Contradictory to its effects on thrombin, C1-inhibitor reduces plasmin generation in the presence of thrombomodulin

Tarandovskiy, Ivan D.; Rajabi, Amin; Karnaukhova, Elena; Buehler, Paul W.

doi:10.1007/s11239-019-01869-y

Cited by 23 publications

(17 citation statements)

References 43 publications

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“…Simultaneous thrombin and plasmin generation assay (STPGA ) : Simultaneous evaluation of thrombin and plasmin generation (TG and PG, respectively) was performed as described previously [ 25 ]. Briefly, plasma samples were mixed with either thrombin specific substrate, Z-Gly-Gly-Arg-AMC (Bachem, Bubendorf, Switzerland) or plasmin specific substrate, Boc-Glu-Lys-Lys-AMC (Bubendorf, Switzerland), and 16 nM of thrombomodulin (PeproTech, Rocky Hill, NJ, USA).…”

Section: Methodsmentioning

confidence: 99%

Biological and Clinical Factors Contributing to the Metabolic Heterogeneity of Hospitalized Patients with and without COVID-19

D’Alessandro

Thomas

Akpan

et al. 2021

Cells

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The Corona Virus Disease 2019 (COVID-19) pandemic represents an ongoing worldwide challenge. The present large study sought to understand independent and overlapping metabolic features of samples from acutely ill patients (n = 831) that tested positive (n = 543) or negative (n = 288) for COVID-19. High-throughput metabolomics analyses were complemented with antigen and enzymatic activity assays on plasma from acutely ill patients collected while in the emergency department, at admission, or during hospitalization. Lipidomics analyses were also performed on COVID-19-positive or -negative subjects with the lowest and highest body mass index (n = 60/group). Significant changes in amino acid and fatty acid/acylcarnitine metabolism emerged as highly relevant markers of disease severity, progression, and prognosis as a function of biological and clinical variables in these patients. Further, machine learning models were trained by entering all metabolomics and clinical data from half of the COVID-19 patient cohort and then tested on the other half, yielding ~78% prediction accuracy. Finally, the extensive amount of information accumulated in this large, prospective, observational study provides a foundation for mechanistic follow-up studies and data sharing opportunities, which will advance our understanding of the characteristics of the plasma metabolism in COVID-19 and other acute critical illnesses.

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Section: Methodsmentioning

confidence: 99%

Biological and Clinical Factors Contributing to the Metabolic Heterogeneity of Hospitalized Patients with and without COVID-19

D’Alessandro

Thomas

Akpan

et al. 2021

Cells

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“…The first STPGA parameters distributions. The peak height (PH) and Production Rate (PR) values were calculated as the main parameters of the STPGA curves as previously reported 26 . Figure 4 shows box-plots of the…”

Section: Stpga Curves Rangesmentioning

confidence: 99%

“…Since 2011, several hemostasis assays have focused on simultaneous registration of thrombin and plasmin generation (PG) in plasma using tissue factor (TF) and tissue plasminogen activator (tPA), respectively 18-21 . These approaches suggest high sensitivity to assessment of coagulation and fibrinolysis and to the impairment of these systems [21][22][23][24][25] . PG is a novel assay, and until the present study it has not been applied to interspecies comparisons of fibrinolysis.…”

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confidence: 99%

Interspecies comparison of simultaneous thrombin and plasmin generation

Tarandovskiy

Shin

Baek

et al. 2020

Sci Rep

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Animal models of hemostasis are often extrapolated to humans; however, only a few studies have compared coagulation and fibrinolysis across species. Simultaneous thrombin (TG) and plasmin (PG) generation is useful to assessing coagulation and fibrinolysis within the same sample. In this study, we performed simultaneous TG and PG analysis in blood plasma samples from humans and 6 species commonly evaluated in pre-clinical research. TG and PG were investigated in male and female donor platelet-poor plasmas (PPP) obtained from 28 healthy humans, 10 baboons, 12 rhesus monkeys, 20 Yorkshire pigs, 20 Sprague-Dawley rats, 10 New Zealand White rabbits and 14 Hartley guinea pigs. The continuous generation of the 7-amino-4-methylcoumarin (AMC) from substrates specific to thrombin or plasmin was monitored. The thrombin and plasmin concentration peak heights (PH) and production rates (PR) were calculated. TG and PG parameters from baboon and rhesus macaque plasma approximated that of humans. The other species differed significantly from both human and nonhuman primates. For example, swine and rat plasmas demonstrated similar TG, but swine plasmas did not generate plasmin. TG and PG parameters from Guinea pig samples were extremely low, while rabbit plasmas showed variable PG curves demonstrating one or two peaks with low and high PR values, respectively. Correlations between PH and PR values were significant with the exceptions of human PG, baboon TG, rat TG and Guinea pig PG. These findings are informative to pre-clinical animal species selection and optimization of coagulation and fibrinolysis translational research.Animal models of hemostasis and thrombosis are widely used in basic and pharmaceutical research 1 . Results are frequently extrapolated to humans; however, data obtained from animal models often falls short of accurate predictions in human response 2 . Further, assays have limited relevant comparisons of hemostasis in human blood with that of differing animal species. The novel global assays of hemostasis such as thrombin generation (TG) and thromboelastography (TEG) or thromboelastometry (ROTEM) provide an opportunity to assess similarities in coagulation and fibrinolysis ex vivo on blood obtained from different species. Although TG and thromboelastographic assays are often used for analysis of hemostasis in different animals 1,3-9 , comparison among different species is rarely made. There are limited studies that compare blood coagulation and fibrinolysis in various animals under the same conditions 10-17 . TG assays are sensitive for use in clinical and basic research studies; however, fibrinolysis testing primarily focused on clot lysis time, is often insufficiently sensitive and demonstrates high data variability 8,9,11 . Since 2011, several hemostasis assays have focused on simultaneous registration of thrombin and plasmin generation (PG) in plasma using tissue factor (TF) and tissue plasminogen activator (tPA), respectively 18-21 . These approaches suggest high sensitivity to assessment of coagulation an...

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“…Thrombin generation (TG) and plasmin generation (PG) were performed to elucidate procoagulant action(s) of emicizumab underlying ACT changes in the presence or absence of FVIII inhibitors. The two tests were assessed in parallel as previously described with modifications 16 . Briefly, plasma samples collected at T1, T2 and T4 were mixed at 1:1 vol/vol with either PNP or FVIII inhibitor plasma as above.…”

Section: Methodsmentioning

confidence: 99%

In vitro effects of emicizumab on activated clotting time in blood samples from cardiac surgical patients

et al. 2021

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Background Heparin management in hemophilia A (HA) patients with a factor VIII (FVIII) inhibitor can be challenging due to severe activated clotting time (ACT) prolongations. It is important to better understand the impact of emicizumab, a FVIII mimetic on ACT, and tissue factor (TF)‐based coagulation assays. Methods Whole blood from 18 patients undergoing cardiopulmonary bypass (CPB) were mixed in vitro with pooled normal plasma, FVIII‐deficient or FVIII‐inhibitor plasma to affect functional FVIII levels. ACTs and heparin concentration by protamine titration were measured in whole blood mixture with/without emicizumab (50‐100 μg/ml). Thrombin generation and plasmin generation were measured in the patient's plasma mixed with normal plasma or FVIII‐inhibitor plasma to assess the impact of emicizumab under low TF activation. Results FVIII inhibitors prolonged ACTs by 2.2‐fold compared to those in normal plasma mixture at baseline. During CPB, ACTs in normal plasma mixture, and FVIII‐deficient mixture were in 400s, but ACTs reached 900s in FVIII‐inhibitor mixture. Emicizumab shortened ACTs by up to 100s in normal plasma mixture, and FVIII‐deficient mixtures. ACTs remained over 600s in FVIII‐inhibitor mixture, despite adding emicizumab at 100 μg/ml. Heparin concentration measured by TF‐based protamine titration was unaffected. Emicizumab enhanced thrombin peak in the presence of FVIII inhibitors, whereas plasmin generation was mainly affected by thrombin generation, and systemic use of ɛ‐aminocaproic acid. Conclusions FVIII inhibitors extensively prolong ACTs in heparinized whole blood, and clinical levels of emicizumab partially reverse ACT values. Protamine titration should be considered for optimal heparin monitoring in emicizumab‐treated patients with FVIII inhibitors.

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Contradictory to its effects on thrombin, C1-inhibitor reduces plasmin generation in the presence of thrombomodulin

Cited by 23 publications

References 43 publications

Biological and Clinical Factors Contributing to the Metabolic Heterogeneity of Hospitalized Patients with and without COVID-19

Biological and Clinical Factors Contributing to the Metabolic Heterogeneity of Hospitalized Patients with and without COVID-19

Interspecies comparison of simultaneous thrombin and plasmin generation

In vitro effects of emicizumab on activated clotting time in blood samples from cardiac surgical patients

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