Post-translational modifications in the insoluble fraction of platelet-poor plasma distinguish pre-COVID-19 Postural Orthostatic Tachycardia Syndrome, Long COVID, and Long COVID-POTS: a preliminary study.
10 affiliations
- 1Department of Physiological Sciences, Stellenbosch University, Private Bag Z1, Stellenbosch, 7599, South Africa. [email protected].
- 2Department of Physiological Sciences, Stellenbosch University, Private Bag Z1, Stellenbosch, 7599, South Africa.
- 3Trace Labs, Cape Town, South Africa.
- 4Department of Genetics, Stellenbosch University, Private Bag Z1, Stellenbosch, 7599, South Africa.
- 5Libin Cardiovascular Institute, University of Calgary, Calgary, CA, Canada.
- 6Pulmonologist and sleep physician (medically retired), Manchester, UK.
- 7Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK.
- 8Libin Cardiovascular Institute, University of Calgary, Calgary, CA, Canada. [email protected].
- 9Department of Physiological Sciences, Stellenbosch University, Private Bag Z1, Stellenbosch, 7599, South Africa. [email protected].
- 10Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB, UK. [email protected].
Abstract
Background
Pre-COVID-19 Postural Orthostatic Tachycardia Syndrome (PC-POTS), Long COVID with initial orthostatic hypotension (LC-IOH), and Long COVID-POTS (LC-POTS) are primarily chronic post-viral conditions with debilitating symptoms, despite routine laboratory findings often being normal. We previously identified amyloidogenic fibrinaloid microclot complexes (FMCs) in the insoluble fraction of platelet-poor plasma (PPP-IF) in Long COVID, but it remains unclear whether similar abnormalities occur in PC-POTS and LC-POTS, or whether post-translational modifications (PTMs) contribute to disease mechanisms.Methods
Platelet-poor plasma from healthy controls (n = 18), PC-POTS (n = 20), LC-IOH (n = 19), and LC-POTS (n = 18) participants underwent proteomic analysis of the PPP-IF using double trypsin digestion and data-independent LC-MS/MS. Differential protein abundance, PTMs, and amyloidogenicity were compared across groups.Results
Although few proteins were significantly dysregulated, extensive disease-specific PTM alterations were identified across coagulation, immune, and metabolic pathways. LC-IOH demonstrated prominent AGE- and oxidation-related PTMs on fibrinogen subunits, particularly fibrinogen alpha chain (FIBA), resembling diabetic glycation profiles. PC-POTS showed fewer fibrinogen PTMs but marked metabolic and immune dysregulation, including oxidised apoA1 and apoB and complement-associated proteins (C3, C4A/B, IC1), IGG1, and A2MG. LC-POTS shared coagulation-related features with LC-IOH and immune-related features with PC-POTS. Many dysregulated peptides were highly amyloidogenic in silico, consistent with β-sheet-rich FMCs. PTM dysregulation was substantially greater than protein-level changes.Conclusions
This study provides the first evidence that PTMs within the PPP-IF has the potential to distinctly differentiate PC-POTS, LC-IOH, and LC-POTS. Because PC-POTS samples predated SARS-CoV-2, their PTM signatures reflect intrinsic disease biology independent of COVID-19. PTM profiling revealed pro-coagulant fibrinogen changes in LC-IOH and LC-POTS, metabolic-oxidative dysregulation in LC-IOH and PC-POTS, and immune dysregulation in PC-POTS and LC-POTS. These abnormalities were not detectable by routine assays and may contribute to microvascular dysfunction. The findings support disease-specific biomarker development and targeted therapeutic strategies across autonomic and post-viral disorders.
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BibTeX
@article{booyens2026posttranslational,
title = {{Post-translational modifications in the insoluble fraction of platelet-poor plasma distinguish pre-COVID-19 Postural Orthostatic Tachycardia Syndrome, Long COVID, and Long COVID-POTS: a preliminary study.}},
author = {Renata M Booyens and Mare Vlok and Cecile Bester and Rashmin Hira and M Asad Khan and Douglas B Kell and Satish R Raj and Etheresia Pretorius},
journal = {Cardiovascular diabetology},
year = {2026},
month = jul,
doi = {10.1186/s12933-026-03296-9},
url = {https://europepmc.org/article/MED/42897639},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Post-translational modifications in the insoluble fraction of platelet-poor plasma distinguish pre-COVID-19 Postural Orthostatic Tachycardia Syndrome, Long COVID, and Long COVID-POTS: a preliminary study.
AU - Renata M Booyens
AU - Mare Vlok
AU - Cecile Bester
AU - Rashmin Hira
AU - M Asad Khan
AU - Douglas B Kell
AU - Satish R Raj
AU - Etheresia Pretorius
PY - 2026
DA - 2026/07/01
JO - Cardiovascular diabetology
DO - 10.1186/s12933-026-03296-9
UR - https://europepmc.org/article/MED/42897639
AB - Background Pre-COVID-19 Postural Orthostatic Tachycardia Syndrome (PC-POTS), Long COVID with initial orthostatic hypotension (LC-IOH), and Long COVID-POTS (LC-POTS) are primarily chronic post-viral conditions with debilitating symptoms, despite routine laboratory findings often being normal. We previously identified amyloidogenic fibrinaloid microclot complexes (FMCs) in the insoluble fraction of platelet-poor plasma (PPP-IF) in Long COVID, but it remains unclear whether similar abnormalities occur in PC-POTS and LC-POTS, or whether post-translational modifications (PTMs) contribute to disease mechanisms.Methods Platelet-poor plasma from healthy controls (n = 18), PC-POTS (n = 20), LC-IOH (n = 19), and LC-POTS (n = 18) participants underwent proteomic analysis of the PPP-IF using double trypsin digestion and data-independent LC-MS/MS. Differential protein abundance, PTMs, and amyloidogenicity were compared across groups.Results Although few proteins were significantly dysregulated, extensive disease-specific PTM alterations were identified across coagulation, immune, and metabolic pathways. LC-IOH demonstrated prominent AGE- and oxidation-related PTMs on fibrinogen subunits, particularly fibrinogen alpha chain (FIBA), resembling diabetic glycation profiles. PC-POTS showed fewer fibrinogen PTMs but marked metabolic and immune dysregulation, including oxidised apoA1 and apoB and complement-associated proteins (C3, C4A/B, IC1), IGG1, and A2MG. LC-POTS shared coagulation-related features with LC-IOH and immune-related features with PC-POTS. Many dysregulated peptides were highly amyloidogenic in silico, consistent with β-sheet-rich FMCs. PTM dysregulation was substantially greater than protein-level changes.Conclusions This study provides the first evidence that PTMs within the PPP-IF has the potential to distinctly differentiate PC-POTS, LC-IOH, and LC-POTS. Because PC-POTS samples predated SARS-CoV-2, their PTM signatures reflect intrinsic disease biology independent of COVID-19. PTM profiling revealed pro-coagulant fibrinogen changes in LC-IOH and LC-POTS, metabolic-oxidative dysregulation in LC-IOH and PC-POTS, and immune dysregulation in PC-POTS and LC-POTS. These abnormalities were not detectable by routine assays and may contribute to microvascular dysfunction. The findings support disease-specific biomarker development and targeted therapeutic strategies across autonomic and post-viral disorders.
SN - 1475-2840
ER -