SummaryThis is the first report of skin testing, graded challenge and desensitization for VWF replacement products in patients with VWF deficiency. Patients who have experienced reactions to VWF products may benefit from these protocols.
Keywordsdesensitization; drug allergy; pediatric patient; skin testing; anaphylaxis; von Willebrand factor; factor VIII To the editor von Willebrand disease (VWD) is the most common inherited disorder of hemostasis, affecting approximately 1 in 1000 individuals in the population. VWD is caused by defects in the quantity or quality of von Willebrand factor (VWF), a multimeric glycoprotein that binds to collagen and platelets upon activation, leading to hemostasis. Clinical manifestations vary greatly between patients, and can range from mild mucocutaneous bleeding to musculoskeletal bleeding and stroke. 1,2 Type III VWD is the most severe form of the disorder and can be fatal. It affects about one in 1 million live births. 1 For these severe cases of VWD there are a variety of VWF replacement products. Unfortunately, a small number of patients, generally those with severe deleterious mutations, develop alloantibodies (most commonly polyclonal IgG) to such products, with estimates ranging from 5.8% to 9.5%. 3,4 Such antibodies, called inhibitors, Address correspondence to: Ana Dioun Broyles, Division of Immunology, Boston Children's Hospital, Boston, Massachusetts 02115, USA, Phone: 617-355 -6117, ana.broyles@childrens.harvard.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 5 There have also been reports of patients experiencing symptoms consistent with anaphylaxis when exposed to VWF or factor VIII replacement products (some of which contain VWF). [3][4][5][6] Prior studies have identified immune complex formation and complement activation as mediators of these reactions, rather than IgE. 3 Here, we describe two VWD patients with inhibitory alloantibodies to VWF who developed VWF infusion reactions, some of which were clinically consistent with anaphylaxis given documentation of urticaria, respiratory distress and hypotension. Evaluation and treatment was ultimately made possible through skin prick and intradermal testing, graded challenge and/or desensitization.
HHS Public AccessPatient 1 is a 2-year-old male from the United Arab Emirates who is one of several affected siblings with Type III VWD from a consanguineous marriage. Genetic analysis revealed a large deletion in the VWF gene (c.658_7887del: p.G220_L2629del). He required frequent VWF replacement infusions for recurrent bleeding episodes. Given the high frequency of these bl...