Research Spotlight

Projects that help to improve care and preserve access to high quality care are our priority. Currently ATHN’s three current projects are actively recruiting sites and patients. Each is highlighted below and we welcome your involvement.

Plasminogen Deficiency Registry – Powered by ATHN

The plasminogen deficiency registry is up, running and ready to register your patients with plasminogen deficiency.The registry will begin to determine the approximate number and type of patients in the U.S. and Canada who present with signs and symptoms of this disorder. Click here to register your patients. PlasminogenRegistry.org.

Plasminogen is a coagulation enzyme, which, when deficient, leads to a variety of conditions that can affect multiple sites, including the eye, gingiva, cervix, bronchial tree, renal collecting system, ear and sinuses. Because the prevalence of plasminogen deficiency has been poorly documented, researchers, Rakesh Mehta, M.D., Assistant Professor of Clinical Medicine, Section of Hematology/Oncology at the Indiana University School of Medicine and Amy D. Shapiro, M.D., Medical Director of the Indiana Hemophilia and Thrombosis Center in Indianapolis have developed a plasminogen deficiency registry.

ATHN assisted Drs. Mehta and Shapiro in developing and hosting this web-based registry to help identify patients with this disorder. The registry will collect information from the network of federally-funded HTCs. The registry will also be open to the broad base of providers who are not associated with HTCs and who are caring for patients with plasminogen deficiency, such as ophthalmology, oral surgery, otolaryngology and hematology.

Case documentation is essential to establish the need for developing new therapies. Drs. Mehta and Shapiro need provider assistance to identify cases to determine the

• prevalence of plasminogen deficiency;
• range of clinical manifestations experienced; and
• present therapeutic interventions used.

The registry takes approximately 10 minutes to complete, and ATHN is encouraging HTC providers to report their case experience with plasminogen deficiency via this web-based data collection tool. No individual patient identifying information is required. Click here to go directly to the survey PlasminogenRegistry.org.

The data collected will serve as a foundation for developing a network of health care providers interested in information sharing and ultimately for identifying potential subjects for future clinical trials for a plasminogen replacement product.

Severe Factor X Deficiency Study – Patients Needed

Who are the sites that treat severe factor X deficiency patients in the U.S.? That’s the question ATHN attempted to answer for Bio Products Laboratory as they prepare for an international trial
to investigate the pharmacokinetics, safety and efficacy of a high purity factor X concentrate in patients with severe factor X deficiency. The feasibility study conducted by ATHN is complete, but the need to identify sites with patients that meet the study criteria continues.

Factor X deficiency is a rare coagulation disorder and one of the most severe of the inherited coagulation disorders. Currently, there are no factor X concentrates available and fresh-frozen plasma (FFP) is normally used as treatment. Prothrombin Complex concentrates (PCCs) have been used in patients, but the amount of factor X in each product has not been consistent. There has also been a reported risk of thromboembolic complications with PCC product usage. U.K.-based Bio Products Laboratory (BPL) hopes to change treatment options with development of a high-purity plasma-derived factor X concentrate. The company has an international clinical trial planned for 2009, with enrollment of U.S. patients starting in the spring.

BPL hopes that its high-purity plasma-derived factor X concentrate will offer advantages over the current standard treatment of PCC or FFP. Based on the feasibility study, potential U.S. clinical trial sites have been identified, with more in several countries across Europe. BPL is seeking more sites to join the trial.

BPL welcomes inquiries about the trial from clinicians treating one or more adult or pediatric patients with severe or moderate hereditary factor X deficiency. Please contact ATHN at info@athn.org or Miranda Norton, BPL Clinical Study Manager, at miranda.norton@bpl.co.uk or phone on +44 20 8258 2661 for more information.

Von Willebrand Disease

The von Willebrand Disease Prophylaxis Network is actively seeking participation from treatment centers. The ATHN project review panel has endorsed the study and encourages investigators that might be interested to contact the Network for more information. The following article by Thomas C. Abshire, M.D., Director, Emory University Comprehensive Hemophilia Program Professor of Pediatrics at Emory University School of Medicine in Atlanta, GA, describes a new study being conducted to improve prophylactic treatment regimens for von Willebrand Disease, a common hereditary bleeding disorder. After reading the article, consider becoming involved in this ground-breaking effort.

Improving Prophylactic Treatment Regimens for von Willebrand Disease

by Thomas C. Abshire, M.D.
Director, Emory University Comprehensive Hemophilia Program Professor of Pediatrics, Emory University School of Medicine

Von Willebrand disease (VWD) is a common hereditary bleeding disorder that may affect as much as 1% of the general population¹. Clinically, the predominant bleeding symptom in VWD is mucosal bleeding. In more severe forms of VWD with lower levels of factor VIII (FVIII), spontaneous and traumatic joint and muscle bleeding, resembling that observed in hemophilia A, may also be observed. Strategies for treatment vary by type and severity and include DDAVP (1-desamino-8-D-arginine vasopressin), use of antifibrinolytics and replacement therapy with a VWF/FVIII product.

Investigators participating in a survey of 74 treatment centers conducted during 2005-2006 reported that, in the last 12 months, approximately 70% of their patients with type 3 VWD had been treated with VWF containing plasma-derived products. Twenty-two percent were on prophylaxis. The most common reasons for initiating prophylaxis were joint (40%), epistaxis/oral (23%), gastrointestinal (GI) bleeding (14%), and menorrhagia (5%)² .

Long-term prophylaxis in VWD has been successfully used in severe hemophilia and prevention of bleeding and its consequences is possible,³ which provided the rationale for considering its use. Data to support prophylaxis in VWD come from a multi-center study conducted in Sweden. Investigators concluded that long-term prophylactic treatment in VWD is warranted in the majority of cases with type 3 disease and, in some cases, depending on the clinical phenotype, for those with type 1 or type 2⁴.

The von Willebrand Disease Prophylaxis Network’s VIP Study

The von Willebrand Disease Prophylaxis Network (vWD PN) was formed to investigate the role of prophylaxis in clinically severe VWD that is non-responsive to other treatments through prospective and retrospective study. The VWD International Prophylaxis (VIP) study is an initiative of the vWD PN⁵.

The primary objectives of the VIP study are to:

1. Study the effect of prophylaxis on bleeding frequency
2. Establish optimal treatment regimens for the predominant bleeding manifestations:
   
   1. joint bleeding;
   2. GI bleeding;
   3. epistaxis; and
   4. menorrhagia.

The prospective component of the VIP study is a multi-center, non-randomized study in which participants will undergo an escalation of treatment from one to three doses of VWD product per week, similar to the Canadian prophylaxis trial using dose escalation in subjects with hemophilia⁶.

The retrospective studies are being conducted in parallel with the prospective study. They are multi-center with the following objectives:

1. Examine the effect of prophylaxis on bleeding frequency in patients currently on prophylaxis; and
2. Characterize the natural history of GI bleeding.

The retrospective study of the effect of prophylaxis on bleeding frequency is comprised of people on a prophylactic regimen that was initiated at least 6 months prior to enrollment. Data from subjects who have a history of GI bleeding due either to proven angiodysplasia or unexplained by other factors are being collected to document the number of bleeding episodes, management and outcome.

Status of the Study

The vWD PN currently includes 27 centers in Europe and North America. We believe that the efforts to identify and implement optimal prophylactic treatment regimens for VWD will greatly benefit a substantial proportion of people, especially those with type 3 disease, who are most severely affected. We are actively engaging treatment centers to participate with us in this effort and to encourage investigators that might be interested to contact us for more information (Thomas.Abshire@emory.edu; Erik.Berntorp@med.lu.se; SDonfield@rhoworld.com).

The VIP study has been approved by the American Thrombosis and Hemostasis Network (ATHN), the Hemophilia and Thrombosis Research Society (HTRS), and is officially recognized by the Von Willebrand Factor SSC of the ISTH. It is registered at www.ClinicalTrials.gov.

¹Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand’s disease. Blood 1987;69: 454-459.
²Berntorp E and Abshire T, for the von Willebrand Disease Prophylaxis Network. The von Willebrand Disease Prophylaxis Network: exploring a treatment concept. Journal of Thrombosis and Haemostasis 2006; 4(11):2511-2.
³Nilsson IM, Berntorp E, Löfquist T, Pettersson H. Twenty-five years’ experience of prophylactic treatment in severe haemophilia A and B. Journal of Internal Medicine 1992;232(1):25-32.
Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, Ingram JD, Manco-Johnson ML, Funk S, Jacobson L, Valentino LA, Hoots WK, Buchanan GR, DiMichele D, Recht M, Brown D, Leissinger C, Bleak S, Cohen A, Mathew P, Matsunaga A, Medeiros D, Nugent D, Thomas GA, Thompson AA, McRedmond K, Soucie JM, Austin H, and Evatt BL. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. New England Journal of Medicine 2007;357(6):535-44.
⁴Berntorp E and Petrini P. Long-term prophylaxis in von Willebrand disease. Blood Coagulation and Fibrinolysis 2005;16 Supplement 1:S23-6.
⁵The VIP study is an initiative of the vWD PN, an investigator-initiated study funded through an unrestricted grant by CSL Behring, Marburg, Germany.
⁶Blanchette VS, Manco-Johnson M, Santagostino E, Ljung R. Optimizing factor prophylaxis for the haemophilia population: where do we stand? Haemophilia 2004;10 Supplement 4:97-104.