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The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension.

ABSTRACT: Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism that is associated with abnormalities in haemostasis. We investigated the ADAMTS13-von Willebrand factor (VWF) axis in CTEPH, including its relationship with disease severity, inflammation, ABO groups and ADAMTS13 genetic variants.ADAMTS13 and VWF plasma antigen levels were measured in patients with CTEPH (n=208), chronic thromboembolic disease without pulmonary hypertension (CTED) (n=35), resolved pulmonary embolism (n=28), idiopathic pulmonary arterial hypertension (n=30) and healthy controls (n=68). CTEPH genetic ABO associations and protein quantitative trait loci were investigated. ADAMTS13-VWF axis abnormalities were assessed in CTEPH and healthy control subsets by measuring ADAMTS13 activity, D-dimers and VWF multimeric size.Patients with CTEPH had decreased ADAMTS13 (adjusted β -23.4%, 95% CI -30.9- -15.1%, p<0.001) and increased VWF levels (β +75.5%, 95% CI 44.8-113%, p<0.001) compared to healthy controls. ADAMTS13 levels remained low after reversal of pulmonary hypertension by pulmonary endarterectomy surgery and were equally reduced in CTED. We identified a genetic variant near the ADAMTS13 gene associated with ADAMTS13 protein that accounted for ∼8% of the variation in levels.The ADAMTS13-VWF axis is dysregulated in CTEPH. This is unrelated to pulmonary hypertension, disease severity or markers of systemic inflammation and implicates the ADAMTS13-VWF axis in CTEPH pathobiology.

SUBMITTER: Newnham M

PROVIDER: S-EPMC6437602 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension.

Newnham Michael M South Kieron K Bleda Marta M Auger William R WR Barberà Joan A JA Bogaard Harm H Bunclark Katherine K Cannon John E JE Delcroix Marion M Hadinnapola Charaka C Howard Luke S LS Jenkins David D Mayer Eckhard E Ng Choo C Rhodes Christopher J CJ Screaton Nicholas N Sheares Karen K Simpson Michael A MA Southwood Mark M Su Li L Taboada Dolores D Traylor Matthew M Trembath Richard C RC Villar Sofia S SS Wilkins Martin R MR Wharton John J Gräf Stefan S Pepke-Zaba Joanna J Laffan Michael M Lane David A DA Morrell Nicholas W NW Toshner Mark M

The European respiratory journal 20190328 3

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important consequence of pulmonary embolism that is associated with abnormalities in haemostasis. We investigated the ADAMTS13-von Willebrand factor (VWF) axis in CTEPH, including its relationship with disease severity, inflammation, <i>ABO</i> groups and <i>ADAMTS13</i> genetic variants.ADAMTS13 and VWF plasma antigen levels were measured in patients with CTEPH (n=208), chronic thromboembolic disease without pulmonary hypertension (CTE ...[more]

PMID: 30655285

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Project description:Chronic thromboembolic pulmonary hypertension (CTEPH) is one of the leading causes of severe pulmonary hypertension (PH). The disease is still underdiagnosed, and the true prevalence is unknown. CTEPH is characterized by intraluminal non-resolving thrombus organization and fibrous stenosis, or complete obliteration of pulmonary arteries, promoted by progressive remodeling of the pulmonary vasculature. One consequence of this is an increase in pulmonary vascular resistance and pressure, resulting in PH and progressive right heart failure, leading to death if left untreated. Endovascular disobliteration by pulmonary endarterectomy (PEA) is the preferred treatment for CTEPH patients. PEA surgery is the only technique that can potentially cure CTEPH disease, especially in patients with fresh or organized thrombi of the proximal branches of pulmonary arteries. However, not all patients are eligible for PEA surgery. Recent research has provided evidence suggesting balloon pulmonary angioplasty (BPA) and targeted medical therapy as additional promising available treatments options for inoperable CTEPH and recurrent/persistent PH after PEA surgery. Studies on BPA have shown it to improve pulmonary hemodynamics, symptoms, exercise capacity and RV function in inoperable CTEPH. Subsequently, BPA has developed into an essential component of the modern era of CTEPH treatment. Large randomized controlled trials have demonstrated varying significant improvements with targeted medical therapy in technically inoperable CTEPH patients. Thus, treatment of CTEPH requires a comprehensive multidisciplinary assessment, including an experienced PEA surgeon, PH specialist, BPA interventionist and CTEPH-trained radiologist at expert centers. In this comprehensive review, we address the latest developments in the fast-evolving field of CTEPH. These include advancements in imaging modalities and developments in operative and interventional techniques, which have widened the range of patients who may benefit from these procedures. The efficacy and safety of targeted medical therapies in CTEPH patients are also discussed. As the treatment options for CTEPH improve, hybrid management involving multiple treatments in the same patient may become a viable option in the near future.

Dataset Information

The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension.

Publications

The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension.

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