Endogenous anticoagulation during extracorporeal perfusion: generation of a heparinlike inhibitor.
Studies were done to define the coagulation defect that develops in hemodynamically stable anesthetized dogs perfused on our arteriovenous extracorporeal system without added heparin. After 45 min, the dogs developed whole blood clotting times (WBCT) greater than 24 h. There was an associated decrease in ADP-induced platelet aggregation and a drop in factor V, VIII, and X levels of 75.8, 33.5, and 46.8%, respectively. Despite an increase in fibrinogen degradation products, there was no significant change in fibrinogen level or platelet count. An inhibitor of thrombin and factor Xa clotting of plasma appeared that was "heparinlike", because it stimulated the inactivation of factor Xa by antithrombin III (ATIII) but not by O-methyl isoureamodified ATIII. Thrombin inhibition by ATIII was also stimulated. The inhibitor was heat stable, adsorbed by BaSO4, and neutralized by protamine. Infusion of protamine sulfate into two perfused dogs neutralized the inhibitor and brought the WBCT from greater than 24 h to less than control. Six dogs developed inhibitor levels equivalent to 0.98 to 6.15 U/ml heparin. Five eviscerated dogs in which the hepatic artery was ligated developed peak plasma inhibitor levels of 3.2 +/- 1.0 U/ml. Thus, the endogenous heparinlike inhibitor is a major contributor to the anticoagulated state induced with our perfusion system and may have an extrahepatic origin.
D000818:Animals; D000990:Antithrombin III / Q000032:analysis; D001779:Blood Coagulation Factors / Q000032:analysis*; D004285:Dogs; D005112:Extracorporeal Circulation; D005170:Factor X / Q000037:antagonists & inhibitors; D006493:Heparin / Q000097:blood*; D010974:Platelet Aggregation / Q000187:drug effects; D011479:Protamines / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors; D014914:Whole Blood Coagulation Time
D001779:Blood Coagulation Factors; D011479:Protamines; D000990:Antithrombin III; D005170:Factor X; D006493:Heparin; D013917:Thrombin