The incidence of FIX inhibitors in severe hemophilia B (SHB) is not well defined. Frequencies of 3-5% have been reported but most studies to date were small, including patients with different ...severities, and without prospective follow-up for inhibitor incidence. Study objective was to investigate inhibitor incidence in patients with SHB followed up to 500 exposure days (ED), the frequency of allergic reactions, and the relationship with genotypes. Consecutive previously untreated patients (PUPs) with SHB enrolled into the PedNet cohort were included. Detailed data was collected for the first 50 ED, followed by annual collection of inhibitor status and allergic reactions. Presence of inhibitors was defined by at least two consecutive positive samples. Additionally, data on factor IX gene mutation was collected. 154 PUPs with SHB were included; 75% were followed until 75 ED, and 43% until 500 ED. Inhibitors developed in 14 patients (7 high-titre). Median number of ED at inhibitor manifestation was 11 (IQR 6.5-36.5). Cumulative inhibitor incidence was 9.3% (95%CI 4.4-14.1) at 75 ED, and 10.2% (5.1-15.3) at 500 ED. Allergic reactions occurred in 4 (28.6%) inhibitor patients. Missense mutations were most frequent (46.8%) overall but not associated with inhibitors. Nonsense mutations and deletions with large structural changes comprised all mutations among inhibitor patients and were associated with an inhibitor risk of 26.9% and 33.3%, respectively. In an unselected, well-defined cohort of PUPs with SHB, cumulative inhibitor incidence was 10.2% at 500 ED. Nonsense mutations and large deletions were strongly associated with the risk of inhibitor development. The PedNet Registry is registered at clinicaltrials.gov; identifier: NCT02979119.
Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 ...motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.
•Headaches, lethargy, and abdominal pain are recurring features of nonovert cTTP disease and are highly responsive to prophylactic therapy.•The incidence of cerebrovascular events is significantly lower in cTTP patients on regular prophylactic therapy.
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The age-adjusted incidence of new factor VIII inhibitors was analyzed in all United Kingdom patients with severe hemophilia A between 1990 and 2009. Three hundred fifteen new inhibitors were reported ...to the National Hemophilia Database in 2528 patients with severe hemophilia who were followed up for a median (interquartile range) of 12 (4-19) years. One hundred sixty (51%) of these arose in patients ≥ 5 years of age after a median (interquartile range) of 6 (4-11) years' follow-up. The incidence of new inhibitors was 64.29 per 1000 treatment-years in patients < 5 years of age and 5.31 per 1000 treatment-years at age 10-49 years, rising significantly (P = .01) to 10.49 per 1000 treatment-years in patients more than 60 years of age. Factor VIII inhibitors arise in patients with hemophilia A throughout life with a bimodal risk, being greatest in early childhood and in old age. HIV was associated with significantly fewer new inhibitors. The inhibitor incidence rate ratio in HIV-seropositive patients was 0.32 times that observed in HIV-seronegative patients (P < .001). Further study is required to explore the natural history of later-onset factor VIII inhibitors and to investigate other potential risk factors for inhibitor development in previously treated patients.
Abstract
Introduction
FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors ...developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line.
Methods
The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C <1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL
−1
(≥0.6 to <5 low-titre, ≥5 high titre).
Results
A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0–23.5) were treated with simoctocog alfa.
F8
mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null
F8
mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null
F8
mutations developed inhibitors.
Conclusion
In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null
F8
mutations.
Summary
Bruising and bleeding are commonly seen in children and are usually associated with minor injury and trauma. However, in two groups of children the bruising may be more significant than ...expected: those with an underlying haemostatic abnormality, such as an inherited bleeding disorder, or those who have been subjected to non‐accidental injury (NAI). Diagnosing inherited bleeding disorders in children is fraught with difficulty, from venous access to interpretation of results; the possibility of NAI should be borne in mind, even in those children with proven significant bleeding disorders when the severity of the injury and the history are non‐compatible. We describe the investigation of the haemostatic system in children with bruising and/or bleeding with emphasis on the key haemostatic disorders that need to be excluded.
Summary
The inherited platelet disorders are an uncommon cause of symptomatic bleeding. They may be difficult to diagnose (and are likely to be under‐diagnosed) and pose problems in management. This ...review discusses the inherited platelet disorders summarising the current state of the art with respect to investigation and diagnosis and suggests how to manage bleeding manifestations with particular attention to surgical interventions and the management of pregnancy.
There is a lack of functional performance measures for children and young people with haemophilia (CYPwH) with associated control data from typically developing boys (TDB). The literature advocates ...development of a core set of outcome measures for different chronic conditions. As medical treatment improves, CYPwH are experiencing better outcomes; therefore, more challenging measures are required to monitor physical performance. Such testing is not performed routinely, due to practical and safety concerns.
Evaluate the feasibility, safety and acceptability of select outcome measures as part of a study protocol testing CYPwH; including myometry, 10 metre incremental shuttle walk test (10-m ISWT), iSTEP (an incremental step test, with data from TDB), and 1 week of accelerometry-wear at home.
Sixty-six boys aged 6-15 years with mild, moderate or severe haemophilia A or B (including inhibitors) attending routine clinics at Great Ormond Street Hospital were approached to participate. Descriptive statistics and content analysis were used to assess outcomes of feasibility, safety and acceptability, which included recruitment/retention rates, protocol completion within routine appointment timeframes, performance testing without serious adverse events/reactions (SAE/SARs), and acceptability to CYPwH of high-level performance measures.
Outcomes were met: 43 boys completed testing at clinic review (Jan-Nov 2018) within a 10-month timeframe, retention was 95% at completion of protocol and no SAE/SARs were reported throughout testing.
Feasibility, safety and acceptability of the study protocol have been established in this population. Both high-level performance tests, iSTEP and 10-m ISWT, were an acceptable addition to boys' routine clinic appointments and could be safe, acceptable choices of outcome measure as part of a core set of tests for CYPwH. Further investigation of the psychometric properties for the iSTEP is now justified, in order for it to be used as a standardised, validated, reliable outcome measure in clinical or research settings.
Retrospectively registered on September 3, 2019, on ClinicalTrials.gov (ID: NCT04076306 ).
Summary
This report presents seven children with congenital thrombotic thrombocytopenic purpura (TTP). Six had a history of severe neonatal unconjugated hyperbilirubinaemia and thrombocytopenia. The ...seventh child had no neonatal problems but has suffered three episodes of acute TTP. The subsequent clinical course of the children varied. Five had a relapsing–remitting course and one had chronic microangiopathic haemolytic anaemia. The five oldest children initially received plasma infusions but, because of viral safety issues and easier administration, they now receive intermediate purity US‐sourced plasma‐derived factor VIII concentrate: BPL 8Y. Effective prophylaxis and treatment is possible in congenital TTP using BPL 8Y.
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