Inhaled nitric oxide to control platelet hyper-reactivity in patients with acute submassive pulmonary embolism

Jeffrey A. Kline, Michael A. Puskarich, Jonathan W. Pike, John Zagorski, Nathan J. Alves

Research output: Contribution to journalArticlepeer-review

Abstract

Background: We test if inhaled nitric oxide (NO) attenuates platelet functional and metabolic hyper-reactivity in subjects with submassive pulmonary embolism (PE). Methods: Participants with PE were randomized to either 50 ppm NO + O2 or O2 only for 24 h with blood sampling at enrollment and after treatment; results were compared with healthy controls. Platelet metabolic activity was assessed by oxygen consumption (basal and uncoupled) and reactivity was assessed with agonist-stimulated thromboelastography (TEG) and fluorometric measurement of agonist-stimulated cytosolic [Ca++] without and with pharmacological soluble guanylate (sGC) modulation. Results: Participants (N = 38 per group) were well-matched at enrollment for PE severity, comorbidities as well as TEG parameters and platelet O2 consumption. NO treatment doubled the mean plasma [NO3-] (P < 0.001) indicating successful delivery, but placebo treatment produced no change. After 24 h, neither TEG nor O2 consumption parameters differed significantly between treatment groups. Platelet cytosolic [Ca++] was elevated with PE versus controls, and was decreased by treatment with cinaciguat (an sGC activator), but not riociguat (an sGC stimulator). Stimulated platelet lysate sGC activity was increased with PE compared with controls. Conclusions: In patients with acute submassive PE, despite evidence of adequate drug delivery, inhaled NO had no major effect on platelet O2 consumption or agonist-stimulated parameters on TEG. Pharmacological activation, but not stimulation, of sGC effectively decreased platelet cytosolic [Ca++], and platelet sGC activity was increased with PE, confirming the viability of sGC as a therapeutic target.

Original languageEnglish (US)
Pages (from-to)20-28
Number of pages9
JournalNitric Oxide - Biology and Chemistry
Volume96
DOIs
StatePublished - Mar 1 2020

Bibliographical note

Funding Information:
This study was supported by NHLBI ( 1UM1HL113203-01A1 ) and. Dr. Puskarich received salary support from NIGMS for a study of platelet activation in septic shock ( K23GM113041-01 ), as well as support from the NIH Loan Repayment Program . Bayer pharmaceuticals provided the author with cinaciguat in-kind. Cinaciguat was provided in-kind throuh a materials transfer agreement from Bayer.

Keywords

  • Blood platelets
  • Comorbidity
  • Humans
  • Nitric oxide
  • Oxygen consumption
  • Platelet activation
  • Pulmonary embolism
  • Pyrazoles
  • Pyrimidines
  • Riociguat
  • Thrombelastography

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Multicenter Study
  • Randomized Controlled Trial

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