Inhalational use of antithrombotics in humans: Review of the literature

Monagle, Kate; Ryan, Anna; Hepponstall, Michele; Mertyn, Eliza; Monagle, Paul; Ignjatović, Vera; Newall, Fiona

doi:10.1016/j.thromres.2015.10.011

Cited by 16 publications

(23 citation statements)

References 40 publications

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“…Importantly, previous studies have shown that following nebulisation, UFH does not enter the systemic circulation significantly which means it can be used in addition to systemic therapeutic or prophylactic anti-coagulation without concerns of furthering systemic anti-coagulation. The use of nebulised UFH in other respiratory settings was not associated with local side effects in the lung including bleeding [85][86][87][88][89].…”

Section: Anti-coagulant Effectsmentioning

confidence: 96%

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

et al. 2020

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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.

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Section: Anti-coagulant Effectsmentioning

confidence: 96%

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

et al. 2020

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“…This suggests that inhaled heparin is safe and may be effective in patients with SI-ALI. 65,70–74 Moreover, a high dose of UFH (10,000 IU) + N-acetylcysteine + salbutamol administered every 4 h significantly promoted pulmonary function and decreased mortality in patients with SI-ALI. 54,55 Hadjiliadis and colleagues found that using a UFH dose from 50,000 IU to 400,000 IU was safe and feasible for the treatment of SI-ALI.…”

Section: Latest Treatment Progress For Si-alimentioning

confidence: 97%

“…Anticoagulants include unfractionated heparin (UFH) and low-molecular-weight heparin. 65 Anticoagulants have been widely used as prevention and treatment approaches for thrombosis in the treatment of cardiovascular diseases. UFH is currently increasingly applied to extravascular spaces, such as by local administration and intrapulmonary application.…”

Section: Intratracheal Instillation Of Perfluorohexane (Pfc)mentioning

confidence: 99%

Preclinical and clinical studies of smoke-inhalation-induced acute lung injury: update on both pathogenesis and innovative therapy

Guo

Bai

et al. 2019

Ther Adv Respir Dis

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Smoke-inhalation-induced acute lung injury (SI-ALI) is a leading cause of morbidity and mortality in victims of fire tragedies. SI-ALI contributes to an estimated 30% of burn-caused patient deaths, and recently, more attention has been paid to the specific interventions for this devastating respiratory illness. In the last decade, much progress has been made in the understanding of SI-ALI patho-mechanisms and in the development of new therapeutic strategies in both preclinical and clinical studies. This article reviews the recent progress in the treatment of SI-ALI, based on pathophysiology, thermal damage, airway obstruction, the nuclear-factor kappa-B signaling pathway, and oxidative stress. Preclinical therapeutic strategies include use of mesenchymal stem cells, hydrogen sulfide, peroxynitrite decomposition catalysts, and proton-pump inhibitors. Clinical interventions include high-frequency percussive ventilation, perfluorohexane, inhaled anticoagulants, and nebulized epinephrine. The animal model, dose, clinical application, and pharmacology of these medications are summarized. Future directions and further needs for developing innovative therapies are discussed.

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“…Of note, inhaled heparin has a proven broad distribution in the respiratory tract including the alveolar space. 7,[30][31][32] Specifically, the antiviral activity of heparin is based on affinity of viral glycoproteins to negatively charged glycosaminoglycans such as sulfated heparan, which are ubiquitously expressed on the surface of mammalian cells. It has recently been demonstrated in a published and a preprint article that soluble heparin interacts with the SARS-CoV-2 spike protein 28,33 and inhibits SARS-CoV-2 spike pseudovirus entry.…”

Section: Heparin Exerts Direct Antiviral Activitymentioning

confidence: 99%

Inhaled and systemic heparin as a repurposed direct antiviral drug for prevention and treatment of COVID-19

Conzelmann¹,

Müller

Perkhofer

et al. 2020

Clinical Medicine

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Here, we advocate a highly favourable opportunity for the treatment of COVID-19 disease by repurposing a long-serving medical agent with an excellent history of clinical use, namely heparin. Heparin is best known as an anticoagulant, but it also exhibits direct antiviral activity against many enveloped viruses and has anti-inflammatory activity. The high incidence of thromboembolic events in COVID-19 patients suggests that coagulopathy plays an important role in the SARS-CoV-2 pathogenesis. This already makes heparin a unique, potentially curative agent that can be used immediately to help resolve the ongoing crisis associated with SARS-CoV-2 infection and COVID-19 disease. We demonstrate here in vitro that heparin does indeed inhibit SARS-CoV-2 infection. The three concurrent modes of activity of heparin (antiviral, anticoagulant and antiinflammatory) against SARS-CoV-2/COVID-19 form a unique therapeutic combination. Thus, repurposing of heparin to fight SARS-CoV-2 and COVID-19 appears to be a powerful, readily available measure to address the current pandemic.

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Inhalational use of antithrombotics in humans: Review of the literature

Cited by 16 publications

References 40 publications

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

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

Preclinical and clinical studies of smoke-inhalation-induced acute lung injury: update on both pathogenesis and innovative therapy

Inhaled and systemic heparin as a repurposed direct antiviral drug for prevention and treatment of COVID-19

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