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Hemophilia A and B: sharing differences
It is interesting to note that the results of a recent study by Cooley et al.39 also suggest that the total amount of FIX is approximately three times larger than what can be measured in the intravascular compartment.
The accessible intravascular compartment from which we collect our plasma samples to measure FIX activity might not, therefore, be reflecting the overall coagulative capacity of the endogenous FIX, but may only reveal information about the fraction that is freely circulating. This adds up to the inter-laboratory differences in FVIII:C and FIX:C measurements and it should be borne in mind that also misclassification might explain, at least in part, the discrepancy in the bleeding tendency between severe HA and HB patients.
Altogether, the information available so far on the phar- macokinetic and pharmacodynamic characteristics of FIX suggest some potential mechanisms that could explain a difference in bleeding tendency between HB and HA patients.
Inhibitor development - the occurrence of high affinity anti-FVIII or anti-FIX antibodies that neutralize the activi- ty of the infused clotting factor is a major complication of replacement therapy in hemophilia patients. Inhibitor antibodies against FVIII can develop in approximately 25- 30% of severe HA patients; in contrast, in patients with HB, inhibitors develop in only 3-5% of patients treated with factor concentrates.44 Immune tolerance induction (ITI) via long-term, intravenous administrations of factor concentrates is the only proven strategy to eradicate inhibitors. However, this approach is expensive and impractical for the patients.45 Overall, it is successful in approximately 60-70% of HA patients. The results of a
randomized, controlled study comparing high-dose (200 IU/Kg/day) and low-dose (50 IU/Kg/3 times a week) pro- tocols in a cohort of severe HA patients with high-titer inhibitor showed a similar overall success rate and no sta- tistically significant differences in time to achieve toler- ance, but the median time to negative inhibitor titer was 4.6 months (range: 2.8-13.8).46
Although the development of inhibitors to FIX is a much less common event, ITI treatment is not as success- ful (only approx. 30%), and the development of anti-FIX antibodies may be associated with anaphylactic reactions which may prevent or complicate ITI regimes in a signifi- cant proportion of cases.47 HB patients undergoing ITI can also develop nephrotic syndrome.48,49 However, a few anecdotal experiences suggest that ITI could be successful- ly achieved by adding immunosuppression treatment, especially in patients with anaphylactic reactions.50
Conclusions
Different lines of evidence seem to support a difference in bleeding severity between HA and HB. The pathophys- iology of the two disorders is, indeed, diverse, with a dif- ferent distribution of the factors in the body and, in keep- ing with this, the PK characteristics of infused factors are significantly different. However, because of the rarity of the disorders, no prospective, head-to-head comparative studies have been carried out, and the modern approach in the pediatric hemophilia population (i.e. starting prophy- laxis very early) does not allow us to acquire a better understanding of the possible clinical differences during follow up. Improved replacement therapy with extended half-life concentrates with 10- to 14-day intervals between infusions and sustained high FIX troughs51 are greatly
Figure 2. Possible mechanisms involved in the differences in clinical evolution between hemophilia A and hemophilia B patients. FIX: factor IX.
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