Diagnosing PNH

Diagnosing PNH

Early diagnosis of PNH is essential for improved patient management and prognosis1

Testing patients for PNH 2

It is essential that paroxysmal nocturnal haemoglobinuria (PNH) is diagnosed rapidly and accurately to ensure that patients can be managed effectively. Diagnosis of PNH is based on clinical history and laboratory data, including flow cytometry, to assess the presence and size of a PNH clone. Diagnosis of PNH is often delayed, sometimes by several years,2 resulting in unnecessary clinical investigations and inappropriate treatments. The impact on patient outcomes is considerable and can result in increased morbidity or even death.

Peter Hillmen discusses the need for accurate PNH testing

Testing patients for PNH

Use reflex testing to identify patients with PNH early within high-risk groups1,3-22

Reflex testing facilitates the diagnosis of clinically unsuspected PNH when a peripheral blood or bone marrow sample is submitted for flow cytometric analysis in the workup of other conditions.

International Clinical Cytometry Society (ICCS) guidelines and multiple other experts suggest that the clinical presentations outlined below increase the likelihood of PNH.  Positive test results for the following conditions should be considered suggestive of PNH and lead to reflex confirmatory testing for PNH:


aAnaemia, neutropenia, thrombocytopenia or pancytopenia; bUnusual sites include hepatic veins (Budd-Chiari syndrome), other intra-abdominal veins (portal, splenic, splanchnic), cerebral sinuses and dermal veins; cDetects PNH cells down to a 0.01% clone size
IDA, iron deficiency anaemia; LDH, lactate dehydrogenase; MDS, myelodysplastic syndrome
The information on this page is intended as an educational resource for healthcare professionals. It does not replace a healthcare provider’s professional judgement or clinical diagnosis

The presence of monocytes that lack CD14 expression in combination with granulocytes that display diminished expression of CD16 in a peripheral blood or bone marrow sample is also highly associated with PNH. Therefore, this combination of abnormalities should lead to reflex confirmatory testing.21


Reflex testing facilitates the diagnosis of clinically unsuspected PNH

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Screening by flow cytometry should be considered even in patients with a normal lactate dehydrogenase (LDH) level. PNH patients in whom LDH levels may not be raised include patients with a predominant Type II (partially deficient of glycosylphosphatidylinositol [GPI]-linked proteins) red cell population in which haemolysis may be minimal, patients who are heavily red cell transfusion dependent and patients with a small percentage of PNH cells who have experienced thrombosis.15

Prevalence of PNH clones in high-risk patient groups

Testing high-risk patient groups will maximise the chance of detecting PNH clones, thus enabling accurate diagnosis. According to data from a recent study, PNH clones were identified in:

  • bone marrow failure syndrome (33%)23
  • aplastic anaemia (AA; 45%)23
  • myelodysplastic syndrome (MDS; 10%)23
  • haemolytic anaemia (19%)23
  • haemoglobinuria (48%)23
  • unexplained cytopenias (9%)23
  • unexplained thrombosis (1.5%)23

Importance of continued monitoring in patients with PNH

PNH clone size can expand rapidly and unpredictably over time, making continued monitoring a necessity in patients with PNH. Annual monitoring should be considered for patients with a PNH clone size of <0.1%. For patients with a PNH clone size of >1%, monitoring at least semi-annually is recommended.24

From Movalia MK et al. Poster 886 presented at EHA, Amsterdam, The Netherlands; 14-17 June, 2012. Reproduced with permission from Movalia MK et al.
FLAER, fluorescent aerolysin
  • References
    1. Borowitz MJ et al; for Clinical Cytometry Society. Cytometry B Clin Cytom 2010; 78B: 211-230.
    2. Bessler M, Hiken J. Hematology Am Soc Hematol Educ Program 2008; 104-110.
    3. Brodsky RA. Blood Rev 2008; 22: 65-74.
    4. Brodsky R. In: R. Hoffman et al, eds. Hematology: Basic Principles and Practices. 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2005: 419-427.
    5. Rother RP et al. JAMA 2005; 293: 1653-1662.
    6. Hillmen P et al. Am J Hematol 2010; 85: 553-559.
    7. Rachidi S et al. Eur J Intern Med 2010; 21: 260-267.
    8. Kelly R et al. Ther Clin Risk Manag 2009; 5: 911-921.
    9. Hill A et al. Br J Haematol 2007; 137: 181-192.
    10. Hillmen P et al. Blood 2007; 110: 4123-4128.
    11. Adams T et al. Dig Dis Sci 2002; 47: 58-64.
    12. Rosse WF. In: R. Hoffman R et al, eds. Hematology: Basic Principles and Practices. 3rd ed. New York, NY: Churchill Livingstone; 2000: 331-342.
    13. Rother RP et al. Nat Biotechnol 2007; 25: 1256-1264. [Published correction appears in Nat Biotechnol 2007; 25: 1488].
    14. Hillmen P et al. N Engl J Med 1995; 333: 1253-1258.
    15. Hill A et al. Blood 2013; 121: 4985-4996.
    16. Socié G et al; for the French Society of Haematology. Lancet. 1996; 348: 573-577.
    17. Dacie JV, Lewis SM. Ser Haematol 1972; 5: 3-23.
    18. Nishimura J-I et al. Medicine 2004; 83: 193-207.
    19. Lee JW et al. Int J Hematol 2013; 97: 749-757.
    20. Brodsky RA. Blood 2014; 124: 2804-2811.
    21. Thomason RW et al. Am J Clin Pathol 2004; 122: 128-134.
    22. Killick SB et al. Br J Haematol 2016; 172: 187-207.
    23. Morado M et al. Cytom B Clin Cytom 2016; DOI: 10.1002/cyto.b.21480.
    24. Movalia MK et al. Poster 886 presented at EHA, Amsterdam, The Netherlands; 14-17 June, 2012.

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