D-dimer in Coronavirus 2019: An Acute Phase Reactant?

D-dimers are released following the breakdown of blood clots, essentially representing a byproduct of the degradation of fibrin by plasmin activity. Normal values are less than 0.50 mg/L (in fibrinogen equivalent units), and the negative predictive values of D-dimer measurements are excellent to rule out pulmonary embolism, deep vein thrombosis, and disseminated intravascular coagulation, since it would otherwise increase substantially in those settings. However, the D-dimer assay only represents a screening test and should be interpreted in the context of the patient’s clinical signs and symptoms.[1] Overt coagulation abnormalities are common in patients with coronavirus disease 2019 (COVID-19) and have led to an increase in requests of laboratory biomarkers, such as blood cell counts, acute phase reactants, coagulation tests, and platelet function assays, as aids in the clinical decision-making processes throughout the pandemic.[2] [3] D-dimer levels are among the most frequently and thoroughly studied, and the International COVID-19 Thrombosis Biomarkers Colloquium concluded that they were associated with patient prognosis and were helpful in clinical decision-making in patients requiring imaging studies, in the administration of thromboprophylaxis, and to detect and prevent complications.[4] While the consensus suggests that an elevated D-dimer is associated with worse disease outcomes,[5] the literature is not consistent in terms of whether the increase in D-dimer in COVID-19 can predict thrombotic events. Moreover, some issues have been identified in various publications, whereby comparisons between studies reporting D-dimer levels in different hospital units only reach confusing conclusions on their clinical significance.[6]

Previous studies have shown that patients with D-dimer values >2.0 mg/L had a greater mortality risk[3] [7] and warranted intubation more frequently.[8] Other studies have suggested that D-dimer is increased in most patients with COVID-19, so clinical decisions should not be based on this biomarker alone.[9] It appears that D-dimer values increase as one of many defense mechanisms against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; normally, the activation of broncho-alveolar hemostasis shifts toward fibrinolysis, thus allowing normal gas exchange and leading to elevated D-dimer in most patients during the onset of the disease. The extensive inflammation that develops in complicated COVID-19 patients leads to elevated extravascular fibrinogen levels, which do not merely indicate an increased risk of thrombosis but could actually be of use in the prediction of clinical outcomes and complications.[10] [11] Further, elevated D-dimer has been observed in patients with no other coagulation abnormalities, such as altered prothrombin time/international normalized ratio, activated partial thromboplastin time, fibrinogen level, or platelet counts, unlike the clinical presentation of disseminated intravascular coagulation of bacterial or traumatic origin.[12] Postmortem studies of COVID-19 patients have revealed that platelets play a predominant role in COVID-19-associated coagulopathy, as a result of their activation due to the inflammatory response, and the interaction of SARS-CoV-2 and ACE2 receptors on their surface.[13]

In a limited experience with 23 consecutive COVID-19 patients (74% male, median age: 56 years [27–81]), studied and treated at the Centro de Hematología y Medicina Interna de Puebla, 83% (n = 19) had D-dimer levels > 0.5 mg/L in the first 5 days of infection and 42% (n = 10) had D-dimer values > 2.0 mg/L. Of these, none developed thrombotic complications, but 5 required mechanical ventilation and 10 were admitted to the hospital. To examine the correlation between D-dimer levels and other acute phase reactants, we performed Pearson's correlation test based on the blood levels of lactic dehydrogenase (LDH), ferritin, C-reactive protein (CRP), platelets, white blood cells (WBC), absolute lymphocyte count, hemoglobin levels, and erythrocyte sedimentation rate (ESR). We found a strong positive correlation between D-dimer levels and LDH (r = 0.94), as well as between DD values and WBC count (r = 0.90). A moderate association was established between D-dimer levels and the ESR, and there was no association between D-dimer and other acute phase reactants. Interestingly, an elevated serum LDH correlated positively and significantly with a high ESR (r = 0.81), CRP (r = 0.96), and higher total WBC counts (r = 0.95). [Fig. 1] shows these associations.

Fig. 1 Correlation matrix of acute phase reactants.

Most of our data are similar to that currently reported in the literature[3] [14]; however, in this small cohort, elevated D-dimer levels were not associated with thrombotic complications, even in hospitalized patients. In our cohort, two patients had D-dimer values 10x above the normal value, five patients had a 5x increase, and in seven cases, D-dimer levels were at least twice above the normal value; interestingly, none of these patients developed a thrombotic event.

After 3 years of global experience managing patients with COVID-19, the association between the mechanisms of infection and the pathophysiological havoc it leads to[15] remain under study; sequelae develop after the infection has cleared and in asymptomatic convalescent patients. The association with elevated D-dimer and VTE is clear, but during the acute phase of COVID-19, D-dimer values increase in concert with other acute phase reactants and do not necessarily lead to thrombotic complications. This is especially true in ambulatory patients with mild-to-moderate symptoms. The literature has asserted that D-dimer levels do correlate with thrombotic episodes in hospitalized patients,[16] but this phenomenon could also result from the nature of the hospitalization itself rather than a direct effect of the SARS-CoV-2 infection. Few studies have monitored asymptomatic or mildly affected ambulatory patients and their laboratory results after convalescence, although post-COVID-19 complications have been identified.[17] Long COVID includes a wide array of multiorgan effects that can persist over weeks,[18] and even years, in both adults and children. D-dimer levels that are persistently elevated during convalescence are associated with lingering COVID-19 symptoms and complications in children[19] and adults.[17] Some have recommended that persons with high D-dimers after COVID-19 should be kept on anticoagulants.[4]

While the WHO declared the COVID-19 state of emergency officially over on May 4th, 2023, it will remain an ongoing health issue, especially as a result of the manifestations of the long COVID syndrome. While vaccination dramatically reduced the number of severe COVID-19 cases, a few studies show that patients with moderate and mild disease courses still manifest related complications. Understanding the role of acute phase reactants and other laboratory biomarkers will allow clinicians to better manage and treat possible complications.

Although traditionally elevated in association with thrombotic phenomena, D-dimer can be classified as an acute phase reactant that appears to be helpful when following individuals with COVID-19; D-dimer levels should, ideally, be correlated with every patient's clinical findings. Our data in this small series suggest that it may not be mandatory to keep COVID-19 patients on anticoagulants when displaying high D-dimer levels, since there is always a risk of bleeding on anticoagulants to be considered. However, we accept that additional studies are needed to support this suggestion.

Publication History

Article published online:
23 June 2023

• References

• 1 Bounds EJ, Kok SJ. D Dimer. In: StatPearls. StatPearls Publishing; 2023
• 2 Li J, Tang M, Liu D, Xie Z, Wang F, Yang Y. Serum biomarker panel for disease severity and prognosis in patients with COVID-19. J Clin Lab Anal 2023; 37 (02) e24831
• 3 Battaglini D, Lopes-Pacheco M, Castro-Faria-Neto HC, Pelosi P, Rocco PRM. Laboratory biomarkers for diagnosis and prognosis in COVID-19. Front Immunol 2022; 13: 857573
• 4 Gorog DA, Storey RF, Gurbel PA. et al. Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium. Nat Rev Cardiol 2022; 19 (07) 475-495
• 5 Popovska Jovičić B, Raković I, Gavrilović J. et al. Vitamin D, albumin, and D-Dimer as significant prognostic markers in early hospitalization in patients with COVID-19. J Clin Med 2023; 12 (08) 2825
• 6 Favaloro EJ, Thachil J. Reporting of D-dimer data in COVID-19: some confusion and potential for misinformation. Clin Chem Lab Med 2020; 58 (08) 1191-1199
• 7 Zhang L, Yan X, Fan Q. et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost 2020; 18 (06) 1324-1329
• 8 Nemec HM, Ferenczy A, Christie III BD, Ashley DW, Montgomery A. Correlation of D-dimer and outcomes in COVID-19 patients. Am Surg 2022; 88 (09) 2115-2118
• 9 Auron M, Porres-Aguilar M, Cameron SJ. COVID-19 and elevated D-Dimer: a tale of caution. J Gen Intern Med 2022; 37 (05) 1304-1305
• 10 Ibañez C, Perdomo J, Calvo A. et al. High D dimers and low global fibrinolysis coexist in COVID19 patients: what is going on in there?. J Thromb Thrombolysis 2021; 51 (02) 308-312
• 11 Thachil J. All those D-dimers in COVID-19. J Thromb Haemost 2020; 18 (08) 2075-2076
• 12 Wool GD, Miller JL. The impact of COVID-19 disease on platelets and coagulation. Pathobiology 2021; 88 (01) 15-27
• 13 Iba T, Wada H, Levy JH. Platelet activation and thrombosis in COVID-19. Semin Thromb Hemost 2023; 49 (01) 55-61
• 14 Rostami M, Mansouritorghabeh H. D-dimer level in COVID-19 infection: a systematic review. Expert Rev Hematol 2020; 13 (11) 1265-1275
• 15 D'Ardes D, Boccatonda A, Cocco G. et al. Impaired coagulation, liver dysfunction and COVID-19: discovering an intriguing relationship. World J Gastroenterol 2022; 28 (11) 1102-1112
• 16 Gómez-Mesa JE, Galindo-Coral S, Montes MC, Muñoz Martin AJ. Thrombosis and coagulopathy in COVID-19. Curr Probl Cardiol 2021; 46 (03) 100742
• 17 Townsend L, Fogarty H, Dyer A. et al. Prolonged elevation of D-dimer levels in convalescent COVID-19 patients is independent of the acute phase response. J Thromb Haemost 2021; 19 (04) 1064-1070
• 18 Chippa V, Aleem A, Anjum F. Post-acute coronavirus (COVID-19) Syndrome. In: StatPearls. StatPearls Publishing; 2023
• 19 Di Gennaro L, Valentini P, Sorrentino S. et al. Extended coagulation profile of children with long Covid: a prospective study. Sci Rep 2022; 12 (01) 18392