Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A

Abstract

High plasma levels of soluble P-selectin are associated with thrombotic disorders and may predict future cardiovascular events. Mice with high levels of soluble P-selectin have more microparticles in their plasma than do normal mice. Here we show that chimeras of P-selectin and immunoglobulin (P-sel-Ig) induced formation of procoagulant microparticles in human blood through P-selectin glycoprotein ligand-1 (PSGL-1; encoded by the Psgl1 gene, officially known as Selpl). In addition, Psgl1-/- mice produced fewer microparticles after P-sel-Ig infusion and did not spontaneously increase their microparticle count in old age as do wild-type mice. Injected microparticles specifically bound to thrombi and thus could be involved in thrombin generation at sites of injury. Infusion of P-sel-Ig into hemophilia A mice produced a 20-fold increase over control immunoglobulin in microparticles containing tissue factor. This significantly improved the kinetics of fibrin formation in the hemophilia A mice and normalized their tail-bleeding time. P-sel-Ig treatment could become a new approach to sustained control of bleeding in hemophilia.

Absence of hematopoietic tissue factor pathway inhibitor mitigates bleeding in mice with hemophilia

“…Based on these findings, we suggested that a physiological activity of platelet TFPI is the inhibition of blood-borne TF procoagulant activity accumulating within a growing thrombus (24). This hypothesis is supported by the work of Hrachovinová and coworkers, who demonstrated that TF-bearing microparticles, generated by infusion of P-selectin-Ig chimeras, corrected the plasma clotting time and tail vein bleeding time of F8 −/− mice (28). In addition, Massberg and coworkers demonstrated that following vascular injury, TFPI is captured by externalized neutrophil nucleosomes and then efficiently degraded by neutrophil serine proteases, producing localized intravascular thrombosis (29).…”

Microparticle‐associated tissue factor activity: a link between cancer and thrombosis?

“…Whether the minute amounts of MP-associated TF activity observed in the plasma of healthy volunteers (0.5-4 fM) are sufficient to stimulate fibrin formation is unknown; TFdependent FXa generation might be too low to overcome the natural thresholds of the anticoagulant systems [35]. In patients with progressive mucinous cancer tumor-derived MUC1 + -MP may display enhanced binding to P and/or L selectin on platelets or other hematopoietic cells or on MP derived from such cells [36,37]. Study of the co-expression of MUC1 and platelet antigen CD61 on MP by confocal immunofluorescence microscopy revealed that a small part of circulating MP seemed to result from fusion of cellular vesicles originating from malignant epithelial cells and platelets in patients with disseminated breast and pancreatic adenocarcinoma.…”

“…Healthy controls and non-disseminated breast cancer patients were all alive at the end of the study, with a median follow-up of 36 months (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). Median survival after collection of the blood samples was 12 months (range: 1-44) in metastatic breast cancer patients and 3 months (range: 1-13) in pancreatic cancer patients.…”

Platelet Microvesicles (Microparticles) in Cardiac Surgery

“…26 TF expressed on the surface of PMV initiates coagulation by activating factor VII to recruit platelets and initiate the pathway to thrombus formation in the response to vascular injury. 27 However increased TF expression does not always correlate with increased coagulation, suggesting that other factors are similarly important. 22,28 Integrin α 11b β 3 , another receptor expressed on the outer PMV surface, has a role in binding PMV to fibrinogen to cause platelet adhesion.…”