Emicizumab is a bispecific monoclonal antibody that bridges activated factor IX and factor X to replace the function of missing activated factor VIII, thereby restoring hemostasis. In a phase 3, ...multicenter trial, we investigated its use as prophylaxis in persons who have hemophilia A without factor VIII inhibitors.
We randomly assigned, in a 2:2:1 ratio, participants 12 years of age or older who had been receiving episodic treatment with factor VIII to receive a subcutaneous maintenance dose of emicizumab of 1.5 mg per kilogram of body weight per week (group A) or 3.0 mg per kilogram every 2 weeks (group B) or no prophylaxis (group C). The primary end point was the difference in rates of treated bleeding (group A vs. group C and group B vs. group C). Participants who had been receiving factor VIII prophylaxis received emicizumab at a maintenance dose of 1.5 mg per kilogram per week (group D); intraindividual comparisons were performed in those who had participated in a noninterventional study.
A total of 152 participants were enrolled. The annualized bleeding rate was 1.5 events (95% confidence interval CI, 0.9 to 2.5) in group A and 1.3 events (95% CI, 0.8 to 2.3) in group B, as compared with 38.2 events (95% CI, 22.9 to 63.8) in group C; thus, the rate was 96% lower in group A and 97% lower in group B (P<0.001 for both comparisons). A total of 56% of the participants in group A and 60% of those in group B had no treated bleeding events, as compared with those in group C, who all had treated bleeding events. In the intraindividual comparison involving 48 participants, emicizumab prophylaxis resulted in an annualized bleeding rate that was 68% lower than the rate with previous factor VIII prophylaxis (P<0.001). The most frequent adverse event was low-grade injection-site reaction. There were no thrombotic or thrombotic microangiopathy events, development of antidrug antibodies, or new development of factor VIII inhibitors.
Emicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no prophylaxis among persons with hemophilia A without inhibitors; more than half the participants who received prophylaxis had no treated bleeding events. In an intraindividual comparison, emicizumab therapy led to a significantly lower bleeding rate than previous factor VIII prophylaxis. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 3 ClinicalTrials.gov number, NCT02847637 .).
Background: Reagent‐supported thromboelastometry with the rotation thrombelastography (e.g. ROTEM®) is a whole blood assay that evaluates the visco‐elastic properties during blood clot formation and ...clot lysis. A hemostatic monitor capable of rapid and accurate detection of clinical coagulopathy within the resuscitation room could improve management of bleeding after trauma. Objectives: The goals of this study were to establish whether ROTEM correlated with standard coagulation parameters to rapidly detect bleeding disorders and whether it can help to guide transfusion. Methods: Ninety trauma patients were included in the study. At admission, standard coagulation assays were performed and ROTEM parameters such as clot formation time (CFT) and clot amplitude (CA) were obtained at 15 min (CA15) with two activated tests (INTEM, EXTEM) and at 10 min (CA10) with a test analyzing specifically the fibrin component of coagulation (FIBTEM). Results: Trauma induced significant modifications of coagulation as assessed by standard assays and ROTEM. A significant correlation was found between prothrombin time (PT) and CA15‐EXTEM (r = 0.66, P < 0.0001), between activated partial thromboplastin time and CFT‐INTEM (r = 0.91, P < 0.0001), between fibrinogen level and CA10‐FIBTEM (r = 0.85, P < 0.0001), and between platelet count and CA15‐INTEM (r = 0.57, P < 0.0001). A cutoff value of CA15‐EXTEM at 32 mm and CA10‐FIBTEM at 5 mm presented a good sensitivity (87% and 91%) and specificity (100% and 85%) to detect a PT > 1.5 of control value and a fibrinogen less than 1 g L−1, respectively. Conclusions: ROTEM is a point‐of‐care device that rapidly detects systemic changes of in vivo coagulation in trauma patients, and it might be a helpful device in guiding transfusion.
Blood loss and uncontrollable bleeding are major factors affecting survival in trauma patients. Because treatment with antifibrinolytic drugs may be effective, early detection of hyperfibrinolysis ...with rotation thrombelastography (ROTEM®) may be beneficial.
Eighty-seven trauma patients were included in this prospective observational study. Blood samples were collected at admission. After in vitro activation with tissue factor (EXTEM) and inhibition with aprotinin (APTEM), ROTEM® parameters including maximal clot firmness (MCF) and clot lysis index at 30 min (CLI30) were determined. Hyperfibrinolysis was defined as a euglobulin lysis time (ELT) <90 min. Threshold for ROTEM® parameters were determined with receiver-operating characteristic curves (ROC) analysis according to the ELT results.
ELT was determined in a subgroup of 23 patients. In this group of patients, ROC analysis showed that for a threshold of 18 mm (MCF-EXTEM), 71% (CLI30) and 7% (increase of MCF-APTEM), sensitivity was, respectively, 100%, 75%, and 80% with a specificity of 100%. With the application of these thresholds to the whole trauma cohort, ROTEM® analysis detected hyperfibrinolysis in five patients 6%, 95% confidence interval (CI): 2–13%. As expected, patients with hyperfibrinolysis were more severely injured (median Injury Severity Score: 75 vs 20, P<0.05), had greater coagulation abnormalities international normalized ratio (INR): 8.2 vs 1.3, P<0.05; fibrinogen: 0.0 vs 2.2 g litre−1, P<0.05, and a higher mortality rate (100%, CI: 48–100% vs 11% CI: 5–20%, P<0.05).
ROTEM® provided rapid and accurate detection of hyperfibrinolysis in severely injured trauma patients.
Background
Prophylactic replacement with factor concentrate is the optimal treatment for persons with severe haemophilia to avoid or minimize bleeding. This ultimately prevents or reduces joint ...disease and improves life expectancy and quality of life towards values matching those in the normal population. However, uncertainty still exists around the optimal regimens to be prescribed for prophylaxis. An increasing number of treating physicians and patients are showing interest in patient‐tailored approaches to prophylaxis, which aim to harmonize the prophylaxis regimen with the patients’ bleeding phenotype, levels of physical activity and a variety of other variables.
Methods
A modified Delphi technique was adopted to generate consensus. The expert panel met in person to set the objectives, be trained on the Delphi technique and agree on the desired level of consensus. Three iterations were used to identify the targets, the scenarios and their combinations.
Results
Twenty‐eight scenarios and eight target levels were identified and used to issue recommendations. The panel reached the desired level of consensus on positive or negative recommendations. Areas where consensus was not reached were identified and proposed as areas for future research. Prospective assessment of the validity of most of the proposed targets is recommended.
Conclusions
We have generated, by expert consensus, target plasma levels of factor concentrate to be used to tailor treatment for persons with haemophilia.
Summary
Most health care professionals involved in the management of people with haemophilia (PWH) believe that exercise is beneficial and its practice is widely encouraged. This article aims to ...demonstrate that appropriate exercise (adapted to the special needs of the individual PWH) may be beneficial for all PWH through improved physical, psychosocial and medical status. Based on evidence gathered from the literature, many PWH, particularly those using long‐term prophylaxis or exhibiting a mild/moderate bleeding phenotype, are as active as their healthy peers. PWH experience the same benefits of exercise as the general population, being physically healthier than if sedentary and enjoying a higher quality of life (QoL) through social inclusion and higher self‐esteem. PWH can also gain physically from increased muscle strength, joint health, balance and flexibility achieved through physiotherapy, physical activity, exercise and sport. Conversely, very little data exist on activity levels of PWH in countries with limited resources. However, regarding specific exercise recommendations in PWH, there is a lack of randomized clinical trials, and consequently formal, evidence‐based guidelines have not been produced. Based on published evidence from this review of the literature, together with the clinical experience of the authors, a series of recommendations for the safe participation of PWH in regular physical activities, exercises and sport are now proposed. In summary, we believe that appropriately modified programmes can potentially allow all PWH to experience the physical and psychosocial benefits of being physically active which may ultimately lead to an improved QoL.
Introduction
For individuals with haemophilia A, prophylaxis with factor VIII (FVIII) is typically directed towards trough activity >1 IU/dL; however, some patients still experience spontaneous ...bleeding events (sBEs).
Aim
Aims were to evaluate relationships of endogenous thrombin potential (ETP) and FVIII:C with occurrence of clinical bleeding.
Methods
GENA‐21 was a prospective, open‐label, phase IIIb study investigating the safety and efficacy of Nuwiq® (human‐cl rhFVIII) in previously treated adults with severe haemophilia A. The study included a 72‐hour pharmacokinetic (PK) evaluation phase and a 6‐month personalized prophylaxis phase in which treatment was guided by PK parameters. This subanalysis assessed FVIII:C by one‐stage assay and ETP by thrombin generation assay in blood samples.
Results
Baseline mean ETP was lower in the 7 patients who experienced sBEs during personalized prophylaxis versus 25 who did not (n = 32 with data from PK phase and prophylaxis phase; P = .0002). During personalized prophylaxis (n = 49), only patients with lower median trough ETP experienced sBEs (8/49 patients; ROC AUC = 0.9421; P < .0001); there was no significant relationship for FVIII:C in predicting sBEs (ROC AUC = 0.5838; P = .4750). Directly following infusion of human‐cl rhFVIII, ETP was lower in patients who experienced sBEs versus those who did not (P = .0002), whereas FVIII:C did not differ significantly between these groups.
Conclusions
In adults with severe haemophilia A and reduced thrombin generation, increased frequency of spontaneous bleeding was observed irrespective of trough FVIII levels. Thus, personalized prophylaxis should take into account variables other than FVIII:C. Large prospective trials are needed to verify ETP as a marker for spontaneous bleeding.
Patients with haemophilia can now look forward to greater life expectancy than ever before – a development that can be attributed to improved healthcare strategies and more effective treatments. In ...the last few decades, the treatment of haemophilia patients with inhibitors has also witnessed dramatic improvements through the development of bypassing agents, including recombinant activated factor VII (rFVIIa, NovoSeven®; Novo Nordisk, Bagsværd, Denmark). Growing evidence suggests that early initiation of treatment with rFVIIa results in greater haemostatic efficacy with fewer doses, leading to improved overall outcome. The new NovoSeven® room temperature stable formulation has been designed to optimize on‐demand treatment by facilitating early initiation of therapy for haemorrhagic episodes, which brings the potential benefits of faster bleed resolution, reduced frequency of re‐bleeding and reduced product consumption. This is particularly important for inhibitor patients, in whom orthopaedic complications are more severe than in non‐inhibitor patients. Early treatment might help improve musculoskeletal status and therefore reduce disability, which improves patient quality of life and aids integration into society. These clinical advantages are also accompanied by both short‐term and long‐term economic benefits. NovoSeven® room temperature stable might also improve patient compliance and treatment convenience, as patients can carry their treatment with them and administer it wherever they are, without being restricted by the need for a refrigerator and without the need to visit a hospital or to return home. The potential benefits of NovoSeven® room temperature stable make this new formulation a valuable addition to our armamentarium in the ongoing effort to improve haemophilia care.
Introduction
Aim: To use Pharmacokinetic (PK) simulations to illustrate potential differences in clinical outcomes between prophylaxis with conventional recombinant factor VIII (rFVIII) and rFVIIIFc, ...an extended half‐life rFVIII covalently fused to the Fc domain of human IgG1. Methods: Population PK estimates from 180 (rFVIIIFc) and 46 (rFVIII) severe haemophilia A patients were used to simulate FVIII activity over time at various rFVIIIFc dosing regimens compared to rFVIII 30 IU kg−1 three times weekly in a typical adult patient. Results: rFVIII dosed 3x30 IU kg−1 weekly gave trough levels of 2.7, 2.8 and 0.7 IU dL−1, and time spent below 1, 3 and 5 IU dL−1 of 0.2/1.2/2.3 days week−1. rFVIIIFc 2 x 45 IU kg−1 gave higher troughs (4.4 and 1.7 IU dL−1) and shorter time spent below 1, 3 and 5 IU dL−1 (0/0.6/1.3 days week−1), with same total factor consumption. rFVIIIFc 2 x 30 IU kg−1 gave similar troughs (3.0 and 1.2 IU kg−1) and time spent below 1, 3 and 5 IU dL−1 (0/1.0/2.1 days week−1), despite total factor consumption being reduced by one‐third. The same dose and interval of rFVIIIFc (3 x 30 IU kg−1) gave substantially higher troughs (7.8, 8.5 and 3.3 IU dL−1) and markedly shorter time spent below 1, 3 and 5 IU dL−1 (0/0/0.4 days week−1). Conclusion: The lower clearance of rFVIIIFc compared to conventional rFVIII gives rFVIIIFc the potential of improved bleed prevention and reduced injection frequency at similar factor consumption. Although additional clinical data are required to confirm the conclusions, the simulations clearly show the potential of rFVIIIFc of increased flexibility to tailor treatment to the individual patient, and to advance the standard of care in haemophilia.
Summary
Thirty per cent of patients with mild haemophilia A (MHA) present markedly different FVIII: C level when assayed by one‐stage clotting and two‐stage chromogenic assays. It is, therefore, a ...real clinical challenge to predict the individual bleeding risk of these patients. The aim of the present work was to study the relationship between the bleeding tendency of these patients with the results of a panel of phenotypic and genotypic tools. Thirty‐six patients with MHA were included in this multicentre prospective clinical study. The severity of bleeding symptoms was evaluated using the ISTH/SSC score. FVIII:C levels were measured using an activated partial thromboplastin time‐based one‐stage FVIII assay (FVIII: C1) and three commercial chromogenic kits (FVIII:CR). FVIII antigen levels, thrombin generation measurement and FVIII gene mutation analysis were also performed. Our results showed that a one‐stage FVIII: C assay cannot rule out the diagnosis of MHA, a combined use of FVIII:C1 with a FVIII:CR is suitable for detecting MHA. We observed that FVIII:CR results better reflected the clinical bleeding tendency of patients compared to FVIII:C1. We also observed a relationship between thrombin generation (TG) capacity and FVIII:CR of these patients. FVIII gene mutation analysis showed mutations previously reported in MHA patients with discrepant FVIII:C measurements, but with no predictive value of the individual bleeding phenotype of patients. Overall, we observed a relationship between chromogenic FVIII:C results, TG assay and bleeding tendency of patients with discrepant FVIII:C measurements, while FVIII:C1 was not well correlated with clinical bleeding phenotype in this particular population.
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