Factor Ix Levels in Patients With Hemophilia B (Christmas Disease) Following Transfusion With Concentrates of Factor Ix or Fresh Frozen Plasma (Ffp)

Zauber, N. Peter; Levin, Jack

doi:10.1097/00005792-197705000-00003

Cited by 38 publications

(26 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our data agree with previous clearance studies that showed that the pharmacokinetics of factor IX could be divided into 2 phases. [15][16][17] We found that the half-time of the first phase was similar to that reported by Fuchs et al 18 for normal mice. Half-lives reported for the slower second phase vary considerably (5-14 hours).…”

Section: Discussionsupporting

confidence: 89%

See 1 more Smart Citation

Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in vivo

Gui

Lin

Jin

et al. 2002

Blood

View full text Add to dashboard Cite

Residue K5 in factor IX ␥-carboxyglutamic acid (Gla) domain participates in binding endothelial cells/collagen IV. We injected recombinant factor IX containing mutations at residue 5 (K5A, K5R) into factor IX-deficient mice and compared their behavior with that of wild-type factor IX. The plasma concentration of factor IX that binds to endothelial cells/collagen IV (recombinant wild type and K5R) was consistently lower than that of the one that does not bind (K5A). Mice treated with wild type or K5R had 79% of the injected factor IX in the liver after 2 minutes, whereas 17% remained in circulation. In mice injected with K5A, 59% of the injected factor IX was found in liver and 31% was found in plasma. When we blocked the liver circulation before factor IX injection, 74% of K5A and 64% of K5R remained in the blood. When we treated the mouse with EDTA after injecting exogenous factor IX, the blood levels of factor IX that bind to endothelial cells/collagen IV increased, presumably because of release from endothelial cell/collagen IV binding sites. In contrast, the levels of the mutants that do not bind were unaffected by EDTA. In immunohistochemical studies, factor IX appears on the endothelial surfaces of mouse arteries after factor IX injection and of human arteries from surgical specimens. Thus, we have demonstrated that factor IX binds in vivo to endothelial cell-collagen IV surfaces. Our results suggest that factor IX Gla-domain mediated binding to endothelial cells/ collagen IV plays a role in controlling factor IX concentration in the blood. IntroductionFactor IX is the zymogen of a serine protease involved in blood coagulation. Activated factor IX (factor IXa) contains 4 identifiable structural domains. Starting from the N-terminus, these are the ␥-carboxyglutamic acid (Gla) domain, the 2 epidermal growth factor-like domains, and the proteolytic domain. Factors IX and IXa bind to a specific site on the surface of cultured vascular endothelial cells. The binding is calcium-dependent, saturable, and reversible in vitro. [1][2][3] Our previous studies on cultured endothelial cells demonstrate that the binding regions in factor IX are in the Gla domain. 4 Furthermore, mutations within the Gla domain, including lysine 5 to alanine (K5A) and valine 10 to lysine (V10K), produced factor IX that did not have measurable affinity for endothelial cells but retained normal clotting activity. In contrast, changing lysine 5 to arginine (K5R) increased factor IX affinity 3-fold for cultured bovine vascular endothelial cells. 5 Cheung et al 6 demonstrated that collagen IV was a strong candidate for the factor IX endothelial cell-associated binding site. Further, results from atomic force scanning microscopy indicate that factor IX molecules bind specifically to 2 sites on collagen IV, 98 and 50 nm from its C-terminus. 7 Although the binding of factor IX to endothelial cells/collagen IV is well documented, little is known about the physiologic significance of binding. The hemophilia B mouse produced using gene-targeting te...

show abstract

Section: Discussionsupporting

confidence: 89%

“…Previous reports indicate this ␣ phase represents diffusion of factor IX into certain tissues and extravascular fluid. 16,20 For example, Fuchs et al 18 showed that 80% of injected factor IX is in the liver of normal mice after 2 minutes. This is similar to our results with wild-type factor IX and K5R (Figure 2).…”

mentioning

confidence: 99%

Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in vivo

Gui

Lin

Jin

et al. 2002

Blood

View full text Add to dashboard Cite

show abstract

“…In humans and animals, F.IX disappearance from plasma can be described in terms of a 2-component model, with a rapid disappearance (termed ␣), corresponding to distribution into the tissues, followed by a much slower decay (termed ␤), thought to correspond to F.IX catabolism. 45 The t 1/2 for plasma-derived F.IX was 2.19 hours, and for myotube-synthesized F.IX it was 2.58 hours. The CHO-synthesized F.IX (Benefix; Genetic Institute) showed the longest half-life, 4.2 hours (n ϭ 3 mice) (Figure 7).…”

Section: Serine Phosphorylationmentioning

confidence: 98%

Posttranslational modifications of recombinant myotube-synthesized human factor IX

Arruda

Hagstrom

Deitch

et al. 2001

Blood

116

View full text Add to dashboard Cite

Recent data demonstrate that the introduction into skeletal muscle of an adenoassociated viral (AAV) vector expressing blood coagulation factor IX (F.IX) can result in long-term expression of the transgene product and amelioration of the bleeding diathesis in animals with hemophilia B. These data suggest that biologically active F.IX can be synthesized in skeletal muscle. Factor IX undergoes extensive posttranslational modifications in the liver, the normal site of synthesis. In addition to affecting specific activity, these posttranslational modifications can also affect recovery, half-life in the circulation, and the immunogenicity of the protein. Before initiating a human trial of an AAV-mediated, muscle-directed approach for treating hemophilia B, a detailed biochemical analysis of F.IX synthesized in skeletal muscle was carried out. As a model system, human myotubes transduced with an AAV vector expressing F.IX was used. F.IX was purified from conditioned medium using a novel strategy designed to purify material representative of all species of rF.IX in the medium. Purified F.IX was analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), N-terminal sequence analysis, chemical ␥-carboxyglutamyl analysis, carbohydrate analysis, assays for tyrosine sulfation, and serine phosphorylation, and for specific activity.Results show that myotube-synthesized F.IX has specific activity similar to that of liver-synthesized F.IX. Posttranslational modifications critical for specific activity, including removal of the signal sequence and propeptide, and ␥-carboxylation of the N-terminal glutamic acid residues, are also similar, but carbohydrate analysis and assessment of tyrosine sulfation and serine phosphorylation disclose differences. In vivo experiments in mice showed that these differences affect recovery but not half-life of muscle-synthesized F.IX. (Blood. 2001;97:130-138)

show abstract

“…No difference was seen between Nanotiv, Preconativ, and Mononine regarding in vivo recovery and half-life irrespective of protocol used, whereas Immunine and Prothromplex TIM4 both showed lower in vivo recovery values and shorter half-lives. The clearance was also higher for Immunine and Prothrom plex TIM4, and the mean residence time was shorter [2], It is known from other studies that the half-life of fac tor IX differs between different studies and in general there is a good correlation between sampling time and half-life, e.g., a less extensive sampling time gives a short er half-life [3][4][5][6][7], This observation prompted us to per form another pharmacokinetic study [2], the aim of which …”

Section: In Vivo Studiesmentioning

confidence: 99%

Properties of Factor IX Concentrates

Berntorp¹

1995

Acta Haematol

View full text Add to dashboard Cite

Five purified concentrates – Nanotiv (Kabi Pharmacia), Immunine (Immuno), Factor IX VHP (Biotransfusion), Alphanine (Alpha Therapeutic Corporation), and Mononine (Armour Pharmaceutical Company) – were characterized biochemically and their in vivo pharmacokinetic and thrombogenic properties evaluated. The results were compared with those for two prothrombin complex concentrates (PCCs): Preconativ (Kabi Pharmacia) and Prothromplex TIM4 (Immuno). The measured values for factor IX coagulant activity (FIX:C) generally agreed with the manufacturers’ labeled values. The purified concentrates were virtually devoid of other vitamin K-dependent coagulation factors, the inhibitor proteins C and S, and either fibrinogen, fibronectin, or immunoglobulins. Indicators of thrombin generation (i.e., prothrombin fragments F₁₊₂ and thrombin-antithrombin complex) were present in varying amounts in all preparations. The level of specific activity in the purified concentrates exceeded that in the PCCs by a factor of 50- to 100-fold. Pharmacokinetic variables were studied in severe hemophilia B patients: Nanotiv was compared with Preconativ; Immunine was compared with Prothromplex TIM4 in crossover studies; and Mononine was tested in a single-drug study. No differences were apparent between Nanotiv, Preconativ, and Mononine, but recovery rates were lower, clearance rates higher, and FIX:C half-life shorter for Immunine and Prothromplex TIM4, although the disparate results might have been attributable to methodologic differences. Purified factor IX concentrates were used successfully as cover for surgery and in immune tolerance induction without observable adverse effects.

show abstract

Factor Ix Levels in Patients With Hemophilia B (Christmas Disease) Following Transfusion With Concentrates of Factor Ix or Fresh Frozen Plasma (Ffp)

Cited by 38 publications

References 0 publications

Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in vivo

Circulating and binding characteristics of wild-type factor IX and certain Gla domain mutants in vivo

Posttranslational modifications of recombinant myotube-synthesized human factor IX

Properties of Factor IX Concentrates

Contact Info

Product

Resources

About