title: Safety and antithrombotic efficacy of moderate platelet count reduction by thrombopoietin inhibition in primates.
abstract: Most heart attacks and strokes are caused by blood clots (thrombi) that block the vasculature. Because disease-causing arterial thrombosis depends on blood platelets, platelet inhibitors such as aspirin and clopidogrel effectively decrease the risk of thrombosis; however, they also impair platelet-dependent hemostasis that staunches bleeding from wounds and can therefore produce excessive bleeding. Experimental studies show that a reduction in the number of platelets also inhibits thrombosis, but these treatments also interfere with platelet function. Because normal hemostasis requires that the platelet concentration remain within a physiological range in the circulation, we evaluated whether lowering the number of circulating platelets--but only to a value still within the normal range--by inhibiting platelet formation in the bone marrow inhibits acute thrombogenesis in baboons. We reduced the platelet count with an inhibitor against the megakaryocyte-promoting hormone thrombopoietin and then showed that experimental occlusive thrombogenesis on collagen-coated vascular grafts was reduced, without impairment of primary hemostasis. These results suggest that suppressing platelet production without interfering with the hemostatic function of platelets may offer a safe alternative to current therapies for prevention of stroke and heart attack triggered by blood clotting.
authors.affiliation: Department of Biomedical Engineering, Oregon Health & Science University School of Medicine, 3303 Southwest Bond Avenue, CH13B, Portland, OR 97239, USA.
authors.forename: Erik I
authors.initials: EI
authors.lastname: Tucker
authors.forename: Ulla M
authors.initials: UM
authors.lastname: Marzec
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Berny
authors.forename: Sawan
authors.initials: S
authors.lastname: Hurst
authors.forename: Stuart
authors.initials: S
authors.lastname: Bunting
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
authors.forename: András
authors.initials: A
authors.lastname: Gruber
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Hanson
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000009:adverse effects* / Q000494:pharmacology*; D001760:Bleeding Time; D001807:Blood Vessel Prosthesis; D006323:Heart Arrest / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D008297:Male; D010215:Papio; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects* / Q000494:pharmacology*; D010976:Platelet Count; D020521:Stroke / Q000209:etiology / Q000517:prevention & control; D013926:Thrombopoietin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000097:blood / Q000150:complications / Q000473:pathology / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D000991:Antithrombins; D010975:Platelet Aggregation Inhibitors; D013926:Thrombopoietin