D-dimer is a marker of coagulation activation and thrombotic activity. The analysis of D-dimer levels is used to diagnose deep vein thrombosis (DVT), pulmonary embolism (PE), or disseminated intravascular coagulation (DIC) . In addition, D-dimer has been proposed as a useful marker to predict the risk of recurrent thrombosis when anticoagulant therapy is stopped, and it is included in the risk scores to predict the risk of venous thromboembolism (VTE) in cancer patients [2,3].
What is D-dimer
D-dimer is a subproduct of fibrinogen degradation by plasmin, produced during blood clot degradation by fibrinolysis.
Fibrinogen is a symmetrical dimer composed of three paired polypeptide chains (Aα, Bβ, γ). The amino terminus of each chain that composes the dimer joins to form the E domain, while the carboxy terminus forms two D domains at each side of the molecule .
Fibrinogen is cleaved into fibrin monomers by thrombin. The fibrin monomers self-associate in a nonenzymatic reaction to form polymers that are further cross-linked together by factor XIIIa, a transglutaminase, to form a network. In this network, the D-domains of adjacent fibrin monomers are cross-linked .
When plasmin cleaves fibrin polymers, fibrin degradation products (FDP) of different sizes are formed. One of these FDP, composed of two D-domains, is the D-dimer .
Challenges in testing D-dimer levels
D-dimer levels in blood mirror the level of fibrinolysis activation and associate with hypercoagulable states .
D-dimer levels are generally tested using monoclonal antibody-based assays, starting from plasma, serum, or whole blood, depending on the assay used. Using a cut-off (or threshold), D-dimer levels are divided into “positive” and “negative.” The cut-off is determined by the manufacturer of the test .
Results can be reported using two different definitions of the units: fibrinogen-equivalent-units (FEU) or D-dimer units (DDU).
The first one expresses the mass of the D-dimer to the mass of fibrinogen (340 kDa). In this case, the calibrator is purified fibrinogen degraded in a controlled way using plasmin and clotted with thrombin and factor XIII .
DDU expresses the estimated weight of the D-dimer unit (195 kDa), and the calibrator is the purified D-dimer fragment .
For their nature, FEU is 1.75-fold higher than DDU, and this discrepancy may create confusion or error in the interpretation of the results if clinicians are not aware of the difference .
The discrepancy in units used and the lack of transparency in unit measurements in laboratory reports make it difficult to develop standard D-dimer cut-offs and compare cut-off limits in different studies. Therefore, researchers should clearly state the assay and the D-dimer unit type used in their studies .
Another obstacle in developing a standard D-dimer reference level is the change of D-dimer levels with age or with inflammatory states that are not linked to the activation of the coagulation system .
For these reasons, a D-dimer test alone is not enough to diagnose VTE because elevated D-dimer levels alone are not suffiently predictive of VTE. Therefore, to confirm suspected VTE, a diagnostic algorithm combining D-dimer measurement and other tests should be used .
D-dimer and VTE
A study exploring several blood biomarkers to increase the accuracy of VTE risk prediction in ambulatory cancer patients showed that D-dimer is the most predictive one for VTE risk in cancer patients receiving ambulatory chemotherapy .
Pabinger et al. validated a risk score that utilizes only two variables: the type of cancer and a continuous scale of D-dimer levels. The model is available for clinical use as a printed nomogram and as an online prediction tool. The model showed an improvement of 30% compared with the Khorana score, and it can be used for cancers that are excluded by the Khorana score, such as lung, breast, and colon cancer .
A longitudinal substudy of the prospective Vienna Cancer and Thrombosis Study (CATS) indicates that longitudinal trajectories of the D-dimer levels can improve the assessment of VTE risk in patients with cancer, compared to a single D-dimer measurement in time. D-dimer levels increased before the onset of cancer-associated thrombosis but remained constant in patients that did not develop VTE .
These results indicate that the variation in time of D-dimer levels rather than the base level in a certain time point for each patient is a better prediction marker for VTE risk, indicating the possibility of highly personalized dynamic predictions.
D-dimer and recurrent VTE
D-dimer levels can also be useful in predicting recurrent VTE and anticoagulant therapy discontinuation, even though their role in this setting is controversial. For example, the highest risk of recurrent VTE is observed within 6 months of anticoagulant discontinuation. Therefore, evaluating the D-dimer levels within this period might be useful to predict VTE risk .
After anticoagulant therapy discontinuation, persistent positive D-dimer might indicate coagulation activation and support the decision to extend anticoagulation. Although D-dimer alone as a marker in clinical practice might not be straightforward .
A systematic review linked a persistent abnormal level of D-dimer after anticoagulation discontinuation with a 10% increase in absolute risk of recurrence compared with normal levels (16.1% of absolute risk of recurrence in patients with a persistent abnormal level of D-dimer vs 7.4% of those with normal levels) . However, it has to be noted that this review includes heterogeneous studies and follow-up time after the index VTE and anticoagulant discontinuation (from 3 to 62 months) .
A prospective study performed in cancer patients indicates D-dimer as a potential biomarker to predict the risk of recurrent VTE after anticoagulant therapy cessation. Still, these results were not confirmed by another study [12, 13].
A meta-analysis concluded that D-dimer could be a predictor for recurrent VTE risk and increased VTE risk in the presence of chemotherapy. However, the analysis failed in identifying an optimal D-dimer cut-off value .
D-dimer and Covid 19
The novel coronavirus disease 2019 (COVID-19) can cause thrombotic complications, especially in patients with a severe clinical course. In patients with COVID-19, D-dimer might be predictive for a higher risk of VTE.
A study examined D-dimer predictive capability in patients who had COVID-19 but were not mechanically ventilated. The results suggest that, among non-severe COVID-19 patients, admission D-dimer levels above 1 µg/ml increased VTE risk between 2.3- and 10-fold, meaning that D-dimer can help identify patients with a higher risk of VTE .
Another recent review suggests that D-dimer tests can predict thrombotic events and prognosis in COVID-19 . In patients with COVID-19, a 4-fold increase of D-dimer level can predict COVID-19-related mortality .
D-dimer levels are higher in patients with COVID-19 of all ages, and concomitant diseases (e.g., diabetes, cancer, stroke) or pregnancy can raise the levels. Still, the relationship between high levels of D-dimer and mortality highlights the importance of detecting D-dimer levels in patients with COVID-19 .
Another literature review suggests that abnormal D-dimer levels indicate starting coagulation treatment, even though anticoagulation in COVID-19 patients needs further investigation .
D-dimer is a marker used to diagnose DVT, PE, or DIC. It has been proposed as a useful marker to predict the risk of recurrent thrombosis and VTE in cancer patients. However, elevated D-dimer levels alone are not predictive for VTE, and a diagnostic algorithm combining D-dimer measurement and other tests should be used.
The discrepancy in units used and the lack of transparency in unit measurements in laboratory reports is a limiting factor to develop standard D-dimer cut-offs and comparing cut-off limits in different studies. For this reason, it is essential to find an agreement on D-dimer standard units.
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