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Blood-clotting protein modified for people with hard-to-treat hemophilia

Pathologists at The University of Texas Health Science Center at Houston have developed a chemically modified protein that may help people with a hard-to-treat form of a genetic bleeding disorder known as Hemophilia A. The discovery and the results of pre-clinical tests appear in the May 2 issue of the Journal of Biological Chemistry.

With a shortage of the blood-clotting protein Factor VIII (FVIII), people with Hemophilia A typically receive injections of FVIII derived from plasma or produced synthetically to control potentially life-threatening episodes of bleeding. Unfortunately as many as 1 in 3 people with Hemophilia A produce inhibitor antibodies, which attack the externally-administered FVIII and negate its blood-clotting benefits.

To combat this problem, scientists in the laboratory of Sudhir Paul, Ph.D., at The University of Texas Medical School at Houston, developed a chemically modified version of FVIII which during laboratory tests neutralized these inhibitor antibodies, thus paving the way for the correction of the blood-coagulating process. The modification is called electrophilic FVIII analog (E-FVIII).

Its a two-step process, said Paul, the senior author. The E-FVIII permanently inactivates the antibodies that inhibit blood clotting in 20 to 30 percent of patients receiving Factor VIII replacement therapy. Once the antibodies are cleared, additional FVIII can be injected. The study involved blood donated by eight people with FVIII-resistant Hemophilia A.

Today, people with FVIII-resistant Hemophilia A have limited treatment options, said co-author Keri Smith, Ph.D., an assistant professor of pathology and laboratory medicine at the UT Medical School at Houston. Those options include bypass therapy or multiple FVIII injections. Both are prohibitively expensive and often ineffective to meet emergency blood-clotting needs.

E-FVIII might provide a more economically feasible method of treating inhibitor antibodies, Smith said.

There is no cure for Hemophilia A, and it primarily affects males. About one of every 7,000 males born in the United States has this condition. A person with hemophilia bleeds longer than a person without hemophilia.

Stephanie Planque, who is lead author and is working towards her Ph.D. degree, helped conceive the chemical inactivation principle behind the study. The modified FVIII analog was produced by pathology faculty Hiroaki Taguchi, Ph.D., and Yasuhiro Nishiyama, Ph.D., using newly developed synthesis methods. Miguel Escobar, M.D., of the department of pediatrics and internal medicine at the UT Medical School at Houston and the Gulf States Hemophilia and Thrombophilia Center, led the clinical aspects of the work, and Kathleen Pratt, Ph.D., at the Puget Sound Blood Center and Division of Hematology, University of Washington, Seattle, contributed a genetically-produced protein that helped the study reach its conclusions.

According to Paul, the next step involves clinical trials. E-FVIII is a first generation reagent. Future genetic and chemical manipulations may help develop improved E-FVIII analogs, Paul wrote in the paper.


Contact: Robert Cahill
University of Texas Health Science Center at Houston

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