Synergies of phosphatidylserine and protein disulfide isomerase in tissue factor activation

Abstract

Summary Tissue factor (TF), the cellular receptor and cofactor for factor VII/VIIa, initiates haemostasis and thrombosis. Initial tissue distribution studies suggested that TF was sequestered from the circulation and only present at perivascular sites. However, there is now clear evidence that TF also exists as a blood-borne form with critical contributions not only to arterial thrombosis following plaque rupture and to venous thrombosis following endothelial perturbation, but also to various other clotting abnormalities associated with trauma, infection, or cancer. Because thrombin generation, fibrin deposition, and platelet aggregation in the contexts of haemostasis, thrombosis, and pathogen defence frequently occur without TF de novo synthesis, considerable efforts are still directed to understanding the molecular events underlying the conversion of predominantly non-coagulant or cryptic TF on the surface of haematopoietic cells to a highly procoagulant molecule following cellular injury or stimulation. This article will review some of the still controversial mechanisms implicated in cellular TF activation or decryption with particular focus on the coordinated effects of outer leaflet phosphatidylserine exposure and thiol-disulfide exchange pathways involving protein disulfide isomerase (PDI). In this regard, our recent findings of ATP-triggered stimulation of the purinergic P2X7 receptor on myeloid and smooth muscle cells resulting in potent TF activation and shedding of procoagulant microparticles as well as of rapid monocyte TF decryption following antithymocyte globulin-dependent membrane complement fixation have delineated specific PDI-dependent pathways of cellular TF activation and thus illustrated additional and novel links in the coupling of inflammation and coagulation.

Targeting clotting proteins in cancer therapy – progress and challenges

“…TF is maintained in a cryptic state by protein disulfide isomerase (PDI) dependent thiol-disulfide exchange reactions that modify an allosteric disulfide bond in the TF extracellular domain (14;15). Activating stimuli, including Ca2 + fluxes (15;16), can convert cryptic TF to a high affinity receptor for FVIIa and fully procoagulant state in the context of cell surface exposure of negatively charged phosphatidylserine (PS) (17). Subsequent studies have shown that TF prothrombotic activity and fibrin formation in vivo is indeed dependent on PDI-activity (18-20).…”

Sphingomyelin encrypts tissue factor: ATP-induced activation of A-SMase leads to tissue factor decryption and microvesicle shedding

“…8–10 A consensus now held in the field is that most of the TF expressed on cell surfaces is maintained in a cryptic, coagulantly inactive state and that an activation step (decryption) is essential for the transformation of cryptic TF to procoagulant active TF. 9,11,12 However, molecular differences between cryptic and procoagulant TF and the mechanisms that are responsible for the conversion from one to the other form are poorly understood and often controversial. 11,13 Nonetheless, most of the evidence in the literature suggests that externalization of phosphatidylserine (PS) to the outer leaflet of the plasma membrane plays a critical role in regulating TF procoagulant activity at the cell surface.…”

“…9,11,12 However, molecular differences between cryptic and procoagulant TF and the mechanisms that are responsible for the conversion from one to the other form are poorly understood and often controversial. 11,13 Nonetheless, most of the evidence in the literature suggests that externalization of phosphatidylserine (PS) to the outer leaflet of the plasma membrane plays a critical role in regulating TF procoagulant activity at the cell surface. 9 However, other pathways, such as the thioredoxin system or thiol-disulfide exchange pathways involving protein-disulfide isomerase (PDI), may also contribute to TF activation by altering TF structure 14–16 or through the modulation of PS exposure.…”

Tissue Factor Prothrombotic Activity Is Regulated by Integrin-arf6 Trafficking

“…In cells of the myelo-monocytic lineage, which are central to the crosstalk of inflammation and coagulation, TF remains predominantly in a non-coagulant, encrypted form. Secondary signals can activate TF procoagulant function and thus cause thrombotic complications in disease 1 . Relevant injury and danger signals in this context are degradation of TF pathway inhibitor (TFPI) by neutrophil proteases 2 , complement activation 3–5 , protein disulfide isomerase (PDI) release by injured cells 6, 7 , and triggers of neutrophil extracellular traps incorporating TF 8–11 .…”

“…However, PS exposure is also influenced by PDI 12, 18 and concomitantly induced by stimuli that promote TF activation 1, 16, 19, 20 ; thus it remains controversial whether TF structural changes induced by PDI are relevant for enhancing TF procoagulant activity or whether PS exposure is sufficient 21–23 . Alternative conformations of TF are indicated by measurements of affinity for its ligand, FVIIa.…”