key: cord-0942819-xyicht60
authors: Zong, Xiaolong; Gu, Yajun; Yu, Hongjian; Li, Zhenyu; Wang, Yuliang
title: Thrombocytopenia Is Associated with COVID-19 Severity and Outcome: An Updated Meta-Analysis of 5637 Patients with Multiple Outcomes
date: 2020-09-15
journal: Lab Med
DOI: 10.1093/labmed/lmaa067
sha: 5f5404676565b9986d5a7efce791a812f6d9a892
doc_id: 942819
cord_uid: xyicht60

The COVID-19 pandemic is persistent worldwide. A prior meta-analysis suggested the association of thrombocytopenia (TCP) with more severe COVID-19 illness and high mortality. Considering newly published studies, we updated the previous meta-analysis to confirm and explain the association of TCP with COVID-19 severity and multiple outcomes. Twenty-four studies with 5637 patients with COVID-19 were included in this study. The weighted incidence of TCP in COVID-19 was 12.4% (95% confidence interval [CI], 7.9%–17.7%). Data synthesis showed that the platelet number was lower in patients with either more severe illness or poor outcomes and even lower in nonsurvivors, with weighted mean differences of −24.56 × 10(9)/L, −22.48 × 10(9)/L, and −49.02 × 10(9)/L, respectively. The meta-analysis of binary outcomes (with and without TCP) indicated the association between TCP and 3-fold enhanced risk of a composite outcome of intensive care unit admission, progression to acute respiratory distress syndrome, and mortality (odds ratio [OR], 3.49; 95% CI, 1.57–7.78). Subgroup analysis by endpoint events suggested TCP to be significantly associated with mortality (OR, 7.37; 95% CI, 2.08–26.14). Overall, the present comprehensive meta-analysis indicated that approximately 12% of hospitalized patients with COVID-19 have TCP, which also represents a sign of more severe illness and poor outcomes.

outcomes (with and without TCP) indicated the association between TCP and 3-fold enhanced risk of a composite outcome of intensive care unit admission, progression to acute respiratory distress syndrome, and mortality (odds ratio [OR], 3.49; 95% CI, 1.57-7.78). Subgroup analysis by endpoint events suggested TCP to be significantly associated with mortality (OR, 7.37; 95% CI, 2.08-26.14). Overall, the present comprehensive meta-analysis indicated that approximately 12% of hospitalized patients with COVID- 19 have TCP, which also represents a sign of more severe illness and poor outcomes.

Keywords: coronavirus disease 2019, COVID-19, SARS-CoV-2, platelet, thrombocytopenia, prognosis

The coronavirus disease 2019 (COVID-19) pandemic has affected more than 12 million people and caused more than 500,000 deaths worldwide. 1 Although most patients develop mild or uncomplicated illness, those with older age and pre-existing comorbidities are more susceptible to severe disease and have a higher risk of poor outcomes such as admission to the intensive care unit (ICU), progression to acute respiratory distress syndrome (ARDS), and even death. 2, 3 Thrombocytopenia (TCP) is commonly associated with viral infections and serves as a sign of sepsis progression and exacerbation. 4, 5 A prior meta-analysis suggested that low platelet count was associated with high mortality and more severe COVID-19 illness. 6 Because new studies have been published, we conducted an update of the previous meta-analysis to confirm and explain the association of platelet number with COVID-19 severity and provide a direct comparison of the risk of multiple endpoints in patients with COVID-19 with and without TCP.

This systematic review was performed following the PRISMA statement (see Supplemental Material 1). 7 The study protocol is provided in Supplemental Material 2. Briefly, PubMed, Embase, and Web of Science were searched to identify studies between December 1, 2019, and March 15, 2020, without language restriction. The following terms were used: "COVID-19" OR "Corona Virus Disease 2019" OR "coronavirus disease-19" OR "severe acute respiratory syndrome coronavirus 2" OR "SARS-COV-2" OR "2019 novel coronavirus" OR "2019-nCoV" OR "new coronavirus pneumonia." Because new articles on COVID-19 are daily published, eligible articles published between March 15, 2020, and April 18, 2020, were also identified via PubMed using the aforementioned terms with AND for the following terms: "platelet" OR "thrombocytopenia" OR "thrombo*" OR "hemato*." Studies were included in this meta-analysis if they met the following criteria: (i) adult population (older than 18), (ii) COVID-19 was confirmed by laboratory testing, (iii) platelet count or TCP frequency was reported, and (iv) English or Chinese full text was available. Studies involving patients with a particular illness or emergency conditions were excluded (eg, cancer and cardiovascular attack). When studies had significant overlapping data, the most comprehensive study was included.

For pooled analysis, data on platelet count and TCP frequency in the overall population and subgroups based on disease severity or outcomes were extracted by 2 independent investigators. COVID-19 severity was defined as per the World Health Organization or local interim guidance, and studies without definite criteria were excluded. We used a composite of admission to ICU, progression to ARDS, or all-cause mortality to define adverse outcomes of COVID-19. Double-arcsine-transformed proportion, weighted mean difference (WMD), and odds ratio (OR) with 95% confidence interval (CI) were calculated and pooled in the meta-analysis as appropriate. In their absence, the mean and standard deviation of the platelet count were estimated from sample size, median, and interquartile range. 8 A random-effects model was selected to account for clinical heterogeneity. Subgroup analyses were conducted based on endpoint events and TCP definition. The quality of the included studies was evaluated by 2 independent reviewers following the Newcastle-Ottawa scale (see Supplemental Material 3: Table 1 ). Discrepancies in data extraction and quality assessment were resolved through discussion with a third author. Statistical analyses were performed using the RStudio software.

After initial screening and full-text review, 24 studies 2,3,9-30 with 5637 patients with COVID-19 were included in this systematic review. The study selection procedure is illustrated in Supplemental Material 3: Figure 1 ; the excluded studies and reasons for exclusion are detailed in Supplemental Material 3: Table 2 . Table 1 shows the quality and general characteristics of the included studies. Seventeen studies 2, 3, [9] [10] [11] [12] [13] 15, [17] [18] [19] 21, 24, [26] [27] [28] [29] including 4671 patients reported the incidence of TCP in hospitalized patients with COVID-19 (see Supplemental Material 3: Figure 2 ). Our meta-analysis indicated a weighted incidence of 12.4% (I 2 = 95%; 95% CI, 7.9%-17.7%; Table  2 and Supplemental Material 3: Figure 3 ). This result was consistent with that of a previous meta-analysis of 218 patients that reported a combined estimation of 11.5%. 31 Notably, the TCP frequency across included studies is inconsistent, with a wide range from 0% to 36.5%. This inconsistency may be attributed to different criteria applied for defining TCP and the heterogeneous disease severity spectrum among study populations. The results of subgroup analysis by cutoff values of 150, 125, and 100 × 109/L for TCP were 28.7% (95% CI, 15.6%-43.9%), 17.3% (95% CI, 14.9%-19.9%), and 3.1% (95% CI, 0.4%-8.4%), respectively, as detailed in Table 2 and Supplemental Material 3: Figure 4 .

Seven studies 11, 14, 20, 23, 25, 26, 30 with 389 patients with severe COVID-19 and 1399 control patients with nonsevere COVID-19 showed a combined WMD of −24.56 (I 2 = 53%; 95% CI, −33.73 to −15.39), indicating that the platelet number was lower in patients with more severe COVID-19 ( Table 2 and Supplemental Material 3: Figure 5 ). Consistent with these results, a meta-analysis of 8 stu dies 2, 3, 11, 12, 16, 21, 22, 24 including 510 patients with adverse events (including admission to ICU, progression to ARDS, or death) and 1950 patients without adverse events revealed a combined WMD of −22.48 (I 2 = 78%; 95% CI, −40.97 to −3.99; Table 2 and Supplemental Material 3: Figure 6 ). Subgroup analysis indicated the platelet count to be even lower in patients who succumbed to the disease (WMD, −49.02; I 2 = 0%; 95% CI, −60.26 to −37.78]); however, no significant difference was observed between patients admitted to the ICU and those who were not (WMD, 0.41; I 2 = 0%; 95% CI, −20.04 to 20.87]; Table 2 and Supplemental Material 3: Figure 7 ). Taken together, these results highlight the lower platelet number in patients with either more severe COVID-19 or poor outcomes. These findings are consistent with those reported by Lippi et al, 6 who first conducted a meta-analysis on 1779 patients to investigate the association between TCP and COVID-19 severity. Figure 8 ). Furthermore, the subgroup analysis by endpoint events showed that TCP was associated with a 7-fold enhanced risk of mortality in COVID-19 (OR, 7.37; I 2 = 36%; 95% CI, 2.08-26.14). A recent study indicated that platelet count was associated with in-hospital mortality in a dose-dependent manner. 28 Consistent with this finding, we found a stronger association between TCP and poor outcomes of COVID-19 when a lower cutoff TCP value was applied ( Table 2 and Supplemental Material 3: Figure 9 ).

To some extent, ARDS onset, admission to ICU, and mortality can be considered as sequential events reflective of COVID-19 progression and deterioration. 3 One advantage of the current study was the inclusion of many patients with multiple outcomes, allowing subgroup analysis to investigate the association of TCP with distinct endpoints. A surprising but interesting finding of the subgroup analysis is that TCP (both platelet number decrease and TCP rate) may not be significantly related to ICU admission ( Table 2 and Supplemental Material 3: Figures 7, 10 ) despite the trend of association between TCP and mortality and the composite endpoint (admission to ICU, use of mechanical ventilation, and mortality). A possible explanation for this result is that TCP tends to reach a significant level in the late clinical stage of COVID-19. This speculation can be supported by a prior study that reported a lower platelet number in patients hospitalized for more than 10 days after symptom onset than in those hospitalized within 10 days of symptom onset. 19 Two recent studies that investigated the dynamic change in platelet count of patients with COVID-19 described a trend of persistent drop in platelet number for nonsurvivors, with a decline to 100 × 10 9 /L after approximately 2 weeks after admission. 28, 29 These results suggest that TCP is associated with COVID-19 progression and deterioration, highlighting the significance of monitoring platelet count. However, the results of the subgroup analysis may be limited by the small subgroup size and need further validation.

Although the role of TCP in COVID-19 has been well studied, the causal relationship between them is not yet established. Several possible mechanisms may be involved in platelet count fluctuations during the pathophysiological process of this viral disease. COVID-19 is a systemic infection characterized by hyperinflammation and hypercoagulable state in patients with severe disease. 32 Hence, TCP in COVID-19 may be explained by the irreversible consumption of platelets during the execution of procoagulant and immune modulation functions. Viral infection of megakaryocytes can increase their apoptosis and decrease maturation and ploidy.

Although there is no evidence that SARS-CoV-2 can directly infect the bone marrow or hematopoietic stem cells, the virus may modulate platelet production at other stages of development. For example, thrombopoietin (TPO), which is primarily produced in liver parenchymal cells, is a critical regulator of megakaryopoiesis and platelet production. Several reports have suggested that liver injury is a common complication of COVID-19. 33, 34 A drop in TPO production after parenchymal liver injury may at least in part explain TCP in COVID-19. Recently, a series of case reports suggested that COVID-19 is associated with the onset or reoccurrence of immune thrombocytopenia (ITP), which is characterized by isolated TCP, without thrombosis tendency and bone marrow abnormal cellularity. [35] [36] [37] [38] These findings suggested that the differential diagnosis of TCP in COVID-19 is indispensable; for SARS-CoV-2 infection-induced ITP, accurate diagnosis and specialized treatment are necessary to guarantee the prevention of bleeding episodes. Further investigation of the mechanisms of TCP can provide a more comprehensive understanding of this disease and provide a theoretical basis for clinical treatment.

In conclusion, this systematic review shows that TCP is common in COVID-19, as evident from a weighted incidence of 12.4%, and is associated with COVID-19 severity and outcome. Thus, TCP may serve as a potential biomarker to predict mortality in patients with COVID-19. A limitation of this study is that only 17 of the 24 included studies were available for synthesis for primary outcome, whereas all other subgroup analyses included data from <10 studies. Therefore, the results from subgroup analyses are uncertain and should be regarded with extreme caution. Further, most of the included studies were cross-sectional investigations, and the asymmetrical shape of the funnel plot (Supplemental Material 3: Figure 11 ) shows evidence of publication bias, suggestive of the high risk of bias involved in our metaanalysis. Because studies with strong quality evidence such as randomized controlled trials and case-control studies are not feasible or available in the context of the COVID-19 pandemic, individual patient data meta-analysis is warranted to address these questions in the future.

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Supplemental figures and tables can be found in the online version of this article at www.labmedicine.com. LM