Treatment of Hemophilia B with a New Clotting-Factor Concentrate

Ms, Hoag; Ff, Johnson; Ja, Robinson; Pm, Aggeler

doi:10.1056/nejm196903132801103

Cited by 85 publications

(39 citation statements)

References 20 publications

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“…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%

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

Gui

Lin

Jin

et al. 2002

Blood

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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...

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Section: Discussionsupporting

confidence: 89%

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

Gui

Lin

Jin

et al. 2002

Blood

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“…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

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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.

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“…2 Early treatments for hemophilias used partially purified coagulation factor concentrates. 3,4 These concentrates, however, were also associated with thromboembolic complications and viral infections. [5][6][7] During the last two decades, monoclonal antibodypurified factor VIII and IX concentrates 8,9 and recombinant factors VIII 10 and IX 11 have become the desired therapy for hemophilia A and B.…”

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confidence: 99%

Influence of Factor VIIa and Phospholipids on Coagulation in “Acquired” Hemophilia

Butenas

Brummel

Paradis

et al. 2003

ATVB

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Objective-This study was performed to evaluate the influences of phospholipids and recombinant factor VIIa (rFVIIa) on thrombin generation and clot formation in "acquired" hemophilia B. Methods and Results-A synthetic mixture corresponding to hemophilia A (SHA) and "acquired" hemophilia B blood (AHBB) manufactured in vitro by an anti-FIX antibody were used in this study. With 10 pmol/L tissue factor (TF), 10 nmol/L rFVIIa, and saturating phospholipid, established thrombin generation in SHA was similar to that observed in the presence of factor VIII and rFVIIa at physiological concentrations. At lower phospholipid concentrations, thrombin generation was delayed and reduced. With 5 pmol/L TF, contact pathway-inhibited AHBB clotted later than normal blood and showed reduced clot stability and thrombin generation. These parameters of effectiveness were increased by the addition of phospholipids to AHBB, which restored clot stability and increased thrombin generation. No correction of clot formation or thrombin generation was observed when rFVIIa and phospholipids were added to AHBB in the absence of TF. Conclusions-The

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Treatment of Hemophilia B with a New Clotting-Factor Concentrate

Cited by 85 publications

References 20 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

Properties of Factor IX Concentrates

Influence of Factor VIIa and Phospholipids on Coagulation in “Acquired” Hemophilia

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