Plasma ADAMTS13 and von Willebrand factor in diagnosis and prediction of prognosis in pulmonary arterial hypertension

Abstract

To improve outcome in pulmonary arterial hypertension, earlier diagnosis and better prognostic assessments are required. We aimed to investigate the diagnostic and prognostic potential of plasma proteins related to pathways recognized in pulmonary arterial hypertension including coagulation, inflammation, and metabolism. Forty-two proteins were analysed with proximity extension assay from plasma of 20 healthy controls and 150 patients, including (pulmonary arterial hypertension, n = 48, whereof 33 also during early treatment follow-ups); chronic thromboembolic pulmonary hypertension (CTEPH, n = 20); pulmonary hypertension (PH) due to heart failure (HF) with preserved ejection fraction (HFpEF-PH, n = 31); PH due to HF with reduced ejection fraction (HFrEF-PH, n = 36); and HF without PH (Dyspnoea/HF-non-PH, n = 15). Patients' haemodynamics were assessed by right heart catheterization. Plasma ADAMTS13 in incident pulmonary arterial hypertension was lower compared to the healthy controls (p = 0.055), as well as CTEPH (p < 0.0001), HFrEF-PH (p < 0.0001), HFrEF-PH (p < 0.0001), and Dyspnoea/HF-non-PH (p < 0.0001). Adjusted for age and sex, ADAMTS13 discriminated pulmonary arterial hypertension from the other disease groups with an AUC of 0.91 (sensitivity = 87.5%, and specificity = 78.4%). Higher plasma von Willebrand factor was associated with worse survival (log-rank p = 0.0029), and a higher mortality rate (adjusted hazard ratio 1.002, 95% confidence interval 1-1.004; p = 0.041). Adjusted for age, sex, and combined with the ESC/ERS risk score, von Willebrand factor predicted mortality (median follow-up 3.6 years) in pulmonary arterial hypertension with an AUC of 0.94 (sensitivity = 81.3%, and specificity=93.8%). ADAMTS13 may be a promising biomarker for early detection of PAH and von Willebrand factor as a candidate prognostic biomarker. The putative additional value of von Willebrand factor to the European multiparametric risk assessment strategy remains to be elucidated.

Keywords: Biomarkers; diagnosis; prognosis; pulmonary arterial hypertension.

Figure 1.

Biomarker candidates for differentiation and diagnosis of pulmonary arterial hypertension. In (a–c), levels of PAH patients versus controls are depicted in scatterplots for ADAMTS13, spondin-2 and tissue factor. D-F, levels of ADAMTS13, spondin-2 and tissue factor in PAH, compared to CTEPH, HFpEF-PH, HFrEF-PH, and Dyspnoea/HF-non-PH. G, ROC-curves (based on multivariable logistic regression models) displaying the discriminatory ability of each model in identifying PAH from the other disease groups. (a–c), statistical significance was considered p < 0.015; false discovery rate (FDR<0.05) and in (d–f), p < 0.05;(FDR<0.1). *Indicates p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. ADAMTS13: a disintegrin and metalloproteinase with thrombospondin motifs 13; AU: arbitrary unit; CTEPH: chronic thromboembolic pulmonary hypertension; HF: heart failure; HFrEF-PH: pulmonary hypertension due to heart failure with reduced ejection fraction; HFpEF-PH: pulmonary hypertension due to heart failure with preserved ejection fraction; PAH: pulmonary arterial hypertension; PH: pulmonary hypertension.

Figure 2.

Plasma von Willebrand factor in relation to survival and prognosis prediction in pulmonary arterial hypertension. (a) Scatterplots of von Willebrand factor levels of incident PAH patients, comparing survivors vs. non-survivors. The optimal threshold using Youden’s index for discrimination is plotted as a dotted line. (b) using the optimal threshold, survival of patients was plotted using the Kaplan-Meier method. (c) ROC-curves (based on multivariable logistic regression models), displaying the discriminatory ability of each model in prognostication of PAH patients, based on the follow-up time, median (IQR): 3.6 (2.1–4.8) years. AU: arbitrary unit; PAH: pulmonary arterial hypertension; vWF: von Willebrand factor.

Figure 3.

von Willebrand factor and ADAMTS13 in pulmonary arterial hypertension. Decreased availability of nitric oxide and prostacyclin as well as increased endothelin establishes the hallmarks of endothelial dysfunction in PAH, with impact on pulmonary vasoconstriction and vascular remodelling. Hypothetically, dysfunctional endothelium may furthermore be an important cause of higher plasma von Willebrand factor and lower plasma levels of ADAMTS13. Plasma ADAMTS13 cleaves large von Willebrand factor (vWF) multimers into light weight polymers, rendering reduced anticoagulant activity. The elevated levels of plasma vWF consist of paradoxically low levels of large multimers and high levels of low molecular weight polymers, despite low levels of plasma ADAMTS13. This may be due to increased consumption of large vWF multimers, increased release of deranged vWF polymers characterized by low biological activity, or potentially by other proteolytic activity besides that of ADAMTS13.