Emicizumab: a novel drug in hemophilia A prophylaxis - a narrative review.

INTRODUCTION: Hemophilia A is a genetically conditioned disease leading to hemostatic disorders due to factor VIII (FVIII) deficiency. The treatment of hemophilia has evolved throughout the past years and has significantly changed. One of the newest drugs for prophylactic treatment is the humanized bispecific IgG antibody - emicizumab, which binds with factor IXa and factor X, bridging those factors and thus mimicking the activity of factor VIII. AREAS COVERED: The literature search was done via the PubMed database, with the emphasis on clinical trials and case reports, describing the off-label emicizumab use. This review presents an extensive summary and considers the advantages and disadvantages (side-effects) of emicizumab, describing additional clinical situations, where emicizumab has been successfully used. In our review, we cover information about the mechanisms of action, indications, and efficacy and discuss some chosen case reports about off-label emicizumab use. EXPERT OPINION: Its convenient administration method (subcutaneous) and frequency of injections (from once a week to once a month) makes it a more comfortable treatment, limiting injection-site reactions, hospital stays, costs of prophylaxis, and significantly increasing patients' quality of life. Adverse effects are scarce and rarely serious - the most common ones are reactions at the injection-site and upper respiratory tract infections.

Inhibitors among patients with hemophilia in Basra, Iraq - A single center experience.

INTRODUCTION: Inhibitor formation is a major complication of hemophilia treatment because it interferes with the clinical response to factor replacement and causes significant morbidity. This cross-sectional study was conducted to assess the presence and frequency of inhibitors among registered person with hemophilia and to identify risk factors associated with inhibitor development. PATIENTS AND METHODS: A total of 143 hemophilics, 118 with hemophilia A (HA) and 25 with hemophilia B (HB), were enrolled for the study. Participant's clinical data were obtained through patient's medical records. Factor VIII and IX levels and the presence of inhibitors were assessed using a fully automated coagulometer. From the results of a Bethesda assay, patients were divided into those with high titers (≥5 BU) and those with low titers (<5 BU). RESULTS: The patient's age ranged from 1 to 67 years with median of 13.8 years. Inhibitors were detected in 18.6% and none of HA and HB patients, respectively. Of the 22 patients with HA and inhibitors, 18 (82%) had high titer inhibitors. The frequency of inhibitors was significantly higher among patients with severe hemophilia, a history of early exposure (≤3 months) to factor VIII concentrate, and family histories of autoimmune disease and immune system challenges (P < 0.05). The independent risk factors associated with inhibitor development were severe hemophilia (95% CIs = 1.02-55.6, OR = 7.5) and immune system challenges (95% CIs = 1.14-5.99, OR = 2.6). CONCLUSION: Inhibitors were common among HA patients, and both severe HA and immune system challenges (surgery and trauma) are independent risk factors for inhibitor development.

A reversible aptamer improves outcome and safety in murine models of stroke and hemorrhage.

Treatment of acute ischemic stroke with intravenous tissue-type plasminogen activator is underutilized partly due to the risk of life-threatening hemorrhage. In response to the clinical need for safer stroke therapy, we explored using an aptamer-based therapeutic strategy to promote cerebral reperfusion in a murine model of ischemic stroke. Aptamers are nucleic acid ligands that bind to their targets with high affinity and specificity, and can be rapidly reversed with an antidote. Here we show that a Factor IXa aptamer administered intravenously after 60 minutes of cerebral ischemia and reperfusion improved neurological function and was associated with reduced thrombin generation and decreased inflammation. Moreover, when the aptamer was administered in the setting of intracranial hemorrhage, treatment with its specific antidote reduced hematoma volume and improved survival. The ability to rapidly reverse a pharmacologic agent that improves neurological function after ischemic stroke should intracranial hemorrhage arise indicates that aptamer-antidote pairs may represent a novel, safer approach to treatment of stroke.

Clinical experience with the use of clotting factor concentrates in oral anticoagulation reversal.

We report the clinical experience of a large Haemophilia Centre and Haemostasis Unit in reversing oral anticoagulation (OAC) using clotting factor concentrates. This is a retrospective study extending over 2 years (January 1996-December 1997). Reversal was performed using a combination of factor IX and factor VII concentrates administered by intravenous infusion. in a dose varying between 12 i.u./kg and 50 i.u./kg. We identified 20 episodes of OAC reversal in 18 patients, with a prevalence of 10 reversal episodes/1000 OAC patients/year. The median age was 77 years old (range 53-92 years). Indications for OAC reversal were divided into major bleeds (muscle haematoma [9], haematuria [3], subarachnoid haemorrhage [1], oesophageal bleeding [1], haemoptysis [1], haemarthrosis [1]); minor bleeds (extensive bruising [9], epistaxis [3], oral cavity bleeding [1]); and emergency invasive investigation (2). Pre-reversal, the international normalized ration (INR) was greater than 6.0 in 15/18 patients. Post-infusion. there was an immediate reduction in the INR towards normal (mean 1.3; range 1.1-2.3). There were no thrombotic complications or other adverse effects. The median use of factor 9 A concentrate was 2300 units/patient (range 570-4195), at a cost of 645 Pounds/patient and for factor VII concentrate 2200 units/patient (range 815-3630), at a cost of 664 Pounds/patient. Clotting factor concentrates provide a safe, rapid and effective means for OAC reversal and although expensive it is the treatment of choice in the over anticoagulated, bleeding patient.

High purity factor IX and prothrombin complex concentrate (PCC): pharmacokinetics and evidence that factor IXa is the thrombogenic trigger in PCC.

Recent studies using assays for surrogate markers of thrombogenicity in man have demonstrated that activation of the coagulation system occurs following infusion of clinical doses of prothrombin complex concentrates (PCC) but not after the same doses of high-purity factor IX concentrates (HP-FIX) in patients with haemophilia B. Here we have investigated the mechanism of such thrombogenesis by applying assays that detect early-through to late-events in coagulation system activation in a pharmacokinetic cross-over study of 50 IU/kg PCC and a new HP-FIX product in haemophilia B patients. Satisfactory recoveries and half-lives were observed for both concentrates. HP-FIX caused no increases in thrombin-antithrombin III complex (TAT), prothrombin activation peptide fragment F1+2 (F1+2), factor X activation peptide (FXAP) or factor VIIa (FVIIa). In contrast the same dose of factor IX in the form of PCC was followed by significant increases over pre-infusion levels of TAT, F1+2 and FXAP, but not FVIIa. Elevations of FIXAP occurred after both HP-FIX and PCC but did not reach normal levels and were attributed to normalisation of the FIX concentration in those patients whose levels of FIXAP were initially low. We conclude that the thrombogenic trigger associated with PCC infusion occurs at the level of factor X activation. In the absence of any increase in FVIIa, we would attribute this to the likely presence of FIXa in the PCC.

The problem of therapeutic equivalence with paired qualitative data: an example from a clinical trial using haemophiliacs with an inhibitor to factor VIII.

The problem of demonstrating the equivalence of two treatments or drugs occurs fairly frequently in medicine, but is quite often misformulated. The common error is to assume equivalence is demonstrated if the usual null hypothesis of no difference is not rejected, which ignores the potential of a substantial beta-error. We describe here two procedures for testing equivalence when the data are paired and dichotomous, and provide sample size formulas. We give an example based on a clinical trial of haemophiliacs with inhibitor to Factor VIII.