key: cord-0881159-y49cs8vd authors: Sanfilippo, Filippo; La Rosa, Valeria; Oliveri, Francesco; Astuto, Marinella title: COVID-19, Hypercoagulability, and Cautiousness with Convalescent Plasma date: 2021-01-15 journal: Am J Respir Crit Care Med DOI: 10.1164/rccm.202008-3139le sha: 9725806ead0827bdecad1f11d31cbc0e017289c5 doc_id: 881159 cord_uid: y49cs8vd nan To the Editor: We read with great interest the elegant study conducted by Patel and colleagues (1) regarding the alterations at pulmonary vessel level in patients with severe coronavirus disease (COVID-19). The authors meticulously presented the combination of physiologic data, the results of high-resolution imaging, and the hematologic observations in a cohort of 39 patients. They showed that the activation of inflammatory and coagulation pathways has a pivotal role in the development of acute respiratory failure induced by COVID-19, demonstrating the great impact of hypercoagulability and reduction of fibrinolysis on the pulmonary vasculature. Such a prothrombotic state finally induces pulmonary (and likely systemic) perfusion abnormalities, heavily contributing to the peculiar phenotype of COVID-19-induced respiratory failure (2) . We believe that the results shown by Patel and colleagues (1), highlighting the presence of dilated peripheral lung vessels (roughly two-thirds of patients) and perfusion defects in all patients, are of great importance in cautiously interpreting the results of a recent study on the use of convalescent plasma (CP) in COVID-19. Indeed, this study evaluated the use of CP in more than 5,000 patients with severe or life-threatening COVID-19 (3) and prompted great (and in our opinion excessive) enthusiasm as the authors reported low incidence of serious adverse effects after CP. However, this safety endpoint was evaluated in a particularly short period of observation (4 h), which is far too limited to entirely account for subtle progression of an underlying hypercoagulability state. For instance, plasma is administered in the setting of hemorrhagic shock for its ability to improve hemostasis; thus, the idea of administering plasma to any patient with underlying hypercoagulability should be undertaken very watchfully. Depending on the methods for aiming at inactivating residual virus during the preparation of CP, the content of coagulation factors also may decrease, which would eventually blunt its procoagulant effects (4) . However, in the presence of an already stimulated coagulation pathway as demonstrated by Patel and colleagues (1), even small amounts of residual coagulation factors in CP may potentiate the coagulation cascade in patients with COVID-19, representing a source of potential harm. In our opinion, the progression of thrombosis should not be evaluated only as evidence of new pulmonary embolism, but it may result in worsening oxygenations and gas exchanges. This could be the result of thrombosis and progression of perfusion defects with further dilatation of peripheral lung vessels. Moreover, considering the systemic impact of the underlying hypercoagulability, administration of CP may worsen perfusion in other vital organs, potentially increasing, among others, risks of myocardial and cerebral ischemia. Thus, great caution is warranted in looking for specific adverse events related to CP in patients with COVID-19. To add more uncertainty on the use of CP, its efficacy for the treatment of COVID-19 has been questioned by a Cochrane systematic review (5) . Moreover, according to another recent meta-analysis of randomized controlled trials at low risk of bias, administration of CP to patients with severe influenza has not been shown to reduce mortality, number of days in the ICU, or number of days on mechanical ventilation (6) . In summary, we think the results of the study of Patel and colleagues greatly contribute to the definition of pathogenesis and clinical characteristics of COVID-19, but they are also of great value when considering potential therapeutic strategies and the right approach to control for their safety. New studies on CP in patients with COVID-19 should be encouraged to report the methods of preparation for CP. n Pulmonary Angiopathy in Severe COVID-19: Physiological Conclusions Derived from Ventilatory Ratio? To the Editor: We read with interest the article by Patel and colleagues (1) in which they describe imaging, functional, and hematological aspects in 39 patients with acute respiratory distress syndrome due to coronavirus disease (COVID-19). As the authors describe, ventilatory ratio (VR) was calculated in two opportunities, once at admission and once after computed tomographic scan, and it was increased in both. From that, they draw a conclusion about the presence of increased physiological respiratory dead space (VDphys/VT) based on a single surrogate parameter, the VR = (V : E 3 actual Pa CO 2 )/(predicted V : E 3 predicted Pa CO 2 ), where V : E represents actual minute volume. VR includes assumptions in normalizing data and does not consider CO 2 production (V : CO 2 ) as a variable (2) . Furthermore, VR was introduced as a simple bedside method to estimate efficiency of ventilation but not as a means to measure VDphys/VT (2) . Moreover, VR has not been validated under extracorporeal membrane oxygenation (ECMO) conditions (44% of patients at admission), so because of these reasons, those assumptions lessen support to their conclusion. Important adjustments are included in the VR formula, where Pa CO 2 is controlled by the physician on the mechanical ventilator, and it excludes V : CO 2 . So, if a patient suffers changes in his inflammatory behavior, or in his spontaneous ventilatory efforts, the independent variable V : CO 2 will increase, but Pa CO 2 is controlled on the ventilator and will remain constant. In this case, V : E and VR increase but do not properly represent VDphys/VT. Even more, in patients under ECMO, Pa CO 2 specifically depends on the airflow in the oxygenating machine, and to the best of our knowledge, VR index has not been validated under this condition. 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