Paroxysmal nocturnal hemoglobinuria clone in 103 Brazilian patients:
               diagnosis and classiﬁcation

Azambuja, Ana Paula de; Malvezzi, Mariester; Bitencourt, Marco Antonio; Oliveira, Michel Michels; Medeiros, Larissa Alessandra; Pasquini, Ricardo

doi:10.1016/j.bjhh.2015.01.001

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Revista Brasileira de Hematologia e Hemoterapia

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Original Articles • Rev. Bras. Hematol. Hemoter. 37 (2) • Mar-Apr 2015 • https://doi.org/10.1016/j.bjhh.2015.01.001 copy

Paroxysmal nocturnal hemoglobinuria clone in 103 Brazilian patients: diagnosis and classiﬁcation

Authorship SCIMAGO INSTITUTIONS RANKINGS

Background:

Paroxysmal nocturnal hemoglobinuria is an acquired chronic hemolytic ane- mia, which often manifests as peripheral blood cytopenias and thrombosis.

Objective:

The aim of this study is to describe a Brazilian population of paroxysmal nocturnal hemoglobinuria patients.

Methods:

One hundred and three paroxysmal nocturnal hemoglobinuria cases were retrospectively reviewed and the clinical presentation, thrombosis, survival, and clone size were assessed. Diagnosis was established by ﬂow cytometry.

Results:

Fifty-two male and 51 female patients with a median age of 24.1 years (5.5-62 years) were studied. Clinical symptoms included hemoglobinuria (18.4%), infection (46.6%) and thrombosis (16.5%), and 80.6% had pancytopenia. Patients were classiﬁed as classic parox- ysmal nocturnal hemoglobinuria (10), paroxysmal nocturnal hemoglobinuria with aplastic anemia (39), and paroxysmal nocturnal hemoglobinuria with subclinical features and aplas- tic anemia (54). There were signiﬁcant differences in terms of median age, size of clone, clinical symptoms, and peripheral blood cell counts between the three subcategories. The clone size in erythrocytes and granulocytes were respectively 0.04% (range: 0-18%) and 7.3% (range: 0.3-68.7%) in patients with subclinical features and aplastic anemia, 15.8% (range: 0-99.7%) and 63.0% (range: 1.7-99.8%) in patients with aplastic anemia alone, and 82.2% (range: 0-99.85%) and 98.0% (81.3-100.0%) in Classic disease. Statistical differences were identiﬁed for platelets (p-value = 0.001), lactate dehydrogenase (p-value = 0.002) and the clone size (p-value < 0.001) in patients who suffered thrombotic events compared to those who did not. Overall survival was 81.7%, with patients with subclinical features and aplastic anemia having lower overall survival (76.5%).

Conclusion:

This retrospective review of 103 patients over an 11-year period represents the largest collection of paroxysmal nocturnal hemoglobinuria cases from a single center in Brazil. Flow cytometry showed that a larger clone was associated with classical symptoms and increased risk of thrombosis, even in patients with bone marrow failure, whereas a smaller clone was associated with bone marrow aplasia.

Hemoglobinuria Paroxysmal; Bone marrow diseases; Flow cytometry

Characteristic
Gender, male – n (%)	52 (50.5)
Median age – years (range)	24.1 (5.5–62.0)
Clinical symptoms at presentation – n (%
Asthenia/fatigue	98 (95.1)
Infection/fever	48 (46.6)
Hemoglobinuria	19 (18.4)
Bleeding (petechiae and ecchymosis)	33 (47.1)
Abdominal pain	33 (32.0)
Jaundice	26 (25.2)
Renal insufficiency	14 (13.6)
Thrombosis	17 (16.5)
Hemolysis	24 (23.3)
Peripheral blood abnormalities at presentation – n (%)
Anemia alone	4 (3.9)
Anemia and thrombocytopenia	12 (11.6)
Anemia and neutropenia	4 (3.9)
Pancytopenia	83 (80.6)
Bone marrow biopsy – n (%)
Aplasia (<5%)	52 (50.5)
Hypocellular bone marrow (6–49%)	38 (36.9)
Normo or hypercellular bone marrow (≥50%)	13 (12.6)

PNH category	Total (n = 103)	a – PNH-sc/AA (n = 54)	b – PNH/AA (n = 39)	c – Classic PNH (n = 10)	p-Value^a (a × b × c)	p-Value (a × b)	p-Value (a × c)	p-Value (b × c)
Age	24.1 (5.5–62.0)	25.1 (7.5–62.0)	21.5 (5.5–49.4)	34.7 (26.7–55.9)	0.016	0.322	0.017	0.004
Asthenia/fatigue	98 (95.1%)	51 (94.4%)	37 (94.9%)	10 (100%)
Infection/fever	48 (46.6%)	23 (42.6%)	25 (64.1%)	0 (0%)	0.001
Hemoglobinuria	43 (41.7%)	4 (7.4%)	30 (76.9%)	9 (90%)	<0.001
Thrombosis	17 (16.5%)	2 (3.7%)	9 (23.1%)	6 (60%)	<0.001
Hemolysis	49 (47.6%)	0 (0%)	39 (100%)	10 (100%)	<0.001
Hemoglobin (g/L)	88 (38–145)	80 (38–132)	94 (45–145)	89.5 (51–117)	0.062^a
Leucocytes (×10³/μL)	2970 (1140–8800)	2675 (1140–8800)	3110 (1470–7780)	4490 (1600–6680)	0.008^a	0.05	0.005	0.106
ANC (×10⁹/L)	0.94 (0.26–4.95)	0.825 (0.26–4.66)	1.06 (0.59–4.95)	2.724 (0.16–3.90)	0.000^a	0.084	0.000	0.001
Platelets (×10⁹/L)	25 (2–294)	20 (2–99)	27 (3–137)	1815 (6–294)	<0.001^a	0.041	0.00	0.00
ARC (×10⁹/L)	53.8 (2.4–437)	35.4 (2.4–153)	70.8 (3.2–214)	240 (78–437)	<0.001^a	0.002	0.00	0.00
LDH (U/L)	328.5 (30–7690)	234 (30–783)	517 (187–4550)	1608 (328–7690)	0.001^b	0.002	0.00	0.004
Bilirubin (mg/dL)	0.9 (0.17–7.1)	0.7 (0.17–4.93)	1.06 (0.39–3.32)	2.54 (0.39–7.1)	<0.001^a	0.004	0.00	0.00
Bone marrow cellularity	5% (0–100%)	5%	10%	70%	<0.001^a	0.00	0.00	0.00
Flow cytometry
Neutrophil clone size (median)	25.2 (0.3–100)	7.3 (0.3–68.7)	63 (1.7–99.8)	98 (81.3–100)	<0.001^a	0.00	0.00	0.001
Erythrocyte clone size (median)	2.2 (0–92.2)	0.04 (0–18)	15.8 (0–99.7)	82.2% (0–99.85)	<0.001b	0.00	0.00	0.018

	PNH clone <10%	PNH clone 10–50%	PNH clone ≥50%	p-Value (χ² test)
Neutrophil clone size – n (%)	1 (5.9)	3 (17.6)	13 (76.5)	<0.001
Erythrocyte clone size – n (%)	5 (29.4)	6 (35.3)	6 (35.3)	0.005

Thrombosis	Yes	No	p-Value (χ² test)
Bone marrow cellularity – % Hemoglobin (g/L) Leukocyte (x10³/µL) ARC (x10⁹/L) Platelets (x10⁹/L) LDH (U/L) Neutrophil clone size (median) – % Erythrocyte clone size (median) – % Death – n (%)	10 8.8 3500 78.2 67.0 607 92.7% 31.8% 6/17 (35.3%)	5 6.5 2600 48.6 31.5 299 21.5% 1.2% 8/86 (9.3%)	0.166 0.682 0.663 0.046 0.001 0.002 <0.001 0.008 <0.001

Associação Brasileira de Hematologia e Hemoterapia e Terapia Celular R. Dr. Diogo de Faria, 775 cj 114, 04037-002 São Paulo/SP/Brasil, Tel. (55 11) 2369-7767/2338-6764 - São Paulo - SP - Brazil
E-mail: secretaria@rbhh.org

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[1] Corresponding author at: Hospital de Clínicas, Universidade Federal do Paraná (UFPR), Rua Flavio Dallegrave, 1580, apto 31B, 80045-315 Alto da XV, Curitiba, PR, Brazil. E-mail address: apazamb@gmail.com (A.P. de Azambuja).