Rutger A. Middelburg

Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study

The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations.

The role of donor antibodies in the pathogenesis of transfusion-related acute lung injury: a systematic review

BACKGROUND: The majority of cases of transfusion‐related acute lung injury (TRALI) are thought to be caused by the presence of leukocyte antibodies in the blood of the donor. We performed a systematic search of the literature to quantify the contribution of donor antibodies to the occurrence of TRALI.

Blood transfusions: good or bad? Confounding by indication, an underestimated problem in clinical transfusion research.

C onfounding by indication is a serious potential problem in clinical observational research and can easily lead to unjustified conclusions, as has also been described previously. In transfusion medicine such a conclusion could be “blood transfusions kill,” since patients receiving more transfusions are almost invariably more likely to die. Even though most would agree that blood transfusions save lives, this erroneous conclusion did find its way into the literature. Although this example might seem overly obvious, confounding by indication can be indirect and much more subtle and difficult to detect. It is therefore of the utmost importance to thoroughly understand the nature of confounding by indication, to be able to recognize it and avoid unjustified conclusions. We introduce the problem of confounding by indication with examples from clinical transfusion research and provide a general explanation to help identify this form of bias in the literature and in the every day clinical research settings (for guidelines on detection and handling, see Table 1).

Male‐only fresh‐frozen plasma for transfusion‐related acute lung injury prevention: before‐and‐after comparative cohort study

BACKGROUND: Transfusion‐related acute lung injury (TRALI) is one of the most serious complications of blood transfusion. It can be caused by incompatible white blood cell antibodies in transfused plasma. The objective of this study was to quantify the reduction of TRALI after introduction of male‐only plasma for transfusion as a preventive measure, which took effect in 2007.

Prevalence of leucocyte antibodies in the Dutch donor population

Introduction  Donor leucocyte antibodies have been associated with transfusion‐related acute lung injury (TRALI) and can be present in allo‐exposed donors. Donor deferral policies aiming at excluding allo‐exposed donors are increasingly implemented worldwide. We aimed at assessing the prevalence of leucocyte antibodies in different subgroups of allo‐exposed donors in the Dutch donor population.

Storage time of blood products and transfusion-related acute lung injury.

BACKGROUND: Besides white blood cell antibodies in plasma‐rich products, another cause of transfusion‐related acute lung injury (TRALI) could be release of biologically active substances during storage of cellular blood products. We aimed to investigate the association of storage time and risk of TRALI for different product types.

Storage Time of Red Blood Cells and Mortality of Transfusion Recipients

Storage of red cells and the associated storage lesion have been suggested to contribute to adverse clinical outcomes. The aim of this study was to investigate whether increasing storage time of red cells is associated with mortality of recipients. From all patients who received red cell transfusions between January 2005 and May 2009, in the Leiden University Medical Center, we selected those who received only-young or only-old red cells, defined as below or above the median storage time. Mortality was compared in a Cox regression model. Subsequently, similar comparisons were made between subgroups with increasing contrast between old and young red cells. Among adult patients, after correction for potential confounders, the hazard ratio of death within 1 year after receiving red cells stored for more than 17 days compared with 17 days or less was 0.98 (95% confidence interval, 0.83-1.2). With increasing contrast, the hazard ratio decreased to 0.56 (95% confidence interval, 0.32-0.97) for red cells stored for more than 24 days compared with less than 10 days. In contrast to what has previously been suggested, we find an almost 2-fold increase in mortality rate after the transfusion of fresh red cells compared with old red cells. Results dependent on analyses chosen and previous studies may not have used optimal analyses. The tendency to demand ever-fresher blood could actually be detrimental for at least some patient groups.

Female donors and transfusion-related acute lung injury: A case-referent study from the International TRALI Unisex Research Group

BACKGROUND: Although quantitative evidence is lacking, it is generally believed that the majority of cases of transfusion‐related acute lung injury (TRALI) are caused by female blood donors. We aimed to examine the relation between female donors and the occurrence of TRALI.

Flow cytometric assessment of agonist-induced P-selectin expression as a measure of platelet quality in stored platelet concentrates

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.

Intensive red blood cell transfusions and risk of alloimmunization.

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.