Nephrotic Syndrome as a Complication of Immune Tolerance in Hemophilia B

Ewenstein, Bruce M.; Takemoto, Clifford M.; Warrier, Indira; Lusher, Jeanne M.; Saidi, Parvin; Eisele, Joan; Ettinger, Lawrence J.; DiMichele, Donna

doi:10.1182/blood.v89.3.1115

Cited by 129 publications

(109 citation statements)

References 6 publications

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“…All 13 patients who developed nephrotic syndrome developed this complication 8-9 months into the ITI regimen with high dose FIX concentrate (100-325 IU kg )1 per day). Clinically, patients presented with periorbital edema, proteinuria and hypoalbuminemia [11]. Eleven of 13 (84%) developed nephrotic syndrome while receiving a purified FIX product alone.…”

Section: Resultsmentioning

confidence: 99%

“…It has been postulated that the smaller molecular weight of FIX (55 000 Daltons) allows its distribution in both the intra and extravascular space compared with FVIII, which complexed with von Willebrand factor (VWF) stays confined to the intravascular space [1]. The extravascular distribution may facilitate mast cell activation and IgE mediated hypersensitivity [11]. Most of the inhibitory antibodies are known to be polyclonal and predominantly of the IgG4 subclass [14].…”

Section: Discussionmentioning

confidence: 99%

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Inhibitors in factor IX deficiency a report of the ISTH‐SSC international FIX inhibitor registry (1997–2006)

et al. 2009

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Haemophilia B is an X-linked disorder resulting in coagulation factor IX deficiency. Patients with severe deficiency (<1% factor IX activity) may have significant bleeding complications similar to patients with haemophilia A or factor VIII deficiency. The development of inhibitory antibodies to the missing coagulation factor is a major complication in patients with haemophilia. While the incidence of inhibitors in patients with haemophilia A is higher than that in haemophilia B, the occurrence of allergic and or anaphylactic reactions with the development of inhibitors is unique to haemophilia B patients. Since haemophilia B is a rare bleeding disorder and the incidence of inhibitors is an even rarer entity, a registry was established by Dr Indira Warrier under the auspices of the FVIII/FIX subcommittee of the International Society of Thrombosis and Haemostasis, to gather information on the occurrence and characteristics of patients with inhibitors and also the incidence of allergic and anaphylactic reactions in this group of patients. This is the first report from this registry and helps us to gather some insight on haemophilia B patients with inhibitors and complications related to inhibitor development and difficulties with immune tolerance.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibitors in factor IX deficiency a report of the ISTH‐SSC international FIX inhibitor registry (1997–2006)

et al. 2009

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“…More recent data from the NAIT reported a poor success rate (36%), influenced primarily by the high degree of IT failure in those patients demonstrating the allergic phenotype. Furthermore, data from this registry and others identified the potential for nephrotic syndrome as a complication of IT in this subset of FIX inhibitor patients [50,53,54].…”

Section: Immune Tolerancementioning

confidence: 99%

Inhibitors: resolving diagnostic and therapeutic dilemmas

2002

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The good quality of life now anticipated by individuals with haemophilia A and B can be drastically altered by the unpredictable development of an inhibitor, a polyclonal high-affinity IgG antibody directed against factor VIII or IX. This paper discusses our current state of knowledge about inhibitors within the context of: (1) the extent and nature of the problem, including its incidence and prevalence, diagnostic options, and the characteristics of the individual immunologic response; (2) possible underlying aetiological factors, both inherited and situational; and (3) existing and future therapeutic options for both the interim treatment of haemorrhage and the ultimate restoration of normal clotting factor recovery and survival. Current and future strategies for immune tolerisation are also reviewed.

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“…Anaphylactic reactions and nephrotic syndrome constitute serious complications impairing the success rate of immune tolerance induction (ITI) in patients with FIX inhibitors. 23 While associated with the absence of FIX due to large gene deletions, the pathogenetic mechanisms underlying these conditions are not understood. However, the large protein quantities of FIX required during replacement therapy (normal FIX plasma concentration exceeds that of FVIII 50-fold), ITI, and the rapid extravascular distribution of FIX, may contribute.…”

Section: Immune and Allergic Reactionsmentioning

confidence: 99%

Phenotypic characterization of haemophilia B – Understanding the underlying biology of coagulation factor IX

Tjärnlund-Wolf

Lassila

2019

Haemophilia

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Haemophilia B is a recessive, X‐linked bleeding disorder due to inherited deficiency in vitamin K‐dependent coagulation factor IX (FIX). FIX activity levels, as a basis for the definition of disease severity, do not clearly correlate with bleeding phenotype, likely due to the multiple steps regulating coagulation. Timely, with the availability of extended half‐life products and successful steps in gene therapy, haemophilia B therapy is in an active developmental phase. Therefore, increased knowledge of the factors contributing to the variation of haemostatic and clinical outcome and response to therapy is welcomed. FIX acts at the crossroads of both the extrinsic and intrinsic pathways, and on the platelet procoagulant membrane at the site of vascular injury, and therefore, FIX biology is targeted for multiple effectors and regulators. The synthesis, cellular and molecular interactions, and elimination routes of FIX are not as well studied as for FVIII. The specific roles of magnesium in both platelet adhesion and FIX activation, and of vascular collagen at the haemostatic site of platelet adhesion and FIX residence are of particular interest. Biochemical and translational research on these issues should improve our understanding of the mechanisms involved, leading to the development of relevant assays that measure both haemostasis and treatment response. The latter is becoming increasingly important in the new era of haemophilia management and ultimately may lead to improved treatment strategies individually tailored to a patient's needs and cost‐efficiency.

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Nephrotic Syndrome as a Complication of Immune Tolerance in Hemophilia B

Cited by 129 publications

References 6 publications

Inhibitors in factor IX deficiency a report of the ISTH‐SSC international FIX inhibitor registry (1997–2006)

Inhibitors in factor IX deficiency a report of the ISTH‐SSC international FIX inhibitor registry (1997–2006)

Inhibitors: resolving diagnostic and therapeutic dilemmas

Phenotypic characterization of haemophilia B – Understanding the underlying biology of coagulation factor IX

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