Background

Welcome to the Part 1 of the 2022 Forum on Complement Case Discussion.

PNH is an ultra-rare, and under-recognized complement-mediated disease. Despite its rarity this disease warrants our attention because without adequate management, mortality from PNH is significant (35% at 5 years). In December 2021 – January 2022, insights on current perceptions and practice patterns were collected from hematology specialists across Canada via a needs assessment questionnaire.

Key learning from the assessment:

  • While many respondents indicated they are comfortable identifying PNH patients, there was agreement that there is a need for more sufficient testing and that there are still patients that are missed/differentially diagnosed.

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

See the Appendix for more data gathered from the assessment on testing and diagnosis!

(Click on Image to Enlarge)

The intent of this 2-part series is to shed light on the education gaps identified through the assessment, and the challenges many PNH patients encounter during their (often-convoluted) patient journey. Each issue will include a case study and provide additional information on best practices. This issue, Part 1, covers from the time the patient starts experiencing symptoms, to getting a correct PNH diagnosis. Part 2 will focus on management and treatment following a confirmed PNH Diagnosis.

We are pleased to have Dr. Christopher Patriquin (University Health Network, Toronto) provide the content contained in this issue.

Introduction

Hemolysis is the central, constant feature of PNH that significantly contributes to the progression and diverse range of symptoms throughout the course of their disease. Patients often suffer from a poor quality of life from these symptoms and are at risk for life threatening complications, such as thromboembolism, kidney disease, and pulmonary hypertension. Due to the wide spectrum of symptoms associated with PNH and their often broad differential diagnosis, it is not unusual for months or even years to pass before the correct diagnosis is established.

Prominent manifestations of PNH and their frequencies as reported in the international PNH registry include¹:

  • Fatigue/weakness, 85.4%
  • Hemoglobinuria, 69.5%
  • Dyspnea, 52.5%
  • Abdominal pain, 49.8%
  • Dysphagia, 24.4%
  • Erectile dysfunction, 31.6%
  • Thromboembolism, 17.6%

The following case study explores implications of a delayed diagnosis, and in turn delayed treatment, on patient outcomes.

“Due to the wide spectrum of symptoms associated with PNH and their often broad differential diagnosis, it is not unusual for months or even years to pass before the correct diagnosis is established.”

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).² 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.³ 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!

Stay Tuned- Part 2 of the Forum on Complement Case Discussion will continue with information on best practices for PNH treatment in today’s landscape and will touch on where we are headed with novel options.

“When the signs and symptoms of PNH are identified,
do not wait to test and refer!”
References

¹ 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.

² 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.

³ 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.

Appendix: Relevant Data from Needs Assessment- Diagnosis and Testing

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)