Infection with the virus SARS-CoV-2 can result in pneumonia and multi-organ failure.1-4 In severe cases, patients experience potentially lethal respiratory failure and hypoxia.1,4 After recovering from COVID-19, up to 30% of individuals who had severe, or even mild disease, have persistent sequelae, typically manifesting as fatigue, shortness of beath, sleep difficulties, and central nervous system symptoms.5,6 These effects are commonly known as Long COVID.
At the start of the global pandemic, COVID-19 was thought to be a typical viral pneumonia with acute disseminated intravascular coagulopathy.4 However, it is now accepted that COVID-19 is primarily an endothelial4,7 and vascular4,8 disease, which may help to explain why some patients experience long-term symptoms and why COVID-19 affects so many tissues and organ systems.
“Over 10 years ago now, Professor Etheresia Pretorius from Stellenbosch University in South Africa, who’s my long-term collaborator, had been looking at clots with an electron microscope. Abnormal clots looked a bit like half cooked spaghetti and referred to as dense matted deposits resulting from fibrin polymerization,” Douglas B. Kell, CBE, DSc, MA, DPhil, FAAAS, FLSW, FSB, of the University of Liverpool in the United Kingdom, said to Hematology Advisor. “She found that these deposits could be induced by things like unliganded iron, and later, we discovered, also by very low concentrations of bacterial cell wall components.”
Figure 1.4,9 (A) Pictorial depiction of healthy and pathological biochemistry, in which the uncoiling of fibrin(ogen) causes whole blood and plasma hypercoagulability. (B/C) Scanning electron microscopy micrographs of (B) a healthy sample and (C) an abnormal sample induced by adding thrombin to a sample from a patient with diabetes who had platelet-poor plasma.
Dr Kell continued, “We used a special stain (thioflavin T) that only fluoresces when these deposits adopted amyloid-like structures which reflect structural changes in the 3-dimentional structure (but not the primary sequence) of the proteins. We found that this was happening in a variety of chronic inflammatory diseases, such as Alzheimer disease or Parkinson disease. For example, when we added thrombin to a blood sample from someone with asthma, it induced clotting into the amyloid form that bound our fluorogenic stain and then fluoresced.”
In acute COVID-19 and Long COVID, they found that no thrombin was needed to start the fibrinogen amyloid microclot process because the SARS-CoV-2 Spike protein was capable of starting the microclot process.
To investigate the role of amyloid microclots in Long COVID, Drs Pretorius and Kell and colleagues evaluated blood samples from 80 patients included in the South African Long COVID/Post-Acute Sequelae of COVID-19 (PASC) registry. All patients were experiencing lingering symptoms of shortness of breath, low oxygen levels, heart palpitations, constant fatigue, joint and muscle pain, brain fog, sleep disturbances, digestive problems, or kidney problems.6
Analysis of patient blood samples found that microclots and platelet pathologies were present in all 80 patients. Using a spreading, clumping, and microclot scoring system, 30 of the 80 patients were found to have moderate activation.6
Figure 2 depicts the microclot and platelet activation process posited by Drs Pretorius and Kell. After activation, platelets express P-selectin on their membranes and form a platelet-T cell complex. Macrophages recognize P-selectin on the platelet cell surface triggering either binding or phagocytosis. Platelets then release CD40L that is shed as soluble CD40L which binds to αIIbβ3 or CD40 receptors. P-selectin on CD40L-activated platelet surfaces can form complexes with monocytes and neutrophils.6,10
Figure 2.6,10 Microclot and platelet activation process.
“The general principle is that if you acquire a scientific understanding of what’s gone wrong with a disease, you can use that knowledge to fix it. I think we have now acquired a scientific understanding of a key element of what in particular has gone wrong in COVID-19 and in Long COVID. These microclots are the central element to everything,” Dr Kell explained. “If you’ve got these microclots, they block up the microcapillaries, preventing red blood cells from going through so oxygen doesn’t get to the tissues. The tissues that have been blocked from getting oxygen are the ones that are going to manifest disease.”
Dr Kell continued, “The microclots account for all the obvious symptoms like fatigue, where patients are gasping for oxygen. We think that a lot of sequelae is caused by microclots that lead to a variety of problems, not only due directly to hypoxia, but also ischemia reperfusion injury, which causes so-called post-exertional malaise. You’ve got to break the cycle somewhere and the easy place to break it is the microclots because they’re really the chief bad guys.”
One of the possible treatments will be to prevent microclots from forming and to prevent platelet hyperactivation. Oral anticoagulants or nutraceuticals might be an option to investigate, and some clinicians have embarked upon clinician-initiated treatment regimens that include such treatments.11 However, such treatment regimens should be tested in randomized controlled trials to determine dosage, as well as efficacy in large patient populations. Various adjuvant medications may also assist in patient symptom relief and other research groups have suggested a combination of statins and antihistamines.6,11
Going forward there are still many aspects of SARS-CoV-2 infections that remain elusive. Prof Kell explained that symptoms of COVID-19 can persist for months, or even longer ¾ much as with myalgic encephalomyelitis/chronic fatigue syndrome ¾ after recovery and viral clearance. This suggests that there may be a replicating viral reservoir remaining long term, in some cases. Finding that reservoir ¾ most likely in the gut microbiome that may well contain microbial hosts for the virus ¾ should be the next mystery to investigate.
- Wiersinga WJ, RhodesA, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (COVID-19): a review. JAMA. 2020;324(8):782-793. doi:10.1001/jama.2020.12839
- Wynants L, Van Calster B, Collins GS, et al. Prediction models for diagnosis and prognosis of COVID-19 infection: systematic review and critical appraisal. BMJ. 2020;369. doi:10.1136/bmj.m132
- Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020;369:m1985. doi:10.1136/bmj.m1985
- Laubscher GJ, Lourens PJ, Venter C, Kell DB, Pretorius E. TEG®, microclot and platelet mapping for guiding early management of severe COVID-19 coagulopathy. J Clin Med. 2021;10(22):5381. doi:10.3390/jcm10225381
- Lopez-Leon S, Wegman-Ostrosky T, Perelman C, et al. More than 50 long-term effects of COVID-19: a systematic review and meta-analysis. Res Sq. 2021;rs.3.rs-266574. doi:10.21203/rs.3.rs-266574/v1
- Pretorius E, Venter C, Laubscher GJ, et al. Prevalence of symptoms, comorbidities, fibrin amyloid microclots and platelet pathology in individuals with Long COVID/ post-acute sequelae of COVID-19 (PASC). Res Sq. Published online May 9, 2022. doi:10.21203/rs.3.rs-1205453/v2
- Libby P, Lüscher T. COVID-19 is, in the end, an endothelial disease. Eur. Heart J. 2020, 41, 3038–3044. doi:10.1093/eurheartj/ehaa623
- Siddiqi HK, Libby P, Ridker PM. COVID-19—a vascular disease. Trends Cardiovasc Med. 2021, 31, 1–5. doi:10.1016/j.tcm.2020.10.005
- Randeria SN, Thomson GJA, Nell TA, Roberts T, Pretorius E. Inflammatory cytokines in type 2 diabetes mellitus as facilitators of hypercoagulation and abnormal clot formation. Cardiovasc Diabetol. 2019;18(1):72. doi:10.1186/s12933-019-0870-9
- Pretorius, E. Platelets in HIV: a guardian of host defence or transient reservoir of the virus? Front Immunol. 2021;12:649465. doi:10.3389/fimmu.2021.649465
- Kell DB, Laubscher GJ, Pretorius E. A central role for amyloid fibrin microclots in long COVID/PASC: origins and therapeutic implications. Biochem J. 2022;479(4):537-559. doi:10.1042/BCJ20220016