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Blood, 1 August 2007, Vol. 110, No. 3, pp. 1074-1075.

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CORRESPONDENCE

Response: Plasma-derived or recombinant factor VIII products and inhibitors in previously untreated patients with severe hemophilia

We appreciate the letter by Calvez et al and we agree that analytic decisions affect the findings from studies. Calvez et al propose 2 explanations for the observed differences between the findings of the study by Goudemand et al,1 the study by Chalmers et al,2 and our analyses of the Concerted Action on Neutralizing Antibodies in severe hemophilia A (CANAL) study.3 It was suggested that we found a smaller effect from recombinant products as opposed to plasma-derived products because we misclassified the exposure days of patients who received Beriate. Calvez et al proposed that Beriate should not have been included in the high–von Willebrand factor group. To examine this possibility, we repeated our analyses after excluding all 32 patients who had been treated with Beriate. In accordance with our previous findings, we found that patients on recombinant factor VIII products have the same risk as the patients on plasma-derived products with high–von Willebrand factor content (Table 1). Thus, Beriate did not explain the difference between our findings and the ones from Goudemand et al.1


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Table 1. Relative rate of developing inhibitory antibodies against factor VIII in severe hemophilia A patients receiving recombinant factor VIII products as compared to plasma-derived factor VIII products

 
The other explanation concerned the fact that we had considered the factor VIII product as a time-varying variable, implying that the patients on plasma-derived products who switched to recombinant products during follow-up contribute their early exposure days to the plasma-derived group, and, immediately after the switch, they contribute exposure days to the recombinant product group. To evaluate this possibility, we excluded all postswitch exposure days and again repeated our analyses. The findings confirmed that the risk of inhibitors is not clearly increased in patients who received recombinant products as opposed to plasma-derived products with high–von Willebrand factor content (Table 1). In the table, we also present the findings of the CANAL study in the subgroup of patients who did not receive Beriate and whose exposure days are censored after switching from one product to another.

We have shown that the proposed explanations for differences between our study and the study by Goudemand et al1 do not hold. Two other explanations could be the subject of future research: (i) other risk factors for inhibitors, such as intensity of treatment,4 may have confounded the study by Goudemand et al1; (ii) some plasma-derived products indeed confer a lower risk of inhibitors. Yet, it seems unlikely that von Willebrand factor is a major player in this.


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Correspondence: Johanna G. van der Bom, Department of Clinical Epidemiology, Leiden University Medical Center and van Creveldkliniek/Department of Hematology, University Medical Center Utrecht, The Netherlands; e-mail: j.g.vanderbom{at}lumc.nl.

Johanna G. van der Bom, Samantha C. Gouw, and H. Marijke van den Berg


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  1. Goudemand J, Rothschild C, Demiguel V, et al. Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A. Blood 2006; 107:46–51.[Abstract/Free Full Text]

  2. Chalmers EA, Brown SA, Keeling D, et al. Early factor VIII exposure and subsequent inhibitor development in children with severe haemophilia A. Haemophilia 2007; 13:149–155.[CrossRef][Medline] [Order article via Infotrieve]

  3. Gouw SC, van der Bom JG, Auerswald G, Escuriola EC, Tedgard U, van den Berg HM. Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study. Blood 2007; 109:4693–4697.[Abstract/Free Full Text]

  4. Gouw SC, van der Bom JG, van den Berg HM. Treatment-related risk factors of inhibitor development in previously untreated patients with hemophilia A: the CANAL cohort study. Blood 2007; 109:4648–4654.[Abstract/Free Full Text]


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Associations between type of product and inhibitors in previously untreated patients (PUPs) with severe hemophilia: switches and particular products can disturb analysis
Thierry Calvez, Yves Laurian, and Jenny Goudemand
Blood 2007 110: 1073-1074. [Full Text] [PDF]

Recombinant versus plasma-derived factor VIII products and the development of inhibitors in previously untreated patients with severe hemophilia A: the CANAL cohort study
Samantha C. Gouw, Johanna G. van der Bom, Günter Auerswald, Carmen Escuriola Ettinghausen, Ulf Tedgård, and H. Marijke van den Berg, for the CANAL Study group
Blood 2007 109: 4693-4697. [Abstract] [Full Text] [PDF]




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