Cost analysis of the impact of caplacizumab in the treatment of acquired thrombotic thrombocytopenic purpura from a US hospital perspective

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening thrombotic microangiopathy caused by severe ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin motifs 13) deficiency, recurring in 30–50% of patients. The common human leukocyte antigen (HLA) variant rs6903608 was found to be associated with prevalent iTTP, but whether this variant is associated with disease relapse is unknown. To estimate the impact of rs6903608 on iTTP onset and relapse, we performed a case-control and cohort study in 161 Italian patients with a first iTTP episode between 2002 and 2018, and in 456 Italian controls. Variation in rs6903608 was strongly associated with iTTP onset (homozygotes odds ratio (OR) 4.68 (95% confidence interval (CI) 2.67 to 8.23); heterozygotes OR 1.64 (95%CI 0.95 to 2.83)), which occurred over three years earlier for each extra risk allele (β −3.34, 95%CI −6.69 to 0.02). Of 153 survivors (median follow-up 4.9 years (95%CI 3.7 to 6.1)), 44 (29%) relapsed. The risk allele homozygotes had a 46% (95%CI 36 to 57%) absolute risk of relapse by year 6, which was significantly higher than both heterozygotes (22% (95%CI 16 to 29%)) and reference allele homozygotes (30% (95%CI 23 to 39%)). In conclusion, HLA variant rs6903608 is a risk factor for both iTTP onset and relapse. This newly identified biomarker may help with recognizing patients at high risk of relapse, who would benefit from close monitoring or intensified immunosuppressive therapy.

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Thrombotic Thrombocytopenic Purpura Misdiagnosed As Autoimmune Cytopenia: Causes of Diagnostic Errors and Consequence on Outcome. Experience of the French Thrombotic Microangiopathies Reference Centre

Blood ◽

10.1182/blood.v128.22.3730.3730 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3730-3730

Author(s):

Maximilien Grall ◽

Ygal Benhamou ◽

Elie Azoulay ◽

Eric Mariotte ◽

Lionel Galicier ◽

...

Keyword(s):

Organ Failure ◽

Thrombotic Thrombocytopenic Purpura ◽

Conflicts Of Interest ◽

Diagnostic Errors ◽

Hemoglobin Level ◽

Thrombocytopenic Purpura ◽

Platelet Recovery ◽

Reference Centre ◽

Adamts13 Deficiency ◽

The Impact

Abstract Introduction: Thrombotic thrombocytopenic purpura (TTP) is a life threatening disease defined by the association of a hemolytic mechanical anemia, a profound thrombopenia and organ failure with a severe ADAMTS13 deficiency. A rapid diagnosis represents a major goal and sources of misdiagnosis need to be identified to avoid diagnostic wandering and delayed adapted treatment that may translate in increased morbi-mortality. The main objective of this study is to describe the characteristics of TTP initially misdiagnosed and analyse the impact of a late diagnosis on patient's outcomes. Methods: From May 2000 to May 2014, all patients with acquired TTP and severe ADAMTS13 deficiency enrolled prospectively in the French TMA Reference Centre registry were included. A misdiagnosis was retained if initial diagnosis was not TTP and if patients did not receive TPE as initial treatment. Results: Among the 423 studied patients, 84 (20%) were initially misdiagnosed and not received plasma exchange. Main diagnostic errors were attributed to an Evans syndrome and an auto-immune thrombopenic purpura in 51% and 37% of cases respectively. Median time to diagnosis was longer in the misdiagnosed group than in the accurately diagnosed (5 [IQR, 2-8] vs. 1 [IQR, 0-3] days, P=.008). At admission, compared to the accurately diagnosed patients, misdiagnosed patients had a higher rate of low or undetectable schizocytosis (57.5% vs. 32%, P=.001), higher hemoglobin level (8.4 [IQR, 6.7-9.7] g/dl vs. 7.7 [IQR, 6.5-9.1] g/dl, P=.008) and rate of positive DAT (18% vs. 4%, P=.008). Anti-nuclear antibodies (65% vs. 51%, P=.045) and an associated auto-immune disease (24% vs. 13%, P=.017) were also more frequent. In multivariate analysis, a positive DAT and hemoglobin level were retained as risk factor (OR= 8.71, 95% CI [1.759-43.181], P=.008 and OR= 1.27, 95% CI [1.002-1.602], P=.048), respectively. Platelet count recovery over time was significantly longer in the misdiagnosed group (log-rank test: P=.041) without any consequence on overall mortality, exacerbation and relapse. However, specific causes of death probably differed between groups: in the accurately diagnosed group, patients died more frequently on early stage from a fulminant form of TTP within the first week, whereas in the misdiagnosed group patients died later (13 [IQR, 3-20] vs. 6 [IQR, 2-9] days; P=.023), had less organ involvement at early diagnosis (49% vs.64%, P=.019) and received more salvage therapies (80% vs. 35%, P=.009), suggesting that prognosis could have been improved with an earlier treatment. Conclusion: TTP is frequently misdiagnosed with auto-immune cytopenias and usual biological parameters may be initially absent. In a context of hemolysis and thrombocytopenia, a low or undetectable rate of schizocytosis at admission, and a positive DAT should not rule out the diagnosis of TTP, especially when associated with organ failure. A rapid accurate diagnosis of TTP may result in a shorter time to platelet recovery and could improve prognosis. Disclosures No relevant conflicts of interest to declare.

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Identification of ADAMTS13 Peptide Sequences Recognized by Autoantibodies in Patients with Acquired Thrombotic Thrombocytopenic Purpura.

Blood ◽

10.1182/blood.v112.11.2286.2286 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2286-2286

Author(s):

Yusuke Yamaguchi ◽

Takanori Moriki ◽

Hideo Wada ◽

Masanori Matsumoto ◽

Yoshihiro Fujimura ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Peptide Sequence ◽

Adamts13 Activity ◽

Lambda Phage ◽

Thrombocytopenic Purpura ◽

C Terminus ◽

Epitope Sequence ◽

Von Willebrand ◽

The Impact ◽

Inhibitor Titer

Abstract Anti-ADAMTS13 autoantibodies are considered to play pivotal roles in the pathophysiology of acquired thrombotic thrombocytopenic purpura (TTP). They inhibit the ADAMTS13 function resulting in the appearance of ultra-large von Willebrand factor (VWF) multimers. Major binding sites of the autoantibodies were reported to be in the cysteine-rich/spacer domains. To clarify the precise peptide sequences recognized by anti-ADAMTS13 IgG autoantibodies, we constructed a random cDNA fragment library expressing various peptides of ADAMTS13 on the surface of lambda phage and screened the library using purified IgG from 13 TTP patients. Diverse peptide sequences were obtained from almost entire ADAMTS13 domains such as metalloprotease, disintegrin, TSP1-1, cysteine-rich, spacer, TSP1- 2, 3, 4, 5, 7, 8 and CUB1. In particular, we detected an identical 26 amino-acid epitope sequence in the C-terminus of spacer domain from Gly662 to Val687 (sp662–687) shared by 5 TTP patients. Moreover, the peptide sequence was exactly included in one of the VWF binding epitope sites that we previously determined (Blood110 (11), 795a, 2007). We then assessed the impact of specific autoantibody to ADAMTS13 activity measured by FRETS-VWF73 or EIA and ADAMTS13 inhibitor titer in each of TTP patient plasma. However, both of the ADAMTS13 activity and inhibitor titer seemed not correlated with the existence of specific sp662–687 IgG autoantibody. These observations suggest that the autoantibody to sp662–687 may be one specific feature of TTP, although other epitopes are also involved in the pathogenesis of the disorder.

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Outcomes in 1096 patients with severe thrombotic thrombocytopenic purpura before the Caplacizumab era

PLoS ONE ◽

10.1371/journal.pone.0256024 ◽

2021 ◽

Vol 16 (8) ◽

pp. e0256024

Author(s):

Andry Van de Louw ◽

Eric Mariotte ◽

Michael Darmon ◽

Austin Cohrs ◽

Douglas Leslie ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Standard Of Care ◽

First Line ◽

Thrombocytopenic Purpura ◽

Initial Management ◽

Icu Admission ◽

Emerging Treatments ◽

Hospital Resources ◽

The Impact ◽

Over Time

Introduction Thrombotic thrombocytopenic purpura (TTP) is a diagnostic and therapeutic emergency. Therapeutic plasma exchange (TPE) combined with immunosuppression has been the cornerstone of the initial management. To produce optimal benefits, emerging treatments must be used against a background of best standard of care. Clarifying current uncertainties is therefore crucial. Methods The objective of this study was to analyze a large high-quality database (Marketscan) of TTP patients managed between 2005 and 2014, in the pre-caplacizumab era, in order to assess the impact of time to first TPE and use of first-line rituximab on mortality, and whether mortality declines over time. Results Among the 1096 included patients (median age 46 [IQR 35–55], 70% female), 28.8% received TPE before day 2 in the ICU. Hospital mortality was 7.6% (83 deaths). Mortality was independently associated with older age (hazard ratio [HR], 1.024/year; 95% confidence interval [95%CI], [1.009–1.040]), diagnosis of sepsis (HR, 2.360; 95%CI [1.552–3.588]), and the need for mechanical ventilation (HR, 4.103; 95%CI, [2.749–6.126]). Factors independently associated with lower mortality were TPE at ICU admission (HR, 0.284; 95%CI, [0.112–0.717]), TPE within one day after ICU admission (HR, 0.449; 95%CI, [0.275–0.907]), and early rituximab therapy (HR, 0.229; 95% CI, [0.111–0.471]). Delayed TPE was associated with significantly higher costs. Conclusions Immediate TPE and early rituximab are associated with improved survival in TTP patients. Improved treatments have led to a decline in mortality over time, and alternate outcome variables such as the use of hospital resources or longer term outcomes therefore need to be considered.

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Factors Associated with Mortality in Patients Experiencing First Episodes of Acquired Thrombotic Thrombocytopenic Purpura (aTTP). Results of the Spanish TTP Registry

Blood ◽

10.1182/blood-2019-122665 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1082-1082

Author(s):

Julio del Rio-Garma ◽

Sabela Bobillo ◽

Javier De La Rubia ◽

Maria Cristina Pascual Izquierdo ◽

Faustino García-Candel ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Laboratory Data ◽

Complete Information ◽

Biological Factor ◽

First Episode ◽

Severe Thrombocytopenia ◽

Adamts13 Activity ◽

International Consensus ◽

Thrombocytopenic Purpura ◽

The Impact

Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare, but life-threatening, hematological disorder characterized by severe thrombocytopenia, hemolytic microangiopathic anemia, and frequent organ damage. The underlying pathophysiology of aTTP is a functional deficiency of plasma ADAMTS13 activity caused by antibodies directed against the ADAMTS13 protease. Despite plasma exchange (PEX) and immunosuppression with corticosteroids, and, more recently, rituximab, which achieve remission in most patients with aTTP, 10-20% of patients are refractory to treatment and die as a result of disease progression. Most of such deaths occur during first episodes of aTTP, as subsequent relapses tend to be milder. These patients would probably benefit from new therapies aimed at temporarily halting the microvascular thrombosis. This study was aimed at identifying predictive factors of mortality during a first episode of aTTP. Methods: We searched the Spanish TTP Registry (REPTT, Registro Español de la Purpura Trombocitopénica Trombótica) for patients with a clinical diagnosis of TTP (n = 345) with ADAMTS13 activity <10%, and anti-ADAMTS13 inhibitors in plasma (n = 143). Among these, we selected 103 patients with complete information on their first episode of aTTP. The patients were diagnosed between 2004 and 2018, and all were treated with daily PEX and corticosteroids. Additional treatments (rituximab, vincristine, etc.) were used at the discretion of the attending hematologist. Clinical and laboratory data of the episodes were analyzed at diagnosis and during the course of the treatment. The impact of refractoriness, exacerbations (as defined by the international consensus; DOI: 10.1111/jth.13571) and platelet transfusions on mortality was also studied. Results: The 103 patients examined suffered a total of 111 episodes of aTTP (103 with a first episode and 8 with a relapse). Eight deaths (7.7%) took place during an initial episode of aTTP and none during relapses. The time elapsed from the diagnosis to the events of death ranged from a few hours to 36 days (Figure). One patient died before starting the treatment. In the multivariate analysis, stupor or coma at diagnosis was the only clinical and biological factor associated with mortality, as 6 out of 18 patients with stupor or coma died vs. 2 out of 85 without these symptoms (OR: 21.95% CI: 4-114; p = 0.001). Persistently low platelet counts during PEX (i.e. refractoriness) were also strong predictors of subsequent mortality, with a platelet count <20 x109/L after 6 PEX procedures yielding the highest positive and negative values (Table). Exacerbation of aTTP while on treatment occurred in 44 of the 95 patients, all of whom eventually achieved remission with no events of death. Patients with exacerbations required a higher number of PEX procedures to achieve clinical remission (23, IQR: 19-31 vs. 12, IQR: 8-16; p <0.001) and were more likely to receive rituximab (39% vs. 9%; p = 0.001). Platelets were transfused into 16 patients, including 2 patients who died a few days later and 14 survivors. Conclusions: Stupor or coma at diagnosis and lack of response to PEX by the 6th-7th day in patients experiencing first episodes of aTTP are strong predictors of mortality. These patients are candidates for new treatments aimed at controlling the microvascular thrombotic phenomena until effective immunosuppression is achieved. Disease exacerbation does not seem to increase mortality but requires a more intensive treatment. Disclosures De La Rubia: Celgene Corporation: Consultancy; AbbVie: Consultancy; AMGEN: Consultancy; Janssen: Consultancy; Takeda: Consultancy. Pascual Izquierdo:Novartis: Consultancy; Sanofi: Consultancy.

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