JAK inhibitors in COVID-19: need for vigilance regarding increased inherent thrombotic risk

摘要

There is accumulating evidence that COVID-19 is a hypercoagulable state. Reports of thrombotic events and autopsy findings of pulmonary thrombotic microangiopathy [1] in patients with COVID-19 are rising. Bompard recently reported a cohort study of 137 patients with COVID-19 pneumonia, in which retrospective review of computed tomography pulmonary angiography (CTPA) scans demonstrated a cumulative incidence of pulmonary emboli (PE) of 24% overall and 50% in intensive care [2]. Although it was initially thought that insidious venous thromboembolic events (VTE) were mainly confined to ventilated patients [3], we now understand thrombotic risk to be a wider problem in COVID-19. An overexuberant host inflammatory response, in selected patients with severe COVID-19, may contribute to the high mortality. We recently recommended screening for virally-driven hyperinflammation in COVID-19 and proposed that immunomodulation in this subgroup of patients, may improve outcomes [4]. There are several ongoing, randomised controlled trials evaluating the therapeutic potential of Janus Kinase inhibitors (JAKi) in severe COVID-19 (table 1). JAKi have a purported advantage over other immunomodulatory strategies in COVID-19, as they may exert dual anti-inflammatory (blockade of multiple, pro-inflammatory cytokines simultaneously) and anti-viral effects (impeding cellular viral endocytosis [5, 6]) and have convenient oral administration, with relatively short half-lives. JAKi may interrupt the signalling of several pro-inflammatory cytokines implicated in the pathogenesis of hyperinflammation, including interleukin (IL)-6, which has been the focus of several clinical trials in COVID-19. JAKi may also inhibit the entry of the SARS-CoV-2 virus into the AT2 alveolar epithelial cells; baricitinib (a JAK1/2 inhibitor), is a numb-associated kinase (NAK) inhibitor, with a particularly high affinity for AP2-associated protein kinase 1 (AAK1), a pivotal regulator of clathrin-mediated viral endocytosis [5]. We recommend vigilance to the potentially increased thrombotic risk associated with JAKi, given the hypercoagulability of COVID-19 and our recent thromboprophylaxis recommendations for all hospitalised patients with COVID-19 [7].