Searching for the role of primary prophylaxis in preventing inhibitor development in hemophilia A

Coppola, Antonio; Tagliaferri, Annarita; Franchini, Massimo

doi:10.1111/j.1538-7836.2012.04840.x

Cited by 4 publications

(2 citation statements)

References 42 publications

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“…With this promising background, a subsequent prospective study (early prophylaxis immunologic challenge) was designed to explore more in depth the strategy of early prophylaxis in severe hemophilia A, but the study was stopped prematurely because of a very high rate of inhibitors . Finally, Coppola and colleagues carried out a systematic review on the role of prophylaxis in the prevention of inhibitors and found, among 2661 patients from 27 studies, fewer inhibitors in those treated with prophylaxis (14.2%) than in those treated on demand (32.5%; odds ratio 0.34, 95% CI 0.22–0.54) . Cumulatively, these data suggest a potential protective role against inhibitor development of early and continuous prophylaxis started in the absence of immunological challenges.…”

Section: On‐demand Vs Prophylatic Regimensmentioning

confidence: 99%

Tailoring hemostatic therapies to lower inhibitor development in previously untreated patients with severe hemophilia A

Mannucci

Mancuso

Franchini

2016

Journal of Thrombosis and Haemostasis

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To cite this article: Mannucci PM, Mancuso ME, Franchini M. Tailoring hemostatic therapies to lower inhibitor development in previously untreated patients with severe hemophilia A. J Thromb Haemost 2016; 14: 1330-6.Summary. After technological progress provided safer therapeutic products for patients with hemophilia A, the development of alloantibodies (inhibitors) neutralizing the coagulant activity of infused factor VIII (FVIII) remains the most serious complication of replacement therapy, predisposing patients to greater morbidity and causing higher treatment costs. The pathogenesis of inhibitors, which develop at a high rate in previously untreated children with severe hemophilia A, is multifactorial, resulting from complex interactions between genetic and environmental factors. Among non-genetic determinants, a key role is played by treatment-related factors, including the source of FVIII product (i.e., plasma derived or recombinant) and the mode of replacement therapy delivery (i.e., intensity, prophylaxis vs. on demand). We review the potential interventions on these modifiable factors that may help to lower the rate of inhibitor development. In addition, interest is currently directed toward the potential for lesser immunogenicity of novel hemostatic agents designed to decrease the dosing frequency or avoid/delay the need of FVIII replacement therapy.

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Section: On‐demand Vs Prophylatic Regimensmentioning

confidence: 99%

Tailoring hemostatic therapies to lower inhibitor development in previously untreated patients with severe hemophilia A

Mannucci

Mancuso

Franchini

2016

Journal of Thrombosis and Haemostasis

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“…In hemophilia, based on clinical observations of an association between inhibitor development and events such as bleeding, infections, and surgery, it has been proposed that immunological danger signals in concomitance with supplemental FVIII can promote FVIIIspecific immune responses (50,51). Avoiding danger signals with an appropriate prophylaxis regimen would, in contrast, reduce inhibitor incidence rate (52). Tregs play an important role in the maintenance of homeostasis and the prevention of inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII

Matino

Gargaro

Santagostino

et al. 2015

Journal of Clinical Investigation

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The development of inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor-positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein.

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Prevention of inhibitor development in hemophilia A in 2016. A glimpse into the future?

Franchini

Lippi

2016

Thrombosis Research

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Searching for the role of primary prophylaxis in preventing inhibitor development in hemophilia A

Cited by 4 publications

References 42 publications

Tailoring hemostatic therapies to lower inhibitor development in previously untreated patients with severe hemophilia A

Tailoring hemostatic therapies to lower inhibitor development in previously untreated patients with severe hemophilia A

IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII

Prevention of inhibitor development in hemophilia A in 2016. A glimpse into the future?

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