Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations

Berntorp, Erik; Ekman, Maj; Gunnarsson, Mikael; Nilsson, Inga Marie

doi:10.1111/j.1365-2516.1996.tb00022.x

Cited by 66 publications

(81 citation statements)

References 19 publications

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“…Cumulative evidence stemming from national and international registries [5][6][7][8][9] identified the following as potential prognostic factors for a positive response: young age at ITI, recent onset of inhibitors, low anamnestic peak titres and low titres at ITI start-up. Recently, case series [22,21] and in vitro studies [16,29] have suggested a potential additional role for FVIII concentrates with a high content of VWF in the induction of immune tolerance. We report, herewith, the results of the first prospective study on ITI using exclusively a high purity VWF/FVIII complex concentrate, involving 17 patients at high risk of poor response treated with different dosages of the study concentrate.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

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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“…38 Several clinical observations and in vitro studies suggested that von Willebrand factor in factor VIII concentrates protects factor VIII from circulating inhibitory antibodies by masking antibody epitopes on the C2 domain. 37,39,40 Additionally, hemophilic mice treated with factor VIII products without von Willebrand factor developed higher peak inhibitor titers than those treated with factor VIII products that contained von Willebrand factor. 41 We showed that there is no decreasing trend in inhibitor development with an increasing von Willebrand factor content.…”

Section: Fviii Product Type and Inhibitors Inmentioning

confidence: 99%

Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study

Gouw

Bom

Auerswald

et al. 2007

Blood

215

209

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It has been suggested that plasma-derived factor VIII products induce fewer inhibitors than recombinant factor VIII products. We investigated the relationship of factor VIII product type and switching between factor VIII products with the risk to develop inhibitors. This multicenter retrospective cohort study included 316 patients with severe hemophilia A born between 1990 and 2000. The outcome was clinically relevant inhibitor development, defined as the occurrence of at least 2 positive inhibitor titers with decreased recovery. The risk of inhibitor development was not clearly lower in plasma-derived compared with recombinant factor VIII products (relative risk [RR], 0.8; 95% confidence interval [CI], 0.5-1.3). Among high-titer inhibitors, the possible reduction in risk was even less pronounced (RR, 0.9; CI, 0.5-1.5). Plasma-derived products with considerable quantities of von Willebrand factor (VWF) carried the same risk for inhibitor development as recombinant factor VIII products (RR, 1.0; CI, 0.6-1.6). Switching between factor VIII products did not increase the risk for inhibitors (RR, 1.1; CI, 0.6-1.8). In conclusion, our findings support neither the notion that plasmaderived factor VIII products with considerable concentrations of VWF confer a lower risk to develop inhibitory antibodies than recombinant factor VIII products, nor that switching between factor VIII product brands increases inhibitor risks in previously untreated patients with severe hemophilia A. IntroductionAt present, the main concern in the treatment of children with severe hemophilia A is the development of inhibitory antibodies that neutralize infused factor VIII, occurring in 10% to 30% of patients. 1 Several patient-related factors have been associated with the risk of developing inhibitors, such as factor VIII gene mutation, 2-4 other genetic factors, 5-8 family history of inhibitors, 9-11 and ethnicity. 11,12 In addition to these determinants, a number of treatment-related factors have been suggested to affect the risk of inhibitor development, such as prophylaxis, 13,14 age at first exposure, 15,16 and intensity of treatment. 17 One of the most intensively discussed potential risk factors is the factor VIII product type.Indications for a potential role of the factor VIII product type in inhibitor development arose when prospective registration studies of recombinant factor VIII products among previously untreated hemophilia A patients reported inhibitor incidences between 29% and 32%. [18][19][20][21][22][23] These incidences were considerably higher than the previously observed 0% to 12% in patients treated with single plasma-derived products. 1,24 However, methodologic differences between studies rendered comparisons inconclusive. 25 More convincing were the findings of a recent comparative study in which the inhibitor risk in patients treated with full-length recombinant factor VIII was again higher than the risk in patients treated with a high-purity plasma-derived factor VIII product containing von Willebrand factor (VWF)...

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“…Based on the previously mentioned in vivo finding on varying recoveries with two different types of FVIII concentrates, we have shown that some plasmas from patients with inhibitors display less reactivity against VWF containing concentrates when compared with highly purified plasma-derived concentrates or recombinant FVIII concentrates [11]. These findings have since been corroborated by others [12,13].…”

Section: In Vitro Observations On Antibody Reactivity With Fviii Concmentioning

confidence: 80%

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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Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations

Cited by 66 publications

References 19 publications

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

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

Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study

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

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