Is it possible to make a common reference standard for D-dimer measurements? Communication from the ISTH SSC Subcommittee on Fibrinolysis

Background D-dimer antigen is a heterogeneous mixture of fibrin degradation products that when present at high levels in plasma indicate ongoing coagulation and fibrinolysis. The heterogeneous nature of the target D-dimer antigen and the variety of assay systems means that it is difficult to compare results from different methods. Objectives To identify a universally agreed D-dimer standard that could help harmonize results from different methods. Methods A pool of patient plasma with high D-dimer levels was freeze-dried and investigated as a long-term World Health Organization international standard for D-dimer. Fibrin degradation products from clot lysis reactions were also freeze-dried in various formulations and investigated in commutability studies with patient plasma. Results Problems of instability of D-dimer plasma emerged suggesting loss of reactivity after freeze-drying and storage at -20 degrees C of 10%-18% per year. Freeze-dried fibrin degradation products added to plasma were also unstable, but the sugar trehalose was found to improve stability. However, this preparation was not suitable as a standard in widely used assay platforms. Previous studies suggest fibrin degradation products are prone to structural rearrangements and amyloid formation, which may explain the instability of candidate D-dimer standards. Conclusions The known difficulties of D-dimer standardization are compounded by instability of D-dimer antigen after freeze-drying, described in this report. Fibrin degradation products added to plasma and stabilized by trehalose are not suitable as a standard for D-dimer measurement harmonization. Trehalose stabilization of pooled patient plasma containing high D-dimer levels may produce a useful standard, but this requires confirmation.