Abstract
Introduction:
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease caused by mutations that impair formation of GPI anchors. Absence of GPI-linked molecules CD55 and CD59 renders blood cells sensitive to complement-mediated damage. The classic presentation includes intravascular hemolysis, thrombophilia, and marrow failure. Other symptoms, such as fatigue, dysphagia, and abdominal pain may also occur. Eculizumab inhibits complement protein C5 and has drastically improved outcomes in PNH. Despite greater awareness of PNH since eculizumab's approval, it remains a rare disease and patients may go years without a diagnosis. To investigate this, we reviewed our centre's experience to identify areas that could be improved upon.
Methods:
A retrospective review was completed of PNH patients followed at our centre over the last 5 years. Data was collected via chart review and interviews. Information collected included age of symptom onset, time from symptoms to assessment, hematology referral, diagnosis, and to start of therapy. Laboratory investigations were also recorded. Patients with small clones (<10%) were excluded as they would not qualify for eculizumab.
Results:
Nine patients were enrolled (6 male, 3 female). Table 1 summarizes their presenting features. For reference, the same categories are presented for Canadian patients in the International PNH Registry. Figure 1 shows symptom progression from onset, diagnosis, and start of therapy.
Average age at symptom onset was 38.2±20.5 years. Cytopenia was the most common presentation (78%). Dark urine occurred in 88%. Three patients (33%) reported fatigue as their first symptom. One, with aplastic anemia (AA) and treated with immunosuppression, developed abdominal pain and dark urine 7 years later and was found to have PNH despite negative initial testing.
Table 2 summarizes individual patient timelines for diagnosis and treatment. Average time from initial symptom to medical assessment was 2.7±6.6 years, though 7 (78%) presented within several weeks. One did not present until 20 years after anemia and jaundice occurred, as she was asymptomatic. Another patient waited 4 years before assessment because he occasionally experienced dark urine with exertion and attributed this to exercise.
Median duration from presentation to diagnosis was 3 years (range: 0.05-30); however, 3 (33%) patients were diagnosed within one month. One was diagnosed when he presented with worsening anemia one year after initial presentation. Another presented in 1975 with renal dysfunction, underwent extensive evaluation, but not diagnosed with PNH for 30 years. Dark urine with anemia prompted evaluation in 79%. Three reported abdominal pain, 22% jaundice, 22% dysphagia, 11% dyspnea, and 67% were fatigued.
Only one patient in our cohort developed thromboembolism (11%), compared to 19% of Canadians in the International PNH Registry. This patient was anemic and jaundiced for many years but only after developing hepatic vein thrombosis was she was evaluated for PNH.
Patients saw a median of 4 health care providers (HCP) (range: 2-8) before diagnosis. Six saw general practitioners (GP) and emergency physicians before hematology and 3 saw other specialists first. One saw dermatology for a rash not initially realized to be thrombocytopenic petechiae. He was then referred to hematology after developing severe anemia as well. One saw several nephrologists for dark urine; he was diagnosed with glomerulonephritis, and this was not re-evaluated for 20 years. One saw urology and gastroenterology before hematology referral. Two were worked up for PNH after their GPs retired and were reviewed by new ones.
Eight patients (89%) are currently on eculizumab. One does not meet funding criteria. The average time between diagnosis and initiation of therapy was 1.3±1.7 years.
Conclusion:
PNH is rare and can present in heterogeneous ways. Outside hematology, HCPs may rarely encounter patients, if ever. Time interval between onset of symptoms to formal diagnosis in our cohort had the greatest duration and variation. Once diagnosed, all patients in our cohort were initiated on therapy quite rapidly save for one who had a nine-year delay between diagnosis and availability of eculizumab in Canada. The greatest delay in this cohort was the time from symptom onset to diagnosis, suggesting that a focus on increasing awareness of PNH may be the area where most efforts should be placed.
Disclosures
Patriquin: Octapharma: Honoraria; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Other: Travel Support and is site investigator for clinical trials with the company; Ra Pharmaceuticals: Consultancy, Research Funding.
COVID-19 and Stress: A Young Male Presenting with Central Cyanosis, Dark Urine, Oliguria, Jaundice and Anemia due to Methemoglobinemia as a result of Suicidal Naphthalene Mothball Poisoning Recovered with Exchange Transfusion
