A combined immunostimulatory and immunoinhibitory short interference RNA reduces hypercoagulability in a rat model of acute promyelocytic leukaemia.
Acute promyelocytic leukaemia (APL) confers an increased risk of thrombosis and bleeding. Current treatments are insufficient to inhibit these complications. We recently showed that a combined immunoinhibitory and immunostimulatory short interference (si) RNA effectively inhibited leukaemic growth and metastasis in rats with APL. We now asked if the reported anti-leukaemic effects of siRNA treatment could be explained by inhibition of hypercoagulability. We measured markers of coagulation and fibrinolysis in plasma collected from APL rats with overt leukaemia using conventional assays. Coagulopathy developed in untreated leukaemic rats evidenced by increase in several haemostatic markers. Treatment of leukaemic rats with the siRNA reduced (p < 0.05) the concentration of thrombin-anti-thrombin complex (a marker of coagulation) by 40% compared with rats treated with an inactive, control siRNA. Substantial reductions (p < 0.05) were also obtained for two markers of fibrinolysis: D-dimer (72%) and plasminogen activator inhibitor type 1 (51%). The activity of tissue factor, the main initiator of coagulation, was not increased (p > 0.05) in untreated leukaemic rats compared with healthy rats, and did not change (p > 0.05) upon treatment with the siRNA. The bifunctional siRNA reduces the hypercoagulable state in APL in addition to its direct anti-leukaemic properties, supporting testing of this small molecule in human APL.
Iversen
Per Ole
PO
Department of Nutrition, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. p.o.iversen@medisin.uio.no
Sørensen
Dag Reidar
DR
Sioud
Mouldy
M
D000818:Animals; D000990:Antithrombin III; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000235:genetics; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation*; D004195:Disease Models, Animal; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008297:Male; D010447:Peptide Hydrolases / Q000097:blood; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000096:biosynthesis*; D051381:Rats; D011914:Rats, Inbred BN; D019851:Thrombophilia / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D013925:Thromboplastin / Q000378:metabolism; D014162:Transfection
D015415:Biomarkers; D005338:Fibrin Fibrinogen Degradation Products; D017395:Plasminogen Activator Inhibitor 1; D034741:RNA, Small Interfering; C046193:antithrombin III-protease complex; C036309:fibrin fragment D; D016753:Interleukin-10; D000990:Antithrombin III; D005340:Fibrinogen; D013925:Thromboplastin; D010447:Peptide Hydrolases