Immune-mediated Thrombotic Thrombocytopenic Purpura Research Articles

Impaired Cognitive Function in Immune-TTP Is Better Predicted By Serum Thrombomodulin Than ADAMTS13 Activity: Results of a Longitudinal Multicenter Pilot Study

Background: High rates of mood disorders and cognitive dysfunction in immune-mediated thrombotic thrombocytopenic purpura (iTTP) survivors have been observed. However, there are no long-term prospective studies to precisely define the proportion of affected patients, rate of progression, and underlying mechanisms. We hypothesized that a large-scale multicenter study is essential to determine the natural history of these complications. Thus, we conducted a multicenter pilot study of iTTP patients in remission to assess feasibility, study design, and explore novel biomarkers. Given ADAMTS13 deficiency during remission is a risk factor for stroke, we also hypothesized that low ADAMTS13 activity predisposes patients to cognitive impairment. Methods: We aimed to enroll 50 participants from 3 USTMA Consortium sites, prospectively including adult iTTP patients (age ≥ 18 years) in clinical remission (ADAMTS13 remission was not required) for at least 90 days. Diagnosis of iTTP relied on ADAMTS13 activity <10% during an acute TMA episode. Over 2 years, participants underwent comprehensive assessments of mental and physical health, cognition, ADAMTS13 activity, and biomarker sample collection every 3 months. Study assessments included: Beck Anxiety Index (BAI), Beck Depression Index-II (BDI), Headache Impact Test (HIT-6), SF-36v2 (health-related quality of life), and CPT-3 (computer-based assessment of reaction-time, attention, and processing speed). Cognition was assessed annually (entry, year 1 and close) using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), with the Montreal Cognitive Assessment (MoCA) substituted the other visits. Results: Between September 2019 and July 2022, we enrolled 38 of 50 planned participants. Of the 38 enrolled, 16 completed the study (42.1%) 11 were lost to follow up because they did not complete the close-out visit (29%), and 11 have not yet completed the study (29%). After excluding lost subjects, we found that 131 of 221 visits were completed (59%). Demographics and burden of mental and physical health impairments are shown (Figure A). At enrollment, 45% (15/33) had at least moderate anxiety on BAI, and 45 % (15/33) had at least moderate depression on BDI. HIT-6 revealed69.7 % (23/33) had clinically significant headaches warranting referral to a specialist (median score 57, IQR 47-63). SF-36 found increased fatigue (median fatigue score of 30, population mean 52.15) and pain (median 57.5, population mean 78.77), as well as impairments in social functioning (median 50, population mean 78.77) and general health (median 35, population mean 56.99). The The CPT-3 test (see table) was highly unacceptable to some participants at all sites. RBANS scores at enrollment detected overall cognitive impairment (median score 18 th %ile) with marked deficiencies in immediate memory (median score 11 th %ile), visuospatial construction (median score 10 th %ile), and milder impairments in language and delayed memory with no evidence of attention deficits. We collected several novel biomarkers and observed a correlation between serum CD141 (thrombomodulin) and overall RBANS scores (Figure B) when compared between participants above and below the median baseline CD141. This association was not seen with ADAMTS13, or the other biomarkers collected (Syndecan-1, Vascular adhesion protein-1, E-selectin). Conclusions: In this pilot study, we found a high attrition rate, likely due to the frequency of study visits and the COVID-19 pandemic. We conclude a larger study is feasible but should account for high attrition, employ less frequent study visits, and avoid unacceptable study assessments to reduce lost subjects. Enrollment findings confirmed previous single-center reports of high prevalence of mental health disorders, reduced physical health, and subtle but measurable cognitive deficits. The CPT-3 test should be excluded from future studies due to poor acceptance. Surprisingly, we found no association between lower ADAMTS13 activity and cognitive impairment but observed a significant link between serum CD141 and cognitive impairment. These findings suggest CD141 is potentially a sensitive biomarker for risk of cognitive impairment during remission and may suggest a novel mechanism. A longer-term study with more subjects will be essential to fully explore the clinical and therapeutic implications of these findings.

Persistent ADAMTS13 Inhibitor May Lead to Delayed ADAMTS13 Recovery in Japanese Patients with Caplacizumab-Treated Immune-Mediated Thrombotic Thrombocytopenic Purpura

Introduction Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare condition that causes fatal ischemic end-organ damage due to autoantibodies against ADAMTS13. iTTP patients treated with caplacizumab in addition to standard treatments show a faster time to platelet recovery and fewer incidences of TTP-related organ damage and death. Caplacizumab got approval in Japan in December 2022, while it had been approved in Western countries as far back as 2018 and 2019. Recently, it has been reported that caplacizumab may delay the recovery of ADAMTS13 activity. Therefore, we analyzed the temporal changes of ADAMTS13 activity and its inhibitor in acute iTTP cases before and after the introduction of caplacizumab. Methods iTTP was diagnosed when ADAMTS13 activity was severely decreased (<10%) and ADAMTS13 inhibitor level was ≥0.5 BU/mL. Patients with caplacizumab-treated iTTP underwent once a week or more monitoring for ADAMTS13 activity and inhibitor during the acute phase (caplacizumab group). In addition, cases not treated with caplacizumab were selected that matched the inhibitor levels of the TTP registry since 2019 (non-caplacizumab group). The activity of the plasma ADAMTS13 and its inhibitor were measured using a chromogenic ADAMTS13 activity ELISA (Kinos Laboratories, Tokyo, Japan). Anti-ADAMTS13 IgG levels were analyzed using the TECHNOZYM ADAMTS13 INH ELISA (Tecnoclone, Vienna, Austria). The ADAMTS13 activity, ADAMTS13 inhibitor, and anti-ADAMTS13 IgG antibody levels in both groups were compared on day of onset, day 7, day 14, day 21, and day 28 from the initial therapeutic plasma exchange (TPE) (error margin of ±2 days for each time point). Continuous data were statistically compared using the Mann-Whitney U test. P values of <0.05 were judged as statistically significant. This study was approved by the ethics committee of our university. Results Of the 22 patients included in this study, 11 were treated with caplacizumab (caplacizumab group) and 11 were not (non-caplacizumab group). The median follow-up period was 55 and 74 days in the caplacizumab and non-caplacizumab groups, respectively. The demographic data for both groups are shown in Table. The median duration of caplacizumab administration in the caplacizumab group was 46 days. ADAMTS13 activity was less than 0.5% on admission in all cases. The ADAMTS13 inhibitor was detected in all cases, with no significant difference in the median titer between the caplacizumab group (7.2 BU/mL) and the non-caplacizumab group (5.0 BU/mL) (p=0.2). There was also no statistical significance in the median value of anti-ADAMTS13 IgG antibody between the caplacizumab group (133.6 U/mL) and non-caplacizumab group (73.9 U/mL) (p=0.439). All patients received TPE and corticosteroids. The median number of TPE in the caplacizumab group was significantly lower than that in the non-caplacizumab group (8 vs. 16 days, p=0.003). There was no significant difference in the median number of days from the first TPE to the start of rituximab administration, or in the proportion of rituximab administered between the two groups. After the final TPE, the caplacizumab group took a median of 43 days compared to the non-caplacizumab group (median, 3 days; p=0.003) to achieve ≥20% ADAMTS13 activity, which was significantly longer. The median ADAMTS13 activity level was significantly lower in the caplacizumab group than in the non-caplacizumab group on days 14 (<0.5% vs. 8.7%, p=0.029), 21 (<0.5% vs. 25.5%, p=0.003), and 28 (<0.5% vs. 27.8%, p<0.001), whereas the median ADAMTS13 inhibitor level was significantly higher in the caplacizumab group on the same days: day 14 (5.6 vs. <0.5 BU/mL, p=0.005), day 21 (2.0 vs. <0.5 BU/mL, p=0.009), and day 28 (0.8 vs. <0.5 BU/mL, p<0.001). Similarly, the median level of the anti-ADAMTS13 IgG antibody was significantly higher in the caplacizumab group compared to the non-caplacizumab group at identical time points on day 14 (55.4 vs. 8.3 U/mL, p=0.005) and 21 (median, 27.6 vs. 7.0 U/mL; p=0.016), and day 28 (median, 17.5 vs. 3.7 U/mL; p=0.008). Conclusion We found a delay in the recovery of ADAMTS13 activity in patients treated with caplacizumab, especially after the final TPE. This is potentially due to the persistent presence of ADAMTS13 inhibitor. When administering caplacizumab, closely monitoring for ADAMTS13 activity and its inhibitor is necessary in order to discontinue caplacizumab at the appropriate time.

A Long-Term Follow-Up Study in Immune-Mediated Thrombotic Thrombocytopenic Purpura: What Are the Outcomes?

Endothelium damage triggers the multimeric protein von Willebrand factor (VWF) release and subsequent binding to platelets, which are recruited at sites of vascular injury. A complex and fragile equilibrium between circulating levels of von Willebrand factor and its metalloprotease, ADAMTS13, is responsible for the hemostatic balance. However, the presence of autoantibodies targeting ADAMTS13 results in an increase in von Willebrand factor, mainly in its ultra-large multimers. The latter lead to platelet aggregation, the formation of thrombi and microangiopathic hemolytic anemia. This pathologic condition, known as immune-mediated thrombotic thrombocytopenic purpura (iTTP), occurs with high morbidity and a high rate of relapses. In this work, the long-term follow-up of 40 patients with iTTP is reported. We assessed ADAMTS13 activity, plasmatic VWF levels and the ADAMTS13/VWF ratio, comparing iTTP relapsing patients with remitting ones. A decrease in the ADAMTS13/VWF ratio, along with a reduced ADAMTS13 activity, could serve as predictive and sensitive biomarkers of incoming relapses.

Open ADAMTS-13 conformation index predicts earlier relapse in immune-mediated thrombotic thrombocytopenic purpura

BackgroundADAMTS-13 adopts an open conformation in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in acute phase while being closed in healthy donors. We reported that a substantial number of patients with iTTP in remission with restored ADAMTS-13 activity (>50%) still had an open ADAMTS-13 conformation, although a closed conformation is expected given the extent of remission. ObjectivesTo investigate whether open ADAMTS-13, represented by a conformation index >0.5, is associated with a risk of earlier ADAMTS-13 and/or clinical relapse. MethodsWe collected follow-up data (ADAMTS-13 parameters, ADAMTS-13 and clinical relapse, and treatment) from 81 patients with iTTP in remission with ADAMTS-13 activity >50%. ResultsDuring follow-up, 19 ADAMTS-13 and 10 clinical relapses were reported (median follow-up period, 20 months). First, open or closed ADAMTS-13 conformation was dichotomized based on the 0.5 conformation index cutoff. Open ADAMTS-13 (conformation index, >0.5) was not identified as a risk factor for ADAMTS-13 and clinical relapse (log-rank test and Cox regression model). In contrast, by identifying the optimal conformation index cutoff for relapse prediction, using classification and regression tree analysis, a conformation index >0.645 and >0.835 was shown to be a risk factor for ADAMTS-13 relapse (hazard ratio, 3.3; 95% CI, 1.3-8.3; P = .01) and clinical relapse (hazard ratio, 4.4; 95% CI, 1.3-15.3; P = .02), respectively. ConclusionPatients with open ADAMTS-13 with a conformation index >0.645 and >0.835 have a >3- and >4-fold higher risk of earlier ADAMTS-13 and clinical relapse, respectively. Hence, ADAMTS-13 conformation index could be used to complement ADAMTS-13 activity monitoring to timely notice ADAMTS-13 relapse and prevent clinical relapse.

PB0333 Therapeutic Plasma Exchange-Related Complications in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura

PB0333 Therapeutic Plasma Exchange-Related Complications in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura

PB0312 Assessment of Post-Treatment Anti-Drug Antibodies to Caplacizumab in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura

PB0312 Assessment of Post-Treatment Anti-Drug Antibodies to Caplacizumab in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura

PB0330 Relevance of ADAMTS13 Antigenic Levels in the Characterization of Pathological Mechanisms Associated with Immune-Mediated Thrombotic Thrombocytopenic Purpura (iTTP)

PB0330 Relevance of ADAMTS13 Antigenic Levels in the Characterization of Pathological Mechanisms Associated with Immune-Mediated Thrombotic Thrombocytopenic Purpura (iTTP)

OC 42.2 Incidence and Risk Factors of Major Adverse Cardiovascular Events in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura during Remission

OC 42.2 Incidence and Risk Factors of Major Adverse Cardiovascular Events in Patients with Immune-Mediated Thrombotic Thrombocytopenic Purpura during Remission

PB0316 Bortezomib for the Treatment of Multi-Refractory Immune-Mediated Thrombotic Thrombocytopenic Purpura: An Italian Multicenter Survey

PB0316 Bortezomib for the Treatment of Multi-Refractory Immune-Mediated Thrombotic Thrombocytopenic Purpura: An Italian Multicenter Survey

OC 26.3 Main Features of Ischemic Stroke in Patients with Acute Immune-Mediated Thrombotic Thrombocytopenic Purpura

OC 26.3 Main Features of Ischemic Stroke in Patients with Acute Immune-Mediated Thrombotic Thrombocytopenic Purpura

PB0328 Outcomes of Immune-Mediated Thrombotic Thrombocytopenic Purpura at a Single Center in Japan

PB0328 Outcomes of Immune-Mediated Thrombotic Thrombocytopenic Purpura at a Single Center in Japan

PB0334 Immune-Mediated Thrombotic Thrombocytopenic Purpura Landscaping in Gulf Countries: A Real-World Evidence Study (ATHENA Study)

PB0334 Immune-Mediated Thrombotic Thrombocytopenic Purpura Landscaping in Gulf Countries: A Real-World Evidence Study (ATHENA Study)

ADAMTS13 and Non-ADAMTS13 Biomarkers in Immune-Mediated Thrombotic Thrombocytopenic Purpura.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare medical emergency for which a correct and early diagnosis is essential. As a severe deficiency in A Disintegrin And Metalloproteinase with ThromboSpondin type 1 repeats, member 13 (ADAMTS13) is the underlying pathophysiology, diagnostic strategies require timely monitoring of ADAMTS13 parameters to differentiate TTP from alternative thrombotic microangiopathies (TMAs) and to guide initial patient management. Assays for conventional ADAMTS13 testing focus on the enzyme activity and presence of (inhibitory) anti-ADAMTS13 antibodies to discriminate immune-mediated TTP (iTTP) from congenital TTP and guide patient management. However, diagnosis of iTTP remains challenging when patients present borderline ADAMTS13 activity. Therefore, additional biomarkers would be helpful to support correct clinical judgment. Over the last few years, the evaluation of ADAMTS13 conformation has proven to be a valuable tool to confirm the diagnosis of acute iTTP when ADAMST13 activity is between 10 and 20%. Screening of ADAMTS13 conformation during long-term patient follow-up suggests it is a surrogate marker for undetectable antibodies. Moreover, some non-ADAMTS13 parameters gained notable interest in predicting disease outcome, proposing meticulous follow-up of iTTP patients. This review summarizes non-ADAMTS13 biomarkers for which inclusion in routine clinical testing could largely benefit differential diagnosis and follow-up of iTTP patients.

Diagnostic and treatment guidelines for thrombotic thrombocytopenic purpura (TTP) in Japan 2023.

Thrombotic thrombocytopenic purpura (TTP) can rapidly become a life-threatening condition, and the importance of its appropriate diagnosis and treatment cannot be overstated. Until recently, TTP has mainly been diagnosed by clinical findings such as thrombocytopenia and hemolytic anemia. In addition to these clinical findings, however, reduced activity of a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) below 10% has become internationally accepted as a diagnostic criterion for TTP. TTP is classified as immune-mediated TTP (iTTP) if the patient is positive for anti-ADAMTS13 autoantibodies, and as congenital TTP (cTTP) if ADAMTS13 gene abnormalities are detected. Fresh frozen plasma (FFP) transfusion is performed in patients with cTTP to supplement ADAMTS13. Plasma exchange therapy using FFP is conducted in patients with iTTP to supplement ADAMTS13 and to remove both anti-ADAMTS13 autoantibodies and unusually large von Willebrand factor (VWF) multimers. To suppress autoantibody production, corticosteroid therapy is administered in conjunction with plasma exchange. The monoclonal anti-CD-20 antibody rituximab is effective in patients with iTTP. In addition, caplacizumab, an anti-VWF A1 domain nanobody, has a novel mechanism of action, involving direct inhibition of platelet glycoprotein Ib-VWF binding. The recommended first-line treatments of iTTP in Japan are plasma exchange and corticosteroids, as well as caplacizumab.

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.

Predictors of acute ischemic cerebral lesions in immune-mediated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.

The immune form of thrombotic thrombocytopenic purpura (iTTP) and the hemolytic and uremic syndrome (HUS) are two major forms of thrombotic microangiopathy (TMA). Their treatment has been recently greatly improved. In this new era, both the prevalence and predictors of cerebral lesions occurring during the acute phase of these severe conditions remain poorly known. The prevalence and predictors of cerebral lesions appearing during the acute phase of iTTP and Shiga toxin-producing Escherichia coli-HUS or atypical HUS were evaluated in a prospective multicenter study. Univariate analysis was performed to report the main differences between patients with iTTP and those with HUS or between patients with acute cerebral lesions and the others. Multivariable logistic regression analysis was used to identify the potential predictors of these lesions. Among 73 TMA cases (mean age 46.9 ± 16years (range 21-87years) with iTTP (n = 57) or HUS (n = 16), one-third presented with acute ischemic cerebral lesions on magnetic resonance imagery (MRI); two individuals also had hemorrhagic lesions. One in ten patients had acute ischemic lesions without any neurological symptom. The neurological manifestations did not differ between iTTP and HUS. In multivariable analysis, three factors predicted the occurrence of acute ischemic lesions on cerebral MRI: (1) the presence of old infarcts on cerebral MRI, (2) the level of blood pulse pressure, (3) the diagnosis of iTTP. At the acute phase of iTTP or HUS, both symptomatic and covert ischemic lesions are detected in one third of cases on MRI. Diagnosis of iTTP and the presence of old infarcts on MRI are associated with the occurrence of such acute lesions as well as increased blood pulse pressure, that may represent a potential target to further improve the therapeutic management of these conditions.

More on the use of frontline caplacizumab in immune-mediated thrombotic thrombocytopenic purpura.

More on the use of frontline caplacizumab in immune-mediated thrombotic thrombocytopenic purpura.

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.

Clinical characteristics, treatments, and outcomes of thrombotic thrombocytopenic purpura treated with plasma exchange in Japan: a nationwide inpatient database study

BackgroundPlasma exchange (PEX) has been the primary treatment for immune-mediated thrombotic thrombocytopenic purpura (iTTP) since the 1990s. Daily PEX is recommended in international guidelines, but PEX was only reimbursed up to three times weekly under the Japanese national health insurance system until March 2018. This study was conducted to analyze practice patterns and outcomes in patients with TTP in Japan.MethodsWe used the Japanese Diagnosis Procedure Combination inpatient database, including data from approximately 1,200 acute care hospitals. We identified all hospitalized adult patients who were diagnosed with TTP on admission from July 2010 to March 2017 and who received at least one PEX during hospitalization, which we defined as TTP treated with PEX. We revealed patient characteristics, treatment patterns, and outcomes.ResultsThere were 1,559 patients with TTP treated with PEX. The median age was 64 (interquartile range [IQR] 46–74) years. There were slightly more women (59%) than men enrolled into this study. The median PEX frequency within 7 days of the initial PEX was three (IQR 2–5) times. The median total PEX number during hospitalization was six (IQR 3–10), while the median PEX duration was 10 (IQR 4–22) days. The median time from admission to the initial PEX was 4 (IQR 2–11) days. Overall, in-hospital mortality was 32%. Thirty-three percent (144/437) of hospitals reported only one case of TTP during the study period.ConclusionsOur data demonstrated that clinical practice in Japan considerably varied and its standardization is warranted.

Daratumumab for refractory immune-mediated thrombotic thrombocytopenic purpura.

Daratumumab for refractory immune-mediated thrombotic thrombocytopenic purpura.