Arthropathy in people with mild haemophilia: Exploring risk factors.

BACKGROUND: It is important to investigate which factors are associated with the development of arthropathy in people with mild haemophilia (PWMH), in order to prevent it and to limit its effect on function and quality of life. PURPOSE: To examine the risk factors associated with arthropathy and to predict its presence and degree of involvement in our PWMH population. METHODS: This was an observational, cross-sectional cohort study of 85 PWMH under follow-up in our centre. Patient variables (age, body mass index, haemophilia type, genetic mutations, baseline factor levels, age at diagnosis, history of inhibitor, level of physical activity and years of practice, history of haemarthrosis and muscle haematoma) were analysed and related to the presence or absence of arthropathy and the degree of arthropathy (measured with HJHS and HEAD-US). Multivariable models were performed. RESULTS: Some 36.5% of PWMH had arthropathy. The variables that showed an independent association with the presence of arthropathy were patient age (median 42 years) and clotting factor levels (median 10.5 IU/dL). The risk of developing arthropathy increased by 7.9% for each additional year of age and decreased by 7.7% for each 1 IU/dL increase in clotting factor. When arthropathy developed, its degree of involvement might have been influenced by the type of physical activity performed. CONCLUSIONS: Patient age and factor levels appear to be the most determinant risk factors associated with the development of arthropathy in mild haemophilia. Monitoring joint health is desirable in this patient population. In patients with arthropathy, physical activities with a low risk of bleeding are the most recommended.

Applying World Health Organization 2020 guidelines on physical activity and sedentary behavior to people with hemophilia.

Introduction: The new World Health Organization (WHO) guidelines on physical activity incorporate new concepts, such as sedentary behavior, recommendations for specific age groups and for people living with chronic conditions and disability. This could be extrapolated for the first time to people with hemophilia (PWH) within the framework in which these recommendations are applicable. The benefits of physical activity for PWH include physical, psychological and social benefits.Areas covered: This is a narrative review of the literature. We searched the MEDLINE and the Cochrane Library for WHO guidelines and articles related to physical activity in PWH. For all population groups, the benefits of performing exercise outweigh the possible harms. In PWH, there is a perceived increased risk of bleeding associated with physical activity. However, research suggests that this risk is associated with trauma during activity rather than intensity of physical activity, which offers the most health benefits.Expert opinion: Given the hematological, physical and functional conditions of PWH are highly variable, individualized counseling is needed based on age, therapeutic strategy, degree of arthropathy and level of disability. In this article, we analyze the applicability of the WHO recommendations to PWH, which is important to further promote healthy lifestyle motivation.

What COVID-19 can mean for people with hemophilia beyond the infection risk.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic represents an unprecedented global health crisis. To combat its effects, many governments have opted for strategies of social isolation that involve a radical change in people's behavior. AREAS COVERED: For patients with hemophilia, the negative consequences of these measures can be greater, given they modify aspects of health care and lifestyles needed to counteract the adverse effects of hemophilia. The long-term consequences of the pandemic on patients with hemophilia are not well known. The aim of this special report is to show what COVID-19 could mean for this population, beyond the risk of infection. EXPERT OPINION: Considerations of the clinical, care, therapeutic, physical, nutritional, mental health, pain, and disability aspects that might be affected are included. Strategies are also suggested to minimize the effects that these issues can have on patients' lives. Patients, health professionals, and society as a whole must work together to mitigate the effects of the pandemic on people with hemophilia.

'Do not Do' Recommendations in Hemophilia.

BACKGROUND: It is important to discard those practices that do not add value. As a result, several initiatives have emerged. All of them try to improve patient safety and the use of health resources. PURPOSE: To present a compendium of "do not do recommendations" in the context of hemophilia. METHODS: A review of the literature and current clinical guidelines has been made, based on the best evidence available to date. RESULTS: The following 13 recommendations stand out: 1) Do not delay the administration of factor after trauma; 2) do not use fresh frozen plasma or cryoprecipitate; 3) do not use desmopressin in case of hematuria; 4) do not change the product in the first 50 prophylaxis exposures; 5) do not interrupt immunotolerance; 6) do not administer aspirin or NSAIDs; 7) do not administer intramuscular injections; 8) do not do routine radiographs of the joint in case of acute hemarthrosis; 9) Do not apply closed casts for fractures; 10) do not discourage the performance of physical activities; 11) do not deny surgery to a patient with an inhibitor; 12) do not perform instrumental deliveries in fetuses with hemophilia; 13) do not use factor IX (FIX) in patients with hemophilia B with inhibitor and a history of anaphylaxis after administration of FIX. CONCLUSION: The information mentioned previously can be useful in the management of hemophilia, from different levels of care. As far as we know, this is the first initiative of this type regarding hemophilia.

Evaluation of EC50 of factor VIII as predictor of prophylaxis efficacy in patients with severe haemophilia A.

Trough factor (F) VIII level is a not reliable bleeding risk indicator to predict prophylaxis efficacy in severe haemophilia A (SHA), therefore, accurate biomarkers are much needed. Thrombelastography (TEG) monitors both thrombin and clot formation addressing the global haemostatic status but its usefulness to tailor prophylaxis in haemophilia has been poorly evaluated. In this study, correspondence between individual pharmacodynamic/pharmacokinetic profile of FVIII and joint condition, physical activity and bleeding phenotype of SHA patients under prophylactic treatment was assessed. Nineteen SHA patients < 18 years old on long-term prophylaxis treatment with FVIII were studied in an observational cross-sectional study. Whole blood was withdrawn before FVIII administration and at five time-points after infusion for a TEG-based pharmacodynamic- and pharmacokinetic-study. Type of prophylaxis and joint condition at inclusion and physical activity as well as onset of treated spontaneous bleeding events in the previous two years were retrospectively assessed. Six patients had suffered at least one treated spontaneous bleeding event and were named as "bleeders". The rest were named as "non-bleeders". Only the half maximal effective concentration of FVIII (FVIII-EC50) for TEG parameters R-time, K-time and α-angle correlated with the bleeding phenotype being significantly higher in bleeders suggestive of a poorer response to FVIII. Poorer joint condition, trough FVIII levels or type of prophylaxis were not definitive predicting variables of bleeding phenotype. In conclusion, this study reveals FVIII-EC50 for the first time as a valuable biomarker to anticipate individual efficacy of prophylaxis in SHA.

Head trauma in the haemophilic child and management in a paediatric emergency department: Descriptive study.

INTRODUCTION: Haemophilia is one of the most common inherited bleeding disorders in the Emergency Department (ED). The most dangerous site of bleeding is the central nervous system. AIMS: To describe the characteristics of haemophiliacs arrived to our ED following a head trauma and to analyse the incidence of intracranial haemorrhage (ICH). MATERIALS AND METHODS: Retrospective, analytical, observational study, conducted in a Paediatric ED. We included haemophilic patients aged from birth to 16 years who consulted after a head trauma over a 6-year period. Data collected included age, type of haemophilia and head trauma, symptoms, prophylaxis status, CT imaging, treatment and number of visits to the ED. RESULTS: About 46 males and 85 episodes were analysed. The median age was 2.38 years. Severe haemophilia A was the most frequent type of disease (50%). All head injuries were mild, and the most frequent mechanism was a collision with an object (38.8%). In 62 episodes (72.9%) the patients were asymptomatic. The rest 23 events had symptomatology, being the most common headache (26%), emesis (21.7%) and drowsiness (17.4%). Head CT was obtained in 31 episodes, founding altered results in 10 (6 of them corresponding to ICH). All the patients with ICH had symptomatology. About 37 episodes required admission. CONCLUSION: Intracranial haemorrhage is one of the most dangerous events in haemophiliacs and it may occur after a head trauma. Our study suggests that, in case of head trauma, CT must be obtained in symptomatic patients and in those with additional risk factors. Asymptomatic patients must have prolonged observation.

The value of HEAD-US system in detecting subclinical abnormalities in joints of patients with hemophilia.

BACKGROUND: Prevention of hemarthrosis is the key factor in the adequate management of people with hemophilia (PWH). If hemarthrosis occurs, early diagnosis of joint damage is essential to make personalized treatments. This study is aimed at gaining an understanding of the ability of point-of-care ultrasound (US) using the `Hemophilia Early Arthropathy Detection with Ultrasound´ (HEAD-US) protocol to detect abnormalities in joints without history of hemarthrosis and clinically asymptomatic joints of PWH. METHODS: The sample included 976 joints from 167 PWH (mean age 24.86 years). Data were collected from routine practice over a 3-year period and analyzed based on history of hemarthrosis and results of clinical (HJHS 2.1) and HEAD-US examinations. RESULTS: In our series, 14% of patients exhibited HEAD-US signs of incipient arthropathy in joints with no history of bleeding and with a HJHS 2.1 score of 0. The most severely involved joint was the right ankle. Synovitis, articular cartilage and subchondral bone damage scores in joints with subclinical findings were slower than in joints with previous hemarthroses or HJHS 2.1 > 1 Conclusions: Our study demonstrates that HEAD-US is better than hemarthrosis records and the HJHS 2.1 scale in detecting the early signs of joint damage in PWH.

Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A.

INTRODUCTION: Primary factor VIII (FVIII) prophylaxis is the optimal treatment in children with severe haemophilia A. They are expected to benefit from extended half-life (T1/2 ) FVIII coverage by reduced infusion frequency while maintaining haemostatic efficacy. AIMS: To determine immunogenicity, pharmacokinetics (PK), efficacy, safety and quality of life of prophylaxis with a polyethylene glycol (peg)-ylated FVIII (BAX 855) based on full-length recombinant FVIII (ADVATE) in paediatric previously treated patients (PTPs) with severe haemophilia A. METHODS: PTPs <12 years without history of FVIII inhibitors received twice-weekly infusions of 50 ± 10 IU kg-1 BAX 855 for ≥50 exposure days. Prophylactic dose increases to ≤80 IU kg-1 were allowed under predefined conditions. PK was evaluated after single infusions of 60 ± 5 IU kg-1 . RESULTS: T1/2 and mean residence time were extended 1.3- to 1.5-fold compared to ADVATE (n = 31), depending on the analysis used. The point estimate for the mean annualized bleeding rate in 66 subjects receiving a median of 1.9 weekly infusions of 51.3 IU kg-1 of BAX 855 each was 3.04 (median 2.0); 1.10 (median 0) for joint and 1.16 (median 0) for spontaneous bleeds. Overall, 38% of subjects had zero bleeds. No bleeds were severe. Haemostatic efficacy was rated excellent or good for 90% of bleeds; 91% were treated with one or two infusions. In 8/14 subjects all target joints resolved. No subject developed FVIII inhibitors or persistent binding antibodies that affected safety or efficacy. No adverse reactions occurred. CONCLUSION: Twice-weekly prophylaxis with BAX 855 was safe and efficacious in paediatric PTPs with severe haemophilia A.

European retrospective study of real-life haemophilia treatment.

INTRODUCTION: Haemophilia treatment varies significantly between individuals, countries and regions and details of bleed rates, factor consumption and injection frequency are often not available. AIM: To provide an overview of the FVIII/FIX treatment practice and outcome for patients with haemophilia A (HA) or haemophilia B (HB) across Europe. METHODS: Non-interventional, 12-month retrospective study where anonymized data were retrieved from haemophilia centres/registers in Belgium, France, Germany, Italy, Spain, Sweden and the United Kingdom. Male patients (all ages) receiving coagulation factor treatment 24 months prior to the study, with basal FVIII/FIX levels ≤5 IU dL-1 , without inhibitors, were included. Data were summarized descriptively. RESULTS: In total, 1346 patients with HA and 312 with HB were included in the analysis; 75% and 57% had severe disease (FVIII/FIX < 1 IU dL-1 ) respectively. Prophylaxis was most common for severe haemophilia, especially for children, whereas on-demand treatment was more common for moderate haemophilia in most countries. The mean (SD) prescribed prophylactic treatment ranged from 67.9 (30.4) to 108.4 (78.1) (HA) and 32.3 (10.2) to 97.7 (32.1) (HB) IU kg-1 per week, across countries. Most patients on prophylaxis were treated ≥3 times/week (HA) or two times/week (HB). The median annual bleeding rate (ABR) for patients on prophylaxis ranged from 1.0 to 4.0 for severe HA, and from 1.0 to 6.0 for severe HB, while those with moderate haemophilia generally had slightly higher ABRs. Median ABRs for on-demand-treated severe HA ranged from 4.5 to 18.0, and for HB, 1.5 to 14.0. CONCLUSION: Treatment practice varied greatly between centres and countries and patients treated on-demand and prophylactically both experienced bleeds, emphasizing the need for further optimization of care.

Coexistence of Factor VII Deficiency and Hereditary Spastic Paraplegia in Two Siblings.

We present the case of two patients aged 12 years and 7 years who were referred to our hospital for factor VII deficiency inherited in an autosomal recessive pattern, who had suffered from previous multiple joint haemarthroses. They presented with fine motor symptoms and difficulty in walking. During physical examination we observed neurological symptoms (general hypotonia, muscular hypotrophy, exaggerated tendon reflexes, pes cavus, and spastic gait). Given that the symptoms were not justified by the deficiency of coagulation factor VII and on suspicion of hereditary spastic paraplegia (HSP), tests were carried out. Findings from the tests confirmed the diagnosis of HSP (axonal degeneration of the central motor pathway and pyramidal tracts), further complicated by mixed neuropathy. This disease was also inherited in an autosomal recessive pattern with no direct genetic association with factor VII deficiency. Neurological symptoms had gone unnoticed due to a history of multiple joint haemarthrosis; musculoskeletal examination led to a satisfactory differential diagnosis. Haematological prophylaxis was commenced with rFVIIa at 30 mcg/kg, three days per week. A rehabilitation programme was prescribed so that the patient could remain independent for as long as possible, based on orthosis, physiotherapy, and occupational therapy. Response to treatment is currently satisfactory and no new bleeding has presented. As far as we are aware, the coexistence of these two diseases (factor VII deficiency and HSP) has not been previously reported in the literature.

Cost analysis of prophylaxis with activated prothrombin complex concentrate vs. on-demand therapy with activated factor VII in severe haemophilia A patients with inhibitors, in Spain.

OBJECTIVE: A cost analysis model was developed to compare annual cost of prophylaxis with activated prothrombin complex concentrate (aPCC) vs. on-demand therapy with activated recombinant factor VII (rFVIIa) in severe haemophilia A patients with inhibitors for the Spanish National Health System (NHS). METHODS: Model inputs were drug cost for prophylaxis (aPCC) and for on-demand treatment (rFVIIa or aPCC); bleeding episodes management (excluding bypassing agent cost); surgical costs and disease management (excluding bleeding episodes). Annual bleeding episodes treated on-demand was assumed to be 25, whereas breakthrough bleeds on prophylaxis was 8. Dose for prophylaxis was 75.72 U kg(-1) , three times per week. The total on-demand dose/bleeding episode was 679.66 µg kg(-1) (rFVIIa) and 235.28 U kg(-1) (aPCC). The average bleeding cost (€2998) considered different bleeding sites (62.5% joints, 28.6% muscles and soft tissues, 3.6% mucocutaneous tissues and 5.4% other areas). A 7.5% deduction was applied to ex-factory drug prices. Unitary costs (€2013) derived from local databases. Sensitivity analyses (SA) were performed. RESULTS: Annual cost of aPCC prophylaxis (€524,358) was 16% lower than on-demand treatment with rFVIIa (€627,876). Yearly drug costs were €497,017 for aPCC (€73,166 for on-demand treatment and €423,850 for prophylaxis), and €548,870 for rFVIIa. Disease management cost (€2645 per year) and surgical procedures (€708 per year) were common for both strategies. In the SA prophylactic treatment led to savings between €26,225 and €-1,008,960. CONCLUSION: Prophylaxis with aPCC reduces number of bleeding episodes in severe haemophilia A patients with inhibitors. aPCC prophylaxis resulted in savings in excess of €100,000 per-patient per year, being 16% less costly than on-demand treatment with rFVIIa, for the Spanish NHS.

Effects of thrombopoietin receptor agonists on procoagulant state in patients with immune thrombocytopenia.

Thrombopoietin receptor agonists (TPO-RA) have recently been introduced for the treatment of immune thrombocytopenia (ITP), an anti-platelet-antibodies autoimmune disease. The observation of a low frequency of bleeding episodes despite their thrombocytopenia suggests the existence of a compensatory mechanism. This study aimed to evaluate the effect of TPO-RA treatment on platelet function and on the procoagulant state in ITP patients before (ITP-bR) and after responding (ITP-aR) to treatment. Plasma- and microparticle (MP)-associated procoagulant capacity from ITP patients was similar before and after responding to the TPO-RA regimen but higher than the healthy control values. High MP-associated procoagulant activity did not seem to be due to increased platelet activation, since platelet stimulation by agonists was reduced in ITP-bR and ITP-aR patients. It could be related to increased platelet apoptosis, evaluated in terms of surface phosphatidylserine (PS), observed in both ITP groups. In summary, TPO-RA treatment increased platelet count but did not ameliorate their function and did not change plasma- and MP-associated procoagulant state of ITP patient responders to this therapy.

Surgery in haemophilia patients with inhibitors, with special emphasis on orthopaedics: Madrid experience.

We report on a series of 92 surgical procedures (90 patients). It includes 35 orthopaedic procedures (33 patients) and 57 non-orthopaedic procedures (57 patients). The orthopaedic procedures include 27 radiosynovectomies (minor surgery) and eight major orthopaedic procedures. The non-orthopaedic procedures include 52 minor interventions and five major procedures. The average age of patients was 34 years (range: 8-56), and the average follow-up time was 3 years (range: 1-6). Of the 92 surgical procedures, 42 were performed with activated prothrombin complex concentrates [factor eight inhibitor bypassing agent (FEIBA)] and 47 with recombinant-activated factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark). Regarding FEIBA treatment in minor surgery, the initial dose was 100 IU kg(-1). After 6 h, we continued with 50 IU kg(-1) every 12 h for at least 4 days (radiosynovectomies). In minor non-orthopaedic procedures, the dose was continued until day 14. In patients who underwent surgery with the haemostatic control achieved by means of rFVIIa, the initial dose of rFVIIa in minor procedures (both orthopaedic and non-orthopaedic) was 90-120 microg kg(-1). In postoperative days 1-5, the dose was 2-4 x 90-120 microg kg(-1) q3-6 h for 24 h. In major procedures (both orthopaedic and non-orthopaedic), the dose was 120 microg kg(-1) pre-operatively, 120 microg kg(-1) q 3 h day 2/day 3-5, and then 90-120 microg kg(-1) q 6 h until day 14. There were 87 good results, four fair results and one poor result. Our study has shown that haemophilic patients with inhibitors requiring surgery can undergo orthopaedic and non-orthopaedic procedures with a high expectation of success. In other words, surgery (orthopaedic and non-orthopaedic) is now possible in haemophilia patients with inhibitors, leading to an improved quality of life for these patients.