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Von Willebrand's disease (VWD) is the most common hereditary blood-clotting disorder caused by a deficiency of von Willebrand Factor (VWF) and characterized by a defective platelet adhesion and aggregation.1 Replacement therapy with plasma-derived von Willebrand factor-containing factor VIII concentrate (pdVWF/FVIII) is indicated as treatment of choice for surgical and invasive procedures in adult and paediatric patients with severe VWD, when desmopressin (DDAVP) is either ineffective or contraindicated.2,3 The presence of functional VWF is estimated by the VWF:RCo/FVIII:C ratio and may vary among pdVWF/FVIII concentrates.4 Fanhdi SP ® sp (Instituto Grifols S.A., Barcelona, Spain) is a pdVWF/FVIII concentrate characterized by a high content in VWF, with a VWF:RCo/FVIII:C ratio of 1.58±.20.5 Clinical efficacy of Fanhdi SP ® sp has been assessed extensively in VWD patients, to prevent recurrent bleedings in the management of surgery.5-7 However, the available data is retrospective and the only prospective study supporting its use reported interim results only.8 The preliminary interim analysis showed that Fanhdi SP ® sp could be successfully used as a replacement therapy in VWD patients requiring prophylactic treatment during surgeries.8 We report here the final efficacy and safety analysis of this multicentre prospective clinical trial. During the post-surgery period, minor surgeries were treated with 30.6 (19.6-41.7) IU/kg FVIII and 43.6 (25.6-61.7) IU/kg VWF:RCo; and major surgeries with 245.0 (12.5-520.7) IU/kg FVIII and 416.9 (24.6-924.1) IU/kg VWF:RCo. Efficacy and safety evaluation of Fanhdi®, a plasma-derived factor VIII/ von Willebrand factor concentrate, in Von Willebrand's disease patients undergoing surgery or invasive procedures: A prospective clinical study Successful treatment for patients with von Willebrand disease undergoing urgent surgery using factor VIII/VWF concentrate (Humate-P). [Extracted from the article]

Introduction: As a result of the new treatment paradigm that the haemophilia community will face with the availability of novel (non‐factor) therapies, an updated consensus on ITI recommendations and inhibitor management strategies is needed. Aim: The Future of Immunotolerance Treatment (FIT) group was established to contemplate, determine and recommend the best management options for patients with haemophilia A and inhibitors. Discussion and Conclusions: Despite the considerable success of emicizumab in the management of inhibitor patients, the FIT group still sees the importance of eradicating inhibitors. However, the availability of emicizumab and other non‐factor therapies in the future might impact greatly on how ITI is undertaken. Theoretically, concomitant use of emicizumab and FVIII might allow emicizumab to effectively prevent bleeding with lower dose ITI regimens. This might allow for the greater adoption of low‐dose/low‐frequency FVIII ITI regimens, which may result in a reduced need for central venous access devices while still maintaining a reasonable likelihood of ITI success. The FIT group proposes a new management algorithm for current ITI (without emicizumab) and a hypothetical new approach with the availability of emicizumab. As there are no published data regarding the concomitant use of emicizumab and FVIII for ITI, the FIT Expert group encourages the undertaking of properly conducted prospective studies to explore these approaches further. [ABSTRACT FROM AUTHOR]

Hemophilia is the major congenital hemorrhagic disorder. The administration of the deficient factor can trigger the development of antibodies, also known as inhibitors, capable of neutralizing the infused protein function. This is considered the most serious complication in hemophilia and usually occurs in the first years of life after the first doses of factor concentrate are given; hence, the main objective in these patients is to permanently eradicate these inhibitors. Current treatments are based on immunotolerance induction (ITI) involving continued exposure to the deficient factor. The prognosis factors for success in ITI in severe hemophilia A have been obtained mainly from four registries and from several patient series. The strongest predictors of success are a low inhibitor titer at the beginning of the ITI and a maximum inhibitor titer. However, there are many other points to clarify: FVIII doses; the use of plasma-derived or recombinant concentrates, especially whether the plasma-derived concentrate contains large amounts of von Willebrand factor or not; concomitant infections during ITI; age at the start of ITI and delay in beginning it. Another controversial point is the use of immunosuppressants to help in the treatment of patients with a poor prognosis or in rescue treatments. In mild-moderate hemophilia, the incidence of inhibitors is lower and immunosuppressants can play an important role. Inhibitors in hemophilia B are rare. ITI usually leads to allergenic events and nephrotic syndrome, and the success rate is lower than in hemophilia A; therefore, ITI in hemophilia B must be carefully studied. [ABSTRACT FROM AUTHOR]

Hemophilia is the major congenital hemorrhagic disorder. The administration of the deficient factor can trigger the development of antibodies, also known as inhibitors, capable of neutralizing the infused protein function. This is considered the most serious complication in hemophilia and usually occurs in the first years of life after the first doses of factor concentrate are given; hence, the main objective in these patients is to permanently eradicate these inhibitors. Current treatments are based on immunotolerance induction (ITI) involving continued exposure to the deficient factor. The prognosis factors for success in ITI in severe hemophilia A have been obtained mainly from four registries and from several patient series. The strongest predictors of success are a low inhibitor titer at the beginning of the ITI and a maximum inhibitor titer. However, there are many other points to clarify: FVIII doses; the use of plasma-derived or recombinant concentrates, especially whether the plasma-derived concentrate contains large amounts of von Willebrand factor or not; concomitant infections during ITI; age at the start of ITI and delay in beginning it. Another controversial point is the use of immunosuppressants to help in the treatment of patients with a poor prognosis or in rescue treatments. In mild-moderate hemophilia, the incidence of inhibitors is lower and immunosuppressants can play an important role. Inhibitors in hemophilia B are rare. ITI usually leads to allergenic events and nephrotic syndrome, and the success rate is lower than in hemophilia A; therefore, ITI in hemophilia B must be carefully studied. [ABSTRACT FROM AUTHOR]

Hemophilia A is an X-linked recessive disorder caused by a lack or decrease of factor VIII activity. Its socio-economic impact is high given its high bleeding expression and treatment cost. Our aim was to establish the mutation of each patient to improve family management. A total of 116 unrelated families with severe and moderate hemophilia A were involved. Non-carriers of intron 22 and intron 1 rearrangements were included in F8 gene screening. Intron 1 and 22 inversion frequencies were 3% and 52.5% respectively. Putative mutations were identified in all the families; 38 were new. The cumulative inhibitor incidence was 22%. Approximately half the families carry non-recurrent mutations, which were unique in around one third. Harmful effects for mutations predicting null alleles are expected. Missense mutation consequences are not easily predictable, despite the help of some bio-informatics tools.

To date, few mutations associated with a dominant quantitative deficiency of von Willebrand factor (VWF) and a high penetrance have been reported. This phenotype was confirmed in seven unrelated families of several patients diagnosed with von Willebrand's disease out of 70 who requested genetic studies of the VWF gene. The mutations linked to this type were identified: R1205H in five families; T1156M in one family; and the new P1824H alteration in one other family. The R1205H mutation linked to the different haplotypes might well be frequent among this variant. The P1824H in the A3 domain is associated with very low VWF levels and with a moderate-to-severe bleeding tendency, unlike the other mutations reported in this domain.