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Thromb Haemost 1996; 76(01): 023-028
DOI: 10.1055/s-0038-1650516
Original Article
Schattauer GmbH Stuttgart

High Purity Factor IX and Prothrombin Complex Concentrate (PCC): Pharmacokinetics and Evidence that Factor IXa Is the Thrombogenic Trigger in PCC

H Philippou
1   The Dept. of Haematology, Charing Cross and Westminster Medical School, London
,
A Adami
1   The Dept. of Haematology, Charing Cross and Westminster Medical School, London
,
D A Lane
1   The Dept. of Haematology, Charing Cross and Westminster Medical School, London
,
I R MacGregor
2   The National Science Laboratory, Scottish National Blood Transfusion Service, Edinburgh
,
E G D Tuddenam
3   The MRC Clinical Sciences Centre, Royal Postgraduate Medical School, London
,
G D O Lowe
4   The Haemostasis and Thrombosis Unit, University Dept. of Medicine, Royal Infirmary, Glasgow, London
,
A Rumley
4   The Haemostasis and Thrombosis Unit, University Dept. of Medicine, Royal Infirmary, Glasgow, London
,
C A Ludlam
5   The Dept. of Haematology, Royal Infirmary, Edinburgh, United Kingdom
› Author Affiliations
Further Information

Publication History

Received: 18 December 1995

Accepted after resubmission22 March 1996

Publication Date:
10 July 2018 (online)

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Summary

Recent studies using assays for surrogate markers of thrombogenic-ity in man have demonstrated that activation of the coagulation system occurs following infusion of clinical doses of prothrombin complex concentrates (PCC) but not after the same doses of high-purity factor IX concentrates (HP-FIX) in patients with haemophilia B. Here we have investigated the mechanism of such thrombogenesis by applying assays that detect early-through to late-events in coagulation system activation in a pharmacokinetic cross-over study of 50 IU/kg PCC and a new HP-FIX product in haemophilia B patients. Satisfactory recoveries and half-lives were observed for both concentrates.

HP-FIX caused no increases in thrombin-antithrombin III complex (TAT), prothrombin activation peptide fragment F1+2 (F1+2), factor X activation peptide (FXAP) or factor Vila (FVIIa). In contrast the same dose of factor IX in the form of PCC was followed by significant increases over pre-infusion levels of TAT, F1+2 and FXAP, but not FVIIa. Elevations of FIXAP occurred after both HP-FIX and PCC but did not reach normal levels and were attributed to normalisation of the FIX concentration in those patients whose levels of FIXAP were initially low. We conclude that the thrombogenic trigger associated with PCC infusion occurs at the level of factor X activation. In the absence of any increase in FVIIa, we would attribute this to the likely presence of FIXa in the PCC.

 

  • References

  • 1 Menache D. Prothrombin complex concentrates: clinical use. Ann New York Acad Sci 1981; 370: 747-756
    CrossrefPubMedGoogle Scholar
  • 2 Thompson AR. Factor-IX concentrates for clinical use. Sem Thromb Hemost 1993; 19: 25-36
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Seremetis SV, Aledort LM. Congenital Bleeding Disorders - Rational Treatment Options. Drugs 1993; 45: 541-547
    CrossrefPubMedGoogle Scholar
  • 4 Prowse C, Cash JD. The use of factor IX concentrates in man: a 9-year experience of Scottish concentrates in the South-East of Scotland. Br J Haemat 1981; 47: 91-104
    CrossrefPubMedGoogle Scholar
  • 5 Lusher JM. Perspectives on the use of factor-IX complex concentrates in the treatment of bleeding in persons with acquired factor-VIII inhibition. Am J Med 1991; 91 Suppl (Suppl. 05) S30-S34
    PubMedGoogle Scholar
  • 6 Aledort LM. Factor IX and thrombosis. Sc J Haemat 1977; Suppl 30: 40-42
    PubMedGoogle Scholar
  • 7 Lusher JM. Prediction and management of adverse events associated with the use of factor-IX complex concentrates. Sem Hemat 1993; (Suppl. 30) Suppl 1: 36-40
    PubMedGoogle Scholar
  • 8 Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Gungor T, Krackhardt B, Komhuber B. Incidence of development of factor-VIII and factor-IX inhibitors in haemophiliacs. Lancet 1992; 339: 594-598
    CrossrefPubMedGoogle Scholar
  • 9 Johnson AJ, Mathews RW, Fulton AJ. Approaches to plasma fractionation for improved recovery and the development of potentially useful clinical factors. Clin Haemat 1984; 13: 3-15
    PubMedGoogle Scholar
  • 10 Edwards CA, Pier MP, Chin S, Horowitz B. Tri(n-butyl) phosphate/detergent treatment of licensed therapeutic and experimental blood derivatives. Vox Sang 1987; 52: 53-59
    CrossrefPubMedGoogle Scholar
  • 11 Menache D. New concentrates of factors VII, IX and X. Prog Clin Biol Res 1990; 324: 177-187
    PubMedGoogle Scholar
  • 12 Menache D, Behre HE, Miner CL, Nunez H, Anderson HD, Triantaphyl-lopoulos DC, Kosow DP. Coagulation factor IX concentrate: method of preparation and assessment of potential in vivo thrombogenicity in animal models. Blood 1984; 64: 1220-1227
    PubMedGoogle Scholar
  • 13 Harrison J, Abildgaard C, Lazerson J, Culbertson R, Anderson G. Assessment of thrombogenicity of prothrombin complex concentrates in a porcine model. Thromb Res 1985; 38: 173-188
    CrossrefPubMedGoogle Scholar
  • 14 Smith KJ. Immunoaffinity purification of factor IX from commercial concentrates and infusion studies in animals. Blood 1988; 72: 1269-1277
    PubMedGoogle Scholar
  • 15 Herring SW, Abildgaard C, Shitanishi KT, Harrison J, Gendler S, Helde-brant CM. Human coagulation factor-IX - assessment of thrombogenicity in animal models and viral safety. J Lab Clin Med 1993; 121: 394-405
    PubMedGoogle Scholar
  • 16 MacGregor IR, Ferguson JM, McLaughlin LF, Bumouf T, Prowse CV. Comparison of high purity factor-IX concentrates and a prothrombin complex concentrate in a canine model of thrombogenicity. Thromb Haemost 1991; 66: 609-613
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Mannucci PM, Bauer KA, Gringeri A, Barzegar S, Santagostino E, Tradati FC, Rosenberg RD. No activation of the common pathway of the coagulation cascade after a highly purified factor-IX concentrate. Br J Haemat 1991; 79: 606-611
    CrossrefPubMedGoogle Scholar
  • 18 Goudemand J, Marey A, Caron C, Wibaut B, Mizon P. Clinical efficacy of a highly purified SD-treated factor IX concentrate prepared by conventional chromatography. Trans Med 1993; 3: 299-305
    CrossrefPubMedGoogle Scholar
  • 19 Bemtorp E, Bjorkman S, Carlsson M, Lethagen S, Nilsson IM. Biochemical and in-vivo properties of high purity factor-IX concentrates. Thromb Haemost 1993; 70: 768-773
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Santagostino E, Mannucci PM, Gringeri A, Tagariello G, Baudo F, Bauer KA, Rosenberg RD. Markers of hypercoagulability in patients with hemophilia B given repeated, large doses of factor IX concentrates during and after surgery. Thromb Haemost 1994; 71: 737-740
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Thomas DP, Hampton KK, Dasani H, Lee CA, Giangrande PLF, Harman C, Lee ML, Preston FE. A cross-over pharmacokinetic and thrombogenic-ity study of a prothrombin complex concentrate and a purified factor IX concentrate. Br J Haemat 1994; 87: 782-788
    CrossrefPubMedGoogle Scholar
  • 22 Mannucci PM, Bauer KA, Gringeri A, Barzegar S, Bottasso B, Simoni L, Rosenberg RD. Thrombin generation is not increased in the blood of hemo-philia-B patients after the infusion of a purified factor-IX concentrate. Blood 1990; 76: 2540-2545
    PubMedGoogle Scholar
  • 23 Hampton KK, Makris M, Kitchen S, Preston FE. Potential thrombogenicity of heat-treated prothrombin complex concentrates in haemophilia-B. Blood Coag Fibrin 1991; 2: 637-641
    CrossrefPubMedGoogle Scholar
  • 24 Kim HC, Matts L, Eisele J, Czachur M, Saidi P. Monoclonal antibody-purified factor IX: comparative thrombogenicity to prothrombin complex concentrate. Sem Hemat 1991; (Suppl. 28) Suppl 6: 15-19
    PubMedGoogle Scholar
  • 25 Middleton SM, Bennett IH, Smith JK. A therapeutic concentrate of coagulation factors II, IX and X from citrated, factor VUI-depleted plasma. Vox Sang 1973; 24: 441-456
    PubMedGoogle Scholar
  • 26 Littlewood JD, Dawes J, Smith JK, Feldman PA, Haddon ME, McQuillan TA, Foster PR, Ferguson J, Prowse CV. Studies on the effect of heat treatment on the thrombogenicity of factor IX concentrates in dogs. Br J Haemat 1987; 65: 463-468
    CrossrefPubMedGoogle Scholar
  • 27 Bumouf T, Michalski C, Goudemand M, Huart JJ. Properties of a highly purified human plasma factor IX: c therapeutic concentrate prepared by conventional chromatography. Vox Sang 1989; 57: 225-232
    PubMedGoogle Scholar
  • 28 Boisclair MD, Lane DA, Philippou H, Esnouf MP, Sheikh S, Hunt B, Smith KJ. Mechanisms of thrombin generation during surgery and cardiopulmonary bypass. Blood 1993; 82: 3350-3357
    PubMedGoogle Scholar
  • 29 Boisclair MD, Lane DA, Philippou H, Sheikh S, Hunt B. Thrombin production, inactivation and expression during open heart surgery measured by assays for activation fragments including a new ELISA for prothrombin fragment-F(]+2). Thromb Haemost 1993; 70: 253-258
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Collins P, Roderick A, Obrien D, Tuddenham E, O’Driscoll A, Chopra R, Goldstone A, Newland A. Factor Vila and other haemostatic variables following bone marrow transplantation. Thromb Haemost 1994; 72: 28-32
    PubMedGoogle Scholar
  • 31 Philippou H, Adami A, Boisclair MD, Lane DA. An ELISA for factor X activation peptide: Application to the investigation of thrombogenesis in cardiopulmonary bypass. Br J Haemat 1995; 90: 432-437
    CrossrefPubMedGoogle Scholar
  • 32 Morfini M, Lee M, Messori A. The design and analysis of half-life and recovery studies for factor-VIII and factor-IX. Thromb Haemost 1991; 6: 384-386
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Bauer KA, Mannucci PM, Gringeri A, Tradati F, Barzegar S, Kass BL, Tencate H, Kestin AS, Brettler DB, Rosenberg RD. Factor-IXa- Factor-VUIaCell surface complex does not contribute to the basal activation of the coagulation mechanism in vivo. Blood 1992; 79: 2039-2047
    PubMedGoogle Scholar
  • 34 Kim HC, Mcmillan CW, White GC, Bergman GE, Horton MW, Saidi P. Purified factor-IX using monoclonal immunoaffinity technique - clinical trials in hemophilia-B and comparison to prothrombin complex concentrates. Blood 1992; 79: 568-575
    PubMedGoogle Scholar
  • 35 Goldsmith JC, Kasper CK, Blatt PM, Gomperts ED, Kessler CM, Thompson AR, Herring SW, Novak PL. Coagulation factor-IX - successful surgical experience with a purified factor-IX concentrate. Am J Hemat 1992; 40: 210-215
    CrossrefPubMedGoogle Scholar
  • 36 Hampton KK, Preston FE, Lowe GDO, Walker ID, Sampson B. Reduced coagulation activation following infusion of a highly purified factor IX concentrate compared to a prothrombin complex concentrate. Br J Haemat 1993; 84: 279-284
    CrossrefPubMedGoogle Scholar
  • 37 Boisclair MD, Ireland H, Lane DA. Assessment of hypercoagulable states by measurement of activation fragments and peptides. Blood Rev 1990; 4: 25-40
    CrossrefPubMedGoogle Scholar
  • 38 Shifman MA, Pizzo SV. The in-vivo metabolism of antithrombin III and antithrombin complexes. J Biol Chem 1982; 257: 3243-3247
    PubMedGoogle Scholar
  • 39 Bauer KA, Broekmans AW, Bertina RM, Conard J, Horellou MH, Samama MM, Rosenberg RD. Hemostatic enzyme generation in the blood of patients with hereditary protein C deficiency. Blood 1988; 71: 1418-1426
    PubMedGoogle Scholar
  • 40 Bauer KA, Kass BL, ten Cate H, Bednarek MA, Hawiger JJ, Rosenberg RD. Detection of factor X activation in humans. Blood 1989; 74: 2007-2015
    PubMedGoogle Scholar
  • 41 Bauer KA, Kass BL, ten Cate H, Hawiger JJ, Rosenberg RD. Factor-IX is activated in-vivo by the tissue factor mechanism. Blood 1990; 76: 731-736
    PubMedGoogle Scholar
  • 42 Bauer KA. Laboratory markers of coagulation activation. Arch Path Lab Med 1993; 117: 71-77
    PubMedGoogle Scholar
  • 43 Boisclair MD, Philippou H, Lane DA. Thrombogenic mechanisms in the human - fresh insights obtained by immunodiagnostic studies of coagulation markers. Blood Coag Fibrin 1993; 4: 1007-1021
    CrossrefPubMedGoogle Scholar
  • 44 Wildgoose P, Nemerson Y, Hansen LL, Nielsen FE, Glazer S, Hedner U. Measurement of basal levels of factor Vila in hemophilia-A and hemophilia-B patients. Blood 1992; 80: 25-28
    PubMedGoogle Scholar
  • 45 Gitel S, Stephenson RC, Wessler S. In vitro and in vivo correlation of clotting protease activity: effect of heparin. Proc Natl Acad Sci USA 1977; 74: 3028-3032
    CrossrefPubMedGoogle Scholar
  • 46 Gray E, Tubbs J, Thomas S, Oates A, Boisclair M, Kemball-Cook MG, Barrowcliffe TW. Measurement of activated factor IX in factor IX concentrates: correlation with in vivo thrombogenicity. Thromb Haemost 1995; 73: 675-679
    Article in Thieme ConnectPubMedGoogle Scholar
  • 47 Hrinda ME, Huang C, Tarr GC, Weeks R, Feldman F, Schreiber AB. Pre-clinical studies of a monoclonal antibody-purified factor IX, Mononine. Sem Hemat 1991; 28 (Suppl. 06) Suppl 6-14
    PubMedGoogle Scholar