Moreover, the economic burden of such a complication is the highest reported for a chronic Venetoclax disease [6]. Over the past two decades, significant advances in genetics and molecular immunology and multinational efforts in conducting clinical studies enabled us to understand that inhibitors in haemophilia are not simply generated as a result of the immune response which recognizes the transfused FVIII as a foreign protein. There is an interplay of many genetic and non-genetic factors when replacement FVIII infusions

are first given, and this may affect the interaction of such an exogenous protein with the patient’s immune system [8,9]. In the light of growing knowledge of these mechanisms and risk factors, inhibitor development is no longer considered a completely unpredictable event and therefore tools to aid in risk stratification, which are useful in clinical practice, have been recently proposed [10]. In keeping with this knowledge,

epidemiological data of inhibitor formation may be revisited [1,11] and the identification of non-genetic, potentially modifiable, risk factors may provide a key for defining prevention strategies, particularly for patients having a high-risk genetic profile. The first and most extensively studied genetic Selleckchem Ceritinib factor is the causative FVIII gene (F8) mutation. A series of studies showed that the development of inhibitors correlates with the type and

location of F8 mutations [9,12–16]. There is general agreement that patients carrying mutations, which cause severe rearrangements of F8 and preclude the synthesis of the gene product, defined as null mutations (large deletions, inversions and nonsense mutations) are more susceptible to developing inhibitors to FVIII. On the other hand, missense mutations, associated with the synthesis of an endogenous but functionally abnormal protein, usually confer a low risk of inhibitor development. Leukocyte receptor tyrosine kinase Small insertions/deletions and splice site mutations are also considered lower risk genotypes, but this risk is reported more variable with respect to the location of the gene defect and its effects on the gene product. In patients with small deletions/insertions, the risk of inhibitor development is lower for mutations that occur within the A-runs compared with non-A-run abnormalities [13,15]; inhibitors were found from 17% to 44% of patients carrying splice site mutations [13–16]. Therefore, a more detailed stratification of mutation subclasses according to inhibitor risk has recently been proposed [16], but globally most patients carry mutations with a similar risk profile [9,13]. The Malmö International Brother Study (MIBS) clearly showed that for siblings, a family history of inhibitor development is associated with an approximately threefold higher risk to develop an inhibitor [17].