A single-centre approach for a safe and individualized tolerization phase for the treatment of PUPs with severe haemophilia A

 

Introduction Pediatricians treating newly diagnosed severe haemophilia A patients are confronted with the challenge to protect the children against bleeds that are potentially life-threatening or may have long-term damaging effects on joints. The protection that early prophylaxis with coagulation factor VIII (FVIII) provides, may however put the patients at risk for inhibitor development. We report our experience with an individualized approach to managing PUPs at a single haemophilia treatment center (HTC) in Germany.

Method PUPs with severe hemophilia A (FVIII:C <1%) treated at the Gerinnungszentrum Rhein-Ruhr (GZRR), Germany, between January 2013 and August 2022 were followed prospectively. Our treatment approach includes early prophylactic physiotherapy and treatment with a human plasma-derived FVIII (pdFVIII/VWF) concentrate for at least the first 50 exposure days (EDs). Prophylaxis was adapted with individualized dose escalations according to bleeding tendency and prolonged on-demand treatment was avoided where possible, by choosing doses up to 80 IU/kg. Close contact between parents and haemophilia center ensures that decisions to treat with factor VIII concentrate can be done on a case-by-case basis. Non-urgent surgical procedures were postponed within the first 100 EDs. Ultrasound was performed every 3–6 months to check for joint bleeds. In addition, patients receive individualized physiotherapy to preserve joint health. In contrast to this patient group, between 2003 and 2012 9 PUPs with severe haemophilia A were treated predominantly with recombinant factor concentrate and with less selectiveness in treating bleeds.

Inhibitor levels were measured using the modified Bethesda assay every 3–4 EDs until ED 100, and every 3 months thereafter for 2 years for all patients.

Results Data from 39 consecutive PUPs were collected, of which 36 had started treatment. At the time of data cut-off 29 patients had received over 50 EDs of FVIII treatment, 8 patients had more than 20 EDs. 27 patients had started prophylaxis within the first 10 EDs. The initial schedule was tailored to each patient and ranged from 21 IU/kg every 10 days up to 40 IU/kg twice per week. One patient was treated on-demand for an intracranial bleed from ED 1–100. Only 3 spontaneous bleeds in 3 patients were treated; 33 patients (92%) remained free of treated spontaneous bleeds during prophylaxis. 1 of 36 treated patients had developed an inhibitor after the 4th exposure day (2.8 %). Of the 9 patients treated conventionally before 2013, 9 (44%) patients had developed an inhibitor. Ultrasound and MRI assessment showed no sign of joint modification.

Conclusion The individualized management approach with a close monitoring of the patients during the high-risk phase for development of an inhibitor, choice of FVIII concentrate and its restricted use in on-demand treatment seems to be a safe way to guide the patients to be tolerant to FVIII while protecting from consequences of serious bleeds.

Publication History

Article published online:
20 February 2023

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