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Biomed Environ Sci, 2022; 35(10): 957-961 957

Letter to the Editor

Survival Analysis of COVID-19 Patients Based on Different

Levels of D-dimer and Coagulation Factors

Abolfazl Zendehdel1, Saeidreza Jamalimoghadamsiahkal2, Maedeh Arshadi3, Forough Godarzi3,

Shokouh SHahrousvand3, Hamidreza Hekmat4, Ehsan Sekhavatimoghadam4,
Seyedeh Zahra Badrkhahan5, Mina Riahi6, Isa Akbarzadeh3,#, and
Mohammad Bidkhori3,#

COVID-19 is a systemic disease that affects the the time of admission and a 3–4-fold increase over
respiratory, gastrointestinal, cardiovascular, time have a significant relationship with mortality
hematopoietic, and immune systems[1]. Several due to diffuse intravascular coagulation disorder
studies have shown that the SARS-CoV-2 can cause (DIC), cytokine storm, limb failure and infection/
blood clots (thrombosis) in veins and arteries. sepsis[1,2].
Therefore, COVID-19 patients are prone to deep vein Over 6.5 million people worldwide have died due
thrombosis (DVT) and pulmonary embolism (PE)[2]. to COVID-19 since the beginning of the pandemic.
Arterial and venous thrombotic complications and Therefore, the use of survival analysis models will
coagulation disorders represent one of the major help to identify risk factors related to patient death.
causes of mortality, especially in patients admitted When time-to-event (or survival) data are available,
to the intensive care units, patients hospitalized for an option is to use the Cox Proportional Hazards
long durations, and those on artificial respiration[3]. Model. In the logistic regression model, final
Approximately 20% of patients with COVID-19 have outcome is a binary variable; however, in the Cox
significant coagulation disorders and about one model, the exact time of each outcome and the
quarter of patients who are prone to thrombotic duration between the outcomes are also
events and hospitalized in the intensive care unit investigated. Therefore, the estimate obtained from
receive anticoagulant prophylaxis[4]. Among the the Cox model has greater validity than the logistic
deceased COVID-19 patients, 71.4% displayed model. A better understanding of the pathogenic
symptoms of diffuse intravascular coagulation and mechanisms created by the COVID-19 virus and
only 0.6% of patients with diffuse intravascular predicting the prognosis of the disease through
coagulation symptoms survived[5]. validated biomarkers will help to more appropriately
Coagulation Factors such as D-dimer levels, manage patients with COVID-19 and develop more
prothrombin time (PT), partial thromboplastin time suitable treatment strategies. In Iran, there have
(PTT), and international normalized ratio (INR) are been limited studies on laboratory signs and
currently considered to be the most important predictors of mortality from SARS-CoV-2 (especially
prognostic tools and the best indicators of a in high sample sizes). Therefore, the aim of this study
laboratory diagnosis for homeostasis abnormalities was to determine how levels of D-dimer and
related to COVID-19. D-dimer is the product of fibrin coagulation factors affect the risk of COVID-19
protein degradation by the enzyme, plasmin. The mortality by Cox regression.
presence of D-dimer levels in the blood indicate the This study was a retrospective cohort of patients
activation of coagulation systems and fibrinolysis. hospitalized with COVID-19 at Ziaeian Hospital in
Studies have shown that high levels of D-dimer at Tehran. Patients in this study displayed one of the

doi: 10.3967/bes2022.122
1. Geriatric Department, Associate professor of internal medicine, Ziaeian Hospital, Tehran University of Medical
Sciences, Tehran, Iran; 2. Ziaeian Hospital, Tehran University of Medical Sciences, Tehran, Iran; 3. Department of
Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; 4. Department
of Cardiology, School of Medicine, Ziaeian Hospital, Tehran University of Medical Sciences, Tehran, Iran; 5. Department of
Geriatric Medicine, School of Medicine, Ziaeian Hospital, Tehran, Iran; 6. Department of Health Services Management,
School of Health Managment and Information Sciences, Iran University of Medical Sciences, Tehran, Iran
958 Biomed Environ Sci, 2022; 35(10): 957-961

laboratory or radiological signs of COVID-19, a typical residuals. If the PH assumption was met, the
COVID-19 appearance on a CT scan, or a positive PCR association between the included variables and the
test, and were hospitalized. The required initial time to event (death was investigated using a Cox
information was extracted from the patients’ proportional hazard model). First, a univariable
records. Hospitalized patients were followed up, analysis using single variables at each model was
until discharge or death occurred. performed (α = 0.2). In the next step, significant
Background information, symptoms, and variables were entered into the multivariable Cox
underlying diseases were recorded in patients’ files regression model (α = 0.05). D-dimer levels were
(by asking patients or their families). The patients’ investigated separately and adjusted only for age
laboratory data, including blood factors (PTT, INR, D- and sex due to a high number of missing data. Data
dimer, and white blood cells) were measured at the were analyzed using STATA 14.
time of hospital admission. PT and PTT were A total of 870 COVID-19 patients were included
measured using a coagulation analyzer. The in this study. The mean age was 56.8 years and the
international sensitivity index and mean PT normal majority of the participants were male (58.0%),
range were defined as 1.02 and 13.5, respectively married (51.3%), and hospitalized on ward (77.3%).
and the INR was obtained D-dimer levels in the The mean white blood cells (WBC) was 7.33 × 109/L
plasma were measured using a commercial and 43.7% of participants were D-dimer negative.
qualitative test kit (SARANTASHKHIS). The decision Most of the patients displayed between 1.0 to 1.1
regarding the categories of laboratory parameters (82.9%) for INR, and a PTT of 25 and 36 s (83.5%)
was made based on the guidelines issued by the (Table 1).
Iranian Ministry of Health and Medical Education, The number of deaths was 43 (28.7%) in patients
expert opinion, and upper limit of normal defined by with an INR greater than 1.1 and 76 (10.6%) for INR
our hospital laboratory. Hospitalization category was between 1.0 to 1.1. Mortality in patients with PPT ≤
divided into two categories as ward and others 24 s, 25–36 s, and > 36 s was 21.4%, 12.2%, and
(emergency, ICU, and ICU-ward). The patients’ 20.9%, respectively. A total of 8.6% of patients
information was extracted from the patients’ files negative for D-dimer died and the highest
during the hospitalization period using a researcher- percentage of death was in patients with high D-
created data collection checklist. All missing or dimer level (1,600 to 3,200) (Table 2).
unknown records were covered by reviewing the The majority of surviving patients: 86.12% had
hospital medical record units or asking patients and INR = 1.0–1.1, 84.9% had PTT = 25–36 s, and 45.42%
their families. Missing blood parameter values were had negative D-dimer. However, in the majority of
completed by reading the blood test results in the deceased patients: 63.86% had INR = 1.0–1.1,
patients’ medical files. 74.78% had PTT = 25–36 s, and 31.25% were
Since the necessary data for the present study negative for D-dimer levels.
were extracted from the hospital data of hospitalized At the first the univariable analysis using single
patients, the sample size included all 1,050 patients variables was performed. As shown in Table 3, all
admitted due to COVID-19 at Ziaeian Hospital in variables except sex and PTT were statistically
Tehran. This study was approved by the ethics significant in this analysis. In the next step,
committee of Tehran University of Medical Sciences significant variables were entered into the Cox
(registered as: IR.TUMS.MEDICINE.REC.1400.379). proportional hazard model. Based on these results,
Percentage and frequency were used to describe age, INR, hospitalization section, and D-dimer levels
qualitative variables and the mean and standard were statistically significant in the fitted
deviation were used for quantitative variables. A Cox multivariable model (P < 0.05). Based on the
proportional hazards model was used in this study adjusted hazard ratio (HR), each year increase in age
because follow-up information was available. Since increased the probability of dying by 1.01 times. In
Cox models use the exact time of the event, they are addition, those with an INR of 1.0–1.1 were 1.99
more efficient compared to logistic and Poisson times more likely to die than those with an INR
regression models. The effect size obtained from the higher than 1.1. The risk of mortality in hospitalized
Cox hazards ratio indicates how many times the patients was 4.69 times higher than in other
variables affect the probability of dying. Before patients.
performing the analysis, the proportional hazard Due to the high number of missing data for D-
(PH) assumption was examined using the log-log of dimer levels compared to other variables, it was
survival and the statistical test based on Schoenfeld investigated separately. The HR for the univariable
Survival of COVID-19 patients and coagulation factors 959

analysis was 1.37 for D-dimer, which was statistically SARS-CoV-2 virus. Clinical manifestations of COVID-
significant (P = 0.02). Consequently, an adjustment 19 include fever, cough, diarrhea, shortness of
for only age and sex was performed and the results breath, fatigue, and pneumonia. Most patients
showed an HR of 1.29 (P = 0.01). This data indicates exhibit non-severe illness; however, some can
that for every increase in the level of D-dimer, develop serious COVID-19. In severe cases, SARS-
hazard of mortality increases by 29%. CoV-2 infection can lead to acute respiratory distress
COVID-19 is an infectious disease caused by the syndrome and even death. COVID-19 causes

Table 1. Baseline characteristics of under study patients

COVID-19 patients
Variable Missing (n)
(n = 870)
Age (years), mean ± SD 56.84 ± 17.96 −
Sex, n (%)
Male 505 (58.05) −
Female 365 (41.95)
Marital status, n (%)
Single 411 (47.85)
11
Married 441 (51.34)
Divorced 7 (0.8)
Hospitalization, n (%)
Ward 673 (77.36) −
Other 197 (22.64)
Outcome, n (%)
Discharged 751 (86.32) −
Died 119 (13.68)
INR
1.0–1.1 720 (82.95) 2
> 1.1 148 (17.05)
PTT (seconds)
≤ 24 14 (1.61)
−
25–36 727 (83.56)
> 36 129 (14.83)
WBC (× 109/L)†, mean ± SD 7.33 ± 5.68 −
D-dimer (ng/mL), n (%)
Negative (< 200) 174 (43.72)
One-plus (200−399) 127 (31.91)
472
Two-plus (400−99) 50 (12.56)
Three-plus (800−1,599) 29 (7.29)
Four-plus (1,600−3,200) 18 (4.52)
Note. INR, international normalized ratio; PTT, prothrombin time test (seconds); WBC, white blood cells.
†
Adjusted for age and sex.

Table 2. Clinical characteristics according to patient survival

Variable Survivors, n (%) Non-survivors, n (%)
INR
1.0–1.1 664 (89.4) 76 (10.6)
> 1.1 107 (71.3) 43 (28.7)
PTT (seconds)
≤ 24 11 (78.6) 3 (21.4)
25–36 638 (87.8) 89 (12.2)
> 36 102 (79.1) 27 (20.9)
D-dimer (ng/mL), n (%)
Negative 159 (91.4) 15 (8.6)
One-plus 119 (93.7) 8 (6.3)
Two-plus 40 (80) 10 (20)
Three-plus 20 (69) 9 (31)
Four-plus 12 (66.7) 6 (33.3)
Note. INR, international normalized ratio; PTT, prothrombin time test (seconds).
960 Biomed Environ Sci, 2022; 35(10): 957-961

thrombosis in the veins and arteries, and thus, complications, such as thrombosis. In addition, a
COVID-19 patients are prone to deep vein high INR and coagulation system disorders can cause
thrombosis and pulmonary embolism. This study ischemia, heart failure, and dysfunction in other
aimed to investigate the relationship between D- organs. High INR and dysfunction of the coagulation
dimer levels and mortality rate in hospitalized system can cause ischemia, heart failure, disorders in
COVID-19 patients using a survival analysis. other organs, and even death.
Based on the results of this study, D-dimer and The results of a retrospective cohort study
INR levels were associated with the survival of revealed that abnormal PTT was significantly
COVID-19 patients. Patients with a negative D-dimer associated with patient mortality[9]. However, no
test result had a lower risk of dying from COVID-19, significant relationship was found in the present
and this risk increased in association with higher D- study. The results of another meta-analysis study
dimer levels. According to one meta-analysis, D- showed that no differences were found regarding
dimer levels were found to be significantly higher in the levels of PTT between two groups of patients
patients with severe clinical conditions. Moreover, with severe and non-severe clinical conditions, as
patients who died had higher D-dimer levels well as surviving and deceased patients. According to
compared to surviving patients[3]. Elevated D-dimer meta-analysis results, PTT is unlikely to have an
levels in COVID-19 patients might be attributed to effect on the severity and mortality of COVID-19
several factors, including viral infections. Viral patients.
infections can cause an uncontrolled inflammatory This study had some limitations. First, the patient
response in the body and lead to the production of information was extracted from medical records and
excess thrombin via endothelial cell dysfunction[6,7]. was not available for some variables. Second, since
One of the other factors evaluated in the present this study was conducted at a single center, its
study was hospitalization and the risk of death from generalizability is limited. However, the hospital
COVID-19. The results demonstrated that there was under study is a referral hospital for COVID-19
a significant association between hospitalization and patients in Tehran, the capital of Iran.
the risk of death in patients. The clinical condition of The results of this study revealed that higher D-
those who were hospitalized was confirmed to be dimer and coagulation factor levels were associated
more severe. with a lower survival among COVID-19 patients.
In the current study, INR was associated with Since thrombosis and blood clots represent serious
patient survival. According to the results of this complications of COVID-19, there is a need to
study, COVID-19 patients with an INR greater than diagnose these disorders early in COVID-19 patients.
1.1 was found to increase the hazard of mortality by Therefore, it is recommended that coagulation
approximately two times compared to those with factor tests, including D-dimer and INR levels be
values less than 1.1. Another meta-analysis also performed on patients who require hospitalization.
showed that COVID-19 patients with severe clinical Furthermore, patients with high levels of these
conditions or those who died during follow-up had a factors should be treated with anticoagulants to
significantly prolonged INR during the first days of reduce the risk of death.
admission compared to those with mild disease[8]. Funding Details This project was not supported by
Although COVID-19 often affects the respiratory any institution and did not receive any funding.
system, it can also cause other serious Conflict of Interest The authors declare no conflict
Table 3. Cox Survival analysis results

Covariates Univariable Multivariable

(Baseline group) Hazard ratio 95% CI P-value Hazard ratio 95% CI P-value
Sex (female) 1.00 (0.69, 1.45) 0.900
Age 1.02 (1.01, 1.04) < 0.001 1.01 (1.00, 1.02) 0.004
WBC 1.02 (1.01, 1.04) 0.002 1.00 (0.97, 1.03) 0.633
INR (1.0–1.1) 2.79 (1.90, 4.09) < 0.001 1.99 (1.30, 3.04) 0.001
PTT 1.37 (0.90, 2.09) 0.125 1.36 (0.91, 2.04) 0.102
Hospitalization (ward) 5.50 (3.65, 8.29) < 0.001 4.69 (3.09, 7.12) < 0.001
D-dimer (negative) 1.37 (1.12, 1.68) 0.02 1.29† (1.04, 1.59) 0.010

Note. INR, international normalized ratio; PTT, prothrombin time test (seconds); WBC, white blood cells
(cell per microliter). †Adjusted for age and sex.
Survival of COVID-19 patients and coagulation factors 961

of interest. 2. Rostami M, Mansouritorghabeh H. D-dimer level in COVID-19

infection: a systematic review. Expert Rev Hematol, 2020; 13,
Acknowledgement The authors would like to
1265−75.
express their deepest gratitude to the Ziaeian 3. Gungor B, Atici A, Baycan OF, et al. Elevated D-dimer levels on
Hospital. admission are associated with severity and increased risk of
# mortality in COVID-19: a systematic review and meta-analysis.
Correspondence should be addressed to Isa
Am J Emerg Med, 2021; 39, 173−9.
Akbarzadeh, Tel: 98-903-601-8200, E-mail: iakbarzade@
4. Mihaila RG, Mihaila MD. Coagulation disorders in SARS-CoV-2
razi.tums.ac.ir; Mohammad Bidkhori, Tel: 98-990-250- infection. Biomed Pap Med Fac Univ Palacky Olomouc Czech
7302, E-mail: Bidkhori.mohammad93@gmail.com Repub, 2020; 164, 226−35.
Biographical note of the first author: Abolfazl 5. Bauer W, Galtung N, Neuwinger N, et al. A matter of caution:
coagulation parameters in COVID-19 do not differ from patients
Zendehdel, male, born in 1979, Doctor, Associate
with ruled-out SARS-CoV-2 infection in the emergency
Professor, faculty member of Tehran University of Medical department. TH Open, 2021; 5, e43−55.
Sciences, internist. 6. Levi M, van der Poll T. Coagulation and sepsis. Thromb Res,
Received: June 29, 2022; 2017; 149, 38−44.
7. Wong JP, Viswanathan S, Wang M, et al. Current and future
Accepted: August 29, 2022
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hypercytokinemia. Future Med Chem, 2017; 9, 169−78.
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