Protein disulfide-isomerase – a trigger of tissue factor-dependent thrombosis
Issue title: Selected Presentations held at the 35th Conference of the German Society for Clinical Microcirculation and Hemorheology, Mainz, Germany, 4-5 November, 2016
Affiliations: Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University of Mainz, Mainz, Germany
Correspondence:
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Corresponding author: Christoph Reinhardt, Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University of Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany. Tel.: +49 6131 17 8280; Fax: +49 6131 17 6238; E-mail: Christoph.Reinhardt@unimedizin-mainz.de.
Abstract: The plasmatic coagulation system is tightly controlled by natural anticoagulant mechanisms, preventing thrombosis to ensure the supply of tissues with oxygen and nutrients without provoking susceptibility to bleeding diatheses. The membrane receptor tissue factor (TF) is the principal initiator of coagulation, forming a high affinity complex with coagulation factor VIIa, thus catalyzing quantitative formation of the coagulation factor Xa. While it has been well-established that the TF-VIIa complex is efficiently blocked by factor Xa associated with tissue factor pathway inhibitor (TFPI), it was uncovered during the last decade that TF contains an intramolecular allosteric disulfide, which is prone to reduction and is crucial for TF’s procoagulant and prothrombotic function. The compromised integrity of the allosteric TF disulfide pair Cys186/Cys209 was demonstrated to be responsible for the cryptic nature of TF procoagulant activity on monocytes and other cell types as well as in mouse thrombosis models. Cell surface associated protein disulfide-isomerases (PDI) were identified as activators of cryptic tissue factor. Here, we review this current concept of TF de-encryption by PDI oxidoreductases that have become interesting targets for the development of new antithrombotic treatment strategies.
Keywords: Thrombosis, tissue factor, protein disulfide-isomerase, PDI
