A role for coagulation factor Xa in experimental pulmonary arterial hypertension

Delbeck, Martina; Nickel, Katrin F.; Perzborn, Elisabeth; Ellinghaus, Peter; Strassburger, J; Kast, Raimund; Laux, Volker; Schäfer, Stefan; Schermuly, Ralph Theo; Degenfeld, Georges von

doi:10.1093/cvr/cvr168

Cited by 31 publications

(25 citation statements)

References 38 publications

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“…47 Recent studies demonstrated that rivaroxaban treatment, as well as PAR-2 or IL-6 deficiency, attenuates PH in animal models. [48][49][50] Also, there is at least 1 case report in which PH For personal use only. on May 10, 2018. by guest www.bloodjournal.org From improved in a patient treated with an IL-6 receptor-blocking antibody.…”

Section: Discussionmentioning

confidence: 99%

Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease

Sparkenbaugh

Chantrathammachart

Mickelson

et al. 2014

Blood

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Section: Discussionmentioning

confidence: 99%

Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease

Sparkenbaugh

Chantrathammachart

Mickelson

et al. 2014

Blood

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“…43 Moreover, Delbeck et al recently reported that selective inhibition of factor Xa prevents RV dysfunction and hypertrophy in monocrotaline-injected rats; however, the potential role of PAR-2 was not assessed. 44 Future studies are required to investigate whether further mechanisms exist by which PAR-2 contributes to the development of PH and whether activators other than tryptase are crucially involved.…”

Section: Kwapiszewska Et Al Par-2 In Ph 1189mentioning

confidence: 99%

PAR-2 Inhibition Reverses Experimental Pulmonary Hypertension

Kwapiszewska

Markart

Dahal

et al. 2012

Circulation Research

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Rationale: A hallmark of the vascular remodeling process underlying pulmonary hypertension (PH) is the aberrant proliferation and migration of pulmonary arterial smooth muscle cells (PASMC). Accumulating evidence suggests that mast cell mediators play a role in the pathogenesis of PH.Objective: In the present study we investigated the importance of protease-activated receptor (PAR)-2 and its ligand mast cell tryptase in the development of PH. Methods and Results:Our results revealed strong increase in PAR-2 and tryptase expression in the lungs of idiopathic pulmonary arterial hypertension (IPAH) patients, hypoxia-exposed mice, and monocrotaline (MCT)-treated rats. Elevated tryptase levels were also detected in plasma samples from IPAH patients. Hypoxia and platelet-derived growth factor (PDGF)-BB upregulated PAR-2 expression in PASMC. This effect was reversed by HIF (hypoxia inducible factor)-1␣ depletion, PDGF-BB neutralizing antibody, or the PDGF-BB receptor antagonist Imatinib. Attenuation of PAR-2 expression was also observed in smooth muscle cells of pulmonary vessels of mice exposed to hypoxia and rats challenged with MCT in response to Imatinib treatment. Tryptase induced PASMC proliferation and migration as well as enhanced synthesis of fibronectin and matrix metalloproteinase-2 in a PAR-2-and ERK1/2-dependent manner, suggesting that PAR-2-dependent signaling contributes to vascular remodeling by various mechanisms. Furthermore, PAR-2 ؊/؊ mice were protected against hypoxia-induced PH, and PAR-2 antagonist application reversed established PH in the hypoxia mouse model. Key Words: pulmonary arterial hypertension Ⅲ protease-activated receptor-2 Ⅲ mast cells P ulmonary hypertension (PH) is characterized by a persistent increase in pulmonary arterial pressure, which can ultimately lead to right ventricular failure and death. Factors that contribute to the increased vascular resistance in PH include vasoconstriction, vascular remodeling, and thrombosis. 1 Pulmonary vasoconstriction can result from the imbalance of vasoactive mediators such as nitric oxide, endothelin-1, prostacyclin, and serotonin. Another potent stimulator of arterial contraction is alveolar hypoxia. Low oxygen levels down-regulate voltage-gated potassium channels, leading to depolarization of smooth muscle cells (SMC), subsequent Ca 2ϩ influx, and vasoconstriction. [2][3][4] Prolonged contraction stimulates the proliferation and migration of SMC and fibroblasts leading to medial or adventitial thickening of the pulmonary arteries. 1 Remodeling can also be triggered by a dysfunction of endothelial cells, thereby altering vascular homeostasis by changing cytokine/growth factor levels and procoagulant potential. 1 Vascular damage and endothelial dysfunction can alter the composition of the extracellular matrix by the induction of matrix metalloproteinases (MMPs), resulting in SMC migration and proliferation. 5 Accumulating evidence suggests that inflammatory cells may play an active role in the development of PH. 6,7 The number of mast cells...

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“…Moreover, although much more rarely than in thalassemia major, when LIC increases, labile pool iron rises quickly and may enter the heart, facilitating the occurrence of arrhythmias and heart failure. The huge variability in iron overload in NTDT patients has been hitherto attributed to age and degree of ineffective erythropoiesis, and we recently showed that ineffective erythropoiesis follows a steady increase from HbH to mild TI and severe TI patients [7]. Previous studies have suggested that TMPRSS6 is a genetic modifier of the beta-thalassemia phenotype in animal models [1].…”

Section: Dasatinib Therapy Can Results In Significant Pulmonary Toxicitymentioning

confidence: 93%

“…Although a study of the low molecular weight heparin, tinzaparin showed a reduction in the duration of pain crisis and hospitalization [6], most studies of anticoagulants in SCD have been small and poorly controlled. Treatment with the factor Xa inhibitor, rivaroxaban, as well as PAR-2 or IL-6 deficiency have been reported to attenuate PHT in animal models [7]. A study of rivaroxaban in SCD is ongoing to assess its pharmacodynamics effects (www.clinical trials.gov.…”

mentioning

confidence: 99%

Dasatinib therapy can result in significant pulmonary toxicity

et al. 2015

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thromboembolism (VTE) in SCD, with a higher mortality observed in patients with VTE compared to those without this complication [5].There are few studies specifically addressing treatment of PHT in SCD. Current strategies include optimizing SCD therapy and identifying potentially modifiable etiologies such as obstructive sleep apnea, pulmonary thrombosis, and left ventricular dysfunction. Hydroxyurea, approved for treatment of severe anemia and frequent vaso-occlusive episodes, has the potential benefit of being an NO donor. Endothelin receptor antagonists and prostaglandin therapy are approved for treatment of pulmonary arterial hypertension and have been recommended for select SCD patients with marked elevation of pulmonary vascular resistance and normal pulmonary artery occlusion pressure on RHC, and related symptoms [1]. Phosphodiesterase-5 inhibitor therapy is presently not recommended as first-line treatment for RHC-confirmed PHT due to the association of sildenafil with increased hospitalizations for pain crises. Riociguat, a soluble guanylate cyclase stimulator, is a vasodilator that bypasses the NO pathway. It has shown promise in CTEPH and PAH, but has not yet been studied in SCD. Although a study of the low molecular weight heparin, tinzaparin showed a reduction in the duration of pain crisis and hospitalization [6], most studies of anticoagulants in SCD have been small and poorly controlled. Treatment with the factor Xa inhibitor, rivaroxaban, as well as PAR-2 or IL-6 deficiency have been reported to attenuate PHT in animal models [7]. A study of rivaroxaban in SCD is ongoing to assess its pharmacodynamics effects (www.clinical trials.gov. identifier NCT02072668). Finally, pulmonary endarterectomy is standard for non-SCD patients with CTEPH, but the experience in SCD is limited, possibly due to concerns for a high risk of perioperative complications. Pulmonary endarterectomy requires cardiopulmonary bypass, hypothermia, and periods of circulatory arrest, which will likely increase the risk of sickling. These two cases, along with the previously published reports of four patients who underwent pulmonary endarterectomy [8][9][10], demonstrate that patients can undergo this procedure safely, with symptomatic and hemodynamic benefit. In summary, SCD patients with CTEPH, should be considered for pulmonary endarterectomy. AcknowledgmentAuthors thank Ertan Pamuklar, MD for help with the figure.

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A role for coagulation factor Xa in experimental pulmonary arterial hypertension

Cited by 31 publications

References 38 publications

Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease

Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease

PAR-2 Inhibition Reverses Experimental Pulmonary Hypertension

Dasatinib therapy can result in significant pulmonary toxicity

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