IntroductionAllogeneic serum from blood donors is starting to be used to treat patients with dry eye disease (DED). However, the optimal dose is not known. We therefore aimed to evaluate the... Show moreIntroductionAllogeneic serum from blood donors is starting to be used to treat patients with dry eye disease (DED). However, the optimal dose is not known. We therefore aimed to evaluate the clinical efficaciousness and user-friendliness of micro-sized versus conventional-sized allogeneic serum eye drops (SEDs).MethodsIn a randomized trial, patients with DED first receive micro-sized SEDs (7 mu l/unit) for 1 month, followed by a 1-month washout, before receiving conventional-sized SEDs (50 mu l/unit) for 1 month; or vice versa. The primary endpoint was the Ocular Surface Disease Index (OSDI) score. Secondary endpoints were tear break-up time (TBT), tear production (TP), and presence of corneal punctate lesions (CP). The user-friendliness of both application systems was also compared. A linear mixed model for cross-over design was applied to compare both treatments.ResultsForty-nine patients completed the trial. The mean OSDI score significantly improved from 52 +/- 3 to 41 +/- 3 for micro-sized SEDs, and from 54 +/- 3 to 45 +/- 3 for conventional-sized SEDs. Non-inferiority (margin = 6) of micro-sized SEDs was established. We demonstrate a significant improvement for TBT in case of conventional-sized SEDs and for CP in both treatment groups. TP trended towards an improvement in both treatment groups. The user-friendliness of the conventional drop system was significantly higher.ConclusionsFor the first time, non-inferiority of micro-sized allogeneic SEDs was established. The beneficial effect of both SED volumes was similar as measured by the OSDI score. Although user-friendliness of the micro drop system was significantly lower, it is an attractive alternative as it saves valuable donor serum.Trial RegistrationClinicalTrials.gov (NCT03539159). Show less
Background The formation of alloantibodies directed against class I human leukocyte antigens (HLA) continues to be a clinically challenging complication after platelet transfusions, which can lead... Show moreBackground The formation of alloantibodies directed against class I human leukocyte antigens (HLA) continues to be a clinically challenging complication after platelet transfusions, which can lead to platelet refractoriness (PR) and occurs in approximately 5%-15% of patients with chronic platelet support. Interestingly, anti-HLA IgG levels in alloimmunized patients do not seem to predict PR, suggesting functional or qualitative differences among anti-HLA IgG. The binding of these alloantibodies to donor platelets can result in rapid clearance after transfusion, presumably via Fc gamma R-mediated phagocytosis and/or complement activation, which both are affected by the IgG-Fc glycosylation. Objectives To characterize the Fc glycosylation profile of anti-HLA class I antibodies formed after platelet transfusion and to investigate its effect on clinical outcome. Patients/Methods We screened and captured anti-HLA class I antibodies (anti-HLA A2, anti-HLA A24, and anti-HLA B7) developed after platelet transfusions in hemato-oncology patients, who were included in the PREPAReS Trial. Using liquid chromatography-mass spectrometry, we analyzed the glycosylation profiles of total and anti-HLA IgG1 developed over time. Subsequently, the glycosylation data was linked to the patients' clinical information and posttransfusion increments. Results The glycosylation profile of anti-HLA antibodies was highly variable between patients. In general, Fc galactosylation and sialylation levels were elevated compared to total plasma IgG, which correlated negatively with the platelet count increment. Furthermore, high levels of afucosylation were observed for two patients. Conclusions These differences in composition of anti-HLA Fc-glycosylation profiles could potentially explain the variation in clinical severity between patients. Show less
Ypma, P.F.; Geloven, N. van; Kerkhoffs, J.L.H.; Boekhorst, P. te; Zwaginga, J.J.; Beckers, E.A.M.; ... ; Eikenboom, J.C.J. 2019
In daily haematological practice, predicting bleeding in thrombocytopenic patients is difficult, and clinicians adhere to transfusion triggers to guide patients through the aplastic phase of... Show moreIn daily haematological practice, predicting bleeding in thrombocytopenic patients is difficult, and clinicians adhere to transfusion triggers to guide patients through the aplastic phase of chemotherapy. Platelet count is not the only determinant of bleeding and additional mechanisms for impending haemostasis are likely. Beside clot formation, platelets are essential for the maintenance of integrity of vascular beds. We therefore prospectively investigated associations between biomarkers for endothelial damage (urine albumin excretion) and inflammation (C-reactive protein) and bleeding (WHO grading) in 88 patients with 116 on-protocol episodes. We found an increase in grade 2 bleeding with a higher urine albumin/creatinine ratio one day after the measurement [odds ratio (OR) 1·24 for every doubling of the ratio, 95% CI 1·05-1·46, P-value 0·01] and a 29% increase in the odds of grade 2 bleeding for every doubling of serum C-reactive protein (CRP) (95% CI 1·04-1·60, P-value 0·02) after correction for morning platelet count. The 24 h post-transfusion corrected count increment (CCI24 ) showed a significant association with these biomarkers: increasing urine albumin/creatinine ratio and CRP were associated with lower CCI24. We report two inexpensive and easy-to-apply biomarkers that could be useful in designing a prediction model for bleeding risk in thrombocytopenic patients Show less
Hout, F.M.A. van; Middelburg, R.A.; Meer, P.F. van der; Pors, A.; Wiersum-Osselton, J.C.; Schipperus, M.R.; ... ; Bom, J.G. van der 2019
BACKGROUND Reports on the clinical consequences of longer storage time of platelet concentrates are contradictory. The objective of this study was to assess whether longer storage times are... Show moreBACKGROUND Reports on the clinical consequences of longer storage time of platelet concentrates are contradictory. The objective of this study was to assess whether longer storage times are associated with a higher risk of transfusion reactions. STUDY DESIGN AND METHODS We gathered storage times of pooled platelet concentrates related to transfusion reactions reported to the national hemovigilance office from 2004 to 2015. These were combined with storage times of platelet concentrates in the reference population to compare incidences of transfusion-associated circulatory overload, transfusion-related acute lung injury, allergic reactions, febrile nonhemolytic reactions, and "other" reactions between storage time categories. RESULTS A total of 567,053 platelet concentrates and 1870 transfusion reactions were analyzed. Among platelet additive solution (PAS)-B platelet recipients, the odds ratio of a storage time of 4 to 5 days compared to 1 to 3 days was 1.60 (95% confidence interval [CI], 1.17-2.18) for allergic, and 1.47 (1.09-1.98) for febrile reactions. For PAS-C platelet recipients, the odds ratio for allergic reactions was 3.78 (95% CI, 1.31-10.9) for 4 to 5 days, and 4.57 (95% CI, 1.57-13.4) for 6- to 7-day-old platelets when compared to 1- to 3-day-old units. In all other studied reaction types, no statistically significant association was observed in platelets in plasma, PAS-B, and PAS-C. CONCLUSIONS In plasma platelets, longer storage time was not associated with a higher incidence of transfusion reactions. In PAS platelets, longer storage time was associated with higher transfusion reaction incidences, in particular for allergic reactions with both PAS fluids and febrile reactions with PAS-B. This indicates that the effect of storage time is different for different reaction types and depends on the storage fluid. Show less
Saris, A.; Kreuger, A.L.; Brinke, A. ten; Kerkhoffs, J.L.H.; Middelburg, R.A.; Zwaginga, J.J.; Meer, P.F. van der 2019
Patients refractory to platelet transfusions because of alloimmunization require HLA-matched platelets, which is only possible if a large HLA-typed donor pool is available. However, even then,... Show morePatients refractory to platelet transfusions because of alloimmunization require HLA-matched platelets, which is only possible if a large HLA-typed donor pool is available. However, even then, patients with broad immunization or rare haplotypes may not have suitable donors. In these patients, transfusions with platelets showing low HLA class I expression may be an alternative to fully HLA-matched transfusions. In this study, we quantified the proportion of donors with consistently low HLA-B8, -B12, and -B35 expression on platelets using human monoclonal antibodies specific for these antigens. Furthermore, as model for in vivo clearance, antibody-mediated internalization of these platelets by macrophages was investigated. The expression of HLA-B8, -B12, or -B35 on platelets was extremely variable between individuals (coefficients of variation, 41.4% to 73.6%). For HLA-B8, but not for HLA-B12 or -B35, this variation was in part explained by zygosity. The variation was most pronounced in, but not exclusive to, platelets. Expression within one donor was consistent over time. Remarkably, 32% of 113 HLA-B8, 34% of 98 HLA-B12, and 9% of 66 HLA-B35 donors showed platelet antigen expression that was not or only minimally above background. Antibody-mediated internalization of platelets by macrophages correlated with antibody opsonization and antigen expression and was absent in platelets with low or minimal HLA expression. In conclusion, our findings indicate that a substantial proportion of donors have platelets with consistently low expression of specific HLA class I antigens. These platelets may be used to treat refractory patients with antibodies directed against these particular antigens, despite HLA mismatches. Show less
Saris, A.; Tomson, B.; Brand, A.; Mulder, A.; Claas, F.H.; Lorinser, J.; ... ; Meer, P.F. van der 2018
