D-dimer is a fibrin degradation product that is often used to measure and assess clot formation. Amid the COVID-19 pandemic, elevated D-dimer levels have been associated with disease severity and mortality trends.
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How is D-dimer generated?
The liver produces several important proteins involved in the coagulation process, one of which includes fibrinogen. A single fibrinogen molecule is a symmetrical dimer that is made up of three pairs of three different polypeptide chains, which include a, b and g.
Each of the intertwined polypeptide chains that comprise a single fibrinogen molecule is held together by disulfide bonds.
The formation of fibrin begins with the cleaving of the a and b polypeptide chains of the fibrinogen molecule, which is achieved by thrombin. This cleaving event causes the fibrin monomers to spontaneously polymerize, which results in the formation of double-stranded fibrin protofibrils.
To strengthen a normally weak network that exists between the fibrin monomers and the protofibrils, a transglutaminase enzyme known as factor XIIa is activated.
If an injury occurs, the fibrinolytic system will activate to limit the size of the clot. This system begins with the release of the plasminogen activator from the vascular endothelial cells to allow this molecule to bind to the fibrin surface of plasmin.
Fibrin-bound plasmin will then degrade the fibrin network into several soluble fragments, of which will include the D-dimer of the (DD)E complex.
What is D-dimer measured?
The presence of D-dimer in the blood plasma, which has a half-life of roughly 8 hours until kidney clearance occurs, is often used as a clinical biomarker to identify thrombotic activity and therefore diagnose conditions like pulmonary embolism (PE), deep vein thrombosis (DVT), venous thromboembolism (VTE) and disseminated intravascular coagulation (DIC).
Some of the risk factors for conditions like VTE that will support a clinician’s interest in quantifying D-dimer levels include active cancer, immobilization, or recent surgery. Other conditions that can cause D-dimer levels to rise include advanced age, pregnancy, and chronic inflammatory diseases.
Methods to quantify D-dimer levels
There are currently four major types of commercial assays that can be used to measure D-dimer levels, of which include whole blood analysis, enzyme-linked immunosorbent assay (ELISA), enzyme-linked immunofluorescence assay (ELFA) and Latex-enhanced immunoturbidimetric assay.
Several studies have found the ELFA method to provide the highest sensitivity for detecting D-dimer levels; however, the specificity of this method is approximately 46%. Similar sensitivity to D-dimer levels of 94% and 93% are reported with the ELISA and Latex methods, respectively; however, these methods are also limited in their specificity capabilities that both average at 53%.
Although the sensitivity of these assays is valuable, they are limited in cases in which there is a high probability that the patient has DVT, PE, or is experiencing some other type of serious thrombotic event. In these situations, clinicians will often order compression ultrasonography and computed tomography pulmonary angiography to confirm DVT or PE diagnoses, respectively.
Importance of identifying COVID-19 biomarkers
It is estimated that 10-15% of COVID-19 patients will experience critical forms of this disease that progress to severe pneumonia, hypoxia, and respiratory failure, all of which will require supportive care and supplemental nasal oxygen.
Furthermore, about 5% of these severe COVID-19 cases have been found to decline even further to acute respiratory distress syndrome (ARDS) or multiple organ failure (MOF), both of which require intensive care unit (ICU) admittance with mechanical ventilation or extracorporeal membrane oxygenation (ECMO).
Despite the widespread cases and severe forms of COVID-19 that have been reported, there remains a limited understanding as to why certain individuals develop ARDS and MOF and others do not.
To improve the early identification of these severe forms of COVID-19, many researchers have committed themselves and their teams to identify reliable biomarkers.
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D-dimer and COVID-19
Several different studies have looked to measure D-dimer levels in hospitalized COVID-19 patients to determine whether this biomarker could be useful in predicting patient outcomes. In one study conducted in China between January 31 and February 12, 2020, the biological characteristics of a total of 274 COVID-19 patients with a median age of 62 were analyzed.
Of the 113 patients who did not survive, it was reported that their D-dimer levels were higher at a median of 4.6 µg/mL, whereas the surviving 161 patients had D-dimer levels that averaged at 0.6 µg/mL.
Similar results were reported in another study conducted in China between January 1 and February 13, 2020. In this work conducted by Tang et al., the D-dimer levels of 134 deceased COVID-19 patients averaged at 4.7 µg/ml, whereas 315 patients who had survived following severe COVID-19 effects had median D-dimer levels of 1.47 µg/ml.
Although these data indicate that D-dimer testing, in combination with the analysis of other biomarkers, can be of assistance during the treatment of COVID-19 patients, further studies must be performed to fully validate the role that D-dimer testing can have in the decision-making process.
References
- Linkins, L. A., & Lapner, S. T. (2017). Review of D-dimer testing: Good, Bad, and Ugly. International Journal of Laboratory Hematology 39(51). doi:10.1111/ijlh.12665.
- Palta, S., Saroa, R., & Palta, A. (2014). Overview of the coagulation system. Indian Journal of Anaesthesia 58(5); 515-523. doi:10.4103/0019-5049.144643.
- Sakka, M., Connors, J. M., Hekimian, G., Martin-Toutain, I., et al. (2020). Association between D-Dimer levels and mortality in patients with coronavirus disease 2019 (COVID-19): a systematic review and pooled analysis. Journal de Medicine Vasculaire. doi:10.1016/j.jdmv.2020.05.003.
- Weitz, J. I., Fredenburgh, J. C., & Eikelboom, J. W. (2017). A Test in Context: D-Dimer. Journal of the American College of Cardiology 70(19); 2411-2420. doi:10.1016/j.jacc.2017.09.024.
- World Health Organization. What we know about long-term effects of COVID-19. World Health Organization. Available from: https://www.who.int/docs/default-source/coronaviruse/risk-comms-updates/update-36-long-term-symptoms.pdf
Further Reading
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