Fibrinogen A  Thr312Ala polymorphism is associated with chronic thromboembolic pulmonary hypertension

Suntharalingam, Jay; Goldsmith, Kimberley; Marion, Vincent; Lü, Long; Treacy, Carmen; Dudbridge, Frank; Toshner, Mark; Pepke‐Zaba, Joanna; Eikenboom, Jeroen; Morrell, Nicholas W.

doi:10.1183/09031936.00055107

Cited by 86 publications

(49 citation statements)

References 45 publications

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“…In most cases it is associated with a history of acute venous thromboembolism [19], but why thrombi do not resolve after an acute event in a low percentage of patients is unclear. The current knowledge is based on a triad of enhanced thrombosis [12,20], disturbed thrombolysis [21][22][23] and inflammation [3]. These mechanisms were all investigated in the current experiments regarding CRP effects.…”

Section: Discussionmentioning

confidence: 99%

Effects of C-reactive protein on human pulmonary vascular cells in chronic thromboembolic pulmonary hypertension

et al. 2012

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Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by proximal pulmonary vascular obstruction by thrombo-fibrotic material, the origin of which has not been elucidated. Enhanced inflammation could contribute to persistent obstruction by impairing pulmonary vascular cell function in CTEPH. We investigated C-reactive protein (CRP) effects on pulmonary vascular cell function in vitro.Primary cultures of proximal pulmonary endothelial cells (ECs) and smooth muscle cells (SMCs) from CTEPH and nonthromboembolic pulmonary hypertension (PH) patients were established. Recombinant CRP effects on mitogenic activity, adhesion capacity, endothelin-1 and von Willebrand factor (vWF) secretion and intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule-1 expression were investigated in ECs and/or SMCs. Expression of the CRP receptor, lectin-like oxidised low-density lipoprotein receptor (LOX)-1, was evaluated in proximal pulmonary arterial tissue and cells by Western blotting and immunofluorescence.CRP increased CTEPH-SMC proliferation by 250%. CRP increased adhesion capacity, endothelin-1 and vWF secretion by CTEPH-ECs by 37%, 129% and 694%, respectively. CRP-induced adhesion of CTEPH-ECs to monocytes was mediated by ICAM-1. CRP had no effect on cells from nonthromboembolic PH patients, probably because of overexpression of LOX-1 in CTEPH. Local expression of CRP was detected in ECs and SMCs within pulmonary arterial tissue.CRP may contribute to persistent obstruction of proximal pulmonary arteries in CTEPH by promoting vascular remodelling, endothelial dysfunction and in situ thrombosis. KEYWORDS: C-reactive protein, chronic thromboembolic pulmonary hypertension, endothelial cells, inflammation, smooth muscle cells C hronic thromboembolic pulmonary hypertension (CTEPH) is one of the main causes of severe pulmonary hypertension. CTEPH is characterised by intraluminal thrombus organisation and fibrous stenosis or complete obliteration of proximal pulmonary arteries. The consequence is an increased pulmonary vascular resistance resulting in pulmonary hypertension (PH) and progressive right heart failure. Pulmonary embolism, either as single or recurrent episodes, is thought to be the initiating event followed by progressive pulmonary vascular remodelling. CTEPH mainly differs from pulmonary arterial hypertension (PAH) by the proximal location of pulmonary artery obliteration [1].To date, the physiopathology of CTEPH remains poorly understood. Proximal lesions share similarities with atherosclerotic plaques, including media thickening and neointima formation [2]. Besides evidence of dysregulated thrombosis and/or thrombolysis, an elevated prevalence of inflammatory diseases has been observed in CTEPH patients [3]. Accordingly, plasma levels of tumour necrosis factor-a are elevated in CTEPH [4] and elevated pulmonary vascular resistance is correlated with increased expression of the CCL2 chemokine monocyte chemoattractant protein-1 in the plasma and large pulmonary arteries of CTE...

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Section: Discussionmentioning

confidence: 99%

Effects of C-reactive protein on human pulmonary vascular cells in chronic thromboembolic pulmonary hypertension

et al. 2012

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“…In a recent study, a significant difference was demonstrated in fibrinogen (Fg)-Aa Thr312Ala genotype and allele frequencies between CTEPH subjects and controls [52]. In addition, the Fg-Aa Thr312Ala allele has been associated with an increased risk of VTE [53].…”

Section: The Concept Of ''Deficient Angiogenesis''mentioning

confidence: 99%

Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding

et al. 2012

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All available evidence today indicates that chronic thromboembolic pulmonary hypertension (CTEPH) is primarily caused by venous thromboembolism, as opposed to primary pulmonary vascular in situ thrombosis. Both the initial magnitude of clot and pulmonary embolism (PE) recurrence may contribute to the development of CTEPH. Only few specific thrombophilic factors, such as phospholipid antibodies, lupus anticoagulant and elevated factor VIII, are statistically associated with CTEPH.A mechanistic view of CTEPH as a disease caused by obliteration of central pulmonary arteries by pulmonary emboli is too simplistic. Based on available data one may speculate that PE may be followed by a pulmonary vascular remodelling process modified by infection, immune phenomena, inflammation, circulating and vascular-resident progenitor cells, thyroid hormone replacement or malignancy. Both plasmatic factors (hypercoagulation, ''sticky'' red blood cells, high platelet counts and uncleavable fibrinogens) and a misguided vascular remodelling process contribute to major vessel and small vessel obliteration. Endothelial dysfunction and endothelialmesenchymal transition may be important, but their precise roles remain obscure. There exists no animal model for CTEPH; therefore, experimentation in the future must include human tissues and clinical data in parallel.

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“…These include a significant association between CTEPH and the fibrinogen Aα polymorphism Thr312Ala, which has been shown to increase the resistance of fibrin to typical lytic processes [53,54]. Taken together, these observations demonstrate a number of pathophysiological modalities that between them probably account for the non-resolution of thromboembolic material seen in CTEPH, although further investigation is required.…”

Section: Coagulation and Thrombus Resolutionmentioning

confidence: 77%

Chronic thromboembolic pulmonary hypertension: a distinct disease entity

Lang

2015

Eur Respir Rev

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Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct subtype of pulmonary hypertension (PH). One disease hypothesis is that CTEPH results from the non-resolution of venous thromboembolism. CTEPH is characterised by the presence of obstructive fibrotic thromboembolic material in the major pulmonary vessels, with concomitant microvascular arteriopathy, resulting in progressive PH. The clinical presentation of CTEPH is similar to pulmonary arterial hypertension with nonspecific symptoms, but it is distinguished from pulmonary arterial hypertension by the presence of mismatched segmental defects on the ventilation/perfusion scan. The exact prevalence and incidence of CTEPH are unknown, but are thought to have been underestimated in the past. CTEPH is unique among the subgroups of PH in that it is potentially curable with pulmonary endarterectomy, a surgical intervention intended to remove the occlusive material from the pulmonary vasculature. However, in some patients the obstructions are technically inaccessible or the risk/benefit ratios are unfavourable, making the condition inoperable. It is thought that the involvement of the smaller, more distal vessels is a target for medical treatment. Untreated, CTEPH may result in right heart failure and death. The pathophysiological mechanisms which cause CTEPH are complex and have not yet been fully elucidated. @ERSpublications CTEPH is distinct from other types of pulmonary hypertension, both in terms of its pathophysiology and treatment http://ow.ly/L54ag

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Fibrinogen A Thr312Ala polymorphism is associated with chronic thromboembolic pulmonary hypertension

Cited by 86 publications

References 45 publications

Effects of C-reactive protein on human pulmonary vascular cells in chronic thromboembolic pulmonary hypertension

Effects of C-reactive protein on human pulmonary vascular cells in chronic thromboembolic pulmonary hypertension

Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding

Chronic thromboembolic pulmonary hypertension: a distinct disease entity

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