Phase 3 Trial of Concizumab in Hemophilia with Inhibitors.

BACKGROUND: Concizumab is an anti-tissue factor pathway inhibitor monoclonal antibody designed to achieve hemostasis in all hemophilia types, with subcutaneous administration. A previous trial of concizumab (explorer4) established proof of concept in patients with hemophilia A or B with inhibitors. METHODS: We conducted the explorer7 trial to assess the safety and efficacy of concizumab in patients with hemophilia A or B with inhibitors. Patients were randomly assigned in a 1:2 ratio to receive no prophylaxis for at least 24 weeks (group 1) or concizumab prophylaxis for at least 32 weeks (group 2) or were nonrandomly assigned to receive concizumab prophylaxis for at least 24 weeks (groups 3 and 4). After a treatment pause due to nonfatal thromboembolic events in three patients receiving concizumab, including one from the explorer7 trial, concizumab therapy was restarted with a loading dose of 1.0 mg per kilogram of body weight, followed by 0.2 mg per kilogram daily (potentially adjusted on the basis of concizumab plasma concentration as measured at week 4). The primary end-point analysis compared treated spontaneous and traumatic bleeding episodes in group 1 and group 2. Safety, patient-reported outcomes, and pharmacokinetics and pharmacodynamics were also assessed. RESULTS: Of 133 enrolled patients, 19 were randomly assigned to group 1 and 33 to group 2; the remaining 81 were assigned to groups 3 and 4. The estimated mean annualized bleeding rate in group 1 was 11.8 episodes (95% confidence interval [CI], 7.0 to 19.9), as compared with 1.7 episodes (95% CI, 1.0 to 2.9) in group 2 (rate ratio, 0.14 [95% CI, 0.07 to 0.29]; P<0.001). The overall median annualized bleeding rate for patients receiving concizumab (groups 2, 3, and 4) was 0 episodes. No thromboembolic events were reported after concizumab therapy was restarted. The plasma concentrations of concizumab remained stable over time. CONCLUSIONS: Among patients with hemophilia A or B with inhibitors, the annualized bleeding rate was lower with concizumab prophylaxis than with no prophylaxis. (Funded by Novo Nordisk; explorer7 ClinicalTrials.gov number, NCT04083781.).

Haemophilia care in Asia: Learning from clinical practice in some Asian countries.

BACKGROUND: The healthcare systems in Asia vary greatly due to the socio-economic and cultural diversities which impact haemophilia management. METHODS: An advisory board meeting was conducted with experts in haemophilia care from Asia to understand the heterogeneity in clinical practices and care provision in the region. FINDINGS: The overall prevalence of haemophilia in Asia ranges between 3 and 8.58/100,000 patients. Haemophilia A was more prevalent as compared to haemophilia B with a ratio of around 5:1. There is under-diagnosis in the region due to lack of diagnosis, registries and/or lack of appropriate facilities in suburban areas. Most patients are referred to the haematologists by their families or primary care physicians, while some are identified during bleeding episodes. Genetic testing faces obstacles like resource constraints, services available at limited centres and unwillingness of patients to participate. Prophylaxis is offered for people with haemophilia (PWH) with a severe bleeding phenotype. Recombinant factors are approved in most countries across the region and are the preferred therapy. The challenges highlighted for not receiving a high standard of care include patients' reluctance to use an intravenous treatment, poor patient compliance due to frequency of infusions, budget constraints and lack of funding, insurance, availability and accessibility of factor concentrates. Prevalence of neutralizing antibodies ranged from 5% to 20% in the region. Use of immune tolerance induction and bypassing agents to treat inhibitors depends on their cost and availability. CONCLUSION: Haemophilia care in Asia has evolved to a great extent. However, some challenges remain for which a strategic approach along with multi-stakeholder involvement are needed.

Incidence of anti-platelet factor4/polyanionic antibodies, thrombocytopenia, and thrombosis after COVID-19 vaccination with ChAdOx1 nCoV-19 in Thais.

BACKGROUND: The prevalence of anti-platelet factor 4 (PF4)/polyanionic antibodies occurring after vaccination with ChAdOx1 nCoV-19 is low. Most of these antibodies are not associated with vaccine-induced thrombotic thrombocytopenia. It remains unknown whether these antibodies are preexisting or occur as a result of vaccination. In this study, we demonstrated the incidence of anti-PF4/polyanionic antibodies, thrombocytopenia, and thrombosis after vaccination with ChAdOx1 nCoV-19 in a large cohort of Thais. METHODS: We conducted a prospective study in a cohort of health care workers and members of the general population who received COVID-19 vaccination with ChAdOx1 nCoV-19. Blood collection for complete blood count, D-dimer, and anti-PF4/polyanionic antibodies was performed before vaccination (day 0), day 10, and day 28 after vaccination. Anti-PF4/polyanionic antibodies were detected using enzyme-link immunosorbent assay (ELISA). Functional assay was performed for all positive ELISA tests. RESULTS: A total of 720 participants were included in the study. 214 participants received both the first and second doses, 91 participants received only the first, 51 received only the second, and 364 received the third booster dose of ChAdOx1 nCoV-19. Median age was 42 years (IQR, 34-53). 67% of participants were female. Three participants developed seroconversion, yielding an incidence of vaccination-induced anti-PF4/polyanionic antibodies of 0.42% (95% confidence interval 0.08, 1.23). Fourteen (1.9%) participants had preexisting anti-PF4/polyanionic antibodies before the vaccination but their optical density of anti-PF4/polyanionic antibodies did not significantly increase over time. None of the anti-PF4/polyanionic positive sera induced platelet aggregation. Abnormal D-dimer levels following vaccination were not different among the positive and negative anti-PF4/polyanionic groups (11.8% vs. 13.2%, p = 0.86). Thrombocytopenia occurred in one person with negative anti-PF4/polyanionic antibodies. No clinical thrombosis or bleeding occurred. CONCLUSION: We found a low incidence of seroconversion of anti-PF4/polyanionic antibodies after vaccination with ChAdOx1 nCoV-19 in Thais. Most of the anti-PF4/polyanionic antibodies were preexisting and did not significantly increase after vaccination with ChAdOx1 nCoV-19. Following vaccination, some participants with anti-PF4/polyanionic antibodies had elevated D-dimer levels, while only one developed thrombocytopenia and no thrombotic events were observed.

Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results.

Results from the main parts (24 weeks) of 2 concizumab phase 2 trials are presented: explorer4 in hemophilia A (HA) or B (HB) with inhibitors (HAwI/HBwI) and explorer5 in HA. The trials aimed to evaluate the efficacy of daily subcutaneous concizumab prophylaxis (evaluated as annualized bleeding rate [ABR] at last dose level), with secondary objectives being safety and immunogenicity (assessed as number of adverse events [AEs] and antidrug antibodies [ADAs]). Patients received 0.15 mg/kg concizumab, with potential dose escalation to 0.20 and 0.25 mg/kg (if ≥3 spontaneous bleeding episodes within 12 weeks of concizumab treatment). Relevant pharmacokinetic/pharmacodynamic (PK/PD) parameters were assessed. Thirty-six HA, 9 HAwI, and 8 HBwI patients were exposed to concizumab. Most inhibitor patients (15 of 17; 88.2%) did not escalate the dose; all patients chose to continue to the extension phase of the trials. Clinical proof of concept for prevention of bleeding episodes was demonstrated in both trials. Estimated ABRs in HAwI and HBwI were lower vs HA: 3.0 (95% confidence interval [CI], 1.7; 5.3) and 5.9 (95% CI, 4.2; 8.5) vs 7.0 (95% CI, 4.6; 10.7), respectively. PK/PD results were as expected, with no difference between hemophilia subtypes for concizumab exposure, free tissue factor pathway inhibitor, thrombin generation, prothrombin fragment 1+2, and d-dimers. Concizumab was safe and well tolerated (no severe AEs, AE-related withdrawals, or thromboembolic events). Three patients had (very low to medium titer) ADA+ tests in each trial, with no observed clinical effect. These results support further development of concizumab as a daily prophylactic treatment in all hemophilia patients. These trials were registered at www.clinicaltrials.gov as #NCT03196284 and #NCT03196297.

Incidence of thromboembolism in patients with COVID-19: a systematic review and meta-analysis.

BACKGROUND: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, the incidence of thromboembolism has been increasingly reported. The aim of this systematic review was to explore the incidence of venous and arterial thromboembolism among COVID-19 patients requiring hospitalization. METHODS: Medline, Embase, Scopus, and grey literature were searched until June 2020. Observational studies reported on the incidence of venous thromboembolism (VTE), including pulmonary embolism (PE) and deep vein thrombosis (DVT) or arterial thromboembolism (ATE) were included. The pool incidences and their 95% confidence intervals (CI) were calculated using the random-effects model. RESULTS: A total of 36 studies were included. In the intensive care unit (ICU) setting, the pooled incidence of VTE was 28% (95% CI, 22-34%). Subgroups based on compression ultrasound (CUS) screening revealed a higher incidence of DVT in the CUS screening group than in the no CUS screening group (32% [95% CI, 18-45%] vs. 6% [95% CI, 4-9%]). The pooled incidence of ATE in ICU was 3% (95% CI, 2-5%). In the non-ICU setting, the pooled incidence of VTE was 10% (95% CI, 6-14%,). CONCLUSIONS: The incidence of VTE in COVID-19 patients was higher in the ICU setting than in the non-ICU setting, and also significantly higher in studies that incorporated the CUS screening protocol. The incidence of ATE in the ICU setting was low. VTE prophylactic measures should be given to all hospitalized patients diagnosed with COVID-19.

Cancer associated thrombosis in everyday practice: perspectives from GARFIELD-VTE.

Venous thromboembolism (VTE) is common in cancer patients and is an important cause of morbidity and mortality. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE (ClinicalTrials.gov: NCT02155491) is a prospective, observational study of 10,684 patients with objectively diagnosed VTE from 415 sites in 28 countries. We compared baseline characteristics, VTE treatment patterns, and 1-year outcomes (mortality, recurrent VTE and major bleeding) in 1075 patients with active cancer, 674 patients with a history of cancer, and 8935 patients without cancer. Patients with active cancer and history of cancer were older than cancer-free patients, with median ages of 64.8, 68.9, and 58.4 years, respectively. The most common sites of active cancer were lung (14.5%), colorectal (11.0%), breast (10.6%), and gynaecological (10.3%). Active cancer patients had a higher incidence of upper limb and vena cava thrombosis than cancer-free patients (9.0% vs 4.8% and 5.1% vs 1.4%, respectively), and were more likely to receive parenteral anticoagulation as monotherapy than cancer-free patients (57.8% vs 12.1%), and less likely to receive DOACs (14.2% vs 50.6%). Rates of death, recurrent VTE, and major bleeding were higher in active cancer patients than in cancer-free patients, with hazard ratios (95% confidence intervals) of 14.2 (12.1-16.6), 1.6 (1.2-2.0) and 3.8 (2.9-5.0), respectively. VTE was the second most common cause of death in patients with active cancer or history of cancer. In patients with VTE, those with active cancer are at higher risk of death, recurrence, and major bleeding than those without cancer.

Predictors of NOAC versus VKA use for stroke prevention in patients with newly diagnosed atrial fibrillation: Results from GARFIELD-AF.

INTRODUCTION: A principal aim of the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) was to document changes in treatment practice for patients with newly diagnosed atrial fibrillation during an era when non-vitamin K antagonist oral anticoagulants (NOACs) were becoming more widely adopted. In these analyses, the key factors which determined the choice between NOACs and vitamin K antagonists (VKAs) are explored. METHODS: Logistic least absolute shrinkage and selection operator regression determined predictors of NOAC and VKA use. Data were collected from 24,137 patients who were initiated on AC ±â€¯antiplatelet (AP) therapy (NOAC [51.4%] or VKA [48.6%]) between April 2013 and August 2016. RESULTS: The most significant predictors of AC therapy were country, enrolment year, care setting at diagnosis, AF type, concomitant AP, and kidney disease. Patients enrolled in emergency care or in the outpatient setting were more likely to receive a NOAC than those enrolled in hospital (OR 1.16 [95% CI: 1.04-1.30], OR: 1.15 [95% CI: 1.05-1.25], respectively). NOAC prescribing seemed to be favored in lower-risk groups, namely, patients with paroxysmal AF, normotensive patients, and those with moderate alcohol consumption, but also the elderly and patients with acute coronary syndrome. By contrast, VKAs were preferentially used in patients with permanent AF, moderate to severe kidney disease, heart failure, vascular disease, and diabetes and with concomitant AP. CONCLUSION: GARFIELD-AF data highlight marked heterogeneity in stroke prevention strategies globally. Physicians are adopting an individualized approach to stroke prevention where NOACs are favored in patients with a lower stroke risk but also in the elderly and patients with acute coronary syndrome.

Concizumab restores thrombin generation potential in patients with haemophilia: Pharmacokinetic/pharmacodynamic modelling results of concizumab phase 1/1b data.

INTRODUCTION: Concizumab enhances thrombin generation (TG) potential in haemophilia patients by inhibiting tissue factor pathway inhibitor (TFPI). In EXPLORER3 (phase 1b), a dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) relationship was confirmed between concizumab dose, free TFPI and TG potential. AIM: Determine the association between concizumab exposure, PD markers (free TFPI; peak TG) and bleeding episodes to establish the minimum concizumab concentration for achieving sufficient efficacy. METHODS: Free TFPI predictions were generated using an estimated concizumab-free TFPI exposure-response (Emax ) model based on concizumab phase 1/1b data for which simultaneously collected concizumab and free TFPI samples were available. Concizumab concentration at the time of a bleed was predicted using a PK model, based on available data for concizumab doses >50 µg/kg to ≤9 mg/kg. Peak TG vs concizumab concentration analyses and an Emax model were constructed based on EXPLORER3 observations. RESULTS: The Emax model showed a tight PK/PD relationship between concizumab exposure and free TFPI; free TFPI decreased with increasing concizumab concentration. A strong correlation between concizumab concentration and peak TG was observed; concizumab >100 ng/mL re-established TG potential to within the normal reference range. Estimated EC50 values for the identified concizumab-free TFPI and concizumab-TG potential models were very similar, supporting free TFPI as an important biomarker. A correlation between bleeding episode frequency and concizumab concentration was indicated; patients with a concizumab concentration >100 ng/mL experienced less frequent bleeding. The PK model predicted that once-daily dosing would minimize within-patient concizumab PK variability. CONCLUSION: Concizumab phase 2 trials will target an exposure ≥100 ng/mL, with a once-daily regimen.

Characteristics of patients with atrial fibrillation prescribed antiplatelet monotherapy compared with those on anticoagulants: insights from the GARFIELD-AF registry.

Aims: Current atrial fibrillation (AF) guidelines discourage antiplatelet (AP) monotherapy as alternative to anticoagulants (ACs). Why AP only is still used is largely unknown. Methods and results: Factors associated with AP monotherapy prescription were analysed in GARFIELD-AF, a registry of patients with newly diagnosed (≤6 weeks) AF and ≥1 investigator-determined stroke risk factor. We analysed 51 270 patients from 35 countries enrolled into five sequential cohorts between 2010 and 2016. Overall, 20.7% of patients received AP monotherapy, 52.1% AC monotherapy, and 14.1% AP + AC. Most AP monotherapy (82.5%) and AC monotherapy (86.8%) patients were CHA2DS2-VASc ≥2. Compared with patients on AC monotherapy, AP monotherapy patients were frequently Chinese (vs. Caucasian, odds ratio 2.73) and more likely to have persistent AF (1.32), history of coronary artery disease (2.41) or other vascular disease (1.67), bleeding (2.11), or dementia (1.81). The odds for AP monotherapy increased with 5 years of age increments for patients ≥75 years (1.24) but decreased with age increments for patients 55-75 years (0.86). Antiplatelet monotherapy patients were less likely to have paroxysmal (0.67) or permanent AF (0.57), history of embolism (0.56), or alcohol use (0.90). With each cohort, AP monotherapy declined (P<0.0001), especially non-indicated use. AP + AC and no antithrombotic therapy were unchanged. However, even in 2015 and 2016, about 50% of AP-treated patients had no indication except AF (71% were CHA2DS2-VASc ≥2). Conclusion: Prescribing AP monotherapy in newly diagnosed AF has declined, but even nowadays a substantial proportion of AP-treated patients with AF have no indication for AP. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362.

Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial.

This multinational, randomized, single-blind trial investigated the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in 74 previously treated patients with hemophilia B (FIX activity ≤2 IU/dL). Patients received prophylaxis for 52 weeks, randomized to either 10 IU/kg or 40 IU/kg once weekly or to on-demand treatment of 28 weeks. No patients developed inhibitors, and no safety concerns were identified. Three hundred forty-five bleeding episodes were treated, with an estimated success rate of 92.2%. The median annualized bleeding rates (ABRs) were 1.04 in the 40 IU/kg prophylaxis group, 2.93 in the 10 IU/kg prophylaxis group, and 15.58 in the on-demand treatment group. In the 40 IU/kg group, 10 (66.7%) of 15 patients experienced no bleeding episodes into target joints compared with 1 (7.7%) of 13 patients in the 10 IU/kg group. Health-related quality of life (HR-QoL) assessed with the EuroQoL-5 Dimensions visual analog scale score improved from a median of 75 to 90 in the 40 IU/kg prophylaxis group. Nonacog beta pegol was well tolerated and efficacious for the treatment of bleeding episodes and was associated with low ABRs in patients receiving prophylaxis. Once-weekly prophylaxis with 40 IU/kg resolved target joint bleeds in 66.7% of the affected patients and improved HR-QoL. This trial was registered at www.clinicaltrials.gov as #NCT01333111.

Cancer-associated thrombosis in Asia.

Thrombosis is a common complication in cancer patients. Although the major inherited risk factors for thrombophilia are different between Asians and Caucasians, the main acquired risk factors that are associated with the development of venous thromboembolism (VTE) in Asians appear to be similar to those for Caucasians. Malignancy is the most important acquired risk factor for VTE in Asians. Recent studies have shown that the incidence of VTE is significant in Asian patients with cancer, particularly those in an advanced stage. Cancer associated VTE is more severe and associated with higher morbidity and mortality. Unprovoked VTE is associated with an increased risk of subsequent cancer diagnosis. A number of international and national guidelines are available to provide guidance to healthcare providers to treat and prevent this serious complication based on best-available evidence. Identifying cancer patients at risk for VTE and use of appropriate thromboprophylaxis in these patients can potentially improve morbidity and mortality. Although direct oral anticoagulants (DOACs) may become an attractive treatment for cancer-associated VTE, further clinical trials are needed to evaluate the safety and efficacy of DOACs directly against LMWH in cancer patients.

Thrombosis: a major contributor to global disease burden.

Thrombosis is a common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused one in four deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. We performed a systematic review of the literature on the global disease burden due to VTE in low-, middle-, and high-income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1,000 individuals in the population. The incidence increased to between 2 and 7 per 1,000 among those 70 years of age or more. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted-life-years (DALYs) lost in low- and middle-income countries, and second in high-income countries, responsible for more DALYs lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. VTE causes a major burden of disease across low-, middle-, and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems, and to evaluate if improved utilization of preventive measures will reduce the burden.

Low incidence of deep vein thrombosis in critically ill medical patients in Thais: a prospective study.

Background: Critically ill medical patients face a heightened risk of developing venous thromboembolism. In Thailand, routine thromboprophylaxis is not employed. The incidence of deep vein thrombosis (DVT) in the medical intensive care unit (ICU) has not been elucidated in the Thai population. Objectives: The aims were to evaluate the incidence of DVT and identify associated risk factors in critically ill medical patients. Methods: A single-center, prospective cohort study was conducted from 2019 to 2020. Consecutive patients underwent screening for proximal DVT by duplex ultrasound of both legs. Results: A total of 200 patients were enrolled, with 115 being male (57%). The mean (SD) age was 66.5 (16.4) years. The mean (SD) Acute Physiology and Chronic Health Evaluation II score was 27 (8). The cumulative incidence of DVT over 5 days was 7% (95% CI, 3.4%-10.6%). No clinically or radiologically diagnosed pulmonary embolism occurred in patients with DVT. No independent risk factor associated with DVT was identified. Hospital mortality in those with and those without DVT was 42.9% and 32.3%, respectively. There was no significant difference in the length of ICU or hospital stay or inpatient mortality between those with and those without DVT. Conclusion: Without thromboprophylaxis, the incidence of DVT in the Thai population remains low. A strategy of screening ultrasound 5 to 7 days after admission to the ICU may be a suitable alternative to anticoagulant prophylaxis in critically ill Thai patients without symptoms of venous thromboembolism.

Site-directed mutagenesis of tissue factor pathway inhibitor-binding exosite D60A on factor VII results in a new factor VII variant with lower coagulant activity.

Background: Recombinant factor (F)VIIa (rFVIIa) has been approved by the US Food and Drug Administration for the treatment of hemophilia A and B with inhibitors and congenital FVII deficiency. Moreover, the investigational uses of rFVIIa are becoming of interest since it can be used to treat various clinical bleeding conditions. However, there is evidence showing that rFVIIa is a potent procoagulant agent that potentially leads to an increased risk of thrombotic complications. Objectives: To design a new rFVII with lower coagulant activity that could potentially be used as an alternative hemostatic agent aiming to minimize the risk of thrombogenicity. Methods: D60A was introduced into the F7 sequence by polymerase chain reaction-based mutagenesis. Wild type (WT) and D60A were generated in human embryonic kidney 293T cells by stable transfection. FVII coagulant activities were determined by amidolytic cleavage of the FVIIa-specific substrate, 2-step FXa generation, thrombin generation (TG), and clot-based assays. Results: WT and D60A demonstrated similar FVIIa amidolytic activity. However, D60A showed approximately 50% activity on FX activation and significantly longer lag time in the TG assay than that shown by WT. The clotting time produced by D60A spiked in FVII-deficient plasma was significantly prolonged than that of WT. Additionally, the ex vivo plasma half-lives of WT and D60A were comparable. Conclusion: D60A demonstrated lower coagulant activities, most likely due to the weakening of FX binding, leading to impaired FX activation and delayed TG and fibrin formation. Considering that a plasma FVII level of 15% to 25% is adequate for normal hemostasis, D60A is a molecule of interest for future development of an rFVII with a lesser extent of thrombogenicity.

International Society on Thrombosis and Haemostasis clinical practice guideline for treatment of congenital hemophilia A and B based on the Grading of Recommendations Assessment, Development, and Evaluation methodology.

BACKGROUND: Hemophilia is a rare congenital bleeding disorder that results from complete or partial deficiency of blood coagulation factor (F)VIII (hemophilia A) or FIX (hemophilia B) due to pathogenic variants in their coding genes. Hemophilia requires complex management. To date, there is no evidence-based clinical practice guideline on hemophilia treatment based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. OBJECTIVES: This evidence-based clinical practice guideline from the International Society on Thrombosis and Haemostasis aims to provide an overview of evidence and support patients, caregivers, hematologists, pediatricians, other clinicians, researchers, and stakeholders in treatment decisions about congenital hemophilia A and B. METHODS: The International Society on Thrombosis and Haemostasis formed a multidisciplinary guideline panel of physicians and patients with global representation, balanced to minimize potential bias from conflicts of interest. The panel prioritized a set of clinical questions and outcomes according to their importance for clinicians and patients. A methodological team supported the guideline development process, including searching for evidence and performing systematic reviews. The GRADE approach was used, including GRADE Evidence to Decision frameworks. The recommendations were subject to public comment. RESULTS: The panel selected 13 questions, of which 11 addressed the treatment of hemophilia A and 2 the treatment of hemophilia B. Specifically, the panel addressed questions on prophylactic and episodic treatment with FVIII concentrates, bypassing agents, and nonfactor therapy (emicizumab) for hemophilia A (with and without inhibitors) as well as immune tolerance induction for hemophilia A. For hemophilia B, the panel addressed questions on prophylactic and episodic treatment of bleeding events with FIX concentrates. Agreement was reached for all 13 recommendations, of which 7 (54%) were based on evidence from randomized clinical trials, 3 (23%) on observational studies, and 3 (23%) on indirect comparisons. CONCLUSION: Strong recommendations were issued for prophylactic over episodic treatment for severe and moderately severe hemophilia A and B. Only conditional recommendations were issued for the remaining questions. Future research should focus on direct treatment comparisons and the treatment of hemophilia B with and without inhibitors. Future updates of this guideline will provide an updated evidence synthesis on the current questions and focus on new FVIII and FIX concentrates, novel nonfactor therapies, and gene therapy for severe and nonsevere hemophilia A and B.

Unmet needs and barriers in venous thromboembolism education and awareness among people living with cancer: a global survey.

BACKGROUND: Venous thromboembolism (VTE) is a major preventable cause of morbidity, disability, and mortality in subjects with cancer. A global appraisal of cancer-associated VTE education and awareness is not available. OBJECTIVES: To evaluate VTE-related education, awareness, and unmet needs from the perspective of people living with cancer using a quantitative and qualitative approach. METHODS: This cross-sectional study used data from an online-based survey covering multidimensional domains of cancer-associated VTE. Data are presented descriptively. Potential differences across participant subgroups were explored. RESULTS: Among 2262 patients with cancer from 42 countries worldwide, 55.3% received no VTE education throughout their cancer journey, and an additional 8.2% received education at the time of VTE diagnosis only, leading to 63.5% receiving no or inappropriately delayed education. When education was delivered, only 67.8% received instructions to seek medical attention in case of VTE suspicion, and 36.9% reported scarce understanding. One-third of participants (32.4%) felt psychologically distressed when becoming aware of the potential risks and implications connected with cancer-associated VTE. Most responders (78.8%) deemed VTE awareness highly relevant, but almost half expressed concerns about the quality of education received. While overall consistent, findings in selected survey domains appeared to numerically differ across age group, ethnicity, continent of residence, educational level, metastatic status, and VTE history. CONCLUSION: This study involving a large and diverse population of individuals living with cancer identifies important unmet needs in VTE-related education, awareness, and support across healthcare systems globally. These findings unveil multilevel opportunities to expedite patient-centered care in cancer-associated VTE prevention and management.

ASH living guidelines on use of anticoagulation for thromboprophylaxis in patients with COVID-19: executive summary.

COVID-19-related critical and acute illness are associated with an increased risk of venous thromboembolism (VTE). These evidence-based recommendations of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other healthcare professionals in decisions about the use of anticoagulation for thromboprophylaxis in patients with COVID-19-related critical illness, acute illness, and those being discharged from the hospital, who do not have suspected or confirmed VTE. ASH formed a multidisciplinary panel, including three patient representatives, and applied a conflicts of interest management policy to minimize potential bias. The Michael G. DeGroote Cochrane Canada and MacGRADE Centres at McMaster University supported the guideline development process, including performing systematic evidence reviews (up to June 2023). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess certainty of the evidence and make recommendations, which were subject to public comment. This is an executive summary of three updated recommendations that have been published which concludes the living phase of the guidelines. For critically ill patients with COVID-19, the panel issued conditional recommendations in favor of (a) prophylactic-intensity over therapeutic-intensity anticoagulation and (b) prophylactic-intensity over intermediate-intensity anticoagulation. For acutely ill patients with COVID-19, conditional recommendations were made in favor of (a) prophylactic-intensity over intermediate-intensity anticoagulation and (b) therapeutic-intensity over prophylactic-intensity anticoagulation. The panel also issued a conditional recommendation against the use of post-discharge extended pharmacologic thromboprophylaxis. These three conditional recommendations were made based on low or very low certainty in the evidence, underscoring the need for additional, high-quality randomized controlled trials in patients with COVID-19-related illness.

Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls.

Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.

Practices and challenges for hemophilia management under resource constraints in Thailand.

Hemophilia is an inherited bleeding disorder caused by deficiency of a specific coagulation factor. Factor VIII deficiency is responsible for hemophilia A while factor IX deficiency is responsible for hemophilia B. As per the 2020 annual global survey by the World Federation of Hemophilia, only 1828 Thai hemophiliacs have been registered to the national healthcare system. The reason for the low number is the underdiagnosis which is a major concern in the real-world practice among Asian countries. In Thailand, most hemophiliacs are diagnosed by general practitioners, pediatricians or internists at rural hospitals and are referred to hemophilia specialists at the Hemophilia Treatment Centers (HTCs). Despite the challenges pertaining to infrastructure and cost of treatment, Thailand has progressed substantially in providing the required hemophilia care, as evidenced by an evolution in acquiring and sharing knowledge as well as collaborative efforts among multiple stakeholders over the past three decades. In this letter-to-the-editor, the authors have summarized the practices for and challenges faced with hemophilia management in Thailand.