Generation and optimization of the self-administered pediatric bleeding questionnaire and its validation as a screening tool for von Willebrand disease

Discriminating children who have a bleeding disorder using their personal history remains difficult and several bleeding scores have been developed to discern children at increased probability for a bleeding disorder from those without. While most bleeding questionnaires have been expert-administered, this article presents an evaluation of a newly developed self-administered bleeding score (Self-PBQ, administered by caregivers or children).
This study was set up in three different phases: Phase 1: Translation of existing pediatric bleeding questionnaire items into lay language targeting reading level grade 4 and evaluation of the correlation with expert-administered questionnaires using known patients with von Willebrand disease type I (vWD I). Phase 2: Establishment of the normal range of the bleeding scores with the Self-PBQ in children with and without vWD I. Phase 3: Evaluation of the developed Self-PBQ for screening in first-time referrals (complaint being bleeding symptoms or family history) to the hematology clinic.
Phase I was performed on 38 patients with vWD I and without bleeding disorders (controls) and showed good correlation between the Self-PBQ and expert-administered bleeding scores after several rounds of revisions. Phase 2 using 56 children with and without vWD I showed that all tested controls had bleeding scores of 0-2 which led to the definition of a bleeding score cutoff of >2 being abnormal. Phase 3 in 155 children referred to a hematology clinic showed excellent correlation of the Self-PBQ and the expert-administered PBQ. Of 23 patients with VWD I, 5 were assigned a negative BS, all of them had a positive family history of vWD. The negative predictive value was 91%. Median time for completion was 10 minutes.
The same limitations apply to all existing bleeding scores, they perform moderately well to rule out minor bleeding disorders (vWD I). Particularly young children might be missed as they haven't faced major hemostatic challenges. So far, this bleeding score has only been evaluated for vWD I, it would be highly desirable to test it in other bleeding disorders. Family history seems needed to adequately assess individual patients' risks for a bleeding disorder which is not part of the Self-PBQ.
Pediatric bleeding scores are a valuable tool to assess the pretest probability in patients referred to a hematology clinic for a possible bleeding disorder. This self-administered tool (Self-PBQ) performs equally well compared to expert-administered questionnaires and is a useful tool to assess referrals before consultation to a hematologist.

Targeting novel mechanisms of pain in sickle cell disease

In this review article, the authors look at the underlying pathophysiological mechanisms of pain in Sickle Cell Disease and potential strategies/ targets to reduce pain in Sickle Cell Disease.

Long-term safety and efficacy of deferasirox in young pediatric patients with transfusional hemosiderosis: Results from a 5-year observational study (ENTRUST)

The oral, once-daily iron chelator deferasirox is indicated for the treatment of adult and pediatric patients with chronic iron overload. However, fewer than 10% of patients in the registration studies were aged 2 to less than 6 years. Therefore, further collection of efficacy and safety data in young patients was necessary.
This observational 5-year ENTRUST study enrolled patients aged 2 to less than 6 years with transfusional hemosiderosis. They received deferasirox according to local prescribing information. The primary objective was the evaluation of safety, specifically renal (serum creatinine) and hepatic (ALT) function. Serum ferritin was also observed as a surrogate efficacy parameter.
267 patients were enrolled. Mean age was 3.2 years. The most frequent diagnosis was 𝛽-thalassemia. 145 patients (54.3%) completed 5 years’ treatment. The proportion of patients with two or more consecutive post-baseline measurements (≥7 days apart) of serum creatinine higher than age-adjusted upper limit of normal (ULN) and ALT more than five times the ULN was 4.4% and 4.0%, respectively. Median serum ferritin decreased from 1,702 ng/ml at baseline to 1,127 ng/ml at 5 years. No new or unexpected safety findings were observed with regard to adverse effects or laboratory abnormalities, with a limited number of patient discontinuations as a direct result of adverse effects.
Almost half of enrolled patients discontinued the study before the end. This is a considerable proportion of the patients enrolled. Even if the main reason of discontinuation was not adverse effects (only 6,7%), it is possible that this high proportion of discontinuations introduced some biases. Also, because this study was observational without predefined therapy protocol, it did not determine if more aggressive therapy could result in a higher incidence of AEs. Finally, this study was funded by Novartis and some of the authors reported consultancy and some research funding from Novartis.
This study provides real-world evidence that supports the manageable safety profile and sustained efficacy of long-term deferasirox therapy in pediatric patients aged 2 to less than 6 years at enrollment with transfusional hemosiderosis.

Minimal Factor XIII activity level to prevent major spontaneous bleeds

Factor XIII deficiency is a rare but serious bleeding disorder. This study aimed to validate a bleeding severity classification, and to identify the minimal FXIII level at which patients remain asymptomatic, in order to guide factor prophylaxis.
This was an international multi-center cross-sectional study. 64 patients from 12 countries were identified as part of the European Prospective Rare Bleeding Disorders Database (PRO-RBDD). A previous retrospective study had suggested the following bleeding severity classification: severe (undetectable FXIII), moderate (0-29 U/dl), and mild (>30 U/dl). The patients were analyzed according to this classification in order to validate it. FXIII levels were tested using the ammonia release assay and centralized testing was attempted. Bleeding severity was classified as follows: Grade 1 (asymptomatic), Grade 2 (spontaneous minor - mucocutaneous), Grade 3 (spontaneous major - umbilical, GI, CNS, hemarthrosis, hematoma).
FXIII level correlated with bleeding severity, with 90% of patients with severe FXIII deficiency exhibiting Gr.3 bleeding, as compared to 46% of moderate, and 0% of mild patients. Conversely, 43% of mild patients were asymptomatic. Unsurprisingly, patients with severe FXIII deficiency presented at a younger age (median 0 years) and were most likely to be symptomatic. All patients suffering from Gr.3 bleeding had a FXIII level under 16 U/dl. Thus using a cut-off of 15 U/dl was predicted to have a sensitivity of 97% and specificity of 76% in discriminating between patients at risk of having Gr.3 bleeds.
Limitations include a study population that is skewed towards symptomatic patients as the majority of patients were identified by presenting to the hospital with bleeding. In addition, less than half of the samples were sent to the central laboratory to confirm FXIII level, though there was high concordance in the samples that were sent. Strengths include a relatively large sample size for a rare disorder, and a heterogeneous group of patients from multiple countries. Moreover, as the population will be studied prospectively there is an opportunity to test the validity of the cut-off of 15 U/dl as a trough level for prophylaxis.
The severity classification accurately categorizes patients in bleeding phenotype. A FXIII level 15 U/dl greatly increases the likelihood of spontaneous major bleeding. As such, the use of 15 U/dl as a trough target level for prophylaxis is reasonable.

Indications for and Adverse Effects of Red-Cell Transfusion

A helpful review of red cell transfusions encompassing evidence underlying current transfusion guidelines, trends in use, the infectious and non-infectious risks of transfusion, ongoing research, and effects in children.

Frequency and epitope specificity of anti-factor VIII C1 domain antibodies in acquired and congenital hemophilia A

Inhibitor development is the most challenging treatment-related complication in congenital Hemophilia, and autoantibody development in adults is associated with the equally challenging acquired Hemophilia A. Earlier studies suggested that the majority of both allo- and auto-antibodies were directed against the A2 and C2 domains of Factor VIII (F.VIII), with the autoantibody more likely to be restricted to a particular domain. Recently, inhibitors developing in a patient with mild Hemophilia A were found to target the C1 domain. Subsequent studies identified anti-C1 antibodies in up to 60% of inhibitors, and the response was greater to human than porcine F.VIII.
This study analyzed the frequency and epitope specificity of anti-C1 antibodies in patients with both acquired and congenital hemophilia.178 patients (63 congenital, 115 acquired) were studied by a variety of protein based and molecular methods. Human and porcine protein sources were studied in tandem, primarily because of the potential role of porcine replacement factor in patients with inhibitors and those with acquired hemophilia A.
The median inhibitor titre of the population was 5.4 BU (ranging from 1.9-20). C1-specific antibodies were found to contribute significantly to the total population of cross-reactive (human and porcine sequence) anti-F.VIII IgG. The C1 domain was noted to be important in binding to phospholipid membranes, F.V, and von Willebrand Factor, which could explain its impact in coagulation.
As a primary in vitro study, it is difficult to determine the true in vivo impact of these antibodies, or to compare them to the effects of antibodies against other epitopes. Some patients may also have antibodies to multiple epitopes, particularly in congenital hemophilia, with a more complex impact on coagulation and treatment.
Recent studies are highlighting both treatment and patient-related risk factors for inhibitor development. Given the clinical importance of inhibitor development, a better understanding of the nature and variability of inhibitors should contribute to the ability to better prevent and eradicate them with new approaches.

Age of Red Cells for Transfusion and Outcomes in Critically Ill Adults

Packed red cells stored over time tend to develop a series of biochemical changes known as a "storage lesion". Clinicians have long been concerned that these storage lesions have an effect on outcomes for patients receiving transfusions. Although two previous RCTs have shown that this is not true, criticisms were levelled against each. Specifically, the INFORM trial had a low overall mortality potentially reducing its power while the ABLE trial evaluated only transfusions given soon after ICU admission. This multicenter RCT (TRANSFUSE) aimed to address these issues.
Nearly 5000 adults admitted to ICUs in 5 countries and receiving red cell transfusions were randomized to the freshest blood product available or the oldest blood product available. The primary outcome was 90-day mortality with a number of other secondary outcomes. Randomization was computerized and patients, caregivers, and research personnel were blinded to treatment allocation.
There was no overall difference in mortality between the two groups (24.1% vs 24.8%). A pre-specified subgroup analysis showed a higher mortality in patients with high APACHE III scores (higher risk of ICU death) receiving fresh red cells and a lower mortality in patients with low APACHE III scores receiving fresh red cells. Other subgroup analyses (blood group, SOFA score) and secondary outcomes had no difference between treatment allocations other than a slightly higher non-hemolytic febrile transfusion reaction rate in the fresh pRBC group.
Several exclusion criteria limit generalizability. One exclusion criteria was physician preference to give a particular blood product which may have subtly biased the results. No children were included and all these patients were critically ill.
Overall, a large and important study once again indicating that the age of red blood cells should not be a major factor in the clinical decision making around transfusions.

How I manage children with neutropenia

This is a review on the management of children with neutropenia with a special emphasis on clinical finding, laboratory tests, and treatment, particularly the use of granulocyte colony-stimulating factor.

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

Fitusiran is an RNA interference molecule that targets antithrombin RNA (and thereby decreases the amount of circulating antithrombin). This approach is theorized to decrease the number of bleeds in patients with hemophilia of any type and to potentially lower the requirement for prophylactic factor.
This phase I study addressed the safety, pharmacodynamics, and pharmacokinetics of fitusiran. 4 healthy controls and 30 adults with hemophilia were enrolled. The primary outcome was plasma antithrombin levels.
Antithrombin levels decreased and thrombin levels concurrently increased both with weekly and monthly dosing. In an exploratory analysis, there were fewer bleeds/month after treatment than before. The safety profile was tolerable.
This is a phase I study and so clinical utility is still limited.
A new avenue for treatment of hemophilia and one of the few examples of clinical use of RNA interference therapy. The safety profile is encouraging - it will likely have phase III results reported shortly.

Bleeding risk of surgery and its prevention in patients with inherited platelet disorders

Inherited platelet disorders are a heterogenous group of diseases with a wide spectrum of clinical severity. Individually, they are rare and thus challenging to study. As such, the majority of data available is from small studies and guidelines are based on expert opinion. This paper was a retrospective study aimed at evaluating the bleeding complications associated with surgical procedures in all inherited platelet disorders.
This was a multi-center, retrospective cohort study by the Scientific Working Group on Thrombocytopenias and Platelet Function Disorders of the European Hematology Association. Participating centers were asked to review records of patients with inherited bleeding disorders that underwent surgical procedures. Patients were divided into those with platelet number disorders (IPND) and those with platelet function disorders (IPFD). Data on procedures, bleeding, and use of prophylactic regimens were collected.
There were 423 patients and 829 procedures in total. Baseline bleeding scores were higher for patients with IPFD and these patients were twice as likely to have excessive bleeding after surgery as compared to patients with IPND (25% compared to 13%). Cardiovascular and urologic surgery were associated with an increased likelihood of bleeding, while the use of pre-operative pro-hemostatic agents was associated with less bleeding. ddAVP with or without anti-fibrinolytic agents was found to be the preventative treatment associated with the lowest bleeding rate. For patients with IPND, a platelet count below 68 was found to be the cutoff under which bleeding rate increased significantly.
There are numerous limitations to this study: Firstly, it is retrospective and relies on the survey filled by participating centres. It also included patient/family responses mixed in with data from medical records. Second, given the rarity of many of platelet disorders, the cohort is heavily influenced by a subset of diagnoses. While the authors make attempts to do sub-analyses, there are insufficient data to make reasonable conclusions. Third, the decision to use prophylaxis and choice of agents used was entirely dependent on the treating physician. Fourth, the authors conclusions that ddAVP and anti-fibrinolytic therapy is the most efficacious therapy for IPFD is misleading. As this was the most commonly used therapy for IPFD with a milder bleeding phenotype, it is not surprising that it was efficacious. Clearly, it would not be advisable as the only pro-hemostatic therapy for an IPFD with a severe bleeding phenotype, such as Glanzmann Thrombasthenia or another where the underlying hemostatic defect in not affected by ddAVP. Fifth, they do not provide any data on complications of using prophylaxis (ex. thrombosis with rFVIIa).
This paper supports previous anecdotal data and expert-derived guidelines: Patients with inherited platelet function disorders bleed more than those with thrombocytopenias. Patients with a history of bleeding are more likely to have severe bleeding. Use of pre-operative prophylaxis reduces surgical bleeding. There is insufficient evidence to recommend specific interventions to minimize bleeding in these patients.

Family cord blood banking for sickle cell disease: a twenty-year experience in two dedicated public cord blood banks

Hematopoetic stem cell transplantation (HSCT) is currently the only curative therapy for sickle cell disease. However, there remain challenges in both identifying appropriate donors, and reluctance to proceed to HSCT due to transplant-related toxicity. Umbilical cord blood transplant (CBT) from family donors has cure rates exceeding 90%, with low rates of GvHD. This retrospective review aimed to assess the characteristics, utilization, and transplant outcomes of family-directed cord blood of patients with sickle cell disease. This study was driven, at least in part, by the cost and technical challenges of collecting and storing units
Free cord blood banking in public cord banks was offered to women who had previously delivered a child with sickle cell disease. Despite being a public bank, cords were reserved for the use of that family. All cords were stored and HLA-testing was not done (due to cost) unless requested by treating physician. Data were collected retrospectively from the cord blood bank, Eurocord registry and hospital patient records.
338 units were collected from 302 families. 28 units were used for transplantation, giving a utilization rate of 8% over 20 years. Interestingly, one center accounted for 41% of all cords banked, and utilization of 25/28 cords. This suggests that close collaboration with transplant teams is likely to increase cord blood use. There was a 96% engraftment rate and 100% survival, with all patients achieving a minimum of 80% donor chimerism. 5/28 patients had Gr.II-IV aGvHD requiring steroids.
There are no data reported on cost of cord blood banking. This is a significant omission in discussing publicly funded cord banking, particularly in light of low utilization rates.
HLA-matched family donor CBT results in good outcomes in patients with SCD. However, utilization rates remain low and data on cost of publicly funding such banks is not available.

Emicizumab Prophylaxis in Hemophilia A with Inhibitors

Hemophilia A patients with inhibitors face high morbidity including multiple bleeds and arthropathies. Emicizumab is a bispecific antibody that brings factors IX and X into close proximity thereby providing a tenase complex for the production of thrombin without the need for FVIII. This industry-sponsored phase III randomized open-label trial addressed the efficacy of this antibody in patients with hemophilia A and high inhibitor levels (BU > 5).
Patients who previously received only episodic bypassing agents were randomized to receive either emicizumab or no prophylaxis. Patients >12 years who received prophylaxis with bypassing agents were non-randomly assigned to receive emicizumab. The primary endpoint was the rate of bleeding events.
In a comparison of the randomized arm, bleeding events were markedly decreased with emicizumab and ~60% of patients receiving the antibody had no bleeding over 24 weeks (only 1 patient was bleed-free in the control group). Adverse events were thrombotic (CSVT, TMA, superficial thrombophlebitis) and seemed to be highly correlated with concurrent receipt of emicizumab and activated PCC.
Numbers were small but the effect was large enough that the size of the trial didn't need to be larger. The trial was also open label which may introduce a small amount of bias. The antibody hasn't been priced yet however and this may be a major clinical limitation in its use.
Emicizumab is a highly efficacious prophylactic agent for patients with hemophilia A and high inhibitor levels. In the same issue there is an accompanying editorial by David Lillicrap, the world famous hemostasis specialist from Kingston, Canada.

Sickle Cell Disease

This is a very nice review article on Sickle Cell Disease focusing on genetic and non-genetic modifiers of the disease.

Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia

For pediatric patients with a diagnosis of Aplastic Anemia and without matched-related donor, immune suppressive treatment (IST) is the treatment of choice and leads to an initial response in about 2/3 of patients with about 1/3 of initial responders relapsing over time and 10-20% developing clonal evolution. This article addresses the question whether addition of eltrombopag, an oral thrombopoietin-receptor agonist leads to an increase in response to IST. Eltrombopag was previously shown to lead to a response in a subset of IST-refractory patients with aplastic anemia, particularly in those with a higher reticulocyte count. The authors are among the most established people performing research on aplastic anemia and are affiliated to the NIH.
This is a phase I/II study with 92 patients divided into three groups with varying timing of addition of eltrombopag: either from day 14 to 6 months, from day 14 to 3 months, or from day 1 to 6 months after IST (cohorts 1, 2, and 3 respectively). The main outcome was complete response (CR) after 6 months.
In this trial, the best results were seen in the group starting eltrombopag with IST and continuing to 6 months (cohort 3) with 58% CR and 94% overall response (OR). The other treatment groups led to CR of 33% and 26% (87% and 80% OR) in cohort 1 and cohort 2, respectively. This is far better than what was seen in the historical controls used in this trial with 10% CR and 66% OR.
A major limitation to this trial was that there were only historical controls and no direct comparison group without eltrombopag. The retic counts in the eltrombopag group were slightly higher compared to controls which might point towards a “milder” disease. The whole cohort consisted of a mixed group of adults and kids with a wide age range (3-82 years). Finally, there was an amendment in the middle of the study period extending the time of cyclosporine A treatment from 6 months to 24 months adding further uncertainty what caused the better response in cohort 3 which was treated last.
Eltrombopag was shown to increase response rate in a mixed cohort of pediatric and adult patients when being added to IST upfront together with a prolonged duration of cyclosporine A treatment of 24 months. While these results are very promising, further data will be needed from pediatric cohorts.

Thrombophilia risk is not increased in children after perinatal stroke

Perinatal stroke is the leading cause of hemi-paretic cerebral palsy. This study aimed to prospectively identify the rates of thrombophilia in children with perinatal stroke and compare it to healthy case-controls, thus determine the need for thrombophilia testing in this population.
This was a single-center, prospective, population-based, case-control study. 135 patients with perinatal stroke were identified throught the Alberta Perinatal Stroke Project registry. They were classified as having non-ischemic arterial stroke (NAIS), arterial presumed perinatal stroke (APPIS), or fetal periventricular venous infarction (PVI) based on MRI finding and absence of identifiable etiologies. These patients had thrombophilia testing at 12 months of age or at the time of presentation (if older than 12 months as with cases of APPIS). Testing included quantified proteins C and S, antithrombin, factors VIII/ IX/ XI, fibrinogen, lipoprotein(a), homocysteine, lupus anticoagulant, anticadiolipin antibodies, and genotyping Factor V Leiden (FVL), Factor II G20210A, and MTHFR C677T mutations. 77 Control participants were age and sex matched from healthy patients undergoing elective procedures. Control patient samples were used to identify normal ranges for the laboratory measures and as comparison to values from the prothrombotic group. The primary outcome measure was to determine any association between perinatal stroke diseases and thrombophila.
No difference was seen in 12 out of the 14 parameters, including all the thrombophilias. Mean INR and PTT were marginally shorter in children with NAIS. The rates of FVL, FII, and MTHFR mutations were similar to controls. Antiphospholipid antibodies were also comparable to controls and resolved on repeat testing. The total number of abnormalities was also comparable between the groups. There were no cases of stroke recurrence.
Limitations included failing to test mothers of neonates and not testing some described thrombophilias associated with stroke (ex. ADAMTS13). Thrombophilia testing done at 12 months does not account for possibility of disordered coagulation during the acute time of stroke. Data on family history of thrombosis was not included.
There is no clear association between thrombophilia and idiopathic perinatal stoke. Due to an extremely low risk of stroke recurrence, thrombophilia testing in this population is not indicated.

Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation

Congenital fibrinogen disorders are usually caused by deficiency or functional defects in the molecule. Hypodysfibrinogenemia has features of both quantitative and qualitative defects, and is often misdiagnosed as simply hypofibrinogenemia. Various genetic aberrations were reported in previous publications, including heterozygosity and compound heterozygosity for nonsense and missense mutations.
The authors describe a case suggesting hypodysfibrinogenemia and leading to genetic analysis of the three fibrinogen genes (FGA, FGB, FGG). Subsequently, the authors performed a systematic review of the literature for studies of hypodysfibrinogenemia and compiled these results to identify the breadth of genetic aberrations associated with this entity.
The literature review identified 32 single mutations in 51 patients with hypodysfibrinogenemia, which were mainly missense and nonsense mutations. Compound heterozygosity for mutations known to cause both hypo- and dys-fibrinogenemia was also noted. Clinically, these patients had a wide variety of clinical symptoms, including both bleeding (45%) and thrombosis (44%).
This is a systematic review of case reports and small series. While the literature search was thorough, this is a major limitation, and subject to both reporting and publication bias.
Hypodysfibrinogenemia is a rare condition caused by a wide variety of molecular abnormalities and leading to a wide range of clinical presentations. Both antigenic and functional measurements of fibrinogen are necessary to ensure that it is not misdiagnosed as hypofibrinogenemia.

Safety, efficacy and pharmacokinetics of rVIII-SingleChain in children with severe hemophilia A: results of a multicenter clinical trial

rVIII-SingleChain is a new recombinant Factor VIII (F.VIII) molecule in which the heavy and light chains are fused to achieve a single protein, which is indistinguishable from endogenous F.VIII. It has an increased binding to von Willebrand factor (vWF) leading to a potentially increased half life and decreased risk of F.VIII inhibitors.
This prospective phase III trial recruited previously treated pediatric patients (younger than 12 years) with no personal or family history of inhibitors. They received either prophylaxis or on-demand therapy and were dosed at investigator's discretion. Efficacy and safety were regularly assessed, and inhibitor screening was performed. Pharmacokinetic evaluation was done using the chromogenic substrate assay, which has been shown to be more accurate with this molecule.
84 patients were followed across 19 countries: PK studies showed a mean half life of just over 10 hours. Efficacy was demonstrated for treatment of acute bleeds, and there were no safety concerns or development of new inhibitors. For patients on prophylaxis, the annualized bleeding rate (ABR) was 3.69, and the annualized spontaneous bleeding rate was 0. The ABR was noted to be slightly higher in the 6-12 year old group, likely reflecting their increased activity. Many patients were able to decrease the frequency of their prophylactic injections, although a few required more frequent infusions.
Since the treatment regimen, including dosing, was left to the discretion of the investigator, there is a significant potential for bias. It also makes it challenging to compare the ABR across the different prophylactic groups.
rVIII-SingleChain is a safe and effective option for treatment of severe Hemophilia A, but it is unclear whether it offers an advantage over the other products currently available.

Modulating immunogenicity of factor IX by fusion to an immunoglobulin Fc domain: a study using a hemophilia B mouse model

Fusion of therapeutic molecules to the Fc domain of immunoglobulin has been used to increase plasma half-life through the neonatal Fc receptor recycling mechanism. Recently this has been used in hemophilia for Factor VIII and Factor IX (F.IX) replacement. Fc-fusion was noted to alter the development of anti-F.IX and F.IX inhibitory antibodies, although the mechanism was not clear from clinical studies.
The authors developed a F.IX fusion product with mouse Fc, to allow the evaluation of immunological response in a mouse model of hemophilia B. These mice were administered either recombinant human F.IX (hFIX), hFIX with a mouse Fc fusion (hFIX-mFC), and hFIX with a human Fc fusion (hFIX-hFC). Anti-F.IX IgG was measured, and IgE levels were also monitored. Inhibitory antibodies to F.IX were determined by a modified Bethesda assay. Cytokine and immunological (B, memory B, and T cell) repertoires were also measured from cultured splenic cells.
Mice showed a strong immunological response to hFIX-hFC, highlighting the importance of using the murine Fc in the study. Mice treated with the hFIX-mFC had higher levels of anti-F.IX IgG and inhibitory antibodies compared with only hFIX treated mice, but lower IgE titres. The authors postulated that Fc fusion modulates the T-cell response to hFIX, switching from a Th2 to a Th1 response, and further evaluated this with cytokine profiles. Further evaluation of the interaction with cell surface receptors reveal that hFIX-mFC, but not hFIX, bound specifically to Fc receptors on professional antigen presenting cells (APCs). Targeting of the F.IX antigen to these APCs allows enhanced presentation and priming of immunity, and this strong signalling may also encourage the Th1 phenotype.
Because these studies were conducted in a mouse model, the extrapolation of results to humans is always uncertain. However, there is good validity and plausibility in the results.
Fc-fusion to Factor IX may alter its immunogenicity, affecting both the development of inhibitory antibodies and the risk of anaphylactic reactions. If these results hold true in humans, it implies a lower risk of anaphylaxis but a higher risk of inhibitor development likely driven by a Th1 to Th2 switch.

Prophylaxis usage, bleeding rates, and joint outcomes of hemophilia, 1999 to 2010: a surveillance project

Joint arthropathy in hemophilia is caused by recurrent hemorrhage into joints and ultimately may lead to destruction of the joint, chronic pain, and limited function which ultimately impacts on patient quality of life and employment. Prophylaxis has been shown to prevent joint bleeding and arthropathy. The adoption of prophylaxis in the US and Canada has increased in all age groups but generally has been greater in younger age groups compared to adults.
The Universal Data Collection (UDC) system collected predefined data from the annual visits of hemophilia patients from 134 US Hemophilia Centers. Data was analyzed in a cross-sectional manner for each study year as well as longitudinal analysis performed on data from participants who had more than 1 clinic visit during the study period.Data was collected from 6196 males with severe hemophilia A. Longitudinal data were available for 3078 participants.
Joint bleeding rates fell by 22% in prophylaxis patients during the study period. A similar decrease (23%) was noted in nonprophylaxis individuals, however the rates of joint bleed and total bleeding events were twice that of patients on prophylaxis. The number of target joints and the rate of target joint bleeding fell significantly in both prophylaxis (80% reduction) and nonprophylaxis (60% reduction) groups. Over time, joint range of motion (ROM) decreased with age regardless of prophylaxis. Decreased rate of joint ROM loss was significantly associated with primary prophylaxis institution before 4 years of age while it was increased by obesity.
The cross-sectional data could limit the conclusions regarding the association between prophylaxis use and decreased bleeding rates but the longitudinal analysis of a smaller group mitigates this weakness. In addition, bleed events were by patient self-report. Interestingly, the nonprophylaxis groups also displayed improved joint outcomes but the reasons for this are unclear - it is hypothesized that the group, over time, may have lost patients to prophylaxis, while other factors such as increased education, and effect of study surveillance may have affected the use of on-demand treatment and preventive measures in both groups.
This paper shows that bleeding rates (joint and overall) have decreased with a concomitant increase in prophylaxis usage in severe hemophilia A patients in the United States between 1999 and 2010 providing further evidence supporting the use of primary prophylaxis. Still, joint range of motion was decreased over time regardless of prophylaxis which highlights room for improvement. Primary prophylaxis institution before 4 years of age was protective while obesity was associated with worse outcomes.

Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial

Vaso-occlusion crises account for the vast majority of sickle cell-related hospital admissions. The pathophysiology has been increasingly linked to inflammation which exacerbates sickling in experimental models and correlates with clinical disease severity. Statins are known to improve endothelial function independent of their lipid-lowering effects, by suppressing inflammation and restoring nitric oxide (NO) production. This study assesses the efficacy of simvastatin in reducing daily vaso-occlusive pain events in paediatric and adult patients with SCA.
The study was a single centre, open label, non-randomized trial in 19 subjects. All subjects received simvastatin in a single oral dose according to weight once daily for 3 months. The frequency and intensity of pain was measured using a daily e-diary record for 3 months of treatment with simvastatin. The total study duration with follow-up was 5 months. The adherence to treatment with simvastatin, was assessed by verbal report and monthly pill count.
Simvastatin was associated with an 85% reduction in the frequency of self-reported pain events and a parallel reduction in analgesic use. Despite the marked decline in pain rate, pain intensity did not change with simvastatin. There was also improvement in soluble biomarkers of inflammation and an acceptable safety profile.
Open label non-randomized trial with a small sample size with possible selection bias. A much larger and well controlled study is needed to understand the long-term safety and efficacy of simvastatin in SCA.
Simvastatin is an interesting & novel potential preventative treatment for VOC that needs further exploration before clinical use

Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII

This study is a pharmaceutical company sponsored trial with the aim to assess the efficacy and safety of a recombinant factor VIII (FVIII) product with prolonged-half-life for prophylaxis and treatment of bleeds in patients with severe hemophilia A. This is a multinational, phase 2/3, partially randomized, open-label trial.
The study included 132 patients with severe haemophilia A, aged 12-65 years. Patients were treated in three individually tailored dose regimens for prophylaxis (according to individual bleeding rate either twice weekly if >1 bleed present in the run-in phase of the study, or randomised to once every 5 days or once every 7 days if no or one bleed occurred in the initial stage). Patients also received the product on demand if there was bleeding. The study period was 10 weeks run-in period followed by 26 weeks of treatment. The study outcome was annualized bleeding rate, response to treatment of bleeds (excellent, good, moderate or poor) and the number of infusions to treat bleeds.
The prolonged half-life of BAY 94-9027 resulted in effective prophylaxis at dose intervals up to every 7 days, given it being tailored to the patient's individual bleeding tendency. It was also effective in treating acute bleeds. No patient developed inhibitors to FVIII during the study.
Open-label design and subjective nature of the patient-reported assessment of treatment of bleeds. Study period may not be long enough to detect development of inhibitors.
New factor VIII products with prolonged half life can offer some hemophilia A patients the convenience of less frequent prophylaxis, which may improve the compliance and quality of life. Their benefits, however, will have to be weighed against their cost.

Evolution Of Disease Activity And Biomarkers On And Off Rapamycin In 28 Patients With Autoimmune Lymphoproliferative Syndrome

This is a Letter to the Editor describing 28 cases of autoimmune lymphoproliferative syndrome (ALPS) treated with rapamycin therapy, addressing first- versus second-line therapy, comprehensive biomarker responses, and the consequences of stopping rapamycin.
Very useful description of a patient cohort treated with rapamycin. Also giving advice on levels of rapamycin that are usually active in this particular cohort.

An international registry of survivors with Hb Bart's hydrops fetalis syndrome

Hb Barts Hydrops Fetalis was universally fatal until the advent of intrauterine transfusions. As the first cohort of survivors grows up, data about their long term outcomes can be collected and reported.
This is an updated report from a multicentre registry of survivors.
69 patients are in the registry including 39 who have survived past 5 years of age. Intrauterine transfusion resulted in a lower incidence of hydrops (17% vs 55%) but were not associated with differences in long term outcomes. As expected, all patients remained transfusion dependent except for those who underwent HSCT. 64% of patients had at least one congenital anomaly - limb defects being the most common. 31% of survivors had severe height and weight undergrowth. 11/33 survivors older than 5 who had neurodevelopmental testing had moderate to severe delay.
Registry data - no control over interventions.
Survivors with Hb Barts may have significant developmental issues as they grow older. Hematologists managing these patients should be aware of this complication in order to include it in counselling and to be able to implement early referral.