Plasma D-dimer measurement as a predictor of venous thrombosis

We read with interest the article of Cushman and colleagues¹  entitled “Fibrin fragment D-dimer and the risk of future venous thrombosis.” The article reports that plasma D-dimer is strongly and positively related to the occurrence of future venous thrombosis. Based on this finding the authors make a forceful statement that “the strength of the association observed here, and its consistency in various subgroups, suggests potential clinical roles for D-dimer assessment that could be tested in future clinical studies.” While we agree that the findings of this study are interesting and should be investigated further, we would also like to point out that a number of issues need to be addressed by the investigators in any follow-up study.

First, studies need to be carried out to find out whether plasma D-dimer levels are stable enough over a period in a particular individual (ie, not subject to wide fluctuations) to permit reliable and accurate interpretations. If not, it will be impossible to make any meaningful interpretations or clinical judgements. In order to establish whether plasma D-dimer levels are “stable” in healthy individuals, we measured our own D-dimer levels weekly over a 6-week period. The measurement of D-dimer was carried out using a commercial kit (Instrumentation Laboratory, Warrington, United Kingdom). As shown in Figure 1, the D-dimer levels of Muttuswamy Sivakumaran (MS) showed noticeable fluctuations, with values ranging from 52 ng/mL to 195 ng/mL (first quintile to the fourth in Cushman et al's distribution curve). This observation raises the question of whether one could use a single measurement of D-dimer level to predict thrombotic risk.

Second, it is important that, as in the case of other parameters used in thrombophilia screening (eg, protein C, protein S, and antithrombin III), one should have a normal range or at least an upper level for the plasma D-dimer level above which the values could be considered abnormal. Do Cushman and colleagues propose the value between the fourth and the fifth quintiles (277 ng/mL) or a figure derived from the median of the cohort plus a standard deviation of 2 as that cutoff figure?

Finally, one should consider the implications of extreme values. A significant number of controls in Cushman's cohort had very high D-dimer levels (over 1000 ng/mL). As in the case of Neil Malton (NM; Figure 1), these individuals probably have, for hitherto unexplained reasons, abnormally high baseline D-dimer levels (“hyperfibrinemia” or “hyper D-dimeremia”). The important question is whether the high plasma levels are due to increased production or to reduced clearance of D-dimers from the circulation. The authors measured their own random urine D-dimer levels on the day they had their last blood test. The plasma and urine D-dimer levels of NM were 775 ng/mL and 57 ng/mL, respectively, whereas those of MS were 52 ng/mL and 74 ng/mL, respectively. In other words, the random urine D-dimer levels of NM and MS were 7.4% and 142% of plasma levels, respectively. This finding may suggest that the extreme values recorded in some otherwise healthy individuals may be at least partly due to slower clearance of D-dimers, thus raising the question of whether a ratio of plasma and urine D-dimer levels may be more informative than an isolated plasma level for thrombotic risk assessment of aymptomatic individuals. Obviously, larger studies are required to answer this question. Whatever the cause of these extreme values, they do raise an important question that has a direct clinical relevance: How can we distinguish these asymptomatic individuals with high plasma D-dimer levels from those with raised levels due to an underlying active thrombotic state to prevent making erroneous clinical decisions?