A role for coagulation factor Xa in experimental pulmonary arterial hypertension

• Published in: Cardiovascular research 2011-10, Vol.92 (1), p.159-168
• Main Authors: Delbeck, Martina, Nickel, Katrin F., Perzborn, Elisabeth, Ellinghaus, Peter, Strassburger, Julia, Kast, Raimund, Laux, Volker, Schäfer, Stefan, Schermuly, Ralph T., von Degenfeld, Georges
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Coagulation; Cardiology. Vascular system; Enoxaparin - pharmacology; Factor Xa - physiology; Factor Xa Inhibitors; Familial Primary Pulmonary Hypertension; Hemodynamics - drug effects; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - etiology; Hypertrophy, Right Ventricular - prevention & control; Male; Medical sciences; Monocrotaline; Morpholines - pharmacology; Pneumology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Rats; Rats, Sprague-Dawley; Rats, Wistar; Rivaroxaban; Thiophenes - pharmacology; Thrombosis - etiology; Warfarin - pharmacology
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvr168

Aims Anticoagulation with warfarin is recommended for the treatment of patients with pulmonary arterial hypertension (PAH). However, the therapeutic benefit of anticoagulation has not yet been demonstrated experimentally or clinically. Here, rivaroxaban, an oral, direct factor Xa (FXa) inhibitor, was compared with warfarin and enoxaparin in the prevention of right ventricular (RV) dysfunction and hypertrophy in the monocrotaline (MCT) model of pulmonary hypertension. Methods and results Sprague-Dawley rats (n = 10 per group) were randomized to receive rivaroxaban, warfarin, enoxaparin, or placebo before receiving a subcutaneous injection of MCT 60 mg/kg or saline. Rivaroxaban and enoxaparin were administered for 28 days starting 4 h before MCT injection; warfarin was given for 35 days initiated 7 days before MCT injection. RV haemodynamics and hypertrophy were assessed 28 days after MCT administration. Rivaroxaban dose-dependently reduced systolic and end-diastolic RV pressure increase and RV hypertrophy. Warfarin reduced RV pressure increase only. Enoxaparin had no effect on either parameter. Severe bleeding occurred in four and five rats treated with warfarin and enoxaparin, respectively, whereas no overt bleeding was observed in rats treated with rivaroxaban. Conclusion Selective, direct inhibition of FXa by rivaroxaban effectively prevented RV dysfunction and hypertrophy in MCT-injected rats, indicating a role for coagulation factors in experimental pulmonary hypertension. Clinical investigation of the impact of early and continued administration of a specific FXa inhibitor such as rivaroxaban on the course of PAH should be considered.