Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence

Frank M P van Haren, Clive Page, John G Laffey, Antonio Artigas, Marta Camprubi-Rimblas, Quentin Nunes, Roger Smith, Janis Shute, Mary Carroll, Julia Tree, Miles Carroll, Dave Singh, Tom Wilkinson, Barry Dixon, Frank M P van Haren, Clive Page, John G Laffey, Antonio Artigas, Marta Camprubi-Rimblas, Quentin Nunes, Roger Smith, Janis Shute, Mary Carroll, Julia Tree, Miles Carroll, Dave Singh, Tom Wilkinson, Barry Dixon

Abstract

Nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale and warrants urgent investigation of its therapeutic potential, for COVID-19-induced acute respiratory distress syndrome (ARDS). COVID-19 ARDS displays the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. Patients infected with SARS-CoV-2 who manifest severe disease have high levels of inflammatory cytokines in plasma and bronchoalveolar lavage fluid and significant coagulopathy. There is a strong association between the extent of the coagulopathy and poor clinical outcomes.The anti-coagulant actions of nebulised UFH limit fibrin deposition and microvascular thrombosis. Trials in patients with acute lung injury and related conditions found inhaled UFH reduced pulmonary dead space, coagulation activation, microvascular thrombosis and clinical deterioration, resulting in increased time free of ventilatory support. In addition, UFH has anti-inflammatory, mucolytic and anti-viral properties and, specifically, has been shown to inactivate the SARS-CoV-2 virus and prevent its entry into mammalian cells, thereby inhibiting pulmonary infection by SARS-CoV-2. Furthermore, clinical studies have shown that inhaled UFH safely improves outcomes in other inflammatory respiratory diseases and also acts as an effective mucolytic in sputum-producing respiratory patients. UFH is widely available and inexpensive, which may make this treatment also accessible for low- and middle-income countries.These potentially important therapeutic properties of nebulised UFH underline the need for expedited large-scale clinical trials to test its potential to reduce mortality in COVID-19 patients.

Keywords: ARDS; COVID-19; Nebulised heparin; SARS; SARS-CoV-2; Unfractionated heparin.

Conflict of interest statement

FvH, CP, JL, QN, RS, BD, JT and MC have nothing to disclose. TW is Chief Investigator of the ACCORD COVID Research Programme. AA and MCR report grants from Grifols, outside the submitted work. JS is the Scientific Director of Ockham Biotech Ltd., a company that owns patents around the use of inhaled heparin. DS reports personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from Cipla, personal fees from Genentech, personal fees from GlaxoSmithKline, personal fees from Glenmark, personal fees from Gossamerbio, personal fees from Menarini, personal fees from Mundipharma, personal fees from Novartis, personal fees from Peptinnovate, personal fees from Pfizer, personal fees from Pulmatrix, personal fees from Theravance and personal fees from Verona, outside the submitted work.

Figures

Fig. 1
Fig. 1
a Lung injury in coronavirus disease 2019 (COVID-19). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin-converting enzyme 2 (ACE-2) primarily on type II alveolar cells. After endocytosis of the viral complex, surface ACE-2 is downregulated, resulting in unopposed angiotensin II accumulation. SARS-CoV-2 further causes lung injury through activation of residential macrophages, lymphocyte apoptosis and neutrophils. The macrophages produce cytokines and chemokines, resulting in a cytokine storm. Inflammatory exudate rich in plasma-borne coagulation factors enters the alveolar space, followed by expression of tissue factor by alveolar epithelial cells and macrophages and the formation of fibrin and the hyaline membrane. Neutrophils in the alveoli cause formation of NETs, composed of extracellular DNA, cytotoxic histones and neutrophil elastase, which cause further lung injury. COVID-19 also induces microvascular endothelial damage leading to increased permeability, expression of tissue factor with coagulation activation and thrombus formation. b Proposed effects of inhaled nebulised unfractionated heparin (UFH) in COVID-19 lung injury. UFH prevents SARS-CoV-2 from binding to ACE-2 and from entering the alveolar cells. UFH reduces formation of the hyaline membrane and microvascular thrombosis, counteracts the hyperinflammation and the formation of NETs, increases NO release with vasodilation and also has mucolytic properties. NETs, neutrophil extracellular traps; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ACE-2, angiotensin-converting enzyme 2; COVID-19, coronavirus disease 2019. Permission was granted by © Beth Croce, Bioperspective.com to reuse this figure

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