title: Elevated prothrombin promotes venous, but not arterial, thrombosis in mice.
abstract: OBJECTIVE
  Individuals with elevated prothrombin, including those with the prothrombin G20210A mutation, have increased risk of venous thrombosis. Although these individuals do not have increased circulating prothrombotic biomarkers, their plasma demonstrates increased tissue factor-dependent thrombin generation in vitro. The objectives of this study were to determine the pathological role of elevated prothrombin in venous and arterial thrombosis in vivo, and distinguish thrombogenic mechanisms in these vessels.
  
  
  RESULTS
  Prothrombin was infused into mice to raise circulating levels. Venous thrombosis was induced by electrolytic stimulus to the femoral vein or inferior vena cava ligation. Arterial thrombosis was induced by electrolytic stimulus or ferric chloride application to the carotid artery. Mice infused with prothrombin demonstrated increased tissue factor-triggered thrombin generation measured ex vivo, but did not have increased circulating prothrombotic biomarkers in the absence of vessel injury. After venous injury, elevated prothrombin increased thrombin generation and the fibrin accumulation rate and total amount of fibrin ≈ 3-fold, producing extended thrombi with increased mass. However, elevated prothrombin did not accelerate platelet accumulation, increase the fibrin accumulation rate, or shorten the vessel occlusion time after arterial injury.
  
  
  CONCLUSIONS
  These findings reconcile previously discordant findings on thrombin generation in hyperprothrombinemic individuals measured ex vivo and in vitro, and show elevated prothrombin promotes venous, but not arterial, thrombosis in vivo.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, NC 27599-7525, USA.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Aleman
authors.forename: Bethany L
authors.initials: BL
authors.lastname: Walton
authors.forename: James R
authors.initials: JR
authors.lastname: Byrnes
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Wang
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Heisler
authors.forename: Kellie R
authors.initials: KR
authors.lastname: Machlus
authors.forename: Brian C
authors.initials: BC
authors.lastname: Cooley
authors.forename: Alisa S
authors.initials: AS
authors.lastname: Wolberg
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology*; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D002339:Carotid Arteries / Q000502:physiology; D002712:Chlorides / Q000494:pharmacology; D004195:Disease Models, Animal; D005268:Femoral Vein / Q000502:physiology; D005290:Ferric Compounds / Q000494:pharmacology; D005337:Fibrin / Q000378:metabolism; D006801:Humans; D051379:Mice; D009676:Noxae / Q000494:pharmacology; D011516:Prothrombin / Q000378:metabolism* / Q000494:pharmacology; D012307:Risk Factors; D019851:Thrombophilia / Q000139:chemically induced / Q000453:epidemiology / Q000378:metabolism*; D014682:Vena Cava, Inferior / Q000502:physiology; D020246:Venous Thrombosis / Q000139:chemically induced / Q000453:epidemiology / Q000378:metabolism*
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D009676:Noxae; D011516:Prothrombin; D005337:Fibrin; C024555:ferric chloride
keywords: arterial; fibrin; hyperprothrombinemia; platelet; prothrombin; thrombosis; venous