A US Pilot Data Registry for Patients with Congenital Thrombotic Thombocytopenic Purpura (CTTP): The Unexpected Results
Authors: Singleton Tammuella , Aledort Louis M. , Cindy Leissinger , Ulsh Paula , Bergman Garrett E. 
Published: October 2019

Abstract
Congenital thrombotic thrombocytopenic purpura (cTTP), due to a deficiency of ADAMTS-13, the cleaving enzyme for ultrahigh-molecular weight multimers of von Willebrand Factor, has been considered to be very rare. Clinically it is characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and intravascular thrombosis, especially involving the kidney and brain. Patients affected can have recurrent acute episodes throughout their life, separated by asymptomatic time periods; episodes often begin neonatally. Initially, it was thought that there were fewer than 100 patients in the world, an incidence of < 1:100,000,000. Although extremely rare, cTTP has been reported in all continents. The International Hereditary TTP Registry (www.ttpregistry. net), established at Bern University, in 2009, has previously reported on 123 patients and family members from 18 countries. The International Rare Bleeding Disorders Database (RBDD; www.rbdd.org) and the Thrombotic Thrombocytopenia Purpura (TTP) Database (www.ttpdatabase.org) were established at University of Milan and are beginning to collect clinical, genetic and laboratory data on over 250 patients with cTTP reported globally.
Baxter International has been developing a recombinant form of ADAMTS-13 for several years, to treat patients with TTP; recently a plasma-derived factor VIII concentrate, Koate-DVI (Grifols; Kedrion Biopharma, Inc. in the US) was found to contain ADAMTS-13 (Peyvandi et al A J Hematol 2012). Although standard therapy for those with recurrent episodes of symptoms has been periodic infusions of fresh-frozen plasma (FFP), this product was reported to have been successfully used to treat and prevent recurrent episodes in a patient, when he developed severe reactions and could no longer tolerate treatment with fresh-frozen plasma (FFP). Another similar factor VIII concentrate, 8Y (BPL), was earlier reported to be successful in treating several children with cTTP; it, too, was later found to contain ADAMTS-13. Only minimal anecdotal information in the literature is available to guide dosing. As a first step in collecting data to describe the clinical courses and management of patients with cTTP, we sought to ascertain more accurately the number of patients with cTTP in the US.
First, forty-eight (48) adult and pediatric hematologists in the US were contacted by telephone and follow-up email communications. Fifteen (15) additional pediatric hematologists were queried at national meetings. Through the initial telephone encounter, thirty-five (35) known cTTP patients were identified who were being followed. Six (6) additional patients were discovered with email follow up contact of the original 48 hematologists. In-person discussions with 15 additional pediatric hematologists uncovered thirty (30) additional cTTP patients. Thus, seventy-one (71) patients with congenital TTP were identified in 25 US states within 6 months in this pilot data registry. Most patients needed ongoing therapy because of recurrent clinical episodes of TTP, and at least 7 were being treated with FVIII concentrate, after they could no longer tolerate FFP.
Conclusions: There appear to be more patients with cTTP in the US than previously thought. There has been no previous coordinated effort to identify these patients, or to aggregate information on their clinical course; each center, having only one or two such patients, treats them empirically with FFP. The availability of a commercial FVIII concentrate containing ADAMTS-13 may offer a safer and more convenient alternative.

Disclosures
Singleton: Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Baxter: Consultancy, Honoraria, Speakers Bureau; Grifols: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; CSL Behering: Consultancy, Honoraria; Kedrion: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria. Off Label Use: A report of patients with congenital TTP that require chronic therapy with a number of patients successfully being treated with Koate DVI. Aledort:Kedrion BIopharma, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxter International: Data Safety Monitoring Board Other. Cindy:CSL Behring: Consultancy, Research Funding; Baxter : Consultancy, Research Funding. Ulsh:Kedrion Biopharma, Inc.: Employment. Bergman:Kedrion Biopharma, Inc.: Employment.