Elsevier

Thrombosis Research

Volume 136, Issue 6, December 2015, Pages 1059-1066
Thrombosis Research

Review Article
Inhalational use of antithrombotics in humans: Review of the literature

https://doi.org/10.1016/j.thromres.2015.10.011Get rights and content

Highlights

  • There may be benefit in delivering antithrombotic therapies directly to lung tissue.

  • Studies in this area are heterogeneous and many have small sample sizes.

  • Risk:benefit profile of inhaled antithrombotic therapy cannot yet be confirmed.

  • Studies investigating specific mechanism of actions in different diseases are needed.

Abstract

Introduction

Off label use of anticoagulants is common. The association between fibrin deposition in the lungs and primary lung disease, injury or prematurity affords a strong theoretical basis for the potential benefit of antithrombotic therapies administered directly to the lung tissue. This review offers a critical appraisal of current evidence related to the inhalational administration of antithrombotic therapy in humans.

Materials and methods

An interrogation of 2 databases across a 13 year period of time was undertaken using key words selected a priori. Identified publications were categorized according to the following themes:

  • 1.

    Inhaled antithrombotic therapy in healthy subjects

  • 2.

    Inhaled antithrombotic therapy for vascular thromboprophylaxis

  • 3.

    Inhaled antithrombotic therapy in smoke inhalation and lung injury

  • 4.

    Inhaled antithrombotic therapy in asthma or allergy

  • 5.

    Inhaled antithrombotic therapy for plastic bronchitis post-Fontan surgery

  • 6.

    Inhaled antithrombotic therapy for other indications.

Results

33 articles were identified consistent with the inclusion criteria developed for this review. Unfractionated heparin, LMWH, activated protein C and thrombolytic agents have been administered via the respiratory track, with asthma and smoke inhalation/lung injury being the most frequently investigated clinical scenarios described. All studies reported had significant methodological limitations.

Conclusions

The safety and clinical utility of inhaled antithrombotic therapies have not been adequately investigated to support the generation of any firm evidence. This review highlights where inhaled antithrombotic therapies have shown promise and importantly, the further research required to confirm mechanism of action and a definitive risk: benefit profile.

Section snippets

Materials and Methods

The MEDLINE and Pubmed databases were interrogated in order to identify all publications reporting the use of antithrombotic therapies administered via the respiratory tract between 1990 and December 31st 2013. The following search strategy was employed using “inhalation” and: heparin; warfarin; low molecular weight heparin; tissue plasminogen activator; urokinase; streptokinase; activated protein C.

The literature search inclusion criteria were:

  • Any study design, including case reports, trials,

Results

The database interrogation identified a total of 231 publications using various antithrombotic therapies including UFH (167 articles), warfarin (17 articles), low molecular weight heparin (LMWH) (13 articles), tissue plasminogen activator (33 articles), urokinase (20 articles), streptokinase (7 articles) and activated protein C (13 articles). No eligible publications were identified via review of reference lists of publications identified through the database interrogations. After application

Discussion

Anticoagulants and thrombolytics have been given by the inhaled route to humans for multiple indications across the last two and a half decades. Researchers have investigated the dose-requirements, safety, and efficacy of a range of agents with the aim of determining whether improved clinical outcomes can be achieved via the inhaled use of these agents. Preliminary data suggests positive clinical outcomes can be achieved in scenarios including plastic bronchitis secondary to Fontan surgery and

Conflict of Interest

None to declare.

Sources of Support

No sources of support supplied.

Acknowledgements

None.

References (48)

  • R. Mueller et al.

    History of drugs for thrombotic disease: discovery, development and directions for the future

    Circulation

    (1994)
  • C. Crafoord

    Preliminary report on post-operative treatment with heparin as a preventative of thrombosis

    Acta Chir. Scand.

    (1937)
  • D. Murray et al.

    Heparin and the thrombosis of veins following injury

    Surgery

    (1937)
  • K.E. Bendstrup et al.

    Lung deposition and clearance of inhaled (99m)Tc-heparin in healthy volunteers

    Am. J. Respir. Crit. Care Med.

    (1999)
  • K.E. Bendstrup et al.

    Effect of inhaled heparin on lung function and coagulation in healthy volunteers

    Eur. Respir. J.

    (2002)
  • J. Harenberg et al.

    Anticoagulant effects and tissue factor pathway inhibitor after intrapulmonary low-molecular-weight heparin

    Blood Coagul. Fibrinolysis

    (1996)
  • A. Markiewicz et al.

    Morning vs evening effects of intrapulmonary administration of heparin in healthy men

    Int. J. Clin. Pharmacol. Ther. Toxicol.

    (1992)
  • G. Scheuch et al.

    Anticoagulative effects of the inhaled low molecular weight heparin certoparin in healthy subjects

    J. Physiol. Pharmacol.

    (2007)
  • E.L. Kanabrocki et al.

    Heparin as a therapy for atherosclerosis: preliminary observations on the intrapulmonary administration of low-dose heparin in the morning versus evening gauged by its effect on blood variables

    Chronobiol. Int.

    (1991)
  • K. Zawilska et al.

    Nebulized heparin and anabolic steroid in the prevention of postoperative deep vein thrombosis following elective abdominal surgery

    Folia Haematol Int Mag Klin Morphol Blutforsch.

    (1990)
  • W. Geerts et al.

    Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-based Clinical Practice Guidelines

    (2008)
  • M.H. Desai et al.

    Reduction in mortality in pediatric patients with inhalation injury with aerosolized heparin/N-acetylcystine [correction of acetylcystine] therapy

    J. Burn Care Rehabil.

    (1998)
  • B. Dixon et al.

    A phase 1 trial of nebulised heparin in acute lung injury

    Crit. Care

    (2008)
  • J. Holt et al.

    Use of inhaled heparin/N-acetylcystine in inhalation injury: does it help?

    J. Burn Care Res.

    (2008)
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