First case of very late-onset FHL2 in Spain with two variants in the PRF1 gene.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but fatal disorder characterized by the proliferation and infiltration of macrophages and hyperactivated T lymphocytes that escape from the physiological control pathways and favour the existence of an environment of excessive inflammation and tissue destruction. HLH has been classified into two types: a primary or familial autosomal recessive form, caused by mutations in genes encoding proteins involved in the granule-dependent cytotoxic pathway (familial hemophagocytic lymphohistiocytosis [FHL] types 1-5); and other secondary or acquired form, generally associated with infections, malignancy, autoimmune diseases, metabolic disorders or primary immunodeficiencies. Since the first familial hemophagocytic lymphohistiocytosis-2 (FHL2) causative mutation in the PRF1 gene was described in 1999, more than 200 mutations have been identified to date. Here, we report the first case of very late-onset FHL2 in a Spanish 72-year-old female with splenomegaly, hypertriglyceridemia, hypofibrinogenemia, pancytopenia and marrow hemophagocytosis harbouring in heterozygosity two PRF1 variants proposed as causative in this study. The heterozygous mutation c.445G>A (p.Gly149Ser) identified in the exon 2 results in a missense mutation previously described as a probable pathogenic variant associated with the development of FHL2. Affecting the same exon, c.272C>T (p.Ala91Val) is the most prevalent variant of this gene. Although it was initially classified as benign, recent studies support its potential pathogenic role, considering it a variant of uncertain significance associated with a risk of developing FHL2. The genetic confirmation of FHL made possible an adequate counselling to the patient and direct relatives and provided important information for her control and follow-up.

Correction to: Long-term effectiveness and safety of self-management of oral anticoagulants in real-world settings.

After publication of the original article [1], we were notified that the name of the software mentioned in the Background section is TAONET and not Tao Net.

Long-term effectiveness and safety of self-management of oral anticoagulants in real-world settings.

BACKGROUND: The patient self-management (PSM) is an effective approach for controlling the international normalized ratio, INR, within the therapeutic range. Nevertheless, most of the literature derives from randomized clinical trials, and no from routine clinical practice. The main objective of the present study was to evaluate long-term effectiveness and safety of PSM of oral anticoagulants (OACs) in real-world settings. METHODS: This prospective cohort study involved 808 patients who were trained for PSM between July 2009 and March 2012, and followed-up for a maximum observational period of 5 years. The follow-up consisted of a visit to the physician every 6 months. All patients used the same type of portable coagulometer, able to store digitally up to 100 INR measurements. Effectiveness outcomes included the percentage of patients within the therapeutic range, the time within therapeutic range (TTR), and the evolution of the TTR over 365 days of follow-up. Long-term safety profile of PSM included the incidence of all-cause deaths and complications (thromboembolic or hemorrhagic) reported between July 2009 and June 2014, and the time to event. RESULTS: The median follow-up was 3.3 years. The percentage of patients within therapeutic INR target range was 67.5%. The median TTR was 71.5%. The TTR increased over the follow-up period, either overall and regarding target INR. All-cause mortality was 2.4 per 100 patient-years (59 cases). The thromboembolic event rate was 0.9 per 100 patient-years (24 cases). The rate of major hemorrhages was 0.45 per 100 patient-years. Patients who drop out the PSM to perform the conventional management had greater rates of complications: 2.4, 1.8, and 3.4 per 100 patient-years for thromboembolic complications, major hemorrhagic events, and mortality, respectively. CONCLUSIONS: The PSM of OACs is effective for maintaining patients within the INR therapeutic range for a long period of time in routine clinical practice. Results of the present study suggest that its effectiveness is at least comparable to the conventional management. Moreover, it seems safe in real-world settings, by preventing all-cause mortality, and thromboembolic and major hemorrhagic complications. TRIAL REGISTRATION: This study was not a trial, thus registration was not required.

Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data.

BACKGROUND: Uptake of self-testing and self-management of oral anticoagulation [corrected] has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism. METHODS: We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat. FINDINGS: Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12,800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0·51; 95% CI 0·31-0·85) but not for major haemorrhagic events (0·88, 0·74-1·06) or death (0·82, 0·62-1·09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0·33, 95% CI 0·17-0·66), as did participants with mechanical heart valve (0·52, 0·35-0·77). Analysis of major outcomes in the very elderly (age ≥85 years, n=99) showed no significant adverse effects of the intervention for all outcomes. INTERPRETATION: Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up. FUNDING: UK National Institute for Health Research (NIHR) Technology Assessment Programme, UK NIHR National School for Primary Care Research.

Comparing self-management of oral anticoagulant therapy with clinic management: a randomized trial.

BACKGROUND: Control of oral anticoagulant treatment has been reported to be suboptimal, but previous studies suggest that patient self-management improves control. OBJECTIVE: To compare the quality of control and the clinical outcomes of oral anticoagulant treatment in self-managed patients versus patients following conventional management. DESIGN: Randomized, controlled trial. SETTING: University-affiliated hospital in Spain. PATIENTS: 737 patients with indications for anticoagulant treatment. INTERVENTION: The self-management group (n = 368) received simple instructions for using a portable coagulometer weekly and self-adjusting treatment dose. The conventional management group (n = 369) received usual care in an anticoagulation clinic (monthly measurement and control of international normalized ratio [INR], managed by hematologists). MEASUREMENTS: Percentage of INR values within the target range and major related complications. RESULTS: The median follow-up period was 11.8 months (range, 0.3 to 16.9 months). The unadjusted percentages of in-range INRs were 58.6% in the self-management group and 55.6% in the conventional management group (difference, 3.0 percentage points [95% CI, 0.4 to 5.4 percentage points]). Twenty-seven patients (7.3%) in the conventional management group and 8 (2.2%) in the self-management group had major complications related to anticoagulant treatment. The unadjusted risk difference for major complications between groups was 5.1 percentage points (exact 95% CI, 1.7 to 8.5 percentage points). Fewer patients had minor hemorrhages in the self-management group (14.9%) than in the conventional management group (36.4%). Fifteen patients (4.1%) in the conventional management group and 6 (1.6%) in the self-management group died (unadjusted risk difference, 2.5 percentage points [exact 95% CI, 0.0 to 5.1 percentage points]). LIMITATIONS: The trial was performed at only 1 center and was not blinded. The dropout rate in the intervention group was 21%. CONCLUSIONS: Compared with conventional management by an anticoagulation clinic, self-management of oral anticoagulant treatment achieved a similar level of control. Of note, major complications and minor hemorrhages were less common in the self-management group.