# PTH-driven modulation of platelet activity via the NOX2 pathway in postsurgical hypoparathyroidism

## TL;DR

This study shows that patients with hypoparathyroidism have increased platelet activity and oxidative stress, which may be worsened by PTH therapy, suggesting a need for cardiovascular monitoring.

## Contribution

The study identifies a PTH1R–calcium–PKC–NOX2 signaling pathway in platelets that links PTH therapy to increased thrombotic risk in hypoparathyroidism.

## Key findings

- HypoPT patients show heightened platelet activation and oxidative stress compared to controls.
- PTH (1–34) therapy increases platelet activation and thrombus formation in HypoPT patients.
- In vitro, PTH (1–34) affects platelet function only in HypoPT-derived platelets via NOX2-dependent ROS generation.

## Abstract

Postsurgical chronic hypoparathyroidism (HypoPT) has been linked to an increased cardiovascular risk, but the underlying pathophysiological mechanisms remain incompletely understood. Emerging evidence suggests a potential direct role of parathyroid hormone (PTH) in modulating platelet function and oxidative stress, both contributors to atherothrombosis.

Our study aimed to investigate the impact of PTH on platelet function and activation, with a particular focus on NOX2-mediated platelet activation in patients with HypoPT.

We conducted a cross-sectional study involving 24 patients with HypoPT and 40 age- and sex-matched healthy controls. Clinical, biochemical, and platelet function parameters were assessed. In a subgroup of five HypoPT patients, changes were evaluated after 24 months of PTH (1–34) therapy. Platelet aggregation, oxidative stress biomarkers (sNOX2-dp, H2O2, 8-OHdG), and thrombus formation (T-TAS) were measured. The in vitro effect of PTH (1–34) was tested on isolated platelets.

Patients with HypoPT exhibited enhanced platelet activation, increased oxidative stress, and accelerated thrombus formation compared to controls. Enhanced platelet activation and increased oxidative stress observed in HypoPT were further amplified in HypoPT subjects treated with PTH (1–34). In vitro, PTH (1–34) increased oxidative stress and platelet aggregation only in platelets from HypoPT patients, through a specific signaling pathway involving PTH1R activation, intracellular calcium release, protein kinase C (PKC) activation and NOX2-dependent ROS generation.

HypoPT is associated with heightened platelet reactivity and thrombotic risk. PTH therapy may exacerbate these alterations through a defined molecular mechanism. These findings highlight the need for careful cardiovascular monitoring in HypoPT patients, particularly those receiving PTH analogues.

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•Hypoparathyroidism is linked to enhanced oxidative stress and platelet activation.•Recombinant PTH (1–34) exacerbates platelet activation and thrombus formation in HypoPT.•PTH signaling involves PTH1R–calcium–PKC–NOX2 axis in platelets.•In vitro, PTH increases oxidative stress and platelet aggregation in HypoPT but not in control platelets.•Findings support cardiovascular risk evaluation in HypoPT patients on PTH analogues.

Hypoparathyroidism is linked to enhanced oxidative stress and platelet activation.

Recombinant PTH (1–34) exacerbates platelet activation and thrombus formation in HypoPT.

PTH signaling involves PTH1R–calcium–PKC–NOX2 axis in platelets.

In vitro, PTH increases oxidative stress and platelet aggregation in HypoPT but not in control platelets.

Findings support cardiovascular risk evaluation in HypoPT patients on PTH analogues.