Long COVID and Coagulation
by Donna Castellone, MS, MT(ASCP)S • September 07, 2023
I haven't done any blogs on COVID for a long time since it is one topic that most of us would like to forget, but for sure is here to stay as noted with the recent uptick. This month we will explore Long COVID and it’s relationship to coagulation. Some people have lingering symptoms from COVID and when it persists for at least 28 days it has been coined as post- acute sequelae SARS-CoV-2 infection (PASC). It is important to differentiate PASC from other post viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome [ME/CFS). The best differentiator between PASC and ME/CFS was loss of taste and smell as well as unrefreshing sleep and flu-like symptoms in PASC.1
INTRODUCTION:
It has been estimated that at least 65 million individuals worldwide are estimated to have long COVID, or PASC which translated to up to 10% of all people infected. However, it could be much higher due to undocumented cases. There have been more than 200 symptoms that have impacts on multiple organ symptoms.2 The incidence is estimated at 10–30% of non-hospitalized cases, 50–70% of hospitalized cases and 10–12% of vaccinated cases. The highest percentage of diagnoses is in those between the ages of 36 and 50 years. Most long COVID cases are in non-hospitalized patients with a mild acute illness as this population represents the majority of overall COVID-19 cases. There are no validated or effective treatments for long COVID.2
Up to 45% of COVID patients may suffer several unresolved symptoms. Older adults are less likely to experience long COVID than younger adults and is greater in women than men. Symptoms include neurological, neuropsychiatric, cardiopulmonary and gastrointestinal. Symptoms more frequently associated with long COVID are fatigue (29–58%), headache (10–44%), and anxiety or depression (22–28%) (5–8). Shortness of breath or difficulty breathing (21–24%) and loss of taste or smell (12–15%).3
Identified from 28 studies and representing six biological classifications, 113 biomarkers were significantly associated with long COVID: (1) Cytokine/Chemokine (38, 33.6%); (2) Biochemical markers (24, 21.2%); (3) Vascular markers (20, 17.7%);(4) Neurological markers (6, 5.3%); (5) Acute phase protein (5, 4.4%); and (6) Others (20, 17.7%). Compared with healthy control or recovered patients without long COVID symptoms, 79 biomarkers were increased, 29 were decreased, and 5 required further determination in the long COVID patients. Of these, up-regulated Interleukin 6, C-reactive protein, and tumor necrosis factor alpha might serve as the potential diagnostic biomarkers for long COVID. Moreover, long COVID patients with neurological symptoms exhibited higher levels of neurofilament light chain and glial fibrillary acidic protein whereas those with pulmonary symptoms exhibited a higher level of transforming growth factor beta.3
PATHOGENESIS:
Several hypotheses for the pathogenesis of long COVID have been suggested. These include persistent SARS-CoV2 present in tissues, immune dysregulation including reactivation of underlying pathogens including Epstein-Barr, human herpes virus, microvascular blood clotting with endothelial dysfunction as well as dysfunctional signaling in the brainstem or vagus nerve. Possible risk factors include females, type 2 diabetes, EBV reactivation, possible connective tissue disorders, ADD, chronic urticaria and allergic rhinitis. It has also been more prevalent in certain ethnicities in particular Hispanic or Latino. Up to one third of people with long COVID have no identified pre-existing conditions.4
Cellular damage resulting from SARS-CoV-2 has been attributed to immune mediated response and inflammation as opposed to direct infection of cells by the virus. Increased risks of DVT, PE and bleeding events are downstream events due to circulatory system disruption including endothelial dysfunction. Microclots in long COVID contribute to thrombosis. Also found in long COVID were long term changes to the size and stiffness of blood cells which may impact oxygen delivery. Up to 18 months post infection a reduction in vascular density of small capillaries was found in long COVID patients when compared to controls. As a results, angiogenesis marker ANG1 and P-selectin both had high sensitivity and specificity for predicting long COVID status.4
One theory that has been looked at are the formation of microclots which appear to have different shapes in different diseases as well as finding damaged platelets and other blood vessel issues. It is believed that activated platelets interact with microclots and inflammatory factors causes widespread endothelial dysfunction. Microclots are large enough to prevent oxygen from getting to tissues producing ischemic events. In SARS-CoV2 the spike protein the virus uses to infect cells can induce clotting. In long COVID it has been proposed that microclots, inflamed blood vessels, iron dysregulation and platelet activation contribute to this, when oxygen rich blood then flows into a hypoxic environment produces enormous amounts of free radicals and a reperfusion injury resulting in post-exertional malaise. It appears the body slowly removes these amyloid microclots over time therefore resolving long COVID may be in stopping the formation of them. To date the technique to observe microclots has not been validated by other labs and the testing process needs to be automated to rule out the question of subjectivity.5
COAGULATION AND LONG COVID:
Long COVID may be related to clotting issues. In a study that looked at 50 people who were reviewed after 68 days post COVID, it was observed that they had significantly higher coagulation markers when compared with a healthy control group. This was evident in COVID patients who were hospitalized and those who remained at home. These patients present with new returning or ongoing health problems about 4 weeks after the initial presentation of COVID. It is still a poorly defined syndrome. It includes cognitive changes and fatigue, however newer strains have shown newer symptoms not seen earlier in the pandemic. This study highlighted the correlation between elevated clotting factors as an indication to identify patients at a higher risk of long-term COVID symptoms.6
Symptoms in long COVID are heterogeneous across multiple organ systems. Evidence points to linking thrombo- inflammation to post-acute sequelae of COVID-19. This is seen in with the persistence of vascular damage. Coagulation abnormalities include heightened thrombin generation capacity, and abnormalities of platelet counts which may be linked by elevated platelet-neutrophil aggregate formation. This can result in a hyper-coaguable state which can lead to microvascular thrombosis which results in microclots, elevated D-dimers and perfusion abnormalities in the lungs and brains. These patients have an increased rate of arterial and venous thrombotic events. A hypothesis is contributing to thrombo-inflammation in long COVID is structural changes, such as endothelial damage which is caused during the initial infection and the immunopathology driven by a misguided immune system.7
Endothelial dysfunction is a critical aspect of COVID-19 and due to its inflammatory nature causes thrombo- inflammation. As a result, increased levels of VWF, FVIII, and thrombomodulin are seen along with endothelial colony forming cells indicating endothelial injury. ADAMTS-13 levels are reduced suggesting a prothrombotic state. Reports have also shown enhanced thrombin-generating capacity demonstrated by thrombinography with a plasma hypofibrinolytic state. Fibrinogen levels and PT return to normal 4 months after hospitalization. The D-dimer and IL-6 was still elevated up to 18 months later pointing to systemic inflammation in some patients. This was also seen in 29% of patients who did not require hospitalization.7
A meta-analysis that included 47,910 adults D-dimer was elevated in 20% of patients which was greater than CRP which was elevated in 8% of patients. This suggests persistent coagulation activation. This point to some features in PASC could be linked to small vessel occlusion causing dyspnea.7
Research on long COVID in children looked at biomarkers of endothelial damage and their coagulation profile versus controls. Samples were taken 8 and 12 weeks post diagnosis and tested for (fibrinogen, prothrombin time, international normalized ratio, activated partial thromboplastin time, d-dimers, factor VIII coagulant activity, plasma von Willebrand factor (VWF) antigen and VWF ristocetin cofactor (RC)). Seventy-five children were tested. Children with post COVID complications (PCC) had abnormal D-dimer, as well as VWF, FVIII, and Fibrinogen, but not significant when compared to controls. Only the D-dimer was statistically significantly elevated, however most were in the normal reference range.8
There was no clinical evidence of macrothrombosis, but microthrombosis can’t be ruled out, which was similar to
circulating microclots found in adults along with lung perfusion defects. This points to chronic endothelial inflammation as
playing a role in pediatric post COVID complications.8
CONCLUSION:
LONG COVID is as complicated as the initial viral infection. There are still no definitive tests nor treatment for PASC. Patients struggle with symptoms and clinicians can treat some symptoms but not the cause. There is a connection within the coagulation system due to the role it plays in inflammation. Research will continue to explore causes as well as treatments, because as we all know, COVID is here to stay.
REFERENCES:
- Leonard Jason, PhD, and Nicole Hansel Challenges in Developing Long COVID Criteria, July 29, 2023 https://www.medpagetoday.com/opinion/second-opinions/105683? xid=nl_secondopinion_2023-08-01&eun=g1632299d0r
- Hannah E. Davis, Lisa McCorkell, Julia Moore Vogel & Eric J. Topol, Long COVID: major findings, mechanisms and recommendations, Nature Reviews Microbiology volume 21, pages133–146 (2023).
- Yun-Ju Lai, Shou-Hou Liu, Sumatchara Manachevakul, Te-An Lee, Chun-Tse Kuo, and Dhimiter Bello, Biomarkers in long COVID-19: A systematic review, Front Med (Lausanne). 2023 Jan 20, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC98951 10/
- Hannah E. Davis, Lisa McCorkell, Julia Moore Vogel & Eric J. Topol, Long COVID: major findings, mechanisms and recommendations, Nature Reviews Microbiology volume 21, pages133–146 (2023).
- Cort JohnsonThe Coagulation Controversy in Long COVID and ME/CFS | Oct 29, 2022 | Cardiovascular, Clotting, COVID-19, Homepage, long COVID, Research
- George Citroner, What Is Behind Long COVID? It Could Start with Blood Clotting Issues, August 20, 2021, https://www.healthline.com/health-news/what-is-behind-long-covid-it-could-start-with-blood-clotting- issues
- Leo Nicolai1,2 | Rainer Kaiser1,2 | Konstantin Stark1 Thromboinflammation in long COVID—the elusive key to postinfection sequelae?, J Thromb Haemost. 2023;21:2020–2031.
- Leonardo Di Gennaro, Piero Valentini, Silvia Sorrentino, Maria Antonietta Ferretti, Erica De Candia, Maria Basso, etal. Extended coagulation profile of children with Long Covid: a prospective study Scientific Reports volume 12.