Persistent Clotting Protein Pathology in Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) is Accompanied by Increased Levels of Antiplasmin

Abstract

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-Cov-2)-induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by acute clinical pathologies, including various coagulopathies that may be accompanied by hypercoagulation and platelet hyperactivation. Recently, a new COVID-19 phenotype has been noted in patients after they have ostensibly recovered from acute COVID-19 symptoms. This new syndrome is commonly termed Long COVID/Post-Acute Sequelae of COVID-19 (PASC). Here we refer to it as Long COVID/PASC. Lingering symptoms persist for as much as 6 months (or longer) after acute infection, where COVID-19 survivors complain of recurring fatigue or muscle weakness, being out of breath, sleep difficulties, and anxiety or depression. MethodsGiven that blood clots can block microcapillaries and thereby inhibit oxygen exchange, we here investigate if the lingering symptoms that individuals with Long COVID/PASC manifest might be due to the presence of persistent circulating plasma clots that are resistant to fibrinolysis. We use techniques including proteomics and fluorescence microscopy to study plasma samples from healthy individuals, individuals with Type 2 Diabetes Mellitus (T2DM), with acute COVID-19, and those with Long COVID/PASC symptoms. ResultsWe show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits (microclots). We also show that these microclots in both acute COVID-19 and Long COVID/PASC plasma samples are resistant to fibrinolysis (compared to plasma from controls and T2DM), even after trypsinisation. After a second trypsinization, the persistent pellet deposits were solubilized. We detected various inflammatory molecules that are substantially increased in both the supernatant and trapped in the solubilized pellet deposits of acute COVID-19 and Long COVID/PASC, versus the equivalent volume of fully digested fluid of the control samples and T2DM. Of particular interest was a substantial increase in α(2)-antiplasmin (α2AP), various fibrinogen chains, as well as Serum Amyloid A (SAA) that were trapped in the solubilized fibrinolytic-resistant pellet deposits. ConclusionsClotting pathologies in both acute COVID-19 infection and in Long COVID/PASC might therefore benefit from following a regime of continued anticlotting therapy to support the fibrinolytic system function.

Post-Acute Sequelae and Adaptive Immune Responses in People Living With Hiv Recovering From Sars-Cov-2 Infection

“…Further immune perturbations related to COVID-19 may therefore lead to a higher prevalence of PASC among PWH. Additional factors could also predispose PWH to PASC, such as autoimmunity [33], localized tissue inflammation [34], human herpesvirus reactivation [13], and microvascular dysfunction [14], among others. Other comorbidities including substance use and metabolic disorders may further contribute.…”

“…While the mechanisms underlying PASC have yet to be fully delineated, early studies have suggested that a combination of factors might contribute [9][10][11][12][13][14]. Higher prevalence of certain socioeconomic factors and medical comorbidities among PWH, along with differences in immune responses to SARS-CoV-2 [6,7] and persistent inflammation and immune dysregulation in the presence of antiretroviral therapy (ART) [15][16][17][18], may make PWH selectively vulnerable to developing persistent COVID-19-attributed symptoms following SARS-CoV-2 infection.…”

“…While the mechanisms underlying PASC have yet to be fully delineated, early studies have suggested that a combination of factors might contribute. These include innate and adaptive immune dysregulation [17][18][19][20], autoimmunity [21][22][23], human herpes virus reactivation [24], and microvascular dysfunction [25,26], among others [24]. Certain sociodemographic factors (e.g., income status, access to care) [27,28] and a greater number and/or certain types of medical comorbidities (e.g., obesity, diabetes mellitus, pre-existing cardiovascular or neurologic disease) [27,29,30] may also increase the likelihood of an individual developing PASC.…”

Descriptive and Narrative Study of Long Covid Cases in General Practice and Diagnostic Value of Single Photon Emission Computed Tomography (SPECT scan)

“…70 Hypercoagulation, vascular complications 71 and microclots formation in Covid-19 have already been identified 72 . Long Covid is accompanied by increased levels of antiplasmin, 73 and pericytes, the multipotent parietal cells of capillaries, may play an important role in microvascular Long Covid alterations 74…”

Early clues regarding the pathogenesis of long-COVID

“…In yet another recent study, Liu and colleagues found differences in the gut microbiome associated with neuropsychiatric and pulmonary PASC symptoms [5]. These studies add to a growing body of literature suggesting that a combination of virus and host factors, including potential viral antigen persistence (preliminary) [6], residual inflammation [7,8], microvascular dysregulation [9], and autoimmune phenomena [10] might contribute to PASC (Figure 1). These studies are not without limitations.…”