Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin

Abstract

Background Severe 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. Given 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 microclots that are resistant to fibrinolysis. Methods 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. Results We 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 (microclots) 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. Conclusions Clotting pathologies in both acute COVID-19 infection and in Long COVID/PASC might benefit from following a regime of continued anticlotting therapy to support the fibrinolytic system function.

Metabolic Influences Modulating Erythrocyte Deformability and Eryptosis

“…We concluded that the spike protein may have direct pathological effects on blood rheology [251]. Significant pathological changes in microcirculation and the presence of persistent microclots have also been noted in Long COVID/PASC [250].…”

“…This poor prognosis is further worsened by a substantial deposition of microclots in the lungs [244][245][246]. The plasma of COVID-19 patients also carries a massive load of preformed amyloid clots and there are numerous reports of damage to erythrocytes [247][248][249] and platelets and the dysregulation of inflammatory biomarkers [240][241][242][243]250]. Recently, we also determined whether the spike protein may interfere with blood flow by comparing naïve healthy plasma samples with and without added spike protein to plasma samples from COVID-19-positive patients (before treatment).…”

TEG®, Microclot and Platelet Mapping for Guiding Early Management of Severe COVID-19 Coagulopathy

“…A possible reason might be because the extent of systemic hypercoagulation was too significant for the medication to have a substantial enough effect. Hypercoagulability, resulting in a profoundly prothrombotic state, is a distinct feature of the early stages of COVID-19 and is accentuated by a high incidence of fibrinolysis shutdown [20][21][22][23][24][25][26][27][28][29][30]. In fact, Chaudhary and co-workers in 2021 reported that all current studies support COVID-19 as a hypercoagulable and hypofibrinolytic state in the ICU setting [31].…”

“…We have also recently shown that in COVID-19, the healthy fibrinogen changes to an amyloid form (fibrin(ogen)), and that platelets are hyperactivated, and that they may form complexes with erythrocytes [21,22]. Proteomics also revealed that there are significantly dysregulated clotting proteins in microclots, including significant increases in the molecule a-(2)-antiplasmin, which prevents fibrinolysis [23].…”

Pros and Cons of CAD/CAM Technology for Infection Prevention in Dental Settings during COVID-19 Outbreak

“…It is unknown if arterial and venous thromboembolism and higher blood clot risk caused by insoluble micro clots during COVID-19 and in vaccinated patients can influence digital impression acquisition on deeper surfaces of a stump or implant [ 114 ]. Caution is needed because of the links between vascular damage, periodontal disease, and SARS-CoV-2 presence in oral tissues.…”