Factor IX(a) inhibitors: an updated patent review (2003-present)

SummaryAbetalipoproteinaemia is a rare disorder of apolipoprotein B metabolism associated with extremely low plasma concentrations of triglyce-ride. To discover whether the general positive association between factor VII and triglyceride levels extends to this condition, 5 patients were compared with 18 controls. All patients had a triglyceride below 100 μmol/l. Plasma unesterified fatty acid concentration was normal. Although factor IX activity was only slightly reduced (mean 88% standard) and factor IX antigen was normal, mean activated factor VII in patients was strikingly reduced to 34% of that in controls, a level similar to that found in haemophilia B. The patients’ mean factor VII activity and factor VII antigen were also significantly reduced to 54% and 63% of those in controls, respectively. Mean factor XI activity and tissue factor pathway inhibitor activity were reduced in patients to 70% and 75% of control values respectively, while factor XII, factor XI antigen, factor X, prothrombin and protein C were normal.

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ITI with high-dose FIX and combined immunosuppressive therapy in a patient with severe haemophilia B and inhibitor

Hämostaseologie ◽

10.1055/s-0037-1617018 ◽

2009 ◽

Vol 29 (02) ◽

pp. 155-157 ◽

Cited By ~ 22

Author(s):

H. Hauch ◽

J. Rischewski ◽

U. Kordes ◽

J. Schneppenheim ◽

R. Schneppenheim ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Immunosuppressive Agents ◽

Tolerance Induction ◽

Intravenous Immunoglobulins ◽

Factor Ix ◽

High Dose ◽

Allergic Reactions ◽

Success Rates ◽

Serious Infections ◽

History Of

SummaryInhibitor development is a rare but serious event in hemophilia B patients. Management is hampered by the frequent occurrence of allergic reactions to factor IX, low success rates of current inhibitor elimination protocols and the risk of development of nephrotic syndrome. Single cases of immune tolerance induction (ITI) including immunosuppressive agents like mycophenolat mofetil (MMF) or rituximab have been reported. We present a case of successful inhibitor elimination with a combined immune-modulating therapy and high-dose factor IX (FIX). This boy had developed a FIX inhibitor at the age of 5 years and had a history of allergic reactions to FIX and to FEIBA→. Under on-demand treatment with recombinant activated FVII the inhibitor became undetectable but the boy suffered from multiple joint and muscle bleeds. At the age of 11.5 years ITI was attempted with a combination of rituximab, MMF, dexamethasone, intravenous immunoglobulins and high-dose FIX. The inhibitor did not reappear and FIX half-life normalized. No allergic reaction, no signs of nephrotic syndrome and no serious infections were observed.

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Markers of Hypercoagulability in Patients with Hemophilia B Given Repeated, Large Doses of Factor IX Concentrates during and after Surgery

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642515 ◽

1994 ◽

Vol 71 (06) ◽

pp. 737-740 ◽

Cited By ~ 18

Author(s):

E Santagostino ◽

P M Mannucci ◽

A Gringeri ◽

G Tagariello ◽

F Baudo ◽

...

Keyword(s):

High Risk ◽

Ex Vivo ◽

Factor Ix ◽

Hemophilia B ◽

Coagulation System ◽

Prolonged Treatment ◽

Orthopedic Procedures ◽

Factor X ◽

Prothrombin Complex Concentrates ◽

Increased Risk

SummaryPurer factor IX (FIX) concentrates have been produced for the treatment of hemophilia B in the attempt to reduce the risk of thrombotic complications associated with the use of prothrombin complex concentrates. To evaluate ex vivo whether or not FIX concentrates activate the coagulation system in conditions associated with a high risk for thrombosis, we measured markers of hypercoagulability in 10 patients with hemophilia B who underwent surgery, mainly orthopedic procedures, covered by multiple concentrate infusions (40-80 U/kg/day). Postinfusion plasma levels of prothrombin fragment 1+2 and factor X activation peptide did not differ significantly from the presurgical levels, neither before nor after each concentrate dose. Therefore, it appears that prolonged treatment of patients with hemophilia B undergoing high risk surgical procedures with high doses of FIX concentrate does not cause systemic activation of coagulation. This suggests that purified FIX concentrates are preferable to prothrombin complex concentrates for conditions associated with an increased risk of thrombosis.

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The Activation of Human Factor IX

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647849 ◽

1975 ◽

Vol 33 (03) ◽

pp. 553-563 ◽

Cited By ~ 7

Author(s):

B Østerud ◽

K Laake ◽

H Prydz

Keyword(s):

Molecular Weight ◽

Sodium Dodecyl ◽

Apparent Molecular Weight ◽

Factor Ix ◽

Factor Vii ◽

Activate Factor ◽

Human Factor Ix ◽

Factor Xia ◽

Tissue Thromboplastin ◽

Native Factor

SummaryThe activation of factor IX purified from human plasma has been studied. Factor XIa and kallikrein separately activated factor IX to factor IXa. In both cases factor IX a had an apparent molecular weight of about 42–45000 in sodium dodecyl sul-phate-polyacrylamide disc gel electrophoresis compared with a molecular weight of about 70000 for the native factor IX. The activation by XIa required Ca2+-ions whereas Ca2+-ions did not influence the activation by kallikrein. A mixture of tissue thromboplastin and factor VII or RusselPs-viper venom alone did not activate factor IX. Trypsin activated and plasmin inactivated factor IX.

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Performances of an Artificial Reagent for the One-stage Factor IX Assay

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647848 ◽

1975 ◽

Vol 33 (03) ◽

pp. 547-552 ◽

Cited By ~ 4

Author(s):

L Meunier ◽

J. P Allain ◽

D Frommel

Keyword(s):

Human Plasma ◽

Factor Ix ◽

Severe Haemophilia ◽

Normal Human Plasma ◽

Haemophilia B ◽

One Stage ◽

Normal Human ◽

The One

SummaryA mixture of adsorbed normal human plasma and chicken plasma was prepared as reagent for factor IX measurement using a one-stage method. The substrate was found to be specific for factor IX. Its performances tested on samples displaying factor IX activity ranging from <l%–2,500% compared favorably with those obtained when using the plasma of severe haemophilia B patients as substrate.

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The Clinical Use of Factor IX Concentrates

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647900 ◽

1975 ◽

Vol 33 (03) ◽

pp. 403-404

Author(s):

Rosemary Biggs

Keyword(s):

Factor Ix ◽

Clinical Use

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Potentially Thrombogenic Materials in Factor IX Concentrates

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647857 ◽

1975 ◽

Vol 33 (03) ◽

pp. 617-631 ◽

Cited By ~ 47

Author(s):

H. S Kingdon ◽

R. L Lundblad ◽

J. J Veltkamp ◽

D. L Aronson

Keyword(s):

Human Plasma ◽

Antithrombin Iii ◽

Factor Ix ◽

In Vitro Assays ◽

Substantial Agreement ◽

Coefficient Of Correlation

SummaryFactor IX concentrates manufactured from human plasma and intended for therapeutic infusion in man have been suspected for some time of being potentially thrombogenic. In the current studies, assays were carried out in vitro and in vivo for potentially thrombogenic materials. It was possible to rank the various materials tested according to the amount of thrombogenic material detected. For concentrates not containing heparin, there was substantial agreement between the in vivo and in vitro assays, with a coefficient of correlation of 0.77. There was no correlation between the assays for thrombogenicity and the antithrombin III content. We conclude that many presently available concentrates of Factor IX contain substantial amounts of potentially thrombogenic enzymes, and that this fact must be considered in arriving at the decision whether or not to use them therapeutically.

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

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646468 ◽

1991 ◽

Vol 66 (05) ◽

pp. 609-613 ◽

Cited By ~ 14

Author(s):

I R MacGregor ◽

J M Ferguson ◽

L F McLaughlin ◽

T Burnouf ◽

C V Prowse

Keyword(s):

High Purity ◽

Time Course ◽

Prothrombin Complex Concentrate ◽

Degradation Products ◽

Canine Model ◽

Factor Ix ◽

In Vitro Tests ◽

Albumin Infusion

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.

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