Over the last decade, the world of hemophilia has experienced an unprecedented therapeutic advance, thanks to the progress in bioengineering technologies, leading to the introduction of drugs with novel mechanisms of action based on restoring thrombin generation or coagulation factor VIII mimicking. Apart from the bispecific monoclonal antibody emicizumab, already approved for patients with severe hemophilia A with and without inhibitors, novel non-replacement drugs designed to reduce the treatment burden of patients with hemophilia A or B with or without inhibitors are undergoing evaluation in clinical trials. Thanks to their innovative mechanism of action and subcutaneous administration, these drugs promise to provide effective bleeding protection together with improved adherence and improve health-related quality of life for patients with hemophilia. On the other hand, rare thromboembolic events have been reported with some of these drugs and warrant continuous post-marketing surveillance and investigation of predisposing factors, although the overall safety profile of most of these drugs is good. Finally, new challenges need to be faced in the clinical and laboratory monitoring of the hemostatic status in patients treated with these innovative therapies. In this review, we provide an update on the available data on novel non-replacement drugs currently undergoing evaluation in clinical trials for patients with hemophilia.
Congenital thrombotic thrombocytopenic purpura (cTTP) is a very rare thrombotic microangiopathy. Its rarity and great phenotype heterogeneity may account for misdiagnosis. We report the history of a middle‐aged woman with cTTP, misdiagnosed until adulthood. Accurate clinical history is crucial for early diagnosis to prevent long‐term sequelae. Summary Thrombotic thrombocytopenic purpura (TTP) is an acute life‐threatening disorder characterized by multiple organ ischemia due to disseminated thrombus formation in the microvasculature. The congenital form of the disease (Upshaw‐Schulman syndrome) is related to ADAMTS13 mutations. Adulthood‐onset of TTP does not exclude the congenital form of the disease and a diagnostic delay may account for a great morbidity burden in these patients. We describe the case of a middle‐aged woman who presented to our attention with a clinical diagnosis of a chronic relapsing form of TTP. The medical history of the patient raised the suspicion of a congenital form of TTP. Phenotype and genotype tests were performed, and clinical diagnosis was confirmed. Upshaw‐Schulman syndrome is a rare congenital disease with a great phenotype heterogeneity that can be diagnosed also in adulthood. Accurate clinical history is crucial. Early diagnosis can prevent recurrences and long‐term organ damage with long‐term sequelae.
Prophylactic therapy has become the standard of care for patients with hemophilia A (HA); however, prophylaxis regimens that require 2 to 3 weekly infusions of drug are challenging. In the past decade, new factor VIII (FVIII) molecules with extended plasma half-life have been produced with the goal of reducing the number of infusions while maintaining higher trough levels of FVIII in plasma. [1][2][3][4] One of the most established approaches to prolong the circulation time while preserving the biological activity is the covalent link of polyethylene glycol (PEG) chains to therapeutic proteins. To date, several PEGylated drugs are available for the treatment of a variety of chronic diseases including the recently marketed SARS-CoV-2 vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), containing PEGylated lipids. [5][6][7] Moreover, PEG is widely used in the formulation of common personal care products. 8 Concerning the treatment of HA, 3 novel PEGylated recombinant FVIII (rFVIII) products, rurioctocog alfa pegol, turoctocog alfa pegol, and damoctocog alfa pegol, have been authorized by the Food and Drug Administration and European Medicines Agency; these rFVIII molecules have a mean half-life 1.3 to 1.7 times longer than the standard rFVIII and show comparable safety and pharmacokinetic (PK) profiles. 9Although PEG is a nonimmunogenic polymer, pre-existing anti-PEG antibodies (APAs) have been reported in persons never treated with PEGylated biopharmaceutics with increasing incidence up to 72% over the years. 10,11 Usually, pre-existing APAs have no clinical relevance but in few cases showed the potential to bind a PEGylated drug, enhancing its blood clearance and reducing therapeutic efficacy. 12,13 In this report, we describe the poor plasma FVIII recovery observed in 2 patients with HA following their first infusion with the PEGylated rFVIII products associated with the presence of anti-PEGylated rFVIII antibodies after the BNT162b2 SARS-CoV-2 vaccination.Patient 1 is a 42-year-old man on prophylaxis with 37 IU/kg every 3 days of a standard rFVIII product (NovoEight, Novo Nordisk A/S). In April and May 2021, the patient received his first and second dose of the BNT162b2 vaccine. In June 2021, 52 days after the first and 25 days after the second dose, before his switch to a novel PEGylated rFVIII, he underwent the PK study by the injection of 50 IU/kg of turoctocog alfa pegol (Figure 1).Patient 2 is a 24-year-old male on prophylaxis with 32 IU/kg 2 times a week of a standard rFVIII product (Kovaltry, Bayer AG). In October and November 2021, he received his first and second dose of the BNT162b2 vaccine. In December 2021, 57 days after the first dose and 26 days after the second dose, he underwent the PK study with the injection of 50 IU/kg of damoctocog alfa pegol (Figure 1). Plasma samples from both patients were collected before and after the PEGylated rFVIII infusion as well as before the first SARS-CoV-2 vaccination. For patient 1, a further plasma sample was obtained almost 1 year after the second ...
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