Comparison of High Purity Factor IX Concentrates and a Prothrombin Complex Concentrate in a Canine Model of Thrombogenicity

Abstract

SummaryA non-stasis canine model of thrombogenicity has been used to evaluate batches of high purity factor IX concentrates from 4 manufacturers and a conventional prothrombin complex concentrate (PCC). Platelets, activated partial thromboplastin time (APTT), fibrinogen, fibrin(ogen) degradation products and fibrinopeptide A (FPA) were monitored before and after infusion of concentrate. Changes in FPA were found to be the most sensitive and reproducible indicator of thrombogenicity after infusion of batches of the PCC at doses of between 60 and 180 IU/kg, with a dose related delayed increase in FPA occurring. Total FPA generated after 100-120 IU/kg of 3 batches of PCC over the 3 h time course was 9-12 times that generated after albumin infusion. In contrast the amounts of FPA generated after 200 IU/kg of the 4 high purity factor IX products were in all cases similar to albumin infusion. It was noted that some batches of high purity concentrates had short NAPTTs indicating that current in vitro tests for potential thrombogenicity may be misleading in predicting the effects of these concentrates in vivo.

In vivo Models of Thrombogenic Potential: Usefulness and Limitations

“…Subsequently, HP- FIX concentrates have been produced in which the levels of factors II, VII, and X are extremely low compared with the factor IX level. We have published other results assessing a number of these products in our models and comparing them with typical PCCs [7,20]. Figure 2 shows the concentrations of canine FPA after infusions of albumin, thrombin, and PCC, indicating the delayed effect of PCC compared with thrombin, and also demonstrates that an activation of coagulation caused by the PCC infusion is not purely due to endogenous throm bin in the vial.…”

Factor IX Concentrates for Clinical Use

“…The Factor IX concentrate prepared by Bio-Transfusion (Lille, France) has some heparin added 54 but less than 1% contamination by the other three vitamin K-dependent clotting factors. 55 The Netherlands Red Cross concentrate 56 has no detectable Factor X or prothrombin following elution from heparin agarose.…”

“…69 A direct comparison of the thrombogenicity of different purified preparations comes from infusion of high doses into a canine, nonstasis model (Table 3). 55 Elevations of FPA following infusion of 120 U/kg over 30 minutes of a crude concentrate made in Great Britain were marked by the middle of the infusion, peaked 30 minutes following the end of the infusion and remained elevated 1½ hours after the infusion. Although there was over a threefold variability in baseline FPA levels, several purified Factor IX concentrates (Bio-Transfusion, 55 where values were averaged from two or three infusions of each product.…”

“…55 Elevations of FPA following infusion of 120 U/kg over 30 minutes of a crude concentrate made in Great Britain were marked by the middle of the infusion, peaked 30 minutes following the end of the infusion and remained elevated 1½ hours after the infusion. Although there was over a threefold variability in baseline FPA levels, several purified Factor IX concentrates (Bio-Transfusion, 55 where values were averaged from two or three infusions of each product. For the crude concentration (prepared in the United Kingdom as a DEAE-cellulose eluate) and the Bio-Transfusion concentrate, two additional animals each gave comparable results and are not included.…”

Factor VII and Activated- Factor-VII Content of Prothrombin Complex Concentrates

“…Thrombogenicity has mainly been attributed to activated clotting factors [9][10][11][12][13] or procoagulant phospholipid 156 Vox Sang 1997;73:155-161 Hellstern/Beeck/Fellhauer/Fischer/ Faller-Stöckl [14]. Three-factor PCC are now gradually being replaced by high-purity FIX concentrates, which are obviously less thrombogenic [15][16][17][18][19].…”