Adeno-associated viral (AAV) vector gene therapy has shown promise as a possible cure for hemophilia. However, immune responses directed against AAV vectors remain a hurdle to the broader use of this gene transfer platform. Both innate and adaptive immune responses can affect the safety and efficacy of AAV vector–mediated gene transfer in humans. These immune responses may be triggered by the viral capsid, the vector’s nucleic acid payload, or other vector contaminants or excipients, or by the transgene product encoded by the vector itself. Various preclinical and clinical strategies have been explored to overcome the issues of AAV vector immunogenicity and transgene-related immune responses. Although results of these strategies are encouraging, more efficient approaches are needed to deliver safe, predictable, and durable outcomes for people with hemophilia. In addition to durability, long-term follow-up of gene therapy trial participants will allow us to address potential safety concerns related to vector integration. Herein, we describe the challenges with current methodologies to deliver optimal outcomes for people with hemophilia who choose to undergo AAV vector gene therapy and the potential opportunities to improve on the results.

Introduction: A recombinant porcine factor VIII B‐domain‐deleted product (rpFVIII; OBIZUR, Baxalta Incorporated, Deerfield, IL 60015, USA) was recently approved for treatment of bleeding episodes in adults with acquired haemophilia A (AHA) in the United States. To date, no clinical experience outside the registration study has been reported.Aim: To describe early clinical experience using rpFVIII for AHA.Methods: A retrospective chart review of seven patients with AHA treated with rpFVIII at four institutions from November 2014 to October 2015.Results: The time to diagnosis of AHA ranged from 5 days to 6 weeks. Six major and one other bleed were treated with rpFVIII following unsatisfactory bypassing agent (BPA) therapy. Good haemostatic efficacy was seen in five of seven cases. rpFVIII loading doses of 100 (n = 6) or 200 U kg⁻¹ (n = 1) increased FVIII activity from <1 to 9% at baseline to 109–650% within 0.25–7 h in six of seven cases. Subsequent median doses ranged from 30 to 100 U kg⁻¹ for 3–26 days. No rpFVIII‐related adverse events were reported. Three patients survived with inhibitor eradication, one with persistent inhibitor, two died with inhibitors present and one was discharged and later died from unrelated causes.Conclusions: rpFVIII showed good haemostatic efficacy with no recurrences in most cases, with consumption substantially less than in the registration study. Treatment decisions were based on FVIII activity levels and clinical assessment. The ability to titrate rpFVIII dose using FVIII activity was considered advantageous compared with BPA therapy. Notable delays in diagnosis were observed.

The rollout of the SARS-CoV-2 vaccine is underway, and millions have already been vaccinated. At least 25 reports of “immune thrombocytopenia” (ITP) or “thrombocytopenia” following the Moderna or Pfizer vaccine have been added to the Vaccine Adverse Event Reporting System (VAERS) in the US. ITP is a rare but known complication of several vaccinations. SARS-CoV-2 vaccine is new, with a novel mechanism of action, and understanding the epidemiology, clinical manifestations, treatment success and natural history of post-vaccination thrombocytopenia is evolving. We report a 74-year-old man who developed refractory thrombocytopenia within one day of receiving the Moderna SARS-CoV-2 vaccine. Several hours after vaccination, he developed significant epistaxis and cutaneous purpura. Severe thrombocytopenia was documented the following day, and he developed extremity weakness and encephalopathy with facial muscle weakness. Over a 14-day period, thrombocytopenia was treated first with high dose dexamethasone, intravenous immunoglobulin, platelet transfusions, rituximab, plasma exchange (for presumed acute inflammatory demyelinating polyneuropathy (AIDP)), and four daily doses of the thrombopoietin receptor agonist (TPO-RA) eltrombopag (Promacta™), without a platelet response. Three days later, he received the TPO-RA romiplostim (Nplate™). Five days later, his platelet count began to rise and by post-vaccination day 25, his platelet count was in the normal range. Thrombocytopenia was refractory to frontline and second-line treatment. The eventual rise in his platelet count suggests that one or both TPO-RAs may have impacted platelet recovery. Possibly, but less likely given the temporality, the drug-induced thrombocytopenia was subsiding. The aggressive use of immunosuppressive treatment may jeopardize the intended purpose of the SARS-CoV-2 vaccine, and earlier use of non-immunosuppressive second-line treatment for vaccine-related severe thrombocytopenia, such as with TPO-RAs, should be considered. While it is imperative to continue the global vaccination program, vigilance to the occurrence of post-vaccination severe thrombocytopenia is warranted.

Children with immune thrombocytopenia ≥6 months completing a romiplostim study received weekly subcutaneous romiplostim (1-10 mg/kg targeting platelet counts of 50-200x10⁹/L) in this extension to examine romiplostim's long-term safety and efficacy. Sixty-five children received romiplostim for a median (range) of 2.6 (0.1-7.0) years. Median baseline age was 11 (3-18) years and platelet count was 28 (2-458)x10⁹/L. No patient discontinued treatment for an adverse event. Median average weekly dose was 4.8 (0.1-10) mg/kg; median platelet counts remained >50x10⁹/L, starting at week 2. Nearly all patients (94%) had ≥1 platelet response (≥50x10⁹/L, no rescue medication in the prior 4 weeks), 72% responded at ≥75% of visits, and 58% responded at ≥90% of visits. Treatment-free response (platelets ≥50x10⁹/L ≥24 weeks without immune thrombocytopenia treatment) was seen in 15/65 patients while withholding romiplostim doses. At onset of treatment-free response, the nine girls and six boys had a median immune thrombocytopenia duration of 4 (1-12) years and had received romiplostim for 2 (1-6) years. At last observation, treatment-free responses lasted for a median of 1 (0.4-2.1) year, with 14/15 patients still in treatment-free response. Younger age at first dose and platelet count >200x10⁹/L in the first 4 weeks were associated with treatment-free responses. In this 7-year open-label extension, three-fourths of the patients responded ≥75% of the time, and romiplostim was well tolerated, with no substantial treatment-related adverse events. Importantly, 23% of children maintained treatment-free platelet responses while withholding romiplostim and all other immune thrombocytopenia medications for ≥6 months. (ClinicalTrials.gov #NCT01071954)

Antiphospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis with antiphospholipid antibodies. Dysregulation of the complement pathway has been implicated in APS pathophysiology. We report the successful use of eculizumab, an anti-C5 monoclonal antibody, in controlling and preventing recurrent thrombosis in a refractory case of APS. An 18-year-old female was diagnosed with APS after developing extensive, unprovoked deep vein thrombosis (DVT) of axillary, inferior vena cava, and brachiocephalic veins. Thrombophilia evaluation revealed triple-positive lupus anticoagulant, β-2 glycoprotein IgM, IgA, and anticardiolipin antibodies (each >40 U/mL) with persistently positive titers after 12 weeks. She was refractory to multiple anticoagulants alone (enoxaparin, fondaparinux, apixaban, rivaroxaban, and warfarin) with antiplatelet (aspirin and clopidogrel) and adjunctive therapies (hydroxychloroquine, immunosuppression with steroids and rituximab, and plasmapheresis). Despite these, she continued to develop recurrent thrombosis and additionally developed hepatic infarction and pulmonary embolism with failure to decrease titers after 6 weeks of plasma exchange. Following this event, eculizumab (600 mg weekly × 4 weeks followed by 900 mg every 2 weeks) was initiated in combination with fondaparinux, aspirin, clopidogrel, and hydroxychloroquine. She has remained on this regimen without recurrence of thrombosis. Our case suggests that eculizumab may have a role as a therapeutic option in refractory thrombosis in APS.