Background-The aim of this study was to estimate the impact of thrombophilia on risk of first childhood stroke through a meta-analysis of published observational studies. Methods and Results-A systematic search of electronic databases (Medline via PubMed, EMBASE, OVID, Web ofScience, The Cochrane Library) for studies published from 1970 to 2009 was conducted. Data on year of publication, study design, country of origin, number of patients/control subjects, ethnicity, stroke type (arterial ischemic stroke [AIS], cerebral venous sinus thrombosis [CSVT]) were abstracted. Publication bias indicator and heterogeneity across studies were evaluated, and summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with fixed-effects or random-effects models. Twenty-two of 185 references met inclusion criteria. Thus, 1764 patients (arterial ischemic stroke [AIS], 1526; cerebral sinus venous thrombosis [CSVT], 238) and 2799 control subjects (neonate to 18 years of age) were enrolled. No significant heterogeneity was discerned across studies, and no publication bias was detected. A statistically significant association with first stroke was demonstrated for each thrombophilia trait evaluated, with no difference found between AIS and CSVT. Summary ORs (fixed-effects model) were as follows: antithrombin deficiency, 7.06 (95% CI, 2.44 to 22.42); protein C deficiency, 8.76 (95% CI, 4.53 to 16.96); protein S deficiency, 3.20 (95% CI, 1.22 to 8.40), factor V G1691A, 3.26 (95% CI, 2.59 to 4.10); factor II G20210A, 2.43 (95% CI, 1.67 to 3.51); MTHFR C677T (AIS), 1.58 (95% CI, 1.20 to 2.08); antiphospholipid antibodies (AIS) [CSVT]) is estimated to be between 2.6 and 6.4 per 100 000 per year, reflecting a trend toward a higher frequency in more current literature. 1-3 Underlying conditions in children with symptomatic cerebrovascular accidents include congenital heart malformations, hemolytic anemias, and collagen vascular diseases, as well as some rare inborn metabolic disorders. 4 In addition, risk factors include trauma and infectious diseases. Apart from acquired thrombophilic risk factors such as the presence of antiphospholipid antibodies, 5,6 inherited thrombophilia, particularly antithrombin, protein C, and protein S deficiency, variants of coagulation factor V (G1691A) and factor II (G20210A), and elevated lipoprotein(a), have been found in small case series and case-control studies to be associated with AIS or CSVT in infants and children. Furthermore, an association of the thermolabile MTHFR C677T genotype with stroke is controversial in both adults and children. 5353 In fact, the increased likelihood of having a blood clot in the vasculature is related to elevated homocysteine levels, and mutations in the MTHFR gene only exploit their effect by contributing to the elevated homocysteine plasma level. Because adequate folate levels essentially cancel out the impaired regulation of homocysteine induced by MTHFR mutations, not all people will develop high homocysteine levels. [53][54][55][56] , Editori...

Evidence suggests greater doses of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) than currently administered may result in enhanced haemostasis and convenience for patients with haemophilia A and B with inhibitors. This study evaluated efficacy and safety of rFVIIa and an activated prothrombin complex concentrate (APCC; Factor Eight Inhibitor Bypassing Activity [FEIBA], Baxter AG, Vienna, Austria) for controlling joint bleeds in a home-treatment setting. Patients received each of three treatments in one of six possible sequences: 270 microg kg(-1) rFVIIa at hour 0 + placebo at hours 3 and 6, 90 microg kg(-1) rFVIIa at hours 0, 3 and 6, and 75 U kg(-1) APCC at hour 0. Efficacy was assessed by the requirement for additional haemostatics within 9 h and by a novel global response algorithm. The percentage of rFVIIa 270 microg kg(-1) group patients requiring additional haemostatics within 9 h (8.3%) was significantly lower than that for the APCC group (36.4%, P = 0.032). The percentage of rFVIIa 90 x 3 microg kg(-1) group patients requiring such rescue medication (9.1%) was also lower compared to the APCC group. This result approached, but did not reach statistical significance (P = 0.069). Both rFVIIa treatment groups showed similar use of rescue medication (8.3% and 9.1% of episodes for rFVIIa 270 microg kg(-1) and rFVIIa 90 x 3 microg kg(-1) groups respectively). No significant differences in treatment response were observed with the global response algorithm (P = 0.173). No safety issues were identified. A single dose of rFVIIa 270 microg kg(-1) is as safe and effective as rFVIIa 90 x 3 microg kg(-1) dosing, and may be considered a potentially more effective alternative to APCCs for the management of joint bleeding in this population.

previously untreated hemophilia A patients treated with plasma-derived or recombinant factor VIII concentrates: a systematic review. J Thromb Haemost 2010; 8: 1256-65.Summary. Background: Different rates of inhibitor development after either plasma-derived (pdFVIII) or recombinant (rFVIII) FVIII have been suggested. However, conflicting results are reported in the literature. Objectives: To systematically review the incidence rates of inhibitor development in previously untreated patients (PUPs) with hemophilia A treated with either pdFVIII or rFVIII and to explore the influence of both study and patient characteristics. Methods: Summary incidence rates (95% confidence interval) from all included studies for both pdFVIII and rFVIII results were recalculated and pooled. Sensitivity analysis was used to investigate the effect of study design, severity of disease and inhibitor characteristics. Meta-regression and analysis-of-variance were used to investigate the effect of covariates (testing frequency, follow-up duration and intensity of treatment). Results: Two thousand and ninety-four patients (1167 treated with pdFVIII, 927 with rFVIII; median age, 9.6 months) from 24 studies were investigated and 420 patients were observed to develop inhibitors. Pooled incidence rate was 14.3% (10.4-19.4) for pdFVIII and 27.4% (23.6-31.5) for rFVIII; high responding inhibitor incidence rate was 9.3% (6.2-13.7) for pdFVIII and 17.4% (14.2-21.2) for rFVIII. In the multi-way ANOVA study design, study period, testing frequency and median follow-up explained most of the variability, while the source of concentrate lost statistical significance. It was not possible to analyse the effect of intensity of treatment or trigger events such as surgery, and to completely exclude multiple reports of the same patient or changes of concentrate. Conclusions: These findings underscore the need for randomized controlled trials to address whether or not the risk of inhibitor in PUPs with hemophilia A differs between rFVIII and pdFVIII.

Prophylaxis with emicizumab-a subcutaneously administered, bispecific, humanized, monoclonal antibody-promotes effective hemostasis in persons with hemophilia A (PwHA). The primary efficacy, safety and pharmacokinetics of emicizumab were reported previously, but long-term data were limited. Here, data from 401 pediatric and adult PwHA with/without factor VIII inhibitors who were enrolled in the Phase III HAVEN 1, HAVEN 2, HAVEN 3, and HAVEN 4 studies have been pooled to establish a long-term efficacy, safety and pharmacokinetic profile. Across a median (interquartile range) efficacy period of 120.4 (89.0-164.4) weeks (data cut-off May 15, 2020), the model-based treated annualized bleed rate (ABR) was 1.4 (95% confidence interval, 1.1-1.7). ABRs declined and then maintained at <1 in an analysis of 24-week treatment intervals; at Weeks 121-144 (n=170) the mean treated ABR was 0.7 (0-5.0). During Weeks 121-144, 82.4% of participants had zero treated bleeds, 97.6% had ≤3 treated bleeds, and 94.1% reported zero treated target joint bleeds. Bleeding into target joints decreased substantially. Emicizumab was well tolerated, and no participants discontinued due to adverse events beyond the five previously described. This data-cut includes the previously reported 3 thrombotic microangiopathies (1 in the PwHA with fatal rectal hemorrhage), and 2 thromboembolic events, all associated with activated prothrombin complex concentrate use; and additionally, a myocardial infarction and a venous device occlusion. With 970.3 patient-years of exposure, emicizumab prophylaxis maintained low bleed rates in PwHA of all ages with/without FVIII inhibitors and remains well tolerated, with no new safety concerns identified. Clinical trials registered as NCT02622321, NCT02795767, NCT02847637, NCT03020160.

No abstract

IntroductionAs a result of the new treatment paradigm that the haemophilia community will face with the availability of novel (non‐factor) therapies, an updated consensus on ITI recommendations and inhibitor management strategies is needed.AimThe Future of Immunotolerance Treatment (FIT) group was established to contemplate, determine and recommend the best management options for patients with haemophilia A and inhibitors.Discussion and ConclusionsDespite the considerable success of emicizumab in the management of inhibitor patients, the FIT group still sees the importance of eradicating inhibitors. However, the availability of emicizumab and other non‐factor therapies in the future might impact greatly on how ITI is undertaken. Theoretically, concomitant use of emicizumab and FVIII might allow emicizumab to effectively prevent bleeding with lower dose ITI regimens. This might allow for the greater adoption of low‐dose/low‐frequency FVIII ITI regimens, which may result in a reduced need for central venous access devices while still maintaining a reasonable likelihood of ITI success. The FIT group proposes a new management algorithm for current ITI (without emicizumab) and a hypothetical new approach with the availability of emicizumab. As there are no published data regarding the concomitant use of emicizumab and FVIII for ITI, the FIT Expert group encourages the undertaking of properly conducted prospective studies to explore these approaches further.

Introduction:The efficacy and safety of recombinant factor VIII Fc fusion protein (rFVIIIFc) as an extended half-life treatment for severe haemophilia A were demonstrated in the Phase 3 A-LONG and Kids A-LONG studies. Eligible subjects who completed A-LONG and Kids A-LONG could enrol in ASPIRE (NCT01454739), an open-label extension study.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

The treatment of bleeding for haemophilic patients with inhibitors relies on the use of the bypassing agents, recombinant factor VIIa and factor eight inhibitor bypass activity (FEIBA). While both therapies are effective in the majority of bleeding episodes, there is a significant amount of interindividual variability when it comes to the response to therapy. As of yet, there is no reliable laboratory parameter that can predict the response to therapy in the same manner that factor VIII and factor IX levels predict response in non-inhibitor patients. Developing such a laboratory parameter is vital in order to maximize the clinical efficacy of these agents. Thromboelastography (TEG) is a device, which assesses clot formation over time in whole blood and has several characteristics which suggest it may be an effective way to monitor bypass agent therapy. We studied the ability of TEG to individualize the treatment regimens of three patients with high titre inhibitors assessing the response to recombinant factor VIIa, FEIBA, and when both were used sequentially. The TEG allowed for individualization of treatment for each of the three patients and resulted in more effective, convenient and less expensive treatment regimens. We thus believe that TEG is a promising device for monitoring of bypass agent therapy and should be studied further.