PNH clone

Paroxysmal Nocturnal Hemoglobinuria in Patients with Aplastic Anemia: Challenges, Characteristics, and Analysis of Clinical Experience

RARE HEMATOLOGICAL TUMORS AND SYNDROMES , , , , ,

ER Shilova1, TV Glazanova1, ZhV Chubukina1, OE Rozanova1, MN Zenina1, AV Seltser1, VI Rugal1, VA Balashova1, VA Kobilyanskaya1, II Krobinets1, VYu Udal’eva1, II Zotova1, LV Stelmashenko1, NA Romanenko1, TB Zamotina1, IV Khorsheva1, SV Voloshin1,2,3

1 Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024

2 SM Kirov Military Medical Academy, 6 Akademika Lebedeva str., Saint Petersburg, Russian Federation, 194044

3 II Mechnikov North-Western State Medical University, 41 Kirochnaya str., Saint Petersburg, Russian Federation, 191015

For correspondence: Elena Romanovna Shilova, 16 2-ya Sovetskaya str., Saint Petersburg, Russian Federation, 191024; Tel.: +7(981)129-09-77; e-mail: rniiht@mail.ru

For citation: Shilova ER, Glazanova TV, Chubukina ZhV, et al. Paroxysmal Nocturnal Hemoglobinuria in Patients with Aplastic Anemia: Challenges, Characteristics, and Analysis of Clinical Experience. Clinical oncohematology. 2019;12(3):319–28 (In Russ).

doi: 10.21320/2500-2139-2019-12-3-319-328

ABSTRACT

Background & Aims. Paroxysmal nocturnal hemoglobinuria (PNH) is a disease caused by an acquired clonal disorder of hematopoietic stem cells with clone cell membrane hypersensitivity to the complement. PNH can exist as an independent disease and can also be associated with other pathological conditions characterized by bone marrow deficiency, first of all with aplastic anemia (AA). In PNH-associated AA (AA/PNH) pathological clones may be initially of different size. In some patients a gradual growth of PNH clone is observed together with occurring signs of intravascular hemolysis and transformation into classical hemolytic PNH. In this case it is important to assess the clinical situation and determine eligibility for complement inhibitor therapy. During targeted therapy it is necessary to assess the efficacy of treatment based on monitoring of complement-mediated hemolysis and to identify probable reasons for insufficient effect.

Materials & Methods. The paper deals with 1 clinical case. A female patient born in 1964, with initial diagnosis of AA was followed-up from 1989 till present at the Russian Research Institute of Hematology and Transfusiology. Her treatment included blood-component therapy, the use of antilymphocyte immunoglobulin, cyclosporine, plasmapheresis, eculizumab, and symptom-relieving drugs.

Results. The study deals with the case of transformation of non-severe AA with remission after immune-suppressive therapy into classical hemolytic PNH. The case report describes the characteristic features, AA/PNH diagnosis and treatment issues at different stages of the disease, and the reasons for incomplete effect of targeted therapy.

Conclusion. The case under discussion confirms the relevance of current methods of detecting PNH clone at early stages of AA diagnosis and dynamic follow-up with respect to a probable growth of clone with PNH phenotype, especially at the stage of hematopoietic recovery. Determination of PNH clone size and lactate dehydrogenase serum level is required for timely amendment of treatment strategy with a switch to long-term targeted monitoring of hemolysis which allows to prevent irreversible visceral changes and severe complications. In case of insufficient effect of targeted therapy with ongoing anemia Coombs test is recommended because of probability of C3-mediated extravascular hemolysis.

Keywords: aplastic anemia, paroxysmal nocturnal hemoglobinuria, PNH phenotype, PNH clone, targeted therapy, C3-mediated hemolysis.

Received: December 24, 2018

Accepted: May 29, 2019

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Clinical Manifestation and Errors in the Diagnosis of Classical Paroxysmal Nocturnal Hemoglobinuria: A clinical case series of 150 patients

RARE HEMATOLOGICAL TUMORS AND SYNDROMES , , , ,

AD Kulagin, OU Klimova, AV Dobronravov, MO Ivanova, TA Rudakova, EV Babenko, VA Dobronravov, BV Afanas’ev

Pavlov First Saint Petersburg State Medical University, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022

For correspondence: Aleksander Dmitrievich Kulagin, DSci, 6/8 L’va Tolstogo str., Saint Petersburg, Russian Federation, 197022; Теl.: +7(812)338-62-36; e-mail: kulagingem@rambler.ru

For citation: Kulagin AD, Klimova OU, Dobronravov AV, et al. Clinical Manifestation and Errors in the Diagnosis of Classical Paroxysmal Nocturnal Hemoglobinuria: A clinical case series of 150 patient. Clinical oncohematology. 2017;10(3):333–41 (In Russ).

DOI: 10.21320/2500-2139-2017-10-3-333-341

ABSTRACT

Background. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disease of the blood system, characterized by intravascular hemolysis, cytopenia and thrombosis. Diagnostic errors with delayed diagnosis of PNH are often due to the variety of the clinical presentation and the lack of awareness of the doctors of this rare disease.

Aim. The aim of the study was to characterize the options for clinical manifestation and the complexity of diagnosis of classical PNH.

Materials & Methods. The research included 150 patients with PNH. The inclusion criteria were: 1) clinical and laboratory signs of intravascular hemolysis; 2) verification of the diagnosis using standard flow cytometry; 3) absence of aplastic anemia, myelodysplastic syndrome and primary myelofibrosis. The patients were of 13 to 72 years old (median age 34 years). The study population consisted of 89 (59 %) women and 61 (41 %) men.

Results. The time before the diagnosis ranged from 0 to 455 months (median 33 months). The median size of the PNH clone among granulocytes and erythrocytes was 95 % and 41 %, respectively. The median of the lactic dehydrogenase was 7.2 times the upper limit of normal (ULN). Cytopenia occurred in 65 % of patients, including a combination of thrombocytopenia and neutropenia in 29 % of cases. Weakness and fatigue (99 %), hemoglobinuria (57 %), pain (52 %), icterus (46 %), dysphagia (37 %) and infection/fever (23 %) were the most common symptoms on the onset of the disease. Before the diagnosis of PNH, thrombosis or acute kidney injury was found in 22 % and 18 % of patients, respectively. Only 22 % of patients were initially diagnosed with PNH. In the remaining patients, the primary diagnosis was inadequate.

Conclusion. The clinical manifestation of PNH is characterised by the presence of hemoglobinuria, cytopenia and early thrombosis in 57 %, 65 % and 22 % of patients, respectively. Errors of the primary diagnosis reach 78 % and lead to inadequate treatment. The results of the research showed the need for multidisciplinary approach and strict adherence to diagnostic algorithms of PNH in the risk groups, according to current recommendations.

Keywords: paroxysmal nocturnal hemoglobinurea, PNH clone, cytopenia, clinical manifestation, diagnostic errors.

Received: February 20, 2017

Accepted: May 8, 2017

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