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Well documented thrombotic side effects of II, VII, IX and X concentrates are thought to be due to spontaneous partial activation of one or more coagulation factors. Using the unactivated PTT method of Kingdon and the thrombin time as global assays of activation, we have confirmed this concept. It has been suggested that heparin should be added to the concentrate, but preparations vary in antithrombin content and activated factor. The amount of heparin for each preparation would have to be titrated in order to neutralize the activated factors without anticoagulating the patient. We sought to extend the range of added heparin without producing an anticoagulant effect, by adding heparin to the concentrates prior to use of the PEG fractionation method to remove the hepatitis antigen. Thus, heparin-activated antithrombin III can inhibit activated clotting factors while residual free heparin is removed by PEG fractionation. When 1 unit of heparin per mg of protein in the concentrate was added prior to PEG treatment, the final products from more than 80 runs on 15 batches (3 major manufacturers) were almost invariably neutral; neither anticoagulated nor activated. The thrombin clotting time, when measured, was 6-24 hours. The average yield with use of the PEG fractionation method was 85%; depending on the initial purity of the concentrate, the final product had an additional purification of 1.0-2.5 X that of the starting material.(Supported in part by USPHS Grant HL 15596 and HRC (N.Y.) 1-681.)