UNASSIGNED: @entity3458 ( @entity3458 ) results in @entity432 , @entity5714 , and cumulative organ damage. A conspicuous feature of @entity3458 is @entity32 and coagulation system activation. Thrombin (FIIa) is both a central protease in hemostasis and a key modifier of inflammatory processes. To explore the hypothesis that reduced prothrombin ( @entity10993 ) levels in @entity3458 will limit vaso-occlusion, @entity455 , and @entity32 , we employed two strategies to suppress @entity10993 in @entity19 with @entity3458 . Weekly administration of a @entity10993 antisense oligonucleotide "gapmer" to Berkeley @entity3458 @entity19 to selectively reduce circulating @entity10993 levels to ~10% of normal for 15 weeks significantly diminished early mortality. More comprehensive, long-term comparative studies were done employing @entity19 with genetic diminution of circulating @entity10993 . Here, cohorts of @entity10993 (lox/-) @entity19 (constitutively carrying ~10% normal @entity10993 ) and @entity10993 ( @entity7097 ) @entity19 were tracked in parallel for a year following the imposition of @entity3458 via hematopoietic stem cell transplantation from Berkeley @entity3458 donors. This genetically-imposed chronic suppression of @entity10993 levels resulted in an impressive @entity32 (reduction in leukocytosis, @entity1148 and circulating @entity777 levels), reduced endothelial cell dysfunction (reduced endothelial activation and circulating sVCAM), and a significant improvement in @entity3458 -associated end-organ damage ( @entity8 , @entity120 , @entity55 , liver function, inflammatory infiltration and micro- @entity1188 ). Notably, all of these benefits were achieved with relatively modest 1.25-fold increase in prothrombin times, and in the absence of @entity548 . Taken together, these data establish that prothrombin is a powerful modifier of @entity3458 -induced end-organ damage, and presents a novel therapeutic target to ameliorate @entity3458 pathologies.

Genetic diminution of circulating prothrombin ameliorates multi-organ pathologies in sickle cell disease XXXX .

@entity32 :: ('MESH:D007249', 'Disease') :: ['chronic inflammation', 'inflammation', 'reduction in inflammation'] @entity8 :: ('MESH:D007674', 'Disease') :: ['nephropathy'] @entity455 :: ('MESH:D014652', 'Disease') :: ['vasculopathy'] @entity1148 :: ('MESH:D013922', 'Disease') :: ['thrombocytosis'] @entity548 :: ('MESH:D006470', 'Disease') :: ['hemorrhagic complications'] @entity55 :: ('MESH:D011014', 'Disease') :: ['pulmonary inflammation'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity7097 :: ('MESH:C536751', 'Disease') :: ['WT'] @entity3458 :: ('MESH:D000755', 'Disease') :: ['SCD', 'Sickle cell disease'] @entity120 :: ('MESH:D006976', 'Disease') :: ['pulmonary hypertension'] @entity777 :: ('16193(Tax:10090)', 'Gene') :: ['IL-6'] @entity1188 :: ('MESH:D007238', 'Disease') :: ['infarctions'] @entity5714 :: ('MESH:D000743', 'Disease') :: ['chronic hemolytic anemia'] @entity10993 :: ('14061(Tax:10090)', 'Gene') :: ['FII'] @entity432 :: ('MESH:D001157', 'Disease') :: ['vascular occlusions']
@entity19 :: (10090,Species) :: ['mice']
