FXIa and platelet polyphosphate as therapeutic targets during human blood clotting on collagen/tissue factor surfaces under flow

Abstract

Key Points Contribution of FXIa and platelet-derived polyphosphate in thrombin generation varies depending on surface tissue-factor level. Platelet-derived polyphosphate potentiates pathways downstream of FXIIa that require low participation of extrinsic pathways.

Dynamics of Thrombin Generation and Flux from Clots during Whole Human Blood Flow over Collagen/Tissue Factor Surfaces

“…activation of Factor XIa (FXIa) (5,6). The extrinsic coagulation pathway is triggered by tissue factor/Factor VIIa (TF/FVIIa).…”

“…By recreating hemodynamic flow over procoagulant surfaces, the dynamics and pharmacology of thrombin generation can be studied with human blood ex vivo. In microfluidic clotting assays, fibrin generation is often used as an indirect indicator for thrombin activity (5,(37)(38)(39)(40). Our laboratory previously developed a peptide-based platelet targeting biosensor to report platelet associated thrombin activity in both microfluidic and animal thrombosis models (23,24).…”

“…Using plasma perfusion, our group previously demonstrated in a membrane microfluidic system that both wall shear rate and thrombin flux regulate physical structure of deposited fibrin fibers. Under venous shear condition, a wall thrombin flux of 10 Ϫ11 nmol/m 2 -s is required for platelet-free plasma to form a three-dimensional fibrin network (44), which is the fibrin structure that is usually observed in whole blood thrombi formed on the surface with collagen and TF at venous shear rates (5). In blood, antithrombin (AT) is a potent and rapid thrombin inhibitor (45).…”

Polyphosphatase PPX1 of <i>Saccharomyces cerevisiae</i> as a Tool for Polyphosphate Assay

“…PolyP is believed to be an active scaffold promising for the treatment of bone diseases, 3D cell printing [13], and the development of bioactive hydrogels capable of enhancing bone tissue growth [14]. Platelet polyP plays an essential role in hemostasis, thrombosis and inflammation [15] [16] and is believed to be a therapeutic target during human blood clotting [17]. Polyphosphates are promising candidates in the therapy for bone and blood diseases.…”

Polyphosphates rock! A role in thrombosis?

“…n In this issue of Blood, Wikstrom and colleagues highlight antigen-presenting cell (APC) dysfunction as a potential cause of impaired antiviral immunity in graft-versus-host disease (GVHD). 1 A long with malignant relapse and GVHD, posttransplant immunodeficiency and infections represent major barriers to successful allogeneic hematopoietic transplantation. Cytomegalovirus (CMV) infection in particular is a frequent cause of morbidity posttransplant, especially for recipients of T-cell-depleted and umbilical cord blood allografts as well as patients with GVHD.…”