Summary
Microvascular thrombosis is a major cause of organ damage in Shiga toxin-mediated
hemolytic uremic syndrome (Stx-HUS). In vitro and clinical studies implicate thrombin-mediated mechanisms in the pathogenesis of
Stx microvascular thrombosis. In a greyhound model, administration of 0.03μg/kg to
0.05μg/kg Stx1 or Stx2 causes severe bloody diarrhea and HUS with microvascular thrombosis
requiring humane euthanasia within 65 hours. Using a greyhound model of Stx-HUS we
analyzed early hemostatic changes, and tested the hypothesis that thrombin blockade
with lepirudin would prevent lethal Stx effects. Two Stx1-exposed greyhounds were
analyzed for hemostatic changes prior to onset of clinical manifestations. Serial
hemostasis studies after Stx1 challenge revealed trends of increased aPTT, fibrinogen
levels, and prothrombin fragment 1+2, and appearance of abnormally large von Willebrand
factor multimers. Three greyhounds were anticoagulated with lepirudin to maintain
activated partial thromboplastin times (aPTT) >2.5-fold normal, followed by administration
of Stx2 and observation of clinical responses. Among the 3 lepirudin-treated, Stx2-challenged
greyhounds, one developed severe illness requiring euthanasia. Remarkably, 2 of the
3 greyhounds developed only hypersalivation and restlessness that resolved (P <.03
compared to 14 historical controls). These two greyhounds were clinically, hematologically
and biochemically normal 74 hours after Stx administration, well beyond the time of
euthanasia of any previous greyhound. This study suggests that greyhounds exposed
to Stx develop procoagulant changes similar to humans, and that thrombin may be a
critical factor in the pathogenesis and treatment of Stx-HUS.
Keywords
Shiga toxin - lepirudin - thrombotic microangiopathy - procoagulant
