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

Abstract

BackgroundCatecholamine 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.MethodsWe 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.ResultsSaline 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.ConclusionWe 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.

Beta‐Adrenergic Blockers as a Potential Treatment for COVID‐19 Patients

“…[46] As mentioned earlier, beta2-adrenergic agonists like salbutamol used in the nebulizer solutions, increase the plasma catecholamine level, and produce hypercoagulable state. [31][32][33] Considering the vicious ARAS loop, I suggest beta2-adrenergic agonists should be avoided in the nebulizer solutions, as they may worsen the clinical condition in COVID-19 patients and may produce complications like pulmonary embolism.…”

The effects of submaximal exercise and cold exposure on blood coagulation parameters in coronary artery disease patients

“…Exercise is known to activate sympathetic nervous system and increase blood catecholamine levels in an intensity-dependent manner [29]. Sympathetic activation may lead to increased platelet count and activation, as well as increased FVIII activity and vWF release via betaadrenergic receptor stimulation and endothelial activation [30][31][32][33]. VWF has been shown to have an important role in vascular inflammation and thrombus formation [34].…”

Effects of Acute Stress on Thrombosis

“…This state was accompanied by significant increases in D-dimer and prothrombin fragments 1 þ 2, which are markers of thrombin and fibrin generation and also fibrinolysis. 63 An infusion of isoproterenol (a nonselective β-AR agonist) or salbutamol, but not norepinephrine (an α-AR and β 1 -AR agonist, with no effect on the β 2 -AR), resulted in increased VWF plasma levels. 20,[64][65][66] Accordingly, β-blockade with propranolol (a nonselective β-AR antagonist) was able to abolish adrenaline-induced release of factor VIII 66 and reduce factor VIII levels in patients.…”

“…Other effectors, such as the renin, angiotensin, aldosterone system (RAAS), vasopressin, prolactin, and growth hormone, are also known to be involved in this response. 12,13,[56][57][58][59][60][61][62][63][64][65][66][67][68] The Effect of the Sympathetic Nervous System on Coagulation…”