The investigations on the critically ill patients showed that different pathogenic types might account for the high prevalence of DVT.17-19 Meanwhile, hypercoagulability appears to be a typical feature of patients with COVID-19.20 However, no previous study has compared the DVT risks between the two groups of COVID-19 pneumonia patients and bacterial pneumonia patients. To our knowledge, this study is the first description of DVT difference and hospital mortality in ARDS patients with COVID-19 pneumonia vs Bacterial pneumonia.
In this retrospective cohort study, the 28-days incidence of DVT in the COVID-19 pneumonia patients with ARDS was higher than that in the bacterial pneumonia cohort (57.1% vs 41.5%). Several reasons probably account for the notably higher incidence of DVT in the COVID-19 pneumonia patients with ARDS. First, it is known that the coagulation pathway can be activated through the contact system and kallikrein/kinin system (KKS).21 But it is worth recalling that the KKS is dysregulated by binding of SARS-CoV-2 to the angiotensin-converting enzyme II (ACE-2) receptor of vascular endothelium, this may be a more reasonable mechanism for the noted interaction between COVID-19 and DVT.22,23 Second, coronavirus infections may be a trigger for VTE, and several pathogenetic mechanisms, which include endothelial dysfunction, characterized by increased levels of von Willebrand factor; systemic inflammation, by Toll-like receptor activation; and a hypercoagulable state, by tissue factor pathway activation.24 Third, high plasma levels of proinflammatory cytokines were observed in the severe COVID-19.25 The direct activation of the coagulation cascade by a cytokine storm is conceivable. Lastly, the immune-mediated damage according for the acute coronavirus infections may partially contribute.26 Although it is worth noting that after taking death as competitive risk, Fine-Gray test showed no significant difference in the 28-day cumulative incidence of DVT between these two groups (P=0.220). The results showed that the value of the point estimation was different between these two groups. Meanwhile, the confidence intervals were wide. One reason could be the fact that our sample size was small, which may reduce the power of test.
Fine-Gray competing risk analysis in the bacterial pneumonia group showed that serum creatinine levels and IMV were associated with DVT, whereas there was a stronger association between CK-MB levels, PaO2/FiO2 ratios, D-dimer levels and DVT in COVID-19 group. To further figure out the observed differences in risk factors for DVT between COVID-19 and Bacteria, we utilized interaction terms between COVID status and each risk factor, which suggested that CKMB levels might be independent predictor of DVT in the COVID-19 group compared with bacterial pneumonia.
The incidence of DVT in the COVID-19 pneumonia patients with ARDS increased with the raising of the CK-MB levels. Notwithstanding the incomplete knowledge on its pathophysiology, the mainly suggested mechanisms are: heart and arterial vascular system injury due to increased oxygen demand but in the context of hypoxemia triggered by cytokine storm and systemic immune response, which were most frequently encountered among patients with COVID-19 cases.27-32 Likewise, it has been hypothesized that a direct viral toxicity through the interaction with ACE-2 receptors highly expressed by some pericytes.29 So considering comprehensively above-mentioned factors, it is revealed that severe COVID-19 cases have elevated levels of biomarkers of cardiovascular system injury such as CK-MB. Meanwhile, it is indicated that CK-MB itself might be regarded as a predict marker of DVT. A thorough assessment should therefore be conducted in the follow-up of severe COVID-19 patients with ARDS and adequate measures should be managed to detect, diagnose, and treat VTE at their early stage, considering the high-risk of developing DVT.
We found that serum creatinine may modify the association between the COVID-19 and bacterial pneumonia group and the risk of DVT. The association was stronger among the ARDS patients with bacterial pneumonia. Contrary to findings from our research, some studies have demonstrated that renal impairment is independent risk factor for DVT.33,34 It is worth noting that other studies have shown that LWMH may have different levels of bioaccumulation in the case of renal insufficiency.35,36 So, we speculate that the same dose of LWMH may play a stronger role in the prevention of DVT because of renal insufficiency. The study by Cook et al. indicated that the incidence of DVT for patients with renal insufficiency in ICU who received dalteparin 5,000 IU once daily was 5.1%,37 which was far lower than that in the overall population of critically ill patients who received prophylaxis recommended by the guidelines.38,39 However, we did not find significant association between serum creatinine levels and DVT in patients with COVID-19 pneumonia. There are a number of factors, but one of the biggest reasons is that the patients with COVID-19 had lower serum creatinine levels, lower APACHE Ⅱ scores and lower SOFA scores compared with those with bacterial pneumonia, the protective effect on DVT of higher levels of serum creatinine was weakened obviously. Unfortunately, due to the retrospective nature of the study, on the one hand, the decrease of LWMH metabolism in patients with AKI and higher level of serum creatinine was based on the conjecture of clinical data analysis, on the other hand, we did not monitor the dynamic change of blood coagulation and detect the activities of plasma levels of coagulation/anticoagulation factors in patients with venous thromboembolism.
Multivariant analysis showed an association only among CK-MB levels, PaO2/FiO2 ratios, D-dimer levels ≥ 0.5 µg/mL, and DVT in COVID-19 cohort. Using a ROC analysis, a combination of the corresponding indicators mentioned above yielded a sensitivity of 66.7 % and a specificity of 82.4% for prediction for DVT in these hospitalized patients with COVID-19, and the AUC-ROC was 0.804. Statistical test showed that the prediction power of this model was significantly better than DVT Wells score in COVID-19 patients with ARDS. Although there was no significant difference in AUCs between the prediction models, the prediction sensitivity and specificity of the combined model were improved compared with Padua prediction score. This combined prediction model has also been identified to depict effectively for screening for DVT in this group by drawing a nomogram and its calibration curve. A possible reason for the superiority of this new prediction model is that the commonly used predictive scoring systems such as Padua score and Wells score apply to the general medical and surgical patients in hospital. As a serious clinical pathophysiological syndrome with an overwhelming inflammatory response and coagulation abnormalities, ARDS caused by COVID-19 has unique clinical characteristics and serious complications.
The prognosis in ARDS patients with COVID-19 pneumonia analyses showed that DVT was associated with adverse outcomes compared with Bacteria ARDS cohort, including length of stay in hospital (P < 0.001). To validate the prognosis of DVT in these two cohorts, we further plotted 28-day cumulative incidence curves of DVT, with death as the competitive risk, and found that the mortality increased with rising incidence of DVT, especially in the COVID-19 cohort. The worse outcome in COVID-19 cohort may be a result of the inflammatory response to SARS-CoV-2 infection resulting in thrombo-inflammation and driving thrombosis.40 Coagulation activation could also have been associated with a sustained inflammatory response.41 In addition, there is a 50% chance for patients with untreated proximal DVT to develop symptomatic PE within 3 months.42 PE might aggravate the hypoxemia of ARDS patients and then result in lower actuarial survival rates. If there was any clinical suspicion of PE, a CTPA would be considered and obtained, if possible. Unfortunately, due to the critical condition of ARDS patients, CTPA examination was restricted. We only underwent CTPA examination on 1 patient with highly suspected PE and 1 patient was diagnosed with PE in the COVID-19 cohort. By contrast, in the bacterial pneumonia cohort we had performed 5 CTPA examinations, and 3 patients was diagnosed with PE. Using the figures given above, we may significantly underestimate the incidence of PE. The presence of PE associated with DVT may also be a cause of poor survival in patients with DVT. Although these findings are not surprising, given that our patient population represented older, severely ill patients at high risk for DVT, with other organ-related diseases, our data raised the question of screening for DVT, risk stratification, and potential VTE prophylaxis to improve outcomes in ARDS patients infected with COVID-19 and those infected with bacterial pneumonia.
This study has some limitations. First, this was a retrospective study that included data from two independent single-center cohorts, which may have resulted in selection bias. Second, our sample size was small, which may underestimate the influence on DVT of factors such as obesity, being bedridden, and the insertion of a central venous catheter. Third, due to the critical condition of patients with ARDS, CTPA examinations were restricted, which significantly underestimated the incidence of PE. Finally, the data from the bacterial pneumonia cohort originated from a 6-year span, whereas the data from the COVID-19 cohort originated from only a 1-month span, which may also have affected the study’s results.