Real-world use of thrombopoietin receptor agonists for the management of immune thrombocytopenia in adult patients in the United Kingdom: Results from the TRAIT study.

Few studies have reported the real-world use of both romiplostim and eltrombopag in immune thrombocytopenia (ITP). TRAIT was a retrospective observational study aimed to evaluate the platelet responses and adverse effects associated with the use of these thrombopoietin receptor agonists (TPO-RAs) in adult patients with ITP in the United Kingdom. Of 267 patients (median age at diagnosis, 48 years) with ITP (primary ITP [n = 218], secondary ITP [n = 49]) included in the study, 112 (42%) received eltrombopag and 155 (58%) received romiplostim as the first prescribed TPO-RA. A platelet count ≥30 × 109 /L was achieved in 89% of patients with the first TPO-RA treatments, while 68% achieved a platelet count ≥100 × 109 /L. Treatment-free response (TFR; platelet count ≥30 × 109 /L, 3 months after discontinuing treatment) was achieved by 18% of the total patients. Overall, 61 patients (23%) switched TPO-RAs, most of whom achieved platelet counts ≥30 × 109 /L with the second TPO-RA (23/25 who switched from eltrombopag to romiplostim [92%]; 28/36 who switched from romiplostim to eltrombopag [78%]). TFR was associated with secondary ITP, early TPO-RA initiation after diagnosis, the presence of comorbidity and no prior splenectomy or treatment with steroids or mycophenolate mofetil. Both TPO-RAs had similar efficacy and safety profiles to those reported in clinical studies.

Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B.

BACKGROUND: FLT180a (verbrinacogene setparvovec) is a liver-directed adeno-associated virus (AAV) gene therapy that uses a synthetic capsid and a gain-of-function protein to normalize factor IX levels in patients with hemophilia B. METHODS: In this multicenter, open-label, phase 1-2 trial, we assessed the safety and efficacy of varying doses of FLT180a in patients with severe or moderately severe hemophilia B (factor IX level, ≤2% of normal value). All the patients received glucocorticoids with or without tacrolimus for immunosuppression to decrease the risk of vector-related immune responses. After 26 weeks, patients were enrolled in a long-term follow-up study. The primary end points were safety and efficacy, as assessed by factor IX levels at week 26. RESULTS: Ten patients received one of four FLT180a doses of vector genomes (vg) per kilogram of body weight: 3.84×1011 vg, 6.40×1011 vg, 8.32×1011 vg, or 1.28×1012 vg. After receiving the infusion, all the patients had dose-dependent increases in factor IX levels. At a median follow-up of 27.2 months (range, 19.1 to 42.4), sustained factor IX activity was observed in all the patients except one, who resumed factor IX prophylaxis. As of the data-cutoff date (September 20, 2021), five patients had normal factor IX levels (range, 51 to 78%), three patients had levels from 23 to 43%, and one had a level of 260%. Of the reported adverse events, approximately 10% were related to FLT180a and 24% to immunosuppression. Increases in liver aminotransferase levels were the most common FLT180a-related adverse events. Late increases in aminotransferase levels occurred in patients who had received prolonged tacrolimus beyond the glucocorticoid taper. A serious adverse event of arteriovenous fistula thrombosis occurred in the patient with high factor IX levels. CONCLUSIONS: Sustained factor IX levels in the normal range were observed with low doses of FLT180a but necessitated immunosuppression with glucocorticoids with or without tacrolimus. (Funded by Freeline Therapeutics; ClinicalTrials.gov numbers, NCT03369444 and NCT03641703; EudraCT numbers, 2017-000852-24 and 2017-005080-40.).

Cardiovascular disease in hereditary haemophilia: The challenges of longevity.

The development of effective and safe treatments has significantly increased the life expectancy of persons with haemophilia (PWH). This has been accompanied by an increase in the comorbidities of ageing including cardiovascular disease, which poses particular challenges due to the opposing risks of bleeding from haemophilia and antithrombotic treatments versus thrombosis. Although mortality secondary to coronary artery disease in PWH is less than in the general population, the rate of atherosclerosis appears similar. The prevalence of atrial fibrillation in PWH and risk of secondary thromboembolic stroke are not well established. PWH can be safely supported through acute coronary interventions but data on the safety and efficacy of long-term antithrombotics are scarce. Increased awareness and research on cardiovascular disease in PWH will be crucial to improve primary prevention, acute management, secondary prevention and to best support ageing PWH.

Mycophenolate Mofetil for First-Line Treatment of Immune Thrombocytopenia.

BACKGROUND: Immune thrombocytopenia is a rare autoimmune disorder with associated bleeding risk and fatigue. Recommended first-line treatment for immune thrombocytopenia is high-dose glucocorticoids, but side effects, variable responses, and high relapse rates are serious drawbacks. METHODS: In this multicenter, open-label, randomized, controlled trial conducted in the United Kingdom, we assigned adult patients with immune thrombocytopenia, in a 1:1 ratio, to first-line treatment with a glucocorticoid only (standard care) or combined glucocorticoid and mycophenolate mofetil. The primary efficacy outcome was treatment failure, defined as a platelet count of less than 30×109 per liter and initiation of a second-line treatment, assessed in a time-to-event analysis. Secondary outcomes were response rates, side effects, occurrence of bleeding, patient-reported quality-of-life measures, and serious adverse events. RESULTS: A total of 120 patients with immune thrombocytopenia underwent randomization (52.4% male; mean age, 54 years [range 17 to 87]; mean platelet level, 7×109 per liter) and were followed for up to 2 years after beginning trial treatment. The mycophenolate mofetil group had fewer treatment failures than the glucocorticoid-only group (22% [13 of 59 patients] vs. 44% [27 of 61 patients]; hazard ratio, 0.41; range, 0.21 to 0.80; P = 0.008) and greater response (91.5% of patients having platelet counts greater than 100×109 per liter vs. 63.9%; P<0.001). We found no evidence of a difference between the groups in the occurrence of bleeding, rescue treatments, or treatment side effects, including infection. However, patients in the mycophenolate mofetil group reported worse quality-of-life outcomes regarding physical function and fatigue than those in the glucocorticoid-only group. CONCLUSIONS: The addition of mycophenolate mofetil to a glucocorticoid for first-line treatment of immune thrombocytopenia resulted in greater response and a lower risk of refractory or relapsed immune thrombocytopenia, but with somewhat decreased quality of life. (Funded by the U.K. National Institute for Health Research; FLIGHT ClinicalTrials.gov number, NCT03156452; EudraCT number, 2017-001171-23.).

Current practice and registration patterns among United Kingdom Haemophilia Centre Doctors' Organisation centers for patients with unclassified bleeding disorders.

BACKGROUND: Bleeding of unknown cause (BUC) and unclassified bleeding disorders (UBD) are increasingly recognized. There is no guidance on diagnosis and management. OBJECTIVES: To examine UK haemophilia centre registration patterns and current practice for UBD patients. METHODS: In a two-step process, the UK National Haemophilia Database (NHD) was reviewed for registration patterns of UBD patients and a survey of UK haemophilia centers was conducted (January/February 2021) to capture current practice for diagnosis and management of patients with UBD. RESULTS/DISCUSSION: Overall, registrations with the NHD for UBD patients has sharply risen from 2012 to 2020 and in 2019 accounted for 2.65% of registered patients. For the survey, the response rate was 52/67 (78%). Practice was widely variable; 35/52 (67%) centers register UBD; among these 35 centers, terminology included UBD (28 centers), undiagnosed bleeding disorder (four centers), and BUC (three centers); 34/52 (65%) centers use a formal bleeding assessment tool. For management of dental extraction and high bleeding risk surgery in a fictional UBD patient we found that tranexamic acid was widely used; however, beyond this a variety of hemostatic products were advised including blood products, recombinant factor VIIa/prothrombin complex concentrate, and desmopressin. There was general consensus (≈90%) on avoiding regional anesthesia in pregnancy, but no agreement on the need for fetal precautions to avoid bleeding at delivery (50% would advise these). There was a disparity of opinion on chemical thromboprophylaxis, and management of patients without prior hemostatic challenges and offspring of these patients. CONCLUSION: This study provides a snapshot of current practice and real-world data in this area. Future studies need to address the gaps in evidence.

A comprehensive targeted next-generation sequencing panel for genetic diagnosis of patients with suspected inherited thrombocytopenia.

BACKGROUND: Inherited thrombocytopenias (ITs) are a heterogeneous group of disorders characterized by low platelet counts and often disproportionate bleeding with over 30 genes currently implicated. Previously the UK-GAPP study using whole exome sequencing (WES) identified a pathogenic variant in 19 of 47 (40%) patients of which 71% had variants in genes known to cause IT. AIMS: To employ a targeted next-generation sequencing platform to improve efficiency of diagnostic testing and reduce overall costs. METHODS: We have developed an IT-specific gene panel as a pre-screen for patients prior to WES using the Agilent SureSelectQXT transposon-based enrichment system. RESULTS: Thirty-one patients were analyzed using the panel-based sequencing, of which; 10% (3/31) were identified with a classified pathogenic variant, 16% (5/31) were identified with a likely pathogenic variant, 51% (16/31) were identified with variants of unknown significance, and 23% (7/31) were identified with either no variant or a benign variant. DISCUSSION AND CONCLUSION: Although requiring further clarification of the impact of the genetic variations, the application of an IT-specific next generation sequencing panel is an viable method of pre-screening patients for variants in known IT-causing genes prior to WES. With an added benefit of distinguishing IT from idiopathic thrombocytopenic purpura (ITP) and the potential to identify variants in genes known to have a predisposition to hematological malignancies, it could become a critical step in improving patient clinical management.

EMPOWER! Empowering mothers, providing options with education and relaxation.

Most women within their lifetime will experience pregnancy, birth and motherhood. Despite this almost universal experience, the process is far from uniform. Throughout the childbirth continuum, expectations and experiences of women are diverse and ever-changing (van Teijlingen et al 2017). THis article explores an innovative idea, well placed within this 'Shiny roads' edition of The Practising Midwife. It explores the birth of the EMPOWER project within a NHS trust. EMPOWER was developed to empower mothers and provide options, education and relaxation for pregnancy, birth and the postnatal period.

Prostate cancer: beware of disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is a pathological systemic condition resulting from aberrant activation of the coagulation system. It is characterised by the release and activation of procoagulants into the blood, with an associated consumption coagulopathy. Its association with solid and haematological malignancies is well described in literature. This case describes an elderly man, known to have prostate cancer, who following transurethral resection of the prostate developed DIC with haematuria, spontaneous ecchymoses and mucosal bleeding. Subsequent investigations revealed a prostate-specific antigen (PSA) >1000 µg/L, and staging CT showed multiple sclerotic metastatic lesions affecting the thoracic and lumbar vertebra, as well as infiltration into his left femur. Coagulation normalised with blood products and vitamin K within 1 week, and the patient responded to antiandrogen therapy with a reduction in pain and PSA on discharge.

Thrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes.

Pregnancy can precipitate thrombotic thrombocytopenic purpura (TTP). We present a prospective study of TTP cases from the United Kingdom Thrombotic Thrombocytopenic Purpura (UK TTP) Registry with clinical and laboratory data from the largest cohort of pregnancy-associated TTP and describe management through pregnancy, averting fetal loss and maternal complications. Thirty-five women presented with a first TTP episode during pregnancy: 23/47 with their first congenital TTP (cTTP) episode and 12/47 with acute acquired TTP in pregnancy. TTP presented primarily in the third trimester/postpartum, but fetal loss was highest in the second trimester. Fetal loss occurred in 16/38 pregnancies before cTTP was diagnosed, but in none of the 15 subsequent managed pregnancies. Seventeen of 23 congenital cases had a missense mutation, C3178T, within exon 24 (R1060W). There were 8 novel mutations. In acquired TTP presentations, fetal loss occurred in 5/18 pregnancies and 2 terminations because of disease. We also present data on 12 women with a history of nonpregnancy-associated TTP: 18 subsequent pregnancies have been successfully managed, guided by ADAMTS13 levels. cTTP presents more frequently than acquired TTP during pregnancy and must be differentiated by ADAMTS13 analysis. Careful diagnosis, monitoring, and treatment in congenital and acquired TTP have assisted in excellent pregnancy outcomes.

Thrombin generation: a comparison of assays using platelet-poor and -rich plasma and whole blood samples from healthy controls and patients with a history of venous thromboembolism.

We have developed a whole blood thrombin generation (TG) assay whereby TG is initiated with a low-tissue factor concentration and monitored using a fluorogenic thrombin substrate. Significantly higher values were found in blood samples from 50 patients with a history of venous thromboembolism (VTE) compared with 31 healthy controls (HC), for peak height (P = 0.0034) and endogenous thrombin potential (ETP) (P = 0.0027). Results from 31 VTE patients and the 31 controls in the absence of corn trypsin inhibitor (CTI) showed significantly higher values in the VTE group for peak height (P = 0.0013) and ETP (P = 0.002). In the presence of CTI, significantly higher values were only seen in ETP (P = 0.024). No significant increases in TG were found using platelet poor (PPP) or -rich (PRP) plasma with or without CTI. The whole blood TG assay in the absence or presence of CTI showed a higher proportion (25/50 and 12/31, respectively) of raised peak height and/or ETP values than plasma assays (PPP 9/50 and 5/31 respectively and PRP 13/50 and 6/31, respectively). Our results show the whole blood TG assay is more sensitive for determining the increases in TG in patients with a history of VTE than PPP and PRP TG assays.

Tracking and characterisation of transfused platelets by two colour, whole blood flow cytometry.

We describe a flow cytometric technique to study transfused platelets in patients. By selecting donor/recipient pairs discrepant for HLA-A2, transfused platelets were identified using anti-HLA-A2 with a detection limit of <5%, and accuracy within 4.3% of predicted (r2 > 0.96, P < 0.0001). In two of three episodes, transfused platelets were present in greater numbers than predicted from increment counts. Platelets with bound fibrinogen fell from 20.9 +/- 23.6% of donor platelets pretransfusion to 1.7 +/- 0.3% 1 h post-transfusion, whereas P-selectin-positive platelets fell gradually, from 24.1 +/- 6.7 to 7.3 +/- 3.3% at 6 h. This method avoids radio or chemical labelling, and could be used to assess novel platelet preparations post-transfusion.

Functional benefits and cost/benefit analysis of continuous intrathecal baclofen infusion for the management of severe spasticity.

OBJECT: Intrathecally delivered baclofen has been used as a treatment for severe spasticity since 1984. Despite this, there are uncertainties surrounding the benefits of treatment and the costs involved. The authors assessed the evidence of benefits and identified costs and the cost/benefit ratio for continuous intrathecal baclofen infusion in the treatment of severe spasticity. METHODS: A systematic literature review was conducted to estimate the effect of continuous intrathecal baclofen infusion on function and quality-of-life (QOL) measures in patients with severe spasticity. Outcomes were related to standard QOL scores to estimate potential gains in quality-adjusted life years (QALYs). Information on the costs of continuous intrathecal baclofen infusion was obtained from hospitals in the United Kingdom. This information was combined to estimate the cost/benefit ratio for the use of continuous intrathecal baclofen infusion in patients with different levels of disability from severe spasticity. Studies indicate that bedbound patients are likely to improve their mobility and become able to sit out of bed. Patients with severe spasm-related pain are likely to have major improvement or complete resolution of this pain. Many other benefits are also reported. Such benefits are related to costs per QALY in the range of 6,900 pounds to 12,800 pounds ($10,550-$19,570 US). CONCLUSIONS: In carefully selected patients who have not responded to less invasive treatments, continuous intrathecal baclofen infusion is likely to lead to worthwhile functional benefits. Continuous intrathecal baclofen infusion has an acceptable cost/benefit ratio compared with other interventions that are funded by the health service.