key: cord-0756901-mdny0fk5
authors: Zhang, Litao; Yan, Xinsheng; Fan, Qingkun; Liu, Haiyan; Liu, Xintian; Liu, Zejin; Zhang, Zhenlu
title: D‐dimer levels on admission to predict in‐hospital mortality in patients with Covid‐19
date: 2020-04-19
journal: J Thromb Haemost
DOI: 10.1111/jth.14859
sha: 401fe5e449d17b4092d5ed4ec1c26a8886b8e512
doc_id: 756901
cord_uid: mdny0fk5

BACKGROUND: The outbreak of the coronavirus disease 2019 (Covid‐19) shows a global spreading trend. Early and effective predictors of clinical outcomes is urgent needed to improve management of Covid‐19 patients. OBJECTIVE: The aim of the present study was to evaluate whether elevated D‐dimer levels could predict mortality in patients with Covid‐19. METHODS: Patients with laboratory confirmed Covid‐19 were retrospective enrolled in Wuhan Asia General Hospital from January 12, 2020 to March 15, 2020. D‐dimer levels on admission, and death events were collected to calculate the optimum cutoff using receiver operating characteristic curve. According to the cutoff, the subjects were divided into two groups. Then the in‐hospital mortality between two groups were compared to assess the predictive value of D‐dimer level. RESULTS: A total of 343 eligible patients were enrolled in the study. The optimum cutoff value of D‐dimer to predict in‐hospital mortality was 2.0 µg/ml with a sensitivity of 92.3% and a specificity of 83.3%. There were 67 patients with D‐dimer≥2.0 µg/ml, and 267 patients with D‐dimer <2.0 µg/ml on admission. 13 deaths occurred during hospitalization. Patients with D‐dimer levels≥2.0 µg/ml had a higher incidence of mortality when comparing to those who with D‐dimer levels < 2.0 µg/ml (12/67 vs 1/267, P<0.001, HR:51.5, 95%CI:12.9‐206.7). CONCLUSIONS: D‐dimer on admission greater than 2.0µg/mL (fourfold increase) could effectively predict in‐hospital mortality in patients with Covid‐19, which indicated D‐dimer could be an early and helpful marker to improve management of Covid‐19 patients.

The novel coronavirus, designated SARS-CoV-2, has caused a global outbreak of respiratory illness termed coronavirus disease 2019 since December, 2019 and are still spreading quickly in more than 100 countries. [1] [2] [3] There have been more than 600 thousand patients with confirmed Covid-19 worldwide by the end of March, 2020. [3] [4] [5] One of the key issues has been the very high volume of patients presenting to health centers or hospitals during the outbreak. It clearly overwhelms the human and mechanistic capacities available, especially the need for critical care support. As such, risk stratification measures would clearly be helpful [5, 6] . Therefore, early and effective predictors of clinical outcomes are urgent needed for risk stratification of Covid-19 patients. D-dimer originates from the formation and lysis of cross-linked fibrin and reflects activation of coagulation and fibrinolysis [7] . It has been reported that was associated with hemostatic abnormalities, and markedly elevated D-dimer levels were observed in those non-survivors [8] . However, the prognosis value and the optimal cut-off value for D-dimer on admission to predict mortality have not been well evaluated.

The study was a retrospective study conducted in Wuhan Asia General Hospital (Wuhan, China), which was a designated hospital for Covid-19 patients. Adult (aged 18 years or elder) patients with laboratory-confirmed Covid-19 between January 12, 2020 and March 15, 2020 were retrospectively screened. The diagnosis of Covid-19 was according to World Health Organization interim guidance [9] and confirmed by RNA detection of the SARS-CoV-2 in onsite clinical laboratory. A total of 343 participants who had a D-dimer level on admission and had a definite outcome (dead or survival) were enrolled. The study was approved and the requirement for informed consent was waived by the Ethics Commission (WAGHMEC-KY-202004).

All clinical, laboratory, and outcome data were extracted from electronic medical records using a standardized data collection form. All data were checked by two physicians (SY and XL) and a third researcher (ZL) adjudicated any difference in interpretation between the two primary Accepted Article reviewers.

Blood samples were collected within 24 hours after admission to perform routine laboratory tests, such as blood count, coagulation profile, serum biochemical tests (including renal and liver function) et al in onsite laboratory. D-dimer was determined on CS5100 automatic coagulation analyzer (Sysmex, Kobe, Japan) by utilizing a latex-enhanced photometric immunoassay (Siemens, Marburg, Germany). Inter and intra-day variability coefficients were 3.41% and 4.22%.

The laboratory reference range was 0-0.5 µg/ml. The D-dimer result was expressed in µg/ml FEU (Fibrinogen Equivalent Unit). All measurements were done within 2 hours after blood sampling.

Continuous and categorical variables were presented as mean±standard deviation or median (Inter-quartile range, IQR), as appropriate. Categorical variables were presented as n (%). Event frequencies were compared with chi-square test. Other comparisons between two groups were made with unpaired Student t test or Mann-Whitney U test. The optimal D-dimer cutoff point and C-statistic of routine tests were evaluated by receiver operator characteristic (ROC) curve. The outcomes were compared by Kaplan-Meier survival analysis. Hazard ratio (HR) and 95% confidential interval (95% CI) were calculated by log-rank tests. The prognostic values of D-dimer and clinical variables were analyzed with Cox-proportional hazard models. A value of p<0.05 was accepted as statistically significant. The statistical software package MedCalc Statistical Software (version 16.2, Ostend, Belgium) were used for analyses.

Of 343 eligible patients, the median age was 62 years (IQR, 48-69 years), ranging from 18 years to 92 years. 37.6% (129/343) patients were older than 65 years. 50.3% (174/343) patients were female. Listed in Table 1 are the basic clinical characteristics of the patients, including age, gender, comorbidities, and routine laboratory results on admission. A total of 13 all-cause deaths occurred during hospitalization. The optimum cutoff value for D-dimer to predict all-cause deaths was 2.0 µg/ml using ROC curve ( Figure 1 ) with a sensitivity of 92.3% and a specificity of 83.3%.

This article is protected by copyright. All rights reserved Area under ROC curve for all-cause deaths was 0.89. Among routine laboratory tests, D-dimer has the highest C-index to predict in-hospital mortality in Covid-19 patients (Table 2) . Besides, The C-indices indicates lymphocyte, prothrombin time, and C-reaction protein are also strong predictors for these patients (Table 2) .

According to the optimum cutoff value, 276 patients' D-dimer levels on admission were less than 2.0 µg/ml, and 67 patients had D-dimer levels over 2.0 µg/ml. Compared to those patients with D-dimer levels below 2.0 μ g/ml, patients with D-dimer levels ≥ 2.0 µg/ml had a higher incidence of underlying disease, such as diabetes (p=0.007), hypertension (p<0.001), coronary heart disease (p=0.02) and stroke history (p<0.001). Additionally, lower level of lymphocyte (p<0.001), hemoglobin (p=0.003) , platelet count (p=0.009) and higher level of neutrophil (p<0.001), c-reaction protein (p<0.001), and prothrombin time (p<0.001) were also observed in those with D-dimer levels ≥2.0 µg/ml. 

The main finding of this study is that D-dimer on admission greater than 2.0µg/mL was the independent predictor of in hospital death for patients with Covid-19. This finding provides a well-established cutoff value to identify those patients with Covid-19 who have poor prognosis at an early stage.

D-dimer elevation has been reported to be one of the commonest laboratory findings noted in

This article is protected by copyright. All rights reserved Covid-19 patients requiring hospitalization. Guan and colleagues analyzed 1099 patients with laboratory-confirmed Covid-19 from over 550 hospitals in China [5] , and found the non-survivors had a significantly higher D-dimer (median: 2.12 μg/ml) than that of survivors (median: 0.61 μg/ml). Similarly, Ning T et al also observed abnormal coagulation results, especially markedly elevated D-dimer in deaths with Covid-19 [8] . Fei Zhou et al conducted a retrospective study involved 191 patients with Covid-19 [10] ， and found that d-dimer greater than 1 µg/mL on admission was associated with in-hospital death (HR:18.42, 95%CI: 2.64-128.55). Huang and colleagues showed D-dimer levels on admission were higher in patients needing critical care support than those who did not require it (median: 0.5 µg/ml [1] . However, these previous studies did not provide well evaluated cutoff for D-dimer. Therefore, a recent guidance on recognition and management of coagulopathy in Covid-19 from International Society of Thrombosis and Haemostasis (ISTH) "arbitrarily defined markedly raised D-dimers on admission as three-four folds increase" [6] . In current study, a clear cutoff value (2.0 µg/ml, fourfold increase) for D-dimer was well established by ROC curve. Notably, of 12 non-survivors with D-dimers ≥2.0 µg/ml, 7 of whom had no severity symptoms on admission. Thus, for patients who have markedly raised D-dimers (cut-off: 2.0 µg/ml, four-fold increase), admission to hospital and closely monitoring should be considered even in the absence of other severity symptoms.

Elevation of D-dimer indicated a hypercoagulable state in patient with Covid-19, which might be attributed to several reasons as follows. First, virus infections are usually accompanied by an aggressive pro-inflammatory response and insufficient control of an anti-inflammatory response [11] . It might induce the dysfunction of endothelial cells, resulting in excess thrombin generation [12] . Second, the hypoxia found in severe Covid-19 can stimulate thrombosis through not only increasing blood viscosity, but also a hypoxia-inducible transcription factor-dependent signaling pathway [13, 14] . Third, hospitalized patients, especially severe patients with Covid-19, were more intend to have elder ages, underlying conditions, long-term bed rest and invasive treatment et al., which were all risk factors of hypercoagulation or thrombosis [15] [16] [17] . As evidence, the lung organ dissection of critical patient with Covid-19 have reported occlusion and micro-thrombosis formation in pulmonary small vessels [18] . Forth, some patients might develop

This article is protected by copyright. All rights reserved to sepsis-induced coagulopathy or even disseminated intravascular coagulation [8, 19] . At all events, elevated D-dimer was always associated with unfavorable events [20, 21] . Previously, the lack of specificity has been regarded as a disadvantage of D-dimer [7] . However, low specificity has presently been transformed into one of its advantage in the evaluation of prognosis.

This study has several limitations. First, our study might have selection bias because it was a single-center, retrospective study, even if it had sufficient power to detect the significant differences between groups in mortality. Despite our efforts to include all qualified patients, some patients still excluded in enrollment due to absence of D-dimer level on admission. Second, due to difference of patient's size and medical resources, the lengths from illness onset to admission of the included patients might not be representative, which might influence D-dimer levels on admission. In addition, the half-life of d-dimer was approximately 8 hours [22] . Therefore, dynamic measurement of D-dimer will reveal more information. Third, the fully adjusted model analysis for HR was not performed, given the low number of events. Forth, a multiple-parameter prediction model including D-dimer and other variables might provide better predictive ability for Covid-19 patients.

D-dimer on admission greater than 2.0µg/mL (fourfold increase) could effectively predict in-hospital mortality in patients with Covid-19, which indicated D-dimer could be an early and helpful marker to improve management of Covid-19 patients. 

This article is protected by copyright. All rights reserved Accepted Article

The optimum cutoff point, identified as the point closest to upper left corner, was 2.0 μg/ml with 92.3% for sensitivity and 83.3% for specificity. Area under receiver operator characteristic curve for mortality was 0.89.

Statistical significance of separation between two groups was achieved at seven days after admission. HR: Hazard ratio;

Accepted Article

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. Jama. 2020; Epub ahead of print

Coronavirus disease (COVID-19) Pandemic

The novel coronavirus (2019-nCoV) global

China Medical Treatment Expert Group for C. Clinical Characteristics of Coronavirus Disease 2019 in China

ISTH interim guidance on recognition and management of coagulopathy in COVID-19

Epub ahead of print

Use of D-dimer in oral anticoagulation therapy

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected: interim guidance

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Current and future developments in the treatment of virus-induced hypercytokinemia

Coagulation and sepsis

The stimulation of thrombosis by hypoxia

Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy

D-dimer concentration increases with age reducing the clinical value of the D-dimer assay in the elderly

Accepted Article This article is protected by copyright. All rights reserved

A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score

Inflammation and thrombosis in diabetes

Chinese management guideline for COVID-19 (version 6.0). The 6th edition edn

Standardization Committee on DIC, the S, Standardization Committee on P, Critical Care of the International Society on T, Haemostasis. Diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation

D-dimer to guide the intensity of anticoagulation in Chinese patients after mechanical heart valve replacement: a randomized controlled trial

D-dimer testing in laboratory practice

The authors would like to thank all people who helped or supported Wuhan to battle against to the novel coronavirus outbreak. The authors would like to thank Xuan Zheng and Youping Chen for review of the manuscript.

This article is protected by copyright. All rights reserved