Development of a clinically significant ADAMTS13 inhibitor in a patient with hereditary thrombotic thrombocytopenic purpura

Abstract

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 3 10 9 /L, decreasing to 3 3 10 9 /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.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 ...

Preclinical assessment of a new recombinant ADAMTS‐13 drug product (BAX930) for the treatment of thrombotic thrombocytopenic purpura

“…In humans, the likelihood of formation of inhibitors of rADAMT‐13 is considered to be low, as most hTTP patients are carriers of compound heterozygous mutations for ADAMTS‐13, suggesting that rADAMTS‐13 would not contain neoepitopes for T cells that could elicit an immune response in patients. Also, there is a single report on the formation of inhibitory allo‐antibodies against ADAMTS‐13 in a patient with severe hTTP receiving long‐standing regular prophylactic plasma infusions , which suggests that plasma‐derived ADAMTS‐13 is not very immunogenic. As preliminary physicochemical characterization studies showed that rADAMTS‐13 is similar in structure and function to plasma‐derived ADAMTS‐13 , the immunogenicity of rADAMTS‐13 is likely to be low.…”

What's new in the diagnosis and pathophysiology of thrombotic thrombocytopenic purpura

“…So far, only a single patient with congenital TTP has been reported to develop an apparent alloantibody to ADAMTS13. 25 Therefore, severe ADAMTS13 deficiency with an inhibitor supports a diagnosis of acquired TTP.…”

ADAMTS13: origins, applications, and prospects

“…Patients with congenital TTP are treated with plasma infusions, resulting in exposure to ADAMTS13 from the transfused plasma and possible development of an ADAMTS13 alloantibody in an analogous situation to patients with hemophilia A being treated with FVIII replacement therapy. Development of alloantibodies has been reported in the literature and necessitates a transition in treatment from plasma infusions to TPE and immunosuppression …”