RESUMO
Disease relapse is recognized as a risk in immune-mediated thrombotic thrombocytopenic purpura (iTTP) after treatment of the acute presenting episode. Identification of patients at risk of relapse and its patterns are yet to be clearly established. We reviewed patients with iTTP having had >3 years of follow-up over 10 years in the United Kingdom to identify patient characteristics for relapse, assess relapse rates and patterns, and response to anti-CD20 therapy in those with a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) relapses (ADAMTS13 activity of <20% without thrombocytopenia). We identified 443 patients demonstrating relapse rates of 40% at 5-year follow-up. At 10-year follow-up, no difference in relapse was observed irrespective of whether rituximab was used at acute presentation (P = .39). Black Caribbean ethnicity increased the risk of disease relapse in the British population. There was a distinct population of patients (6%) that relapsed early with subsequent frequent relapses occurring on average within 2 years (average time to relapse in subgroup, 1.7 years). Overall, nearly 60% of relapses described were ADAMTS13 relapses, with subsequent treatment reducing the risk of progression to clinical relapses. We demonstrate that iTTP diagnosed in the latter part of the study period had lower rates of clinical relapses (22.6% vs 11.1%, P = .0004) with the advent of regular monitoring and preemptive rituximab. In ADAMTS13 relapses, 96% responded to anti-CD20 therapy, achieving ADAMTS13 activity of >20%. Anti-CD20 therapy was demonstrated to be an effective long-term treatment regardless of relapse pattern and there was no loss of this treatment response after subsequent treatment episodes.
Assuntos
Púrpura Trombocitopênica Trombótica , Humanos , Rituximab/uso terapêutico , Púrpura Trombocitopênica Trombótica/terapia , Proteína ADAMTS13 , Recidiva , Reino Unido/epidemiologiaRESUMO
The COVID-19 pandemic has resulted in the rapid development of a range of vaccines against SARS-CoV-2. Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare but life-threatening complication of primarily adenoviral-based vaccines associated with the presence of antibodies to a PF4/polyanion neoepitope and measured by using enzyme-linked immunosorbent assays. Presented are serial anti-PF4/polyanion antibody, platelet, and D-dimer measurements in a large cohort of patients and their relation to relapse. Overall, 51% of patients using the Stago assay had persistently positive anti-PF4/polyanion levels 100 days' postdiagnosis, whereas 94% of patients monitored by using the Immucor assay remain positive. The median duration of positivity of the PF4 assay is 87 days, with 72% of patients remaining positive after a median follow-up of 105 days. The use of plasma exchange seemed to reduce anti-PF4/polyanion levels and increase platelet counts in the acute setting more rapidly than other therapies. The rate of relapse in this study was 12.6%, with all relapsed cases exhibiting persistently positive PF4 antibodies and falling platelet counts. Only one patient had extension of their thrombosis. Overall, despite the persistence of PF4 antibodies in 72% of patients, the rate of relapse was low and did not seem to result in recrudescence of the aggressive clinical picture seen at index presentation. Monitoring of these patients in the UK cohort is ongoing and will aid in definition of the natural history of this novel condition.
Assuntos
COVID-19 , Púrpura Trombocitopênica Idiopática , Trombocitopenia , Trombose , Vacinas , Anticorpos/efeitos adversos , Vacinas contra COVID-19/efeitos adversos , ChAdOx1 nCoV-19 , Heparina/efeitos adversos , Humanos , Pandemias , Fator Plaquetário 4 , Recidiva , SARS-CoV-2 , Trombocitopenia/induzido quimicamente , Trombocitopenia/complicações , Vacinas/efeitos adversosRESUMO
A chronic subdural haematoma (CSDH) is a collection of aged blood between the dura and the brain, typically treated with surgical evacuation. Many patients with CSDH have comorbidities requiring the use of antithrombotic medications. The optimal management of these medications in the context of CSDH remains unknown, as the risk of recurrence must be carefully weighed against the risk of vaso-occlusive events. To better understand these risks and inform the development of clinical practice guidelines, we conducted a systematic review and meta-analysis. A systematic review was conducted in accordance with the PRISMA guidelines, searching Medline and Embase databases. The study was registered with PROSPERO (CRD42023397061). A total of 44 studies were included, encompassing 1 prospective cohort study and 43 retrospective cohort studies. Pooled odds ratios (ORs) were calculated for CSDH recurrence and vaso-occlusive events in patients taking anticoagulant or antiplatelet medications compared to patients not receiving antithrombotic therapy. GRADE was used to assess the quality of evidence. In patients on anticoagulant therapy at CSDH diagnosis, the pooled OR for CSDH recurrence was 1.41 (95% CI 1.11 to 1.79; I2 = 28%). For patients on antiplatelet therapy, the pooled OR was 1.31 (95% CI 1.08 to 1.58; I2 = 32%). Patients taking antithrombotic medications had a significantly higher risk of vaso-occlusive events, with a pooled OR of 3.74 (95% CI 2.12 to 6.60; I2 = 0%). There was insufficient evidence to assess the impact of time to recommence antithrombotic medication on CSDH outcomes. We found that baseline antithrombotic use is associated with the risk of CSDH recurrence and vaso-occlusive events following surgical evacuation. The evidence base is of low quality, and decisions regarding antithrombotic therapy should be individualised for each patient. Further high-quality, prospective studies or registry-based designs are needed to better inform clinical decision-making and establish evidence-based guidelines.
RESUMO
Rituximab, an anti-CD20 monoclonal antibody, can be used to treat immune thrombotic thrombocytopenic purpura (iTTP) during acute presentation or disease relapse. Undesirable side-effects include severe hypersensitivity reactions, particularly anaphylaxis and rituximab-induced serum sickness, with a minority not maintaining a response to treatment. Alternative humanised anti-CD20 treatments, obinutuzumab and ofatumumab, have been used. A review of the UK TTP Registry showed 15 patients received these drugs over 26 treatment episodes (eight obinutuzumab and 18 ofatumumab). Indications for alternative anti-CD20 treatment were severe infusion-related reactions, acute rituximab-induced serum sickness and a short duration of disease remission. All patients achieved disease remission (ADAMTS13 [A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13] activity ≥30 iu/dl) after a median 15 days and 92% of episodes achieved complete remission (≥60 iu/dl). Seven patients required further treatment for disease relapse with a median relapse-free survival of 17.4 months. All patients continued to respond to re-treatment with the preceding drug when relapse occurred. There were four adverse events in 26 treatment episodes (15%) - two infections and two infusion reactions. These results suggest that obinutuzumab and ofatumumab may be considered as an alternative option to rituximab in the treatment of iTTP with a comparable safety profile, absence of significant hypersensitivity reactions and sustained normalisation of ADAMTS13.
Assuntos
Anticorpos Monoclonais Humanizados , Púrpura Trombocitopênica Trombótica , Proteína ADAMTS13 , Anticorpos Monoclonais Humanizados/uso terapêutico , Antígenos CD20 , Humanos , Púrpura Trombocitopênica Trombótica/tratamento farmacológico , Recidiva , Rituximab/efeitos adversos , Doença do Soro/induzido quimicamenteRESUMO
Descriptions of passenger lymphocyte syndrome (PLS), immune cytopenias and transplant-associated thrombotic microangiopathy (TA-TMA) after intestine-containing transplants remain scarce. We describe our centre's experience of these complications from 2007 to 2019. Ninety-six patients received 103 transplants. PLS occurred in 9 (9%) patients (median 12 days post-transplant); all due to ABO antibodies. There were 31 minor ABO mismatch transplants. No patient required change in immunosuppression. Immune cytopenias (excluding PLS) occurred in six patients at an incidence of 1·7/100 patient years; three immune haemolysis, one immune thrombocytopenia, one acquired Glanzmann's and one immune neutropenia; 50% occurred with other cytopenias. All cases eventually responded to treatment, with a median of four treatments (range 1-8) and 5/6 were treated with rituximab. One patient with immune haemolysis required bortezomib. Complications were common in patients with immune cytopenias; 4/6 with infection needing intravenous antibiotics and 3/6 with venous thromboembolism. In 3/6 cases, a secondary cause for the immune cytopenia was evident. Switching from tacrolimus to ciclosporin was not necessary. There were five cases of transplant-associated thrombotic microangiopathy (TA-TMA; 1·5/100 patient years) requiring calcineurin inhibitor withdrawal; two cases associated with acute rejection. Two cases were managed with plasma exchange, one with plasma infusions and one with eculizumab. Further research in this patient group is required.
Assuntos
Hemólise/imunologia , Intestinos/transplante , Neutropenia , Transplante de Órgãos/efeitos adversos , Trombastenia , Microangiopatias Trombóticas , Sistema ABO de Grupos Sanguíneos/imunologia , Adulto , Anticorpos Monoclonais Humanizados/administração & dosagem , Bortezomib/administração & dosagem , Feminino , Seguimentos , Humanos , Isoanticorpos/imunologia , Masculino , Pessoa de Meia-Idade , Neutropenia/tratamento farmacológico , Neutropenia/etiologia , Neutropenia/imunologia , Estudos Retrospectivos , Rituximab/administração & dosagem , Trombastenia/tratamento farmacológico , Trombastenia/etiologia , Trombastenia/imunologia , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/imunologiaRESUMO
A targeted high-throughput sequencing (HTS) panel test for clinical diagnostics requires careful consideration of the inclusion of appropriate diagnostic-grade genes, the ability to detect multiple types of genomic variation with high levels of analytic sensitivity and reproducibility, and variant interpretation by a multidisciplinary team (MDT) in the context of the clinical phenotype. We have sequenced 2396 index patients using the ThromboGenomics HTS panel test of diagnostic-grade genes known to harbor variants associated with rare bleeding, thrombotic, or platelet disorders (BTPDs). The molecular diagnostic rate was determined by the clinical phenotype, with an overall rate of 49.2% for all thrombotic, coagulation, platelet count, and function disorder patients and a rate of 3.2% for patients with unexplained bleeding disorders characterized by normal hemostasis test results. The MDT classified 745 unique variants, including copy number variants (CNVs) and intronic variants, as pathogenic, likely pathogenic, or variants of uncertain significance. Half of these variants (50.9%) are novel and 41 unique variants were identified in 7 genes recently found to be implicated in BTPDs. Inspection of canonical hemostasis pathways identified 29 patients with evidence of oligogenic inheritance. A molecular diagnosis has been reported for 894 index patients providing evidence that introducing an HTS genetic test is a valuable addition to laboratory diagnostics in patients with a high likelihood of having an inherited BTPD.
Assuntos
Transtornos Plaquetários , Hemorragia , Sequenciamento de Nucleotídeos em Larga Escala , Trombose , Transtornos Plaquetários/diagnóstico , Transtornos Plaquetários/genética , Feminino , Dosagem de Genes , Hemorragia/diagnóstico , Hemorragia/genética , Hemostasia/genética , Humanos , Masculino , Trombose/diagnóstico , Trombose/genéticaRESUMO
Bleeding of unknown cause (BUC), also known as unclassified bleeding disorders (UBD), has been defined as a clear bleeding tendency in the presence of normal haemostatic tests. There are challenges in the diagnosis and management of these patients. BUC/UBD encompasses a heterogenous group of disorders which may include undiagnosed rare monogenic diseases, polygenic reasons for bleeding; and patients without a clear bleeding disorder but with a previous bleeding event. Nevertheless, these patients may have heavy menstrual bleeding or be at risk of bleeding when undergoing surgical procedures, or childbirth; optimizing haemostasis and establishing a mode of inheritance is important to minimize morbidity. The bleeding score has been used to clinically assess and describe these patients, but its value remains uncertain. In addition, accurate distinction between normal and pathological bleeding remains difficult. Several studies have investigated cohorts of these patients using research haemostasis tests, including thrombin generation and fibrinolytic assays, yet no clear characteristics have consistently emerged. Thus far, detailed genetic analysis of these patients has not been fruitful in unravelling the cause of bleeding. There is a need for standardization of diagnosis and management guidelines for these patients. This review gives an overview of this field with some suggestions for future research.
Assuntos
Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/fisiopatologia , Transtornos da Coagulação Sanguínea/terapia , Transtornos Hemorrágicos/etiologia , Feminino , Transtornos Hemorrágicos/patologia , HumanosRESUMO
This study describes the use of a simple charcoal product (DOAC-RemoveTM ) to allow haemostasis assays on patients taking direct oral anticoagulants (DOAC). In the proposed algorithm, patients taking DOAC are screened using the dilute thrombin time (dTT) and anti-Xa assay. If either are positive then DOAC-Remove is utilised. In a validation, DOAC-Remove did not interfere with coagulation testing in normal plasma or in patients on DOAC with a known lupus anticoagulant (LA). Of 1566 routine patient samples tested, 125 (8%) had evidence of anti-Xa activity (>0·1 iu/ml) or prolonged dTT suggestive of either a direct/indirect Xa inhibitor or direct thrombin inhibitor. All of these 125 patients had a prolonged dilute Russell viper venom time (dRVVT) screening test and 106 had a LA detected by dRVVT after phospholipid correction. After DOAC-Remove, 91 patients (73%) had a negative dRVVT screen. After further investigation only 9 (7%) had a positive LA. DOAC-Remove prevented 5% of patients having a LA inappropriately detected. DOAC did not significantly affect the LA activated partial thromboplastin time (aPTT) ratio, protein S antigen or protein C activity. DOAC cause low intrinsic factor assays, high prothrombin time/aPTT and high activated protein C sensitivity ratio, which DOAC-Remove reversed (P < 0·05). Despite recommendations, haemostasis testing for patients on DOAC continues; this algorithm aids diagnostic accuracy. Further validation and research are warranted.
Assuntos
Inibidores do Fator Xa , Hemostasia/efeitos dos fármacos , Administração Oral , Estudos Transversais , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/farmacocinética , Feminino , Humanos , Inibidor de Coagulação do Lúpus/sangue , Masculino , Tempo de Tromboplastina Parcial , Tempo de TrombinaAssuntos
Assistência Ambulatorial , Biomarcadores/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio , Trombose Venosa/sangue , Trombose Venosa/diagnóstico , Fatores Etários , Diagnóstico Diferencial , Humanos , Tromboflebite/sangue , Tromboflebite/diagnóstico , Ultrassonografia Doppler , Trombose Venosa/etiologiaAssuntos
Índice de Massa Corporal , Edema , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Hiperpigmentação , Perna (Membro) , Obesidade , Tromboembolia Venosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Edema/sangue , Edema/patologia , Edema/fisiopatologia , Feminino , Seguimentos , Humanos , Hiperpigmentação/sangue , Hiperpigmentação/patologia , Hiperpigmentação/fisiopatologia , Perna (Membro)/patologia , Perna (Membro)/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/patologia , Obesidade/fisiopatologia , Tromboembolia Venosa/sangue , Tromboembolia Venosa/patologia , Tromboembolia Venosa/fisiopatologiaRESUMO
PURPOSE: The purpose of this paper is to analyse the impact of reforms designed to address economic and demographic challenges in England with reference to the authors' own empirical work providing a critique of their impact and suggesting a way to improve the quality of social care for older people. DESIGN/METHODOLOGY/APPROACH: The research was a qualitative study conducted in a participatory manner in which older people were positioned as co-creators of the research study. This involved setting the scope of the study and identifying and refining the themes used in the analysis of an inquiry board and interviews. FINDINGS: The research findings highlight the threat of recent moves that emphasise "independence" and "self-management" particularly as they risk marginalising some groups of older people and reducing the quality of care. An alternative approach drawn from the ethics of care is suggested. RESEARCH LIMITATIONS/IMPLICATIONS: The research study focused on a narrow selection of older people and future work will wish to explore concepts of "care" and "independence" in additional contexts and of reforms in other geographies. PRACTICAL IMPLICATIONS: The researchers argue that the current reform agenda threatens the quality of care services and suggest improvements to the way in which services might be organised and presented. SOCIAL IMPLICATIONS: It is intended that the research will contribute to social policy debates and particularly those that focus on social care. The study also looks to contribute to current work in the fields of critical gerontology, feminist ethics and the management of public services more generally. ORIGINALITY/VALUE: The paper presents a novel and critical viewpoint of current social care policy in England and will therefore be of interest to policy-makers and to professionals.
Assuntos
Reforma dos Serviços de Saúde , Serviços de Saúde para Idosos , Qualidade da Assistência à Saúde , Serviço Social/economia , Idoso , Demografia , Inglaterra , Humanos , Pesquisa Qualitativa , Autocuidado , Serviço Social/éticaRESUMO
BACKGROUND: For the treatment of von Willebrand disease (VWD), von Willebrand factor (VWF) concentrates can be used in on-demand, long-term prophylaxis, and surgical prophylaxis regimens. METHODS: This systematic literature review was conducted to evaluate the efficacy, consumption, and safety of plasma-derived human coagulation FVIII/human VWF (pdVWF/FVIII; Voncento/Biostate) for the treatment of patients with any inherited VWD type. An electronic search was conducted in MEDLINE and Cochrane Library databases on VWD therapies. All retrieved publications were assessed against predefined inclusion/exclusion criteria following the Cochrane group recommendations. Associated pharmacovigilance data were collected across the same time period. RESULTS: Eleven publications from eight study cohorts were identified for data retrieval. All were from multicenter studies and included both pediatric and adult patients. Eight publications included evaluations of the efficacy of pdVWF/FVIII for on-demand treatment, eight included long-term prophylactic treatment, and eight included surgical prophylaxis. Treatment protocols and VWF administration methods differed between studies, as did safety evaluations. The clinical response was rated as excellent/good for on-demand treatment in 66 to 100% of nonsurgical bleeds, 89 to 100% in the treatment of breakthrough bleeds during long-term prophylaxis treatment, and hemostatic efficacy in surgical procedures was 75 to 100%. Pharmacovigilance data confirmed a low incidence of adverse events in treated patients. CONCLUSION: This review provides a comprehensive summary of studies that evaluated the use of pdVWF/FVIII in VWD demonstrating the long-term effectiveness and safety of this pdVWF/FVIII across all ages, types of VWD, and treatment settings.
Assuntos
Fator VIII , Hemorragia , Doenças de von Willebrand , Fator de von Willebrand , Humanos , Doenças de von Willebrand/tratamento farmacológico , Doenças de von Willebrand/sangue , Fator de von Willebrand/uso terapêutico , Fator de von Willebrand/efeitos adversos , Fator VIII/uso terapêutico , Fator VIII/efeitos adversos , Fator VIII/administração & dosagem , Resultado do Tratamento , Hemorragia/induzido quimicamente , Adulto , Combinação de Medicamentos , Criança , FarmacovigilânciaRESUMO
BACKGROUND: Bleeding disorder of unknown cause (BDUC) is characterized by a bleeding phenotype in the setting of normal hemostatic testing. No standardized diagnostic criteria or treatment algorithms exist for people with BDUC. To address the unmet need, the International Society on Thrombosis and Haemostasis von Willebrand Factor Scientific Subcommittee performed a real-world survey aimed at addressing knowledge gaps, developing consensus pathways, and ultimately improving care. OBJECTIVES: We sought to determine current international clinical practices in the investigation, registration, and treatment of people with BDUC internationally. METHODS: An online structured survey was conducted of healthcare providers who managed patients with bleeding disorders using the ISTH RedCap tool. RESULTS: Two hundred sixteen respondents from 39 countries were included in the final analysis. The clinical assessment of those with a possible bleeding disorder varied, with only 55% excluding hypermobility but high levels (80%) of bleeding assessment tool usage. In hemostatic testing, only the prothrombin time and activated partial thromboplastin time tests gained universal support. Tranexamic acid was favored for prophylaxis for minor (71%)/major (59%) surgeries and pregnancy (58%), but advice on the treatment if bleeding occurred was heterogeneous. The management of heavy menstrual bleeding in women despite combined oral contraceptive pill use also proved challenging, with healthcare providers selecting multiple alternative strategies. CONCLUSION: Significant variation exists in the recognition, registration, and management of people with BDUC worldwide. This survey emphasizes the need for consensus pathways to diagnose and treat BDUC to standardize and improve care for patients internationally.
RESUMO
In many patients referred with significant bleeding phenotype, laboratory testing fails to define any hemostatic abnormalities. Clinical practice with respect to diagnosis and management of this patient cohort poses significant clinical challenges. We recommend that bleeding history in these patients should be objectively assessed using the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool. Patients with increased bleeding assessment tool scores should progress to hemostasis laboratory testing. To diagnose bleeding disorder of unknown cause (BDUC), normal complete blood count, prothrombin time, activated partial thromboplastin time, thrombin time, von Willebrand factor antigen, von Willebrand factor function, coagulation factors VIII, IX, and XI, and platelet light transmission aggregometry should be the minimum laboratory assessment. In some laboratories, additional specialized hemostasis testing may be performed to identify other rare causes of bleeding. We recommend that patients with a significant bleeding phenotype but normal laboratory investigations should be registered with a diagnosis of BDUC in preference to other terminology. Global hemostatic tests and markers of fibrinolysis demonstrate variable abnormalities, and their clinical significance remains uncertain. Targeted genomic sequencing examining candidate hemostatic genes has a low diagnostic yield. Underlying BDUC should be considered in patients with heavy menstrual bleeding since delays in diagnosis often extend to many years and negatively impact quality of life. Treatment options for BDUC patients include tranexamic acid, desmopressin, and platelet transfusions.