PMID- 34425843 OWN - NLM STAT- MEDLINE DCOM- 20210906 LR - 20230920 IS - 1475-2840 (Electronic) IS - 1475-2840 (Linking) VI - 20 IP - 1 DP - 2021 Aug 23 TI - Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. PG - 172 LID - 10.1186/s12933-021-01359-7 [doi] LID - 172 AB - 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 alpha(2)-antiplasmin (alpha2AP), 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. CI - (c) 2021. The Author(s). FAU - Pretorius, Etheresia AU - Pretorius E AUID- ORCID: 0000-0002-9108-2384 AD - Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch, 7602, South Africa. resiap@sun.ac.za. FAU - Vlok, Mare AU - Vlok M AD - Central Analytical Facility: Mass Spectrometry, Stellenbosch University, Tygerberg Campus, Room 6054, Clinical Building, Francie Van Zijl Drive Tygerberg, Cape Town, 7505, South Africa. FAU - Venter, Chantelle AU - Venter C AD - Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch, 7602, South Africa. FAU - Bezuidenhout, Johannes A AU - Bezuidenhout JA AD - Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch, 7602, South Africa. FAU - Laubscher, Gert Jacobus AU - Laubscher GJ AD - Mediclinic Stellenbosch, Stellenbosch, 7600, South Africa. FAU - Steenkamp, Janami AU - Steenkamp J AD - Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch, 7602, South Africa. AD - PathCare Laboratories, PathCare Business Centre, PathCare Park, Neels Bothma Street, N1 City, Cape Town, 7460, South Africa. FAU - Kell, Douglas B AU - Kell DB AUID- ORCID: 0000-0001-5838-7963 AD - Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Private Bag X1 Matieland, Stellenbosch, 7602, South Africa. dbk@liv.ac.uk. AD - Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, L69 7ZB, UK. dbk@liv.ac.uk. AD - The Novo Nordisk Foundation Centre for Biosustainability, Technical University of Denmark, Kemitorvet 200, 2800, Kgs Lyngby, Denmark. dbk@liv.ac.uk. LA - eng GR - NNF20CC0035580/novo nordisk foundation center for basic metabolic research/ PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210823 PL - England TA - Cardiovasc Diabetol JT - Cardiovascular diabetology JID - 101147637 RN - 0 (Antifibrinolytic Agents) RN - 0 (Blood Coagulation Factors) SB - IM MH - Adult MH - Antifibrinolytic Agents/*metabolism MH - Blood Coagulation Factors/*metabolism MH - COVID-19/*complications MH - Disease Progression MH - Female MH - Humans MH - Male MH - Middle Aged MH - SARS-CoV-2/pathogenicity MH - Post-Acute COVID-19 Syndrome PMC - PMC8381139 OTO - NOTNLM OT - Antiplasmin OT - COVID-19 OT - Fibrin(ogen) OT - Long COVID/PASC OT - Microclots OT - Proteomics OT - Serum Amyloid A COIS- The authors have no competing interests to declare. EDAT- 2021/08/25 06:00 MHDA- 2021/09/07 06:00 PMCR- 2021/08/23 CRDT- 2021/08/24 05:32 PHST- 2021/06/23 00:00 [received] PHST- 2021/08/03 00:00 [accepted] PHST- 2021/08/24 05:32 [entrez] PHST- 2021/08/25 06:00 [pubmed] PHST- 2021/09/07 06:00 [medline] PHST- 2021/08/23 00:00 [pmc-release] AID - 10.1186/s12933-021-01359-7 [pii] AID - 1359 [pii] AID - 10.1186/s12933-021-01359-7 [doi] PST - epublish SO - Cardiovasc Diabetol. 2021 Aug 23;20(1):172. doi: 10.1186/s12933-021-01359-7.