79 Comparing FVIII concentration and activity FVIII product to a haemophilia A patient, or after a high stress test in a volunteer. This would allow investigating the intra-patient variability, potential loss of activity over time and mutated FVIII molecules. Another recommendation for future research is to conduct a study with different types of FVIII products and different batches per FVIII product that are reconstituted, not only with FVIII-deficient plasma (as human material might contain FVIII fragments) but also with solvents (e.g., NaCl 0.9%) to compare OSA, CSA and LC-MS/MS results over time. Since the LC-MS/MS method was development with one FVIII product, the method would benefit from studying multiple product types and batches e.g., to compare different activation rates. Major advantages of LC-MS/MS measuring is the possibility to elucidate the discrepancies between OSA and CSA in different patient populations, to distinguish between neutralizing and clearing anti-FVIII antibodies, and to determine the FVIII concentration variation in the normal population. Other advantages with more clinical implications for the future, are that LC-MS/MS offers the opportunity to patient-friendly telemonitoring (with dried blood spot) facilitating blood sampling from home and a patient-friendly sampling volume, which could be used in neonatal diagnostic screening as 50μl would suffice. In the future, the possibility of mass spectrometry-based techniques to measure multiple samples in one run could be exploited by the combined measurement of multiple clotting and anticlotting factors, thus constructing a personal haemostasis profile and bleeding score [26]. CONCLUSION Despite a strong overall correlation between the two methods, the relative differences between measured FVIII activity and FVIII plasma concentration in individual samples were large, especially in case of the presence of anti-FVIII antibodies or use of exogenous FVIII products. These differences may have impact on clinical decision making regarding diagnosing disease severity and monitoring the treatment of FVIII products. Further research is needed to determine the value of FVIII plasma concentration measurements in comparison with the FVIII activity measurements. Author’s contribution AD designed the study, performed data management, analysis and validation, prepared the first draft of the manuscript, and implemented significant contribution from coauthors up to the final publication. Throughout the process, AD asked and implemented input and feedback from supervision team and co-authors, who performed critical review of the manuscript and provided significant contributions to the study. 4
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