Author: John Murphy, President, COVID-19 Long-haul Foundation

📑 Abstract

Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), affects millions globally and presents with persistent symptoms including fatigue, cognitive dysfunction, and vascular instability. This article synthesizes emerging evidence that implicates neurovascular dysregulation and microclot persistence as central drivers of pathology. We explore endothelial injury, spike protein persistence, platelet hyperactivation, and fibrinolytic resistance, linking these mechanisms to clinical manifestations such as brain fog, autonomic dysfunction, and stroke-like symptoms. We propose a unified model of spike-induced vascular injury and outline diagnostic, therapeutic, and research priorities.

I. Introduction

The COVID-19 pandemic has left a legacy of chronic illness in the form of Long COVID, now affecting over 36% of infected individuals worldwide. Characterized by multisystem symptoms lasting beyond 12 weeks, Long COVID includes fatigue, cognitive impairment, dysautonomia, and cardiovascular instability. While early hypotheses focused on viral persistence or autoimmunity, recent research highlights vascular injury and clotting dysfunction as central to its pathophysiologyMDPI+1.

II. Endothelial Dysfunction and Spike Protein Persistence

SARS-CoV-2 spike protein binds to ACE2 receptors on endothelial cells, triggering inflammation, permeability changes, and immune activation. Studies show spike protein can persist in circulation and tissue for months post-infection or vaccinationCOVID Advisor+1. Endothelial cells exposed to spike protein exhibit increased tissue factor expression and platelet adhesion, contributing to thromboinflammation.

III. Microclot Formation and Fibrinolytic Resistance

Microclots—fibrinaloid aggregates resistant to breakdown—are consistently found in Long COVID patients. These clots impair capillary perfusion and resist plasmin-mediated fibrinolysis due to altered fibrin structure and elevated PAI-1 levelsbioRxiv+1. Pretorius et al. demonstrated amyloid-like clot formation in plasma samples, linking spike protein to clot persistence.

IV. Neurovascular Dysregulation and Cognitive Impairment

Neuroimaging reveals disrupted cerebrovascular reactivity and increased AMPA receptor density in Long COVID patients with brain fog. Transcriptomic studies show blood-brain barrier disruption and neuroinflammationbioRxiv. Meta-analyses confirm persistent cognitive deficits in up to 30% of patients.

V. Diagnostic Biomarkers and Imaging Modalities

Key biomarkers include elevated D-dimer, IL-6, CRP, and fibrinogen. PET imaging with [11C]K-2 reveals synaptic changes linked to cognitive symptomsEuropean Medical Journal+1. MicroRNA profiles and CSF inflammatory markers offer emerging diagnostic tools.

VI. Therapeutic Strategies and Clinical Trials

Therapies targeting microclots include fibrinolytics (nattokinase, lumbrokinase), anticoagulants (DOACs, aspirin), and endothelial support agents (statins, omega-3s). Antibody-based therapies against fibrin-spike complexes show promiseNature. The Microvascular Research Foundation and COVID-19 Long-haul Foundation are leading trials on multi-agent protocols.

VII. Sex-Based and Genetic Vulnerabilities

Women are disproportionately affected by Long COVID, with hormonal and immunological factors contributing to risk. IL-6 receptor polymorphisms and HLA variants influence clotting and immune responseBiology of Sex Differences+1. RECOVER cohort data confirms sex-based disparities in symptom burden and recovery trajectory.

VIII. Long-Term Outcomes and Mortality Risk

Long COVID increases risk for cardiovascular events, stroke, and reduced life expectancy. Actuarial models show cohort-specific mortality impacts, especially in patients with multiple comorbiditiesNews-Medical.Net | MSN+1. Nirmatrelvir-ritonavir reduces long-term risk in older adults.

IX. Research Gaps and Future Directions

Key gaps include lack of standardized diagnostic criteria, limited longitudinal data, and underfunded trials. NIH’s RECOVER initiative and Stanford’s Long COVID symposium highlight the need for interdisciplinary collaboration and patient-led researchStanford Medicine+1. AI-driven biomarker discovery and real-world EHR analysis offer promising tools.

X. Conclusion

Neurovascular dysregulation and microclot persistence represent a central axis of Long COVID pathology. Addressing endothelial injury, spike protein persistence, and clotting dysfunction is essential for diagnosis, treatment, and prevention. A unified vascular model offers a roadmap for clinical trials, biomarker development, and policy reform.

📎 References

1. Sideratou & Papaneophytou. Infectious Disease Reports, 2024.
2. Pereira de Melo et al. Viruses, 2025.
3. COVID-19 Long Haul Foundation. Endothelial Dysfunction Insights, 2025.
4. Simón-Rueda et al. Frontiers in Immunology, 2025.
5. Cell Trends Microbiology, 2023.
6. Cardiology Advisor, 2025.
7. EMJ Radiology, 2025.
8. Uppsala University, 2025.
9. Paval et al. Human Genomics, 2025.
10. Yokohama City University, 2025.
11. SciTech Daily, 2025.
12. OneDayMD, 2025.
13. CVVR, Harvard Medical School, 2025.
14. Lemarchand et al. Biology of Sex Differences, 2025.
15. RECOVER Consortium, JAMA Network Open, 2025.
16. EMJ Microbiology, 2025.
17. NIH RECOVER ROA3, 2025.
18. Stanford Medicine Symposium, 2025.
19. The Lancet Microbe, 2025.
20. Cardiff Metropolitan University, 2025.
21. Carnahan, J. Microclot Review, 2025.
22. Nature, 2024.
23. Gladstone Institute, 2024.
24. Microvascular Research Foundation, 2025.
25. COVID-19 Long Haul Foundation, 2025.
26. Journal of the Royal Society of Medicine, 2025.
27. Pulmonology Advisor, 2025.
28. Lippi & Sanchis-Gomar. MDPI COVID, 2025.
29. RECOVER Research Update, 2025.
30. Society of Actuaries, 2025.
31. CDC Emerging Infectious Diseases, 2025.
32. Sideratou & Papaneophytou. Infectious Disease Reports, 2024.
33. Li et al. Blood, 2024.
34. RPTH Journal, 2024.
35. bioRxiv, 2025.
36. Technology Networks, 2024.
37. Elboraay et al. BMC Neurology, 2025.
38. Panagea et al. Archives of Clinical Neuropsychology, 2025.
39. Pommy et al. Frontiers in Neurology, 2025.
40. Ashfaque et al. bioRxiv, 2025.
41. ScienceDaily, 2025.