title: Inhalation of a Short-Acting β2-Adrenoreceptor Agonist Induces a Hypercoagulable State in Healthy Subjects.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Internal Medicine and J. Recanati Autonomic Dysfunction Center, Tel Aviv "Sourasky" Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Mais
authors.initials: M
authors.lastname: Ali-Saleh
authors.affiliation: Thrombosis and Hemostatic Unit, Rambam Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.
authors.forename: Galit
authors.initials: G
authors.lastname: Sarig
authors.affiliation: Internal Medicine and J. Recanati Autonomic Dysfunction Center, Tel Aviv "Sourasky" Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Jacob N
authors.initials: JN
authors.lastname: Ablin
authors.affiliation: Thrombosis and Hemostatic Unit, Rambam Medical Center, Ruth and Bruce Rappaport Faculty of Medicine, Technion-IIT, Haifa, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Brenner
authors.affiliation: Internal Medicine and J. Recanati Autonomic Dysfunction Center, Tel Aviv "Sourasky" Medical Center, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Giris
authors.initials: G
authors.lastname: Jacob
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000328:Adult; D000420:Albuterol / Q000008:administration & dosage / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D005169:Factor VIII / Q000378:metabolism; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D009330:Nebulizers and Vaporizers; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D011446:Prospective Studies; D011516:Prothrombin / Q000378:metabolism; D016037:Single-Blind Method; D010959:Tissue Plasminogen Activator / Q000097:blood; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D005338:Fibrin Fibrinogen Degradation Products; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; C036309:fibrin fragment D; D014841:von Willebrand Factor; D011516:Prothrombin; D005169:Factor VIII; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D000420:Albuterol