Center for Clinical Transfusion Research

Leiden, Netherlands

Center for Clinical Transfusion Research

Leiden, Netherlands
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Gouw S.C.,Wilhelmina Childrens Hospital | Gouw S.C.,University Utrecht | Van Der Bom J.G.,Leiden University | Van Der Bom J.G.,Center for Clinical Transfusion Research | And 13 more authors.
New England Journal of Medicine | Year: 2013

BACKGROUND: For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development). METHODS: We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels. RESULTS: Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. CONCLUSIONS: Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience). Copyright © 2013 Massachusetts Medical Society.

Mostofsky E.,Beth Israel Deaconess Medical Center | Mostofsky E.,Harvard University | Van Der Bom J.G.,Leiden University | Van Der Bom J.G.,Center for Clinical Transfusion Research | And 7 more authors.
Epidemiology | Year: 2015

Background: Habitual moderate alcohol consumption is associated with a lower risk of acute myocardial infarction (MI), whereas heavy (binge) drinking is associated with higher cardiovascular risk. However, less is known about the immediate effects of alcohol consumption on the risk of acute MI and whether any association differs by beverage type or usual drinking patterns.Methods: We conducted a case-crossover analysis of 3869 participants from the Determinants of Myocardial Infarction Onset Study who were interviewed during hospitalization for acute MI in one of the 64 medical centers across the United States in 1989-1996. We compared the observed number of times that each participant consumed wine, beer, or liquor in the hour preceding MI symptom onset with the expected frequency based on each participant's control information, defined as the number of times the participant consumed alcohol in the past year.Results: Among 3869 participants, 2119 (55%) reported alcohol consumption in the past year, including 76 within 1 hour before acute MI onset. The incidence rate of acute MI onset was elevated 1.72- fold (95% confidence interval [CI] = 1.37-2.16) within 1 hour after alcohol consumption. The association was stronger for liquor than for beer or wine. The higher rate was not apparent for daily drinkers. For the 24 hours after consumption, there was a 14% lower rate (relative risk = 0.86 [95% CI = 0.79-0.95]) of MI compared with periods with no alcohol consumption.Conclusions: Alcohol consumption is associated with an acutely higher risk of MI in the subsequent hour among people who do not typically drink alcohol daily. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Middelburg R.A.,Center for Clinical Transfusion Research | Roest M.,Leiden University | Ham J.,Leiden University | Coccoris M.,Leiden University | And 2 more authors.
Transfusion | Year: 2013

Background Platelet (PLT) function in PLT concentrates declines during storage and is further affected by pathogen reduction treatment. Flow cytometric assessment of agonist-induced P-selectin expression can be used to assess PLT function in patients with thrombocytopenia. The aim of this study was to evaluate how this functional test relates to established in vitro measures of PLT function. Study Design and Methods Six units of PLTs in plasma and 6 units of riboflavin and ultraviolet (Mirasol, TerumoBCT)-treated PLTs in plasma were sampled on Days 2, 6, 8, and 10 after donation. PLT concentration, Annexin 5A staining, ThromboLUX (LightIntegra) thrombelastography, and P-selectin expression, both in unstimulated PLTs and in response to concentration series of adenosine diphosphate, collagen-related peptide, and thrombin receptor-activating peptide (TRAP), were measured. Results For PLTs in plasma Annexin 5A expression increased by 0.60% (95% confidence interval [CI], 0.40%-0.80%) and P-selectin expression increased by 1.2% (95% CI, 0.80%-1.6%) per day. Responsiveness to TRAP simultaneously decreased by 1.3% (95% CI, 0.80%-1.8%) per day. After Mirasol treatment ThromboLUX scores decreased 3.3 points (95% CI, 0.2-6.4 points) from 22 to 19 points, Annexin 5A expression increased by 4.8% (95% CI, 3.3%-6.2%), and P-selectin expression increased by 13% (95% CI, 10%-16%), all averaged over the entire storage period. Responsiveness to TRAP simultaneously decreased by 19% (95% CI, 17%-21%). Conclusions Our results suggest flow cytometric measurement of agonist-induced P-selectin expression can measure PLT quality decline over the entire range encountered during 10-day storage of both standard PLTs and Mirasol-treated PLTs in plasma. © 2012 American Association of Blood Banks.

Melief S.M.,Leiden University | Zwaginga J.J.,Leiden University | Zwaginga J.J.,Center for Clinical Transfusion Research | Fibbe W.E.,Leiden University | Roelofs H.,Leiden University
Stem Cells Translational Medicine | Year: 2013

Adipose tissue-derived multipotent stromal cells (AT-MSCs) are studied as an alternative to bone marrow-derived multipotent stromal cells (BM-MSCs) for immunomodulatory treatment. In this study, we systematically compared the immunomodulatory capacities of BM-MSCs and AT-MSCs derived from age-matched donors. We found that BM-MSCs and AT-MSCs share a similar immuno-phenotype and capacity for in vitro multilineage differentiation. BM-MSCs and AT-MSCs showed comparable immunomodulatory effects as they were both able to suppress proliferation of stimulated peripheral blood mononuclear cells and to inhibit differentiation of monocyte-derived immature dendritic cells. However, at equal cell numbers, the AT-MSCs showed more potent immunomodulatory effects in both assays as compared with BM-MSCs. Moreover, AT-MSCs showed a higher level of secretion of cytokines that have been implicated in the immunomodulatory modes of action of multipotent stromal cells, such as interleukin-6 and transforming growth factor-/!1. This is correlated with higher metabolic activity of AT-MSCs compared with BM-MSCs. We conclude that the immunomodulatory capacities of BM-MSCs and AT-MSCs are similar, but that differences in cytokine secretion cause AT-MSCs to have more potent immunomodulatory effects than BM-MSCs. Therefore, lower numbers of AT-MSCs evoke the same level of immunomodulation. These data indicate that AT-MSCs can be considered as a good alternative to BM-MSCs for immunomodulatory therapy. © AlphaMed Press 2013.

Hogervorst E.,Center for Clinical Transfusion Research | Middelburg R.,Center for Clinical Transfusion Research | Middelburg R.,Leiden University | Brand A.,Leiden University | And 2 more authors.
Transfusion | Year: 2015

Background The formation of red blood cell (RBC) antibodies could be enhanced by the presence of inflammation caused by prolonged RBC storage, as was shown in animal studies. The low occurrence (<10%) of K-antigen in most populations often enables identification of the K+ RBC unit that triggered anti-K formation and determination of its storage time. This study aims to quantify the association of anti-K formation with RBC storage time. Study Design and Methods K- patients who had not been previously transfused and received at least 1 K+ unit between January 2004 and August 2013 were identified. First, the influence of storage time of the K+ units was assessed as mean, maximum, and minimum storage times within one transfusion interval and at various cutoff points for old versus young blood (14, 18, and 21 days). Second, concomitantly transfused K- units were studied within different periods surrounding the K+ unit(s). Results Twenty-three patients formed anti-K, while 274 patients did not. The adjusted relative risks of anti-K formation for mean, maximum, and minimum storage time (days) ranged from 1.01 to 1.03 (95% confidence interval, 0.96-1.08). When analyzing the association between only "younger" and only "older" K+ units at various cutoff points, no association was found. Similarly, no association was found between storage time of the concomitantly transfused K- units and anti-K formation. Conclusion Within the range of storage times used in normal clinical practice in the Netherlands, no association could be found between RBC storage time and anti-K formation. © 2015 AABB.

Zalpuri S.,Center for Clinical Transfusion Research | Middelburg R.A.,Center for Clinical Transfusion Research | Schonewille H.,Center for Clinical Transfusion Research | De Vooght K.M.K.,Center for Clinical Transfusion Research | And 3 more authors.
Transfusion | Year: 2014

Background Exposure to allogenic red blood cells (RBCs) may lead to formation of antibodies against nonself-antigens in transfused patients. While alloimmunization rates are known to increase with the number of transfusions, the transfusion course in patients can vary from receiving multiple units during a single transfusion event or getting them dispersed over a long(er) period. In this study we compared the immunization risk between different transfusion intensities. Study Design and Methods An incident new-user cohort study was conducted among consecutive transfused patients at two university medical centers. All patients who received their first RBC transfusion within the study period from January 2005 to December 2011 were eligible. Intensive transfusions were defined as at least 5, at least 10, and at least 20 RBC units within 48 hours. Alloimmunization hazard ratios (HRs), comparing patients receiving intensive transfusions to patients never receiving intensive transfusions, were estimated. Results The study cohort was composed of 5812 patients who had received a median of 7 (interquartile range, 4-12) units. RBC alloantibodies were formed by 156 patients. The adjusted Cox regression HRs for alloimmunization, with number of units as the time covariate and adjusted for patient age, sex, and follow-up time after first transfusion, ranged from 0.8 to 1.2 (95% confidence interval, 0.4-2.6). Conclusion The occurrence of RBC alloimmunization in patients receiving intensive transfusions did not differ significantly from patients receiving nonintensive transfusions. © 2013 American Association of Blood Banks.

Schonewille H.,Center for Clinical Transfusion Research | Schonewille H.,Leiden University | Doxiadis I.I.N.,Leiden University | Levering W.H.B.M.,Laboratory for Histocompatibility and Immunogenetics | And 3 more authors.
Transfusion | Year: 2014

Background A minority of red blood cell (RBC) alloantigen-exposed persons form antibodies. Responders are at high risk of developing additional antibodies upon subsequent transfusions. Several studies showed an association between particular HLA-DRB1 phenotypes and the development of specific RBC antibodies. This study evaluates the presence of HLA-DRB1 antigens in individuals with single or multiple RBC antibody specificities to explore whether the response against RBC antigens is associated with a summation of particular HLA-DRB1 susceptibility antigens. Study Design and Methods Frequencies of HLA-DRB1 alleles in individuals with antibodies against clinically relevant antigens were compared to a large population cohort to calculate odds ratios (ORs) for alloimmunization to different RBC antigens. Results The study cohort consisted of 941 individuals (female-to-male ratio, 3.8) possessing 1462 antibody specificities elicited by transfusion, pregnancy, transplantation, or a combination of these. Besides confirmation of known associations, new associations were identified for anti-E with DRB109 and for anti-S with DRB107 (ORs, 3.7 and 8.7, respectively). Multiple antibody formation was in a minority of cases associated with the presence of multiple DRB1 susceptibility genes. In multiple responders DRB115 was present in almost 40% of cases compared to approximately 25% in single-antibody responders and in the control population. Conclusion This study suggests that HLA-DRB1 restriction plays an important role for a first RBC antibody response but multiple antibody formation seems less dependent on the presence of particular HLA restriction genes, while HLA-DRB115 may represent a susceptibility phenotype enhancing formation of multiple RBC antibody specificities. © 2014 AABB.

van Velzen A.S.,Emma Childrens Hospital | Peters M.,Emma Childrens Hospital | van der Bom J.G.,Center for Clinical Transfusion Research | van der Bom J.G.,Leiden University | Fijnvandraat K.,Emma Childrens Hospital
British Journal of Haematology | Year: 2014

This systematic review was designed to summarize the reported valid quantitative evidence on the association between use of von Willebrand factor (VWF)-containing Factor VIII (FVIII) concentrates and successful immune tolerance induction (ITI) in patients with severe haemophilia A. The primary outcome was successful ITI; secondary outcomes were time to success, complications of the inhibitor or ITI and relapse of the inhibitor. A systematic literature search identified 26 randomized controlled trials, registries and cohort studies, evaluating a total of 1284 patients. For a pooled meta-analysis, 13 studies evaluating 382 patients were included. Due to incomplete data we were not able to assign pre-ITI risk categories to all patients for risk factor analysis. The meta-analysis did not demonstrate a difference in the proportion of patients with successful inhibitor eradication between those treated with VWF-containing products and those treated with FVIII concentrates devoid of VWF (relative risk [RR] 0·70 (95% confidence interval [CI] 0·52-0·89) and 0·84 (95% CI 0·75-0·93) respectively). Bleeding rate during ITI ranged from 0·00 to 0·85 bleeding episodes per year. The proportion of patients with a relapse of the inhibitor (range 0-20%) was mentioned in four studies that were included in the meta-analysis. The results of this systematic review do not support the idea of a positive effect of VWF-containing products in ITI. © 2014 John Wiley & Sons Ltd.

Middelburg R.A.,Center for Clinical Transfusion Research | Middelburg R.A.,Leiden University | Van Der Bom J.G.,Center for Clinical Transfusion Research | Van Der Bom J.G.,Leiden University
Transfusion | Year: 2015

Background: The etiology of transfusion-related acute lung injury (TRALI) is often referred to as a "two-hit model," the first hit being patient predisposition and the second being a transfusion. This model lumps all patient-related risk factors together and thereby may hamper identification of individual, potentially preventable or modifiable risk factors. Study design and methods Like any disease, TRALI is multicausal in nature. To be able to effectively scrutinize all contributing causes, we need to clearly describe this multicausality as completely as possible. Several models are already commonly used to describe the multicausality of other diseases, including threshold models and the sufficient cause model. Results: Here we describe the application of two different multicausal models to TRALI. These models can readily describe any potential scenario for the etiology of TRALI. First we will introduce the intuitively appealing threshold model, which shows some similarities with the Bux and Sachs threshold model for TRALI. Second we discuss the more abstract sufficient cause model. Conclusions Both models have their strengths and limitations. Both are, however, better equipped than the two-hit model to describe the multicausal nature of TRALI. Further identification of all involved risk factors and the complex interplay between them is facilitated by these models. © 2014 AABB.

Van De Watering L.M.G.,Center for Clinical Transfusion Research
Current Opinion in Hematology | Year: 2013

PURPOSE OF REVIEW: Possible adverse effects of prolonged storage of red blood cell concentrates (RBCs) are being formally assessed both by observational studies and in randomized controlled trials. New mechanisms have been put forth to explain earlier conflicting observations. This review summarizes ongoing investigations into clinical and basic science studies on RBC storage effects. RECENT FINDINGS: Research into possible deleterious clinical effects of prolonged storage of RBCs has explored the contribution of various RBC production aspects (e.g. overnight hold, centrifugation speed, storage solution), seldom previously reported. Other studies investigated putative underlying mechanisms like free iron, inflammation, cytokines, and so on. Many publications include multiple analyses, like different cut-off values for 'old', or taking into account both oldest and average RBC storage time. Also, more studies correct for possible confounding effects to get a better estimate of associations. An alarming and ironic observation is that several studies found higher risks with fresh RBCs after correction for confounding. The results from the first large randomized controlled trials show no differences between old and fresh RBCs. SUMMARY: We still do not know whether older red cells have adverse effects, and if so, what determines such clinical effects after transfusion of 'old' RBCs. RBC production factors, previously seldom reported, may play an important role and should be reported.© 2013 Wolters Kluwer Health Lippincott Williams & Wilkins.

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