Inhalation of a Short-Acting β2-Adrenoreceptor Agonist Induces a Hypercoagulable State in Healthy Subjects

• Published in: PloS one Vol. 11; no. 7; p. e0158652
• Main Authors: Ali-Saleh, Mais, Sarig, Galit, Ablin, Jacob N., Brenner, Benjamin, Jacob, Giris
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.07.2016; Public Library of Science (PLoS)
• Subjects: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists - administration & dosage; Adrenergic beta-2 Receptor Agonists - pharmacology; Adrenergic receptors; Adult; Albuterol - administration & dosage; Albuterol - pharmacology; Anticoagulants; Antigens; Asthma; Biology and Life Sciences; Blood Coagulation - drug effects; Body mass; Body mass index; Body size; Catecholamine; Catecholamines; Chronic obstructive pulmonary disease; Clotting; Critical care; Factor VIII - metabolism; Female; Females; Fibrin; Fibrin Fibrinogen Degradation Products - metabolism; Healthy Volunteers; Hemodynamics; Humans; Inhalation; Internal medicine; Male; Medicine; Medicine and Health Sciences; Mortality; Nebulizers and Vaporizers; Nervous system; Norepinephrine; Partial Thromboplastin Time; Peptide Fragments - metabolism; Physical Sciences; Plasma; Plasma levels; Plasminogen - metabolism; Plasminogen Activator Inhibitor 1 - blood; Prospective Studies; Protein C; Proteins; Prothrombin; Prothrombin - metabolism; Respiration; Salbutamol; Single-Blind Method; Stress; Sulfates; t-Plasminogen activator; Thromboembolism; Thrombosis; Tissue Plasminogen Activator - blood; Von Willebrand factor; von Willebrand Factor - metabolism; Tel Aviv Israel; Israel
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0158652

Catecholamine infusion elicits an increase in clotting factors and this increase has been attributed to stimulation of β2-adrenorecptors (β2AR). Accordingly, we tested the hypothesis that inhalation of a short-acting selective β2AR agonist can induce a procoagulant state in healthy individuals. We recruited 23 healthy volunteers (nine females; mean age: 26±0.8 years; body mass index: 24.7±0.5 kg/m2) and randomly allocated them into two groups, the β2AR arm (seventeen subjects) and the saline arm (six subjects). Hemodynamics, plasma norepinephrine concentration, and procoagulant, anticoagulant, and fibrinolytic profiles of each participant were determined using specific assays before and after inhalation of either 2 mL nebulized normal saline or a mixture of 1 mL saline and 1 mL of salbutamol (5 mg salbutamol sulfate), a selective β2AR agonist, which were delivered by a nebulizer over ten minutes. Saline inhalation had no effect on the procoagulant, anticoagulant and fibrinolytic profiles of the six healthy volunteer in the study's saline arm. Salbutamol inhalation caused (a) a significant increase in the activity or levels of the procoagulant factors; FVIII increased by 11±3% (p = 0.04), von Willebrand factor increased by 7±1% (p = 0.03), and (b) a significant decrease in the activated partial prothrombin time from 27.4±0.4 seconds to 25.5 ±0.5 seconds (p<0.001) in the 17 volunteers in the study's β2AR arm. D-dimer and prothrombin fragments F1+2 were elevated by 200 ±90% and 505.0 ±300.0%, respectively. In addition, the activity of the anticoagulant protein C pathway (demonstrated by the protein C Global assay) decreased from 1.0±0.08 to 0.82±0.06 (p<0.001). Although plasma levels of tissue plasminogen activator decreased, all other indices of the fibrinolytic system did not change following salbutamol inhalation. We found that a single inhalation of salbutamol, a short-acting β2AR agonist, activates the clotting system without affecting the fibrinolytic system. This induction of a procoagulant state in healthy subjects warrants further investigation in patients treated with these agents.