An increase in morbidity and mortality due to thromboembolic events has been shown in patients suffering from COVID-19 infection . The big rate of venous thromboembolism (VTE) has been widely highlighted, but few studies are focused on systemic arterial embolism . There is a growing interest in determining the risk factors involved in the development of thrombosis .
On the one hand, different working groups have reported the relationship between age, gender, cardiovascular disease or cancer history and severity of SARS-CoV2 infection. We present herein two men and two women, whose median age was 69 years old.
Two of the most important retrospective studies taken place in Wuhan, China, showed a clear predominance of men over women in terms of severity and mortality as well as poorer outcomes in the oldest versus the younger patients [4,5]. Other cardiovascular risk factors such as diabetes, overweight, smoking and hypertension have been stablished as predictors of mortality due to COVID-19 [4,6]. It is also known that the risk of severe illness due to SARS-CoV2 infection is higher in patients with cancer history . The cases we present support most of the outcomes previously described [4,5,7].
On the other hand, Zhang et al. have notified that thrombosis is caused by hypercoagulability due to antiphospholipid antibodies, that can arise transiently in patients with critical illness and infections . However, none of the cases that we present here showed positivity in these tests. Moreover, Malentacchi et al. have reported cases of simultaneous occurrence of VTE and arterial thrombosis , but none of the patients we present here evolved in this way.
Furthermore, severity of respiratory symptoms and rate of thrombosis also seem to show some mismatch. To note, in contrast to the few studies taken place in our working environment, none of the patients we present with concomitant COVID-19 infection required invasive oxygen therapy. This observation makes an important difference in contrast to other cases reported, which show clear correlation [10,11].
Additionally, we would like to emphasize that three of the patients we present developed arterial thrombosis independently of the use of antithrombotic treatment . Two of our patients were receiving properly full (therapeutic) dose of anticoagulant therapy due to AF and another one had been receiving LMWH as prophylaxis until platelet count decreased below 30,000/mm3. Due to the above, the prophylactic use of low doses of acetylsalicylic acid (ASA) has been discussed by different groups. It is well known the anti-inflammatory and antithrombotic effect of ASA . In addition to these effects of ASA, in vitro and experimental models support its capacity to reduce replication, propagation, and infectivity of several RNA-enveloped viruses, including human CoV-229E and MERS-CoV . Thus, different working groups advocate the widespread use of ASA prophylactically in COVID19 infection [13,14]. Chow JH et al. described in a large cohort study of 412 COVID-19 infected patients that the use of ASA was independently associated with a lower risk of mechanical ventilation, ICU admission, and in-hospital mortality . Conversely, Aditya Sahai et al. hold that the use of traditional antiplatelet agents may not protect against thrombotic events or mortality in COVID-19 infection. When comparing two study groups, they find that ASA therapy was associated with an increased risk of thrombotic stroke (3.6% vs 0.40%, p=0.036) .
Platelets have a wide range of critical functions and mechanisms of thrombosis in COVID-19 deserve further investigation. Drug trials are necessary to determine the real role ASA could play in these patients.
One more aspect we would like to point out is the unexpected location of the thrombi. Studies that report arterial thrombosis describe the main affected vascular territories. Limbs and mesenteric ischemia, as well as cerebral territories were the most frequently affected areas [11,17,18]. However, we present herein the concomitant finding of a right ventricle thrombus in one of the four patients. This special vascular bed has not been widely reported yet [19-21]. In most of the cases that have been described before, transthoracic echocardiogram (TTE) was obtained given the severity of hypoxemia and hemodynamic instability of patients [22-24]. As far as we know, this is the first case in which right ventricle thrombus was found in a patient with no invasive oxygen therapy or hemodynamic instability. It was an unexpected finding seen in the upper part of CTA performed to diagnose the abdominal aortic thrombosis. Given that the TTE is a minimally invasive test, it could be performed routinely in patients with COVID-19 infection and arterial thrombosis, in order to anticipate severe complications, such as ventricular thrombosis.
Finally, we would like to emphasize the poorly known mechanisms underlying microvascular thrombotic and inflammatory processes seen in patients suffering from COVID-19. Multiple studies have found that they may play an important role in exacerbating ADRS and extrapulmonary events in these patients [3,25-28]. These deleterious complications likely result from dysfunction of the vascular endothelium . Its dysregulation leads to vasoconstriction, hyperinflammation, vascular leakage, thrombosis and improper antiviral immune response. Moreover, endothelial dysregulation is a well stablished actor in reported COVID-19 comorbidities such as hypertension, obesity or diabetes [30-33]. In spite of the fact that abnormal coagulation and inflammation parameters provide evidence for endothelium dysregulation in severe COVID-19 patients, the pathophysiological mechanisms underlying this situation still require further clarification [34,35]. It seems clear, however, that SARS-CoV2 may use two related pathways; either directly through endothelial cell infection or indirectly through the infection of other susceptible cell types, which cause hyperinflammation and aberrant antiviral responses [25,27]. Reports of microangiopathic complications in severe COVID-19 support a role for immunothrombosis in viral pathogenesis. SARS-CoV2 was recently found to promote pro-inflammatory complement activation in association with endothelial damage in severe COVID-19 [36,37]. This may promote the development of complement-suppressing therapeutics aimed at decreasing hyperinflammation in severe COVID-19 .
In conclusion, COVID-19 infection may predispose patients to an increased risk of thrombotic complications through different pathophysiological mechanisms, such as inflammation, immobilization, endothelial dysfunction, and a hypercoagulable state, all of them, still in need of deeper investigation. Further studies should focus on the rate and association of thromboembolic events and SARS-CoV2 infection and identifying the patients at higher risk for arterial thrombosis to determine the best preventive maneuvers.