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New Diagnostic and Therapeutic Aspects of Thrombotic Thrombocytopenic Purpura

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Hematology".

Deadline for manuscript submissions: closed (20 June 2023) | Viewed by 31258

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Special Issue Editors

Dr. Ilaria Mancini

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Guest Editor

Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
Interests: thrombotic thrombocytopenic purpura; thrombotic microangiopathies; ADAMTS13; laboratory ADAMTS13 testing; genetics of hemostasis and thrombotic disorders

Dr. Andrea Artoni

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Guest Editor

Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
Interests: thrombotic thrombocytopenic purpura; thrombotic microangiopathies; coagulation; thrombosis; haemostasis; platelets; platelet aggregation; hematology; hemostasis; blood coagulation; platelet activation; pulmonary embolism

Special Issue Information

Dear Colleagues,

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy caused by the congenital or acquired severe deficiency of the von Willebrand factor cleaving protease, ADAMTS13. Acute TTP is a medical emergency requiring a fast differential diagnosis and immediate treatment, which is often challenging due to the overlap of clinical and laboratory features with other thrombotic microangiopathies. Diagnostic and therapeutic advancements in the last decade, including the increased availability of ADAMTS13 testing and the development of caplacizumab, the first targeted therapy for acquired TTP, have significantly improved the management of acute TTP and reduced the burden of such short-term outcomes as mortality and exacerbation of acute disease. At the same time, new clinical challenges have emerged, to mention one addressing the burden of long-term complications of TTP and cardiovascular comorbidities in TTP patients in remission.

This Special Issue will cover new diagnostic and therapeutic aspects of TTP care, with the scope of advancing our knowledge and clinical intervention to address the current challenges of TTP management. Original, review, and guidance/guidelines papers are welcome.

Dr. Ilaria Mancini
Dr. Andrea Artoni
Guest Editors

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Keywords

thrombotic thrombocytopenic purpura (TTP)
ADAMTS13
ADAMTS13 testing
differential diagnosis of thrombotic microangiopathy
disease awareness
TTP therapy
refractoriness
exacerbation
thromboembolic complications
new therapeutic approaches
long-term outcomes
TTP relapse prevention
pregnancy management
management of predisposing conditions/precipitating factors
hospital resources

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Published Papers (11 papers)

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Review

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12 pages, 259 KiB

Open AccessReview

The Highs and Lows of ADAMTS13 Activity

by Rebecca J. Shaw, Simon T. Abrams, Samuel Badu, Cheng-Hock Toh and Tina Dutt

J. Clin. Med. 2024, 13(17), 5152; https://doi.org/10.3390/jcm13175152 - 30 Aug 2024

Viewed by 3165

Abstract

Severe deficiency of ADAMTS13 (<10 iu/dL) is diagnostic of thrombotic thrombocytopenic purpura (TTP) and leads to accumulation of ultra-large vWF multimers, platelet aggregation, and widespread microthrombi, which can be life-threatening. However, the clinical implications of a low ADAMTS13 activity level are not only important in an acute episode of TTP. In this article, we discuss the effects of low ADAMTS13 activity in congenital and immune-mediated TTP patients not only at presentation but once in a clinical remission. Evidence is emerging of the clinical effects of low ADAMTS13 activity in other disease areas outside of TTP, and here, we explore the wider impact of low ADAMTS13 activity on the vascular endothelium and the potential for recombinant ADAMTS13 therapy in other thrombotic disease states. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Aspects of Thrombotic Thrombocytopenic Purpura)

12 pages, 708 KiB

Open AccessReview

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

by Quintijn Bonnez, Kazuya Sakai and Karen Vanhoorelbeke

J. Clin. Med. 2023, 12(19), 6169; https://doi.org/10.3390/jcm12196169 - 24 Sep 2023

Cited by 8 | Viewed by 2617

Abstract

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. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Aspects of Thrombotic Thrombocytopenic Purpura)

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10 pages, 632 KiB

Open AccessReview

Cardiovascular Disease and Stroke in Immune TTP–Challenges and Opportunities

by Senthil Sukumar, Marshall A. Mazepa and Shruti Chaturvedi

J. Clin. Med. 2023, 12(18), 5961; https://doi.org/10.3390/jcm12185961 - 14 Sep 2023

Cited by 1 | Viewed by 2419

Abstract

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. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Aspects of Thrombotic Thrombocytopenic Purpura)

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10 pages, 458 KiB

Open AccessReview

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

by Cristina Dainese, Federica Valeri, Benedetto Bruno and Alessandra Borchiellini

J. Clin. Med. 2023, 12(17), 5630; https://doi.org/10.3390/jcm12175630 - 29 Aug 2023

Cited by 4 | Viewed by 1877

Abstract

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. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Aspects of Thrombotic Thrombocytopenic Purpura)

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14 pages, 614 KiB

Open AccessReview

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

by Ayesha Butt, Cecily Allen, Adriana Purcell, Satoko Ito and George Goshua

J. Clin. Med. 2023, 12(15), 4887; https://doi.org/10.3390/jcm12154887 - 25 Jul 2023

Cited by 4 | Viewed by 2093

Abstract

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. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Aspects of Thrombotic Thrombocytopenic Purpura)

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12 pages, 683 KiB

Open AccessReview

Clinical Manifestations, Current and Future Therapy, and Long-Term Outcomes in Congenital Thrombotic Thrombocytopenic Purpura

by Kazuya Sakai and Masanori Matsumoto

J. Clin. Med. 2023, 12(10), 3365; https://doi.org/10.3390/jcm12103365 - 9 May 2023

Cited by 4 | Viewed by 3601

Abstract

Congenital thrombotic thrombocytopenic purpura (cTTP) is an extremely rare disease characterized by the severe deficiency of a disintegrin and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13), caused by ADAMTS13 mutations. While ADAMTS13 supplementation by fresh frozen plasma (FFP) infusion immediately corrects platelet consumption and resolves thrombotic symptoms in acute episodes, FFP treatment can lead to intolerant allergic reactions and frequent hospital visits. Up to 70% of patients depend on regular FFP infusions to normalize their platelet counts and avoid systemic symptoms, including headache, fatigue, and weakness. The remaining patients do not receive regular FFP infusions, mainly because their platelet counts are maintained within the normal range or because they are symptom-free without FFP infusions. However, the target peak and trough levels of ADAMTS13 to prevent long-term comorbidity with prophylactic FFP and the necessity of treating FFP-independent patients in terms of long-term clinical outcomes are yet to be determined. Our recent study suggests that the current volumes of FFP infusions are insufficient to prevent frequent thrombotic events and long-term ischemic organ damage. This review focuses on the current management of cTTP and its associated issues, followed by the importance of upcoming recombinant ADAMTS13 therapy. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Aspects of Thrombotic Thrombocytopenic Purpura)

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12 pages, 697 KiB

Open AccessReview

Immune and Hereditary Thrombotic Thrombocytopenic Purpura: Can ADAMTS13 Deficiency Alone Explain the Different Clinical Phenotypes?

by Stefano Lancellotti, Monica Sacco, Maira Tardugno, Antonietta Ferretti and Raimondo De Cristofaro

J. Clin. Med. 2023, 12(9), 3111; https://doi.org/10.3390/jcm12093111 - 25 Apr 2023

Cited by 5 | Viewed by 2880

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy caused by a hereditary or immune-mediated deficiency of the enzyme ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). TTPs are caused by the following pathophysiological mechanisms: (1) the presence of inhibitory autoantibodies against ADAMTS13; and (2) hereditary mutations of the ADAMTS13 gene, which is present on chromosome 9. In both syndromes, TTP results from a severe deficiency of ADAMTS13, which is responsible for the impaired proteolytic processing of high-molecular-weight von Willebrand factor (HMW-VWF) multimers, which avidly interact with platelets and subendothelial collagen and promote tissue and multiorgan ischemia. Although the acute presentation of the occurring symptoms in acquired and hereditary TTPs is similar (microangiopathic hemolytic anemia, thrombocytopenia, and variable ischemic end-organ injury), their intensity, incidence, and precipitating factors are different, although, in both forms, a severe ADAMTS13 deficiency characterizes their physiopathology. This review is aimed at exploring the possible factors responsible for the different clinical and pathological features occurring in hereditary and immune-mediated TTPs. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Aspects of Thrombotic Thrombocytopenic Purpura)

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11 pages, 929 KiB

Open AccessFeature PaperReview

The Specificities of Thrombotic Thrombocytopenic Purpura at Extreme Ages: A Narrative Review

by Adrien Joseph, Bérangère S. Joly, Adrien Picod, Agnès Veyradier and Paul Coppo

J. Clin. Med. 2023, 12(9), 3068; https://doi.org/10.3390/jcm12093068 - 23 Apr 2023

Cited by 6 | Viewed by 3520

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy (TMA) related to a severe ADAMTS13 deficiency, the specific von Willebrand factor (VWF)-cleaving protease. This deficiency is often immune-mediated (iTTP) and related to the presence of anti-ADAMTS13 autoantibodies that enhance its clearance or inhibit its VWF processing activity. iTTP management may be challenging at extreme ages of life. International cohorts of people with TTP report delayed diagnoses and misdiagnoses in children and elderly people. Child-onset iTTP shares many features with adult-onset iTTP: a female predominance, an idiopathic presentation, and the presence of neurological disorders and therapeutic strategies. Long-term follow-ups and a transition from childhood to adulthood are crucial to preventing iTTP relapses, in order to identify the occurrence of other autoimmune disorders and psychosocial sequelae. In contrast, older iTTP patients have an atypical clinical presentation, with delirium, an atypical neurological presentation, and severe renal and cardiac damages. They also have a poorer response to treatment and prognosis. Long-term sequelae are highly prevalent in older patients. Prediction scores for iTTP diagnoses are not used for children and have a lower sensitivity and specificity in patients over 60 years old. ADAMTS13 remains the unique biological marker that is able to definitely confirm or rule out the diagnosis of iTTP and predict relapses during follow-ups. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Aspects of Thrombotic Thrombocytopenic Purpura)

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18 pages, 756 KiB

Open AccessReview

Is Endothelial Activation a Critical Event in Thrombotic Thrombocytopenic Purpura?

by Raphael Cauchois, Romain Muller, Marie Lagarde, Françoise Dignat-George, Edwige Tellier and Gilles Kaplanski

J. Clin. Med. 2023, 12(3), 758; https://doi.org/10.3390/jcm12030758 - 18 Jan 2023

Cited by 8 | Viewed by 2770

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a severe thrombotic microangiopathy. The current pathophysiologic paradigm suggests that the ADAMTS13 deficiency leads to Ultra Large-Von Willebrand Factor multimers accumulation with generation of disseminated microthrombi. Nevertheless, the role of endothelial cells in this pathology remains an issue. In this review, we discuss the various clinical, in vitro and in vivo experimental data that support the important role of the endothelium in this pathology, suggesting that ADAMTS13 deficiency may be a necessary but not sufficient condition to induce TTP. The “second hit” model suggests that in TTP, in addition to ADAMTS13 deficiency, endogenous or exogenous factors induce endothelial activation affecting mainly microvascular cells. This leads to Weibel–Palade bodies degranulation, resulting in UL-VWF accumulation in microcirculation. This endothelial activation seems to be worsened by various amplification loops, such as the complement system, nucleosomes and free heme. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Aspects of Thrombotic Thrombocytopenic Purpura)

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Other

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15 pages, 1684 KiB

Open AccessSystematic Review

Patient-Reported Outcome Measures in Patients with Thrombotic Thrombocytopenic Purpura: A Systematic Review of the Literature

by Alexandre Soares Ferreira Junior, Morgana Pinheiro Maux Lessa, Samantha Kaplan, Theresa M. Coles, Deirdra R. Terrell and Oluwatoyosi A. Onwuemene

J. Clin. Med. 2023, 12(15), 5155; https://doi.org/10.3390/jcm12155155 - 7 Aug 2023

Cited by 2 | Viewed by 2640

Abstract

Health-related quality of life (HRQoL) impacts of thrombotic thrombocytopenic purpura (TTP) have been captured in clinical studies using patient-reported outcome (PRO) measures (PROMs) that are validated for other diseases. However, the validity evidence to support the use of existing PROMs in patients with TTP is unknown. In a systematic review of the literature, including studies of adults and children with TTP, we assessed the validity evidence for use of PROMs in clinical research and clinical practice, characterized HRQoL, described the integration of PROMs in clinical practice and evaluated PRO scores for patients with TTP compared with reference populations. From an initial 4518 studies, we identified 14 studies using 16 PROMs to assess general HRQoL domains in patients in remission. No identified studies assessed the validity of PROMs for the context of use of TTP and no studies described PROM integration into TTP clinical practice or evaluated PROMs that were specific for patients with TTP. Moreover, PRO scores were worse in patients with TTP compared with reference populations and other chronic conditions. We conclude that, in patients with TTP, PROMs pick up on important patient experiences not captured by clinical outcomes at present. There is, therefore, a need for studies that assess the validity of existing PROMs in patients with TTP to determine if TTP-specific PROMs specific to patients with TTP should be developed. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Aspects of Thrombotic Thrombocytopenic Purpura)

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7 pages, 717 KiB

Open AccessCase Report

Hypercoagulability and Inflammatory Markers in a Case of Congenital Thrombotic Thrombocytopenic Purpura Complicated by Fetal Demise

by Leslie Skeith, Kelle Hurd, Shruti Chaturvedi, Lorraine Chow, Joshua Nicholas, Adrienne Lee, Daniel Young, Dawn Goodyear, Jennifer Soucie, Louis Girard, Antoine Dufour and Ejaife O. Agbani

J. Clin. Med. 2022, 11(23), 7115; https://doi.org/10.3390/jcm11237115 - 30 Nov 2022

Cited by 2 | Viewed by 2034

Abstract

Background: Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare disorder caused by an inherited genetic deficiency of ADAMTS13 and affects less than one per million individuals. Patients who are diagnosed with TTP during pregnancy are at increased risk of maternal and fetal complications including fetal demise. We present a case of a 32-year-old G3P0 (gravida 3, para 0) who presented at 20 weeks gestation with a new diagnosis of congenital TTP (cTTP) and fetal demise. Methods: We describe the pathophysiology of pregnancy complications in a patient with cTTP using platelet procoagulant membrane dynamics analysis and quantitative proteomic studies, compared to four pregnant patients with gestational hypertension, four pregnant patients with preeclampsia, and four healthy pregnant controls. Results: The cTTP patient had increased P-selectin, tissue factor expression, annexin-V binding on platelets and neutrophils, and localized thrombin generation, suggestive of hypercoagulability. Among 15 proteins that were upregulated, S100A8 and S100A9 were distinctly overexpressed. Conclusions: There is platelet-neutrophil activation and interaction, platelet hypercoagulability, and proinflammation in our case of cTTP with fetal demise. Full article

(This article belongs to the Special Issue New Diagnostic and Therapeutic Aspects of Thrombotic Thrombocytopenic Purpura)

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