Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder characterised by intravascular hemolysis, thrombosis and an association with bone marrow failure.

Pediatric PNH is rare with 14% of patients presenting with PNH as a child. Aplastic anemia affects 2-3 patients per million per year in the UK, with a peak in 15–25-year-olds, and a later peak over 60. With 40-60% of patients with aplastic anemia having a PNH clone, the incidence of PNH in children may be underestimated. As per current guidelines, all patients with aplastic anemia should have a PNH screen.

Treatment indications for all patients with PNH in the UK include PNH related thrombosis, intravascular hemolysis, PNH related complications and pregnancy (with PNH clone greater than 20% granulocytes/monocytes). Approved treatments for those under 18 years of age include eculizumab (and biosimilars), ravulizumab and latterly crovalimab (over 12 years). Eculizumab was approved in teh UK in 2007.

The United Kingdom is in the unique position of a centralised service for all patients with a PNH clone irrespective of disease status or whether treatment is indicated. We report over 40 years experience of PNH in children.

Methods: Patients referred and reviewed by the PNH service UK were identified within the database. All patients below the age of 18 with a detectable PNH clone were included. Anonymised disease status, symptoms and indications for treatment were assessed, including outcome.

Results:

Currently the PNH service reviews 1121 patients, with 716 on complement inhibition. Sixty-five patients below the age of 18 at identification of a PNH clone were included. Earliest diagnosis of PNH was 1972, with 12 patients diagnosed before complement inhibition was approved and 53 after 2007. Mean age at referral was 13.6 years (range 4-17 years).

Historical or concurrent aplastic anemia diagnosis was present in 53 patients with disease classification of nonsevere in 14/53 (26%), severe 26/53 (49%), very severe 10/53 (19%) with data missing for 3 patients. One additional patient had a myelodysplasia diagnosis.

Treatment of aplastic anemia in the 53 patients included no treatment for 9/53 (17%), anti-thymocyte globulin and ciclosporin in 18/53 (34%), ciclosporin 1/53 (2%), oxymethalone 1/53 (2%) and hematopoietic stem cell transplant (HSCT) for 24/53 (45%) (either first or second line).

Five thrombotic events occurred in 4 patients at diagnosis: 2 cerebral vein thromboses, 1 Budd Chiari and 1 pulmonary embolism (PE) and portal vein thrombosis.

Management of patients with PNH requiring complement inhibition (41/65):

The majority of patients experienced at least 2 symptoms from PNH (30/41), including fatigue (26/41), thrombosis (2/41), abdominal pain (5/41), shortness of breath (7/41), hemoglobinuria (7/41), dysphagia (1/41), bruising/bleeding (18/41) and anemia (27/41). 33/41 patients commenced complement inhibition below 18 years, and 8 after the age of 18 years (due to patients being diagnosed as children before 2007).

Indications for complement inhibition included hemolysis 25/41 (61%); thrombosis 2/41 (5%), HSCT (to reduce PNH complications) 10/41 (24%), pregnancy 2/41 (5% - as adults). Thrombosis and hemolysis 2/41 (5%). 24/65 patients have not required complement inhibition.

The median granulocyte clone for patients at the start of complement inhibition was 79% (Interquartile range 45-92%), with the initial complement inhibitor treatment of eculizumab in 28/41 (68%), ravulizumab 12/41 (30%) and crovalimab 1/41 (2%). Mean treatment duration is 60 months (range 1-277 months). Those with shorter treatment duration were patients undergoing HSCT.

Two patients experienced meningococcal infection (3 episodes) with complete recovery. These occurred aged 18/19 and 1-4 years into treatment.

One patient died of HSCT complications, the remaining 64 reached adulthood, with 2 further deaths from non-PNH related causes.

ConclusionWe report a large cohort of pediatric patients with PNH. Patients present with similar symptoms to adults however the incidence of aplastic anemia is higher, with just under half the patients undergoing hematopoietic stem cell transplant for aplastic anemia. Thrombosis in children is less frequent than in adults. Whilst PNH in children is rare, patients should be tested as per current guidelines. Complement inhibition has been demonstrated to be safe in this pediatric patient cohort

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2025
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