COVID-19 Diagnostics: Icahn Researchers Advocate Using D-Dimer As A Biomarker For COVID-19 Mortality
: Researchers from Icahn School of Medicine-Mount Sinai in a new study have found that D-Dimers, a fragment protein produced by the breakup of fibrin clots can be used as a biomarker to determine which patients are at the risk of dying.
Information such as this which predicts a COVID-19 patient’s risk of mortality is useful in designing clinical treatment protocols, clinical studies and assessing the outcome of various novel treatments. Current methods includes developing a general clinical profile including a variety fo laboratory test, imaging, physical examination etc but these do not give an accurate picture.
The study findings from the new research are published on a preprint server and have yet to be peer reviewed. https://www.medrxiv.org/content/10.1101/2020.09.02.20180984v1
The study team also assessed the role of D-dimer in suspected thromboembolism (VTE). Past studies had shown that when a patient with COVID-19 has high D-dimer levels when admitted in hospital, the risk of death is elevated.
D-dimer is a fibrin degradation product (or FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two D fragments of the fibrin protein joined by a cross-link.
The key role played by D-dimer relates to the high procoagulable state in COVID-19, as shown by the remarkable decline in mortality when those with high D-dimer levels are treated with anticoagulation.
Hence anticoagulants are now recommended in many protocols and guidelines, either using full doses for therapeutic use or intermediate doses for prophylactic use, to prevent thrombotic events in patients with severe COVID-19 infection and especially when D-dimer levels are high.
The study team focused on evolving monitoring and interpretation standards for D-dimer levels in hospitalized patients. The basic premise to be tested was that the mortality risk could be predicted using baseline and changing D-dimer levels, in combination with other risk factors.
The study team exploited a large patient dataset, using records from the Mount Sinai Health System (MSHS) in New York City. This gave them access to baseline sociodemographic data, risk factors like coexisting illnesses, body mass index (BMI), and the presence of smoking. The most abnormal recordings of several vital signs at the point of admission were also retrieved, including the temperature, heart rate, respiratory rate, blood pressure, and oxygen saturation. So was the early laboratory tests sent within 24 hours of admission and before beginning anticoagulant prophylaxis or therapy.
In all there were over 1,800 adult patients, with a median age of 67 years, about 60% being males, who were on therapeutic anticoagulation during their hospital stay. Almost three-quarters of them were discharged, while the rest did not survive.
The Mount Sinai Health System or MSHS protocol for anticoagulant therapy was implemented for hospitalized COVID-19 patients, provided they had no increased risk of bleeding. Therapeutic doses were given to all patients whose assessment showed a risk of or the presen
ce of VTE, or for those with severely impaired breathing. For others, prophylactic doses were started. The drugs used were heparin, enoxaparin and/or apixaban.
For the study, the D-dimer level was used to classify them into four cohorts ie the determinants being the initial concentration and the direction of change with anticoagulation.
The initial group was the high-increase (HI) group with a high baseline level, which went up following treatment. The mortality rate in hospital for this cohort was 49%.
Following this group, the second was the high-decrease (HD) group at 27% mortality.
The subsequent third, or low-increase (LI), group and the last, or low-decrease (LD) group, had a mortality of 21% and 9%, respectively.
It was observed that patients with advanced age, multiple illnesses, more significant breathing impairment, worse kidney function, and signs of inflammation were generally at a higher risk of death during hospitalization and tended to have a longer delay from the start of the hospital period to the institution of anticoagulant therapy.
Significantly, after anticoagulation was provided, the subsequent levels of D-dimer showed higher levels for those patients who died vs. were discharged, with the median concentrations being 3.70 ug/ml and 1.70 ug/ml, respectively. These two groups (died vs. discharged) had a smaller gap at admission, in fact, at 2.02 ug/ml vs. 0.39 ug/ml, respectively.
Interestingly, D-dimer levels were found to rise after anticoagulation for those who died in hospital, but to decline for those who were discharged. Thus, it was markedly easier to predict the risk of in-hospital death using an anticoagulant D-dimer level than the baseline D-dimer level. Using a combination of the two did not improve the predictive value further.
Also observed was the fact that the patient cohort with high D-dimer levels after anticoagulation overlapped with the groups of patients who were older and sicker, with worse respiratory parameters at admission, and signs of more severe disease as marked by increased white cells but lymphopenia, renal disease and elevated inflammatory markers.
Overall, there were ten factors significantly associated with a higher mortality rate.
The study team also then looked at how the individual predictive factors in this model worked by leaving them out one by one and examining the impact. They found that age was most closely related to risk of mortality, but that the HD post-anticoagulant D-dimer group was close behind, followed by the HI post-anticoagulant D-dimer group and the platelet count, oxygen saturation and the LI post-anticoagulant D-dimer group.
It was found that the predictive power was highest with the classification by D-dimer level following anticoagulation, combined with selected baseline variables, and significantly better than that of baseline models alone.
Hence the research on patients hospitalized with severe COVID-19 shows the “high and independent predictive power of post-anticoagulant D-dimer levels for in-hospital mortality, while taking into consideration 65 other important covariates.”
The study team also found the direction of change in D-dimer levels to be important in predicting mortality after anticoagulation. In fact, this is the single most crucial variable among all those examined in the current paper. This demonstrates that “post-anticoagulant D-dimer levels and trends are novel prognostic biomarkers that should be considered in the management of hospitalized COVID-19 patients.”
Importantly this conclusion differs from that of earlier studies showing high D-dimer levels to be markers of poor prognosis in COVID-19 patients when measured at the time of admission. In this study, the post-anticoagulant D-dimer was a reliable and sensitive indicator of mortality risk but not the point-of-admission D-dimer. In fact, the trajectory of the D-dimer was an important marker, since the LI group had higher mortality than the HD group.
The study team considers more research to be critical to improving the accuracy of prediction, using serial measurements to capture the changes in this parameter. If the level remains high or rises even after anticoagulation therapy, it may indicate that the risk of clotting is high in large vessels or the microvasculature.
The practical diagnostic and treatment applications of this study are threefold:
1. This biomarker can be used to clarify treatment decisions by being made part of the therapeutic protocols for severe COVID-19. Since this was an observational study, confounding factors may have altered the outcome. To validate these findings, randomized controlled trials will be needed. In the long interim period, meanwhile, these outcomes will be of use in guiding the immediate management of hospitalized COVID-19 patients.
2. The research shows that post-anticoagulation, the HI group is a subset of patients with a very poor outcome. The possibility of identifying this early will facilitate proper care and guide future studies on the treatment of this condition with antiplatelet drugs or thrombolytics.
3. The study focuses attention on the patients at least risk, namely, the LD group, who will need to be analyzed further to reduce the dose of anticoagulation therapies, possibly as well as to understand if these drugs need to be continued further after their discharge.
The study team noted that there were limitations to this study such as patients were treated at a single tertiary hospital network in New York City may not be representative of the general population in the US and worldwide.
Also there might be imprecisions of laboratory assays, which can alter the assessment of D-dimer.
Also they were unable to account for unmeasured confounders that may affect D-dimer levels, a particular limitation inherent to all observational studies. Ongoing randomized controlled trials assessing the impact of therapeutic anticoagulation on COVID-19 outcomes should validate the ability of post-anticoagulant D-dimer levels to predict mortality. However, it may take significant time for the results of these trials to be reported. Therefore, these findings provide useful and immediate information to help guide management decisions in patients with severe COVID-19 illness.
The team concluded that D-dimer levels and trends following initiation of anticoagulation have high and independent predictive value for in-hospital mortality for COVID-19 patients, and should be considered in management decisions of these patients
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