Prevention of heparin-resistant thrombotic occlusion of hollow-fiber hemodialyzers by synthetic antithrombin.
Because heparin anticoagulation during hemodialysis with hollow-fiber devices is associated with progressive loss of volume of fiber bundles subsequent to thrombotic occlusion, we examined the antithrombotic and antihemostatic effects of the irreversible synthetic thrombin inhibitor D-phenylalanyl-L-prolyl-L-arginyl-chloromethylketone (FPRCH2Cl) during repeated exposure of cupramonium cellulose hollow-fiber hemodialyzers in an extracorporeal blood circuit in baboons. By contrast with full anticoagulating doses of heparin, FPRCH2Cl (100 nmol/kg/min) decreased both the loss of fiber bundle volume (19.1% +/- 7.0% vs 6.4% +/- 3.6% p less than 0.01) and deposition of 111In-labeled platelets within the dialyzer (15.7 +/- 5.9 x 10(9) vs 3.2 +/- 1.2 x 10(9) platelets; p less than 0.01). Additionally, blood markers of thrombus formation in vivo (i.e., plasma beta-thromboglobulin, platelet factor 4, and fibrinopeptide A) remained at low levels throughout infusion of FPRCH2Cl, whereas levels were elevated during heparin therapy (p less than 0.01 in each case). FPRCH2Cl, but not heparin, prolonged bleeding times (p less than 0.001) without affecting the capacity of platelets to aggregate in response to the presence of either collagen or adenosine diphosphate ex vivo. Complement activation by the dialyzer was not affected by FPRCH2Cl. We conclude that the progressive loss of dialyzer hollow fibers is a platelet-dependent, thrombin-mediated process that, although resistant to heparin, is interrupted by the synthetic antithrombin FPRCH2Cl.
Kelly
A B
AB
Department of Basic and Clinical Research, Research Institute of Scripps Clinic, La Jolla, California.
Hanson
S R
SR
Henderson
L W
LW
Harker
L A
LA
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D000991:Antithrombins / Q000138:chemical synthesis / Q000494:pharmacology*; D001772:Blood Cell Count / Q000187:drug effects; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects; D003165:Complement System Proteins / Q000032:analysis; D004351:Drug Resistance; D004868:Equipment Failure; D006493:Heparin / Q000494:pharmacology*; D008297:Male; D010215:Papio; D006435:Renal Dialysis / Q000295:instrumentation
D000590:Amino Acid Chloromethyl Ketones; D000991:Antithrombins; D006493:Heparin; D003165:Complement System Proteins; C040308:phenylalanyl-prolyl-arginine-chloromethyl ketone