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A new mouse model mimicking thrombotic thrombocytopenic purpura: correction of symptoms by recombinant human ADAMTS13.

Abstract
Deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), a VWF-cleaving protease, is the key factor in the pathogenesis of thrombotic thrombocytopenic purpura (TTP), a life-threatening thrombotic microangiopathy. It is well established that ADAMTS13 deficiency results in elevated plasma levels of ultra-large VWF multimers (ULVWF), which are prone to induce platelet aggregation; however, the actual trigger of TTP development remains uncertain. Here we describe a new animal model in which some TTP-like symptoms can be triggered in ADAMTS13 knockout mice by challenge with 2000 units/kg body weight of recombinant human VWF containing ULVWF multimers. Animals rapidly showed clinical symptoms and developed severe thrombocytopenia. Schistocytosis, a decrease in hematocrit, and elevated serum lactate dehydrogenase levels were observed. The heart was identified as the most sensitive target organ with rapid onset of extensive platelet aggregation in the ventricles and myocardial necrosis. Prophylactic administration of 200 units/kg recombinant human ADAMTS13 protected ADAMTS13 knockout mice from developing TTP. Therapeutic administration of 320 units/kg rhADAMTS13 reduced the incidence and severity of TTP findings in a treatment interval-dependent manner. We therefore consider this newly established mouse model of thrombotic microangiopathy highly predictive for investigating the efficacy of new treatments for TTP.
AuthorsAlexandra Schiviz, Kuno Wuersch, Christina Piskernik, Barbara Dietrich, Werner Hoellriegl, Hanspeter Rottensteiner, Friedrich Scheiflinger, Hans Peter Schwarz, Eva-Maria Muchitsch
JournalBlood (Blood) Vol. 119 Issue 25 Pg. 6128-35 (Jun 21 2012) ISSN: 1528-0020 [Electronic] United States
PMID22529289 (Publication Type: Evaluation Study, Journal Article)
Chemical References
  • Recombinant Proteins
  • ADAM Proteins
  • ADAMTS13 protein, mouse
  • Metalloendopeptidases
  • ADAMTS13 Protein
  • ADAMTS13 protein, human
Topics
  • ADAM Proteins (administration & dosage, therapeutic use)
  • ADAMTS13 Protein
  • Animals
  • Body Weight (drug effects)
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Hematocrit
  • Humans
  • Male
  • Metalloendopeptidases (genetics)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Platelet Count
  • Purpura, Thrombotic Thrombocytopenic (blood, drug therapy, genetics, pathology)
  • Recombinant Proteins (administration & dosage, therapeutic use)
  • Treatment Outcome

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