key: cord-0832485-54gddm06
authors: Zhu, Jieyun; Pang, Jielong; Ji, Pan; Zhong, Zhimei; Li, Hongyuan; Li, Bocheng; Zhang, Jianfeng; Lu, Junyu
title: Coagulation dysfunction is associated with severity of COVID‐19: a meta‐analysis
date: 2020-07-24
journal: J Med Virol
DOI: 10.1002/jmv.26336
sha: 8e3189cad7b8537b8689e44ebc7b25c41e29ba3a
doc_id: 832485
cord_uid: 54gddm06

OBJECTIVE: To systematically analyse the blood coagulation features of coronavirus disease 2019 (COVID‐19) patients in order to provide a reference for clinical practice. METHODS: An electronic search in PubMed, EMbase, Web of Science, Scopus, CNKI, WanFang Data and VIP databases to identify studies describing the blood coagulation features of COVID‐19 patients from 1 January 2020 to 21 April 2020. Three reviewers independently screened literature, extracted data and assessed the risk of bias of included studies, then, the meta‐analysis was performed by using Stata12.0 software. RESULTS: Thirty‐four studies involving 6,492 COVID‐19 patients were included. Meta‐analysis showed that patients with severe disease showed significantly lower platelet count (WMD ‐16.29×10(9)/L, 95%CI ‐25.34 to ‐7.23) and shorter activated partial thromboplastin time (APTT; WMD ‐0.81s, 95%CI ‐1.94 to 0.33) but higher D‐dimer levels (WMD 0.44μg/ml, 95%CI 0.29 to 0.58), higher fibrinogen levels (WMD 0.51g/L, 95%CI 0.33 to 0.69) and longer prothrombin time (PT; WMD 0.65s, 95%CI 0.44 to 0.86). Patients who died showed significantly higher D‐dimer levels (WMD 6.58μg/ml, 95%CI 3.59 to 9.57), longer PT (WMD 1.27s, 95%CI 0.49 to 2.06) and lower platelet count (WMD ‐39.73×10(9)/L, 95%CI ‐61.99 to ‐17.45) than patients who survived. CONCLUSION: Coagulation dysfunction is common in severe COVID‐19 patients and it is associated with severity of COVID‐19. This article is protected by copyright. All rights reserved.

Coronavirus disease 2019 (COVID-19) has spread rapidly around the world since its emergence in humans last December [1] [2] . According to data released by WHO, as of 02:00 on April 24, there have been 2,626,321 confirmed cases of COVID-19 patients including 181,938 deaths worldwide, with a fatality rate of approximately 6.93% [2] .

According to a study conducted by Dr Chen and colleagues, 36% of the patients showed an elevated levels of D-dimer, 16% showed a reduced activated partial thromboplastin time (APTT) and 30% showed a shortened prothrombin time (PT) [3] .

Besides, Wang et al conducted a retrospective study of 339 COVID-19 patients, including 80 critical and 159 severe cases. Their results showed that the PT was significantly prolonged, and D-dimer levels was evidently elevated in the death group [4] . Another study by Professor Tang, found that the non-survivors COVID-19 patients revealed significantly higher levels of D-dimer and FDP, longer PT and APTT compared to survivors group on admission [5] . Elevated levels of D-dimer is an independent risk factor for acute respiratory distress syndrome (ARDS) and mortality in COVID-19 patients [6] .

Although the above studies have shown that COVID-19 has been linked to coagulation dysfunction, most of them were single-center studies that were conducted in a specific hospital or region. Due to differences in study design and small samples, the key outcomes of these studies are complicated and unclear. A meta-analysis of nine studies suggested that COVID-19 involves longer PT and elevated D-dimer levels [7] , yet several large clinical studies of the disease have been conducted since then and have reported inconsistent findings about coagulation dysfunction [8] [9] [10] . Therefore we meta-analysed the Accepted Article blood coagulation features of COVID-19 patients in order to provide a reference for clinical decisions and future research.

This meta-analysis was carried out according to Preferred Reporting Items for Meta-Analyses of Observational Studies in Epidemiology (MOOSE) Statement [11] . The databases PubMed, Embase, Web of Science, Scopus, Chinese National Knowledge Infrastructure, WanFang and China Science and Technology Journal Database were systematically searched for studies published from 1 January 2020 to 21 April 2020 without language limits. We also manually searched the lists of included studies to identify additional potentially eligible studies. If there were two or more studies described the same population, only the study with the largest sample size was chosen. There was no language restriction placed in the literature search, but only literature published online was included. The following keywords were used, both separately and in combination, as part of the search strategy in each database: "Coronavirus", "2019-nCoV", "COVID-19", "SARS-CoV-2", "D-dimer", "platelet", "coagulation function", "blood clotting", "coagulation", "activated partial thromboplastin time", "fibrinogen" or, "prothrombin time".

Studies were included in the meta-analysis if they met the following criteria: (1) if they had cohort, case-control, or case series designs involving more than 40 patients with confirmed covid-19; (2) if they reported sufficient details about blood coagulation parameters; (3) the diagnosis and severity classification was based on the New Coronavirus Pneumonia Prevention and Control Program in China or WHO interim guideline, and patients were grouped into different types such as mild, moderate, severe, and critical pneumonia; (4) the coagulation parameters of the covid-19 patients were the findings when they were admitted to the hospital or first visited the hospital without the use of anticoagulant prophylaxis or treatment, disease severity classification was done at the end of the follow-up.

Three reviewers independently selected literature, extracted data to an Excel database. And any disagreement was resolved by another reviewer. When required, the authors were contacted directly to obtain further information and clarifications regarding their study. Data extraction included: The first author's surname and the date of publication of the article, study design, sample size, age, outcome measurement data; relevant elements of bias risk assessment.

The quality of included studies was independently evaluated by the three reviewers based on the Newcastle-Ottawa Scale (NOS) [12] guidelines. Any disagreement was resolved by another reviewer. This evaluation was conducted based on a set of nine criteria, and studies with a score greater than 6 were considered to be of high quality (total score = 9).

Data from studies reporting continuous data as ranges or as median and interquartile ranges were converted to mean ± SD [13] . The weighted mean differences (WMDs) in continuous variables between patient groups were calculated, together with the associated 95% confidence intervals (CIs). All meta-analyses were performed using STATA 12 (StataCorp, TX, USA). A fixed-effects model was used when the I 2 statistic was below 50% and the associated P > 0.10; otherwise, a random-effects model was used. Funnel plot together with Egger's regression asymmetry test and Begg's test were used to evaluate publication bias. A two-tailed P< 0.05 was regarded as statistically significant.

A total of 378 records were identified from the various databases examined. 48 additional records were identified from the Chinese Medical Journal Network. After a detailed assessment based on the inclusion criteria, 34 studies [4,8-10,14-43] involving 6,492 COVID-19 patients were included in the meta-analysis (Fig.1 ).

All studies included in the meta-analysis were conducted in China and published between 24 January 2020 and 16 April 2020. These retrospective studies examined Chinese patients distributed across 31 provinces. Follow-up data was reported for most patients. All studies received quality scores varied from 6 to 9 points, indicating high quality (Table 1) .

Pooled results revealed that patients with severe disease showed significantly lower platelet count (WMD -16.29×10 9 /L, 95%CI -25.34 to -7.23) and shorter activated partial thromboplastin time (APTT; WMD -0.81s, 95%CI -1.94 to 0.33) but higher D-dimer level (WMD 0.44μg/ml, 95%CI 0.29 to 0.58), higher fibrinogen level (WMD 0.51g/L, Another analysis of seven studies [4,14-19] whose primary outcome was death. The results showed that patients who died showed significantly higher D-dimer levels (WMD 6.58μg/ml, 95%CI 3.59 to 9.57), longer prothrombin time (WMD 1.27s, 95%CI 0.49 to 2.06) and lower platelet count (WMD -39.73×10 9 /L, 95%CI -61.99 to -17.45) ( Table 2 ).

There was heterogeneity in the pooled relusts of the platelet count and D-dimer. To determine sensitivity, the meta-analyses of platelet count and D-dimer levels from all included studies were repeated after omitting each study in turn, and the results were similar to those obtained with the entire dataset, indicating the reliability and stability of our meta-analysis (Fig.7) .

A funnel plot based on the outcome of platelet count showed the P-values of Egger's test and Begg's test were 0.516 and 0.529 respectively, suggesting no significant risk of publication bias (Fig.8) .

Previous studies have shown that COVID-19 infection has been linked to coagulation dysfunction and coagulopathy appears to be related to severity of illness and resultant thromboinflammation which may increase risk of associated mortality [23, 44, 45] .This suggested that monitoring blood coagulation parameters during course of the disease may be helpful for the early identification of severe COVID-19 patients, which is essential for healthcare providers in their efforts to treat patients and contain the current outbreak.

Compared to the nine studies involving 1,105 patients in the most recent relevant meta-analysis [7] , the present work includes 34 studies published up to 21 April 2020 and a total pooled population of 6,492 COVID-19 patients. Our results indicate that low platelet count, elevated D-dimer levels and prolonged PT occur more often in severe than mild COVID-19, and they occur more often in patients who die from the disease than in those who survive. Consistent with this, individual studies have reported that COVID-19 patients in the intensive care unit have significantly higher coagulation parameters than those of COVID-19 patients not receiving intensive care [28] , and that more than 70% of patients who die from COVID-19 meet the criteria of disseminated intravascular coagulation [5] . These findings suggest that monitoring blood coagulation parameters in COVID-19 patients may aid in early detection of severe disease.

The coronavirus causing COVID-19 may trigger coagulation dysfunction because it induces abundant release of pro-inflammatory cytokines in various tissues, which can lead to systemic inflammatory response syndrome that damages the microvascular system and thereby activates the coagulation system, leading to generalised small vessel vasculitis and extensive microthrombosis [46, 47] . In particular, patients with severe COVID-19 may be at high risk of venous thromboembolism, which may be present in up to 25% of such patients [48] . Indeed, a study of 1,099 patients across China suggests that 40% of all COVID-19 patients may be at high risk of venous thromboembolism [49] . Risk may be exacerbated by the dehydration due to fever and diarrhea, hypotension, and prolonged bed rest characteristic of the disease, all of which are risk factors for coagulation in their own right [50] , as well as by the use of vasopressors and central venous catheters in the Accepted Article intensive care unit [51] . This has led to the recommendation that patients with severe COVID-19 should be carefully monitored for coagulation function and given prophylactic anticoagulant therapy in the absence of anticoagulant contraindications [47] . Dr Jean and colleagues also reported that the use of an increased prophylactic dose of nadroparin resulted in a significant decrease in D-dimer levels [52] .

Although this study rigorously analyzed coagulation parameters data collected from a large sample of COVID-19 patients, we were unable to eliminate the heterogeneity observed between studies. For example, the course and the severity of the disease varied across studies. Given that most of the studies included in our meta-analysis were single-center, retrospective studies, it was difficult for us to control for the effects of several confounding factors, including bias in patient admission and selection, as well as differences in disease severity and course. Further research is needed to verify and extend our results.

In summary, current evidence showed that coagulation dysfunction is common in severe COVID-19 patients, and it is associated with severity of COVID-19. And thus could be used as early warning indicators of disease progression during hospitalization.

Pan Ji, Hongyuan Li, Zhimei Zhong and Bocheng Li collected and analyzed the data. Jianfeng Zhang acquired the funding. Jieyun Zhu and Jielong Pang designed the study, and wrote the first draft of the manuscript. Jianfeng Zhang and Junyu Lu designed and supervised the study, and finalized the manuscript, which all authors read and approved.

This study was supported by grants from the National Natural Science Foundation of China (81960343,81660132); the Emergency Science and Technology Brainstorm Project for the Prevention and Control of COVID-19, which is part of the Guangxi Key Research and Development Plan (GuikeAB20058002); the High-level Medical Expert Training Program of Guangxi"139"Plan Funding (G201903027) and the Young Scientists Fund of the Natural Science Foundation of Guangxi (2017GXNSFBA198043).

The authors have declared that no competing interests exist.

The data that support the findings of this study are available from the corresponding author upon reasonable request. 

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