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. 2018 Apr;164 Suppl 1(Suppl 1):S130-S135.
doi: 10.1016/j.thromres.2018.01.005.

The Intersection of Protein Disulfide Isomerase and Cancer Associated Thrombosis

Free PMC article

The Intersection of Protein Disulfide Isomerase and Cancer Associated Thrombosis

Jack D Stopa et al. Thromb Res. .
Free PMC article


The mechanisms underlying the hypercoagulability of cancer are complex and include the upregulation coagulation factors or procoagulant proteins, shedding of microparticles, and direct activation of vascular cells. Protein disulfide isomerase (PDI) is a thiol isomerase secreted from activated platelets and endothelial cells and plays a critical role in both platelet aggregation and fibrin generation. A number of potential intravascular targets of PDI have been identified including cell surface receptors (e.g. β-integrins and glycoprotein Ib), receptor ligands (e.g. fibrinogen and von Willebrand factor), serine proteases (e.g. cathepsin G and kallekrein-14), and coagulation factors (e.g. factor XI and factor V). Recent clinical studies demonstrated that a small molecule inhibitor of PDI, isoquercetin, decreases platelet-dependent thrombin generation and PDI activity in plasma following oral administration. This review explores the mechanistic overlap between the molecular drivers of cancer associated thrombosis and the potential roles PDI plays in mediating thrombosis. These molecular insights provide rationale for clinical trials targeting PDI to prevent thrombosis in cancer patients.

Keywords: Antithrombotics; Cancer associated thrombosis; Protein disulfide isomerase.


Figure 1
Figure 1. Schematic Representation of Protein Disulfide Isomerase
The a-b-b’-x-a’-c structure of PDI, with the CGHC active sites displayed in red.
Figure 2
Figure 2. Reduction/Oxidation Mechanism of Protein Disulfide Isomerase
Shown is a reaction scheme diagramming the PDI active site transitioning between a reduced (left) and oxidized (right) state performing disulfide bond reduction (left to right) or oxidation (right to left) on a protein substrate. PDI active site (lower) and protein substrate (upper) are shown. Modified from (8)
Figure 3
Figure 3. Inhibition of PDI with isoquercetin decreases thrombin-induced thrombin generation through FVa
Diagram of the proposed role of PDI in the activation of platelet factor V and the downstream generation of thrombin in the absence (Panel A) and presence (Panel B) of isoquercetin (9) MMN1: Multimerin-1; FV: Platelet Factor V; IIa: Thrombin; FVa: Factor Va; Xa: Factor Xa; II: Prothrombin; IQ: Isoquercetin; a-b-b’-a’: PDI.

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