Winning Spirit Newsletter Winter 2010

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Research Updates

2009 Inhibitor Education Summits for Patients and Families Living with Inhibitors

For the fifth year, the National Hemophilia Foundation (NHF) and the Center for Biomedical Continuing Education (CBCE) hosted Hemophilia Inhibitor Education Summits to connect patients and their families with expert healthcare professionals and fellow patients to address critical topics including pain management, exercise and nutrition and financial security. The summits took place in Los Angeles, California and Washington, DC.

Many families have cultivated a strong sense of community through their participation year after year and value the chance to have access to leading experts and information about the latest advancements in treatment and new technologies for the inhibitor community.

Attendees like Bob Hoyt of Seymour, Connecticut, who participated in the DC Summit, shared that he attends annually to learn about cutting edge research that he may otherwise not have access to through his local network. He learned about knee replacement at a previous summit, which ultimately influenced his decision to undergo the procedure himself — a decision he is glad he made, as it was a huge success.

Led by experts, including summit co-chairs Dr. Leonard Valentino and Dr. Guy Young, sessions profiled research regarding improved bypassing agents with increased potency and faster and longer-acting products with reduced dosing requirements. Ongoing scientific investigations are addressing the potential for inhibitor prevention, better bleed management and inhibitor eradication. In addition, dental issues were discussed.

According to Dr. Leonard Valentino, “Inhibitors are the most serious complication of hemophilia and most certainly the most expensive.” Additionally, the summit addressed healthcare reform including the elimination of lifetime caps and pre-existing condition exclusions as well as a public health insurance option. For more information, visit: www.inhibitorsummits.org.

Investigators Look at Confusing Case of VWD Misdiagnosis

Researchers from the Medical College of Wisconsin recently looked at a puzzling case of laboratory testing for von Willebrand disease (VWD). The lead investigator of the study was Veronica Flood, MD, pediatric oncologist and assistant professor, Division of Hematology/Oncology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee.

VWD and its subtypes are characterized by either quantitative or qualitative defects in von Willebrand factor (VWF) and are associated with bleeding symptoms that, depending on the type, can be mild, moderate or severe. While VWD types I and III signify partial or complete lack of VWF, type II and its variation subtypes (2A, 2B, 2M, 2N) typically signify a dysfunction associated with VWF. Accurate diagnosis of these subtypes is generally considered far more complicated than hemophilia.

In many instances, a battery of tests that measure VWF quantity and function are required to pinpoint a VWD diagnosis. Flood’s study focused on one specific case of type 2M VWD and the limitations in a particular lab test, the VWF ristocetin cofactor activity (VWF:RCo), when determining a diagnosis. VWF:RCo is a relatively simple lab test in which blood cells are separated from a patient’s plasma (liquid component of blood). Ristocetin, an antibiotic that prompts the binding of VWF and platelets together, is then added to the plasma. In reaction, blood with viable VWF will clot and blood with deficient VWF will not clot.

While the patient featured in this study showed a significant decrease in VWF:RCo, the other assay tests of VWF function were normal. In addition, the patient exhibited no bleeding symptoms. Flood and colleagues discovered that while VWF:RCo tests performed outside the body registered poor VWF function, the activity of VWF inside the patient’s body did not appear to be affected. Because of this discrepancy and the lack of bleeding symptoms, investigators called the initial diagnosis of type 2M VWD into question, pointing to the likelihood of an inaccurate diagnosis.

Flood and her colleagues concluded that a correct diagnosis of VWD, regardless of type, needs to be based on not just one test but rather on a comprehensive series of tests and the patient’s symptoms.

Flood’s research was supported, in part, by a Career Development Award from the National Hemophilia Foundation. Her work was also supported by a grant from the National Institutes of Health and a Mentored Research Award from the Hemophilia and Thrombosis Research Society.

source: Flood V, Friedman K, Gill J, et al. Limitations of the Ristocetin Cofactor Assay in Measurement of VWF Function. Journal of Thrombosis and Haemostasis. 2009; Volume 7 (Issue 11): Pages 1832 –1839.–

Duke Study Links Genetic Determinant with HCV Therapy Success

A report published online in the August 6, 2009, issue the journal Nature suggests that the reason for the difference in responses to the standard hepatitis C (HCV) treatment, a combination therapy of interferon and ribavirin, may lie in a specific variation in a patient’s genes. The study was led by David B. Goldstein, PhD, Professor of Molecular Genetics & Microbiology, Institute for Genome Sciences & Policy, Center for Human Genome Variation, Duke University in Durham, NC.

Although the interferon/ribavirin combination effectively treats many chronic HCV patients, nearly 50% do not respond to it. Further, patients who do respond to treatment often experience debilitating side effects that can last the duration of the treatment—either 24 or 48 weeks. Interferon side effects include severe flulike symptoms, depression, fatigue and insomnia. Ribavirin can cause anemia, skin rash and itching, fatigue and birth defects. Hence, it would be beneficial to be able to predict in which patients the therapy will work.

Goldstein and his team used a genetic test known as a genome-wide association study, to screen the three billion sites of the human genome of 1, 671 patients with HCV genotype 1. They found a specific location containing genetic coding that could play a decisive role in HCV therapy response. Investigators believe that the combination of DNA units a person inherits at this location determines the amount of interferon (natural proteins manufactured by human cells to fight viral infections) the body will produce. The amount of interferon, explained researchers, affects an individual’s ability to battle infections such as HCV.

A person inherits two copies of the genome at the site, one from each parent, either a “T” or a “C” unit, with three possible outcomes: CC, TT or CT. A person with the CC version responds much better to interferon/ribavirin than those with the TT version. While C versions are more prevalent in East Asians and Europeans, they are far less common in people of African ancestry. C versions are most common among East Asians.

A comparison of the HCV therapy success rates in each of the three groups highlights the disparity. Approximately 75% of East Asians respond favorably to combination therapy, compared to 55% of Americans of European ancestry. In stark contrast, only an approximate 25% of African-Americans experience a successful round of HCV therapy.

The report, “Genetic Variation in IL28B Predicts Hepatitis C Treatment-Induced Viral Clearance,” was published August 16, 2009, on the Nature website.

Source: The New York Times, August 17, 2009

T Cells are Key Players in Immune Tolerance of Clotting Factor

Researchers from the University of Florida (UF) in Gainesville recently reviewed data that provide convincing evidence that regulatory T cells, called Treg, play a vital role in the prevention of inhibitor antibodies to clotting factors. Treg are a special type of T cell that suppress activation of the immune system. The findings could have positive implications for both factor replacement therapy and potential gene therapies for hemophilia. The lead author of the study was Ou Cao, MD, PhD, Assistant Professor, Division of Cellular and Molecular Therapy at UF.

Inhibitors are a major complication in the clinical management of hemophilia. It is both costly and difficult to treat. Approximately 10% to 30% of hemophilia A patients and 1%-4% of hemophilia B patients develop inhibitors, which occur when the body’s immune system recognizes infused clotting factor as a foreign substance and releases antibodies to it. These antibodies attack the factor, neutralizing its therapeutic effects.

Cao and colleagues explained that Treg are an important part of the mechanism by which inhibitor formation can be prevented and tolerance to clotting factor could be ensured. Investigators concluded that whether naturally occurring or induced, these cells are “invoked” in the suppression of antibody responses to clotting factor. Treg is therefore crucial to tolerance, according to the authors.

While the risk of inhibitors with genetically triggered factor production is not fully understood, investigators believe Treg could apply to gene-based therapies as well, adding that the cells could become a key component in establishing tolerance to clotting factors in “gene- or protein-based therapies.” Cao and fellow authors explained that novel therapies and immune tolerance induction protocols could be developed with this insight into the workings of immune regulation.

Source: Cao O, Loduca P, Herzog R. “Role of Regulatory T Cells in Tolerance to Coagulation Factors.” Journal of Thrombosis and Haemostasis 2009; 7 (Suppl. 1): 88-91.