Short title: An overview of the role of D-dimer in COVID-19
Moran Wang1, Shengling Ma1, Shanshan
Luo1#,
Yu
Hu1#
1Institute of Hematology, Union Hospital, Tongji
Medical College, Huazhong University of Science and Technology, 1277
Jiefang Road, Wuhan 430022, China.
# shared corresponding authors
Yu Hu: Email: dr_huyu@126.com; Tel.: +86-27-85726007; Fax:
+86-27-85726387.
Shanshan Luo: Email: shsh689@126.com; Tel.: +86-27-85726007; Fax:
+86-27-85726387.
Word count
Abstract:145
Text: 1291
Figure count: 2
Table count: 2
Reference count: 39
Abstract
The
great number of patients presenting to health centers or hospitals
during the outbreak of coronavirus disease 2019 (COVID-19) overwhelms
the need for critical care support. Early and effective predictors for
clinical outcomes are urgently needed for risk stratification.
Critically ill patients often develop coagulation disorders, in
particular hypercoagulation. Elevated D-dimer is a prominent indicator
for the initial coagulopathy of COVID-19. To estimate whether D-dimer is
associated with the severity of COVID-19, we performed the analysis of
D-dimer abnormalities in patients with COVID-19. The data demonstrated
that D-dimer levels were significantly higher in deceased patients than
in survivors (weighted mean difference(WMD): 3.70mg/L, 95% confidence
interval(CI):1.41–5.98mg/L), and the levels in severe patients were
also higher than those in mild cases (WMD: 0.39mg/L, 95% CI:
0.22–0.55mg/L). Therefore, we conclude that elevated D-dimer level is
related to the severity and poor prognosis of patients with COVID-19.
(145 words)
Key words :
COVID-19, D-dimer, Coagulopathy,
Severity
Introduction
Since December 2019, the outbreak
of COVID-19 put the health authorities of the whole world on high alert.
According to the latest statistics released by the World Health
Organization on June 17,2020,
severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2 ) has already infected over 8 million people
from over 200 countries worldwide, causing more than 400,000
deaths(”World Health Organization.,”). SARS-CoV-2 can cause serious
diseases, including acute respiratory distress and occasionally
associated with multiple organ dysfunction failure(Mattiuzzi & Lippi,
2020). During the course of SARS-CoV-2 infection, critical patients
developed uncorrectable coagulation dysfunction. Existence of
disseminated intravascular coagulation is common in deaths with
COVID-19(Tang, Li, Wang, & Sun, 2020). The initial coagulopathy of
COVID-19 is accompanied with prominent elevation of D-dimer and
fibrin/fibrinogen degradation products(Connors & Levy, 2020).
Also,
markedly elevated D-dimer levels were reported in the deceased
patients(Tang et al., 2020), suggesting that elevated D-dimer is closely
related to poor prognosis. In this review, we studied the roles of
D-dimer in infections,
then
performed the analysis of D-dimer abnormalities in patients with
COVID-19 to better estimate the role of D-dimer in predicting the
prognosis of SARS-CoV-2 infected patients.
General roles of D-dimer in
infections
On-admission, D-dimer level is usually used to predict disease severity
and mortality in endocarditis and severe patients without obvious
disseminated intravascular coagulation(Shorr, Trotta, Alkins, Hanzel, &
Diehl, 1999; Turak et al., 2014). A cohort study by Michael et al. found
that patients with bacteremia had a higher risk of in-hospital mortality
on the first day of positive blood culture with elevated D-dimer
levels(Schwameis et al., 2015). Elevated D-dimer levels have also been
reported in patients with acute lung injury and acute respiratory
distress syndrome(Wenzel et al., 2002). Lee et al. had reported the
clinical and laboratory features of 138 cases of suspected SARS in Hong
Kong, which was striking that 45% of the patients had elevated D-dimer
levels(Lee et al., 2003). Notably, most SARS-CoV-2 infected patients
with systemic inflammatory response syndrome are associated with
significantly elevated D-dimer, especially in critically ill patients
(Mehta et al., 2020). In a study of 1099 patients with COVID-19 from
over 550 hospitals in China, a D-dimer ≥0.5 mg/L was noted in 260/560
(46.4%) patients, and about 60% of severe patients have elevated
D-dimer(Guan et al., 2020). Furthermore, markedly elevated D-dimer
levels were also observed in the deceased patients with COVID-19 (Tang
et al., 2020).
D-dimer is associated with severity of
COVID-19
Given the important roles of D-dimer in infections, we speculated that
D-dimer can be used to track the severity of COVID-19. To address this
hypothesis, we reviewed studies that reported information on the
difference of D-dimer values from COVID-19 patients with different
backgrounds (i.e., those who need mechanical ventilation, or intensive
care unit (ICU) admission, or those who died) from December 1, 2019 to
June 10, 2020, without language restriction. Based on these literatures,
we performed a pooled analysis with calculation of WMD and 95% CI of
D-dimer values between deceased patients and survivors with COVID-19(Du
et al., 2020; Fogarty et al., 2020; Tang et al., 2020; Wu et al., 2020;
Yan et al., 2020; J. Zhang et al., 2020; Zhou et al., 2020)(subgroup 1,
consisting 7 studies, characteristics presented in Table 1 ),
and between COVID-19 patients with or without severe disease(G. Chen et
al., 2020; Q. Chen et al., 2020; Huang, Wang, & Li, 2020; Ji et al.,
2020; M. Liu et al., 2020; Liu, Liao, Wan, Xiang, & Zhang, 2020; Wei et
al., 2020; Wu et al., 2020; Xie et al., 2020; J. J. Zhang et al., 2020;
Zheng et al., 2020; Zhu et al., 2020; Zou et al., 2020)(subgroup 2,
consisting 13 studies, characteristics presented in Table 2 ),
using R software Version 3.6.3. The severe group met any of the
following criteria: (a) Increased breathing rate (≥30 beats/min), (b)
resting-state oxygen saturation ≤93%, (c) arterial partial pressure of
oxygen/oxygen concentration≤300mm Hg(”Diagnosis and Treatment of
Pneumonia Caused by SARS-CoV-2(version 7).National Health Commission of
the People’s Republic of China,”), or (d) respiratory failure,
mechanical ventilation, shock, or other functional organ failure
requiring ICU monitoring and treatment. Mean and standard deviation were
extrapolated from sample size, median, and interquartile range according
to Wan et al.(Wan, Wang, Liu, & Tong, 2014) and Luo et al.(Luo, Wan,
Liu, & Tong, 2018).
The WMD of subgroup 1 (597 patients in total, 32% were deceased
patients) was summarized inFigure
1, showing that D-dimer levels were significantly higher in deceased
patients than those in survivors with COVID-19 (WMD: 3.70mg/L, 95% CI:
1.41–5.98mg/L), the heterogeneity of subgroup 1 was relatively high
(I-square(I2), 86%; p< 0.01). The WMD of
subgroup 2 (1172 patients in total, 35% with severe disease) was
summarized in Figure 2, showing that D-dimer levels in severe
patients were higher than those in the mild cases (WMD: 0.39mg/L, 95%
CI: 0.22–0.55mg/L), while the heterogeneity of subgroup 2 was
relatively high (I2, 84%; p< 0.01).
Vigilance against elevated D-dimer
levels
D-dimer level at the time of hospital admission is a risk predictor for
the development of acute respiratory distress syndrome, ICU admission
and death(Huang et al., 2020; Wu et al., 2020). An observational study
in COVID-19 patients with elevated D-dimer levels showed that the 28-day
mortality of heparin treated patients was lower than those from
non-treated ones(Zhou et al., 2020). In a trial consisting of 31
patients with COVID-19, dipyridamole supplementation was associated with
significantly decreased concentration of D-dimers,
increased lymphocytes and platelet
recovery in the circulation, suggesting markedly improved clinical
outcomes(X. Liu et al., 2020). Similarly, Escher et al. also reported
that the ”decrease” of D-dimer levels (from 6.26 mg/L to 1.94 mg/L) in a
patient
after
escalating the treatment dose of anticoagulation reflected clinical
improvement(Escher, Breakey, & Lammle, 2020).
High concentration of D-dimer indicates a hypercoagulable state in
patients with COVID-19, which is closely related to
thromboembolism(Kline, Garrett, Sarmiento, Strachan, & Courtney, 2020).
Cui et al. used a D-dimer cut-off of 1.5 µg/mL for predicting venous
thromboembolism and demonstrating sensitivity of 85.0%, specificity of
88.5% and negative predictive value of 94.7%(Cui, Chen, Li, Liu, &
Wang, 2020). The Swiss Society of Hematology proposed that for patients
in ICU with a large increase of D-dimer, severe inflammation, or signs
of hepatic, or renal dysfunction or imminent respiratory failure,
intermediate or therapeutic dosing of low molecular weight heparin or
unfractionated heparin should be applied based on the bleeding
risk(Casini et al., 2020). As for venous thromboembolism prophylaxis,
many centers have increased the dose of anticoagulation as a
risk-adapted strategy based on the levels of D-dimer, fibrinogen, ICU
location, or other factors associated with increased risk(Connors &
Levy, 2020).
Conclusion
In this work, we performed a pooled analysis for D-dimer abnormalities
that occurred in association with COVID-19 based on published data,
found that D-dimer levels were considerably higher in severe or deceased
patients than in mild ones or survivors with COVID-19, suggesting that
elevated D-dimer level is closely related to the severity and poor
prognosis of patients. Thereby, we conclude that D-dimer can be used as
the early and effective predictor for the judgment of the disease
severity, which is of great importance in clinical use. However, larger
prospective studies are needed in the future to classify the mechanism
how SARS-CoV-2 caused hypercoagulation, in particular elevated D-dimer
levels.
Our review has several limitations. First, most of the studies reported
the change of D-dimer levels are observational studies, and there are
few longitudinal comparison studies. In addition, only one literature
which we analyzed is not derived from studies of Chinese patients. Since
race and ethnicity have major effects upon thrombotic risk (Liao et al.,
2014; White & Keenan, 2009), data from other countries need to be
updated.