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.