Relationship between the Binding Sites for von Willebrand Factor, Phospholipid, and Human Factor VIII C2 Inhibitor Alloantibodies within the Factor VIII C2 Domain

Q4 · MEDICINE

Article

Author: Keiji Nogami ; Akira Yoshioka ; Masahiro Takeyama ; Ichiro Tanaka ; Midori Shima ; John C. Giddings

Some factor VIII (FVIII) inhibitor alloantibodies block FVIII binding to von Willebrand factor (VWF) and phospholipid (PL) and recognize a C2 domain epitope that overlaps both binding sites. We previously showed that FVIII peptide 2315-2330 neutralized FVIII inhibitors and that Cys2326 and Glu2327 contributed to the maximum neutralizing effect. In the present study, we investigated the relationship between the essential binding sites for VWF, PL, and anti-C2 inhibitors by means of competitive-inhibition assays with overlapping synthetic peptides that span the C terminus of the C2 domain (residues 2288-2332). We identified 2 peptides (residues 2303-2317 and 2315-2330) that specifically blocked FVIII binding to VWF or PL by approximately 80% (50%-inhibitory concentration [IC50], 9.0 microM) and 95% (IC50, 0.12 microM), respectively. To examine in detail the residues responsible for PL binding, we prepared mutants of peptide 2315-2330 in which we sequentially substituted each residue with Gly. Two residues, Ile2317 and Met2321, were shown to be essential for PL binding. Their substitution with Gly reduced the inhibitory effect by >90%. The data suggest that the binding sites for VWF, PL, and anti-C2 inhibitors in the C2 domain are in very close proximity but are not identical.

01 Jun 1984·Blut

The treatment of haemophilia a inhibitor with high dose intravenous immunoglobulin

Article

Author: H. Rasche ; E. Seifried ; G. Gaedicke ; G. Pindur

In patients with Haemophilia A, the development of inhibitor is a life-threatening complication of treatment. These patients are at high risk for dangerous bleeding as a result of this acquired resistance to human Factor VIII concentrate. Although treatment of bleeding complications has been improved with the introduction of an activated prothrombin complex preparation, therapy remains unsatisfactory. Two patients with Haemophilia A inhibitor were treated with high dose intravenous immunoglobulin in the expectation of an immunosuppressive effect. A rise in the antibody titre at the same time as the administration of factor VIII concentrate showed that this treatment was ineffective in patients with Haemophilia A inhibitor.

100 Deals associated with Human coagulation factor VIII(CSL Behring LLC)

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Indication	Country/Location	Organization	Date
Hemophilia A	IT	CSL Behring LLC	21 Sep 2015
Hemophilia A	ES	CSL Behring LLC	21 Sep 2015
Hemophilia A	AT	CSL Behring LLC	21 Sep 2015
Hemophilia A	DE	CSL Behring LLC	21 Sep 2015
Hemophilia A	BR	CSL Behring LLC	21 Sep 2015
Hemophilia A	CH	CSL Behring LLC	21 Sep 2015

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Indication	Highest Phase	Country/Location	Organization	Date
Hemophilia A	Preclinical	-	CSL Behring LLC	-

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