Risk Factors for Hemoptysis in Idiopathic and Hereditary Pulmonary Arterial Hypertension

Tio, Darryl; Leter, Edward M; Boerrigter, Bart; Boonstra, Anco; Vonk‐Noordegraaf, Anton; Bogaard, Harm Jan

doi:10.1371/journal.pone.0078132

Cited by 30 publications

(27 citation statements)

References 22 publications

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“…GHIGNA et al [12] confirm a previously reported greater frequency of bronchial arterial hypertrophy and haemoptysis in BMPR2 mutation positive patients [16]. The authors also demonstrate an association between BMPR2 mutation status and the presence of SiMFis.…”

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confidence: 54%

Adding complexity to plexogenic arteriopathy

Voelkel

Bogaard

2016

Eur Respir J

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@ERSpublicationsIn PAH, a wide range of abnormal pulmonary vascular manifestations exist, all arising from the endothelium http://ow.ly/IWH2305bXpQIn a landmark paper in the field of pulmonary hypertension research, Donald Heath and Jesse Edwards, in 1958, described the pulmonary vascular pathology that accompanies severe forms of pulmonary hypertension [1]. Examining lung tissue samples from patients with pulmonary hypertension associated with congenital heart disease and patients with primary pulmonary hypertension (now called idiopathic pulmonary arterial hypertension (PAH)), they distinguished six grades of severity and introduced the term "plexiform lesions". Ever since, the plexiform lesions have been a subject of interest and of frequently contentious debates [2][3][4][5]. To touch on just a few of the unresolved issues and questions: why do these lesions form? How many of these lesions are present in a patient's lung and are they haemodynamically important? What are the cellular components and the cell(s) of origin? A few investigators continue to be bored by these questions and have concluded that these complex vascular lesions are important mostly as an entertainment to a handful of pathologists.We believe that these signature lesions of severe forms of PAH are indeed very interesting. Firstly, they are unique to the lung and they can teach us about fundamental principles of vascular biology; for example, the first "law" of vascular biology that the endothelium must be a monolayer [6]. In the plexiform lesions, endothelial cells pile up and the law of the monolayer is broken. This fact opened the gates to further research that has led to the formulation of pathobiological hypotheses and concepts such as endothelial cell injury giving rise to the proliferation of apoptosis-resistant, phenotypically altered, lumen-obliterating cells: "misguided angiogenesis" and "wound healing gone awry" [7]. Indeed, these complex vascular lesions have taught us many lessons and their investigation has greatly enriched our knowledge of the spectrum of cellular responses of the lung circulation to chronic stress. Secondly, plexiform lesions are a hallmark of irreversible and generally very difficult to treat pulmonary vascular syndromes. This is certainly true in PAH and perhaps also in chronic thromboembolic pulmonary hypertension (CTEPH), where some authors have reported that the presence of plexiform lesions is associated with pulmonary hypertension that persists after thromboendarteriectomy [8] (while others have argued that plexiform lesions do not exist in CTEPH [9]). Thirdly, the concept that lumen-obliterating lesions, other than plexiform lesions, are indeed haemodynamically important has led to the search for animal models that present such lesions and are irresponsive to vasodilator treatment. These models are "two hit" models; for example, monocrotaline, the endothelial cell toxic alkaloid, plus high shear stress induced by pneumonectomy as described by OKADA et al. [10], or the combination of the vascular end...

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Section: @Erspublicationssupporting

confidence: 54%

Adding complexity to plexogenic arteriopathy

Voelkel

Bogaard

2016

Eur Respir J

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“…The potentially increased risk of pulmonary bleeding with riociguat in some patients is reflected as a warning in the local prescribing information (summary of product characteristics) and prescribers should regularly assess the individual patient's risk of pulmonary bleeding while on riociguat treatment. However, the risk of haemoptysis/pulmonary haemorrhage may be influenced by other factors, such as age, severity of disease, deterioration in pulmonary haemodynamics and concomitant treatment with anticoagulants [20,21]. The mechanism of FIGURE 4 Kaplan-Meier plots for a) clinical worsening and b) survival in the overall population during CHEST-2.…”

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confidence: 99%

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2)

et al. 2014

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Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of inoperable and persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). In the 16-week CHEST-1 study, riociguat showed a favourable benefit-risk profile and improved several clinically relevant end-points in patients with CTEPH. The CHEST-2 open-label extension evaluated the long-term safety and efficacy of riociguat.Eligible patients from CHEST-1 received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was the safety and tolerability of riociguat; exploratory efficacy endpoints included 6-min walking distance (6MWD) and World Health Organization (WHO) functional class (FC).Overall, 237 patients entered CHEST-2 and 211 (89%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in CHEST-2 was similar to CHEST-1, with no new safety signals. Improvements in 6MWD and WHO FC observed in CHEST-1 persisted for up to 1 year in CHEST-2. In the observed population at 1 year, mean±SD 6MWD had changed by +51±62 m (n=172) versus CHEST-1 baseline (n=237), and WHO FC had improved/stabilised/worsened in 47/50/3% of patients (n=176) versus CHEST-1 baseline (n=236).Long-term riociguat had a favourable benefit-risk profile and apparently showed sustained benefits in exercise and functional capacity for up to 1 year. @ERSpublications Riociguat shows favourable benefit-risk profile in CTEPH patients, with benefits in 6MWD and WHO FC for up to 1 year

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“…Haemoptysis and pulmonary haemorrhage are known complications of PAH [12,13]. The rate of haemoptysis and pulmonary haemorrhage SAEs in the PATENT-2 study was 1.8 cases per 100 patient-years (3% of patients) compared with 4.3 cases per 100 patient-years in the riociguat groups of the PATENT-1 study (1% of patients).…”

Section: Discussionmentioning

confidence: 99%

“…The potentially increased risk of pulmonary bleeding with riociguat in some patients is reflected as a warning in the local prescribing information (summary of product characteristics) and should be considered as drug-related. However, the risk of haemoptysis and pulmonary haemorrhage may be influenced by other factors, such as age, severity of disease, deterioration in pulmonary haemodynamics and concomitant treatment with anticoagulants [12,14]. The mechanism of how riociguat could cause haemoptysis and pulmonary haemorrhage is unclear.…”

Section: Discussionmentioning

confidence: 99%

Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2)

et al. 2015

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Riociguat is a soluble, guanylate cyclase stimulator, approved for pulmonary arterial hypertension. In the 12-week PATENT-1 study, riociguat was well tolerated and improved several clinically relevant end-points in patients with pulmonary arterial hypertension who were treatment naïve or had been pretreated with endothelin-receptor antagonists or prostanoids. The PATENT-2 open-label extension evaluated the long-term safety and efficacy of riociguat.Eligible patients from the PATENT-1 study received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was to assess the safety and tolerability of riociguat; exploratory efficacy assessments included 6-min walking distance and World Health Organization (WHO) functional class.Overall, 396 patients entered the PATENT-2 study and 324 (82%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in PATENT-2 was similar to that observed in PATENT-1, with cases of haemoptysis and pulmonary haemorrhage also being observed in PATENT-2. Improvements in the patients', 6-min walking distance and WHO functional class observed in PATENT-1 persisted for up to 1 year in PATENT-2. In the observed population at the 1-year time point, mean±SD 6-min walking distance had changed by 51±74 m and WHO functional class had improved in 33%, stabilised in 61% and worsened in 6% of the patients versus the PATENT-1 baseline.Long-term riociguat was well tolerated in patients with pulmonary arterial hypertension, and led to sustained improvements in exercise capacity and functional capacity for up to 1 year. @ERSpublications Riociguat was well tolerated in patients with PAH, with sustained benefits in 6MWD and WHO FC for up to 1 year

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Risk Factors for Hemoptysis in Idiopathic and Hereditary Pulmonary Arterial Hypertension

Cited by 30 publications

References 22 publications

Adding complexity to plexogenic arteriopathy

Adding complexity to plexogenic arteriopathy

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2)

Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2)

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