These data show that low levels of FII exert a major survival advantage to sickle mice, conceivably reducing the general severity of SCD complications

These data show that low levels of FII exert a major survival advantage to sickle mice, conceivably reducing the general severity of SCD complications. Open in a separate window Figure 1 Reduction of circulating FII using ASO reduces early mortality in Berkeley sickle mice. normal FII) and FIIWT mice were tracked in parallel for any year following the imposition of SCD via hematopoietic stem cell transplantation. This genetically imposed suppression of FII levels resulted in an impressive reduction in inflammation (reduction in leukocytosis, thrombocytosis, and circulating interleukin-6 levels), reduced endothelial cell dysfunction (reduced endothelial activation and circulating soluble vascular cell adhesion molecule), and a significant improvement in SCD-associated end-organ damage (nephropathy, pulmonary hypertension, pulmonary inflammation, liver function, inflammatory infiltration, and microinfarctions). Notably, all of these benefits were achieved with a relatively modest 1.25-fold increase in prothrombin occasions, and in the absence of hemorrhagic complications. Taken together, these data establish that prothrombin is usually a powerful modifier of SCD-induced end-organ damage, and present a novel therapeutic target to ameliorate SCD pathologies. Introduction Sickle cell disease (SCD) is usually a common monogenic disorder that affects millions worldwide and is caused by a mutant -globin gene. It is characterized by erythrocyte sickling, chronic hemolytic anemia, episodic acute vaso-occlusions, chronic systemic inflammation at baseline, and acute and chronic cumulative organ damage.1-7 Therapeutic options to prevent organ pathologies are limited to chronic transfusions, hydroxyurea, or an allogeneic hematopoietic stem cell transplant (HCT).8-12 A conspicuous feature of SCD is chronic activation HAMNO of the coagulation system, often characterized by high levels of circulating D-dimer, thrombin-antithrombin (TAT) complexes, prothrombin fragment 1.2, increased tissue factor (TF) expression, and high TF-bearing microparticles.13,14 Sickle cellCinduced tissue damage is likely 1 driver of procoagulant activation, but sickle red blood cell (RBC) membrane alterations and phosphatidylserine (PS) exposure may further augment procoagulant function.15,16 Thrombocytosis and platelet activation are also well-recognized features of SCD.4,13,14,16-35 Thrombotic events including pulmonary embolism, deep vein thrombosis, and SCD-related stroke are common.17,36-40 SCD-associated pulmonary hypertension (PHT) is associated with endothelial cell activation (as measured by soluble vascular cell adhesion molecule-1 [sVCAM-1]), which would also support procoagulant activity.14,20,23,41 However, the precise contribution of hemostatic factors to SCD-induced pathobiologies and particularly progressive end-organ damage has not been thoroughly explored. A linkage between hemostatic system activation and inflammation is firmly established and this linkage was underscored in SCD by 2 recent studies in sickle mice.42,43 TF activity on endothelial cells was reported to support increased levels of interleukin-6 (IL-6) in SCD mice, and antibody blockade of TF activity suppressed circulating IL-6, sVCAM-1, and pulmonary neutrophil infiltration.42 Interestingly, rivaroxaban, a small-molecule Rabbit Polyclonal to Pim-1 (phospho-Tyr309) inhibitor of the prothrombin-activating protease, factor Xa (FXa) decreased IL-6, but not sVCAM-1; dabigatran, a small-molecule inhibitor of thrombin (factor IIa [FIIa]), was reported to not suppress either of these parameters. Thus, TF and FXa, but not FIIa, were linked to endothelial activation and/or inflammatory changes in SCD, and it was proposed that HAMNO FIIa-independent signaling mechanism(s) mediated inflammatory effects in mice with SCD.43 However, these interesting studies were short-term in design, and did not explore the influence of hemostatic factors around the wide spectrum of multiorgan pathologies that manifest over long time frames in SCD. Furthermore, human studies exploring the role of coagulation system activation using HAMNO antithrombotics in SCD patients have primarily focused either on reduction in acute sickle episodes and/or circulating markers of thrombin generation/inflammation as study end points (examined in Ataga and Important44). The overall results from human studies show that although low-intensity anticoagulation diminished circulating markers of thrombin generation, effects on acute painful episodes were mixed, with either absent, modest, or significant reduction depending on the study.44,45 The central role of FIIa as a hemostatic protease is underscored by the fact that it controls fibrin deposition and.