The Experts below are selected from a list of 573 Experts worldwide ranked by ideXlab platform
Peter Caravan - One of the best experts on this subject based on the ideXlab platform.
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Fibrin specific peptides derived by phage display characterization of peptides and conjugates for imaging
Bioconjugate Chemistry, 2012Co-Authors: Andrew Kolodziej, Shrikumar A Nair, Philip B Graham, Thomas J Mcmurry, Robert Charles Ladner, Charles R Wescott, Daniel J Sexton, Peter CaravanAbstract:Peptides that bind to Fibrin but not to Fibrinogen or serum albumin were selected from phage display libraries as targeting moieties for thrombus molecular imaging probes. Three classes of cyclic peptides (cyclized via disulfide bond between two Cys) were identified with consensus sequences XArXCPY(G/D)LCArIX (Ar = aromatic, Tn6), X2CXYYGTCLX (Tn7), and NHGCYNSYGVPYCDYS (Tn10). These peptides bound to Fibrin at ∼2 sites with Kd = 4.1 μM, 4.0 μM, and 8.7 μM, respectively, whereas binding to Fibrinogen was at least 100-fold weaker. The peptides also bind to the Fibrin Degradation Product DD(E) with similar affinity to that measured for Fibrin. The Tn7 and Tn10 peptides bind to the same site on Fibrin, while the Tn6 peptides bind to a unique site. Alanine scanning identified the N- and C-terminal ends of the Tn6 and Tn7 peptides as most tolerant to modification. Peptide conjugates with either fluorescein or diethylenetriaminepentaaceto gadolinium(III) (GdDTPA) at the N-terminus were prepared for potential im...
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Fibrin specific peptides derived by phage display characterization of peptides and conjugates for imaging
Bioconjugate Chemistry, 2012Co-Authors: Andrew Kolodziej, Philip B Graham, Thomas J Mcmurry, Robert Charles Ladner, Charles R Wescott, Daniel J Sexton, Shrikumar Nair, Peter CaravanAbstract:Peptides that bind to Fibrin but not to Fibrinogen or serum albumin were selected from phage display libraries as targeting moieties for thrombus molecular imaging probes. Three classes of cyclic peptides (cyclized via disulfide bond between two Cys) were identified with consensus sequences XArXCPY(G/D)LCArIX (Ar=aromatic, Tn6), X2CXYYGTCLX (Tn7), and NHGCYNSYGVPYCDYS (Tn10). These peptides bound to Fibrin at ~2 sites with Kd=4.1 μM, 4.0 μM, and 8.7 μM, respectively, whereas binding to Fibrinogen was at least 100 – fold weaker. The peptides also bind to the Fibrin Degradation Product DD(E) with similar affinity to that measured for Fibrin. The Tn7 and Tn10 peptides bind to the same site on Fibrin while the Tn6 peptides bind to a unique site. Alanine scanning identified the N- and C-terminal ends of the Tn6 and Tn7 peptides as most tolerant to modification. Peptide conjugates with either fluorescein or diethylenetriaminepentaaceto gadolinium(III) (GdDTPA) at the N-terminus were prepared for potential imaging applications and these retained Fibrin binding affinity and specificity in plasma. Relaxivity and binding studies on the GdDTPA derivatives revealed that an N-terminal glycyl linker had modest effect on Fibrin affinity but resulted in lower Fibrin-bound relaxivity.
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Fibrin Specific Peptides Derived by Phage Display: Characterization of Peptides and Conjugates for Imaging
2012Co-Authors: Andrew F. Kolodziej, Shrikumar A Nair, Thomas J Mcmurry, Robert Charles Ladner, Daniel J Sexton, Philip Graham, Charles Wescott, Peter CaravanAbstract:Peptides that bind to Fibrin but not to Fibrinogen or serum albumin were selected from phage display libraries as targeting moieties for thrombus molecular imaging probes. Three classes of cyclic peptides (cyclized via disulfide bond between two Cys) were identified with consensus sequences XArXCPY(G/D)LCArIX (Ar = aromatic, Tn6), X2CXYYGTCLX (Tn7), and NHGCYNSYGVPYCDYS (Tn10). These peptides bound to Fibrin at ∼2 sites with Kd = 4.1 μM, 4.0 μM, and 8.7 μM, respectively, whereas binding to Fibrinogen was at least 100-fold weaker. The peptides also bind to the Fibrin Degradation Product DD(E) with similar affinity to that measured for Fibrin. The Tn7 and Tn10 peptides bind to the same site on Fibrin, while the Tn6 peptides bind to a unique site. Alanine scanning identified the N- and C-terminal ends of the Tn6 and Tn7 peptides as most tolerant to modification. Peptide conjugates with either fluorescein or diethylenetriaminepentaaceto gadolinium(III) (GdDTPA) at the N-terminus were prepared for potential imaging applications, and these retained Fibrin binding affinity and specificity in plasma. Relaxivity and binding studies on the GdDTPA derivatives revealed that an N-terminal glycyl linker had a modest effect on Fibrin affinity but resulted in lower Fibrin-bound relaxivity
Jun Mimuro - One of the best experts on this subject based on the ideXlab platform.
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combination of thrombin antithrombin complex plasminogen activator inhibitor 1 and protein c activity for early identification of severe coagulopathy in initial phase of sepsis a prospective observational study
Critical Care, 2014Co-Authors: Kansuke Koyama, Seiji Madoiwa, Shin Nunomiya, Toshitaka Koinuma, Masahiko Wada, Asuka Sakata, Tsukasa Ohmori, Jun Mimuro, Yoichi SakataAbstract:Current criteria for early diagnosis of coagulopathy in sepsis are limited. We postulated that coagulopathy is already complicated with sepsis in the initial phase, and severe coagulopathy or disseminated intravascular coagulation (DIC) becomes overt after progressive consumption of platelet and coagulation factors. To determine early diagnostic markers for severe coagulopathy, we evaluated plasma biomarkers for association with subsequent development of overt DIC in patients with sepsis. A single-center, prospective observational study was conducted in an adult ICU at a university hospital. Plasma samples were obtained from patients with sepsis at ICU admission. Fourteen biomarkers including global markers (platelet count, prothrombin time, activated partial thromboplastin time, Fibrinogen and Fibrin Degradation Product (FDP)); markers of thrombin generation (thrombin-antithrombin complex (TAT) and soluble Fibrin); markers of anticoagulants (protein C (PC) and antithrombin); markers of Fibrinolysis (plasminogen, α2-plasmin inhibitor (PI), plasmin-α2-PI complex, and plasminogen activator inhibitor (PAI)-1); and a marker of endothelial activation (soluble E-selectin) were assayed. Patients who had overt DIC at baseline were excluded, and the remaining patients were followed for development of overt DIC in 5 days, and for mortality in 28 days. A total of 77 patients were enrolled, and 37 developed overt DIC within the following 5 days. Most patients demonstrated hemostatic abnormalities at baseline with 98.7% TAT, 97.4% FDP and 88.3% PC. Most hemostatic biomarkers at baseline were significantly associated with subsequent development of overt DIC. Notably, TAT, PAI-1 and PC discriminated well between patients with and without developing overt DIC (area under the receiver operating characteristic curve (AUROC), 0.77 (95% confidence interval, 0.64 to 0.86); 0.87 (0.78 to 0.92); 0.85 (0.76 to 0.91), respectively), and using the three together, significantly improved the AUROC up to 0.95 (vs. TAT, PAI-1, and PC). Among the significant diagnostic markers for overt DIC, TAT and PAI-1 were also good predictors of 28-day mortality (AUROC, 0.77 and 0.81, respectively). Severe coagulation and Fibrinolytic abnormalities on ICU admission were associated with subsequent development of overt DIC. A single measurement of TAT, PAI-1, and PC activity could identify patients with ongoing severe coagulopathy, early in the course of sepsis.
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Degradation of cross linked Fibrin by leukocyte elastase as alternative pathway for plasmin mediated Fibrinolysis in sepsis induced disseminated intravascular coagulation
Thrombosis Research, 2011Co-Authors: Seiji Madoiwa, Momoko Dokai, Atsushi Yasumoto, Akira Ishiwata, Yuji Kashiwakura, Asuka Sakata, Tsukasa Ohmori, Yutaka Nagahama, Hideyuki Tanaka, Jun MimuroAbstract:Abstract An alternative pathway for Fibrinolysis that comprises leukocyte elastase and its interaction with the plasminogen activator-plasmin system has been suggested. Plasma levels of cross-linked Fibrin Degradation Product by leukocyte elastase (e-XDP) were significantly increased in patients with sepsis induced disseminated intravascular coagulation (DIC) compared with healthy subjects (18.6 ± 19.9 vs 0.58 ± 0.47 U/mL, p p = 0.005]) were significantly higher than those in patients with e-XDP levels of 3–10 U/mL. These data suggest that leukocyte elastase might contribute to the Degradation of cross-linked Fibrin in sepsis-induced DIC.
Cao Yongping - One of the best experts on this subject based on the ideXlab platform.
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plasma Fibrinogen performs better than plasma d dimer and Fibrin Degradation Product in the diagnosis of periprosthetic joint infection and determination of reimplantation timing
Journal of Arthroplasty, 2020Co-Authors: Zhichao Meng, Liping Pan, Heng Liu, Xin Yang, Cao YongpingAbstract:Abstract Background The accurate and timely diagnosis of periprosthetic joint infection (PJI) is challenging, and no single biomarker can definitively confirm infection before revision arthroplasty. The coagulation cascade has been linked closely to infection. This study was performed to determine the value of plasma d -dimer, plasma Fibrinogen, and plasma Fibrin Degradation Product (FDP) for the diagnosis of PJI and timing of reimplantation. Methods We retrospectively enrolled 136 patients who underwent revision surgery from January 2008 to December 2019. They were assigned to 3 groups: aseptic failure (group A), PJI (group B), and reimplantation (group C). Receiver operating characteristic curves were constructed to estimate the value of plasma Fibrinogen, plasma d -dimer, plasma FDP, erythrocyte sedimentation rate (ESR), and serum C-reactive protein (CRP) for PJI diagnosis and reimplantation timing. Results All biomarker levels were significantly higher in group B than in group A (P d -dimer, plasma FDP, CRP, and ESR were 0.848, 0.914, 0.728, 0.737, and 0.868, respectively, and the threshold values for plasma Fibrinogen, plasma d -dimer, and plasma FDP were 3.61 g/L, 0.41 mg/L, and 3.55 mg/L, respectively. Conclusion Plasma Fibrinogen exhibits good value for the diagnosis of PJI and can be an indicator of residual infection before reimplantation in 2-stage arthroplasty. Plasma d -dimer and FDP are of limited value for PJI diagnosis and cannot be used to determine the timing of reimplantation.
Seiji Madoiwa - One of the best experts on this subject based on the ideXlab platform.
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combination of thrombin antithrombin complex plasminogen activator inhibitor 1 and protein c activity for early identification of severe coagulopathy in initial phase of sepsis a prospective observational study
Critical Care, 2014Co-Authors: Kansuke Koyama, Seiji Madoiwa, Shin Nunomiya, Toshitaka Koinuma, Masahiko Wada, Asuka Sakata, Tsukasa Ohmori, Jun Mimuro, Yoichi SakataAbstract:Current criteria for early diagnosis of coagulopathy in sepsis are limited. We postulated that coagulopathy is already complicated with sepsis in the initial phase, and severe coagulopathy or disseminated intravascular coagulation (DIC) becomes overt after progressive consumption of platelet and coagulation factors. To determine early diagnostic markers for severe coagulopathy, we evaluated plasma biomarkers for association with subsequent development of overt DIC in patients with sepsis. A single-center, prospective observational study was conducted in an adult ICU at a university hospital. Plasma samples were obtained from patients with sepsis at ICU admission. Fourteen biomarkers including global markers (platelet count, prothrombin time, activated partial thromboplastin time, Fibrinogen and Fibrin Degradation Product (FDP)); markers of thrombin generation (thrombin-antithrombin complex (TAT) and soluble Fibrin); markers of anticoagulants (protein C (PC) and antithrombin); markers of Fibrinolysis (plasminogen, α2-plasmin inhibitor (PI), plasmin-α2-PI complex, and plasminogen activator inhibitor (PAI)-1); and a marker of endothelial activation (soluble E-selectin) were assayed. Patients who had overt DIC at baseline were excluded, and the remaining patients were followed for development of overt DIC in 5 days, and for mortality in 28 days. A total of 77 patients were enrolled, and 37 developed overt DIC within the following 5 days. Most patients demonstrated hemostatic abnormalities at baseline with 98.7% TAT, 97.4% FDP and 88.3% PC. Most hemostatic biomarkers at baseline were significantly associated with subsequent development of overt DIC. Notably, TAT, PAI-1 and PC discriminated well between patients with and without developing overt DIC (area under the receiver operating characteristic curve (AUROC), 0.77 (95% confidence interval, 0.64 to 0.86); 0.87 (0.78 to 0.92); 0.85 (0.76 to 0.91), respectively), and using the three together, significantly improved the AUROC up to 0.95 (vs. TAT, PAI-1, and PC). Among the significant diagnostic markers for overt DIC, TAT and PAI-1 were also good predictors of 28-day mortality (AUROC, 0.77 and 0.81, respectively). Severe coagulation and Fibrinolytic abnormalities on ICU admission were associated with subsequent development of overt DIC. A single measurement of TAT, PAI-1, and PC activity could identify patients with ongoing severe coagulopathy, early in the course of sepsis.
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Degradation of cross linked Fibrin by leukocyte elastase as alternative pathway for plasmin mediated Fibrinolysis in sepsis induced disseminated intravascular coagulation
Thrombosis Research, 2011Co-Authors: Seiji Madoiwa, Momoko Dokai, Atsushi Yasumoto, Akira Ishiwata, Yuji Kashiwakura, Asuka Sakata, Tsukasa Ohmori, Yutaka Nagahama, Hideyuki Tanaka, Jun MimuroAbstract:Abstract An alternative pathway for Fibrinolysis that comprises leukocyte elastase and its interaction with the plasminogen activator-plasmin system has been suggested. Plasma levels of cross-linked Fibrin Degradation Product by leukocyte elastase (e-XDP) were significantly increased in patients with sepsis induced disseminated intravascular coagulation (DIC) compared with healthy subjects (18.6 ± 19.9 vs 0.58 ± 0.47 U/mL, p p = 0.005]) were significantly higher than those in patients with e-XDP levels of 3–10 U/mL. These data suggest that leukocyte elastase might contribute to the Degradation of cross-linked Fibrin in sepsis-induced DIC.
Victor Gurewich - One of the best experts on this subject based on the ideXlab platform.
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Fibrinolysis a misunderstood natural defense whose therapeutic potential is unknown
Cardiovascular Drugs and Therapy, 2019Co-Authors: Victor GurewichAbstract:Ever since tissue plasminogen activator (tPA) was approved for therapeutic Fibrinolysis in 1987, it has been the Fibrinolytic of choice. At the same time, it is also recognized that tPA never lived up to its clinical expectations and has more recently been replaced by percutaneous coronary intervention (PCI) as the treatment of choice for acute myocardial infarction (AMI). For other occlusive vascular diseases and for patients in remote areas, tPA remains an essential option. In view of the continued importance of Fibrinolysis, it is disappointing that Fibrinolysis never evolved beyond what it was when tPA replaced streptokinase (SK) 32 years ago. The endovascular procedure replacement for AMI treatment suffers from being technically demanding, time-consuming, and costly. An untested alternative Fibrinolytic paradigm is that of the endogenous, physiological system, which is initiated by tPA but then is followed by the other natural plasminogen activator, urokinase plasminogen activator (uPA). In this combination, it is uPA rather than tPA that has the dominant function. This is also evident from gene knockout studies where deletion of uPA that it has the dominant effect. The Fibrinolytic properties of tPA and uPA are complementary so that their combined effect is synergistic, especially when they are administered sequentially starting with tPA. Endogenous Fibrinolysis functions without bleeding side effects and is ongoing. This is evidenced by the invariable presence in blood of the Fibrin Degradation Product, D-dimer (normal concentration 110–250 ng/ml). This activator combination, consisting of a mini bolus of tPA followed by a 90-min proUK infusion, was once used to treat 101 AMI patients. Compared with the best of the tPA mega trials, this regimen resulted in an almost a doubling of the infarct artery patency rate and reduced mortality sixfold. To date, a second trial has not yet been done.
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Fibrin specific and effective clot lysis requires both plasminogen activators and for them to be in a sequential rather than simultaneous combination
Journal of Thrombosis and Thrombolysis, 2017Co-Authors: Ralph Pannell, Victor GurewichAbstract:Thrombolysis with tissue plasminogen activator (tPA) has been a disappointment and has now been replaced by an endovascular procedure whenever possible. Nevertheless, thrombolysis remains the only means by which circulation in a thrombosed artery can be restored rapidly. In contrast to tPA monotherapy, endogenous Fibrinolysis uses both tPA and urokinase plasminogen activator (uPA), whose native form is a proenzyme, prouPA. This combination is remarkably effective as evidenced by the Fibrin Degradation Product, D-dimer, which is invariably present in plasma. The two activators have complementary mechanisms of plasminogen activation and are synergistic in combination. Since tPA initiates Fibrinolysis when released from the vessel wall and prouPA is in the blood, they induce Fibrinolysis sequentially. It was postulated that this may be more effective and Fibrin-specific. The hypothesis was tested in a model of clot lysis in plasma in which a clot was first exposed to tPA for 5 min, washed and incubated with prouPA. Lysis was compared with that of clots incubated with both activators simultaneously. The sequential combination was almost twice as effective and caused less Fibrinogenolysis than the simultaneous combination (p < 0.0001) despite having significantly less tPA, as a result of the wash. A mechanism is described by which this phenomenon can be explained. The findings are believed to have significant therapeutic implications.