The clinical course of severe acute respiratory syndrome caused by coronavirus type 2 (SARS-CoV-2) meets the criteria for acute respiratory distress syndrome (ARDS) in the majority of patients, whose unfavorable course ultimately leads rapidly to death. In cases with fatal outcome, the pathophysiology of ARDS has been linked to a hyperimmune reaction that enhances the progressive worsening of lung function. SARS-CoV-2 infects alveolar epithelial cells via the surface receptor ACE2 (also present in intestinal epithelium, endothelial cells and smooth muscle arteries). During the hyperimmune inflammatory reaction, complement activation leads to the formation of C3a and C5a, small peptides that induce the recruitment of lymphocytes, macrophages, monocytes and neutrophils, which in turn are responsible for the massive local release of proinflammatory cytokines. Likewise, leukocytes mobilized at the site of injury exert a potent proinflammatory effect, causing extensive vascular-endothelial damage, alveolar epithelial cell damage and microvascular thrombosis.
Acute respiratory distress syndrome
The functional implications of the specific pathogenesis of ARDS contribute to a progressive worsening of the ventilation/perfusion ratio and loss of the reactive hypoxic vasoconstriction mechanism, with a significant component of intrapulmonary microvascular thrombosis. Massive alveolar endothelial damage, causing a progressive pulmonary syndrome with microvascular thrombosis, has been proposed as the main mechanism of COVID-19-associated respiratory distress. This hypothesis is supported by the detection of viral particles in endothelial cells, as well as diffuse endothelial inflammation in the lung, heart, kidney and small intestine described in three patients with SARS-CoV-2 infection who developed progressive respiratory failure and multiorgan failure.
During the early months of the pandemic, researchers from New Orleans, Milan and Oklahoma published autopsies of 50 patients with SARS-CoV-2 and bilateral pneumonia compatible with ARDS. Aged between 32 and 86 years, most had diabetes, hypertension or cardiovascular disorders. Progressive worsening of pulmonary function required intubation and mechanical ventilation. Death occurred in an average time of 16 days from the onset of symptoms. Hemorrhages were identified throughout the peripheral lung parenchyma and, in some cases, small thrombi. Histological examination showed diffuse alveolar damage with mild/moderate lymphocytic infiltration. But the most relevant finding was the presence of platelet and fibrin thrombi within alveolar capillaries and small arterial vessels in 86% of cases. In addition, patchy areas of hemorrhage were frequently detected.
The incidence of pulmonary thrombosis
Given that the incidence of pulmonary thromboembolism is high in critically ill patients with no previous thrombotic risk factors; the D-dimer level is significantly elevated; the mortality rate may be reduced in patients treated with heparin; and the presence of numerous pulmonary microthrombi is a recurrent finding at autopsy, together these may suggest that refractory respiratory failure in these patients is primarily caused by extensive pulmonary micro/macrothrombosis (and less by primary infectious/inflammatory damage).
In COVID-19 pneumonia, pulmonary thrombosis may play a direct and significant role in the development of gas exchange abnormalities and multiorgan failure. Patients with severe respiratory failure present with an abnormal gas exchange pattern compatible with alveolar dead space ventilation and intrapulmonary shunt. These abnormalities suggest the possibility of sudden onset severe pulmonary vascular involvement, the anatomic substrate of which would most likely be acute disseminated intrapulmonary microvascular thrombosis. The preserved pulmonary function during the initial phase of COVID-19 infection in patients with bilateral radiological airspace opacity suggests that pulmonary infiltrates may represent areas of pulmonary infarction and hemorrhage.
According to observational studies, anticoagulation with low-molecular-weight heparin appears to be associated with lower mortality in the subset of patients who meet criteria for sepsis-induced coagulopathy or have a markedly elevated D-dimer. But randomized controlled trials are needed to determine a causal association between heparin use and clinical outcome in patients with severe COVID-19. However, in refractory respiratory failure caused by disseminated intrapulmonary microvascular thrombosis (the main potential mechanism in SARS-CoV-2-induced progressive respiratory distress), anticoagulant therapy could play a limited role in this terminal phase. On the contrary, fibrinolytic agents might be a better alternative during the preagonic phase when clot lysis needs to be promoted as rapidly as possible.
Three recently published series describing the response to fibrinolytic therapy with tissue plasminogen activator (tPA) in mechanically ventilated ARDS-critical COVID-19 patients with persistently high D-dimer levels reinforce the hypothesis of extensive intrapulmonary microvascular thrombosis as the pathophysiological basis of progressive respiratory failure in patients with SARS-CoV-2. In the Mount Sinai Hospital series, three of four patients responded rapidly to an infusion of 50 mg tPA over 2 hours with rapid improvement in alveolar ventilation and respiratory function. In the University of Colorado series, two of three patients also responded to an infusion of 25 mg tPA over 2 hours and 25 mg over the next 22 hours, with rapid improvement in arterial oxygenation. None of the patients treated with tPA suffered hemorrhagic complications. A third series of 15 patients treated at Rutgers University (New Jersey) demonstrated significant improvement in pulmonary ventilation (decreased alveolar dead space) and respiratory function after infusion of 42 mg tPA (average dose) for 2 hours. Two patients suffered hemorrhagic complications (intramuscular and intracranial).
The rationale for the use of fibrinolytic therapy in severe COVID-19 patients is supported by several considerations, the main one being the fact that there are currently very few therapies that have been shown to be effective in the management of ARDS beyond respiratory therapy. If this fails, mortality approaches 100%. On the other hand, virtually all mechanically ventilated patients with COVID-19 show a reduced level of fibrinolysis by thromboelastography. Fibrinolytic therapy in animal models has been shown to be effective in acute lung injury, and a small phase 1 clinical trial in humans with terminal ARDS (unrelated to SARS-CoV-2) showed that treatment with urokinase or streptokinase led to substantial improvement in arterial oxygenation and significantly lower mortality.
Tissue plasminogen activator (tPA) has greater clot lysis efficacy than urokinase and streptokinase without an increased risk of bleeding. The risk of adverse events from tPA treatment (0.4% to 0.8% life-threatening major bleeding) is far outweighed by the certainty of death in COVID-19 patients with this therapeutic indication. Systemic administration of tPA would therefore be potentially justified in critically ill patients with refractory respiratory failure associated with COVID-19. In these cases, fibrinolytic treatment could have an immediate physiological impact with significant improvement in alveolar ventilation, oxygenation and shock. Fibrinolysis would improve alveolar ventilation by restoring blood flow to previously occluded regions. This salvage therapeutic option could be decisive in patients with severe COVID-19 infection and refractory ARDS with no treatment alternative available.