MicroCLOTS pathophysiology in coronavirus disease 2019

Renzi, Samuele; Landoni, Giovanni; Zangrillo, Alberto; Ciceri, Fabio

doi:10.3904/kjim.2020.336

Cited by 20 publications

(21 citation statements)

References 11 publications

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“…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 result in either bleeding and thrombocytopenia, hypercoagulation, pulmonary intravascular coagulation, microangiopathy venous thromboembolism or arterial thrombosis [1][2][3][4][5][6][7][8][9]. Acute COVID-19 infection is also characterized by dysregulated, circulating in ammatory biomarkers, hyperactivated platelets, damaged erythrocytes and substantial deposition of microclots in the lungs [6,[8][9][10][11][12][13][14][15][16]. Acute COVID-19 patients may suffer from thrombocytopenia that may lead to life-threatening disseminated intravascular coagulation (DIC) [17].…”

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

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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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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

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“…During the progression of the various stages of the COVID-19, markers of viral replication, as well as VWF and fibrinogen depletion with increased D-dimer levels and dysregulated P-selectin levels, followed by a cytokine storm, are likely to be indicative of a poor prognosis (Grobler et al, 2020, Pretorius et al, 2020, Venter et al, 2020, Roberts et al, 2020). This poor prognosis is further worsened as together with a substantial deposition of microclots in the lungs (Renzi et al, 2020, Ciceri et al, 2020, Bobrova et al, 2020), plasma of COVID-19 patients also carries a massive load of preformed amyloid clots (Grobler et al, 2020), and there are also numerous reports of damage to erythrocytes (Lam et al, 2020, Berzuini et al, 2020, Akhter et al, 2020), platelets and dysregulation of inflammatory biomarkers (Grobler et al, 2020, Pretorius et al, 2020, Venter et al, 2020, Roberts et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: Implications for microclot formation in COVID-19

Grobbelaar

Venter

Vlok

et al. 2021

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) -induced infection, the cause of coronavirus disease 2019 (COVID-19), is characterized by unprecedented clinical pathologies. One of the most important pathologies, is hypercoagulation and microclots in the lungs of patients. Here we study the effect of isolated SARS-CoV-2 spike protein S1 subunit as potential inflammagen sui generis. Using scanning electron and fluorescence microscopy as well as mass spectrometry, we investigate the potential of this inflammagen to interact with platelets and fibrin(ogen) directly to cause blood hypercoagulation. Using platelet poor plasma (PPP), we show that spike protein may interfere with blood flow. Mass spectrometry also showed that when spike protein S1 is added to healthy PPP, it results in structural changes to β and γ fibrin(ogen), complement 3, and prothrombin. These proteins were substantially resistant to trypsinization, in the presence of spike protein S1. Here we suggest that, in part, the presence of spike protein in circulation may contribute to the hypercoagulation in COVID-19 positive patients and may cause substantial impairment of fibrinolysis. Such lytic impairment may result in the persistent large microclots we have noted here and previously in plasma samples of COVID-19 patients. This observation may have important clinical relevance in the treatment of hypercoagulability in COVID-19 patients.

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“…Second, the increase in mortality might relate to a comparison of two different diseases. In non-COVID-19 patients, OHCAs are mainly caused by ischemic heart disease, while in COVID-19 patients, additional factors, including hypoxia, myocarditis, pulmonary embolism, microvascular thrombosis and endothelial dysfunction play a role [ 32 , 33 , 34 ]. This explanation is supported by the substantial difference in the frequency of shockable rhythms between COVID-19 and non-COVID-19 patients [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Impact of Coronavirus Disease 2019 on Out-of-Hospital Cardiac Arrest Survival Rate: A Systematic Review with Meta-Analysis

Borkowska

Jaguszewski

Koda

et al. 2021

JCM

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Out-of-hospital cardiac arrest (OHCA) is a challenge for medical staff, especially in the COVID-19 period. The COVID-19 disease caused by the SARS-CoV-2 coronavirus is highly infectious, thus requiring additional measures during cardiopulmonary resuscitation (CPR). Since CPR is a highly aerosol-generating procedure, it carries a substantial risk of viral transmission. We hypothesized that patients with diagnosed or suspected COVID-19 might have worse outcomes following OHCA outcomes compared to non-COVID-19 patients. To raise awareness of this potential problem, we performed a systematic review and meta-analysis of studies that reported OHCA in the pandemic period, comparing COVID-19 suspected or diagnosed patients vs. COVID-19 not suspected or diagnosed group. The primary outcome was survival to hospital discharge (SHD). Secondary outcomes were the return of spontaneous circulation (ROSC), survival to hospital admission or survival with favorable neurological outcomes. Data including 4210 patients included in five studies were analyzed. SHD in COVID-19 and non-COVID-19 patients were 0.5% and 2.6%, respectively (odds ratio, OR = 0.25; 95% confidence interval, CI: 0.12, 0.53; p < 0.001). Bystander CPR rate was comparable in the COVID-19 vs. not COVID-19 group (OR = 0.88; 95% CI: 0.63, 1.22; p = 0.43). Shockable rhythms were observed in 5.7% in COVID-19 patients compared with 37.4% in the non-COVID-19 group (OR = 0.19; 95% CI: 0.04, 0.96; p = 0.04; I2 = 95%). ROSC in the COVID-19 and non-COVID-19 patients were 13.3% vs. 26.5%, respectively (OR = 0.67; 95% CI: 0.55, 0.81; p < 0.001). SHD with favorable neurological outcome was observed in 0% in COVID-19 vs. 3.1% in non-COVID-19 patients (OR = 1.35; 95% CI: 0.07, 26.19; p = 0.84). Our meta-analysis suggests that suspected or diagnosed COVID-19 reduces the SHD rate after OHCA, which seems to be due to the lower rate of shockable rhythms in COVID-19 patients, but not due to reluctance to bystander CPR. Future trials are needed to confirm these preliminary results and determine the optimal procedures to increase survival after OHCA in COVID-19 patients.

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MicroCLOTS pathophysiology in coronavirus disease 2019

Cited by 20 publications

References 11 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

SARS-CoV-2 spike protein S1 induces fibrin(ogen) resistant to fibrinolysis: Implications for microclot formation in COVID-19

Impact of Coronavirus Disease 2019 on Out-of-Hospital Cardiac Arrest Survival Rate: A Systematic Review with Meta-Analysis

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