Assessing Plasmin Generation in Health and Disease

Miszta, Adam; Huskens, Dana; Donkervoort, Demy; Roberts, Molly J M; Wolberg, Alisa S.; Laat, Bas de

doi:10.3390/ijms22052758

Cited by 30 publications

(28 citation statements)

References 144 publications

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“…Simpli ed coagulation diagram (adapted from [37,64,65] depicting healthy and pathological processes.…”

Section: Declarations Figuresmentioning

confidence: 99%

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

Pretorius

Vlok

Venter

et al. 2021

Preprint

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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.

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“…Simpli ed coagulation diagram (adapted from [37,64,65] depicting healthy and pathological processes.…”

Section: Declarations Figuresmentioning

confidence: 99%

“…The plasmin-antiplasmin system plays a key role in blood coagulation and brinolysis [36]. Plasmin and α2AP are primarily responsible for a controlled and regulated dissolution of the brin polymers into soluble fragments [36,37].…”

Section: Introductionmentioning

confidence: 99%

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

Pretorius

Vlok

Venter

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Plasmin plays a crucial role in fibrinolysis, wound healing, cell signaling, inflammatory regulation, and atherogenesis [ 185 , 186 , 187 , 188 , 189 ]. Plasmin is secreted as a zymogen (plasminogen) that is activated by proteolytic cleavage by tissue-type plasminogen activator (tPA) or urokinase-type plasminogen activator.…”

Section: Ttr and Wound Healing (Fibrinolysis Vs Thrombosis)mentioning

confidence: 99%

“…Plasmin activity is an important component of the complex regulatory network balancing coagulation (fibrin clot formation) and fibrinolysis (fibrin clot degradation). Perturbation in coagulation and fibrinolytic homeostasis can lead to bleeding disorders or thrombus formation [ 187 ]. Plasmin activity is controlled by inhibitors of plasmin activators or directly by α2-antiplasmin [ 185 ].…”

Section: Ttr and Wound Healing (Fibrinolysis Vs Thrombosis)mentioning

confidence: 99%

Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases

Wieczorek

Ożyhar

2021

Cells

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Transthyretin (TTR) is a tetrameric protein transporting hormones in the plasma and brain, which has many other activities that have not been fully acknowledged. TTR is a positive indicator of nutrition status and is negatively correlated with inflammation. TTR is a neuroprotective and oxidative-stress-suppressing factor. The TTR structure is destabilized by mutations, oxidative modifications, aging, proteolysis, and metal cations, including Ca2+. Destabilized TTR molecules form amyloid deposits, resulting in senile and familial amyloidopathies. This review links structural stability of TTR with the environmental factors, particularly oxidative stress and Ca2+, and the processes involved in the pathogenesis of TTR-related diseases. The roles of TTR in biomineralization, calcification, and osteoarticular and cardiovascular diseases are broadly discussed. The association of TTR-related diseases and vascular and ligament tissue calcification with TTR levels and TTR structure is presented. It is indicated that unaggregated TTR and TTR amyloid are bound by vicious cycles, and that TTR may have an as yet undetermined role(s) at the crossroads of calcification, blood coagulation, and immune response.

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“…Figure 7: Simplified coagulation diagram (adapted from(Kell and Pretorius, 2015, de Waal et al, 2021, Miszta et al, 2021 depicting healthy and pathological processes. (1A) The intrinsic and (1B) extrinsic pathways converge into the (1C) common pathway.…”

mentioning

confidence: 99%

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

Pretorius

Vlok

Venter

et al. 2021

Preprint

View full text Add to dashboard Cite

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 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. We show that plasma samples from Long COVID/PASC still contain large anomalous (amyloid) deposits. We also show that these anomalous deposits 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. 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. Clotting 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.

show abstract

Assessing Plasmin Generation in Health and Disease

Cited by 30 publications

References 144 publications

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

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

Transthyretin: From Structural Stability to Osteoarticular and Cardiovascular Diseases

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

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