Thrombocytopenia Is Associated With COVID-19 Severity and Outcome

An Updated Meta-Analysis of 5637 Patients With Multiple Outcomes

Xiaolong Zong, MD; Yajun Gu, PhD; Hongjian Yu, MD; Zhenyu Li, PhD; Yuliang Wang, PhD

Disclosures

Lab Med. 2021;52(1):10-15. 

In This Article

Results and Discussion

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[2,3,9–13,15,17–19,21,24,26–29] 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% (I2 = 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 (I2 = 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 studies[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 (I2 = 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; I2 = 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; I2 = 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.

To investigate the association of TCP with COVID-19 outcome, 5 studies[3,11,12,27,28] reporting a total of 199 adverse events (65 adverse events with TCP [15.9 per 100 participants] and 134 without TCP [11.5 per 100 participants]) were included. The combined OR of 3.49 (I2 = 67%; 95% CI, 1.57–7.78) suggests TCP as a potential risk factor for poor outcomes in COVID-19 (Table 2 and Supplemental Material 3: 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; I2 = 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 × 109/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.[35–38] 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 meta-analysis. 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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