-
Blood Jun 2023Neonatal thrombocytopenia, defined as the presence of a circulating platelet count <150 × 109/L, is a common abnormality in babies admitted to neonatal intensive care... (Review)
Review
Neonatal thrombocytopenia, defined as the presence of a circulating platelet count <150 × 109/L, is a common abnormality in babies admitted to neonatal intensive care units. Thrombocytopenia that is typically mild and self-limiting often accompanies neonatal stress in scenarios such as premature delivery or intrauterine growth restriction. However, the differential diagnosis of neonatal thrombocytopenia is wide and includes potentially life-threatening disorders, such as bacterial sepsis, viral infection, and necrotizing enterocolitis. Distinguishing these causes of thrombocytopenia from entities such as genetic thrombocytopenia and fetal and neonatal alloimmune thrombocytopenia is critical for the accurate quantitation of significant adverse events, such as intracranial bleeding, and for the selection of treatments, such as platelet transfusion. In this review, we focus on common differential diagnoses of neonatal thrombocytopenia and highlight how the landscape of diagnosis and management is changing with recent advances in genomic technology and the completion of pivotal clinical trials of platelet transfusion practice. Increasing evidence highlights the need for judicious and restrictive use of platelet transfusions in neonates.
Topics: Humans; Infant, Newborn; Intracranial Hemorrhages; Platelet Count; Platelet Transfusion; Prenatal Care; Thrombocytopenia, Neonatal Alloimmune
PubMed: 36787503
DOI: 10.1182/blood.2022018017 -
Frontiers in Immunology 2023Sepsis is accompanied by thrombocytopenia and the severity of the thrombocytopenia is associated with mortality. This thrombocytopenia is characteristic of disseminated... (Review)
Review
Sepsis is accompanied by thrombocytopenia and the severity of the thrombocytopenia is associated with mortality. This thrombocytopenia is characteristic of disseminated intravascular coagulation (DIC), the sepsis-associated coagulopathy. Many of the pathogens, both bacterial and viral, that cause sepsis also directly activate platelets, which suggests that pathogen-induced platelet activation leads to systemic thrombosis and drives the multi-organ failure of DIC. In this paper we review the mechanisms of platelet activation by pathogens and the evidence for a role for anti-platelet agents in the management of sepsis.
Topics: Humans; Blood Platelets; Disseminated Intravascular Coagulation; Thrombocytopenia; Blood Coagulation Disorders; Sepsis; Anemia
PubMed: 37350961
DOI: 10.3389/fimmu.2023.1210219 -
Blood Reviews Sep 2023There are not many publications that provide a holistic view of the management of primary and secondary ITP as a whole, reflecting the similarities and differences... (Review)
Review
There are not many publications that provide a holistic view of the management of primary and secondary ITP as a whole, reflecting the similarities and differences between the two. Given the lack of major clinical trials, we believe that comprehensive reviews are much needed to guide the diagnosis and treatment of ITP today. Therefore, our review addresses the contemporary diagnosis and treatment of ITP in adult patients. With respect to primary ITP we especially focus on establishing the management of ITP based on the different and successive lines of treatment. Life-threatening situations, "bridge therapy" to surgery or invasive procedures and refractory ITP are also comprehensively reviewed here. Secondary ITP is studied according to its pathogenesis by establishing three major differential groups: Immune Thrombocytopenia due to Central Defects, Immune Thrombocytopenia due to Blocked Differentiation and Immune Thrombocytopenia due to Defective Peripheral Immune Response. Here we provide an up-to-date snapshot of the current diagnosis and treatment of ITP, including a special interest in addressing rare causes of this disease in our daily clinical practice. The target population of this review is adult patients only and the target audience is medical professionals.
Topics: Adult; Humans; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Platelet Count; Receptors, Thrombopoietin; Thrombopoietin
PubMed: 37414719
DOI: 10.1016/j.blre.2023.101112 -
Arthritis & Rheumatology (Hoboken, N.J.) Feb 2024Thrombotic microangiopathy (TMA) refers to a diverse group of diseases that share clinical and histopathologic features. TMA is clinically characterized by... (Review)
Review
Thrombotic microangiopathy (TMA) refers to a diverse group of diseases that share clinical and histopathologic features. TMA is clinically characterized by microangiopathic hemolytic anemia, consumptive thrombocytopenia, and organ injury that stems from endothelial damage and vascular occlusion. There are several disease states with distinct pathophysiological mechanisms that manifest as TMA. These conditions are associated with significant morbidity and mortality and require urgent recognition and treatment. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are traditionally considered to be primary forms of TMA, but TMA more commonly occurs in association with a coexisting condition such as infection, pregnancy, autoimmune disease, or malignant hypertension, among others. Determining the cause of TMA is a diagnostic challenge because of limited availability of disease-specific testing. However, identifying the underlying etiology is imperative as treatment strategies differ. Our understanding of the conditions that cause TMA is evolving. Recent advances have led to improved comprehension of the varying pathogenic mechanisms that drive TMA. Development of targeted therapeutics has resulted in significant improvements in patient outcomes. In this article, we review the pathogenesis and clinical features of the different TMA-causing conditions. We outline a practical approach to diagnosis and management and discuss empiric and disease-specific treatment strategies.
Topics: Pregnancy; Female; Humans; Thrombotic Microangiopathies; Purpura, Thrombotic Thrombocytopenic; Thrombosis; Anemia, Hemolytic; Hypertension, Malignant
PubMed: 37610060
DOI: 10.1002/art.42681 -
British Journal of Haematology Oct 2023Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20 000 people. While most patients with ITP are successfully managed with... (Review)
Review
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder affecting approximately 1 in 20 000 people. While most patients with ITP are successfully managed with the current set of standard and approved therapeutics, patients who cannot be adequately managed with these therapies, considered to have refractory ITP, are not uncommon. Therefore, there remains an ongoing need for novel therapeutics and drug development in ITP. Several agents exploiting novel targets and mechanisms in ITP are presently under clinical development, with trials primarily recruiting heavily pretreated patients and those with otherwise refractory disease. Such agents include the neonatal Fc receptor antagonist efgartigimod, the Bruton tyrosine kinase inhibitor rilzabrutinib, the complement inhibitors sutimlimab and iptacopan and anti-CD38 monoclonal antibodies such as daratumumab and mezagitamab, among others. Each of these agents exploits therapeutic targets or other aspects of ITP pathophysiology currently not targeted by the existing approved agents (thrombopoietin receptor agonists and fostamatinib). This manuscript offers an in-depth review of the current available data for novel therapeutics in ITP presently undergoing phase 2 or 3 studies in patients with heavily pretreated or refractory ITP. It additionally highlights the future directions for drug development in refractory ITP, including discussion of innovative clinical trial designs, health-related quality of life as an indispensable clinical trial end-point and balancing potential toxicities of drugs with their potential benefits in a bleeding disorder in which few patients suffer life-threatening bleeding.
Topics: Infant, Newborn; Humans; Purpura, Thrombocytopenic, Idiopathic; Quality of Life; Thrombocytopenia; Complement Inactivating Agents; Drug Development
PubMed: 37735554
DOI: 10.1111/bjh.19078 -
The New England Journal of Medicine Aug 2023
Review
Topics: Female; Humans; Pregnancy; Purpura, Thrombocytopenic, Idiopathic; Pregnancy Complications, Hematologic
PubMed: 37590449
DOI: 10.1056/NEJMra2214617 -
Lancet (London, England) Nov 2023Primary immune thrombocytopenia is an autoimmune disorder mediated partly by platelet autoantibodies, resulting in thrombocytopenia, bleeding, and constitutional... (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of the neonatal Fc receptor inhibitor efgartigimod in adults with primary immune thrombocytopenia (ADVANCE IV): a multicentre, randomised, placebo-controlled, phase 3 trial.
BACKGROUND
Primary immune thrombocytopenia is an autoimmune disorder mediated partly by platelet autoantibodies, resulting in thrombocytopenia, bleeding, and constitutional symptoms. Efgartigimod, a first-in-class novel human IgG1 Fc fragment, binds the neonatal Fc receptor with high affinity and thus reduces serum IgG concentrations, including autoantibodies. The objective of this study was to evaluate the efficacy and safety of efgartigimod in adults with persistent and chronic primary immune thrombocytopenia.
METHODS
This phase 3, multicentre, randomised, double-blinded, placebo-controlled, 24-week study evaluated the efficacy and safety of intravenous efgartigimod in adults aged 18 years or older with chronic or persistent primary immune thrombocytopenia who had an average platelet count of less than 30 000, had responded to at least one previous immune thrombocytopenia therapy, and were on a concurrent therapy at baseline or had received at least a second previous immune thrombocytopenia therapy. The study took place in 71 participating sites from Asia, Europe, and North America. Patients were randomly assigned 2:1 to receive either efgartigimod (10 mg/kg) or placebo intravenously for the first 4 weeks, after which the dosing schedule could be altered to once per week or every other week depending on the patients' platelet count. The primary endpoint, evaluated in the chronic population, was sustained platelet count response (≥50 × 10 for at least 4 of the last 6 weeks). This study is registered with ClinicalTrials.gov (NCT04188379) and is completed.
FINDINGS
A total of 205 patients were screened from Dec 9, 2019, to Feb 3, 2022, and 131 (86 in the efgartigimod group; 45 in the placebo group) were randomly assigned. These patients represented a population with long-term disease who had a mean time since diagnosis of 10·6 years and 67% (88/131) of whom had received at least three previous immune thrombocytopenia treatments. 22% (17/78) of patients with chronic immune thrombocytopenia receiving efgartigimod reached the primary endpoint compared with 5% (2/40) of those receiving placebo (p=0·032; adjusted difference in response, 16% [95% CI 2·6-26·4]). The median number of weeks of disease control in patients with chronic immune thrombocytopenia was 2·0 (IQR 0·0-11·0) for efgartigimod versus 0·0 (0·0-1·0) for placebo (p=0·0009). Efgartigimod was well tolerated; most adverse events were mild to moderate in severity. The most common adverse events of interest in both groups were headache (16% in efgartigimod and 13% in placebo), haematuria (16% in efgartigimod and 16% in placebo), and petechiae (15% in efgartigimod and 27% in placebo).
INTERPRETATION
Efgartigimod significantly increased sustained platelet count responses compared with placebo in patients with chronic immune thrombocytopenia, including those who had received multiple previous immune thrombocytopenia therapies. Upon completion of the ADVANCE IV study, patients could enroll in the ongoing open-label extension. Subcutaneous efgartigimod is currently being evaluated in patients with immune thrombocytopenia in the ADVANCE SC+ trial.
FUNDING
argenx.
Topics: Adult; Humans; Autoantibodies; Double-Blind Method; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Receptors, Fc; Thrombocytopenia; Treatment Outcome
PubMed: 37778358
DOI: 10.1016/S0140-6736(23)01460-5 -
Blood Apr 2024
Topics: Female; Humans; Thrombocytosis
PubMed: 38662384
DOI: 10.1182/blood.2023023702 -
Blood Jun 2023Sustained response off treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in immune thrombocytopenia (ITP). This...
Sustained response off treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in immune thrombocytopenia (ITP). This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response (CR) on TPO-RAs. The primary end point was the proportion of patients achieving SROT (platelet count >30 × 109/L and no bleeding) at week 24 (W24) with no other ITP-specific medications. Secondary end points included the proportion of sustained CR off-treatment (SCROT, platelet count >100 × 109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with a median age of 58.5 years; 30 of 48 had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27 of 48 achieved SROT, 15 of 48 achieved SCROT at W24; 25 of 48 achieved SROT, and 14 of 48 achieved SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients rechallenged with TPO-RA, 11 of 12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA sequencing revealed enrichment of a tumor necrosis factor α signaling via NF-κB signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based on progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. This trial was registered at www.clinicaltrials.gov as #NCT03119974.
Topics: Adult; Humans; Middle Aged; Prospective Studies; Purpura, Thrombocytopenic, Idiopathic; Platelet Count; Thrombocytopenia; Autoimmunity; Thrombopoietin; Recombinant Fusion Proteins; Receptors, Fc; Hydrazines
PubMed: 36893453
DOI: 10.1182/blood.2022018665 -
Nephrology (Carlton, Vic.) Oct 2023A limited number of cases of thrombotic microangiopathy (TMA) have previously been reported in association with COVID-19. Our report describes two cases of TMA...
A limited number of cases of thrombotic microangiopathy (TMA) have previously been reported in association with COVID-19. Our report describes two cases of TMA associated with COVID-19, one of which was successfully treated with eculizumab. The first case was a 23-month-old girl, and the second case was a 9-month-old boy. PCR tests for SARS-CoV-2 were positive in both cases, and laboratory results showed microangiopathic haemolytic anaemia, thrombocytopenia, and acute kidney injury. No known aetiology for TMA was found in either case. Stool tests for Shigatoxin-producing Escherichia coli were negative. Coagulation tests, ADAMTS13 activity, serum complement levels, and homocysteine levels were all within the normal range. No known genetic mutation was found, including mutations of complement, diacylglycerol kinase epsilon, and cobalamin C. In the first case, eculizumab was administered due to persistent haemolysis and prolonged anuria. In conclusion, TMA may be associated with COVID-19 infection. Treatment with eculizumab may be beneficial in selected patients because of the potential activation of the complement system.
Topics: Male; Female; Humans; Infant; Child, Preschool; COVID-19; SARS-CoV-2; Thrombotic Microangiopathies; Purpura, Thrombotic Thrombocytopenic; Acute Kidney Injury
PubMed: 37485596
DOI: 10.1111/nep.14225