von Willebrand factor in factor VIII concentrates protects against neutralization by factor VIII antibodies of haemophilia A patients

Kallas, Ade; Talpsep, T.

doi:10.1111/j.1365-2516.2001.00530.x

Cited by 33 publications

(35 citation statements)

References 14 publications

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“…These findings have since been corroborated by others [12,13]. It has also been reported that VWF containing concentrates are less inhibited by inhibitors directed against the C2 region.…”

Section: In Vitro Observations On Antibody Reactivity With Fviii Concsupporting

confidence: 70%

VWF/FVIII complex and the management of patient with inhibitors: from laboratory to clinical practice

Berntorp¹

2007

Haemophilia

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We and others have previously shown that inhibitor containing plasma from patients with congenital haemophilia A sometimes reacts less with von Willebrand factor (VWF) containing concentrates compared with highly purified plasma-derived or recombinant factor VIII (FVIII) concentrates. To further substantiate the haemostatic role of a variation in inhibitor reactivity with different FVIII concentrates, we compared the inhibitor titres from 11 plasma samples against a panel of FVIII concentrates and correlated titre with the capacity to inhibit thrombin generation. Three plasma-derived concentrates were tested: Fandhi (Grifols) which contains VWF with a final ratio of approximately 1 (VWF IU per IU FVIII:C); Haemate (CSL Behring) with a ratio of 2.5 and Haemofil M (Baxter), a monoclonal antibody-purified concentrate containing only trace amounts of VWF. In addition, the recombinant FVIII concentrate Kogenate Bayer (Bayer) containing no VWF was included in the panel. A statistically significant difference in measured titres against the four concentrates was found. The inhibitor titre needed to inhibit 50% maximum thrombin generation was lowest for Kogenate Bayer and highest and similar for Fandhi and Haemate. This study confirms the results from previous research regarding variation of inhibitor reactivity against different concentrates and further shows that the VWF containing concentrates Fandhi and Haemate added to FVIII-deficient plasma with the presence of inhibitor generate more thrombin than do the purified concentrates Haemofil M and Kogenate Bayer. A further interesting aspect could be that bypass therapy may have an increased efficacy when infused together with FVIII concentrates containing VWF. However, the clinical implications of all these findings in vitro need to be established.

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“…These findings have since been corroborated by others [12,13]. It has also been reported that VWF containing concentrates are less inhibited by inhibitors directed against the C2 region.…”

Section: In Vitro Observations On Antibody Reactivity With Fviii Concsupporting

confidence: 70%

VWF/FVIII complex and the management of patient with inhibitors: from laboratory to clinical practice

Berntorp¹

2007

Haemophilia

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“…In this study, FVIII epitope specificity of inhibitors in this specific cohort seemed to be mainly located in the A2 domain or the light chain of FVIII with a potential effect on the results, although it does not appear to show a direct association between the antibody reactivity and the success to ITI with a VWF/FVIII complex concentrate, as suggested by other authors [15,17,18]. Anyway, the limited number of tested patients and the low sensitivity of the method do not allow us to draw definite conclusions.…”

Section: Discussionmentioning

confidence: 43%

“…VWF, beyond being the physiological FVIII-stabilizing protein [12,13] was shown to protect FVIII from neutralizing antibodies in vitro [14][15][16][17][18][19][20]. Accordingly, a better response to ITI was observed in two case series when ITI carried out with FVIII concentrates rich in VWF [21,22] was compared with ITI carried out with VWF-free FVIII concentrates either plasmaderived monoclonally purified or recombinant.…”

Section: Introductionmentioning

confidence: 99%

Immune tolerance induction with a high purity von Willebrand factor/VIII complex concentrate in haemophilia A patients with inhibitors at high risk of a poor response

et al. 2007

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Summary. Immune tolerance induction (ITI) iseffective in approximately 70% of haemophilia patients with inhibitors. Poor prognostic factors are age >6 years, ITI started >1 year from inhibitor development, inhibitor peaks >200 BU, inhibitor titre >10 BU when ITI is started and previously failed ITI. The objective of this study was to identify the effectiveness in ITI of a high purity von Willebrand factor/factor VIII (VWF/FVIII) complex concentrate in inhibitor patients at high risk of failure. Patients with severe or moderate haemophilia A and high responding inhibitors who had at least one poor prognostic factor for ITI failure were prospectively followed-up. Success was defined by undetectable inhibitor, recovery and half life >66% of expected values. ITI dose regimens were chosen by each haemophilia centre. Seventeen haemophiliacs (16 severe, one moderate), aged 4-54 years (median 23) were followed-up for 6-71 months. Poor prognostic factors were delayed-onset ITI (n ¼ 16), age >6 years (n ¼ 16), previously failed ITI (n ¼ 4), inhibitor peak >200 BU (n ¼ 2) and inhibitor >10 BU when ITI was started (n ¼ 4). Complete success was obtained in nine patients (53%) after 4-30 months of treatment (median 24), including two of four patients who had previously failed ITI. Seven patients achieved a partial success, with sustained low inhibitor titres (median 1.5 BU, range 1.1-2.8) but abnormal recovery and/or half-life, while the remaining patient withdrew ITI after 12 months when the inhibitor titer was still 70 BU. These findings suggest that high purity VWF/ FVIII complex concentrates are effective in ITI, even in patients at high risk of failure.

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“…In general, the higher the VWF content, the lower the inhibitor reactivity [30,31], presumably because of more complete blockade of antilight-chain antibodies [32]. The lower inhibitor reactivity observed with VWF-containing pdFVIII concentrates also translates into greater thrombin generation, according to recent in vitro studies [33], further substantiating a role for VWF in the management of inhibitor patients.…”

Section: Fviii/vwf Complex and The Management Of Patients With Inhibimentioning

confidence: 89%

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

2007

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von Willebrand factor in factor VIII concentrates protects against neutralization by factor VIII antibodies of haemophilia A patients

Cited by 33 publications

References 14 publications

VWF/FVIII complex and the management of patient with inhibitors: from laboratory to clinical practice

VWF/FVIII complex and the management of patient with inhibitors: from laboratory to clinical practice

Immune tolerance induction with a high purity von Willebrand factor/VIII complex concentrate in haemophilia A patients with inhibitors at high risk of a poor response

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

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