Immune Thrombotic Thrombocytopenic Purpura Research Articles

Abstract 17158: Effects of Human Monoclonal Antibodies on ADAMTS13 in Immune Thrombotic Thrombocytopenic Purpura

Introduction: Immune thrombotic thrombocytopenic purpura (iTTP) is caused by antibody-mediated deficiency of the metalloprotease ADAMTS13, which cleaves VWF. Myocardial infarction and ischemic strokes are common and often fatal sequelae of iTTP. Inhibitory anti-ADAMTS13 antibodies appear to affect catalytic turnover more than apparent substrate binding affinity (PMID 37023370). Exploring how antibodies affect VWF cleavage by ADAMTS13 in physiologic conditions is needed to better understand the pathophysiology of iTTP. Hypothesis: Anti-ADAMTS13 antibodies may influence ADAMTS13 function by affecting catalytic turnover and/or apparent substrate binding affinity differently in physiologic conditions than in standard assay conditions. Aims: Characterize how single chain fragments of the variable loop (scFv’s) previously identified from a phage display library derived from several iTTP patients’ antibodies affect ADAMTS13-mediated VWF cleavage in conditions that more closely represent plasma and see if/how they differ from scFv-mediated effects in standard conditions. Methods: ADAMTS13 in normal human plasma was titrated with increasing concentrations of the substrate FRETS-VWF73 to derive maximum velocity ( V max ) and apparent Michaelis constant ( K M,app ) in standard assay conditions (pH 6.0) and conditions closer to physiologic (pH 7.0). The same parameters were derived in the presence of saturating concentrations of scFv’s. Results: Compared to VWF cleavage by ADAMTS13 in the absence of scFv, the inhibitory scFv4-20 decreased V max at both pH 6.0 and pH 7.0; K M,app decreased at pH 6.0 and increased at pH 7.0. The stimulatory scFv3-3 and scFv4-41 increased V max at each pH, while K M,app in the presence of each scFv decreased only at pH 7.0. Conclusions: Anti-ADAMTS13 antibody-mediated effects on VWF cleavage differ when comparing standard and more physiologic pH conditions, guiding future investigative directions into iTTP pathophysiology.

Thermodynamic Effects of Antibodies on VWF73 Cleavage By ADAMTS13

Background and objective: Immune thrombotic thrombocytopenic purpura (iTTP) is an antibody-mediated life-threatening disease, caused by severe deficiency a plasma metalloprotease ADAMTS13 that impairs the cleavage of ultra-large von Willebrand factor (VWF). This leads to catastrophic microvascular thrombosis and angiopathic hemolysis. Exploring the mechanism of antibodies that inhibit ADAMTS13 under physiologic conditions and standard assay conditions for diagnosis of iTTP (pH 6.0) may help better understand the pathophysiology of iTTP. Our previous study suggests that an inhibitory anti-ADAMTS13 antibody may affect catalytic turnover of the enzyme more than its apparent substrate binding affinity. Here, we describe a rigorous method to quantitatively determine thermodynamic linkage between antibody binding and substrate binding affinity under various conditions. We used well-characterized single chain fragments of the variable loop (scFv's) identified from a phage display library derived from several iTTP patients, and compare the apparent Michaelis constant ( K M,app,) and the maximal enzyme velocity ( V max) of ADAMTS13-mediated VWF cleavage in conditions that more closely represent plasma and in standard conditions. We also describe the stimulatory effect of a newly characterized scFv that targets the C-terminus of ADAMTS13. Methods: Single chain fragments of the variable region (scFv4-20, scFv3-3 and scFv4-41), isolated by phage display from a human anti-ADAMTS13 antibody library derived from iTTP patients, were expressed and purified. ADAMTS13 in normal human plasma was titrated with increasing concentrations of the fluorescently labeled surrogate substrate FRETS-VWF73 to derive V maxand K M,appin the standard assay conditions (pH 6.0) and the conditions closer to physiologic pH (pH 7.0). The same parameters were derived in the presence of saturating concentrations of scFv's. Reaction quotient (Q), which defines thermodynamic linkage between an allosteric effector and substrate, is derived from the ratio of K M,app when saturating scFv is present and K M,app without antibodies. Results: The V max of VWF73 cleavage by ADAMTS13 was lower at pH 7.0 than at pH 6.0 (5.23 ± 0.15 ΔFU/sec vs 7.48 ± 0.42 ΔFU/sec, respectively), and K M,app at pH 6.0 (2.54 ± 0.26 µM) was higher than at pH 7.0 (1.48 ± 0.11 µM) in the absence of scFv. Saturating inhibitory scFv4-20 decreased V max at both pH 6.0 and pH 7.0 (4.45 ± 0.16 ΔFU/sec and 1.00 ± 0.14 ΔFU/sec, respectively); K M,app was relatively unaffected at pH 6.0 (2.70 ± 0.07 µM, Q 1.06) and decreased at pH 7.0 (1.08 ± 0.27 µM, Q 0.73). Saturating scFv3-3 and scFv4-41 increased V max at both pH 6.0 (9.86 ± 0.46 ΔFU/sec and 10.05 ± 0.67 ΔFU/sec, respectively) and 7.0 (9.09 ± 0.25 ΔFU/sec and 10.26 ± 0.34 ΔFU/sec, respectively); while in the presence of scFv3-3 and scFv4-41, K M,app decreased slightly at pH 6.0 (2.20 ± 0.08 µM, Q 0.87; and 2.36 ± 0.26 µM, Q 0.93, respectively) and more dramatically at pH 7.0 (1.08 ± 0.05 µM, Q 0.73; and 1.16 ± 0.07 µM, Q 0.78, respectively). (Figure 1). Conclusions: These results indicate that anti-ADAMTS13 IgG-mediated effects on VWF cleavage may differ when comparing the standard and more physiologic pH conditions. At pH 7.0, both inhibitory and stimulatory scFvs exert a stronger effect on V max of VWF73 cleavage by ADAMTS13 than at pH 6.0. The scFv4-41, which was not previously characterized, had a stimulatory effect on ADAMTS13 very similar to the previously characterized scFv3-3. The K M,app decreases with the increasing of pH from 6.0 to 7.0, while the presence of saturated scFvs investigated in the study appears to increase apparent substrate binding affinity in conditions close to physiologic. The change of enzyme kinetics of VWF73 cleavage by ADAMTS13 in presence of saturated antibodies adds the understanding of iTTP pathophysiology and guide future investigative directions. Key words: Immune thrombotic thrombocytopenic purpura; ADAMTS13, inhibitory and stimulatory antibody

The Use of a Large Electronic Health Records System to Define and Characterize a Thrombotic Thrombocytopenic Purpura Population

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening microangiopathy due to a deficiency of the von Willebrand factor (VWF)-cleaving protease ADAMTS13. Microangiopathic hemolytic anemia, severe thrombocytopenia and ischemic end organ injury due to microvascular thrombi are the defining features of TTP. TTP can be caused by auto-antibodies against ADAMTS13 enzyme (immune TTP [ITTP]) or by inherited mutations of the ADAMTS13 gene (congenital TTP [CTTP]). Therapeutic plasma exchange (TPE) to replenish ADAMTS13, with or without steroids, has been the mainstay of treatment. Due to the auto-immune nature of ITTP the International Society on Thrombosis and Hemostasis (ISTH) made a strong recommendation in 2020 to add corticosteroids to TPE for ITTP and a conditional recommendation to add the CD20 inhibitor rituximab as well the VWF monoclonal antibody caplacizumab. Objective: To define and characterize TTP in a living population from a large electronic health record (EHR) database in terms of disease prevalence, demographic characteristics and therapeutic interventions and procedures in light of recent ISTH guidelines. Methods: We conducted a study of data from TriNetX Analytics Network, which contains EHRs from >140 million individuals from 79 Health Care Organizations in the US. We used ICD-10-CM diagnosis codes, ATC and CPT codes applied in the last 10 years to evaluate TTP disease prevalence, therapeutic interventions and procedural interventions respectively. Eligibility criteria applied to define the TTP cohort were as follows: Inclusion criteria: ICD-10 M31.1 diagnosis of thrombotic microangiopathy (TMA)History of thrombocytopenia (platelet volume ≤150,000 per microliter)ICD-10-PCS code for pheresis of plasma or a CPT code for therapeutic apheresis, for plasma pheresis Exclusion criteria: ICD-10-CM codes linked to etiologies of TMA other than TTP (hemopoietic stem cell-associated TMA [M31.11], hemolytic uremic syndrome [D59.3], disseminated intravascular coagulation [D65], antiphospholipid syndrome [D68.61], malignant hypertension [I10, I15])Deceased Results: As of July 31, 2023, there were a total of 142,046,930 living individuals registered in the database in the last 10 years. Of these, 560 individuals met eligibility criteria to define the TTP population (prevalence 0.0004% or 4 cases per million). Demographic characteristics included mean age at diagnosis (39.3 years [SD=14.3]), gender (73% female, 27% male), race (White = 44%, Black or African American = 33%, Asian = 3%, Other or unknown = 20%) and ethnicity (Not Hispanic or Latino = 73%, Unknown = 16%, Hispanic or Latino = 12%). Therapeutic interventions included systemic glucocorticoids (93% [prednisone 84%, methylprednisolone 68%, hydrocortisone 46%, dexamethasone 38%, triamcinolone 14%, betamethasone 9%, prednisolone 5%]), antithrombotics (86% [heparin group 79%, platelet aggregation inhibitors {excluding heparin} 29%, enzymes 27%, other antithrombotic agents {including caplacizumab} 18%, vitamin K antagonists 7%, direct factor Xa inhibitors 7%, direct thrombin inhibitors 2%]) and CD20 inhibitors (including rituximab) (40%). Conclusion: This this is the first report to define and characterize a TTP population from a large US EHR database using a combination administrative codes and laboratory data. The study found a very low prevalence rate; that closely aligns with previously published estimates from registries of 4-5 cases per million for ITTP and 1-2 cases per million for CTTP. It was not possible to differentiate between CTTP and ITTP cases in this study due to a lack of ADAMTS13 genomic data. Demographic findings were consistent with previous registry data (median age of acute TTP presentation in the third to fourth decade of life, typically affecting females more than males). We found a high level of systemic glucocorticoid use as expected, but also high percentage of patients treated with rituximab in line with recent ISTH guidance. The authors are aware of other potential treatments in early development including gene therapy candidates for CTTP and cell therapy candidates for ITTP. This represents a tantalizing prospect for this population; however, to demonstrate efficacy and safety, these new therapies will require scientifically rigorous and well planned clinical studies including robust long-term follow-up.

The challenging follow-up of pregnancy in women with known thrombotic thrombocytopenic purpura: a single-center experience of a preemptive management protocol.

Although thrombotic thrombocytopenic purpura frequently affects women of childbearing age, there is no clear recommendation for the management of subsequent pregnancies in women with established thrombotic thrombocytopenic purpura. This single-center, retrospective, observational study included all women with hereditary thrombotic thrombocytopenic purpura or immune thrombotic thrombocytopenic purpura who had had at least one subsequent pregnancy after thrombotic thrombocytopenic purpura diagnosis between 2003 and 2022. The strategy comprised weekly surveillance of platelet count during pregnancy (and quarterly monitoring of ADAMTS13 activity) for women with immune thrombotic thrombocytopenic purpura, without any routine prophylactic treatment. In case of thrombocytopenia < 150,000/mm3 (with or without hemolysis relapse), women with hereditary thrombotic thrombocytopenic purpura systematically received plasma infusions twice weekly until platelet count normalized. A total of 13 patients were included (7 with hereditary thrombotic thrombocytopenic purpura and 6 with immune thrombotic thrombocytopenic purpura, with 20 planned pregnancies (11 and 9, respectively). All pregnancies resulted in live births, and all mothers survived.There was a marked improvement in pregnancy terms in the hereditary thrombotic thrombocytopenic purpura group compared to index pregnancies (37 [35;39] versus 31 [24;38] weeks, p = 0.037) and birth weights (3265 [3029;3410] versus 2160 [1240;2705] grams, p = 0.016), with need for plasma support mostly starting during the third trimester (5/7 patients, 7/11 pregnancies). A single hereditary thrombotic thrombocytopenic purpura relapse occurred, with rapid resolution after plasma support intensification. There were no relapses in the immune thrombotic thrombocytopenic purpura group, with ADAMTS13 activity systematically above 40% during all monitored pregnancies. These real-life data support the feasibility of a preemptive approach to pregnancy monitoring in women with known thrombotic thrombocytopenic purpura who undergo active surveillance within a multidisciplinary network.

Caplacizumab for immune thrombotic thrombocytopenic purpura: real-world multicenter data.

Given the limited real-world data of caplacizumab, our multicenter real-world study was designed to assess the safety and efficacy of caplacizumab in immune thrombotic thrombocytopenic pupura (iTTP), compared to historic controls. We have studied 70 patients: 23 in the caplacizumab and 47 in the historic control group. Plasma exchange was applied in all episodes except for two patients that denied plasma exchange. Rituximab as first-line treatment was more common in the caplacizumab group compared to historic control. Caplacizumab (10 mg daily) was given at a median on day 7 (1-43) from initial diagnosis for 32 (6-47) dosages. In the caplacizumab group, a median of 12 (8-23) patients required plasma exchange sessions versus 14 (6-32) in the control group. Caplacizumab administration did not produce any grade 3 complications or major hemorrhagic events. After a median of 19.0 (2.6-320) months since the iTTP diagnosis, 5 deaths occurred (4 in the control group and 1 in the caplacizumab group, p = 0.310). Caplacizumab patients achieved early platelet normalization and ADAMTS13 activity normalization at the end of treatment. Relapse was observed only in 2/23 (9%) caplacizumab patients, compared to 29/47 (62%) historic controls (p < 0.001). Overall, caplacizumab is safe and effective in treating iTTP, including cases refractory to plasma exchange, re-administration, and cases without previous plasma exchange treatment. No major hemorrhagic events were observed. Cessation of dosing guided by ADAMTS13 has ensured a low relapse rate.

Immune Thrombotic Thrombocytopenic Purpura in Elderly Patients; the Role for PLASMIC and French Scores.

Immune Thrombotic Thrombocytopenic Purpura in Elderly Patients; the Role for PLASMIC and French Scores.

OC 14.5 Plasma Exchange-free Management of Immune Thrombotic Thrombocytopenic Purpura: The Austrian-German Experience

OC 14.5 Plasma Exchange-free Management of Immune Thrombotic Thrombocytopenic Purpura: The Austrian-German Experience

Immune thrombotic thrombocytopenic purpura in patients over 60 years of age: Diagnostic pitfalls and treatment strategy.

Real-world registry studies of older patients with iTTP highlight diagnostic difficulties in comparison to patients less than 60 years of age with greater risk of renal injury, atypical neurological features and less profound cytopenia, which can result in diagnostic delays. However, there is no clear signal of significantly increased toxicity from full active treatment. Commentary on: Gómez-Seguí et al. Immune thrombotic thrombocytopenic purpura in older patients: results from the Spanish TTP Registry (REPTT). Br J Haematol 2023;203:860-871.

Immune thrombotic thrombocytopenic purpura in older patients: Results from the Spanish TTP Registry (REPTT).

Immune thrombotic thrombocytopenic purpura (iTTP) is an ultra-rare disease that seldom occurs in the elderly. Few reports have studied the clinical course of iTTP in older patients. In this study, we have analysed the clinical characteristics at presentation and response to therapy in a series of 44 patients with iTTP ≥60 years at diagnosis from the Spanish TTP Registry and compared them with 209 patients with <60 years at diagnosis from the same Registry. Similar symptoms and laboratory results were described in both groups, except for a higher incidence of renal dysfunction among older patients (23% vs. 43.1%; p = 0.008). Front-line treatment in patients ≥60 years was like that administered in younger patients. Also, no evidence of a difference in clinical response and overall survival was seen in both groups. Of note, 14 and 25 patients ≥60 years received treatment with caplacizumab and rituximab, respectively, showing a favourable safety and efficacy profile, like that observed in patients <60 years.

Cardiovascular Disease and Stroke in Immune TTP-Challenges and Opportunities.

Advances in the management of immune thrombotic thrombocytopenic purpura (iTTP) have dramatically improved outcomes of acute TTP episodes, and TTP is now treated as a chronic, relapsing disorder. It is now recognized that iTTP survivors are at high risk for vascular disease, with stroke and myocardial infarction occurring at younger ages than in the general population, and cardiovascular disease is the leading cause of premature death in this population. iTTP appears to have a phenotype of accelerated vascular aging with a particular predilection for cerebral circulation, and stroke is much more common than myocardial infarction. In addition to traditional cardiovascular risk factors, low ADAMTS13 activity during clinical remission may be a risk factor for some of these outcomes, such as stroke. Recent studies also suggest that Black patients, who are disproportionately affected by iTTP in the United States, are at higher risk of adverse cardiovascular outcomes, likely due to multifactorial reasons. Additional research is required to establish the risk factors and mechanisms underlying these complications in order to institute optimal screening strategies and identify interventions to improve outcomes.

Immune thrombotic thrombocytopenic purpura: pathogenesis and novel therapies: a narrative review.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, but potentially fatal blood disease, resulting from autoantibodies against A Disintegrin and Metalloprotease with ThromboSpondin Type 1 Repeats, 13 (ADAMTS13). While major progress has been made in past decades concerning early diagnosis and management of iTTP, the mechanisms underlying the formation and the mechanism of action of these autoantibodies against ADMATS13 are still unknown. This review will provide a narrative review of pathogenesis and novel therapeutics of iTTP. We did PubMed literature search using a combination of thrombotic thrombocytopenic purpura and treatment or pathogenesis from 1955 to November 2022. A total of 4,767 articles with full text were found and only relevant articles in English were further reviewed and summarized. We found that the primary mechanism underlying severe ADAMTS13 deficiency in patients with iTTP is autoantibody-mediated inhibition and/or accelerated clearance of ADAMTS13 metalloprotease. Other factors including allosteric regulation and post-translational modifications (i.e., glycosylation and citrullination, and arginine methylation, etc.) may affect ADAMTS13 secretion and function and also contribute to the pathogenesis of iTTP. The standard of care for iTTP today consists of therapeutic plasma exchange, anti-von Willebrand factor (vWF) caplacizumab, and immunosuppressives (e.g., corticosteroids and rituximab), known as the triple therapy, which has significantly reduced exacerbation and mortality rates. We hope that the information provided in the review article helps better understand the pathogenesis of iTTP, which may guide design novel and more effective therapeutics for this potentially fatal disorder.

Anti-ADAMTS13 Autoantibodies: From Pathophysiology to Prognostic Impact-A Review for Clinicians.

Thrombotic thrombocytopenic purpura (TTP) is a fatal disease in which platelet-rich microthrombi cause end-organ ischemia and damage. TTP is caused by markedly reduced ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity. ADAMTS13 autoantibodies (autoAbs) are the major cause of immune TTP (iTTP), determining ADAMTS13 deficiency. The pathophysiology of such autoAbs as well as their prognostic role are continuous objects of scientific studies in iTTP fields. This review aims to provide clinicians with the basic information and updates on autoAbs' structure and function, how they are typically detected in the laboratory and their prognostic implications. This information could be useful in clinical practice and contribute to future research implementations on this specific topic.

Impact of N-glycan mediated shielding of ADAMTS-13 on the binding of pathogenic antibodies in immune thrombotic thrombocytopenic purpura

BackgroundThrombotic thrombocytopenic purpura (TTP) is a rare thrombotic disorder, with 1.5 to 6.0 cases per million per year. The majority of patients with TTP develop inhibitory autoantibodies that predominantly target the spacer domain of ADAMTS-13. ADAMTS-13 is responsible for cleaving von Willebrand factor (VWF) multimers, thereby regulating platelet adhesion at sites of high-vascular shear stress. Inhibition and/or clearance of ADAMTS-13 by pathogenic autoantibodies results in accumulation of VWF multimers that promotes the formation of platelet-rich microthrombi. Previously, we have shown that insertion of a single N-glycan (NGLY) in the spacer domain prevents the binding of antispacer domain antibodies. ObjectivesTo explore whether NGLY mediated shielding of the ADAMTS-13 spacer domain effectively prevents binding of pathogenic antispacer autoantibodies in patients with immune-mediated TTP (iTTP). MethodsWe screened 5 NGLY-ADAMTS-13 variants (NGLY3, NGLY7, NGLY8, NGLY3+7, and NGLY3+8) for binding of autoantibodies and for their activity in the presence and absence of 50 samples derived from patients with iTTP. ResultsNGLY variants showed greatly reduced antibody binding, down to 27% of wild-type (wt) ADAMTS-13 binding. Moreover, NGLY variants of ADAMTS-13 remained more active in FRETS-VWF73 assay in the presence of the plasma samples from these 50 patients with acute phase iTTP when compared with wtADAMTS-13. On average, wtADAMTS-13 activity was reduced to 37% of regular levels in the presence of plasma, while NGLY3 and NGLY3+7 remained 69% and 81% active, respectively. ConclusionThese results reinforce our previous findings that NGLYs shield ADAMTS-13 from antibody binding and hence restore ADAMTS-13 activity in the presence of autoantibodies.

HTRS2023.P4.13 Antibody mediated pathophysiology of immune thrombotic thrombocytopenic purpura

HTRS2023.P4.13 Antibody mediated pathophysiology of immune thrombotic thrombocytopenic purpura

Global Health Resource Utilization and Cost-Effectiveness of Therapeutics and Diagnostics in Immune Thrombotic Thrombocytopenic Purpura (TTP).

In this review, we examine the current landscape of health resource utilization and cost-effectiveness data in the care of patient populations with immune thrombotic thrombocytopenic purpura. We focus on the therapeutic (therapeutic plasma exchange, glucocorticoids, rituximab, caplacizumab) and diagnostic (ADAMTS13 assay) health technologies employed in the care of patients with this rare disease. Health resource utilization and cost-effectiveness data are limited to the high-income country context. Measurement of TTP-specific utility weights in the high-income country context and collection of health resource utilization data in the low- and middle-income country settings would enable an evaluation of country-specific quality-adjusted life expectancy and cost-effectiveness of these therapeutic and diagnostic health technologies. This quantification of value is one way to mitigate cost concerns where they exist.

How should caplacizumab be used for treatment of immune thrombotic thrombocytopenic purpura?

How should caplacizumab be used for treatment of immune thrombotic thrombocytopenic purpura?

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.

Hemostatic Profile and Serological Response of Patients with Immune Thrombotic Thrombocytopenic Purpura after Receiving BNT162b2 Vaccine: A Prospective Study.

Coronavirus disease is a clinical challenge for patients with autoimmune conditions. Patients affected by immune thrombotic thrombocytopenic purpura (iTTP) are particularly vulnerable to SARS-CoV-2 infection. Protecting these patients with vaccination is therefore mandatory, although concerns may exist on a possible increased thrombotic risk or risk of disease relapse after vaccine exposure. So far, there is no information on serological response and hemostatic activation in iTTP patients after SARS-CoV-2 vaccination. In this study, in April 2021, we enrolled iTTP patients in clinical remission and on regular outpatient follow-up to receive the first and second dose BNT162b2 vaccine as a part of a prospective trial aimed at monitoring for 6 months after vaccination the occurrence of subclinical laboratory signs of clotting activation, as well as overt thrombotic complications or disease relapse. The seroconversion response was monitored in parallel. The results were compared with those of control non-iTTP subjects. A moderate decrease of ADAMTS-13 activity was recorded at 3 and 6 months in five patients with normal values at baseline, while an ADAMTS-13 relapse occurred at 6 months in one patient. Abnormalities in the endothelium activation biomarkers postvaccination were observed in iTTP patients compared with controls. The immunological response to vaccine was overall positive. No clinical iTTP relapses or thrombotic events manifested in the 6 month-follow-up after vaccination. The results of this study are in favor of efficacy and safety of mRNA vaccines in patients with iTTP, and highlight the importance of long-term monitoring of iTTP patients.

Adding caplacizumab to standard of care in thrombotic thrombocytopenic purpura: a systematic review and meta-analysis.

Immune thrombotic thrombocytopenic purpura (iTTP) is an acquired, fatal microangiopathy if untreated. Randomized controlled trials (RCTs) demonstrated faster time to response with addition of caplacizumab to standard of care (SOC). However, concerns about RCT selection bias and the high cost of caplacizumab warrant examination of all evidence, including real-world observational studies. In this systematic review and meta-analysis, we searched for comparative studies evaluating SOC with or without caplacizumab for the treatment of iTTP. We assessed risk of bias using the Cochrane risk-of-bias-2 tool (RCTs) and the Newcastle-Ottawa Scale (observational studies). The primary efficacy and safety outcomes were all-cause mortality and treatment-emergent bleeding, respectively. Secondary outcomes included exacerbation and relapse, refractory iTTP, and time to response. We included 2 high-quality RCTs and 3 observational studies at high risk of bias comprising 632 total participants. Compared with SOC, caplacizumab was associated with a nonsignificant reduction in the relative risk [RR] of death in RCTs (RR, 0.21; 95% confidence interval [CI], 0.05-1.74) and observational studies (RR, 0.62; 95% CI, 0.07-4.41). Compared with SOC, caplacizumab was associated with an increased bleeding risk in RCTs (RR, 1.37; 95% CI, 1.06-1.77). In observational studies, bleeding risk was not significantly increased (RR, 7.10; 95% CI, 0.90-56.14). Addition of caplacizumab was associated with a significant reduction in refractory iTTP and exacerbation risks and shortened response time but increased relapse risk. Frontline addition of caplacizumab does not significantly reduce all-cause mortality compared with SOC alone, although it reduces refractory disease risk, shortens time to response, and improves exacerbation rates at the expense of increased relapse and bleeding risk.

In patients with suspected immune TTP, admission source impacts hospital length of stay and time to therapeutic plasma exchange impacts clinical outcomes

IntroductionWhen immune thrombotic thrombocytopenic purpura (TTP) is suspected, outcomes are impacted by time to therapeutic plasma exchange (TPE). We evaluated the impact of time to TPE on outcomes in suspected TTP cases admitted through the Emergency Department (ED) vs. transferred from another facility (Transfer). Materials and methodsIn a retrospective analysis of the National Inpatient Sample, we examined the association between TTP outcomes and admission source (ED vs. Transfer) for the primary outcome of time to TPE. A second stratified analyses within each analytic group examined the association of time to TPE (<1 day, 1 day, 2 days, and >2 days) and outcomes for the composite outcome of mortality, major bleeding and thrombosis. ResultsOf 1195 cases, 793 (66 %) were admitted through the ED and 402 (34 %) were transferred. Compared to ED cases, Transfers had a longer hospital length of stay (14.69 vs. 16.65 days, p = 0.0060). For ED cases, TPE after >2 days was associated with higher odds of the composite outcome (OR = 1.68 95 % CI: 1.11–2.54; p = 0.0150) and mortality (OR = 3.01 95 % CI: 1.38–6.57; p = 0.0056). For Transfers, TPE on day 2 was associated with higher odds of the composite outcome (OR = 3.00 95 % CI: 1.31–6.89; p = 0.0096) and mortality (OR = 4.95 95 % CI: 1.12–21.88; p = 0.0350). ConclusionsIn suspected TTP admitted through the ED or transferred, there was no significant difference in time to TPE. A longer time to TPE was associated with worse outcomes. Future studies should evaluate strategies to decrease initial time to TPE.