Discussion:
In the current case-control study, we tried to assess the clinical, laboratory, and in-hospital characteristics of the patients with thrombotic events following a SARS-CoV-2 infection and find the predisposing factors that make a person prone to thrombotic events. Over 60% of the cases admitted in ICU, experienced the thrombotic event after ICU admission. There are several studies representing the high incidence of these events in critically ill patients, as well (4, 6, 7, 13). Nevertheless, 61.5% of the COVID-19 infected patients had a thrombotic event on-admission or presented it within the first two days. A paucity of knowledge is available regarding the characteristics of COVID-19 for increasingly developing these events.
The studies on general populations insisted on the role of medical conditions including hypertension, diabetes mellitus, chronic pulmonary disorders, chronic renal disorders, and active malignancy on thrombotic events incidence (14), which has been notified in patients with SARS-CoV-2(7). However, none of the comorbid conditions was remarkably different between cases and controls in this study. We assume that better insight may be provided in larger populations.
Among the hemodynamic parameters, oxygen saturation was found the only independent factor associated with the thrombotic events. SARS-CoV-2 pneumonia can lead to improper oxygenation due to acute respiratory distress itself. In addition, inappropriate respiration disables a person from exertion and is causative for immobilization, as well (15-17). It should be noted that approximately 63% of the cases were admitted due to PTE, a condition accompanying by a decrease in oxygen saturation, and CVA, which required intubation due to a similar condition. Therefore, a two-sided association should be considered between the oxygen saturation and thrombotic events.
We found on-admission hemoglobin level as an inverse factor associated with thrombotic events, which has not been noted previously. Furthermore, most of the studies represented an insignificant difference between those with thromboembolic events and the control groups(13, 18).
It is hypothesized that low hemoglobin level, which represents low blood viscosity, reduces stress formation on the endothelial bed of the vessels and, in turn, inhibits the function of the anti-thrombotic mechanism(19). Therefore, patients with lower hemoglobin levels are prone to thrombotic events due to impaired endothelial function as one of the Virchow triad(20). Recent investigations on COVID-19 have notified increased risk of thromboembolism development due to diverse factors such as the imbalance between oxidative and anti-oxidative processes, accumulation of pro-inflammatory and pro-thrombotic factors, and endothelial dysfunction (21-23). It seems that mentioned factors accompanying low levels of hemoglobin reinforce the cascade of thrombosis formation.
Contrary to most of the investigations insisting on the standalone role of low hemoglobin levels on thrombosis in-hospital and long-term adverse events(24-27), studies in the literature have rarely evaluated the predictive value of hemoglobin level for thrombotic events developing. Yamashita et al. reported exceptional lower levels of hemoglobin among the patients with VTE and, in accordance with other presentations, found a predictive role for this index for in-hospital outcomes, long-term adverse events, and all-cause mortality(28). A similar reverse association was presented by Can and colleagues (19). On the other hand, Kalra hesitates to confirm whether low hemoglobin has a role in cardiovascular events and/or is a marker of comorbidities(25). This poor correlation was noted for thromboembolism, as well(29). Therefore, the attitude about hemoglobin’s role in the development of thrombotic events is not unanimous and requires further investigations.
D-dimer was shown to be directly correlated with thrombotic events in our study. It is traditionally known as a marker of inflammation, coagulation activation, and hyperfibrinolysis. The studies assessing these events in COVID-19 patients insisted on the elevated levels of this marker among those who experience a thrombotic event during a course of COVID-19 infection(13, 30). In addition, Lodigiani et al. represented a rapid increase in D-dimer levels among non-survivors of thrombosis in COVID-19 patients(5). Helms and colleagues noted that a rapid rising D-dimer level despite anticoagulation is a reflection of clot formation and a probable thrombotic event. They even recommended imaging assessments for patients with a sudden increase in d-dimer along with the deterioration of the clinical course of the disease (31). The significance of D-dimer is to the extent that guidelines for anticoagulant therapy in this infection have mentioned elevated D-dimer as a factor for high dose anticoagulant treatment (32).
Albumin is the other factor found inversely associated with thrombosis in COVID-19 infection. To the best of our knowledge, despite all the notifications regarding the hypercoagulable state in SARS-CoV-2 infection, albumin level has not been well-studied. Zhang and colleagues determined the proportion of fibrinogen-to-albumin as a determinant for the risk of thrombosis development (33).
The increased probability of thrombosis in hypoalbuminemia has been well-established in chronic conditions such as nephrotic syndrome or cirrhosis(34); however, most of our patients were gathered from the general population infected by COVID-19. Nevertheless, studies on the general population have stated a significant association between albumin levels with VTE incidence (35) and its severity(36). Further studies on other thrombotic events presented similar correlations (37-39).
To evaluate the role of low albumin levels as a risk factor for thrombosis formation, some believe it as a representative of inflammation status(40). This theory has been confirmed by presenting an inverse correlation between serum albumin level with C-reactive protein and estimated erythrocyte sedimentation(36, 38). In other studies, an antagonistic role of oxidation, stagnant, thrombosis, and leukocyte adhesion has been considered for albumin(41). Further investigations, particularly in the critical group of COVID-19 patients, are required.
The clinical outcomes and hospitalization characteristics were not remarkably different between cases and controls that may have occurred because of early anticoagulation administration in both groups. According to the findings of this study in terms of a significant association between anticoagulant prophylaxis and thrombosis formation, and due to the recommendations of the other investigations of SARS-CoV-2 infected patients, prophylactic anticoagulation is strongly recommended, particularly in critical patients (21, 42, 43). It should also be noted that high number of cases in “no anticoagulation” group may be due to this fact that thrombotic events occurred on admission and no anticoagulation was received by them prior to admission. The significance of prophylaxis is clarified, knowing the high incidence of thrombosis even among those under anticoagulation(22). Therefore, detailed investigations are recommended to determine the ultimate anticoagulant dosage in the target populations.