Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice.
Sickle cell disease (SCD) results in vascular occlusions, chronic hemolytic anemia, and cumulative organ damage. A conspicuous feature of SCD is chronic inflammation and coagulation system activation. Thrombin (factor IIa [FIIa]) is both a central protease in hemostasis and a key modifier of inflammatory processes. To explore the hypothesis that reduced prothrombin (factor II [FII]) levels in SCD will limit vaso-occlusion, vasculopathy, and inflammation, we used 2 strategies to suppress FII in SCD mice. Weekly administration of FII antisense oligonucleotide "gapmer" to Berkeley SCD mice to selectively reduce circulating FII levels to ∼10% of normal for 15 weeks significantly diminished early mortality. More comprehensive, long-term comparative studies were done using mice with genetic diminution of circulating FII. Here, cohorts of FII(lox/-) mice (constitutively carrying ∼10% normal FII) and FII(WT) mice were tracked in parallel for a 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 times, and in the absence of hemorrhagic complications. Taken together, these data establish that prothrombin is a powerful modifier of SCD-induced end-organ damage, and present a novel therapeutic target to ameliorate SCD pathologies.
Division of Experimental Hematology and Cancer Biology.
Paritha I
PI
Arumugam
Division of Hematology, Cancer and Blood Diseases Institute, and.
Eric S
http://orcid.org/0000-0002-1544-9068
ES
Mullins
Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;
Shiva Kumar
SK
Shanmukhappa
Department of Antisense Drug Discovery, Isis Pharmaceuticals, Carlsbad, CA; and.
Brett P
BP
Monia
Division of Experimental Hematology and Cancer Biology.
Anastacia
A
Loberg
Division of Hematology, Cancer and Blood Diseases Institute, and.
Maureen A
MA
Shaw
Division of Experimental Hematology and Cancer Biology.
Tilat
T
Rizvi
Imaging Research Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Janaka
J
Wansapura
Division of Experimental Hematology and Cancer Biology.
Jay L
JL
Degen
Division of Experimental Hematology and Cancer Biology, Division of Hematology, Cancer and Blood Diseases Institute, and.
Punam
P
Malik
D000755:Anemia, Sickle Cell / Q000150:complications* / Q000401:mortality / Q000503:physiopathology; D000818:Animals; D001777:Blood Coagulation; D002478:Cells, Cultured; D015316:Genetic Therapy; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000517:prevention & control*; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020320:Oligoribonucleotides, Antisense / Q000494:pharmacology; D011516:Prothrombin / Q000037:antagonists & inhibitors / Q000502:physiology*; D015996:Survival Rate; D013917:Thrombin / Q000378:metabolism; D014652:Vascular Diseases / Q000209:etiology / Q000517:prevention & control*
D020320:Oligoribonucleotides, Antisense; D011516:Prothrombin; C025337:Factor IIa; D013917:Thrombin