hospital discharge in patients before and after the implementation of the PBM programme. Conclusions This trial will determine whether the implementation of a PBM programme is safe and effective in terms of clinical outcome. Data will be compared to data prior to implementation of PBM in (the same?) 20 Germany hospitals.

In patients with non-aneurysmal subarachnoid hemorrhage (NA-SAH), the etiology is unknown and the bleeding source remains unidentified. However, the ABO blood type system has a profound role in patient’s hemostasis and thrombosis. To date, the aspect of ABO blood type in incidence, clinical course, and outcome after NA-SAH has not been investigated. In this retrospective analysis, 81 patients with non-traumatic and non-aneurysmal subarachnoid hemorrhage treated between 2010 and 2014 at the author’s institution were included. WFNS admission status, cerebral vasospasm, delayed infarction, ventriculoperitoneal shunt necessity, the Fisher grade, and the modified Rankin Scale were analyzed for their association with ABO blood type. Four hundred seventy patients with aneurysmal subarachnoid hemorrhage served as a control group. The AB blood type is more frequent in NA-SAH compared to aneurysmal patients and the German population (OR 2.45, p ≤ 0.05). Furthermore, NA-SAH with AB blood type showed a similar sequelae compared to aneurysmal patients in terms of shunt necessity (OR 2.00, p ≥ 0.05), cerebral vasospasm (OR 1.66, p ≥ 0.05), and delayed infarctions (OR 1.07, p ≥ 0.05). The clinical course of NA-SAH AB blood type patients shows similar severity as of aneurysmal subarachnoid hemorrhage. Therefore, patients with AB blood type should be under intensified observation.

Nucleic acid-targeted pathogen inactivation technology using amustaline (S-303) and glutathione (GSH) was developed to reduce the risk of transfusion-transmitted infectious disease and transfusion-associated graft-versus-host disease with red blood cell (RBC) transfusion.A randomized, double-blind, controlled study was performed to assess the in vitro characteristics of amustaline-treated RBCs (test) compared with conventional (control) RBCs and to evaluate safety and efficacy of transfusion during and after cardiac surgery. The primary device efficacy endpoint was the postproduction hemoglobin (Hb) content of RBCs. Exploratory clinical outcomes included renal and hepatic failure, the 6-minute walk test (a surrogate for cardiopulmonary function), adverse events (AEs), and the immune response to amustaline-treated RBCs.A total of 774 RBC unis were produced. Mean treatment difference in Hb content was -2.27 g/unit (95% confidence interval, -2.61 to -1.92 g/unit), within the prespecified equivalence margins (±5 g/unit) to declare noninferiority. Amustaline-treated RBCs met European guidelines for Hb content, hematocrit, and hemolysis. Fifty-one (25 test and 26 control) patients received study RBCs. There were no significant differences in RBC usage or other clinical outcomes. Observed AEs were within the spectrum expected for patients of similar age undergoing cardiovascular surgery requiring RBCs transfusion. No patients exhibited an immune response specific to amustaline-treated RBCs.Amustaline-treated RBCs demonstrated equivalence to control RBCs for Hb content, have appropriate characteristics for transfusion, and were well tolerated when transfused in support of acute anemia. Renal impairment was characterized as a potential efficacy endpoint for pivotal studies of RBC transfusion in cardiac surgery.

Patient Blood Management (PBM) als ein multidisziplinares, evidenzbasiertes Behandlungskonzept zur Reduktion von Anamie und Blutverlust muss am einzelnen Krankenhaus einrichtungsadaptiert verwirklicht werden. Die Implementierung eines PBM-Programms in einer klinischen Einrichtung wird eine herausfordernde, in jedem Fall aber eine lohnende Aufgabe sein. Die Ausstattung zur Erfullung der Schulungsanforderungen fur eine grose Gruppe unterschiedlicher Mitarbeiter kann unzureichend sein. Deshalb ist die nachhaltige Unterstutzung durch die Krankenhausleitung mit Bereitstellung der notwendigen Ressourcen fur Personal und Material unabdingbar. Die Bildung eines PBM-Kernteams, bei uns zu Anfang bestehend aus Anasthesisten, Chirurgen, Internisten und Transfusionsmedizinern sowie – besonders wichtig – aus motivierten Pflegekraften, ist eine der vordringlichen und primaren Aufgaben bei der Etablierung eines PBM-Projekts. Ebenso wichtig ist es, das PBM-Projekt dauerhaft im Krankenhaus zu verankern. Mogliche Schritte und Details hierzu werden anhand aktueller Erfahrungen der Autoren am Universitatsklinikum Frankfurt vorgestellt und in ihrer Wertigkeit diskutiert.

Das multimodale Konzept des Patient Blood Managements tangiert zahlreiche Aspekte der Krankenhausbehandlung eines Patienten. Hauptaugenmerk liegt darauf, patienteneigene Ressourcen zu schonen und zu starken. Dies kann v.a. durch akribische Minimierung des perioperativen Blutverlusts und den Ausbau und die Ausschopfung der individuellen Anamietoleranz erreicht werden. Blutprodukte sollen erst nach Optimierung aller anderen Aspekte leitliniengerecht zur Anwendung kommen, um die mit allogenen Bluttransfusionen verbundenen Risiken zu vermeiden. Das vorgeschlagene Masnahmenbundel besitzt groses Potenzial zur Steigerung der Patientensicherheit!

SummaryMutations in the antithrombin (AT) gene can impair the capacity of AT to bind heparin (AT deficiency type IIHBS), its target proteases such as thrombin (type IIRS), or both (type IIPE). Type II AT deficiencies are almost exclusively caused by missense mutations, whereas type I AT deficiency can originate from missense or null mutations. In a retrospective cohort study, we investigated the impact of the type of mutation and type of AT deficiency on the manifestation of thromboembolic events in 377 patients with hereditary AT deficiencies (133 from our own cohort, 244 reported in the literature). Carriers of missense mutations showed a lower risk of venous thromboembolism (VTE) than those of null mutations (adjusted hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.27–0.58, p

Biotin-labeled red blood cells (BioRBCs) are used for in vivo kinetic studies. Because BioRBC dosing occasionally induces antibodies, a sensitive and specific anti-BioRBC detection assay is needed.Aims were to 1) develop a gel card assay to evaluate existing, naturally occurring and BioRBC-induced plasma antibodies, 2) compare gel card and tube agglutination detection results, and 3) test for a relationship of antibody induction and BioRBC dose. Reagent BioRBCs were prepared using sulfo-NHS biotin ranging from densities 18 (BioRBC-18) to 1458 (BioRBC-1458) µg/mL RBCs.Among BioRBC-exposed subjects, gel card and tube agglutination results were concordant in 21 of 22 adults and all 19 infant plasma samples. Gel card antibody detection sensitivity was more than 10-fold greater than tube agglutination. Twelve to 16 weeks after BioRBC exposure, induced anti-antibodies were detected by gel card in three of 26 adults (12%) at reagent densities BioRBC-256 or less, but in none of 41 infants. Importantly, induced anti-BioRBC antibodies were associated with higher BioRBC dose (p = 0.008); no antibodies were detected in 18 subjects who received BioRBC doses less than or equal to BioRBC-18. For noninduced BioRBC antibodies, six of 1125 naïve adults (0.3%) and none of 46 naïve infants demonstrated existing anti-BioRBC antibodies using reagent BioRBC-140 or -162. Existing anti-BioRBCs were all neutralized by biotin compounds, while induced antibodies were not.The gel card assay is more sensitive than the tube agglutination assay. We recommend reagent BioRBC-256 for identifying anti-BioRBCs. Use of a low total RBC biotin label dose (≤ BioRBC-18) may minimize antibody induction.

Hamotherapie ist ein integraler Bestandteil der modernen Hochleistungsmedizin. Ohne die Transfusion von Erythrozyten- und Thrombozytenkonzentraten sowie Plasma waren Hochdosis-Chemotherapien bei hamatologischen und soliden Tumoren, die Transplantation hamatopoetischer Stammzellen, Organtransplantationen, grose operative Eingriffe sowie ein modernes Traumamanagement nicht denkbar. In diesem Beitrag wird der aktuelle Stand der Hamotherapie, das Risiko unverwunschter Wirkungen sowie Masnahmen zur Risikovermeidung dargestellt. Auf die hamolytischen Transfusionsreaktionen (HTR), die transfusionsassoziierte akute Lungeninsuffizienz (TRALI) und transfusionsassoziierte Infektionen wird im Besonderen eingegangen. Mit der Einfuhrung von Nukleinsaure-Amplifikations-Testen (NAT) fur HIV-1 und Hepatitis-C-Virus (HCV) kann heute die HIV- und HCV-Transmission uber Blutprodukte in Deutschland nahezu vollstandig verhindert werden. Aktuelle Restinfektionsrisiken werden bezogen auf Blutpraparate des Deutschen Roten Kreuzes mit 1:10,8 Millionen fur HCV, 1:4,3 Millionen fur HIV-1 und 1:360.000 fur Hepatitis-B-Viren (HBV) angegeben.

Background: Variant alleles of vitamin K epoxide reductase complex subunit 1 gene (VKORC1), the target molecule of vitamin K antagonists, and of cytochrome P450 (CYP) 2C9, an enzyme involved in coumarin metabolism, affect the anticoagulant response of coumarins, which have a narrow therapeutic window. Genotyping for these variants allows for prediction of therapeutic drug doses. The discussion of the clinical role of genotype-guided coumarin dosing is ongoing. For pharmacogenetic information to be useful, results must be available quickly. Methods: Here we report on the establishment of an allele-specific amplification (ASA)-PCR assay for the three most relevant polymorphisms for coumarin pharmacogenetics. The assay was validated against sequencing data on 100 random samples from Caucasian blood donors, incorporating all genotypes. Divergent results were confirmed by repeating the analysis with both methods. One hundred percent congruence with DNA sequencing was determined as the ‘pass’ criterion for the assay. Results: The ASA-PCR assay reproducibly identified the three informative single nucleotide polymorphisms. Discrepancies between ASA-PCR and sequencing were clarified by retrospective analysis as being due to erroneous analysis or documentation. In summary, the congruence of sequencing and duplex ASA-PCR was 100%. Conclusion: ASA-PCR is significantly faster and less expensive than sequencing. We expect that pharmaco-genetics-based dosing decisions may reduce the frequency of over- and undertreatment with vitamin K antagonists, especially during drug initiation, and thus improve patient safety.

Anticoagulation with vitamin K antagonists (VKAs) is problematic because of difficulties in safely managing dosing. Polymorphisms in cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase genes (VKORC1) have been shown to affect VKA dosing in adults. The association of these polymorphisms on VKA dosing in children has not been investigated. The objective of the study was to assess associations of CYP2C9 and VKORC1 polymorphisms and clinical variables on VKA dosing in children. A nonselected cohort of pediatric patients receiving VKA were tested for CYP2C9 and VKORC1 polymorphisms, and clinical data were collected. Multiple linear regression modeling was used to assess relationships of VKA dose with genetic and clinical variables. Fifty-nine patients were recruited; 55.9% were receiving warfarin, and 44.1% were on phenprocoumon. There was a negative association of age with VKA dose (P < .001). Comparing VKORC1 genotypes, the AA group required significantly lower daily doses than GG group (P = .011). In the full model including age, VKORC1 and CYP2C9 genotypes accounted for 38% of dose variation. Age explained 28.3% of VKA dose variations; VKORC1 and CYP2C9 explained only 3.7% and 0.4%, respectively. In children, the most critical factor in determining VKA dose is age. VKORC1/CYP2C9 genotypes only marginally explain dose variations.

Summary. Female carriers of haemophilia might suffer from increased bleeding tendency therefore the assessment of the bleeding risk is very important for improving care. This single-centre study documents the occurrence of bleedings in 46 carriers of haemophilia A including bleeding after tooth extraction (77%), easy bruising (67%), postsurgical bleeding (61%), menorrhagia (50%) or prolonged postpartum bleeding (43%). The F8 gene mutation of all 46 carriers (median age: 36.5 years, 15–80 years; mean FVIII:C activity: 59 ± 24.45%; normal range: 64–167%) was determined, and family history of haemophilia was recorded. For analysis, the bleeding tendency of the carriers was differentiated by severity into three groups. There was no statistically significant difference of FVIII:C between these groups. However, a correlation was found between the severity of bleeding tendency and the type of F8 gene mutation (P

BACKGROUND: The modulation of Factor (F)VIII activity (FVIII : C), von Willebrand factor antigen (VWF : Ag), and von Willebrand factor ristocetin cofactor (VWF : RCo) by the ABO(H) blood group is well established in adults. Expression of ABH antigens on N-linked glycans of VWF protects plasma VWF from proteolysis and clearance. Protection by H antigens is less effective than by AB antigens, resulting in approximately 25% lower VWF plasma levels in adults with blood group O compared to non-O. Given the reduced branching of ABO(H) bearing structures (I blood group system) with lower numbers of H, A, and B antigen sites during the first 18 months of life, we reasoned that if the relationship between ABO(H) blood group and VWF levels were causal, the difference of ABO(H) blood group–dependent VWF levels should be marginal or not be observed in the first months of life. STUDY DESIGN AND METHODS: We undertook quantification of FVIII : C and VWF in 574 presumably healthy children aged 1 to 210 months and correlated the values with ABO(H) blood type. Moreover, we establish reference intervals for common coagulation variables for several pediatric age groups. RESULTS: Significant differences between blood group O versus non-O values of FVIII : C, VWF : Ag, and VWF : RCo were not observed in the first months of life, started to develop during childhood, and in adolescence reached adult values. CONCLUSION: In comparison to the levels for adults and adolescents, we report fundamental differences of VWF levels in the first year of life, which may be associated with the physiologic development of the ABO(H) and I blood group system.

Background: Vitamin K deficiency is the major cause of coagulopathy-induced intracranial bleeding in term neonates and is considered first in any term neonate with severe hemorrhage. The most common manifestation of hereditary prothrombotic disorders during the neonatal period is thrombosis of the A. cerebri media or sinus thrombosis. Case Report: A 4-day-old newborn was admitted with seizures and hemorrhagic shock. Ultrasound revealed a left-sided intraparenchymatous bleeding. MRI findings supported a subarachnoidal and intracerebral mass bleeding. Vitamin K deficiency-related bleeding or hemophiliac diseases were excluded; however, homozygous protein S deficiency with a new mutation in the protein S (PROS1) gene (c.701A>G, p.Tyr234Cys) was found. The patient experienced an additional thrombosis of the A. abdominalis and expired. Conclusion: Congenital prothrombotic disorders have to be considered in the differential diagnosis of neonatal intracranial hemorrhage. This newly described mutation in the PROS1 gene (c.701A>G, p.Tyr234Cys) appears to be of clinical relevance.

BACKGROUND AND OBJECTIVES: Patient Blood Management (PBM) in Europe is a working group of the European Blood Alliance with the initial objective to identify the starting position of the participating hospitals regarding PBM for benchmarking purposes, and to derive good practices in PBM from the experience and expertise in the participating teams with the further aim of implementing and strengthening these practices in the participating hospitals.METHODS: We conducted two surveys in seven university hospitals in Europe: Survey on top indications for red blood cell use regarding usage of red blood cells during 1 week and Survey on PBM organization and activities.RESULTS: A total of 3320 units of red blood cells were transfused in 1 week at the seven hospitals. Overall, 61% of red cell units were transfused to medical patients and 36% to surgical patients, although there was much variation between hospitals. The organization and activities of PBM in the seven hospitals were variable, but there was a common focus on optimizing the treatment of bleeding patients, monitoring the use of blood components and treatment of preoperative anaemia.CONCLUSION: Although the seven hospitals provide a similar range of clinical services, there was variation in transfusion rates between them. Further, there was variable implementation of PBM activities and monitoring of transfusion practice. These findings provide a baseline to develop joint action plans to further implement and strengthen PBM across a number of hospitals in Europe.

SummaryFor decades coumarins have been the most commonly prescribed drugs for therapy and prophylaxis of thromboembolic conditions. Despite the limitation of their narrow therapeutic dosage window, the broad variation of intra- and inter-individual drug requirement, and the relatively high incidence of bleeding complications,prescriptions for coumarins are increasing due to the aging populations in industrialised countries.The identification of the molecular target of coumarins,VKORC1, has greatly improved the understanding of coumarin treatment and illuminated new perspectives for a safer and more individualized oral anticoagulation therapy. Mutations and SNPs within the translated and non-translated regions of the VKORC1 gene have been shown to cause coumarin resistance and sensitivity,respectively. Besides the known CYP2C9 variants that affect coumarin metabolism, the haplotype VKORC1*2 representing a frequent SNP within the VKORC1 promoter has been identified as a major determinant of coumarin sensitivity,reducingVKORC1 enzyme activity to 50% of wild type. Homozygous carriers of the VKORC1*2 allele are strongly predisposed to coumarin sensitivity. Using individualized dose adaptation, a significant reduction of bleeding complications can be expected, especially in the initial drug saturation phase. Furthermore, concomitant application of low dose vitamin K may significantly reduce intra-individual coumarin dose variation and, thus, may stabilize oral anticoagulation therapy. The use of new pharmacogenetics-based dosing schemes and the concomitant application of low-dose vitamin K with coumarins will decidedly influence the current practice of oral anticoagulation and greatly improve coumarin drug safety.

Background Ebola virus disease is a public health emergency of international concern, and enormous efforts are being made in the development of vaccines and therapies. Ebola virus convalescent plasma is a promising anti-infective treatment of Ebola virus disease. Therefore, we developed and implemented a pathogen-reduced Ebola virus convalescent plasma concept in accordance with national, European and global regulatory framework. Materials and Methods Ebola virus convalescent plasma manufacture and distribution was managed by a collection centre, two medical centres and an expert group from the European Blood Alliance. Ebola virus convalescent plasma was collected twice with an interval of 61 days from a donor recovering from Ebola virus disease in Germany. After pathogen reduction, the plasma was analysed for Ebola virus-specific immunoglobulin G (IgG) antibodies and its Ebola virus neutralizing activity. Results Convalescent plasma could be collected without adverse events. Anti-Ebola virus IgG titres and Ebola-specific neutralizing antibodies in convalescent plasma were only slightly reduced after pathogen reduction treatment with S59 amotosalen/UVA. A patient in Italy with Ebola virus disease was treated with convalescent plasma without apparent adverse effects. Discussion As proof of principle, we describe a concept and practical implementation of pathogen-reduced Ebola virus convalescent plasma manufacture, quality control and its clinical application to an Ebola virus disease patient.

The risk of viral transmission via transfusion of packed red blood cells in Germany has reached an all-time low. The reasons comprise the selection of donors and the screening for pathogens such as hepatitis C virus (HCV) or human immunodeficiency virus (HIV) by molecular and serological methods. Transmission of transfusion-relevant viruses via blood products is nowadays a rare event, found only in isolated cases (1). For example, since the introduction of mandatory HCV-PCR (polymerase chain reaction) in Germany in 1999, there has been one single case of transfusion-related HCV transmission in 16 years. At an annual rate of about 4 million units of packed red cells, over 60 million units were transfused in this period (1). Modern production methods using closed blood bag systems and “inline” leukocyte depletion also contribute towards the safety of modern blood products. All steps of production are subject to quality controls to ensure good manufacturing practice (GMP). The use of blood preparations is closely regulated by: European Union directives The German Transfusion Act (TFG; [2]) The German Medical Association (GMA) guidelines on collection of blood and blood components and use of blood products (hemotherapy) (3) The “Cross-Sectional Guidelines for Therapy with Blood Components and Plasma Derivatives“ of the Scientific Advisory Board of the GMA (4). Safety The risk of viral transmission via transfusion of packed red cells in Germany has reached an all-time low. Transmission of transfusion-relevant viruses via blood products is nowadays a rare event. Germany as well as other member states of the European Union have carried EU directives over into their own laws and guidelines, so that these regulations and recommendations are largely similar in EU member states. Nevertheless, in English-speaking countries, for example, the bedside test and certain laboratory tests are not mandatory, but there is a compulsory ID check by means of the patient’s wrist band.

Congenital combined deficiency of the vitamin-K-dependent coagulation factors (VKCFD) represents a rare autosomal recessive inherited bleeding disorder caused by mutations in either the gamma-glutamyl carboxylase gene (VKCFD type 1) or the vitamin K epoxide reductase gene (VKCFD type 2). Four different mutations of the gamma-glutamyl carboxylase gene (GGCX) have so far been reported in three unrelated patients with VKCFD type 1. Here we report on a fourth patient who presented with two compound heterozygous missense mutations of the GGCX gene, His404Pro and Arg485Pro. The His404Pro mutation has not been described previously, while the Arg485Pro mutation has been reported in another compound heterozygous VKCFD type 1 patient from Germany. Most interestingly, haplotype analysis revealed that Arg485Pro is due to a founder mutation, suggesting that this mutation is present in the German population at some low frequency. The founder mutation explains that the only two compound heterozygous VKCFD type 1 patients known today originated from Germany.

SummaryFactorVIII acts as an essential compound of the tenase complex of the coagulation system. Herein we report the cDNA of the rat factor VIII. The rat cDNA comprises 6777 nucleotides and encodes a protein of 2258 amino acids, 61 amino acids less than mouse and 92 amino acids less than human factor VIII. The overall identity compared to human cDNA is 61% on the cDNA and 51% on the amino acid level. In cDNA, highest levels of sequence identity can be observed in the A and C domains (ranging between 68% and 73%), whereas B domain and the small acidic regions are more divergent (34%-49%). Compared to mouse and human most sites for posttranslational modifications such as sulfatation and glycosylation as well as thrombin and protein C cleavage sites are conserved in rat. Alternative transcripts lacking exon 17 and/or comprising additional 26 bp due to alternative splicing of exon 20 were found. Furthermore, 13 polymorphisms (seven in exon 14, one in exon 20, 23, 24, and 25, two in the 3’UTR) three of which lead to an amino acid exchange could be detected. Our findings might provide new insights into the structure-function analysis of the factor VIII protein and might prove useful for future animal models addressing the function of factor VIII.