Successful Treatment of Acquired Thrombotic Thrombocytopenic Purpura With Caplacizumab Combined With Plasma Exchanges and Immune Suppression in 3 Children.

Acquired thrombotic thrombocytopenic (aTTP) purpura is a life-threatening condition that can lead to devastating thromboembolic events. Recently, caplacizumab has been shown to rapidly restore platelet numbers and reduce the risk of severe end-organ damage when added to plasma exchanges (PEXs) and immunosuppression (IST). Here, we report the outcomes in 3 children with aTTP who were treated with caplacizumab in combination with PEXs and IST. In all 3 patients, platelet count increased to >15,000/mm 3 in 24 h and normalized on day 4, whereas normalization of ADAMTS13 activity >50% and elimination of the inhibitor was achieved after 18 to 89 days. Epistaxis was observed in 2 patients and was the only side effect related to caplacizumab. Caplacizumab is a promising agent for first-line treatment of children with aTTP.

Outcomes and Costs in Patients with Immune Thrombotic Thrombocytopenic Purpura Receiving Front-Line Versus Delayed Caplacizumab: A US Hospital Database Study.

European real-world data indicate that front-line treatment with caplacizumab is associated with improved clinical outcomes compared with delayed caplacizumab treatment. The objective of the study was to describe the characteristics, treatment patterns, and outcomes in hospitalized patients with an immune-mediated thrombotic thrombocytopenic purpura (iTTP) episode treated with front-line versus delayed caplacizumab in the US. This retrospective cohort analysis of a US hospital database included adult patients (≥18 years) with an acute iTTP episode (a diagnosis of thrombotic microangiopathy and ≥1 therapeutic plasma exchange [TPE] procedure) from January 21, 2019, to February 28, 2021. Unadjusted baseline characteristics, treatment patterns, healthcare resource utilization, and costs were compared between patients who received front-line versus delayed (<2 vs ≥2 days after TPE initiation) caplacizumab treatment. Out of 39 patients, 16 (41.0%) received front-line and 23 (59.0%) received delayed treatment with caplacizumab. Baseline characteristics and symptoms were similar between the two groups. Patients who received front-line caplacizumab treatment had significantly fewer TPE administrations (median: 5.0 vs 12.0); and a significantly shorter hospital stay (median: 9.0 days vs 16.0 days) than patients receiving delayed caplacizumab therapy. Both of these were significantly lower in comparison of means (t-test P < .01). Median inpatient costs (inclusive of caplacizumab costs) were 54% higher in the delayed treated patients than in the front-line treated patients (median: $112 711 vs $73 318). TPE-specific cost was lower in the front-line treated cohort (median: $6 989 vs $10 917). In conclusion, front-line treatment with caplacizumab had shorter hospitalizations, lower healthcare resource utilization, and lower costs than delayed caplacizumab treatment after TPE therapy.

Should we consider caplacizumab as routine treatment for acute thrombotic thrombocytopenic purpura? An expert perspective on the pros and cons.

INTRODUCTION: Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening disorder. Caplacizumab has been the latest drug incorporated into the initial treatment of acute episodes, allowing for faster platelet recovery and a decrease in refractoriness, exacerbation, thromboembolic events, and mortality. However, caplacizumab is also associated with a bleeding risk and higher treatment costs, which prevent many centers from using it universally. AREAS COVERED: Studies that included iTTP and/or caplacizumab to date were selected for this review using PubMed and MEDLINE platforms. We describe outcomes in the pre-caplacizumab era and after it, highlighting the benefits and risks of its use early in frontline, and also pointing out special situations that require careful management. EXPERT OPINION: It is clear that the availability of caplacizumab has significantly and favorably impacted the management of iTTP patients. Whether this improvement is cost-effective still remains uncertain, and data on long-term sequelae and different healthcare systems will help to clarify this point. In addition, evidence of the bleeding/thrombotic risk of iTTP patients under this drug needs to be better addressed in future studies.

Magnesium sulphate in patients with thrombotic thrombocytopenic purpura (MAGMAT): a randomised, double-blind, superiority trial.

PURPOSE: Studies have suggested benefits from magnesium sulphate in thrombotic thrombocytopenic purpura (TTP). We aimed to measure the effects of magnesium sulphate supplementation on TTP recovery. METHODS: In this multicenter, randomised, double-blind, controlled, superiority study, we enrolled adults with a clinical diagnosis of TTP. Patients were randomly allocated to receive magnesium sulphate (6 g intravenously followed by a continuous infusion of 6 g/24 h for 3 days) or placebo, in addition to the standard treatment. The primary outcome was the median time to platelet normalisation (defined as a platelet count ≥ 150 G/L). Efficacy and safety were assessed by intention-to-treat. RESULTS: Overall, we enrolled 74 participants, including one who withdrew his/her consent. Seventy-three patients were further analyzed, 35 (48%) allocated to magnesium sulphate and 38 (52%) to placebo. The median time to platelet normalisation was 4 days (95% confidence interval [CI], 3-4) in the magnesium sulphate group and 4 days (95% CI 3-5) in the placebo group. The cause-specific hazard ratio of response was 0.93 (95% CI 0.58-1.48, p = 0.75). The number of patients with ≥ 1 serious adverse reactions was similar in the two groups. By day 90, four patients in the magnesium sulphate group and two patients in the placebo group had died (p = 0.42). The most frequent adverse event was low blood pressure occurring in 34% in the magnesium sulphate group and 29% in the placebo group (p = 0.80). CONCLUSION: Among patients with TTP, the addition of magnesium sulphate to the standard of care did not result in a significant improvement in time to platelet normalisation.

Long-term follow-up of patients with congenital thrombotic thrombocytopenia purpura receiving a plasma-derived factor VIII (Koate) that contains ADAMTS13.

BACKGROUND: Hereditary thrombotic thrombocytopenia purpura (hTTP) is an ultra-rare disorder resulting from an inherited deficiency of ADAMTS13, a von Willebrand factor (VWF)-cleaving metalloprotease. The plasma-derived factor VIII/VWF Koate (FVIII/VWFKoate ) has been shown to contain ADAMTS13, allowing for its use to treat hTTP at home by the patient/caregiver. AIM: Based on prior demonstration of safe and effective use of FVIII/VWFKoate in eight patients with hTTP, we conducted a retrospective study to gather additional data regarding the use of FVIII/VWFKoate for hTTP. METHODS: This was a multicentre, retrospective, noninterventional chart review of patients who had received FVIII/VWFKoate for the management of hTTP. Data collected included demographics, medical history, relevant family history, past use and tolerability of fresh frozen plasma, and details regarding FVIII/VWFKoate therapy. RESULTS: The cohort included 11 patients (seven males, four females) with hTTP, ranging in age at study entry from 2 to 28 years. The average duration of FVIII/VWFKoate therapy was 4.8 years (range, 0.5-6.5 years). Among nine patients using FVIII/VWFKoate as prophylaxis, the normalized annual rate of breakthrough TTP episodes ranged from 0.2 to 1.1 episodes/year. All nine patients who received FVIII/VWFKoate prophylaxis had thrombocytopenia recorded at baseline, while eight (88.9%) did not have thrombocytopenia after using FVIII/VWFKoate . There was one AE (unspecified) attributed to FVIII/VWFKoate . CONCLUSION: These data suggest that FVIII/VWFKoate is a safe and well-tolerated source of the missing ADAMTS13 enzyme in patients with hTTP, producing a marked reduction in thrombocytopenia prevalence, low frequency of TTP episodes, and with the added benefit of self- or caregiver-administration.

[A combined regimen based on bortezomib and glucocorticoids for 6 patients with recurrent/refractory immune thrombotic thrombocytopenic purpura].

Objective: To observe the efficacy and adverse reactions of a combination therapy regimen based on bortezomib and glucocorticoids in recurrent/refractory immune thrombocytopenic purpura (iTTP) . Methods: Six patients with recurrent/refractory TTP were included and treated with a glucocorticoid and two courses of bortezomib-based regimen. The clinical remission status of patients, changes in ADAMTS13 activity/ADAMTS13 inhibitor, and the occurrence of treatment-related adverse reactions were observed. Results: Of the 6 patients, 2 were males and 4 were females, with a median age of 21.5 (18-68) years. Refractory TTP was found in 1 case and recurrent TTP in 5 cases. Glucocorticoids were administered with reference to prednisone at 1 mg·kg(-1)·d(-1), and gradually reduced in dosage after achieving clinical remission. Bortezomib is subcutaneously administered at 1.3 mg/m(2) on days 1, 4, 8, and 11 with a 28-day treatment course consisting of 2 courses. Six patients achieved clinical remission after receiving bortezomib as the main treatment. ADMATS13 activity returned to normal in all patients with TTP after treatment, and the ADAMTS13 inhibitor turned negative. Thrombocytopenia is the most common adverse reaction after treatment, with other adverse reactions, including peripheral neuritis and abdominal pain, but ultimately all patients returned to normal. In a median follow-up of 26 (9-41) months, 5 patients maintained sustained remission, and 1 patient relapsed after 16 months of bortezomib treatment. Conclusion: Combination therapy of bortezomib and glucocorticoids has a satisfactory therapeutic effect and controllable adverse reactions for recurrent/refractory iTTP.

Five years of caplacizumab - lessons learned and remaining controversies in immune-mediated thrombotic thrombocytopenic purpura.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare hematologic disease caused by autoantibodies against ADAMTS-13 that trigger microangiopathic hemolytic anemia. Therapeutic plasma exchange and glucocorticoids have been the mainstay of treatment for the past 30 years. In 2019, caplacizumab was approved as an addition to this regimen for the acute treatment of iTTP. Randomized controlled trials and real-world evidence have shown that caplacizumab reduces the time to platelet count normalization, refractoriness, and exacerbations of the disease, with an acceptable safety profile. In the past 5 years, there have been arguments against the upfront use of caplacizumab in all patients with iTTP, particularly related to the perceived lack of clinical benefit, safety concerns related to bleeding risk, and high costs. This perspective aimed to address these concerns in the context of the experience of expert centers that have used the drug for >5 years.

Effectiveness and safety of caplacizumab in acquired thrombotic thrombocytopenic purpura: health technology assessment and classification according to the methodology established in Colombia.

OBJECTIVES: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare hematological disease whose clinical management includes caplacizumab along with plasma exchange and immunosuppression, according to international guidelines. Caplacizumab has been available in Colombia since 2022. This study seeks to determine the therapeutic classification of caplacizumab according to the methodology of the Instituto de Evaluación Tecnológica en Salud. METHODS: The classification was carried out through a deliberative process following the modified Delphi technique, with a panel of experts, made up of four hemato-oncologists, a pharmaceutical chemist, and a patient. The results of effectiveness and safety obtained through a systematic review, therapeutic thresholds (clinical significance), and degree of acceptability (willingness to use the technology) were used for the classification. RESULTS: Fourteen effectiveness and safety outcomes were submitted for the classification process. Caplacizumab showed clinical significance for some effectiveness outcomes, was not considered inferior in terms of safety, and displayed acceptability of use. Through consensus, the panel determined that caplacizumab plus the standard regimen is superior to the standard regimen in terms of treatment response and composite outcome, and no different for the other effectiveness and safety outcomes. Likewise, in overall terms, the panel determined that caplacizumab together with the standard regimen is superior to the standard regimen. CONCLUSION: Treatment with caplacizumab together with the standard regimen was considered superior to the standard regimen for the treatment of patients with aTTP, as it showed clinically significant benefits in critical outcomes for decision making, and a safety profile no different to its comparator.

Thrombotic thrombocytopenic purpura that developed 3 years after systemic lupus erythematosus had remitted with rituximab therapy.

Patients with systemic lupus erythematosus (SLE) occasionally develop thrombotic thrombocytopenic purpura (TTP), which can be fatal. Here, we report a case of TTP developing 3 years after SLE remitted with rituximab (RTX) therapy. A 50-year-old woman was treated with RTX for marked immune thrombocytopenic purpura and autoimmune haemolytic anaemia due to SLE relapse. After induction of remission, she was treated with prednisolone alone without maintenance therapy with RTX. Approximately 3 years later, she was readmitted with marked thrombocytopenia and severe renal dysfunction. On admission, she was diagnosed with TTP for the first time based on severe reduction in a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity and detection of ADAMTS13 inhibitors. CD19+ B cells in the patient's serum increased to 34%, suggesting that B cells had reactivated once the effect of RTX had subsided. The patient was successfully treated with plasmapheresis, glucocorticoid pulse therapy, and RTX. There are no previous reports of newly diagnosed TTP with ADAMTS13 inhibitor production after having achieved remission of SLE with RTX. Therefore, our report also discusses the potential mechanisms of production of new autoantibodies after B-cell depletion therapy.

Caplacizumab: A game changer also in pregnancy-associated immune-mediated thrombotic thrombocytopenic purpura?

Therapeutic options in immune-mediated thrombotic thrombocytopenic purpura (iTTP) during pregnancy are limited besides therapeutic plasma exchange (TPE) and corticosteroids. The report by Odetola et al. suggests that caplacizumab represents a reasonable option in iTTP during pregnancy, especially when the disease is not rapidly controlled with the standard TPE-corticosteroid association. Commentary on: Odetola et al. Safe and effective use of caplacizumab in pregnancy-related acquired thrombotic thrombocytopenic purpura. Br J Haematol 2023;202:879-882.

Use of n-acetylcysteine therapy in patients with relapsed refractory thrombotic thrombocytopenic purpura.

There is limited data on the use of NAC in the literature. We would like to present the satisfactory results we obtained in our resistant and relapsed patients as a case series.Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy caused by ADAMTS13 (a disintegrin with thrombospondin type 1 motif and metalloprotease activity, member13) deficiency. Von Willebrand factor (vWF) initiates platelet aggregation and thus thrombus formation. The multimers of vWF are cleaved by ADAMTS13. Because of the decreased activity of ADAMTS13, ultra-large multimers accumulate and end-organ damage occurs. TTP is characterized by microangiopathic hemolytic anemia (MAHA), severe thrombocytopenia, and organ ischemia resulting from vascular occlusion caused by thrombi. Plasma exchange therapy (PEX) remains the mainstay of TTP therapy. Patients who do not respond to PEX and corticosteroids require additional treatments such as rituximab and caplacizumab. NAC reduces disulfide bonds in mucin polymers through its free sulfhydryl group. Thus, the size and viscosity of the mucins are reduced. VWF is structurally similar to mucin. Based on this similarity, Chen and colleagues showed that NAC can reduce the size and reactivity of ultralarge multimers of vWF, such as ADAMTS13. Currently, there is not much information to suggest that NAC has any clinical value in the treatment of TTP. In this case series of 4 refractory patients, we would like to present the responses we obtained with the addition of NAC therapy. NAC can be added to PEX and glucocorticoid therapy as supportive therapy, especially in unresponsive patients.

N-Acetylcistein for thrombotic thrombocytopenic purpura: an observational case series study.

Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder. N-Acetylcysteine (NAC) rapidly degrades ultra-large von Willebrand factor multimers by disrupting the disulfide bonds. We report a series of twelve consecutive patients diagnosed with acquired TTP successfully treated with high-dose NAC (150 mg/kg/day) in combination with plasma exchange and steroids. Eight patients also received rituximab. Two patients presented refractory TTP. All patients achieved a quick clinical response in a median time of 5.5 days after starting NAC and are alive after a median follow-up of 29 months. The treatment was feasible and well tolerated. These data provide further evidence of the potential benefit and safety of adding NAC to the standard of care.