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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 40-45

Clinical study of anticoagulant therapy in patients with severe coronavirus disease: A single-center retrospective analysis


1 Department of Vascular Surgery, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
2 Department of Thoracic Surgery, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China
3 Department of Pediatrics, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, Wuhan, China

Date of Submission14-Apr-2021
Date of Decision26-Apr-2021
Date of Acceptance27-Apr-2021
Date of Web Publication28-Jun-2021

Correspondence Address:
Dr. Chao Yang
Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan
China
Dr. Qin Li
Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan
China
Dr. Yi-Qing Li
Department of Vascular Surgery, Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/VIT-D-21-00010

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  Abstract 


OBJECTIVE: The prognosis of COVID-19 is related to thrombotic events. This study investigated prognostic risk factors, anticoagulant therapy effects, and potential instruction of treatment or prognostic with D-dimer in patients with severe COVID-19 receiving anticoagulant therapy.
MATERIALS AND METHODS: We undertook a retrospective study of 87 severe COVID-19 patients who had prophylactic low-molecular-weight heparin (LMWH) therapy. Patients were divided into two groups according to whether high-flow oxygen therapy was required during hospitalization: Better and poor prognoses.
RESULTS: Multivariate logistic regression using risk factors measured before LMWH therapy revealed that older age (P < 0.035) and higher C-reactive protein (CRP) levels (P = 0.002) had a prognostic value. Anticoagulant therapy yielded significant changes in CRP levels (P < 0.001), white blood cell counts (P = 0.001), neutrophil counts (P < 0.001), neutrophil/lymphocyte ratios (P < 0.001), eosinophil counts (P = 0.031), and D-dimer levels (P < 0.001) in the better prognosis group and in D-dimer levels (P = 0.043) only in the poor prognosis group. Prognoses at different D-dimer levels at anticoagulant therapy initiation varied. Among 47 and 40 patients with D-dimer levels ≤4 and >4 μg/ml fibrin equivalent unit (FEU), 33 (70.6%) and 18 (45%) had better prognosis (P = 0.012), respectively.
CONCLUSION: Anticoagulant therapy reduced inflammation in patients with better prognosis; conversely, minimal effect was observed in those with poor prognosis. During LMWH therapy patients with D-dimer levels, patients receiving anticoagulant therapy at D-dimer levels ≤4 μg/ml FEU had a better prognosis than those at >4 μg/ml FEU.

Keywords: Anticoagulant, COVID-19, D-dimer, inflammation, prognosis


How to cite this article:
Zhou P, Cai CQ, Li JS, Jiang HZ, Ke ZX, Zhang S, Wang ZJ, Yang C, Li Q, Li YQ. Clinical study of anticoagulant therapy in patients with severe coronavirus disease: A single-center retrospective analysis. Vasc Invest Ther 2021;4:40-5

How to cite this URL:
Zhou P, Cai CQ, Li JS, Jiang HZ, Ke ZX, Zhang S, Wang ZJ, Yang C, Li Q, Li YQ. Clinical study of anticoagulant therapy in patients with severe coronavirus disease: A single-center retrospective analysis. Vasc Invest Ther [serial online] 2021 [cited 2021 Jul 27];4:40-5. Available from: https://www.vitonline.org/text.asp?2021/4/2/40/319599




  Introduction Top


Coronavirus disease (COVID-19)[1] has rapidly spread worldwide. With the continuous efforts of various countries and international organizations, its pandemic has been gradually controlled. However, recent reports on the emergence of mutations of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes COVID-19 have increased the challenges regarding its management. Although vaccines are gradually being administered, no specific drugs for the management of COVID-19 have been developed to date. Therefore, preventing further disease exacerbation in patients with COVID-19 has become critical.

Several studies have shown that D-dimer levels significantly increased in deceased patients with COVID-19, suggesting the possibility of the occurrence of venous thromboembolism (VTE) as one of the complications.[2] Autopsy results revealed microscopic evidence of lung thrombosis and deep-vein thrombosis (DVT) at occurrence rates of up to 25%, indicating a high risk of VTE in patients with COVID-19.[3],[4] Endothelial injury is an underlying mechanism that may be associated with inflammation and thrombosis in severe COVID-19.[5] One potential hypothesis is that the virus directly or indirectly interferes with coagulation pathways, causing systemic thrombosis.[6] Cai et al. reported that DVT was found in 48% of asymptomatic patients with COVID-19 with an increased Padua score or Caprini index on ultrasound scanning.[7] The incidence of arterial thrombosis is also increasing. Bilaloglu et al. found that among 3334 consecutive patients with COVID-19 hospitalized in a large health system comprising four hospitals in New York City, 11.1% were diagnosed with arterial thrombosis.[8]

Recent studies have shown that anticoagulant therapy reduces COVID-19-related mortality and improves patient prognosis.[9] With further research, preventive anticoagulant therapy has gradually been recommended as the basic treatment for COVID-19.[10] In this study, the clinical data of 87 patients with severe COVID-19 who were treated with anticoagulant therapy were analyzed. This study primarily aimed to analyze prognostic risk factors, potential instruction of treatment or prognostic with D-dimer, and anticoagulant therapy effects among patients with COVID-19.


  Materials and Methods Top


This retrospective cohort study included 87 patients with confirmed COVID-19 pneumonia who were hospitalized at the Infection Division of Union Hospital, Huazhong University of Science and Technology in Wuhan, China from January 25 to March 15, 2020. All patients were diagnosed with COVID-19 pneumonia according to the World Health Organization interim guidance.[11] A retrospective review of the characteristics of these patients was performed using the electronic medical record system of our hospital, which was monitored until April 30, 2020. The study was approved by the Ethics Committee of Union Hospital (Wuhan, China) and was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Informed consent was provided by all patients.

The clinical classification of COVID-19 was based on the Diagnosis and Treatment Plan of COVID-19 suggested by the National Health Commission of China (eighth edition).[12] Mild COVID-19 was defined as the presence of fever, respiratory complications, or other symptoms, but with no imaging findings suggestive of pneumonia. In contrast, severe COVID-19 was defined as the presence of one or more of the following parameters: respiratory rate ≥30 breaths/min, oxygen saturation ≤93% at rest, and PaO2/FiO2 ≤300 mmHg. In this study, patients (better or worse prognosis) were divided according to their demand of body to oxygen. Namely, whether high-flow oxygen therapy was required during hospitalization, including mask oxygen inhalation, noninvasive or invasive mechanical ventilation (NIMV or IMV), or IMV with additional corporeal membrane oxygenation. Further, the association between prognosis and different D-dimer levels at the initiation of anticoagulant therapy was studied. In order to study the prognosis in different cut-off points of D-dimer level, sequential cut-off point of D-dimer level was chosen from 2, 3, and 4 μg/ml fibrin equivalent unit (FEU). All patients were treated with supportive care, if needed, including administration of oxygen, antibiotics, antiviral and anticoagulant drugs, immunomodulators, or methylprednisolone. All patients who were treated with prophylactic anticoagulant therapy received low-molecular-weight heparin (LMWH; 40–60 mg enoxaparin/day) for ≥6 days.

Normally and nonnormally distributed quantitative variables were compared using Student's t-test and the Mann–Whitney U test, respectively. Categorical variables were compared using the Chi-squared test. The results were presented as means ± standard deviations, medians (interquartile ranges), or numbers (percentages), as appropriate. The Kruskal–Wallis test was performed for ordinal variables, such as blood laboratory values. To determine the prognosis risk factors among patients with severe COVID-19 receiving anticoagulant therapy, we used univariate and multivariate logistic regression models. The hematological variables before and after anticoagulant therapy were tested using a paired samples test. P < 0.05 were considered statistically significant. All analyses were performed using Statistical Program for Social Sciences (SPSS software, version 25.0).


  Results Top


Patient characteristics

A total of 87 patients with severe COVID-19 receiving anticoagulant therapy were enrolled in this study. Their baseline clinical and laboratory characteristics are shown in [Table 1]. Among them, 36 had poor prognosis, corresponding to 41.8% of all patients with COVID-19. The median age of patients with poor prognosis was 68.5 (57.8–71.8) years. Decreased lymphocyte (poor: 0.57 [0.46–0.93] × 109/L; better: 0.85 [0.58–1.13] × 109/L, P = 0.024) and eosinophil (poor: 0 [0–0.01] × 109/L; better: 0.02 [0–0.07] × 109/L, P = 0.007) counts were more common in patients with poor prognosis than in those with better prognosis. The C-reactive protein (CRP) level (poor: 88.86 [65.85–134.43] mg/l; better: 39.92 [18.72–75.67] mg/l, P < 0.001), neutrophil/lymphocyte count (N/L) ratio (poor: 11.74 [6.77–15.97]; better: 5.34 [3.58–10.56], P = 0.002), and procalcitonin (PCT) (P = 0.019) were significantly higher in the poor prognosis group.
Table 1: Baseline characteristics in severe anticoagulant coronavirus disease-2019 patients

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Prognostic risk factors among patients with severe COVID-19 on anticoagulant therapy

Univariate and multivariate analyses were performed to identify prognostic risk factors among patients with severe COVID-19 receiving anticoagulant therapy. In the univariate analysis, with the better prognosis group as the reference group, the following factors were associated with poor prognosis: CRP levels (odds ratio [OR], 1.021; 95% confidence interval [CI], 1.010–1.032; P < 0.001) and lymphocyte counts (OR, 0.278; 95% CI, 0.087–0.890; P = 0.031) [Table 2]. Subsequently, the complete data of all 87 patients with severe COVID-19 receiving anticoagulant therapy, including age, comorbidity type, CRP levels, white blood cell (WBC) counts, lymphocyte counts, D-dimer levels, PCT, and N/L ratio, were included in the multivariate logistic regression model. Older age (OR, 0.949; 95% CI, 0.903–0.996; P = 0.035) and higher CRP levels (OR, 1.020; 95% CI, 1.007–1.033; P = 0.002) were associated with poor prognosis among patients with severe COVID-19 receiving anticoagulant therapy [Table 3].
Table 2: Univariate logistic regression analysis of prognostic risk factors in severe anticoagulant coronavirus disease-2019 patients

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Table 3: Multivariable logistic regression analysis of prognostic risk factors in severe anticoagulant coronavirus disease-2019 patients

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Anticoagulant therapy effect on COVID-19

The anticoagulant therapy effect in both prognosis groups was analyzed. Significant changes in the CRP level [P < 0.001, [Figure 1]a], WBC count [P = 0.001, [Figure 1]b], neutrophil count [P < 0.001, [Figure 1]c], N/L ratio [P < 0.001, [Figure 1]e], eosinophil count [P = 0.031, [Figure 1]g], and D-dimer level [P < 0.001, [Figure 1]h] were observed in patients with better prognosis after anticoagulant therapy and in the D-dimer level (P = 0.043) only in patients with poor prognosis [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d, [Figure 1]e, [Figure 1]f, [Figure 1]g, [Figure 1]h.
Figure 1: Anticoagulant therapy effect in patients with severe COVID-19. (a-h) Anticoagulant therapy decreased the CRP level, white blood cell count, neutrophil count, and N/L ratio and increased the eosinophil count in patients with a better prognosis compared with those in patients with poor prognosis. (a) CRP level; (b) white blood cell count; (c) neutrophil count; (d) lymphocyte count; (e) N/L ratio; (f) monocyte count; (g) eosinophil count; (h) D-dimer level. COVID-19, coronavirus disease; CRP, C-reactive protein; N/L, neutrophil/lymphocyte count

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Prognosis at different D-dimer levels

The prognosis in different cut-off points of D-dimer level was analyzed [Supplementary Table 1]. Taking observational data matching and statistical significance of the different prognoses into account, D-dimer level of 4 μg/ml as a cut-off point was chose. All 87 patients were divided into two groups: 47 patients with D-dimer levels ≤4 μg/ml FEU and 40 patients with D-dimer levels >4 μg/ml FEU at the initiation of anticoagulant therapy. Among those patients, 33 (70.6%) who had D-dimer levels ≤4 μg/ml FEU and only 18 (45%) who had D-dimer levels >4 μg/ml FEU had better prognosis (P = 0.012) [Table 4]. Furthermore, the number of days of changes in the lung computed tomography (CT) findings was analyzed in 38 patients with complete lung CT data. Similarly, they were divided according to their D-dimer levels at the initiation of anticoagulant therapy: ≤4 μg/ml FEU (n = 20) and >4 μg/ml FEU (n = 18). The duration of CT changes in the group with D-dimer levels ≤4 μg/ml FEU (12.2 ± 0.76 days) was shorter than that in the group with D-dimer levels >4 μg/ml FEU (16.2 ± 1.5 days) (P = 0.017) [Supplementary Figure 1]a. A pair of representative CT images are shown in [Supplementary Figure 1]b, [Supplementary Figure 1]c, [Supplementary Figure 1]d, [Supplementary Figure 1]e.
Table 4: Prognosis in anticoagulant therapy at different D-dimer level before anticoagulation was started

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  Discussion Top


D-dimers serve as a biomarker of fibrin degradation that can be measured in the plasma. Plasma D-dimer levels show high sensitivity in the diagnosis of VTE, but with only modest specificity. Thus, VTE can be misdiagnosed owing to numerous pathophysiological events associated with increased D-dimer levels, such as inflammation, malignancy, pregnancy, myocardial infarction, disseminated intravascular coagulation, aortic dissection, and liver and kidney dysfunctions.[13] Tang et al. reported a significant increase in D-dimer levels in deceased patients with COVID-19.[14] Furthermore, Wu et al. demonstrated that the D-dimer level was a risk factor associated with the occurrence of acute respiratory distress syndrome and its progression to death.[15] However, in this study, the D-dimer level was not found to be a prognostic risk factor in patients with severe COVID-19 receiving anticoagulant therapy. Tang et al. showed that D-dimer levels could also indicate the effectiveness of anticoagulant therapy.[16] Thus, we speculate that these findings, i.e., changes in D-dimer levels after anticoagulant therapy, might be an anticoagulant therapy effect; however, they can also be attributed to the small sample size.

Preliminary evidence suggested that LMWH, with both anticoagulant and anti-inflammatory effects, can improve the prognosis of patients with severe COVID-19 meeting the SIC criteria.[6] In this study, anticoagulant therapy reduced inflammation in some patients with a better prognosis. However, no significant changes were found in patients with poor prognosis, which may be related to individual differences. Although thrombosis is currently believed to be an important factor affecting the prognosis of patients with COVID-19, other comorbidities, such as hypertension, diabetes, and chronic obstructive pulmonary disease, will also aggravate a patient's condition. One of the underlying mechanisms may be increased plasmin levels in patients with comorbidities. A previous study suggested that plasmin may extracellularly cleave to newly inserted furin sites in the S protein of SARS-CoV-2, thereby increasing its infectivity and virulence.[17] Elevated plasmin levels are common in individuals with underlying medical conditions, such as hypertension, diabetes, cardiovascular disease, cerebrovascular disease, and chronic renal illness. Thus, individuals with these conditions are susceptible to SARS-CoV-2 infection and have a poor prognosis.

Our analysis of the D-dimer levels in patients with different prognoses at the initiation of anticoagulant therapy revealed that the prognosis was better for those with D-dimer levels ≤4 μg/ml FEU than for those with D-dimer levels >4 μg/ml FEU. This result further demonstrates the importance of early administration of VTE drugs. Lin et al. suggested initiating the prophylactic anticoagulation regimen once the D-dimer level has increased four times its normal levels.[18] Nevertheless, larger prospective studies are required to determine whether the D-dimer levels can be used to assess the effectiveness of an anticoagulant therapy; however, abnormal and significant changes in these values can be used as a basis and direction for clinical treatment.

This study has several limitations. First, this study had a retrospective design, which is inherent to observational studies. Second, matching data of patients with severe COVID-19 who were not receiving anticoagulant therapy were unavailable, although the number of such patients is small. Third, owing to the high infectivity and pathogenicity of SARS-CoV-2 that limited the ability to perform routine VTE assessment based on Doppler studies in the lower limb veins and pulmonary artery CT angiography, many potential patients with thrombosis were treated only with prophylactic anticoagulant doses, thereby reducing the therapeutic effect.


  Conclusion Top


The prognosis was better for patients receiving anticoagulant therapy at D-dimer levels ≤4 μg/ml FEU than for those with D-dimer levels >4 μg/ml FEU. Anticoagulant therapy reduced inflammation in patients with better prognosis but yielded only a minimal effect in those with poor prognosis.

Acknowledgments

We would like to thank the National Natural Science Foundation of China (No. 81900432 to Q.L. and No. 82000729 to C.C.) and Hubei Provincial Natural Science Foundation of China (No. 2019CFB499).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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