Alloantibodies and Congenital Bleeding Disorders: New Insights in the Pathogenesis and Management

Abstract

The hemophilia community is living in exciting times, thanks to recent and relevant developments in this field and great expectations for new treatment approaches that are able to significantly and positively affect patients' outcomes and quality of life. 1-5 Interestingly, one most important innovation, a hemostatic agent enabling a very effective prophylaxis of bleeding given subcutaneously (the bispecific antibody against factor [F] X and activated FIX emicizumab), 2,3 is being introduced for patients who developed alloantibodies against FVIII, the so-called inhibitors. The management of these patients has always been considered challenging because inhibitors make the standard effective and safe replacement with FVIII concentrates unfeasible and, therefore, make difficult the treatment of bleeding, leaving patients at a high risk of complications, both in the acute phase and in regard to long-term morbidity. 6 Due to the epidemiological impact of inhibitors (present in 30% of previously FVIII-unexposed patients and persistent/high titer in two-thirds of cases), 6,7 searching for pathophysiological mechanisms and strategies for management is particularly important in hemophilia A (HA). Indeed, a relevant body of literature addressing such issues has been generated over the last decades. However, significant challenges are also raised by the inhibitors encountered, albeit less frequently, in clinical practice in other congenital bleeding disorders (CBDs): (1) in hemophilia B (HB) and von Willebrand's disease (VWD), additional morbidity due to allergic reactions can occur; 6,8 (2) in rare CBDs, little information concerning management is available; 9 and (3) in deficiencies of platelet membrane glycoproteins, the clinical impact of alloantibodies and alternative treatment approaches are poorly understood. 10 With this background, the 11 chapters presented in this latest issue of Seminars in Thrombosis andHemostasis deal with the current state of the art of pathophysiology and management of alloantibodies in CBDs. It is easy to understand why seven of them focus on hemophilia, particularly on HA, discussing, at this current time of possible evolving scenarios, the most recent literature data. Alloantibodies in HB, VWD, rare CBDs, and congenital deficiencies of platelet surface glycoproteins are reviewed in the remaining four chapters.Three chapters focus on novel approaches to gain insight into molecular mechanisms of inhibitor development in hemophilia. In this respect, the role of genetic factors, particularly of the causative mutation type, and their complex interaction with nongenetic risk factors are well established, with extensive studies in HA. 11,12 Margaglione and Intrieri therefore briefly review available evidence concerning both genetic, nonmodifiable and potentially modifiable risk factors, highlighting the so far unanswered need for clinical scoring systems to predict and quantify the inhibitor risk in each patient. 13 These authors also report how complex and multifactorial phenomena, such as inhib...