What are factor VIII inhibitors?

Updated: Feb 07, 2020
  • Author: Bishnu Prasad Devkota, MD, MHI, FRCS(Edin), FRCS(Glasg), FACP; Chief Editor: Eric B Staros, MD  more...
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Factor VIII inhibitors

Factor VIII inhibitors are the inhibitors that occur most commonly in the factor inhibitor assay. Although they are found most often in individuals with hemophilia who are receiving factor replacement, they can also occur in patients with autoimmune diseases and lymphoma and in pregnant (postpartal) or elderly patients.

Factor VIII inhibitors are measured in BU; highly potent inhibitors have levels of more than 10 BU.

A study by Chen et al of three global hemostatic assays—thromboelastography, Innovance ETP (endogenous thrombin potential), and Thrombinoscope—suggested that Thrombinoscope with platelet-poor plasma (PPP) reagent is sensitive enough to factor VIII inhibitors to monitor patients who have hemophilia with inhibitors. The assay, through assessment of thrombin-generation potential, demonstrated a dose-dependent response to different factor VIII–inhibitor concentrations. [13]

A study by Bachelet et al indicated that in replacement therapy for severe hemophilia A, the risk of developing factor VIII inhibitors is greater in patients who are HLA-DRB1*15 positive, with genotype G/A or A/A for IL10 rs1800896. In contrast, the investigators reported that the risk is low in patients who are HLA-DRB1*15/HLA-DQB1*02 negative, with genotype T/T or G/T for CD86 rs2681401. [14]

The Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) study indicated that in children with severe hemophilia A who have previously undergone minimal or no treatment, those who receive therapy with recombinant factor VIII products have twice the chance of developing inhibitors as do those treated with plasma-derived factor VIII, during the first 50 exposure days. A survey by Sande et al of hemophilia providers suggested that the SIPPET results have influenced the choice of factor VIII therapy being used in the United States, with employment of the recombinant agent for patients with minimal or no previous treatment decreasing from 70.5% to 27.8% of the clinicians and utilization of plasma-derived factor VIII rising from 8.2% to 16.7% of the providers. [15, 16, 17]

In order to predict the response of a patient with hemophilia to factor replacement therapy, factor VIII inhibitor should be measured before the patient undergoes any significant invasive procedure. It is important to confirm the patient's response to factor administration before the procedure is begun.

In the short-term, the inhibitors for low titers may be overridden by infusion of factor VIII concentrate, although in some patients, such infusion may increase the inhibitor titer. Infusion of prothrombin complex concentrate (PCC), activated PCC, porcine factor VIII concentrates, and VIIa have been found to be useful for high-titer inhibitors. [18] To manage inhibitors, it is efficacious to use combined immunosuppressant programs that include steroids, cytotoxic agents, plasma processing over columns that remove IgG and IgG-containing immune complexes, [19] and high-dose intravenous immunoglobulin.

Rituximab therapy, while effective in patients with high titers of acquired factor VIII, may not produce a sustained response on its own. It may therefore be better to combine rituximab with other therapies in high-risk individuals. [20, 21, 22, 23]

In persons without hemophilia, inhibitors are more responsive to simple immunosuppressive agents such as prednisone and azathioprine. However, inhibitors must be controlled in such patients to avoid an increase in the risk of bleeding. Owing to the high risk of hemorrhage, an emphasis has been placed on meticulous perioperative hemostatic correction. Following major surgery, it is necessary to maintain the correction for at least 10 days to prevent delayed hemorrhage. [18]

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