Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis (ATLAS-PPX).

Fitusiran, a subcutaneous (SC) investigational siRNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This Phase 3, open-label study (NCT03549871) evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥ 12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary endpoint was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary endpoints included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor/non-inhibitor, n = 19/46) were eligible for ABR analyses. Observed median (IQR) ABRs were 6.5 (2.2, 19.6)/4.4 (2.2, 8.7) with BPA/CFC prophylaxis versus 0.0 (0.0, 0.0)/0.0 (0.0, 2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = 0.0021) and 46.4% (P = 0.0598) versus BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced zero treated bleeds with fitusiran versus 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events versus BPA/CFC prophylaxis in PwHA/B, with or without inhibitors and reported adverse events were generally consistent with previously identified risks of fitusiran.

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.

Socioeconomic deprivation and illness trajectory in the Scottish population after COVID-19 hospitalization.

BACKGROUND: The associations between deprivation and illness trajectory after hospitalisation for coronavirus disease-19 (COVID-19) are uncertain. METHODS: A prospective, multicentre cohort study was conducted on post-COVID-19 patients, enrolled either in-hospital or shortly post-discharge. Two evaluations were carried out: an initial assessment and a follow-up at 28-60 days post-discharge. The study encompassed research blood tests, patient-reported outcome measures, and multisystem imaging (including chest computed tomography (CT) with pulmonary and coronary angiography, cardiovascular and renal magnetic resonance imaging). Primary and secondary outcomes were analysed in relation to socioeconomic status, using the Scottish Index of Multiple Deprivation (SIMD). The EQ-5D-5L, Brief Illness Perception Questionnaire (BIPQ), Patient Health Questionnaire-4 (PHQ-4) for Anxiety and Depression, and the Duke Activity Status Index (DASI) were used to assess health status. RESULTS: Of the 252 enrolled patients (mean age 55.0 ± 12.0 years; 40% female; 23% with diabetes), deprivation status was linked with increased BMI and diabetes prevalence. 186 (74%) returned for the follow-up. Within this group, findings indicated associations between deprivation and lung abnormalities (p = 0.0085), coronary artery disease (p = 0.0128), and renal inflammation (p = 0.0421). Furthermore, patients with higher deprivation exhibited worse scores in health-related quality of life (EQ-5D-5L, p = 0.0084), illness perception (BIPQ, p = 0.0004), anxiety and depression levels (PHQ-4, p = 0.0038), and diminished physical activity (DASI, p = 0.002). At the 3-month mark, those with greater deprivation showed a higher frequency of referrals to secondary care due to ongoing COVID-19 symptoms (p = 0.0438). However, clinical outcomes were not influenced by deprivation. CONCLUSIONS: In a post-hospital COVID-19 population, socioeconomic deprivation was associated with impaired health status and secondary care episodes. Deprivation influences illness trajectory after COVID-19.

In our study, we aimed to understand how socioeconomic factors impact recovery from COVID-19 following hospitalisation. We followed 252 patients, collecting health data and utilising advanced imaging techniques. We discovered that individuals from deprived areas experienced more severe health complications, reported worse quality of life, and required more specialist care. However, their clinical outcomes were not significantly different. This underscores that socioeconomic deprivation affects health recovery, underlining the need for tailored care for these individuals. Our findings emphasise the importance of considering socioeconomic factors in recovery plans post-COVID-19, potentially improving healthcare for those in deprived areas.

Outcomes of total hip and knee arthroplasty in patients with haemophilia: A meta-analysis of comparative studies and clinical practice recommendations.

AIM: We aimed to compare the outcomes of total hip and knee arthroplasty (THA, TKA) in haemophilic patients compared to matched controls. METHODS: Through a literature search we identified all cohort studies comparing perioperative complications and other outcomes of THA and TKA in haemophilic patients and matched controls without haemophilia. Results of the same outcome measure assessed by two or more studies were pooled in meta-analyses; odds ratios (ORs) with 95% confidence intervals (CI) were calculated. The risk of bias in included studies and certainty of evidence of each result were assessed using the Newcastle-Ottawa scale and the GRADE tool respectively. RESULTS: A total of five retrospective studies with matched controls were included; four of them were of good and one of fair quality. Based on moderate certainty evidence, compared to matched controls, patients with haemophilia had a significantly higher incidence of the following complications after a) TKA: periprosthetic joint infection [PJI; OR 1.6 CI (1.3, 1.9)], 1-year revision/re-operation [OR 1.4 CI (1.2, 1.8)] and b) THA: major and minor 90-day complications [major OR 2.2 CI (1.7, 2.9); minor OR 1.4 CI (1.1, 1.8)], venous thromboembolism [OR 3.1 CI (2.1, 4.6)]. PJI incidence in THA was not different in haemophilia compared to controls [OR 1.5 CI (.9, 2.6)]. CONCLUSION: Our results can be used by healthcare professionals counselling patients with haemophilia considering a THA or TKA as part of the informed consent process. We provide detailed clinical recommendations for the perioperative management of THA and TKA in haemophilic patients.

A new population pharmacokinetic model for recombinant factor IX-Fc fusion concentrate including young children with haemophilia B.

AIMS: Recombinant factor IX Fc fusion protein (rFIX-Fc) is an extended half-life factor concentrate administered to haemophilia B patients. So far, a population pharmacokinetic (PK) model has only been published for patients aged ≥12 years. The aim was to externally evaluate the predictive performance of the published rFIX-Fc population PK model for patients of all ages and develop a model that describes rFIX-Fc PK using real-world data. METHODS: We collected prospective and retrospective data from patients with haemophilia B treated with rFIX-Fc and included in the OPTI-CLOT TARGET study (NTR7523) or United Kindom (UK)-EHL Outcomes Registry (NCT02938156). Predictive performance was assessed by comparing predicted with observed FIX activity levels. A new population PK model was constructed using nonlinear mixed-effects modelling. RESULTS: Real-world data were obtained from 37 patients (median age: 16 years, range 2-71) of whom 14 were aged <12 years. Observed FIX activity levels were significantly higher than levels predicted using the published model, with a median prediction error of -48.8%. The new model showed a lower median prediction error (3.4%) and better described rFIX-Fc PK, especially for children aged <12 years. In the new model, an increase in age was correlated with a decrease in clearance (P < .01). CONCLUSIONS: The published population PK model significantly underpredicted FIX activity levels. The new model better describes rFIX-Fc PK, especially for children aged <12 years. This study underlines the necessity to strive for representative population PK models, thereby avoiding extrapolation outside the studied population.

Fibrinogenolysis and fibrinolysis in vaccine-induced immune thrombocytopenia and thrombosis.

BACKGROUND: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare syndrome associated with adenoviral vector vaccines for COVID-19. The syndrome is characterized by thrombosis, anti-platelet factor 4 (PF4) antibodies, thrombocytopenia, high D-dimer, and hypofibrinogenemia. OBJECTIVES: To investigate abnormalities in fibrinolysis that contribute to the clinical features of VITT. METHODS: Plasma samples from 18 suspected VITT cases were tested for anti-PF4 by ELISA and characterized as meeting criteria for VITT (11/18) or deemed unlikely (7/18; non-VITT). Antigen levels of PAI-1, factor XIII (FXIII), plasmin-α2antiplasmin (PAP), and inflammatory markers were quantified. Plasmin generation was quantified by chromogenic substrate. Western blotting was performed with antibodies to fibrinogen, FXIII-A, and plasminogen. RESULTS: VITT patients 10/11 had scores indicative of overt disseminated intravascular coagulation, while 0/7 non-VITT patients met the criteria. VITT patients had significantly higher levels of inflammatory markers, IL-1ß, IL-6, IL-8, TNFα, and C-reactive protein. In VITT patients, both fibrinogen and FXIII levels were significantly lower, while PAP and tPA-mediated plasmin generation were higher compared to non-VITT patients. Evidence of fibrinogenolysis was observed in 9/11 VITT patients but not in non-VITT patients or healthy controls. Fibrinogen degradation products were apparent, with obvious cleavage of the fibrinogen α-chain. PAP complex was evident in those VITT patients with fibrinogenolysis, but not in non-VITT patients or healthy donors. CONCLUSION: VITT patients show evidence of overt disseminated intravascular coagulation and fibrinogenolysis, mediated by dysregulated plasmin generation, as evidenced by increased PAP and plasmin generation. These observations are consistent with the clinical presentation of both thrombosis and bleeding in VITT.

Post-COVID-19 illness and associations with sex and gender.

BACKGROUND: Post-COVID-19 syndromes have associated with female sex, but the pathophysiological basis is uncertain. AIM: There are sex differences in myocardial inflammation identified using cardiac magnetic resonance (CMR) in post-COVID-19 patients, and in patient reported health outcomes following COVID-19 infection. DESIGN: This prospective study investigated the time-course of multiorgan injury in survivors of COVID-19 during convalescence. METHODS: Clinical information, blood biomarkers, and patient reported outcome measures were prospectively acquired at enrolment (visit 1) and 28-60 days post-discharge (visit 2). Chest computed tomography (CT) and CMR were performed at visit 2. Follow-up was carried out for serious adverse events, including death and rehospitalization. RESULTS: Sixty-nine (43%) of 159 patients recruited were female. During the index admission, females had a lower peak C-reactive protein (74 mg/l (21,163) versus 123 mg/l (70, 192) p = 0.008) and peak ferritin (229 µg/l (103, 551) versus 514 µg/l (228, 1122) p < 0.001). Using the Modified Lake-Louise criteria, females were more likely to have definite evidence of myocardial inflammation (54% (37/68) versus 33% (30/90) p = 0.003). At enrolment and 28-60 days post-discharge, enhanced illness perception, higher levels of anxiety and depression and lower predicted maximal oxygen utilization occurred more commonly in women. The mean (SD, range) duration of follow-up after hospital discharge was 450 (88) days (range 290, 627 days). Compared to men, women had lower rates of cardiovascular hospitalization (0% versus 8% (7/90); p = 0.018). CONCLUSIONS: Women demonstrated worse patient reported outcome measures at index admission and 28-60 days follow-up though cardiovascular hospitalization was lower.

Fitusiran prophylaxis in people with severe haemophilia A or haemophilia B without inhibitors (ATLAS-A/B): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Fitusiran, a subcutaneous investigational siRNA therapeutic, targets antithrombin with the goal of rebalancing haemostasis in people with haemophilia A or haemophilia B, regardless of inhibitor status. We aimed to evaluate the efficacy and safety of fitusiran prophylaxis in people with severe haemophilia without inhibitors. METHODS: This multicentre, open-label, randomised phase 3 study was conducted at 45 sites in 17 countries. Male participants aged at least 12 years with severe haemophilia A or B without inhibitors, who had previously been treated on-demand with clotting factor concentrates, were randomly assigned in a 2:1 ratio to receive 80 mg subcutaneous fitusiran prophylaxis once per month or to continue on-demand clotting factor concentrates for a total of 9 months. Randomisation was stratified by the number of bleeding events in the 6 months before screening (≤10 bleeds and >10 bleeds) and by haemophilia type (haemophilia A or B). The primary endpoint was annualised bleeding rate, analysed in the intention-to-treat analysis set. Safety and tolerability were assessed in the safety analysis set. This trial is registered with ClinicalTrials.gov, NCT03417245, and is complete. FINDINGS: Between March 1, 2018, and July 14, 2021, 177 male participants were screened for eligibility and 120 were randomly assigned to receive fitusiran prophylaxis (n=80) or on-demand clotting factor concentrates (n=40). Median follow-up was 7·8 months (IQR 7·8-7·8) in the fitusiran group and 7·8 months (7·8-7·8) in the on-demand clotting factor concentrates group. The median annualised bleeding rate was 0·0 (0·0-3·4) in the fitusiran group and 21·8 (8·4-41·0) in the on-demand clotting factor concentrates group. The estimated mean annualised bleeding rate was significantly lower in the fitusiran prophylaxis group (3·1 [95% CI 2·3-4·3]) than in the on-demand clotting factor concentrates group (31·0 [21·1-45·5]; rate ratio 0·101 [95% CI 0·064-0·159]; p<0·0001). In the fitusiran group, 40 (51%) of 79 treated participants had no treated bleeds compared with two (5%) of 40 participants in the on-demand clotting factor concentrates group. Increased alanine aminotransferase concentration (18 [23%] of 79 participants in the safety analysis set) was the most common treatment-emergent adverse event in the fitusiran group and hypertension (four (10%) of 40 participants) was the most common in the on-demand clotting factor concentrates group. Treatment-emergent serious adverse events were reported in five (6%) participants in the fitusiran group (cholelithiasis [n=2, 3%], cholecystitis [n=1, 1%], lower respiratory tract infection [n=1, 1%], and asthma [n=1, 1%]) and five (13%) participants in the on-demand clotting factor concentrates group (gastroenteritis, pneumonia, suicidal ideation, diplopia, osteoarthritis, epidural haemorrhage, humerus fracture, subdural haemorrhage, and tibia fracture [all n=1, 3%]). No treatment-related thrombosis or deaths were reported. INTERPRETATION: In participants with haemophilia A or B without inhibitors, fitusiran prophylaxis resulted in significant reductions in annualised bleeding rate compared with on-demand clotting factor concentrates and no bleeding events in approximately half of participants. Fitusiran prophylaxis shows haemostatic efficacy in both haemophilia A and haemophilia B, and therefore has the potential to be transformative in the management of all people with haemophilia. FUNDING: Sanofi.

Long-term risk of relapse in immune-mediated thrombotic thrombocytopenic purpura and the role of anti-CD20 therapy.

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.

Desmopressin for bleeding in non-severe hemophilia A: Suboptimal use in a real-world setting.

Background: Desmopressin is an important treatment option in nonsevere hemophilia A because it has several benefits compared with factor (F) concentrates, including no inhibitor risk and much lower costs. Despite these advantages, data are limited on the real-world use of desmopressin in the treatment of bleeds. Objective: To describe the clinical use of desmopressin in relation to other therapeutic modalities in the treatment of bleeding episodes in patients with nonsevere hemophilia A. Methods: Patients with nonsevere hemophilia A aged 12-55 years were included from the DYNAMO cohort study. Data on the desmopressin test response and treated bleeding events in the period January 2009 to July 2020 were retrospectively collected from medical files. An adequate desmopressin test response was defined based on a peak FVIII level of ≥30 IU/dl. Results: A total of 248 patients with a median age of 38 years (interquartile range 25-49) were included. An adequate desmopressin test response was documented in 25% and 73% of patients with moderate and mild hemophilia, respectively. In adequate responders, 51% of bleeds were exclusively treated with FVIII concentrates, 24% exclusively with desmopressin, 21% with a combination of both and 4% with other treatments. In 54% of bleeds treated with a single dose of factor concentrates, the expected FVIII level after desmopressin exceeded the level targeted. Conclusion: Most bleeds in patients with an adequate response to desmopressin are treated with factor concentrates. These findings may indicate a suboptimal use of desmopressin and that barriers to the use of desmopressin should be explored.

The suboptimal fibrinolytic response in COVID-19 is dictated by high PAI-1.

BACKGROUND: Severe COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. This study investigates whether the hemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system. METHODS: This prospective study analyzed fibrinolytic profiles of 113 patients hospitalized with COVID-19 disease with 24 patients with non-COVID-19 respiratory infection and healthy controls. Antigens were quantified by Ella system or ELISA, clot lysis by turbidimetric assay, and plasminogen activator inhibitor-1 (PAI-1)/plasmin activity using chromogenic substrates. Clot structure was visualized by confocal microscopy. RESULTS: PAI-1 and its cofactor, vitronectin, are significantly elevated in patients with COVID-19 disease compared with those with non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in patients with COVID-19 disease relative to healthy controls. PAI-1 and tissue plasminogen activator (tPA) were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fiber length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID-19 disease, while PAI-1 activity was elevated. Clot lysis time significantly correlated with PAI-1 levels. Stratification of COVID-19 samples according to PAI-1 levels reveals significantly faster lysis when using the PAI-1 resistant (tPA) variant, tenecteplase, over alteplase lysis. CONCLUSION: This study shows that the suboptimal fibrinolytic response in COVID-19 disease is directly attributable to elevated levels of PAI-1, which attenuate plasmin generation. These data highlight the important prognostic potential of PAI-1 and the possibility of using pre-existing drugs, such as tenecteplase, to treat COVID-19 disease and potentially other respiratory diseases.

Seroprevalence to adeno-associated virus type 6 in people with hemophilia B from a UK adult cohort.

Background: Gene therapy shows promise as a potential "cure" for hemophilia A and B. Adeno-associated virus (AAV) vectors are the leading platform to deliver modified genetic code of factor VIII or IX to the liver effecting endogenous production. Patient exposure to wild-type AAV leads to the formation of neutralizing factors, which can prevent successful transduction. It is thus important to establish the seroprevalence of the AAV serotypes in people with hemophilia to aid prediction of successful gene transfer. The seroprevalence of AAV6 in UK people with hemophilia B is not yet reported. Objectives: We studied the prevalence of anti-AAV6 neutralizing factors in UK people with hemophilia B (n = 49). We collected data on people's hepatitis C exposure and treatment with plasma-derived factor IX (FIX) to identify if there was correlation with AAV6 exposure. Methods: Serum samples and patient data were collected from 49 people with hemophilia B registered at UK hemophilia comprehensive care centers. The samples were tested for neutralizing factors to AAV6 using a cell-based transduction inhibition assay. Results: Thirty-one percent of patients had serum neutralization against AAV6. There was no correlation between AAV6 seropositivity and previous treatment with plasma-derived FIX products or hepatitis C exposure. Conclusion: Based on limited data, there is no evidence of association between the presence of AAV6 neutralizing factors in people with hemophilia B and exposure to contaminated plasma derivatives. The frequency of AAV6 neutralizing factors in our hemophilia B cohort is similar to UK people with hemophilia A and non-hemophilia populations.

The bleeding phenotype in people with nonsevere hemophilia.

Detailed information on the onset, frequency, and severity of bleeding in nonsevere hemophilia is limited. We aimed to assess the bleeding phenotype of persons with nonsevere hemophilia and to analyze the association between baseline factor VIII/IX (FVIII/IX) levels and the joint bleeding rate. In the DYNAMO (Dynamic Interplay Between Bleeding Phenotype and Baseline Factor Level in Moderate and Mild Hemophilia A and B) study, an international multicenter cohort, we included males with nonsevere hemophilia (FVIII/IX, 0.02-0.35 IU/mL) aged 12 to 55 years. Information on age at first treated (joint) bleed, annual bleeding rates (ABRs), and annual joint bleeding rates (AJBRs) was collected from the medical files. The association between baseline FVIII/IX levels and the joint bleeding rate was assessed by using a frailty model for recurrent events. In total, 304 persons (70 with moderate hemophilia and 234 with mild hemophilia) were included. The median age was 38 years (interquartile range [IQR], 25-49 years), and the median baseline FVIII/IX level was 0.12 IU/mL (IQR, 0.05-0.21 IU/mL). In total, 245 (81%) persons had experienced at least 1 bleed, and 156 (51%) had experienced at least 1 joint bleed. The median age at first bleed and first joint bleed was 8 and 10 years, respectively. The median ABR and AJBR was 0.2 (IQR, 0.1-0.5) and 0.0 (IQR, 0.0-0.2). From baseline FVIII/IX levels 0.02 to 0.05 IU/mL to >0.25 IU/mL, the median ABR decreased from 0.6 (IQR, 0.2-1.4) to 0.1 (IQR, 0.0-0.2) and the AJBR from 0.2 (IQR, 0.0-0.4) to 0.0 (IQR, 0.0-0.0). Baseline FVIII/IX was inversely associated with the joint bleeding rate (P < .001). Low bleeding rates were observed in persons with nonsevere hemophilia. However, one-half of all adolescents and adults had experienced a joint bleed.

A multisystem, cardio-renal investigation of post-COVID-19 illness.

The pathophysiology and trajectory of post-Coronavirus Disease 2019 (COVID-19) syndrome is uncertain. To clarify multisystem involvement, we undertook a prospective cohort study including patients who had been hospitalized with COVID-19 (ClinicalTrials.gov ID NCT04403607 ). Serial blood biomarkers, digital electrocardiography and patient-reported outcome measures were obtained in-hospital and at 28-60 days post-discharge when multisystem imaging using chest computed tomography with pulmonary and coronary angiography and cardio-renal magnetic resonance imaging was also obtained. Longer-term clinical outcomes were assessed using electronic health records. Compared to controls (n = 29), at 28-60 days post-discharge, people with COVID-19 (n = 159; mean age, 55 years; 43% female) had persisting evidence of cardio-renal involvement and hemostasis pathway activation. The adjudicated likelihood of myocarditis was 'very likely' in 21 (13%) patients, 'probable' in 65 (41%) patients, 'unlikely' in 56 (35%) patients and 'not present' in 17 (11%) patients. At 28-60 days post-discharge, COVID-19 was associated with worse health-related quality of life (EQ-5D-5L score 0.77 (0.23) versus 0.87 (0.20)), anxiety and depression (PHQ-4 total score 3.59 (3.71) versus 1.28 (2.67)) and aerobic exercise capacity reflected by predicted maximal oxygen utilization (20.0 (7.6) versus 29.5 (8.0) ml/kg/min) (all P < 0.01). During follow-up (mean, 450 days), 24 (15%) patients and two (7%) controls died or were rehospitalized, and 108 (68%) patients and seven (26%) controls received outpatient secondary care (P = 0.017). The illness trajectory of patients after hospitalization with COVID-19 includes persisting multisystem abnormalities and health impairments that could lead to substantial demand on healthcare services in the future.

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.).

European principles of care for women and girls with inherited bleeding disorders.

INTRODUCTION: Despite increasing awareness of issues faced by women and girls with inherited BDs (WGBD), standards of care are lacking, with disparities in diagnosis and treatment for WGBD across Europe. We aimed to develop practical principles of care (PoC) to promote standardization of care for WGBD within European Haemophilia Treatment and Comprehensive Care Centres (HTC/CCCs). METHODS: The co-creation process, supported by the European Association for Haemophilia and Allied Disorders, consisted of four multidisciplinary meetings with health care providers (HCPs) experienced in WGBD care, and European Haemophilia Consortium representatives, combined with broad patient and HCP consultations in the European haemophilia community. Relevant medical societies outside Europe were contacted for confirmation. RESULTS: We developed ten PoC for WGBD, stressing the importance and benefits of a centralized, multidisciplinary, comprehensive, family-centred approach to support and manage WGBD during all life stages. These PoC emphasise the right to equitable access and quality of care for all people with BDs, irrespective of gender. Multiple medical societies outside Europe also confirmed their support for endorsement. CONCLUSIONS: Ten PoC for WGBD evolved from an iterative process among stakeholders, supported by relevant medical societies worldwide. These PoC can serve as a benchmark for diagnosis and comprehensive multidisciplinary management of WGBD, and improve awareness of their unique challenges. They offer a framework to guide HTC/CCCs in providing equitable care for all WGBD, both in their own services and in other healthcare settings. Implementation of these principles aims to positively impact the health, wellbeing and quality of life for WGBD.

Clinical Features of Vaccine-Induced Immune Thrombocytopenia and Thrombosis.

BACKGROUND: Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a new syndrome associated with the ChAdOx1 nCoV-19 adenoviral vector vaccine against severe acute respiratory syndrome coronavirus 2. Data are lacking on the clinical features of and the prognostic criteria for this disorder. METHODS: We conducted a prospective cohort study involving patients with suspected VITT who presented to hospitals in the United Kingdom between March 22 and June 6, 2021. Data were collected with the use of an anonymized electronic form, and cases were identified as definite or probable VITT according to prespecified criteria. Baseline characteristics and clinicopathological features of the patients, risk factors, treatment, and markers of poor prognosis were determined. RESULTS: Among 294 patients who were evaluated, we identified 170 definite and 50 probable cases of VITT. All the patients had received the first dose of ChAdOx1 nCoV-19 vaccine and presented 5 to 48 days (median, 14) after vaccination. The age range was 18 to 79 years (median, 48), with no sex preponderance and no identifiable medical risk factors. Overall mortality was 22%. The odds of death increased by a factor of 2.7 (95% confidence interval [CI], 1.4 to 5.2) among patients with cerebral venous sinus thrombosis, by a factor of 1.7 (95% CI, 1.3 to 2.3) for every 50% decrease in the baseline platelet count, by a factor of 1.2 (95% CI, 1.0 to 1.3) for every increase of 10,000 fibrinogen-equivalent units in the baseline d-dimer level, and by a factor of 1.7 (95% CI, 1.1 to 2.5) for every 50% decrease in the baseline fibrinogen level. Multivariate analysis identified the baseline platelet count and the presence of intracranial hemorrhage as being independently associated with death; the observed mortality was 73% among patients with platelet counts below 30,000 per cubic millimeter and intracranial hemorrhage. CONCLUSIONS: The high mortality associated with VITT was highest among patients with a low platelet count and intracranial hemorrhage. Treatment remains uncertain, but identification of prognostic markers may help guide effective management. (Funded by the Oxford University Hospitals NHS Foundation Trust.).

Pulmonary thromboembolism in hospitalised patients with COVID-19: a retrospective national study of patients managed in critical care and ward environments in Scotland.

OBJECTIVES: To assess for increase in pulmonary thromboembolism (PTE) in hospitalised patients with COVID-19, in both critical care and ward environments. SETTING: We reviewed all CT pulmonary angiograms (CTPA) performed in Scotland between 23 March 2020 and 31 May 2020 and identified those with COVID-19 using either classical radiological appearances or positive COVID-19 PCR swab. PARTICIPANTS: All hospitalised patients in Scotland with COVID-19 between 23 March 2020 and 31 May 2020 who underwent a CTPA. PRIMARY OUTCOME MEASURE: To assess if the rate of PTE was increased in those with COVID-19 compared with previously published figures of hospitalised patients. SECONDARY OUTCOME MEASURES: To assess the effect of right heart strain or requirement for critical care on mortality. RESULTS: 3401 CTPAs were reviewed. 192 were positive for PTE in patients with evidence of COVID-19 either real-time PCR swab positive for SARS-CoV-2 (n=104) or having radiological changes consistent with COVID-19 (n=88). The total number of hospital admissions in Scotland between 23rd March 2020 and 31st May 2020 with COVID-19 was 5195. The incidence of PTE during this time was 3.7% in all patients admitted to all hospitals in Scotland with COVID-19 during this period. 475 hospitalised patients were managed in critical care (both level 2 and level 3 care), in whom the incidence of PTE was 6% (n=29). 4720 patients did not require admission to critical care, in whom the incidence of PTE was 3.5% (n=163). There was increased risk of death with right heart strain (25/52 vs 128/140 (p<0.01)) and in critical care (15/29 vs 146/163 (p<0.01)). CONCLUSIONS: We have demonstrated an increased risk of PTE in critical care and ward-based environments. Further studies are required to establish effective prophylactic anticoagulation in this group.