Although pneumonia and acute respiratory distress syndrome (ARDS) are the dominant clinical presentations of coronavirus disease 2019 (COVID-19) infection, it is known that there are several conditions that often complicate the course of this disease, including coagulopathy and thrombosis [1, 2]. Various meta-analyses have shown the rate of thromboembolic (TE) events in COVID-19 patients ranges from 11-48.6%, and 90% of them are pulmonary thromboembolism [3-6]. Helms et al. found that patients with COVID-19 ARDS had a 6 times higher rate pulmonary thromboembolic events compared with non-COVID-19 ARDS [7]. An autopsy study also found alveolar capillary microthrombus in pneumonia COVID-19 non-survivors were 9 times more common than for other pneumonias [8].

Pulmonary thromboembolic complications of COVID-19 have their own diagnostic challenges. CT-Pulmonary Angiography (CTPA) as gold standard modality becomes less practical and less feasible to perform during the pandemic, so clinicians often rely on other parameters, such as D-Dimer levels as surrogate markers of the thrombosis process. Previous studies showed an increase in D-Dimer levels have good diagnostic value for pulmonary thromboembolic events in COVID-19 (OR 1.99-10.7) [9, 10].

The effect of ARDS and pneumonia on pulmonary circulation and right ventricle (RV) is already well known [11]. The incidence of pulmonary thrombosis is believed to further aggravate the hemodynamic burden of the pulmonary circulation through an increase in pulmonary arterial resistance. The incidence of pulmonary hypertension (PH) in COVID-19 patients ranges from 12-15% in the general population, and increases to 42% in critically ill patients [11-14]. The presence of PH and RV dysfunction have been shown to affect clinical outcomes in COVID-19 patients, with the mortality rate being 7 times higher in patients with PH and 3.1 times higher in patients with RV dysfunction [14-16].

Although the gold standard method for assessing pulmonary artery pressure (PAP) is using right heart catheterization (RHC), the use echocardiographic parameters including pulmonary artery acceleration time (PAAT) in estimating PAP has been shown to be quite accurate [16-19]. Likewise, several parameters of RV function, especially RV free wall longitudinal strain (RV-FWLS), have good correlation with its gold standard method, which is cardiac magnetic resonance (CMR) [20]. In addition, the practicality of echocardiography during the COVID-19 pandemic make it the preferable diagnostic tool to assess cardiac function and underlying pathological abnormalities. The objective of this study is to seek relationship between D-Dimer levels as a surrogate marker of thrombosis and short-term cardiovascular complications especially PH and RV dysfunction using echocardiography.

The distribution of data based on demographic and laboratory characteristics is shown in Table 1. The mean age of the study population was 55.4 years and predominantly male. Based on WHO criteria of COVID-19 pneumonia severity, 9 patients suffered from moderate degree, 21 with severe degree, and 10 with critical degree. From echocardiographic data, RV dysfunction was found (based on RV-FWLS) in 27 (67.5%) patients. In addition, PH was found in 19 patients (47.5%) with an estimated mPAP ≥25 mmHg obtained through PAAT.

The correlation between D-Dimer levels as well as other laboratory parameters and RV function based on the parameters of RV-FWLS and estimated mPAP is shown in Table 2.

Elevated pulmonary artery pressure (PAP) and RV dysfunction are common in patients with both acute and chronic pulmonary disease [11, 31]. COVID-19 pneumonia is no exception. The present study showed, that at short-term evaluation (median 11 days after negative PCR), PH was found in 47.5% of patients, higher than prevalence in general COVID-19 populations, which ranged from 12-15% [12, 13]. This difference is understandable considering that almost 75% of our study sample were patients with a history of severe and critical COVID-19 who were admitted to the ICU. The severity of ARDS was related to the increase in PAP.

The estimation of PAP by echocardiography can be carried out in several ways, the most common is by using the gradient of the tricuspid regurgitant jet (TR), as used in other studies [29]. However, this method has limitations. Often the TR jet is not visualized, especially in early and mild PH [18, 32, 33]. In our study, TR was only found in 16 patients (40%) of the total sample, so the use of the PAAT parameter was chosen in order to describe the estimation of PA pressure in the entire sample. PAAT for mPAP estimation is easy, feasible, and reproducible in patients with or without TR. In a meta-analysis, PAAT was negatively correlated with PA pressure and had high sensitivity and specificity, especially in patients with mPAP ≥25 mmHg [18].

RV dysfunction in COVID-19 could be the result of various pathomechanical pathways. Increased pulmonary vascular resistance due to ARDS and pulmonary thromboembolism, as well as myocardial injury due to inflammatory cytokines are believed to be the main causes of RV dysfunction in COVID-19 patients [34]. The results of our study showed the prevalence of RV dysfunction is 67.5% when using the RV FWLS parameter, 2-3 times higher than the other conventional parameters which ranged from 14.5-27% [12, 35, 36]. As is well known, one of the advantages of the strain parameter is more sensitive in detecting early and subclinical dysfunction [37]. Longobardo et al. and Morris et al. found that the strain as RV function parameter has the best correlation with its gold standard method, which is CMR and the detection rate of RV dysfunction using strain is 1.5-2 times higher than conventional parameters such as TAPSE and FAC [38, 39]. Likewise, Lamia et al. reported that an abnormal RV FWS value was already seen even in a patient with borderline PH [40]. The free wall section can reflect the contractility of the RV independently, apart from the contribution of the septum which is a combination of LV and RV components.

Our study showed a significant correlation between peak D-Dimer levels with RV-FWLS (r = -0.506; p = 0.001) and mPAP (r = 0.526; p<0.001). This is also consistent with other studies which showed that D-Dimer levels were negatively correlated with parameters of RV function, including by Akkaya et al. (RV FWS; r = -0.557; p<0.001) and Elsayed et al. (FAC; r = -0.34; p = 0.003) [36, 41]. Meanwhile, the correlation of D-Dimer levels with pulmonary arterial pressure was previously reported by Goudot et al. (r = -0.178; p =0 .047) [42].

In the present study peak D-Dimer levels were recorded at a median of 14 days from symptom onset. As is well known, thromboembolic complications occur as the disease severity progresses, and generally occur in the third phase or hyperinflammatory phase [43]. Studies by Pasha et al. and Cerda et al., showed that thromboembolic complications in patients with COVID-19 occurred mostly at 2-4 weeks from symptom onset [44, 45]. In contrast to the increase in D-Dimer in the first week due to the natural immune response to viral infection, D-Dimer levels in the 2nd to 4th week are more likely to represent thrombotic complications in COVID-19 patients [45].

Elevated D-Dimer levels in COVID-19 indicate a hypercoagulable state and have been associated with major thromboembolic events [46]. However, from several meta-analytical studies, it is known that the predictive ability of D-Dimer for pulmonary thromboembolic events has a high sensitivity, but low specificity, considering that in severe COVID-19 extensive endothelial injury and systemic microthrombosis occurs [4, 47]. However, it is important to recognize and diagnose pulmonary thromboembolic complications because of their therapeutic and prognostic value in patients with COVID-19. Several studies evaluated D-Dimer accuracy as a surrogate marker of pulmonary thromboembolic compared with CTPA, including Mouhat et al. (cut-off D-Dimer 2590 µg/L and Diaz et al. (cut-off D-Dimer 2903 µg/L) [41, 42]. Meanwhile, our study found that the peak D-Dimer ≥4530 µg/L was a predictor of PH in the short-term follow-up after COVID-19 pneumonia.

The hemodynamic consequences of pulmonary thromboembolism depend on the degree and location of the thrombus. Generally, thrombus in the PA main branch and extensive thrombus in the pulmonary vascular tree will result in significant hemodynamic changes [48, 50]. Previous studies showed most thrombosis in COVID-19 occurred in the peripheral pulmonary vessels (segmental or subsegmental), in contrast to the incidence of PE in the general population which is more common in the main and proximal pulmonary arteries [46, 48, 51]. This may explain why the cut-off value of D-Dimer for hemodynamic sequelae in this study was higher than the cut-off for pulmonary thrombosis diagnostic values obtained from previous studies.

The dynamics of D-Dimer levels also cannot be separated from the use of anticoagulant thromboprophylaxis. All samples of this study received enoxaparin which is a low molecular weight heparin (LMWH) with doses according to WHO and International Society on Thrombosis and Haemostasis (ISTH) guidelines [52]. During hospitalisation, 4 patients were switched to unfractionated heparin (UFH), with indications of acute kidney injury. Meanwhile, for 6 (15%) samples, the anticoagulant was uptitrated from prophylactic to therapeutic dose because of the rapid increase of D-Dimer levels and respiration worsening out of proportion to pneumonia severity. Patients on therapeutic anticoagulants had a higher mean peak D-Dimer level (16240 vs 5431 µg/L; p=0.001) and also a poorer P/F ratio (94.2 vs 145.1; p=0.05). Patients receiving therapeutic doses of anticoagulants also had significant changes in peak and pre-discharge D-Dimer levels (delta D-Dimer) compared with prophylactic doses (13991 vs 3961 µg/L; p=0.01). This indicates that this group of patients may indeed have thrombotic complications that respond well to higher doses of anticoagulation.

From multivariate analysis, it was seen that peak D-Dimer levels ≥4530 µg/L were associated with the incidence of PH, but not with RV dysfunction. This suggests that other mechanisms may also play a role in causing RV dysfunction in COVID-19. In contrast to PH which is directly caused by increased PA pressure due to ARDS and pulmonary thrombosis, RV dysfunction can occur from two pathomechanical pathways, which are increased pulmonary circulation afterload and impaired RV contractility due to myocardial injury.

Myocardial injury can occur due to various factors, including a cardio-depressant effect of inflammatory cytokines [50-52]. Our study showed CRP levels were not only negatively correlated with RV function parameters, but also with LVEF (r = -0.428; p = 0.011). In previous studies, inflammatory parameters such as interleukin 6 (IL-6), interleukin 1(IL-1), and tumour necrosis factor-alpha (TNF-α) directly affected contractility and triggered apoptosis [53, 55]. A study showed that the IL-6 level was the most significant inflammatory parameter that affects RV function in COVID-19 patients [54]. Myocardial injury characterized by elevated troponin levels has been shown to be associated with a decrease in both LV and RV function as measured using the strain parameter up to 2 months post-infection [56, 57]. However, it cannot be proven objectively in the present study, since measurement of high-sensitivity troponin (hs-Tn) and specific inflammatory biomarkers (IL-6, IL-1, TNF-α) are not routinely carried out in our institution.

The PaO2/FiO2 ratio (P/F ratio) is a simple parameter that is routinely used to evaluate oxygenation capacity in patients with ARDS and closely reflects the severity of lung injury [53-55]. Our study shows that there is a significant correlation between the P/F ratio and mPAP (r = 0.685; p<0.001) and RV-FWLS (r = 0.641; p<0.001). Multivariate analysis also showed that P/F ratio ≤121.9 was the most powerful and consistent parameter that affected both PH and RV dysfunction. This finding confirms the hypothesis that one of the cardiovascular sequelae of post-COVID-19 pneumonia is type 3 PH. In early stages, ARDS directly affects pulmonary vascular hemodynamics through vascular compression due to aatelectasis and alveolar edema and hypoxia-induced vasoconstriction that results in increasing of PA pressure, meanwhile in the chronic phase, hemodynamic changes can be persistent and progressive due to remodeling of the surrounding lung and vascular tissue [58-62]. In the present study, the incidence of PH and RV dysfunction was more common in patients with a history of mechanical ventilation (MV), although not statistically significant. This can be attributed to the very small number of patients (n=4; 15%) with a history of MV in the present study. High Flow Nasal Cannula (HFNC) was widely used in our study sample (42.5%). Several studies reported minimal hemodynamic effects of HFNC on PVR and RV afterload. HFNC increases alveolar recruitment by providing a high level of oxygen flow, not by giving positive end-expiratory pressure (PEEP), so that the resulting positive airway pressure is also low, <4 cmH₂0 [53, 54].

This study has some limitations. First, a relatively small number of patients were included. Second, there was no known baseline echocardiographic data of patients before COVID-19. Third, the possibility of extrapulmonary thrombosis complications cannot be completely ruled out. Last, there was no examination of specific inflammatory parameters such as IL-6, IL-1, and TNF-α as well as cardiac biomarkers such as hs-Tn and N-terminal pro-brain natriuretic peptide (NT-proBNP) because these biomarkers were not routinely measured in our institution.

The present study showed that PH and RV dysfunction were common in short-term evaluation of post-COVID-19 pneumonia patients. Peak D-Dimer levels during hospitalization are correlated with mPAP and RV function as measured by echocardiography at a median of 11 days after patients recovered from COVID-19 pneumonia. We found that peak D-Dimer levels ≥4530 µg/L might increase the risk of PH, but not RV dysfunction after COVID-19 pneumonia.