title: Prophylactic heparinization is ineffective in a primate model of hemolytic uremic syndrome.
abstract: The presence of abundant fibrin within the glomerular capillaries of patients with Shiga toxin (Stx)-mediated (post-diarrheal) hemolytic uremic syndrome (HUS) has suggested that heparin anticoagulation might be useful in the treatment of this disease. Although controlled studies have failed to show benefit, this lack of therapeutic efficacy could be due to administration of heparin after the thrombotic microangiopathy (TMA) had developed. If benefit could be demonstrated by giving heparin prior to the onset of the HUS, one could consider prophylactic heparinization of those at high risk of progressing from Stx colitis to HUS. We have developed a baboon model of Stx-mediated HUS, and have used this model to study the effect of prophylactic heparinization on the clinical expression and glomerular TMA of Stx-mediated HUS. A single intravenous infusion of Stx-1 at a dose that uniformly produces clinical and nephropathologic features of HUS was given with and without the prior administration of regular and low molecular weight heparin. Therapeutic levels of anticoagulation were achieved, but this did not reduce the clinical severity or lessen the TMA. Heparin anticoagulation may be ineffective because the rate of coagulation that occurs on the surfaces of dysfunctional endothelial surfaces exceeds the capacity of heparin/antithrombin-III inhibitor complexes to bind and block the factor Xa and thrombin that are generated on these surfaces. Our observations fail to support the use of heparin in preventing Stx-mediated HUS.
authors.affiliation: Pediatric Nephrology and Hypertension, Department of Pediatrics, University of Utah School of Medicine, 30 North 1900 East, #2B422, Salt Lake City, UT 84132-2204, USA. dick.siegler@hsc.utah.edu
authors.forename: Richard L
authors.initials: RL
authors.lastname: Siegler
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Pysher
authors.forename: Vernon L
authors.initials: VL
authors.lastname: Tesh
authors.forename: Nathaniel D
authors.initials: ND
authors.lastname: Denkers
authors.forename: Fletcher B
authors.initials: FB
authors.lastname: Taylor
mesh_terms: D000743:Anemia, Hemolytic / Q000139:chemically induced / Q000473:pathology; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006463:Hemolytic-Uremic Syndrome / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D006493:Heparin / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D007677:Kidney Function Tests; D008856:Microscopy, Fluorescence; D010215:Papio; D010314:Partial Thromboplastin Time; D010976:Platelet Count; D022621:Shiga Toxin; D013921:Thrombocytopenia / Q000139:chemically induced / Q000473:pathology
chemical_list: D000925:Anticoagulants; D022621:Shiga Toxin; D006493:Heparin