Development of a clinically significant ADAMTS13 inhibitor in a patient with hereditary thrombotic thrombocytopenic purpura
Authors: Jay S. Raval, Anand Padmanabhan, Johanna A. Kremer Hovinga, Joseph E. Kiss
Journal: American Journal of Hematology (2014)

To the Editor: Hereditary thrombotic thrombocytopenic purpura (hTTP), that is, Upshaw-Schulman syndrome, results from the congenital absence of a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13 (ADAMTS13), the von Willebrand factor-cleaving protease 1, 2. The hallmarks of hTTP are repeated episodes of thrombocytopenia and microangiopathic hemolytic anemia usually responsive to plasma infusion 3. Herein, we report the case of a plasma-treated hTTP patient who went on to develop an ADAMTS13 functional inhibitor and required therapeutic plasma exchange (TPE), not plasma infusion, for disease management. Our patient, now a 37-year-old female, was born with thrombocytopenia (platelets 49 × 109/L, decreasing to 3 × 109/L at 2 days of age), Coombs' test negative hemolytic anemia with schistocytes (with associated hematocrit decrease from 62 to 35% over the first 2 days of life), and hemoglobinuria. Family history was noncontributory. Since birth, the patient experienced frequent episodes of thrombocytopenia, hemolytic anemia, and hemoglobinuria requiring transfusion of numerous red blood cell and plasma components. She subsequently developed hemodialysis-dependent chronic renal insufficiency and multiple cerebrovascular events. The patient was eventually diagnosed with hTTP at age 15 years and treatment was escalated with TPE with plasma replacement every 2–3 weeks to control thrombocytopenia. However, since age 26 her TPE frequency required further intensification to once weekly for inadequately controlled thrombocytopenia by the previous treatment schedule. Pre-TPE ADAMTS13 activity was always undetectable. On three separate occasions, ADAMTS13 activity obtained immediately post-TPE was 63, 45, and 30%, with undetectable activities 1 week later. Pre-TPE ADAMTS13 functional inhibitor analysis performed on two separate occasions demonstrated 54 and 88% inhibition (1.1 and 3 BU/mL, respectively; normal <30% inhibition or 0.5 BU/mL). All activity and inhibitor testing was performed with a quantitative assay utilizing fluorescence resonance energy transfer technology (Lifecodes ATS-13 Assay, Immucor GTI Diagnostics, Waukesha, WI). ADAMTS13 gene sequencing performed on all 29 exons and ∼50 bases of flanking noncoding sequence revealed two novel mutations, supporting the diagnosis of hTTP (see Fig. 1). Both were deletions: the first in exon 4 (c.331-2_331-1delAG) was predicted to abolish a consensus splicing acceptor site at the junction between intron 3 and exon 4 4, and the second in exon 26 (c.3587delA) was predicted to result in premature termination (p.His1196ProfsStop30) due to frameshifting. Consent for genetic testing of the patient's family members was not given. ADAMTS13 gene map on chromosome 9q34. Exons are numbered (1–29) and arrows indicate novel deletional mutations identified in patient. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] To our knowledge, this is the first reported case of a hTTP patient with a clinically significant ADAMTS13 inhibitor after repeated exposure to exogenous ADAMTS13. A prior report described a hTTP patient with an evanescent, low-titer ADAMTS13 inhibitor (<1.4 BU/mL), but this did not impact the treatment plan or response to plasma infusion 3. A somewhat analogous situation exists in congenital hemophilia A, in which up to 30% of patients can develop inhibitory alloantibodies to Factor VIII after repeated Factor VIII exposure. In that setting, the cornerstone of treatment is immune tolerance induction and immunomodulation 5. Based on the observations in our patient, we propose that a subset of hTTP patients may be at risk of alloantibody formation to ADAMTS13 on exposure to donor plasma. J.S.R. collected the data, analyzed the data, and wrote the article; A.P. collected the data, analyzed the data, and wrote the article; J.A.K.H. analyzed the data and wrote the article; J.E.K. analyzed the data and wrote the article. Jay S. Raval,1,2 Anand Padmanabhan,1,2 Johanna A. Kremer Hovinga,3 and Joseph E. Kiss1,4* 1 Therapeutic Hemapheresis and Blood Services Division, The Institute for Transfusion Medicine, Pittsburgh, Pennsylvania;2 Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania;3 University Clinic of Hematology and Central Hematology Laboratory, Inselspital, University Hospital and University of Bern, Bern, Switzerland;4 Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania