Heparin and Low Molecular Weight Heparin Prolong Prothrombin Times in Patients on Warfarin Treatment

Abstract

Most commercially available prothrombin (PT) as says are stated to be insensitive to heparin in therapeutic doses. These conclusions are, however, based on studies using normal plasma samples. The aim of the present study was to study the effect of unfractioned heparin, three low molecular heparins, and a heparinoid on six prothrombin assays using plasma samples from patients on warfarin. Plasma samples from 30 patients on warfarin were heparinized in vitro with unfrac tioned heparin, three different low molecular weight heparins (Fragmin® [Pharmacia/Upjohn Inc., Delaware, U.S.A.], Klex ane® [Rhone Poulenc Rorer, Halte, Denmark], and Logiparin- Dinnohep®, [Leo Biological Products, Ballerup, Denmark]) and the heparinoid Org 10172 (Orgaran [Organon, Oss, The Netherlands]) to obtain 0.50-1.50 U/ml plasma. The PT time was then determined with four PT reagents stated to be insen sitive to heparin (Innovin [Dade, Miami, Florida, U.S.A.], Ny coplastin [Nycomed Pharma, Oslo, Norway], Nycotest PT [Ny comed Pharma], and Stago Prothrombin Complex Assay [SPA 50, Diagnostica Stago, Franconville, France]) and two reagents stated to be sensitive to heparin (Manchester Reagent [Manchester Comparative Reagent, Ltd., Stockport, Great Brit ain] and Thrombotest [Nycomed]). All PT assays except Inno vin were sensitive to the heparins. With a heparin concentration of 0.5 U/ml plasma, the increase in INR ranged from 18-55% with Thrombotest and 0-44% with the other assays. The in crease in INR values by 1.5 U/ml plasma differed among the heparins used; Manchester Reagent 6-297%, Thrombotest 43- 247%, Nycoplastin 48-81%, SPA 50 20-74%, Nycotest PT 17-36%, and Innovin 0-5%. Orgaran did not prolong the clot ting time with the Manchester Reagent. With the other five PT assays, Innohep (Leo Biological Products, Ballerup, Denmark) and Orgaran gave the largest increase in INR value. Fragmin, Klexane, and unfractioned heparin caused a similar low in crease in INR. A 3-h delay in testing prolonged the prothrom bin times with the simple PT assays (Manchester Reagent and Nycoplastin). The other assays were little affected. Concomi tant heparin therapy prolongs the PT clotting times with all reagents, except Innovin, to the extent that with three of the assays examined this may lead to underdosing of warfarin.