A newly published clinical case report details the rapid hematologic improvement and subsequent disease course of a 74-year-old patient with congenital thrombotic thrombocytopenic purpura who received the anti-von Willebrand factor nanobody caplacizumab in combination with plasma exchange and corticosteroid therapy. Reporting in Frontiers in Hematology, a clinical team led by Dr. Elisa Quinti from the University of Florence and Careggi University Hospital documented the unusually delayed diagnosis of this ultra-rare inherited microangiopathy in an elderly patient. The condition, driven by an inherited severe deficiency of the von Willebrand factor-cleaving metalloproteinase ADAMTS13, leads to the uncontrolled accumulation of ultra-large von Willebrand factor multimers that precipitate platelet aggregation and microvascular thrombosis. Although caplacizumab is formally approved only for acquired, immune-mediated forms of thrombotic thrombocytopenic purpura, its acute administration in this case provided rapid stabilization prior to genetic confirmation.
Acute episodes typically manifest as thrombotic microangiopathy defined by microangiopathic hemolytic anemia, severe thrombocytopenia, and ischemic organ damage. While male patients most frequently exhibit acute manifestations during the neonatal phase or early childhood, presentation in female patients often remains quiescent until adulthood, frequently unmasked by physiological stressors such as pregnancy. When cases present with milder phenotypes or intermittent relapses, accurate clinical identification can be substantially postponed into late adulthood, frequently leading to misdiagnoses such as immune thrombocytopenia, immune-mediated thrombotic thrombocytopenic purpura, or Evans syndrome, which can expose individuals to suboptimal care and adverse clinical outcomes.
The patient presented in August 2024 displaying acute neurological manifestations, including acute dysarthria, right-sided facial weakness, and a positive Mingazzini test, all consistent with an acute cerebrovascular event. A retrospective evaluation of her medical history uncovered recurrent pregnancy loss as well as a previous ischemic stroke experienced in 2019. Initial routine laboratory evaluations demonstrated isolated thrombocytopenia with a platelet count of 66 × 10³/µL, accompanied by a preserved hemoglobin concentration of 12.7 g/dL, normal baseline coagulation parameters, and preserved renal function and total bilirubin levels. However, serum lactate dehydrogenase was elevated at 585 U/L against a standard reference range of 135 to 214 U/L. Due to the isolated nature of the cytopenia at initial presentation, medical staff initially suspected immune thrombocytopenia and instituted immunosuppressive therapy with methylprednisolone at an initial dose of 1 mg/kg.
Because the patient’s thrombocytopenia persisted despite early corticosteroid intervention, extended diagnostic evaluations were conducted under suspicion of underlying thrombotic thrombocytopenic purpura. Microscopic examination of the peripheral blood smear revealed five percent schistocytes alongside laboratory signs of ongoing intravascular hemolysis, including an undetectable haptoglobin level below 30 mg/dL and a further rise in serum lactate dehydrogenase to 893 U/L. Subsequent enzyme testing using a commercial enzyme-linked immunosorbent assay demonstrated a severely suppressed ADAMTS13 enzymatic activity level of 0.9 percent. In response to these findings, the clinical team initiated emergency treatment for suspected acute immune-mediated thrombotic thrombocytopenic purpura, combining methylprednisolone with daily therapeutic plasma exchange and the anti-von Willebrand factor nanobody caplacizumab.
Following the institution of this triple therapeutic regimen, the patient demonstrated rapid hematological and clinical stabilization, achieving complete normalization of both platelet counts and markers of hemolysis within two days of treatment initiation. This rapid recovery allowed clinicians to terminate therapeutic plasma exchange after only four sessions, significantly abbreviating her stay within the intensive care unit without the occurrence of notable treatment-related adverse events.
Subsequent immunological investigations unexpectedly revealed an absence of anti-ADAMTS13 autoantibodies, measuring 7 U/mL within the normal negative reference range of 0 to 15 U/mL by specific enzyme-linked immunosorbent assay. This absence of measurable neutralizing inhibitors contradicted the presumptive diagnosis of acquired immune-mediated disease and raised immediate suspicion of an underlying hereditary disorder. Confirmatory genetic analysis of the ADAMTS13 gene identified two distinct heterozygous missense mutations: c.3251G>A; p.(Cys1084Tyr), a mutation previously established in peer-reviewed literature as causative for congenital thrombotic thrombocytopenic purpura, and c.1883A>G; p.(Tyr628Cys), a novel variant predicted in silico to exert deleterious consequences on metalloproteinase structure and biological activity.
Following genetic confirmation of congenital disease, caplacizumab was discontinued at the beginning of November 2024. The long-term management of congenital thrombotic thrombocytopenic purpura fundamentally relies on restoring functional ADAMTS13 activity. Historically, this has required regular prophylactic or on-demand infusions of fresh frozen plasma. While recombinant ADAMTS13 (TAK-755, marketed as Adzynma) demonstrated significant advantages over plasma in a phase 3 randomized crossover trial—such as predictable pharmacokinetics, reduced infusion volume burden, and fewer hypersensitivity reactions, earning a strong recommendation in the 2025 updated International Society on Thrombosis and Haemostasis guidelines—the recombinant product was not yet commercially accessible in Italy during 2024. Consequently, the patient was transitioned to weekly maintenance infusions of solvent/detergent-treated fresh frozen plasma at a standard dose of 10 mL/kg.
Late in November 2024, the patient contracted acute bronchopneumonia, an infectious stressor that provoked a sudden and severe relapse of acute thrombotic microangiopathy. Although therapeutic plasma exchange was promptly reinstated upon symptom exacerbation, the intervention failed to achieve hematological or clinical remission. In light of the established congenital diagnosis and existing protocol standards, caplacizumab was not readministered during this second phase of management. The patient experienced a precipitous clinical decline, and despite intensive supportive measures, the secondary exacerbation proved fatal.
In their clinical appraisal, the authors emphasized that the degree of thrombocytopenia in congenital thrombotic thrombocytopenic purpura can often be substantially less pronounced than in immune-mediated presentations, reflecting a milder baseline hematologic phenotype that can mislead clinicians. Consequently, a moderately preserved initial platelet count should never be used to exclude congenital disease, particularly when accompanied by a personal history of unexplained ischemic stroke, microvascular events, or recurrent pregnancy complications. Furthermore, the authors underscore that screening for anti-ADAMTS13 autoantibodies and functional inhibitors remains essential whenever severe enzyme deficiency is detected, regardless of advanced patient age, to reliably differentiate acquired immune pathology from hereditary enzyme deficiency.
The authors concluded that while caplacizumab remains strictly off-label for congenital disease outside of isolated refractory relapses in published literature, its transient use in this case demonstrated rapid clearance of microangiopathic features and allowed early cessation of plasma exchange. As recombinant ADAMTS13 expands into clinical practice, issues such as potential alloantibody formation against infused recombinant protein may emerge, mirroring challenges observed in congenital factor deficiencies such as hemophilia. In such critical clinical contexts, or when volume overload restricts plasma therapy, short-term adjunctive therapy with caplacizumab may represent an important management consideration for severe congenital disease, though the authors emphasize that further clinical studies are necessary to formally delineate its efficacy and safety.
Subject of Research: Off-label caplacizumab therapy and clinical outcomes in late-onset congenital thrombotic thrombocytopenic purpura
Article Title: Case Report: Caplacizumab in a case of very late diagnosis of congenital thrombotic thrombocytopenic purpura
Article References: Quinti, E., Lucarelli, C., Carrai, V., Fossi, F., Artoni, A., Mancini, I., Vannucchi, A. M., & Scappini, B. (2026). Case Report: Caplacizumab in a case of very late diagnosis of congenital thrombotic thrombocytopenic purpura. Frontiers in Hematology, 5, Article 1959616. https://doi.org/10.3389/frhem.2026.1959616
Image Credits: AI Generated
DOI: 10.3389/frhem.2026.1959616
Keywords: congenital thrombotic thrombocytopenic purpura, caplacizumab, ADAMTS13 deficiency, thrombotic microangiopathy, plasma exchange, hematology, case report, enzyme replacement therapy, Case, Report, very, late
Tags: ADAMTS13 deficiencycaplacizumabcasecase reportcongenital thrombotic thrombocytopenic purpuraEnzyme Replacement TherapyHematologyLATEplasma exchangeRepoRTthrombotic microangiopathyvery
