George and Dr. Louann Lawrence have been communicating with a patient through the ASCLS Consumer Web Forum who experienced a DVT and PE in 2014 and has been on Xarelto since then. Her physician routinely orders a D-dimer to assess the risk of a recurrence after discontinuing Xarelto. The patient stops Xarelto for 24 hours before specimen collection, but each time the D-dimer result is around 800 ng/mL, reference limit 240 ng/mL, so she resumes therapy. She has since had her D-dimer performed at another facility using an alternate technology, yielding a result of 230 ng/mL, within the reference interval. She subsequently had a D-dimer performed at a reference laboratory and the results are normal, yet her D-dimer remains elevated to approximately 800 ng/mL when measured at the original site. What could be causing this large difference?
Added April 16, 2016. George attended the Thrombosis and Hemostasis Summit of North America in Chicago, and was able to present this problem to several experts. Dean Willett of Instrumentation Laboratory, Inc sent a reference illustrating the various plasma components that may interfere differentially with the various D-dimer assays. Thay are lipemia, rheumatoid factor, hemolysis, human anti-mouse antibody, and parallel fibrin degradation products. Bob Gosselin, UC Davis, agrees, and confirms that Xarelto would be unlikely to associate with a raised D-dimer. All agreed this was a technique-specific interference issue.
For this patient, George recommended reflexing to a manual ELISA technique, the D-dimer reference technology, which may provide an opportunity to control for interfering substances.
While we are on the topic of
While we are on the topic of D-dimer harmonization, more self-promotion: Lippi et al. International survey on d-dimer test reporting: a call for standardization. Semin Thromb Hemost. 2015;41:287–93; and Longstaff et al. Harmonisation of D-dimer–A call for action. Thromb Res. 2016;137:219–20. There are at least 28 different combinations of measurement units in place!
Thanks to Dr. Low for her
Thanks to Dr. Low for her comment. There are a number of formats for D-dimer reporting and a number of ways to express reference interval limits. I wrote this to the patient whom we are helping: “laboratory medicine experts are painfully aware that D-dimer reporting varies by institution and constantly (but so far unsuccessfully) call for “harmonization.” D-dimer is reported in ng/mL, g/mL, mg/L, g/L, ug/L, and ug/mL; also in “D-dimer units” and “fibrinogen equivalent units.” This sort of thing happens when manufacturers each develop their own assay kit and assign their own units. The key to interpretation is the “decision limit,” also called the “cutoff,” “action limit,” or the “upper limit of the reference interval.” The results we reviewed with the patient were compared to the reference interval limits in each case, however no facilities were using age-related limits, as Dr. Low suggests. Meanwhile, I would like to find a lab that performs an enzyme immunoassay-based D-dimer that is less prone to interference.
I am coming into this
I am coming into this discussion rather late, but I find it interesting that the discussion is being held without actually mentioning the actual D-dimer methods being used by the various laboratories, it being well known (as Vadim mentioned) that different d-dimer methodologies can give different results. Also the reference intervals mentioned of around 240 ng/mL–are these FEU (fibrinogen equivalent units – or twice the d-dimer level) because they seem rather low compared to the literature (about 0.5 mg/L or 500 ng/mL). Also, we should be taking into consideration recommended cut-offs for VTE rather than reference intervals–even age related cutoffs.
Hi George. I wanted to
Hi George. I wanted to provide a comment from a trusted vascular surgeon I know who uses D-dimer testing to determine when to permanently discontinue anticoagulation (AC; warfarin and NOACs) in patients. The algorithm is: determine if D-dimer is normal while the patient is on AC. If it is, then AC is discontinued and the D-dimer is checked in 30 days to be sure it stays normal. If D-dimer is normal at 30 days, it is re-checked in 6 more months, and if normal at this time the AC is permanently discontinued. If D-dimer is ever abnormal, patient is considered to be at high risk of thrombosis and AC is reinstated.
Among possible discrepancies
Among possible discrepancies in D-dimer measurement by different assays two causes are reported:
Degradation by human neutrophil elastase http://www.ncbi.nlm.nih.gov/pubmed/9175235
Interference by heterophilic antibodies http://www.ncbi.nlm.nih.gov/pubmed/18725347