Von Willebrand factor in high‐purity factor VIII complex concentrates: chaperone protein or key to therapies? A meeting report

Federici, Augusto B.; Mannucci, P.M.; Marco, Pascual

doi:10.1111/j.1365-2516.2007.01558.x

Cited by 6 publications

(6 citation statements)

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“…Reports from industry sponsored trials investigating the efficacy of bleed reduction from VWF concentrates have also demonstrated similar results as the study discussed and in the previously noted retrospective studies . Similarly, a recent retrospective study from the VWD PN also demonstrated efficacy .…”

Section: Resultssupporting

confidence: 74%

Prophylaxis escalation in severe von Willebrand disease: a prospective study from the von Willebrand Disease Prophylaxis Network

Abshire

Cox-Gill

Kempton

et al. 2015

Journal of Thrombosis and Haemostasis

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Summary. Background: Treatment of mucosal bleeding (epistaxis, gastrointestinal bleeding, and menorrhagia) and joint bleeding remains problematic in clinically severe von Willebrand disease (VWD). Patients are often unresponsive to treatment (e.g. desmopressin or antifibrinolytic therapy) and may require von Willebrand factor (VWF) replacement therapy. There are little data on the use of prophylaxis in VWD, and none have been applied in a prospective, treatment escalation design. Objective: Evaluate the effect of escalating dose prophylaxis in severe VWD. Methods: Patients eligible for enrollment in this prospective study included those with type 1 VWD with VW factor activity-ristocetin cofactor ratio ≤ 20% and unresponsive to desmopressin, patients with type 2 VWD not responsive to desmopressin and all subjects with type 2B and type 3 VWD. Entry criteria were strictly defined, as were therapy escalation parameters and clinical data collection. Results: Eleven subjects completed the study. Six had type 2A, and five had type 3 VWD. Six patients presented with epistaxis, three with GI bleeding, and two with joint bleeding. Seven had dose escalation above the first level. Among the 10 subjects with evaluable bleeding log data, use of prophylaxis decreased the median annualized bleeding rate from 25 to 6.1 (95% confidence interval of the rate difference: À51.6 to À1.7), and the median annualized bleeding rate was even lower (4.0; 95% confidence interval: À57.5 to À5.3) when the subjects reached their final dosing level. Conclusion: This is the first prospective study to demonstrate that prophylaxis with VW factor concentrates is highly effective in reducing mucosal and joint bleeding rates in clinically severe VWD.

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Section: Resultssupporting

confidence: 74%

Prophylaxis escalation in severe von Willebrand disease: a prospective study from the von Willebrand Disease Prophylaxis Network

Abshire

Cox-Gill

Kempton

et al. 2015

Journal of Thrombosis and Haemostasis

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“…Some of these studies support the hypothesis for a mechanism of inhibitor formation due to the more highly purified factor VIII protein in the recombinant preparations 60. Other interpretations suggest that the association of the natural carrier protein, von Willebrand protein, with the infused therapeutic factor VIII provides some undefined mechanism that decreases the formation of inhibitors 61,62. Inhibitor development is a poorly understood phenomenon, and there are few randomized clinical trials.…”

Section: Complications Of Current Treatment Of Hemophilia Amentioning

confidence: 73%

Recombinant factor VIII in the management of hemophilia A: current use and future promise

Powell

2009

TCRM

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Hemophilia A is a rare inherited bleeding disorder due to mutation of the gene that encodes the coagulation protein factor VIII. Historically, prior to the availability of treatment with factor VIII preparations, most boys died from uncontrolled bleeding, either spontaneous bleeding or after injury, before reaching 20 years of age. One of the most impressive triumphs of modern medicine is that with current recombinant factor VIII replacement therapy, a boy born in the 21st century with severe hemophilia A can anticipate a normal life expectancy with essentially no permanent complications from bleeding. For severe hemophilia A, current optimal treatment should have two goals: first, to provide sufficient factor VIII to prevent spontaneous bleeding, and second, to provide sufficient factor VIII to have normal coagulation function after any trauma. However, the replacement therapy requires tremendous resources for effective use, and remains extraordinarily expensive. Thus there are opportunities for further advances in therapy for hemophilia A. Two major concerns continue to trouble current optimal treatment approaches: some patients will develop neutralizing antibodies during the first 50 infusions of therapeutic factor VIII, and second, to administer therapeutic factor VIII every other day in young boys often requires placement of a central venous access device, and such use carries the life-threatening risks of infection and thrombosis. Because of the effectiveness of current therapy, any new developments in treatment will require significant concerns for safety, both immediate and in the long term. A number of research groups seek to prolong the biological efficacy of infused recombinant factor VIII. Currently, one such promising development is in the advanced stages of clinical trial. The goals will be to improve further the quality of life of an individual with severe hemophilia A, and to reduce the burden of current treatment strategies on families and medical resources. Hopefully, the hemophilia community will continue to participate actively in the clinical trials needed to address these new challenges.

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“…A few additional investigations have been reported using different VWF‐containing concentrates , . Common among these was the finding that prophylaxis appears to be effective at decreasing or eliminating bleeding, and that side effects are mild.…”

Section: Discussionmentioning

confidence: 99%

Prophylaxis in severe forms of von Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN)

Abshire¹,

Federici

Álvarez

et al. 2012

Haemophilia

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Summary The bleeding patterns of severe von Willebrand's disease (VWD) adversely affect quality of life, and may be life threatening. There is a presumed role for prophylaxis with VWF‐containing concentrates, but data are scarce. The von Willebrand Disease Prophylaxis Network (VWD PN) was formed to investigate the role of prophylaxis in clinically severe VWD that is not responsive to other treatment(s).Using a retrospective design, the effect of prophylaxis was studied. Availability of records to document, or reliably assess, the type and frequency of bleeding episodes prior to, and after, the initiation of prophylaxis was required. Annualized bleeding rates were calculated for the period prior to prophylaxis, during prophylaxis and by primary bleeding indication defined as the site accounting for more than half of all bleeding symptoms. The Wilcoxon signed‐rank test of differences in the medians was used. Sixty‐one subjects from 20 centres in 10 countries were enrolled. Data for 59 were used in the analysis. The median age at onset of prophylaxis was 22.4 years. Type 3 VWD accounted for the largest number (N = 34, 57.6%). Differences in bleeding rates within individuals during compared with before prophylaxis were significant for the total group (P < 0.0001), and for those with primary bleeding indications of epistaxis (P = 0.0005), joint bleeding (P = 0.002) and GI bleeding (P = 0.001). The effect of prophylaxis was similar among those age < 18 years and those ≥18. One person developed an inhibitor during treatment. We conclude that prophylactic treatment of VWD is efficacious.

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Von Willebrand factor in high‐purity factor VIII complex concentrates: chaperone protein or key to therapies? A meeting report

Cited by 6 publications

References 44 publications

Prophylaxis escalation in severe von Willebrand disease: a prospective study from the von Willebrand Disease Prophylaxis Network

Prophylaxis escalation in severe von Willebrand disease: a prospective study from the von Willebrand Disease Prophylaxis Network

Recombinant factor VIII in the management of hemophilia A: current use and future promise

Prophylaxis in severe forms of von Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN)

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Von Willebrand factor in high‐purity factor VIII complex concentrates: chaperone protein or key to therapies? A meeting report

Cited by 6 publications

References 44 publications

Prophylaxis escalation in severe von Willebrand disease: a prospective study from the von Willebrand Disease Prophylaxis Network

Prophylaxis escalation in severe von Willebrand disease: a prospective study from the von Willebrand Disease Prophylaxis Network

Recombinant factor&nbsp;VIII in the management of hemophilia A: current use and future promise

Prophylaxis in severe forms of von Willebrand's disease: results from the von Willebrand Disease Prophylaxis Network (VWD PN)

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Recombinant factor VIII in the management of hemophilia A: current use and future promise