key: cord-1050584-yw5wcq1e authors: Belen-Apak, F. Burcu; Sarıalioğlu, F. title: Pulmonary intravascular coagulation in COVID-19: possible pathogenesis and recommendations on anticoagulant/thrombolytic therapy date: 2020-05-05 journal: J Thromb Thrombolysis DOI: 10.1007/s11239-020-02129-0 sha: a8889efee4c7b27b416a163acbce5f127e66d59d doc_id: 1050584 cord_uid: yw5wcq1e nan malignancy before they were symptomatic for COVID-19 and revealed early pathological signs of COVID-19 besides adeno carcinoma in biopsies. [6] . Those signs were intraalveolar fibrin with early organization, proteinaceous exudates in alveoli and mono nuclear inflammatory cells suggesting early start of coagulopathy even when patients were asymptomatic. As PIC is the first step of the disease, the patients fail to respond to classical treatment modalities targeting pulmonary oedema, ARDS and MAS with cytokine storm. The cytokine storm is interpreted as capillary leak syndrome and treatment modalities like IVIG, steroid and anti-IL6, plasma exchange usually fails to manage the clinical picture. Here we provide possible mechanism and treatment strategy for COVID-19 PIC. • SARS-CoV2 binds to ACE2 receptors on type II pneumocytes and possibly on vascular endothelial cells and causes lysis of the cells immediately leading to direct activation of the endothelium causing procoagulant activity and activates accumulation of fibrin deposits in pulmonary microcapillary venous vessels. The fibrin deposits cause a compensatory mechanism of increased plasminogen at the beginning but as the disease progresses fail to break down the fibrin deposits reflected in increased d-dimer levels. The treatment strategy at this level should be blockage of hyper coagulation with low molecular weight heparin (LMWH) as mentioned by Thachil [1] for blocking thrombin and dampen the inflammatory response. LMWH at prophylactic doses should be administered to all symptomatic patients with microbiologically or radiologically documented COVID-19 diagnosis and escalated to therapeutic doses in case of respiratory distress. F. Burcu Belen-Apak and F. Sarıalioğlu have contributed equally to the manuscript. • In case LMWH is insufficient of preventing further activation of PIC and the thromboses extend to pulmonary veins, the process will proceed to secondary pulmonary hypertension and cardiac insufficiency. Increased intravascular pressure in lungs will result in extensive alveolar exudation resulting causing marked hypoxia. As a consequence of decreased pulmonary venous flow, the left ventricular stroke volume will decrease leading to systemic hypotension. The treatment option at this step should be Tissue Plasminogen Activator (TPA) or defibrotide. These two fibrinolytic modalities can prevent intubation and progression to DIC (Fig. 1 ). Plasminogen and TPA has been used in COVID-19 patients in a few studies and have been shown to be beneficial in improving respiratory capacity [7, 8] . As the immune-pathogenesis seems to resemble endothelial dysfunction of sinusoidal obstruction syndrome we think that defibrotide can also be useful or its pro-fibrinolytic, antithrombotic, thrombolytic, anti-ischemic and anti-inflammatory functions that may help to restore the endothelial function [9] . According to the previous literature, we think the major pathogenesis of COVID-19 disease starts with hyper coagulation and PIC. We believe that early anticoagulation and early thrombolytic agents may provide better prognosis in these patients. The authors did not receive any funding for the manuscript. Conflict of interest The authors FBBA and FS declare no conflict of interest. The authors participated together to the hypothesis and writing of the letter. The authors FBBA and FS both give permission for publication. The versatile heparin in COVID-19 Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Why the immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia are distinct from macrophage activation syndrome with disseminated Intravascular coagulation Vander Heide RS (2020) Pulmonary and cardiac pathology in Covid-19: the first autopsy series from New Orleans Pulmonary pathology of early-phase, 2019 novel Coronavirus (COVID-19) pneumonia in two patients with lung cancer Is there a role for plasminogen activator (tPA) as a novel treatment for refractory COVID-19 associated with acute respiratory distress syndrome (ARDS)? Plasminogen improves lung lesions and hypoxemia in patients with COVID-19 Defibrotide: properties and clinical use of an old/new drug