Assessing the Impact of Age and Inhibitor Status on Functional Limitations of Patients with Severe and Moderately Severe Hemophilia a: Analysis from the Hemophilia and Thrombosis Research Society (HTRS) Registry.

Abstract

As many as 30% of patients with severe hemophilia A develop inhibitors that interfere with effective Factor VIII replacement therapy, and result in bleeding episodes that are difficult to treat. Poorly controlled joint bleeds lead to progressive joint disease and mobility dysfunction. It is presumed that the presence of inhibitors negatively impacts activity levels as well as employment and productivity throughout life. Few data exist on the relative impact of age and inhibitor status on activity levels among patients with severe and moderately severe hemophilia A. The Hemophilia and Thrombosis Research Society launched a registry in 1999 to collect information on subjects diagnosed with bleeding disorders and on their bleeding episodes. As of July 2008, there were 2497 patients registered in the database including 1340 with congenital hemophilia A (333 with inhibitors). Data on activity status was available for 330 subjects with hemophilia A who had ever had an inhibitor (inhibitor group), and 251 subjects with FVIII levels ≤ 2% who had never had an inhibitor (non-inhibitor group). The data was analyzed by age to compare children, adolescents, young adults and older adults. The results show that functional impairment increases with age in both the inhibitor group and non-inhibitor group (chi square, p<0.001 for both groups). Ordinal regression analysis shows patients in the inhibitor group demonstrate a trend towards increased physical impairment when compared to the non-inhibitor group when controlling for age effects (p=.053).AgeCurrent Activity< 1313–2122–45>45Without Inhibitors, n2409315049% Unrestricted164 (68.3%)55 (59.1%)57 (38.0%)16 (32.7%)% Full school/wk with limits24 (10.0%)10 (10.8%)35 (23.3%)13 (26.5%)% Limited school/wk2 (0.8%)5 (5.4%)22 (14.7%)8 (16.3%)% Limited school/wk & self care0 (0.0%)0 (0.0%)9 (6.0%)6 (12.2%)% Requires assistance0 (0.0%)1 (1.1%)4 (2.7%)0 (0.0%)% Unknown/Not Recorded50 (20.8%)22 (23.7%)23 (15.3%)6 (12.2%)With Inhibitors, n186586917% Unrestricted127 (68.3%)26 (44.8%)10 (14.5%)3 (17.6%)% Full school/wk with limits17 (9.1%)12 (20.7%)21 (30.4%)3 (17.6%)% Limited school/wk12 (6.5%)7 (12.1%)15 (21.7%)5 (29.4%)% Limited school/wk & self care1 (0.5%)0 (0.0%)4 (5.8%)2 (11.8%)% Requires assistance1 (0.5%)0 (0.0%)6 (8.7%)2 (11.8%)% Unknown/Not Recorded28 (15.1%)13 (22.4%)13 (18.8%)2 (11.8%)Highest and current inhibitor titers were characterized in 301 of 333 patients. Mean highest inhibitor titers (n=301) was 465 BU (median 50, range 0.6–20,000). Current mean inhibitor titer was 26.5 BU (median 0.1, range 0 – 602). Further analysis of the inhibitor group showed that while 67% of the under 13 age group had been exposed to immune tolerance induction (ITI), only 55% of the 13 – 21 age group had been exposed to ITI; the proportion of subjects exposed to ITI falls to 26% in the adults over age 21.The HTRS Registry contains one of the largest prospectively accumulated data sets of patients with congenital hemophilia with alloantibody inhibitors. A key advantage of this registry is that it tracks any patient with a history of inhibitors, rather than just current titers, making analysis of demographic data in this group possible. The most striking results from our review of the registry data are the extent to which inhibitor development poses the risk of progressive physical limitations to patients with severe and moderately severe hemophilia over and above effects of age, and confirms that the increased odds of physical impairment becomes apparent early, in the youngest cohort of patients, and continues to widen with advancing age. These results reaffirm the need for early eradication of inhibitors and better strategies for prevention of bleeds in both inhibitor and non-inhibitor patients. This analysis also highlights the benefit of ongoing study of these patients through HTRS.