Contexte

Bienvenue à la première partie de la discussion de cas du Forum 2022 sur les maladies induites par le complément.

L’hémoglobinurie paroxystique nocturne (HPN) est une maladie médiée par le complément, ultrarare et peu reconnue. Malgré sa rareté, cette maladie exige notre attention, car sans une prise en charge adéquate, le taux de mortalité lié à l’HPN est élevé (35 % à 5 ans).¹ Entre décembre 2021 et janvier 2022, un questionnaire d’évaluation des besoins auquel ont répondu des spécialistes en hématologie de toutes les régions du Canada a permis de recueillir des renseignements sur les perceptions et les modèles de pratique actuels.

Principaux enseignements tirés de l’évaluation :
  • Bien que de nombreux répondants aient indiqué qu’ils se sentent en confiance pour identifier les patients atteints d’HPN, ils conviennent du besoin de tests plus satisfaisants et reconnaissent que certains patients font encore l’objet d’un diagnostic erroné ou d’un diagnostic différentiel.

Dans quelle mesure êtes-vous d’accord avec les énoncés suivants :
[1 = pas du tout d’accord, 3 = sans opinion, 5 = tout à fait d’accord]

Voir l’annexe pour plus de données

Cette série en deux parties a pour but de clarifier les lacunes en matière d’éducation qui ont été identifiées par le biais de l’évaluation, ainsi que les difficultés rencontrées par de nombreux patients atteints d’HPN au cours de leur parcours (souvent complexe).  Chaque numéro présentera une étude de cas et fournira des données supplémentaires sur les meilleures pratiques. Ce numéro, qui constitue la Partie 1, couvre la période entre la survenue des premiers symptômes chez le patient et la pose d’un diagnostic correct d’HPN. Le second numéro, Partie 2, portera sur la prise en charge et le traitement après confirmation du diagnostic d’HPN.

Nous remercions le Dr Christopher Patriquin (University Health Network – réseau public d’hôpitaux , Toronto) pour le contenu du présent numéro.

Introduction

L’hémolyse est la caractéristique essentielle et constante de l’hémoglobinurie paroxystique nocturne (HPN) qui contribue largement à l’évolution et à la diversité des symptômes tout au long de la maladie. Ces symptômes sont souvent la cause d’une mauvaise qualité de vie chez les patients qui sont exposés à des complications potentiellement mortelles, telles que les thromboembolies, les maladies rénales et l’hypertension pulmonaire. En raison du grand nombre de symptômes associés à l’HPN et de leur diagnostic différentiel souvent très large, il n’est pas rare que des mois, voire des années, s’écoulent avant la pose du diagnostic correct.

Les principales manifestations de l’HPN et leur fréquence, telles que rapportées dans le registre international de l’HPN, sont notamment² :

  • fatigue/faiblesse, 85,4 %
  • hémoglobinurie, 69,5 %
  • dyspnée, 52,5 %
  • douleurs abdominales, 49,8 %
  • dysphagie, 24,4 %
  • dysfonctionnement érectile, 31,6 %
  • thromboembolie, 17,6 %

L’étude de cas suivante explore les conséquences d’un diagnostic tardif, et par conséquent d’un traitement tardif, sur les résultats des patients. Elle est présentée, ainsi que la discussion qui suit, dans la langue de l’auteur.

Case Study

A 35-year-old female was admitted with several months of abdominal pain.

Comorbidities: smoker (1 pack per week), irritable bowel syndrome.

Medications: nil     Allergies: nil

Presenting History: 3-month history of intermittent epigastric pain, nausea, non-bloody emesis, with each episode lasting 1-2 weeks. Due to worsening pain, she presented to her local ER, where a CT scan identified Budd-Chiari syndrome. She was started on low molecular weight heparin and referred to a tertiary care hepatology clinic for further work-up. Repeat imaging documented further thrombosis, so she was admitted for observation and hematology consultation.

Course in Hospital: No clear cause explanation for Budd-Chiari was identified. CBC showed only mild thrombocytopenia (123 x 109/L), with hemoglobin 130 g/L and WBC 4.6 (normal differential). Reticulocytes were elevated (125 x 109/L). Bilirubin and ALP were normal, transaminases were mildly elevated (AST 54, ALT 29), and her LDH was felt to be elevated out of keeping (780 u/L; NR 125-220) with undetectable haptoglobin. Given the atypical site thrombosis and elevated LDH, high sensitivity peripheral blood flow cytometry was sent, which confirmed PNH (granulocytes 36.9%, monocytes 39.4%, type-III erythrocytes 4.8%, and type-II erythrocytes 26.2%. She was transitioned to warfarin from LMWH, started on folic acid, and anti-meningococcal vaccinations were administered in anticipation of eculizumab approval.

Follow-Up: Once approval was obtained, she was started on eculizumab which was well-tolerated. Her abdominal pain and nausea resolved. A week after her first eculizumab infusion, she developed a new headache and presented to her home hospital. CT imaging identified a small subdural hemorrhage. Her warfarin was reversed, and she was monitored with serial cranial imaging. She was eventually restarted on intermediate-dose LMWH then transitioned to apixaban, without further bleeding. No further thrombotic extension or progression was noted with serial imaging.

Discussion

What does this case demonstrate about the current state of PNH diagnosis in Canada?
High sensitivity peripheral blood flow cytometry for PNH is available at many centres across Canada, as well as through some community labs. The greatest challenge to identifying PNH patients is not the testing but considering it as a diagnosis given its rarity. The heterogeneity in presentation further complicates this. As expected, most patients are diagnosed when they present with DAT-negative hemolytic anemia and/or hemoglobinuria. This case, however, demonstrates that patients can present with thrombosis in the absence of hemoglobinuria, bone marrow failure, or hemolytic anemia (though hemolysis – without anemia – was eventually identified).

At what point should PNH be suspected?
A mnemonic used by the Canadian PNH Network and other groups to suggest testing indications is “CATCH”: cytopenias, aplastic anemia/myelodysplastic syndromes, thromboembolism, Coombs (DAT)-negative hemolysis, and hemoglobinuria. Broadly, PNH should be considered if one of these presentations cannot otherwise be explained. The presence of additional features may also increase the likelihood of disease (e.g. cytopenias + hemoglobinuria, thrombosis in a patient with aplastic anemia).³ Specifically for thromboembolism, though atypical site thrombosis (e.g. visceral, intracranial) occurs at a higher frequency in PNH, testing in those with “typical site” clots should also be considered if one cannot otherwise identify a provoking event, or if there is progression despite therapeutic anticoagulation. A high index of suspicion must be maintained. Definitive testing, as discussed, is readily available and targeted therapy can significantly alleviate symptoms, reduce thrombotic risk, and improve overall survival.

What testing can be used to confirm a definitive diagnosis of PNH?
High sensitivity flow cytometry on peripheral blood is the confirmatory test for PNH. Other testing should be performed during the diagnostic process to rule out complications of PNH and assess its severity (i.e., bone marrow biopsy, blood tests, x-rays, CT scans, an ultrasound and other specimen tests).

What are the risks associated with a delayed diagnosis?
Without treatment, the 5-year mortality for patients with PNH is approximately 35%, with mortality primarily driven by thrombosis. Being referred quickly allows for rapid assessment of symptoms and hemolytic activity, which will aid in the development of an appropriate management plan. Ultimately, timely diagnosis can improve quality of life (via symptom management) and extend survival.

Additional Resources
Previous issues of Forum on Complement (2017) can be accessed at the following link:
https://careeducation.ca/reports/forum-on-complement-case-series/?_sf_s=PNH

Concluding Remarks

What can we do to improve timeliness of testing to ensure that patients have the shortest, most effective pathway to a confirmed PNH diagnosis?
PNH is an ultra-rare condition with significant heterogeneity of presentation. Some physicians may never identify a case, and others may see only a few during their career. Despite this, maintaining a high index of suspicion is crucial to prompt one to test. Testing is readily available across the country, and identification of PNH can significantly change (and improve) management outcomes. When the signs and symptoms of PNH are identified, do not wait to test and refer!

Restez avec nous – la discussion de cas du Forum 2022 sur les maladies induites par le complément se poursuivra dans la seconde partie qui contiendra des données sur les meilleures pratiques pour le traitement de l’HPN dans le paysage actuel et abordera les nouvelles options vers lesquelles nous nous dirigeons.

Le support pour cette série de cas est fourni par Alexion, AstraZeneca Rare Disease.

References

¹ Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV: Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med 1995, 333: 1253–1258. 10.1056/NEJM199511093331904

² Schrezenmeier H, Röth A, Araten DJ, Kanakura Y, Larratt L, Shammo JM, Wilson A, Shayan G, Maciejewski JP. Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the International PNH Registry. Ann Hematol. 2020 Jul;99(7):1505-1514. doi: 10.1007/s00277-020-04052-z. Epub 2020 May 10. PMID: 32390114; PMCID: PMC7316848.

³ Patriquin CJ, Kiss T, Caplan S, Chin-Yee I, Grewal K, Grossman J, Larratt L, Marceau D, Nevill T, Sutherland DR, Wells RA, Leber B. How we treat paroxysmal nocturnal hemoglobinuria: A consensus statement of the Canadian PNH Network and review of the national registry. Eur J Haematol. 2019 Jan;102(1):36-52. doi: 10.1111/ejh.13176. Epub 2018 Oct 25. PMID: 30242915.

Dezern AE, Borowitz MJ. ICCS/ESCCA consensus guidelines to detect GPI-deficient cells in paroxysmal nocturnal hemoglobinuria (PNH) and related disorders part 1 – clinical utility. Cytometry B Clin Cytom. 2018 Jan;94(1):16-22. doi: 10.1002/cyto.b.21608. PMID: 29236352.

Annexe : Données pertinentes issues de l’évaluation des besoins – Diagnostic et tests

Other than anemia, what presenting feature(s) have led to the diagnosis of PNH in your patients?
[Responders selected all that apply]

What historical or laboratory features do you look to in the determination of a PNH diagnosis?
[Responders selected all that apply]

To what extent do you agree with the following:
[1 being strongly disagree, 3 being neutral and 5 being strongly agree]

(Click on Images to Enlarge)

Le support pour cette série de cas est fourni par AlexionAstraZeneca Rare Disease.