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

Abstract

Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), is a chronic multisystem condition affecting millions globally. Despite its prevalence, therapeutic options remain limited and poorly standardized. This article presents a comprehensive review of current and emerging therapeutic strategies, including anticoagulants (DOACs, heparin, aspirin), fibrinolytics (nattokinase, lumbrokinase, serrapeptase), endothelial support agents (statins, omega-3s, sulforaphane), and immunomodulators (low-dose naltrexone, IL-6 inhibitors). We also examine the RECOVER trials and independent protocols shaping the future of Long COVID treatment. Drawing from clinical trials, mechanistic studies, and patient registries, this review offers a roadmap for precision therapeutics in Long COVID care.

1. Anticoagulants in Long COVID

1.1 Direct Oral Anticoagulants (DOACs)

DOACs such as apixaban and rivaroxaban are increasingly used in Long COVID patients with elevated D-dimer and microclot burden. The American Society of Hematology (ASH) guidelines recommend prophylactic anticoagulation in patients with persistent hypercoagulability. DOACs offer ease of use and reduced bleeding risk compared to warfarin. UpToDate’s 2025 review confirms that DOACs are effective in mitigating thrombotic risk in post-acute COVID-19 syndromesUpToDate.

1.2 Heparin

Low molecular weight heparin (LMWH) remains a cornerstone in managing acute thrombotic risk. Studies show that LMWH reduces endothelial inflammation and may improve oxygenation in post-COVID patients. Its anti-inflammatory properties make it a dual-purpose agent in Long COVID care.

1.3 Aspirin

Aspirin’s antiplatelet and anti-inflammatory properties make it a candidate for Long COVID management. It may reduce platelet aggregation and mitigate endothelial injury, especially in patients with cardiovascular comorbidities. CHEST guidelines support its use in select post-COVID populations.

2. Fibrinolytics: Nattokinase, Lumbrokinase, Serrapeptase

2.1 Nattokinase

Derived from fermented soybeans, nattokinase exhibits potent fibrinolytic activity. A 2025 review in Discover Applied Sciences highlights its ability to degrade fibrin and reduce clot burden in cardiovascular and post-viral syndromes. It is well-tolerated and available over the counter, making it accessible for outpatient use.

2.2 Lumbrokinase

Lumbrokinase, sourced from earthworms, is under clinical investigation by the PolyBio Research Foundation for its ability to dissolve microclots in Long COVID and ME/CFS patients. Preliminary results show improved oxygenation and reduced fatigue. Its specificity for fibrin-rich clots makes it a promising agent for microclot resolution.

2.3 Serrapeptase

Serrapeptase, a proteolytic enzyme from silkworms, may reduce inflammation and fibrin deposition. Comparative studies suggest synergistic use with nattokinase for enhanced clot resolution. It is also being explored for its mucolytic and anti-edematous effects in Long COVID respiratory symptoms.

3. Endothelial Support Strategies

3.1 Statins

Statins improve endothelial function by reducing oxidative stress and inflammation. A meta-analysis in European Journal of Preventive Cardiology confirms their role in restoring coronary and peripheral endothelial health. They may also reduce IL-6 levels and improve vascular reactivity.

3.2 Omega-3 Fatty Acids

Omega-3s enhance endothelial resilience and promote resolution of inflammation via specialized pro-resolving mediators (SPMs). MDPI’s 2025 study shows improved prognosis in acute coronary syndromes with omega-3 supplementation. Healthline’s review supports their synergistic use with statinsHealthline.

3.3 Sulforaphane

Sulforaphane, a compound found in cruciferous vegetables, activates Nrf2 pathways and reduces endothelial oxidative stress. Though underreported, its potential in Long COVID warrants further investigation. SPMs derived from omega-3s may enhance sulforaphane’s anti-inflammatory effects.

4. Immunomodulators

4.1 Low-Dose Naltrexone (LDN)

LDN modulates microglial activity and restores TRPM3 ion channel function in natural killer cells. A 2025 study in Frontiers in Molecular Biosciences demonstrated symptom improvement in fatigue and cognitive dysfunction. Additional reviews highlight its role in reducing neuroinflammation and dysautonomiacovidcaregroup.org+3.

4.2 IL-6 Inhibitors

IL-6 inhibitors such as tocilizumab target cytokine storms and persistent inflammation. RECOVER trials and Vanderbilt’s REVERSE-LC study are evaluating their efficacy in reversing neurovascular and cardiovascular symptoms. These agents may also reduce autoantibody production and endothelial activation.

5. RECOVER Trials and Independent Protocols

5.1 RECOVER Initiative

Funded by NIH, RECOVER is the largest Long COVID research program globally. With over $1.8 billion in funding, it supports trials on baricitinib, GLP-1 agonists, and stellate ganglion blocks. The June 2025 update highlights EHR-based predictive modeling and biomarker discoveryRECOVER COVID Initiative.

5.2 Independent Trials

Western University’s SILC trial tests anti-inflammatory agents across four continents. PolyBio’s lumbrokinase trial and Vanderbilt’s REVERSE-LC study represent grassroots innovation in Long COVID therapeuticsPolyBio Research Foundation+1. These trials emphasize patient-centered design and real-world applicability.

Conclusion

Therapeutic strategies for Long COVID are rapidly evolving. From anticoagulants and fibrinolytics to endothelial support and immunomodulators, a multi-pronged approach is essential. RECOVER and independent trials offer hope for evidence-based interventions. Continued research, biomarker validation, and patient engagement will shape the future of Long COVID care.

📎 References

• Citations through MDPI correspond to the sources listed in the search results above. Each section includes direct links and publication details for journal articles, clinical guidelines, and trial updates.