title: Comparison of the effect of dabigatran and dalteparin on thrombus stability in a murine model of venous thromboembolism.
abstract: ESSENTIALS: Does thrombus stability alter the presentation of venous thromboembolism and do anticoagulants alter this? In a murine model, we imaged a femoral vein thrombus and quantified emboli in the pulmonary arteries. Dabigatran decreases thrombus stability via factor XIII increasing embolization and pulmonary emboli. This cautions against the unapproved use of dabigatran for acute initial treatment of deep vein thrombosis.
  
  
  BACKGROUND
  Venous thromboembolism (VTE) is a collective term for deep vein thrombosis (DVT) and pulmonary embolism (PE). Thrombus instability possibly contributes to progression of DVT to PE, and direct thrombin inhibitors (DTIs) may alter this.
  
  
  OBJECTIVE
  To develop a model to assess thrombus stability and its link to PE burden, and identify whether DTIs, in contrast to low-molecular-weight heparin (LMWH), alter this correlation.
  
  
  METHODS
  Twelve minutes after ferric chloride-induced thrombus formation in the femoral vein of female mice, saline, dalteparin (LMWH) or dabigatran (DTI) was administered. Thrombus size and embolic events breaking off from the thrombus were quantified before treatment and at 10-min intervals after treatment for 2 h using intravital videomicroscopy. Lungs were stained for the presence of PE.
  
  
  RESULTS
  Thrombus size was similar over time and between treatment groups. Total and large embolic events and pulmonary emboli were highest after treatment with dabigatran. Variations in amounts of pulmonary embolic events were not attributed to variations in thrombus size. Large embolic events correlated with the number of emboli per lung slice independent of treatment. Embolization in factor XIII deficient (FXIII(-/-) ) saline-treated mice was greater than that in wild-type (WT) saline-treated mice, but was similar to WT dabigatran-treated mice.
  
  
  CONCLUSIONS
  We have developed a mouse model of VTE that can quantify emboli and correlate this with PE burden. Consistent with clinical data, dabigatran, a DTI, acutely decreases thrombus stability and increases PE burden compared with LMWH or saline, which is a FXIII-dependent effect.
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Canada.|Department of Medical Sciences, McMaster University, Hamilton, Canada.
authors.forename: S A
authors.initials: SA
authors.lastname: Shaya
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Canada.|Department of Medical Sciences, McMaster University, Hamilton, Canada.
authors.forename: L J
authors.initials: LJ
authors.lastname: Saldanha
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Canada.|Department of Medical Sciences, McMaster University, Hamilton, Canada.
authors.forename: N
authors.initials: N
authors.lastname: Vaezzadeh
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Canada.|Department of Medical Sciences, McMaster University, Hamilton, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Ni
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Canada.|Department of Medical Sciences, McMaster University, Hamilton, Canada.|Department of Medicine, McMaster University, Hamilton, Canada.
authors.forename: P L
authors.initials: PL
authors.lastname: Gross
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage; D000991:Antithrombins / Q000627:therapeutic use; D000069604:Dabigatran / Q000008:administration & dosage*; D017985:Dalteparin / Q000008:administration & dosage*; D004195:Disease Models, Animal; D018450:Disease Progression; D004621:Embolization, Therapeutic; D005260:Female; D005268:Femoral Vein / Q000473:pathology; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage; D008168:Lung / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018715:Microscopy, Video; D011655:Pulmonary Embolism / Q000188:drug therapy; D013927:Thrombosis / Q000188:drug therapy*; D054556:Venous Thromboembolism / Q000188:drug therapy*; D020246:Venous Thrombosis / Q000188:drug therapy
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D000069604:Dabigatran; D017985:Dalteparin
keywords: animal model; dabigatran; dalteparin; factor XIII; pulmonary embolism; venous thrombosis