In people with bleeding disorders, the clotting process doesn’t work properly. As a result, people with bleeding disorders can bleed for longer than normal, and some may experience spontaneous bleeding into joints, muscles, or other parts of their bodies. Hemophilia is a bleeding disorder that affects approximately 1 in 10,000 people. People with hemophilia do not have enough clotting factor VIII or IX in their blood. As a result, they can bleed for longer than normal. The most common bleeding disorder is von Willebrand disease (VWD). It is generally less severe than other bleeding disorders. Many people with VWD may not know that they have the disorder because their bleeding symptoms are very mild. Rare clotting factor deficiencies are disorders in which one of several clotting factors is missing or not working properly. Less is known about these disorders because they are diagnosed so rarely. In fact, many have only been discovered in the last 40 years. Finally, inherited platelet disorders are conditions in which platelets don’t work the way they should, resulting in a tendency to bleed or bruise.
About Inhibitors according to The Guideline for Haemophilia Management:
** “Inhibitors” in hemophilia refer to IgG antibodies that neutralize clotting factors.
** In the current era in which clotting factor concentrates have been subjected to appropriate viral inactivation inhibitors to FVIII or FIX are considered to be the most severe treatment related complication in hemophilia.
** The presence of a new inhibitor should be suspected in any patient who fails to respond clinically to clotting factors, particularly if he has been previously responsive. In this situation, the clotting factor are severely diminished.
** Inhibitors are more frequently encountered in persons with severe hemophilia compared to those with moderate or mild hemophilia.
** The cumulative incidence (i.e. lifetime risk) of inhibitor development in severe hemophilia A is in the range of 20-30% and approximately 5-10% in moderate or mild disease.
** In severe hemophilia A, the median age of inhibitor development is three years or less in developed countries. In moderate/mild hemophilia A, it is closer to 30 years of age, and is often seen in conjunction with intensive FVIII exposure with surgery.
** In severe hemophilia, inhibitors do not change the site, frequency, or severity of bleeding. In moderate or mild hemophilia, the inhibitor may neutralize endogenously synthesized FVIII, thereby effectively converting the patient’s phenotype to severe.
** Bleeding manifestations in moderate/mild hemophilia complicated by an inhibitor are more frequently reminiscent of those seen in patients with acquired hemophilia A (due to auto-antibodies to FVIII), with a greater predominance of mucocutaneous, urogenital, and gastrointestinal bleeding sites . Consequently, the risk of severe complications or even death from bleeding may be significant in these patients.
** Inhibitors are much less frequently encountered in hemophilia B, occurring in less than 5% of affected individuals.
** In all cases, inhibitors render treatment with replacement factor concentrates difficult. Patients on clotting factor therapy should therefore be screened for inhibitor development.
** Confirmation of the presence of an inhibitor and quantification of the titre is performed in the laboratory, preferably using the Nijmegen-modified Bethesda assay.
** For children, inhibitors should be screened once every five exposure days until 20 exposure days, every 10 exposure days between 21 and 50 exposure days, and at least two times a year until 150 exposure days.
** For adults with more than 150 exposure days, apart from a 6-12 monthly review, any failure to respond to adequate factor concentrate replacement therapy in a previously responsive patient is an indication to assess for an inhibitor.
** Inhibitor measurement should also be done in all patients who have been intensively treated for more than five days, within four weeks of the last infusion.
** Inhibitors should also be assessed prior to surgery or if recovery assays are not as expected, and when clinical response to treatment of bleeding is sub-optimal in the post-operative period.
** A low responding inhibitor is defined as an inhibitor level that is persistently < 5 BU/ml, whereas a high responding inhibitor is defined by a level ≥ 5 BU/ml.
** High responding inhibitors tend to be persistent. If not treated for a long period, titre levels may fall or even become undetectable, but there will be a recurrent anamnestic response in three to five days when challenged again with specific factor products.
** Some low titre inhibitors may be transient, disappearing within six months of initial documentation, despite recent antigenic challenge with factor concentrate.
** Very low titre inhibitors may not be detected by the Bethesda inhibitor assay, but by a poor recovery and/or shortened half-life (T-1/2) following clotting factor infusions.