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British Journal of Haematology Dec 2023The introduction of thrombopoietin receptor agonists (TPO-RAs) led to a paradigm shift in the management of immune thrombocytopenia (ITP). However, TPO-RAs are not... (Review)
Review
The introduction of thrombopoietin receptor agonists (TPO-RAs) led to a paradigm shift in the management of immune thrombocytopenia (ITP). However, TPO-RAs are not approved for use during pregnancy due to the absence of evidence and concerns for possible effects on the fetus due to their expected transplacental transfer. This comprehensive review examines the safety and efficacy of TPO-RA in 45 pregnancies of women with ITP (romiplostim n = 22; eltrombopag n = 21; both in the same pregnancy n = 2). Mothers experienced failure of the median of three treatment lines during pregnancy prior to TPO-RA administration. A platelet response (>30 × 10 /L) was seen in 86.7% of cases (including a complete response >100 × 10 /L in 66.7%) and was similar between eltrombopag and romiplostim (87.0% and 83.3%, p = 0.99). The maternal safety profile was favourable, with no thromboembolic events encountered. Neonatal thrombocytopenia was noted in one third of cases, with one case of ICH grade 3, and neonatal thrombocytosis was observed in three cases. No other neonatal adverse events attributable to TPO-RAs were seen. This review suggests that the use of TPO-RA during pregnancy is associated with a high response rate and appears safe. Nevertheless, TPO-RA should not be routinely used in pregnancy and should be avoided in the first trimester until further evidence is accumulated.
Topics: Infant, Newborn; Humans; Female; Pregnancy; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Benzoates; Hydrazines; Thrombopoietin; Receptors, Fc; Recombinant Fusion Proteins
PubMed: 37830251
DOI: 10.1111/bjh.19161 -
Journal of Thrombosis and Haemostasis :... Sep 2023Rapid diagnosis and treatment has improved outcome of patients with vaccine-induced immune thrombocytopenia and thrombosis (VITT). However, after the acute episode, many...
BACKGROUND
Rapid diagnosis and treatment has improved outcome of patients with vaccine-induced immune thrombocytopenia and thrombosis (VITT). However, after the acute episode, many questions on long-term management of VITT remained unanswered.
OBJECTIVES
To analyze, in patients with VITT, the long-term course of anti-platelet factor 4 (PF4) antibodies; clinical outcomes, including risk of recurrent thrombosis and/or thrombocytopenia; and the effects of new vaccinations.
METHODS
71 patients with serologically confirmed VITT in Germany were enrolled into a prospective longitudinal study and followed for a mean of 79 weeks from March 2021 to January 2023. The course of anti-PF4 antibodies was analyzed by consecutive anti-PF4/heparin immunoglobulin G enzyme-linked immunosorbent assay and PF4-enhanced platelet activation assay.
RESULTS
Platelet-activating anti-PF4 antibodies became undetectable in 62 of 71 patients (87.3%; 95% CI, 77.6%-93.2%). In 6 patients (8.5%), platelet-activating anti-PF4 antibodies persisted for >18 months. Five of 71 patients (7.0%) showed recurrent episodes of thrombocytopenia and/or thrombosis; in 4 of them (80.0%), alternative explanations beside VITT were present. After further COVID-19 vaccination with a messenger RNA vaccine, no reactivation of platelet-activating anti-PF4 antibodies or new thrombosis was observed. No adverse events occurred in our patients subsequently vaccinated against influenza, tick-borne encephalitis, varicella, tetanus, diphtheria, pertussis, and polio. No new thrombosis occurred in the 24 patients (33.8%) who developed symptomatic SARS-CoV-2 infection following recovery from acute VITT.
CONCLUSION
Once the acute episode of VITT has passed, patients appear to be at low risk for recurrent thrombosis and/or thrombocytopenia.
Topics: Humans; Purpura, Thrombocytopenic, Idiopathic; COVID-19 Vaccines; Longitudinal Studies; Prospective Studies; COVID-19; SARS-CoV-2; Thrombocytopenia; Thrombosis; Influenza Vaccines
PubMed: 37394120
DOI: 10.1016/j.jtha.2023.06.027 -
British Journal of Haematology Oct 2023Immune thrombocytopenia (ITP) is an autoimmune haematological disorder characterized by immune-mediated thrombocytopenia and a variable risk of bleeding. Despite the... (Review)
Review
Immune thrombocytopenia (ITP) is an autoimmune haematological disorder characterized by immune-mediated thrombocytopenia and a variable risk of bleeding. Despite the availability of multiple treatment options, some patients are considered refractory since they do not achieve a platelet count response to multiple treatments and are at risk of bleeding. The term 'refractory' has been used to identify this patient group; however, with the advent of multiple lines of treatment, its meaning has become ambiguous. To address this issue, we reviewed previous definitions of refractory ITP, solicited the views of ITP experts and collected data from registries to inform a definition. Twenty ITP experts who attended the 7th Expert Meeting of the Intercontinental Cooperative ITP Study Group in September 2022 answered a web-based survey: 95% felt that there was a need for a new definition of refractory ITP for clinical and research purposes. The use of the term refractory, accompanied by a clear indication of the type and timing of failed treatments, was supported by 85% of respondents. Preliminary data on the frequency of refractory patients from the McMaster and Norwegian ITP Registries demonstrated that the proportion of adult ITP patients who had failed first-line therapy, rituximab, thrombopoietin receptor agonists, any immune suppressant medication and splenectomy ranged from 0.4% to 3.8%. We propose a definition of refractory ITP that could be evaluated in future studies.
Topics: Humans; Adult; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Platelet Count; Emotions; Immunosuppressive Agents
PubMed: 37642211
DOI: 10.1111/bjh.19075 -
Blood Reviews Jan 2024Immune thrombocytopenia (ITP) is a rare autoimmune condition, due to peripheral platelet destruction through antibody-dependent cellular phagocytosis,... (Review)
Review
Immune thrombocytopenia (ITP) is a rare autoimmune condition, due to peripheral platelet destruction through antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity, cytotoxic T lymphocyte-mediated cytotoxicity, and megakaryopoiesis alteration. This condition may be idiopathic or triggered by drugs, vaccines, infections, cancers, autoimmune disorders and systemic diseases. Recent advances in our understanding of ITP immunobiology support the idea that other forms of thrombocytopenia, for instance, occurring after immunotherapy or cellular therapies, may share a common pathophysiology with possible therapeutic implications. If a decent pipeline of old and new agents is currently deployed for classical ITP, in other more complex immune-mediated thrombocytopenic disorders, clinical management is less harmonized and would deserve further prospective investigations. Here, we seek to provide a fresh overview of pathophysiology and current therapeutical algorithms for adult patients affected by this disorder with specific insights into poorly codified scenarios, including refractory ITP and post-immunotherapy/cellular therapy immune-mediated thrombocytopenia.
Topics: Adult; Humans; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Immunotherapy; Blood Platelets
PubMed: 37980261
DOI: 10.1016/j.blre.2023.101141 -
Tidsskrift For Den Norske Laegeforening... Apr 2024
Topics: Humans; Purpura; Male
PubMed: 38651721
DOI: 10.4045/tidsskr.23.0604 -
British Journal of Haematology Oct 2023Patients with refractory immune thrombocytopenia (rITP) have increased morbidity and mortality. Currently, there is limited understanding of the cause of refractoriness... (Review)
Review
Patients with refractory immune thrombocytopenia (rITP) have increased morbidity and mortality. Currently, there is limited understanding of the cause of refractoriness and no markers to help direct novel treatment options. Understanding the reason(s) for refractoriness is crucial to determining novel treatment options. The pathogenesis underlying rITP has generally been thought to be an underlying genetic predisposition with an environmental trigger. Familial ITP remains rare, and there are few twin studies, suggesting that a simple genetic cause is unlikely. However, genetic mutations provide the background for several autoimmune diseases. In this review, we explore the evidence of either an inherited genetic cause of rITP or an acquired mutation, in particular one resulting in clonal expansion of cytotoxic T cells.
Topics: Humans; Purpura, Thrombocytopenic, Idiopathic; Genetic Predisposition to Disease; Mutation; T-Lymphocytes, Cytotoxic
PubMed: 37735556
DOI: 10.1111/bjh.19110 -
British Journal of Haematology Oct 2023There are discrepancies across guidelines about whether the dosage of antinuclear antibodies (ANAs) is of use at the diagnosis of primary immune thrombocytopenia (ITP).... (Review)
Review
There are discrepancies across guidelines about whether the dosage of antinuclear antibodies (ANAs) is of use at the diagnosis of primary immune thrombocytopenia (ITP). This review describes the current knowledge about ANA prevalence in patients with primary ITP, and their potential usefulness as biomarkers for ITP evolution, response to treatments and increased risk of subsequent development of systemic lupus and thrombosis.
Topics: Humans; Antibodies, Antinuclear; Clinical Relevance; Purpura, Thrombocytopenic, Idiopathic
PubMed: 37646171
DOI: 10.1111/bjh.19069 -
Journal of Translational Medicine Aug 2023Cyclooxygenase (COX)-2 is a rate-limiting enzyme in the biosynthesis of prostanoids, which is mostly inducible by inflammatory cytokines. The participation of COX-2 in...
BACKGROUND
Cyclooxygenase (COX)-2 is a rate-limiting enzyme in the biosynthesis of prostanoids, which is mostly inducible by inflammatory cytokines. The participation of COX-2 in the maturation of megakaryocytes has been reported but barely studied in primary immune thrombocytopenia (ITP).
METHODS
The expressions of COX-2 and Caspase-1, Caspase-3 and Caspase-3 p17 subunit in platelets from ITP patients and healthy controls (HC), and the expressions of COX-2 and CD41 in bone marrow (BM) of ITP patients were measured and analyzed for correlations. The effects of COX-2 inhibitor on megakaryopoiesis and thrombopoiesis were assessed by in vitro culture of Meg01 cells and murine BM-derived megakaryocytes and in vivo experiments of passive ITP mice.
RESULTS
The expression of COX-2 was decreased and Caspase-1 and Caspase-3 p17 were increased in platelets from ITP patients compared to HC. In platelets from ITP patients, the COX-2 expression was positively correlated with platelet count and negatively correlated to the expression of Caspase-1. In ITP patients BM, the expression of CD41 was positively correlated with the expression of COX-2. COX-2 inhibitor inhibited the count of megakaryocytes and impaired the maturation and platelet production in Meg01 cells and bone marrow-derived megakaryocytes. COX-2 inhibitor aggravated thrombocytopenia and damaged megakaryopoiesis in ITP murine model.
CONCLUSION
COX-2 plays a vital role in the physiologic and pathologic conditions of ITP by intervening the survival of platelets and impairing the megakaryopoiesis and thrombopoiesis of megakaryocytes.
Topics: Animals; Mice; Blood Platelets; Caspase 3; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Megakaryocytes; Purpura, Thrombocytopenic, Idiopathic; Thrombopoiesis
PubMed: 37573325
DOI: 10.1186/s12967-023-04389-9 -
The New England Journal of Medicine May 2024In patients with immune thrombotic thrombocytopenic purpura (iTTP), autoantibodies against the metalloprotease ADAMTS13 lead to catastrophic microvascular thrombosis....
In patients with immune thrombotic thrombocytopenic purpura (iTTP), autoantibodies against the metalloprotease ADAMTS13 lead to catastrophic microvascular thrombosis. However, the potential benefits of recombinant human ADAMTS13 (rADAMTS13) in patients with iTTP remain unknown. Here, we report the clinical use of rADAMTS13, which resulted in the rapid suppression of disease activity and complete recovery in a critically ill patient whose condition had proved to be refractory to all available treatments. We also show that rADAMTS13 causes immune complex formation, which saturates the autoantibody and may promote its clearance. Our data support the role of rADAMTS13 as a novel adjunctive therapy in patients with iTTP.
Topics: Female; Humans; ADAMTS13 Protein; Antigen-Antibody Complex; Autoantibodies; Purpura, Thrombotic Thrombocytopenic; Recombinant Proteins; Adult; Black or African American; Plasma Exchange; Treatment Outcome
PubMed: 38718359
DOI: 10.1056/NEJMoa2402567 -
Current Opinion in Hematology Nov 2023The platelet surface harbors a lush forest of glycans (carbohydrate polymers) attached to membrane proteins and lipids. Accumulating evidence suggests that these glycans... (Review)
Review
PURPOSE OF REVIEW
The platelet surface harbors a lush forest of glycans (carbohydrate polymers) attached to membrane proteins and lipids. Accumulating evidence suggests that these glycans may be relevant to the pathophysiology of immune thrombocytopenia (ITP). Here, we critically evaluate data that point to a possible role for loss of sialic acid in driving platelet clearance in ITP, comment on the potential use of neuraminidase inhibitors for treatment of ITP, and highlight open questions in this area.
RECENT FINDINGS
Multiple lines of evidence suggest a role for loss of platelet sialic acid in the pathophysiology of thrombocytopenia. Recent work has tested the hypothesis that neuraminidase-mediated cleavage of platelet sialic acid may trigger clearance of platelets in ITP. Some clinical evidence supports efficacy of the viral neuraminidase inhibitor oseltamivir in ITP, which is surprising given its lack of activity against human neuraminidases.
SUMMARY
Further study of platelet glycobiology in ITP is necessary to fill key knowledge gaps. A deeper understanding of the roles of platelet glycans in ITP pathophysiology will help to guide development of novel therapies.
Topics: Humans; Antiviral Agents; Blood Platelets; Glycomics; N-Acetylneuraminic Acid; Neuraminidase; Polysaccharides; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia
PubMed: 37526945
DOI: 10.1097/MOH.0000000000000781