Overcoming the diagnostic and monitoring challenges for very rare bleeding disorders in the US: the potential benefits of a centralized laboratory.

While there are challenges to understanding more about bleeding disorders through research due to the orphan nature of disorders such as the congenital haemophilias, the challenge is even greater for the much less common group of clotting factor deficiencies, qualitative platelet disorders, and other rare clinical conditions, designated collectively as rare bleeding disorders (RBDs). For haematologists treating these patients, collaboration around global registries is often required to help shed light on best practices in management. Between 2008 and 2011, two registries that provided post-marketing surveillance data around the use of recombinant factor VIIa (rFVIIa) in acquired haemophilia (AH) closed. The EACH-2 registry captured data between 2003 and 2008 and included 501 patients with AH from 117 centres and included data on 474 bleeding episodes, follow-up for post-partum haemorrhage and outcomes of immunosuppression [1– 4]. The Hemostasis and Thrombosis Research Society (HTRS) registry captured data between 2000 and 2011 and included 166 patients with AH with 237 bleeding episodes and 58 surgical procedures [5–7]. In 2011, two additional registries, which were designed in part to capture post-marketing surveillance data around the use of rFVIIa closed, capping a multi-year effort by dedicated haematologists around the world to track treatment of Glanzmann’s thrombasthenia and congenital FVII deficiency, irrespective of treatment product. Initiated in 2006, the Glanzmann’s Thrombasthenia Registry (GTR) captured data on 218 patients with Glanzmann’s thrombasthenia from 45 sites in 15 countries with 1073 admissions for 870 bleeding episodes and 204 surgical procedures [8]. The Seven Treatment Evaluation Registry (STER) captured data on 75 patients with FVII deficiency from 15 countries with 101 bleeding events [9]. STER also captured data on 38 patients with 38 surgical procedures, along with data on 34 patients treated with routine FVII replacement [10,11]. There certainly is the temptation to move right from the ‘need’ to capture data about a rare disorder to choosing a registry or electronic medical record platform. Recent approval of plasma derived replacement for fibrinogen and FXIII, as well as a recombinant FXIII concentrate highlight the need for accumulating such post-approval data. One of the key issues around the accumulation of clinical or registry/trial data is that the data would have little or no utility for either clinical management or scientific research without assurances that the laboratory diagnosis and monitoring assays of the RBDs were accurate and consistent. Many of the participating institutions in clinical studies, registries and database platforms possess their own internal College of American Pathologists – Clinical Laboratory Improvement Act (CAP-CLIA) certified specialty coagulation laboratories and were experienced in supporting clinical research trials in any number of medical diseases, including trials of RBDs that used central laboratories. Yet, most institutions only infrequently perform clotting factor assays for RBDs within their institutions and instead rely on outside commercial concerns for their ‘send outs’. This is a fiscal, reimbursement, and man-power necessity for hospital-based laboratories, particularly since many of these laboratory assays have not been approved for clinical care decision making by the US Food and Drug Administration (FDA) and are thus labelled ‘research use only’ (RUO). Such designation often compromises the ability to obtain insurance reimbursement for testing and limits the number of laboratories where the testing can be performed. One example is testing for congenital FXIII deficiency, where a widely used assay is the clot-solubility test, a screening test for FXIII deficiency only sensitive to levels less than 1%. The standard quantitative functional assay (Berichrom FXIII, Seimens Healthcare, Nederland), used both in clinical trials and for adjusting treatment in routine clinical practice, is insensitive below 5–10% and is RUO [12]. A United Kingdom National External Quality Assessment Service study in Correspondence: Meera Chitlur, Associate Professor of Pediatrics, Wayne State University School of Medicine, Director, Hemophilia Treatment Center and Hemostasis Program, Children’s Hospital of Michigan, 3901, Beaubien Blvd, Detroit, MI 48201, USA. Tel.: 313 745 5515; fax: 313 745 5237; e-mail: [email protected]