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[Thrombogenicity of prothrombin complex concentrates].

PCC's were isolated either by adsorption to DEAE-Sephadex A-50 (particle size 40-120 microns; Pharmacia Uppsala) or by adsorption to Molselect DEAE-50 (particle size 100-320 microns; Reanal Budapest) from human citrated plasma after separation of factor VIII by cryoprecipitation. The two products obtained (without heparin) were both compared by in vitro (NAPTT, TGt50) and in vivo (venous stasis) model in rats acc. to WESSLER) tests. The agent prepared by adsorption to DEAE-Sephadex A-50 showed a significantly higher thrombogenicity than that prepared by Molselect DEAE-50. ED50 values for thrombus formation to amounted 15 Factor IX U/kg for the first product and to 210 factor IX U/kg for the second.

Blood Coagulation↗

Controlled clinical trials with prothrombin complex concentrates.

Since the introduction of PCC for treatment of bleeding episodes in hemophiliacs with inhibitors in 1972, many anecdotal reports and uncontrolled observations have been published, often with conflicting reports of efficacy. To date, three controlled double blind studies have been completed in which PCC have been evaluated. In each of the three studies acute hemarthrosis has been the only (Lusher et al 1980; Lusher et al 1983) or the predominant (Sjamsoedin 1981) type of bleeding evaluated. While acute joint bleeding lends itself well to clinical trial, there are recognized problems in evaluating response to treatment. Despite these limitations, it is noteworthy that non-activated PCC were found to be effective in approximately 50% of episodes in all three trials. Future trials are now being planned in an attempt to determine the role of activated PCC in the management of bleeding episodes in hemophiliacs with inhibitors. In the design of these trials, possible modifications to be considered are the exclusion (or separate randomization) of chronically disabled or "target" joints, more than one dose of unknown product, and longer periods of assessment.

Autoantibodies↗

Treatment of inhibitor patients with activated prothrombin complex concentrates.

Anti-inhibitor protease complex products have demonstrated their efficacy in controlling bleeding in non-hemophilic and hemophilic patients with inhibitors to Factor VIII and IX. Treatment programs have been identified for 1) patients who develop spontaneous, mild to moderate bleeding episodes - low dose, 30 u/Kg at 8 hour intervals; 2) surgical candidates or patients with severe bleeding and high inhibitor levels - high dose, 75-100 u/Kg at 4 to 8 hour intervals; and 3) surgical candidates with low inhibitor levels (less than 40 B.U.) - pheresis, followed by Factor VIII for 6 days, and then activated concentrates. Attempts to identify the anti-inhibitor principle in the product has led us to the conclusion that Factor X is necessary for this activity.

Adolescent↗

Thrombin generation is not increased in the blood of hemophilia B patients after the infusion of a purified factor IX concentrate.

Prothrombin complex concentrates (PCC), licensed for the treatment of hemophilia B, are known to carry a significant risk of thromboembolic complications. Although the reasons for thrombogenicity are not completely understood, several manufacturers have developed purified factor IX concentrates that contain negligible amounts of the other vitamin K-dependent factors. To evaluate whether or not the infusion of such a factor IX concentrate is followed by lesser activation of the hemostatic system than by the infusion of a PCC, we performed a series of coagulation assays on 11 hemophilia B patients before and after the administration of these two types of concentrate using a randomized cross-over design. The levels of prothrombin fragment F1 + 2, a sensitive measure of the in vivo cleavage of prothrombin by factor Xa, was significantly increased in plasma after PCC, but not after factor IX concentrate. Plasma fibrinopeptide A, a sensitive index of the enzymatic activity of thrombin on fibrinogen, also increased significantly after PCC but not after factor IX concentrate. The fragment B beta 15-42, a sensitive index of the enzymatic action of plasmin on fibrin II, did not change after either concentrate. There were also no differences in less sensitive coagulation measurements, such as plasma fibrinogen, antithrombin III, and fibrin monomers, nor in indices of platelet activation, such as beta-thromboglobulin and platelet factor 4. These findings show that the infusion of a purified factor IX concentrate can result in substantially less activation of the coagulation cascade than may be seen with PCC.

Adolescent↗

High sensitivity detection of activated factor IX: application to the analysis of different therapeutical factor IX concentrates and prothrombin complexes.

A very sensitive and highly reliable test system for the detection of activated coagulation factor IX (FIXa) has been established. This assay system is based on the cleavage of a fluorogenic substrate by activated factor X (FXa) which is generated by FIXa. This assay can be used to process a large number of samples at a time and, being based on the convenient microtiter plate format, can easily be adapted to automated processing for routine screening of large sample numbers. With this assay at hand we determined the FIXa content of different commercially available therapeutic FIX sources, such as high purity FIX (HPFIX) and prothrombin complex concentrates (PCC). Here we demonstrate that PCC from several suppliers do not contain significantly higher levels of FIXa as compared to HPFIX from the same supplier. In fact, there is a tendency for HPFIX to contain more FIXa than PCC. Moreover, HPFIX from certain manufacturers who do not produce PCC are characterized by an exceptionally high content of FIXa. Therefore, the higher thrombogenic potential of PCC which is well documented clinically cannot be explained solely -- if at all -- by an increased content of FIXa. Rather, it will be necessary to identify other components responsible for this phenomenon.

Biological Products↗