Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer

Zwicker, Jeffrey I.; Schlechter, Benjamin L.; Stopa, Jack D.; Liebman, Howard A.; Aggarwal, Anita; Puligandla, Mäneka; Caughey, Thomas; Bauer, Kenneth A.; Kuemmerle, Nancy B.; Wong, Ellice; Wun, Ted; McLaughlin, Marilyn; Hidalgo, Manuel; Neuberg, Donna; Furie, Bruce; Flaumenhaft, Robert

doi:10.1172/jci.insight.125851

Cited by 117 publications

(103 citation statements)

References 64 publications

(89 reference statements)

Supporting

Mentioning

100

Contrasting

Unclassified

Order By: Relevance

“…Studies using blocking antibodies and cell-impermeable thiol-reacting agents suggest the importance of cell surface-bound PDI the ligand-binding function of cell surface molecules such as integrins [10][11][12][36][37][38] . Furthermore, the use of small-molecule PDI inhibitors helped to examine how PDI interacts with its binding partners and modulates cellular functions 23,39,40 and to demonstrate that targeting PDI could be a novel therapeutic strategy for treating thrombotic disease 41 . However, it should be noted that many PDI inhibitors and even blocking antibodies (e.g., clone RL90), which have been used in numerous studies, have off-target effects or crossreactivity with other thiol isomerases 10,12,16,42 .…”

Section: Source and Function Of Extracellular Pdimentioning

confidence: 99%

Protein disulfide isomerase in cardiovascular disease

et al. 2020

View full text Add to dashboard Cite

Protein disulfide isomerase (PDI) participates in the pathogenesis of numerous diseases. Increasing evidence indicates that intravascular cell-derived PDI plays an important role in the initiation and progression of cardiovascular diseases, including thrombosis and vascular inflammation. Recent studies with PDI conditional knockout mice have advanced our understanding of the function of cell-specific PDI in disease processes. Furthermore, the identification and development of novel small-molecule PDI inhibitors has led into a new era of PDI research that transitioned from the bench to bedside. In this review, we will discuss recent findings on the regulatory role of PDI in cardiovascular disease.

show abstract

Section: Source and Function Of Extracellular Pdimentioning

confidence: 99%

Protein disulfide isomerase in cardiovascular disease

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In an experimental model with in vitro addition of platelet inhibitors to PRP, aspirin and dipyridamole showed no effect on platelet-dependent endogenous thrombin potential [34]. On the other hand, studies have shown effects of other antithrombotic agents affecting mechanisms beyond cyclooxygenase (COX)-2 inhibition, such as protein disulfide isomerase inhibitors which reduce platelet-dependent thrombin generation by blocking the generation of platelet FVa [35,36]. Recent work explored the use of collagen-induced platelet aggregation (agPRP) for TG measurements in the presence of FXa inhibitors.…”

Section: Platelet-dependent Thrombin Generation In Prothrombotic Condmentioning

confidence: 99%

Clinical Applications, Pitfalls, and Uncertainties of Thrombin Generation in the Presence of Platelets

Panova‐Noeva

Meijden

Cate

2019

JCM

View full text Add to dashboard Cite

Platelet-dependent thrombin generation is a helpful tool to assess ex vivo the interaction between platelets and plasma coagulation factors in the initiation, amplification, and inhibition of thrombin generation (TG). This review article discusses the most relevant available data on the clinical applications of fluorogenic TG, the most widely used TG assay, performed in the presence of platelets, i.e., in platelet-rich plasma. With respect to prothrombotic states, arterial hypertension and obesity were the most prominent cardiovascular conditions linked to increased platelet-dependent TG. In addition, platelet-associated hypercoagulability, assessed by the TG assay, has been shown in individuals with active cancer. In terms of bleeding, platelet-dependent TG has been applied to assess bleeding risk in individuals with hemophilia, von Willebrand disease, and Glanzmann thrombasthenia as well as in subjects with other congenital or acquired coagulation factor deficiencies. In addition to risk prediction, a role of the TG assay has been suggested in monitoring antiplatelet therapy in prothrombotic conditions and replacement therapy in bleeding diathesis. Finally, for the routine clinical use and as a biomarker of disease development and progression, better standardization and clinical validation of platelet-dependent TG are still needed.readings from a fluorometer are recorded and calculated by means of the Thrombinoscope software (Thrombinoscope BV). In principle, the measurements in PRP are assessed in fresh material, whereas TG in PFP is assessed in frozen, stored material. For TG measurements in PRP, coagulation is triggered by adding 20 µL exogenous tissue factor (TF) to 80 µL PRP (with adjusted platelet concentration of 150,000 platelets/µL), whereas for TG measurements in PFP, 20 µL exogenous TF and 4 µM phospholipids are added to 80 µL plasma. After prewarming for 10 min at 37 • C in the fluorimeter, the reaction is started by adding 20 µL of a low-affinity fluorogenic substrate for thrombin (Z-Gly-Gly-Arg-AMC) and calcium chloride mixture (FluCa). TG is measured as a function of a calibration signal obtained in a sample from the same plasma (PRP or PFP) after addition of a fixed amount of thrombin-α2-macroglobulin complex (20 µL of thrombin calibrator) and 20 µL of FluCa. The TG method is extensively reviewed in [5][6][7]. Parameters derived from a TG curve and most frequently reported in the studies are lag time, time to minimum thrombin formed expressed in minutes (min); peak height, maximum concentration of thrombin formed expressed in nM thrombin; and endogenous thrombin potential (ETP) or area under the curve expressed as nM of thrombin formed per minute.The aim of this article was to review the available evidence for the potential clinical application of platelet-dependent TG in both prothrombotic and bleeding conditions, as depicted in Figure 1. Aspects preventing its broader application and routine clinical practice will also be discussed as uncertainties and limitations of thrombin generation in the...

show abstract

“…81 Isoquercetin was subsequently evaluated in a phase II study of patients with advanced cancer to assess its effect on hypercoaguability. 82 The use of high-throughput sequencing has significantly improved scientists and physicians' ability to characterize the genetic mechanisms of bleeding disorders. Over the past decade, there has been a surge of reports identifying candidate sequence variants not only for singlegene Mendelian diseases but also for complex inherited coagulation and platelet disorders and traits.…”

Section: Healthy Cells Cancer Cellsmentioning

confidence: 99%

Illustrated State‐of‐the‐Art Capsules of the ISTH 2019 Congress in Melbourne, Australia

Ward

Andrews

2019

Research and Practice in Thrombosis and Haemostasis

Self Cite

View full text Add to dashboard Cite

The 27th Congress of the International Society of Thrombosis and Haemostasis (ISTH) is an international conference held July 6‐10, 2019, in Melbourne, the capital of the state of Victoria, Australia. The ISTH congress has previously been held every other year, with the Scientific and Standardization Committee (SSC) meeting held annually, until 2019 when it became one combined annual meeting of the ISTH and SSC. The conference covers clinical and basic aspects of hemostasis and thrombosis, and this year includes 5 Plenary lectures and >50 State of Art (SOA) lectures, presented by internationally recognized speakers, as well as numerous oral session and poster presentations selected from submitted abstracts, including many early career and reach the world support recipients. This SOA review article in RPTH contains concise Illustrated Review Articles or ‘Capsules’ consisting of short text, three references and a figure, with topics including stroke, cancer‐associated thrombosis, hemophilia, coagulation, the interface between infection and inflammation, and in the experimental and discovery areas, megakaryocyte biology and platelet production, structure‐function of key receptors and coagulation factors, and emerging new roles for thrombotic/hemostatic factors. Together, these articles highlight novel findings which will advance knowledge and with the potential to change clinical practice and improve outcomes. It is hoped that conference attendees and followers will enjoy utilizing the images for ongoing education and during the conference for live tweeting during sessions, to assist in the broadcasting and promotion of the science to those unable to attend, or who have chosen to attend a concurrent session. Use #IllustratedReview and #ISTH2019 on social media.

show abstract

Targeting protein disulfide isomerase with the flavonoid isoquercetin to improve hypercoagulability in advanced cancer

Cited by 117 publications

References 64 publications

Protein disulfide isomerase in cardiovascular disease

Protein disulfide isomerase in cardiovascular disease

Clinical Applications, Pitfalls, and Uncertainties of Thrombin Generation in the Presence of Platelets

Illustrated State‐of‐the‐Art Capsules of the ISTH 2019 Congress in Melbourne, Australia

Contact Info

Product

Resources

About