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 et al. 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].
Summary of relevant licensed JAK inhibitors and thrombotic concerns
Several JAKi are licenced in rheumatoid arthritis (RA) and have Food and Drug Administration (FDA) black-box warning for venous and arterial thrombotic events (including deep venous thrombosis (DVT), PE and ischaemic stroke), resulting in dose restrictions (table 1). It is unclear whether the presumed prothrombotic risks are dependent on JAK selectivity, drug specificity, dose or treatment duration or are confounded by indication. Whilst there is evidence of dose-dependent increased thrombotic risk associated with tofacitinib (five-fold increased risk of PE compared with tumour necrosis factor therapy in RA) [8], a recent meta-analysis did not show an overall JAKi class pro-thrombotic signal [9]. Although a significantly increased incidence of thrombotic events (DVT and PE) was reported with bariticitinb in RA trials [10], this has not been observed in extension studies and recent trials in atopic dermatitis [11]. Post-marketing surveillance may delineate the true risk and whether this is disease-specific. It is unclear which JAK isoform (selectivity) confers impact on the efficacy or influences safety of these therapies for their licenced indications (e.g. rheumatoid arthritis) or in the new disease setting of COVID-19. It is important to note that at high doses, JAKi can become “pan-JAK” inhibitors and exhibit non-selectivity [12]
Discussion continues regarding whether JAKi have a causal role in thrombotic events, or whether this represents a higher background thrombotic risk [13]. Indeed VTE risk in RA (0.3–0.7/100 patient years) is greater compared with the general population (0.1–0.4/100 patient years) [13]. Intriguingly, ruxolitinib, unlike baricitinib, does not carry a VTE warning, despite both being selective JAK 1/2 inhibitors. Conversely there is a suggestion that ruxolitinib may lower the inherently raised thrombotic risk in myeloproliferative neoplasms [14]. Extrapolating this reassurance for ruxolitinib to COVID-19 is inappropriate as data for baricitinib and ruxolitinib is derived from different disease populations and their respective safety signals may be confounded by indication.
Clinical trials in COVID-19 using immunomodulation, including JAKi, intend to recruit patients with the most severe disease, and it is hypothesised that these patients are more hypercoagulable. We recommend risk mitigation strategies including consideration of exclusion of patients with high thrombotic risk, treatment with standard or intermediate-dose low molecular weight heparin prophlyaxis [7] during hospitalisation and consideration of extended-duration thromboprophylaxis after discharge from hospital, with monitoring for thromboses during the treatment and follow-up periods.
JAKi represent significant therapeutic advances, but are relatively new drugs with evolving safety profiles. Potential prothrombotic risk may be a class effect of JAKi, which is concerning given evidence of hypercoagulability with severe COVID-19. Cross-speciality communication is imperative when drug repurposing in the rapidly evolving pace of a pandemic.
Footnotes
Author contribution: PM drafted the manuscript. All authors contributed to discussions, revised and approved the manuscript.
Conflict of interest: Dr. Mehta reports and PM is an MRC-GSK EMINENT clinical training fellow with project funding outside the submitted work. PM receives co-funding by the NIHR University College London Hospitals Biomedical Research Centre (UCLH BRC).
Conflict of interest: Dr. Ciurtin has nothing to disclose.
Conflict of interest: Professor Scully has nothing to disclose.
Conflict of interest: Dr. Levi has nothing to disclose.
Conflict of interest: Dr. Chambers reports grants from UKRI MRC, grants from GlaxoSmithKline, grants from NIHR ULCH BRC, unrelated to this work.
- Received May 21, 2020.
- Accepted June 27, 2020.
- Copyright ©ERS 2020
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