Using the dog as an animal model, we developed an experimental preparation to compare hemodynamic and hematologic toxicity of
anticoagulation reversal. Currently,
protamine sulfate reversal of standard
unfractionated heparin and
low-molecular-weight heparin (
LMWH) anticoagulation causes adverse side effects, including decreased systemic mean arterial pressure (MAP), decreased cardiac output (CO), decreased oxygen consumption (VO2), and
thrombocytopenia. In addition, standard
protamine is only marginally effective at reversing the
factor Xa inhibition induced by LMWHs. We have produced
protamine-like variant
peptides to decrease the adverse responses attributed to standard
protamine. The hemodynamic, hematologic, and coagulation effects of standard
protamine and the
protamine variant (+18RGD) were assessed after reversal of
LMWH anticoagulation in anesthetized dogs. Flow probes and
vascular catheters were surgically implanted for measurement of hemodynamic parameters including MAP, CO, VO2, and heart rate (HR). Hematologic studies (platelet and white blood cell counts) and coagulation studies (activated clotting time [ACT], activated partial thromboplastin time [aPTT],
thrombin clotting time [TCT], antifactor Xa and antifactor IIa values) also were performed. The
protamine variant +18RGD was less toxic, induced less
thrombocytopenia, and was more effective in
anticoagulation reversal than was standard
protamine sulfate. Results of this study indicate that the dog may be a useful model for investigating important hemodynamic, hematologic, and coagulation parameters during reversal of
LMWH anticoagulation by use of synthetic
protamine variants.