Allergic reaction in a cohort of haemophilia A patients using plasma‐derived factor VIII (FVIII) concentrate is rare and not necessarily triggered by FVIII

Abstract

In contrast to haemophilia B, allergic manifestations are rare complications in haemophilia A (HA) patients treated with factor VIII (FVIII) concentrates. Nevertheless, it can be serious and hamper replacement therapy in these cases. The aims of this study were to evaluate the frequency of allergic reaction in a cohort of HA patients treated only with plasma-derived FVIII (pdFVIII) concentrates, and assess the possible immune mechanisms involved. History of allergic reaction was retrospectively assessed. Patients with allergic manifestations were followed, and had plasma samples collected in different timepoints in relation to the allergic episode. These samples were analysed for the presence of inhibitor and anti-FVIII immunoglobulins subclasses. Three of 322 HA patients (0.9%) developed allergic reaction after exposure to pdFVIII products during the last 15 years in our centre. The first patient, with severe HA, without inhibitor, had anti-pdFVIII IgE and IgG4, but no anti-recombinant FVIII (rFVIII) IgE. The second patient, with severe HA, and high-responding inhibitor, presented allergic manifestation with both, pdFVIII concentrate and activated prothrombin complex concentrate. Although anti-pdFVIII and anti-rFVIII IgG4 were detected, no anti-FVIII IgE was present. The third patient, with moderate HA without inhibitor, atopic, had no anti-FVIII immunoglobulin detected, and allergic symptoms disappeared after switching to rFVIII concentrate. This study corroborates the low incidence of allergic reactions in HA patients. In the three cases presented, the anti-FVIII immunoglobulin profile demonstrated that the allergic manifestation was triggered by other proteins contained in pdFVIII products, and not directed to FVIII.

Anaphylaxis after treatment with recombinant factor VIII: investigation and therapeutic challenge

“…Despite its rarity, FVIII allergy can be life threatening and hamper replacement therapy. There are reports of anaphylactic reactions in patients with HA with allergy either to plasma derivate3–5 7–9 and recombinant FVIII concentrates 3–6 9. When these reactions occur it is mandatory for a clinical investigation to exclude other causes (eg, fast rate of drug administration) and to search for therapeutic alternatives.…”

“…Also, in haemophilia B, allergic reactions are implicated in a higher risk of inhibitors development, which does not happen in HA 2. There are few published reports of anaphylactic reaction in patients treated with FVIII3–10 and the mechanisms involved in these events remain controversial. The allergic investigation is essential to identify a safe alternative treatment for these patients.…”

Rapid desensitization and subsequent immune tolerance induction in a patient with hypersensitivity and inhibitor to factor VIII

“…Allergic reactions with FVIII are uncommon and occur in <1% of patients. 2,3 Initial management of hypersensitivity typically includes pretreatment with antihistamines and corticosteroids, and/or switching to another FVIII preparation. 4 Alternatively, a few patients with hypersensitivity reactions have undergone successful desensitization to FVIII.…”

“…Hypersensitivity reactions have been reported when using both plasma-derived and recombinant FVIII concentrates including one patient who also developed a low-titre inhibitor (Table 2). [3][4][5][6][7][8][9][10] In some of these cases, the hypersensitivity was F I G U R E 1 Time course of factor VIII inhibitor titres and major infusion events as described in the text. BU, Bethesda Unit Desensitization to FVIII has been reported in at least two cases using step-wise increases of FVIII infusions over several weeks, with prolonged use of antihypersensitivity medications.…”

Quality laboratory issues in bleeding disorders

“…Another context regarding the presence of anti‐FVIII antibodies is the occurrence of allergic reactions to FVIII products. In these patients, IgE anti‐FVIII antibodies with or without IgG4, were identified at the time of the allergic reaction .…”