Global Hemostatic Methods to Tailor Treatment With Bypassing Agents in Hemophilia A With Inhibitors- A Single-Center, Pilot Study.

For patients with hemophilia A and high-titer inhibitors treated with bypassing agents there are no reliable methods to assess treatment effect. We investigated the utility of global hemostatic methods in assessing treatment with bypassing agents (rFVIIa or activated prothrombin complex [aPCC]). All patients with hemophilia A and inhibitors followed at the Coagulation Unit or the Pediatric Coagulation Unit at Karolinska University Hospital aged 6 years and above were eligible for this noninterventional study. Baseline plasma samples were spiked with bypassing agents in increasing concentrations (aPCC 50 U/kg, 100 U/kg, 150 U/kg, and rFVIIa 90 µg/kg and 270 µg/kg) in vitro. For patients treated with factor concentrates or bypassing agents follow-up samples were collected (in vivo tests). The samples were analyzed using overall hemostatic potential (OHP), and calibrated automated thrombogram, Calibrated Automated Thrombogram (CAT). Nine patients with hemophilia A with inhibitors were included. Spiking with rFVIIa normalized the coagulation potential in 6/8 samples, in 3 only with high dose. Only one sample did not improve adequately after spiking with aPCC. The improvement in hemostasis was reliably shown by both CAT and OHP. The baseline potential was, however, more often measurable by OHP compared to CAT. Factor concentrate had been administered to 5 patients normalizing the hemostatic potential in vivo in 2 (without spiking). The hemostatic improvement induced by spiking with rFVIIa or aPCC is shown by OHP and CAT, but the results have to be evaluated in larger cohorts.

HRQoL and psychosocial aspects of burden on caregivers to children with moderate or severe von Willebrand disease.

INTRODUCTION: Von Willebrand disease (VWD) is the most widespread congenital bleeding disorder. Caregivers are highly involved in its treatment, and from the time of the child's bleeding diagnosis, they face new demands such as recognition of bleeds and treatment options. AIM: The aim of this study was to assess Health related quality of life (HRQoL) in caregivers of children with moderate and severe VWD in Sweden, and to describe the impact of psychosocial aspects on the burden. METHODS: A multicentre, cross-sectional study. The Short Form 36 Health Survey (SF-36) was used to assess HRQoL. Caregiver burden was measured using The HEMOphilia associated Caregiver Burden scale (HEMOCAB). Children´s clinical data were collected from the Swedish national registry for bleeding disorders. RESULTS: Seventy caregivers of children with moderate or severe VWD were included. Caregivers of children with moderate VWD scored significantly lower in the mental health domains on SF-36, compared to matched normative data. Psychosocial aspects that significantly impacted the caregiver burden negatively measured by HEMOCAB total score were: if the caregiver reported that VWD affected their life in general (p = .001), if the child was absent from preschool/school ≥2 day/12 months due to VWD (p = .002) or that VWD had a financial impact on the family (p = .001). CONCLUSION: This study contributes to knowledge about caregivers' HRQoL and highlights the situation of caregivers of children with moderate VWD. Furthermore, the caregiver burden was negatively affected by psychosocial aspects. Clinical follow-ups should include assessment of psychosocial aspects to identify caregivers that are at risk of high burden.

Haemophilia A and B - evaluation of the Swedish prophylactic regimen by magnetic resonance imaging.

INTRODUCTION: Sweden has been a pioneer in the prophylactic treatment of haemophilia. Magnetic resonance imaging (MRI) can detect small changes in joints and can therefore give an indication of a risk of developing arthropathy. AIM: To use MRI to evaluate the outcome of the Swedish 'high-dose regimen' and correlate the findings to age, bleeds, joint score and physical activity. METHODS: The study group comprised 48 Swedish male patients, mean age 25 years (range 12-33 years), with severe or moderate haemophilia A or B. Data on the Haemophilia Joint Health Score (HJHS) were available and physical activity was evaluated by a self-reported questionnaire. RESULTS: MRI score was recorded in 188 joints. Twenty out of 48 patients had a score of ≥1 (range 1-13) in 31 joints of which 3/31 scores were in the knees and 28/31 in the ankles. No correlation was found between the number of recorded bleeds and the MRI score or between HJHS and MRI score. There was no correlation between the physical activity and the number of joint bleeds per se, but a trend (OR 3.0) that those most physically active (19/48; 39.6%), more frequently had an MRI score of ≥1 with an overweight for the right ankle. CONCLUSION: The Swedish prophylactic model offers protection against haemophilia joint arthropathy but will still not prevent osteochondral changes in some patients at young age. MRI of the ankles can signal risk of future arthropathy and indicate need to modify the prophylactic regimen.

Evaluating international Haemophilia Joint Health Score (HJHS) results combined with expert opinion: Options for a shorter HJHS.

INTRODUCTION: The Hemophilia Joint Health Score (HJHS) was developed to detect early changes in joint health in children and adolescents with haemophilia. The HJHS is considered by some to be too time consuming for clinical use and this may limit broad adoption. AIM: This study was a first step to develop a shorter and/or more convenient version of the HJHS for the measurement of joint function in children and young adults with haemophilia, by combining real-life data and expert opinion. METHODS: A cross-sectional multicenter secondary analysis on pooled data of published studies using the HJHS (0-124, optimum score 0) in persons with haemophilia A/B aged 4-30 was performed. Least informative items, scoring options and/or joints were identified. An expert group of 19 international multidisciplinary experts evaluated the results and voted on suggestions for adaptations in a structured meeting (consensus set at ≥ 80%). RESULTS: Original data on 499 persons with haemophilia from 7 studies were evaluated. Median age was 15.0 years [range 4.0-29.9], 83.2% had severe haemophilia and 61.5% received prophylaxis. Median (IQR) HJHS total was 6.0 (1.0-17.0). The items 'duration swelling' and 'crepitus' were identified as clinically less informative and appointed as candidates for reduction. CONCLUSION: Analysis of 499 children and young adults with haemophilia showed that the HJHS is able to discriminate between children and adults and different treatment regimens. Reduction of the items 'duration swelling' and 'crepitus' resulted in the HJHSshort , which had the same discriminative ability. Additional steps are needed to achieve a substantially shorter HJHS assessment.

Sports participation and physical activity in adult Dutch and Swedish patients with severe haemophilia: A comparison between intermediate- and high-dose prophylaxis.

INTRODUCTION: Differences in treatment and outcome have been reported for persons with haemophilia (PWH) on intermediate-dose (Dutch) and high-dose (Swedish) prophylaxis, but the potential influence of sports participation has not been considered. AIM: To compare sports participation and clinical outcome between adult Dutch and Swedish PWH. METHODS: Self-reported sports participation (type and frequency per week), physical functioning (SF-36PF : 100-0), joint status (HJHS: 0-144), perceived limitations (HALsum : 100-0) and physical activity (IPAQ) were recorded. Sports were classified according to National Haemophilia Foundation classification (5 categories, highest two were classified as high-risk sports). Sports participation and clinical outcome were compared according to country and age (18-22, 23-29, 30-40 years) using non-parametric tests and Spearman correlations (rho). RESULTS: Seventy-one adult PWH (NL: 43, SWE: 28) completed sports questionnaires (mean age: 26 years). All participants engaged in sports, including 59.2% in high-risk sports (33.9% twice weekly). Dutch PWH showed a significant age-related decline in (high-risk) sports participation (7x/wk in PWH 18-22 years to 2x/wk in PWH 30-40 years, P < 0.05), joint health (HJHS: median 2-15.5, P < 0.01) and physical functioning (SF-36PF : median 100 to 77.5, P < 0.01), while Swedish did not. Sports participation was not associated with bleeding (Spearman's rho = -0.119). CONCLUSION: All participants reported sports participation, including 59.2% in high-risk sports. Dutch PWH treated with intermediate-dose prophylaxis showed an age-related decline in sports participation, joint status and physical functioning, whereas Swedish PWH on high-dose prophylaxis did not. Sports participation was not associated with bleeding.

A ROTEM method using APTT reagent and tissue factor as the clotting activators may better define bleeding heterogeneity in moderate or severe haemophilia A (part I: Study in plasma samples).

Bleeding heterogeneity observed in haemophilia A (HA) may attribute to that the available monitoring methods cannot appropriately reflect the coagulation profile. The present study aimed to develop a global approach by changing the clotting initiation way in rotational thromboelastometry (ROTEM) assay. ROTEM was run in Factor VIII (FVIII)-immune-depleted plasma to which different concentrations of recombinant VIII (rFVIII) had been added, and also in 31 patients with HA. The clotting activators were APTT reagent (1.2 × 10-3 of the dose used in the original APTT method) and recombinant tissue factor (0.02 pmol/L). In FVIII-immune-depleted plasma spiked with rFVIII, maximum velocity of coagulation reliably mirrored the rFVIII levels. This dose-response disappeared after the samples were pre-incubated with an antibody against TFPI, protein S, activated prothrombin complex concentrate or rFVIIa known to favour the extrinsic activation. In the HA patients with FVIII 0-0.21 IU/mL, APTT and ROTEM outcomes varied in significant correlations to FVIII activity; however, this correlation became non-significant when only samples with FVIII 0-0.05 IU/mL were included. Conclusions: The decreased coagulation in HA mostly result from deficiency/absence of FVIII; other pro-/anti-thrombotic proteins are also influential. The multiple effects may cause a mismatch between bleeding phenotype and FVIII concentrations. The ROTEM assay with the clotting activators i.e., tiny doses of APTT reagent and TF are more effective than the original APTT method as regards the assay sensitivity to influence by VIII activity and also to that by other pro-/anti-thrombotic proteins, showing the whole coagulation picture behind the phenotypic heterogeneity in HA.

Risk Factors for the Progression from Low to High Titres in 260 Children with Severe Haemophilia A and Newly Developed Inhibitors.

In children with severe haemophilia A, inhibitors to factor VIII (FVIII) usually develop during the first 50 treatment exposure days and are classified as low or high titre depending on the peak inhibitor titre being greater or less than 5 Bethesda units/mL (BU/mL). Classification of the inhibitor may change with time, as some low-titre inhibitors progress to high titre following re-exposure to FVIII concentrate. The aim of this study was to investigate potential risk factors for such a progression in children with severe haemophilia A and newly diagnosed inhibitors. This study was a follow-up study of the PedNet Registry and included 260 children with severe haemophilia A and inhibitors born between 1990 and 2009 and recruited consecutively from 31 haemophilia centres. Clinical and laboratory data were collected from the date of each child's first positive inhibitor test for at least 3 years. At the time of first positive inhibitor test, 49% (n = 127) had low-titre inhibitors, with 50% of them progressing to high titre and only 25% maintaining low titres. The FVIII gene (F8) mutation type was known in 247 patients (95%), and included 202 (82%) null mutations. The progression to high-titre inhibitors was associated with null F8 mutations (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.0­6.5), family history of inhibitors (OR: 7.2; 95% CI: 1.8­28.4) and the use of high-dose immune tolerance induction, defined as ≥100 IU FVIII concentrate/kg/d (OR: 3.9; 95% CI: 1.5­10.0). These results suggest that high-dose immune tolerance induction should be avoided as the initial strategy in patients who develop low-titre FVIII inhibitors.

Intracranial haemorrhage in children and adolescents with severe haemophilia A or B - the impact of prophylactic treatment.

The discussion of prophylactic therapy in haemophilia is largely focused on joint outcomes. The impact of prophylactic therapy on intracranial haemorrhage (ICH) is less known. This study aimed to analyse ICH in children with haemophilia, with a focus on different prophylaxis regimens and sequelae of ICH. We conducted a multicentre retrospective and prospective study that included 33 haemophilia centres from 20 countries. Inclusion criteria were children and adolescents born between 1993 and 2014, with severe haemophilia A or B without inhibitors. Participants were categorized by prophylaxis regimen: full, partial or none, based on dose and dose frequency of regular infusions. The cohort study included 1515 children: 29 cases of ICH over 8038 patient years were reported. The incidence of ICH in the prophylaxis group, 0·00033 cases of ICH/patient year, was significantly lower compared to the no prophylaxis group, 0·017 cases of ICH/patient year (RR 50·06; P < 0·001) and the partial prophylaxis group, 0·0050 cases of ICH/patient year (RR 14·92; P = 0·007). In the on-demand-group, 8% (2/24) children with ICH died and 33% had long-term sequelae, including intellectual and behavioural problems, paresis and epilepsy. Children on regular, frequent prophylaxis have a low risk of ICH compared to those using non-frequent or no prophylaxis.

The second Team Haemophilia Education Meeting, 2016, Frankfurt, Germany.

The first Team Haemophilia Education (THE) Meeting was held on 7-8 May 2015 in Amsterdam, The Netherlands. It aimed to promote the optimal care of patients with haemophilia through education of the multidisciplinary treatment team. This was achieved by reviewing the latest developments in haemophilia management, considering how these can be implemented in the clinic to improve patient care and providing a platform for networking and debate for all haemophilia treatment team members. The second THE Meeting was held on 19-20 May in Frankfurt, Germany, and participants included doctors, nurses, physiotherapists, patient representatives and data management staff from 20 different countries. Topics covered the role of the multidisciplinary team in delivering the best haemophilia care, challenges in the management of haemophilia across Europe, available clotting factor treatments, future treatments and the use of genetics in advising carriers of haemophilia. This report is a summary of the key developments in haemophilia care presented by various investigators and healthcare professionals at THE Meeting 2016.

Increased inhibitor incidence in severe haemophilia A since 1990 attributable to more low titre inhibitors.

Many studies have reported an increased incidence of inhibitors in previously untreated patients (PUPs) with severe haemophilia A after the introduction of recombinant products. It was the objective of this study to investigate whether the inhibitor incidence has increased between 1990 and 2009 in an unselected cohort of PUPs with severe haemophilia A (FVIII< 1 %). Patients were consecutively recruited from 31 haemophilia treatment centres in 16 countries and followed until 50 exposure days or until inhibitor development. Inhibitor development was studied in five-year birth cohorts comparing cumulative incidences. Furthermore the risk for inhibitor development per five-year birth cohort was studied using multivariable Cox regression, adjusting for potential genetic and treatment-related confounders. A total of 926 PUPs were included with a total cumulative inhibitor incidence of 27.5 %. The inhibitor incidence increased from 19.5 % in 1990-1994 (lowest) to 30.9 % in 2000-2004 (highest; p-value 0.011). Low titre inhibitor incidence increased from 3.1 % in 1990-1994 to 10.5 % in 2005-2009 (p-value 0.009). High titre inhibitor incidences remained stable over time. After 2000, risk of all inhibitor development was increased with adjusted hazard ratios 1.96 (95 % CI 1.06-2.83) in 2000-2004 and 2.34 (1.42-4.92) in 2005-2009. Screening for inhibitors was intensified over this 20-year study period from a median of 1.9 to 2.9 tests/year before 2000 to 2.7 to 4.3 tests/year after 2000. In conclusion, the cumulative inhibitor incidence has significantly increased between 1990 and 2009. The high titre inhibitor incidence has remained stable.

Inhibitors in nonsevere haemophilia A: outcome and eradication strategies.

In nonsevere haemophilia A (HA) patients the presence of an inhibitor may exacerbate the bleeding phenotype dramatically. There are very limited data on the optimal therapeutic approach to eradicate inhibitors in these patients. We aimed to describe inhibitor eradication treatment in a large cohort of unselected nonsevere HA patients with inhibitors. We included 101 inhibitor patients from a source population of 2,709 nonsevere HA patients (factor VIII 2-40 IU/dl), treated in Europe and Australia (median age 37 years, interquartile range (IQR) 15-60; median peak titre 7 BU/ml, IQR 2-30). In the majority of the patients (71 %; 72/101) the inhibitor disappeared; either spontaneously (70 %, 51/73) or after eradication treatment (75 %, 21/28). Eradication treatment strategies varied widely, including both immune tolerance induction and immunosuppression. Sustained success (no inhibitor after rechallenge with factor VIII concentrate after inhibitor disappearance) was achieved in 64 % (30/47) of those patients rechallenged with FVIII concentrate. In high-titre inhibitor patients sustained success was associated with eradication treatment (unadjusted relative risk 2.3, 95 % confidence interval 1.3-4.3), compared to no eradication treatment. In conclusion, in nonsevere HA patients most inhibitors disappear spontaneously. However, in 35 % (25/72) of these patients an anamnestic response still can occur when rechallenged, thus disappearance in these patients does not always equal sustained response. Treatment for those requiring eradication has to be decided case by case, as one single approach is unlikely to be appropriate for all.

Individualizing prophylaxis in hemophilia: a review.

Prophylaxis is considered optimal care for patients with severe hemophilia to prevent bleeding, including hemarthroses, which may cause arthropathy with chronic pain, occupational impairment and progressive loss of mobility. Questions remain regarding the optimal delivery of prophylaxis including how to individualize prophylaxis and optimize outcomes for each patient. Designing a prophylactic regimen for severe hemophilia must account for each patient's unique disease course, bleeding pattern, presence/absence of joint damage, pharmacokinetic profile, level of physical activity and adherence to treatment. Standard weight-based prophylaxis regimens and regimens optimized by bleeding phenotype (i.e., patients are 'allowed' to bleed to dose optimization) fail to prevent complications in many patients. Pharmacokinetic-guided dosing enables precise adjustment of dosing level and frequency to maintain adequate hemostatic levels and prevent bleeding. Optimal outcomes, such as reducing or eliminating hemorrhages, preventing or minimizing joint damage, and improving quality of life, can be achieved through an individualized care approach.

Thrombin generation test in children and adolescents with chronic liver disease.

INTRODUCTION: The aim of this study was to evaluate if real-time thrombin generation assay provides additional information to assess the hemostatic balance in children with liver disease as compared to routine coagulation tests. PATIENTS AND METHODS: Sixty-three children with chronic liver disease were enrolled at our tertiary referral center for pediatric hepatology, eight whose routine coagulation tests gave abnormal results (Group A) and 55 whose test results were normal (Group B). Abnormal routine coagulation test was defined as at least one of the following: international normalized ratio≥1.4, activated partial thromboplastin time>44 sec., fibrinogen<1.5 g/L. Platelet-poor plasma was analyzed with the fluorogenic Calibrated Automated Thrombogram to test for thrombin generation, including endogenous thrombin potential. Further, routine coagulation tests and plasma levels of pro- and anticoagulant factors were measured. Twenty age-matched children without liver disease served as controls. RESULTS: The endogenous thrombin potential in the 55 patients with normal routine coagulation tests was not significantly different from that in controls. Group A had significantly lower levels not only of procoagulant factors (II, V, VII, X) but simultaneously also of the anticoagulant factors antithrombin, protein S free, and protein C. These patients had a reduced endogenous thrombin potential compared to Group B, in agreement with their routine coagulation test results. CONCLUSION: Thrombin generation analysis seems to give information on the hemostatic balance consistent with routine coagulation test results in children with liver disease. Further development and clinical evaluation of the method are warranted.

Antithrombin deficiency after prolonged asparaginase treatment in children with acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia (ALL) have several risk factors for deep venous thromboses (DVTs) such as central venous catheters and asparaginase (ASP), related antithrombin (AT) deficiency. After introduction of a new standard and intermediate-risk ALL treatment protocol with prolonged continuous ASP treatment, two symptomatic DVTs in 10 patients were observed at the Children's Hospital, Helsinki, Finland. To prevent further thrombotic complications yet ensuring continuous exposure to ASP, an AT substitution strategy was adopted in Helsinki. The same ALL treatment protocol is used without AT substitution in the other Nordic countries. In this retrospective study, we describe the effect of prolonged ASP treatment on AT and fibrinogen levels in children without AT substitution in Stockholm, Sweden (n = 39) and the AT substitution in children with AT activity below 0.55 kIU/l in Helsinki (n = 36, intervention group). The intervention group is compared with children treated similarly earlier in Helsinki without AT substitution (n = 10). The median lowest AT activity during the ASP treatment without AT substitution was 0.55 kIU/l. Fibrinogen level of 1.0 g/l or less was found in 14% of all routine samples during the ASP treatment. In the intervention group, 23 (64%) received AT concentrate. Two (20%) children had symptomatic DVT before initiation of the AT substitution and two (6%) thereafter. We conclude that most children are exposed to low AT activity during ASP treatment predisposing to thrombosis. The effect of prophylactic AT substitution remains unclear.

Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.

Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.

Intermediate-dose versus high-dose prophylaxis for severe hemophilia: comparing outcome and costs since the 1970s.

Prophylactic treatment in severe hemophilia is very effective but is limited by cost issues. The implementation of 2 different prophylactic regimens in The Netherlands and Sweden since the 1970s may be considered a natural experiment. We compared the costs and outcomes of Dutch intermediate- and Swedish high-dose prophylactic regimens for patients with severe hemophilia (factor VIII/IX < 1 IU/dL) born between 1970 and 1994, using prospective standardized outcome assessment and retrospective collection of cost data. Seventy-eight Dutch and 50 Swedish patients, median age 24 years (range, 14-37 years), were included. Intermediate-dose prophylaxis used less factor concentrate (median: Netherlands, 2100 IU/kg per year [interquartile range (IQR), 1400-2900 IU/kg per year] vs Sweden, 4000 IU/kg per year [IQR, 3000-4900 IU/kg per year]); (P < .01). Clinical outcome was slightly inferior for the intermediate-dose regimen (P < .01) for 5-year bleeding (median, 1.3 [IQR, 0.8-2.7] vs 0 [IQR, 0.0-2.0] joint bleeds/y) and joint health (Haemophilia Joint Health Score >10 of 144 points in 46% vs 11% of participants), although social participation and quality of life were similar. Annual total costs were 66% higher for high-dose prophylaxis (mean, 180 [95% confidence interval, 163 - 196] × US$1000 for Dutch vs 298 [95% confidence interval, 271-325]) × US$1000 for Swedish patients; (P < .01). At group level, the incremental benefits of high-dose prophylaxis appear limited. At the patient level, prophylaxis should be tailored individually, and many patients may do well receiving lower doses of concentrate without compromising safety.

Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study.

The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations.