Haemophilia in the first years of life

Abstract

Summary. Surgery in infants and young children with haemophilia, when preceded by accurate diagnosis and accompanied by safe and effective factor prophylaxis, is not associated with a significant risk of haemorrhage. Haemophilic newborns undergoing circumcision or major surgery prior to diagnosis and in the absence of appropriate haemostatic prophylaxis remain as a concern. Inhibitor development has replaced haemorrhage as the major surgical complication in the developed world, largely because of the intensity of treatment used to secure haemostasis. For that reason only, essential surgery should be performed. Intracranial haemorrhage (ICH) during the neonatal period affects 3.5-4.0% of all haemophilia boys in countries with a good standard of health care, which is considerably (40-80 times) higher than expected in the normal population. Because of the high frequency of sporadic cases, ICH in the neonatal period can only be partially prevented by improved carrier diagnosis and counselling. Infections and thrombosis are the major serious complications of central venous lines. Large differences are seen in the frequency of these complications, the most plausible explanations are probably related to the protocol used for device care, the quality of education and the compliance of the users, an issue addressed in an on-going study.

Recombinant factor VIII in the management of hemophilia A: current use and future promise

“…The above discussion considered only spontaneous joint bleeding, but similar results are typical for spontaneous intracranial hemorrhage in severe hemophilia patients: those on every other day full prophylaxis, with the target goal being factor VIII activity nadirs greater than 1%, very rarely experience intrancranial bleeding, while those patients using on-demand therapy continue to experience spontaneous intracranial bleeding and neurological sequelae 31,32. Whether gradually escalating schedules of factor VIII infusions risk intracranial bleeding is not clear yet.…”

Prenatal diagnosis by droplet digital PCR

“…The use of digital droplet PCR for prenatal diagnosis of hemophilia represents a major improvement over current invasive methods, eg, chorionic villus sampling, amniocentesis, and cordocentesis. Second, knowledge of a hemophilia diagnosis before birth provides for an opportunity for early hemostatic intervention to promote hemostasis before procedures, eg, circumcision, are performed, or to prevent central nervous system and related morbidity and mortality 8 by cesarean delivery, which is recommended to reduce the risk of intracranial hemorrhage when the birth of a child with severe hemophilia is anticipated. 9 Third, prenatal testing is also important to ensure hemostatic support for the mother for whom it may be necessary to prevent bleeding with perinatal anesthesia and/or postpartum bleeding.…”

Design of the INHIBIT trial: preventing inhibitors by avoiding ‘danger’, prolonging half-life and promoting tolerance

“…Among children treated in the first month of life, 41% develop inhibitors, compared with only 18% after 18 months of age, which may be in part related to treatment intensity , as the difference disappears after adjustment for treatment intensity [26]. The FVIII treatment regimen may also influence inhibitor development: high intensity regimens, that is, multiple exposures over a short period of time , are associated with an inhibitor rate of 28% [27], whereas lower intensity regimens, including continuous infusion [29], enhanced episodic treatment (with intense treatment for bleeds) [30] and once-weekly prophylaxis with dose escalation for bleeds [31], are associated with rates of 4.6–6.2%. Yet, whether prophylaxis reduces inhibitor risk remains controversial [32].…”

“…For those initially treated for a surgical procedure , if treatment lasted for 5 or more days, the relative inhibitor risk increased from 2.4 to 3.3 [26]. While the method of infusion is a risk factor, for example, via central line placement , especially in those who bleed with the procedure [26,29], by contrast, the type of product, recombinant versus plasma derived, full length versus B-domain deleted or von Willebrand factor content does not appear to be a risk [28]. Neither is circumcision , a procedure associated with bleeding in as many as 35% of children with hemophilia, associated with inhibitor risk [36,37].…”

“…COMM.] [26,27,29,38]. Our survey suggests that initiating factor before the first bleed, with the exception of circumcision, is an uncommon practice, occurring in fewer than 10% of US HTCs [25]; thus, it is possible that children recruited to the trial before a first bleed or ‘danger’ may represent a ‘low danger signal’ cohort, for example, the RODIN study [14], not representative of all inhibitor patients.…”