Congenital Thrombotic Thrombocytopenia Purpura - Safer Treatment with Plasma-Derived Viral-Attenuated Clotting Factor
Authors: Aledort Louis M. , Boggio Lisa , Davis Joanna A. , Gauger Cynthia , Kobrinsky Nathan L. , Rajasekhar Anita , Shapiro Ralph , Torres Marcela , Ulsh Paula J. 
Published: October 2019

Abstract
Congenital Thrombotic Thrombocytopenia Purpura (cTTP) has been considered a very rare disorder. Several international registries have estimated 250 patients worldwide. While the total number of patients in the U.S. is unknown, an ongoing U.S. Registry has recorded only 89 patients. (Singleton et al NORD 2014) Therapy for this disease, for prophylaxis and treatment, has been replacement of the absent ADAMTS13 with fresh frozen plasma (FFP). The major complication has been allergic reactions including anaphylaxis making this treatment unviable for some patients. Virally- inactivated FFP is not readily available in the U.S. A recombinant ADAMTS13 is in initial PK studies.
There have been anecdotal reports that a plasma-derived FVIII/vWF biologic (Koate-DVI), double virally inactivated, FVIII replacement product, has been successfully used prophylactically in cTTP patients in lieu of FFP therapy to prevent episodes of TTP (Naik et al J Pediatr Hematol Oncol 2013). No other therapeutic biologic has been able to provide this benefit. Pursuant to that observation, two independent laboratories in the U.S. and Italy conducted analyses of the content of ADAMTS13 in several FVIII concentrates. The ADAMTS13 content in reconstituted concentrate of Koate-DVI was up to 9.08 + 0.70 units/ml, and was substantially higher than other FVIII products and pooled plasma. Table 1 and Table 2
We report here a cohort of 10 cTTP patients currently being managed with Koate-DVI prophylaxis. The average age of the patients is 15 years (range 7-22 years). The patients are being treated with a dose range of 25 to 40 IU/kg, at an average of once per week. This dose of Koate-DVI (containing 100 IU FVIII/ml after reconstitution) will provide approximately 2 to 4 IU/kg of ADAMTS13. Patients have been treated for variable lengths of time ranging from less than a year to over 10 years. The patients have responded very well to the Koate-DVI treatment; no severe adverse events or allergic reactions have been reported. We are prospectively comparing the frequency of new TTP episodes in this cohort with the frequency observed prior to initiation of this therapy.
We report a unique experience of 10 cTTP patients being successfully managed prophylactically at home with self-infusion of Koate-DVI (Factor VIII concentrate with a long history of viral safety in the treatment of hemophilia A). These patients are receiving a convenient virally-inactivated alternative to FFP without manifesting life-threatening allergic reactions that require immunosuppression and/or hospitalization.
A prospective clinical study of the safety and efficacy of Koate-DVI is planned.
Table 1. Concentrate ADAMTS13 activity U/mL ADAMTS13 antigen U/mL Koate-DVI (5 lots) 9.08 ± 0.70 8.42 ± 0.12 Product A 0.12 0.13 Product B 0.22 0.61 Product C 2.30 3.87 (Peyvandi et al Am J Hematol 2013)
Table 2. Concentrate ADAMTS13 Units/ml Koate-DVI 5.77 Product A 0.18 Product B 0.23 Product C 1.40 (Konkle Personal Communication 2013)

Disclosures
Aledort: Kedrion BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees, Other: DSMB Participation. Off Label Use: Koate-DVI is indicated for the treatment of classical hemophilia (hemophilia A) in which there is a demonstrated deficiency of activity of the plasma clotting factor, factor VIII. This presentation discusses the use of factor VIII concentrate for ADAMTS13 deficiency.. Boggio:CSL Behring: Consultancy, Research Funding; Baxter: Consultancy, Research Funding; Selexys: Research Funding; Bayer: Consultancy, Research Funding; OctaPharma: Consultancy, Research Funding; OPKO: Research Funding; Novo Nordisk: Consultancy, Research Funding. Kobrinsky:Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Sanofi: Speakers Bureau; Kedrion Biopharma: Membership on an entity's Board of Directors or advisory committees. Rajasekhar:American Society of Hematology: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Baxter Healthcare: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Shapiro:Baxalta: Research Funding; Shire: Speakers Bureau; BioCryst: Research Funding. Ulsh:Kedrion Biopharma: Employment.