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Original Article

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Blood Res 2021; 56(3):

Published online September 30, 2021

https://doi.org/10.5045/br.2021.2021111

© The Korean Society of Hematology

Causes of erythrocytosis and its impact as a risk factor for thrombosis according to etiology: experience in a referral center in Mexico City

Antonio Olivas-Martinez1,2, Eduardo Corona-Rodarte1, Adrián Nuñez-Zuno1, Olga Barrales-Benítez3, Daniel Montante-Montes de Oca4, Jesús Delgado-de la Mora4, Diana León-Aguilar4, Hilda Elizeth Hernández-Juárez3, Elena Tuna-Aguilar3

Author Info. +

1Department of Internal Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico, 2Department of Biostatistics, University of Washington, Seattle, WA, USA, 3Department of Hematology and Oncology, 4Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

Correspondence to : Elena Tuna-Aguilar, M.D.
Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 15 Vasco de Quiroga Avenue, Mexico City 14080, Mexico
E-mail: elenatuna@yahoo.fr

Received: June 5, 2021; Revised: July 23, 2021; Accepted: July 30, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Background
Thrombotic events are well documented in primary erythrocytosis, but it is uncertain if secondary etiologies increase the risk of thrombosis. This study aimed to determine the causes of erythrocytosis and to identify its impact as a risk factor for thrombosis.
Methods
Data were obtained from patients with erythrocytosis between 2000 and 2017 at a referral hospital in Mexico City. Erythrocytosis was defined according to the 2016 WHO classification. Time to thrombosis, major bleeding, or death were compared among groups of patients defined by the etiology of erythrocytosis using a Cox regression model, adjusting for cardiovascular risk factors.
Results
In total, 330 patients with erythrocytosis were studied. The main etiologies of erythrocytosis were obstructive sleep apnea (OSA) in 29%, polycythemia vera (PV) in 18%, and chronic lung disease (CLD) in 9.4% of the patients. The incidence rate of thrombosis was significantly higher in patients with PV and CLD than that in patients with OSA (incidence rates of 4.51 and 6.24 vs. 1.46 cases per 100 person-years, P=0.009), as well as the mortality rate (mortality rates of 2.72 and 2.43 vs. 0.17 cases per 100 person-years, P =0.003).
Conclusion
The risk of thrombosis in CLD with erythrocytosis was comparable to that in patients with PV. Further larger-scale studies are needed to confirm these findings and evaluate the benefits of preventive management of COPD with erythrocytosis similar to PV.

Keywords Polycythemia vera, Secondary erythrocytosis, Thrombosis, Phlebotomy

Article

Original Article

Blood Res 2021; 56(3): 166-174

Published online September 30, 2021 https://doi.org/10.5045/br.2021.2021111

Copyright © The Korean Society of Hematology.

Causes of erythrocytosis and its impact as a risk factor for thrombosis according to etiology: experience in a referral center in Mexico City

Antonio Olivas-Martinez1,2, Eduardo Corona-Rodarte1, Adrián Nuñez-Zuno1, Olga Barrales-Benítez3, Daniel Montante-Montes de Oca4, Jesús Delgado-de la Mora4, Diana León-Aguilar4, Hilda Elizeth Hernández-Juárez3, Elena Tuna-Aguilar3

1Department of Internal Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico, 2Department of Biostatistics, University of Washington, Seattle, WA, USA, 3Department of Hematology and Oncology, 4Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico

Correspondence to:Elena Tuna-Aguilar, M.D.
Department of Hematology and Oncology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 15 Vasco de Quiroga Avenue, Mexico City 14080, Mexico
E-mail: elenatuna@yahoo.fr

Received: June 5, 2021; Revised: July 23, 2021; Accepted: July 30, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background
Thrombotic events are well documented in primary erythrocytosis, but it is uncertain if secondary etiologies increase the risk of thrombosis. This study aimed to determine the causes of erythrocytosis and to identify its impact as a risk factor for thrombosis.
Methods
Data were obtained from patients with erythrocytosis between 2000 and 2017 at a referral hospital in Mexico City. Erythrocytosis was defined according to the 2016 WHO classification. Time to thrombosis, major bleeding, or death were compared among groups of patients defined by the etiology of erythrocytosis using a Cox regression model, adjusting for cardiovascular risk factors.
Results
In total, 330 patients with erythrocytosis were studied. The main etiologies of erythrocytosis were obstructive sleep apnea (OSA) in 29%, polycythemia vera (PV) in 18%, and chronic lung disease (CLD) in 9.4% of the patients. The incidence rate of thrombosis was significantly higher in patients with PV and CLD than that in patients with OSA (incidence rates of 4.51 and 6.24 vs. 1.46 cases per 100 person-years, P=0.009), as well as the mortality rate (mortality rates of 2.72 and 2.43 vs. 0.17 cases per 100 person-years, P =0.003).
Conclusion
The risk of thrombosis in CLD with erythrocytosis was comparable to that in patients with PV. Further larger-scale studies are needed to confirm these findings and evaluate the benefits of preventive management of COPD with erythrocytosis similar to PV.

Keywords: Polycythemia vera, Secondary erythrocytosis, Thrombosis, Phlebotomy

Fig 1.

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Figure 1.Thrombosis free survival by final diagnosis.
Blood Research 2021; 56: 166-174https://doi.org/10.5045/br.2021.2021111

Fig 2.

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Figure 2.Major bleeding free survival by final diagnosis.
Blood Research 2021; 56: 166-174https://doi.org/10.5045/br.2021.2021111

Fig 3.

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Figure 3.Overall survival by final diagnosis.
Blood Research 2021; 56: 166-174https://doi.org/10.5045/br.2021.2021111

Table 1 . Baseline demographic characteristics when erythrocytosis was detected..

CharacteristicOverall (N=330) PV (N=61)OSA (N=96)CLD (N=31)P
Age (yr)44 (31, 58)59 (46, 66)38 (29, 51)57 (40, 64)<0.001
Males251 (76%)28 (46%)82 (85%)20 (65%)<0.001
Weight (kg) (NA=3)75 (66, 90)68 (57, 74)90 (75, 104)73 (64, 91)<0.001
Height (m) (NA=7)1.65 (1.59, 1.71)1.63 (1.57, 1.68)1.66 (1.60, 1.71)1.62 (1.56, 1.67)0.061
BMI (kg/m2) (NA=7)28 (24, 32)25 (22, 27)32 (28, 36)28 (25, 36)<0.001
BMI classification (NA=7)<0.001
Normal86 (27%)25 (43%)12 (13%)6 (19%)
Overweight121 (37%)28 (48%)24 (25%)14 (45%)
Obesity116 (36%)5 (9%)59 (62%)11 (35%)
Diabetes50 (15%)11 (18%)14 (15%)6 (19%)0.8
Hypertension140 (42%)29 (48%)41 (43%)15 (48%)0.8
Smoking124 (38%)20 (33%)34 (35%)15 (48%)0.3
Dyslipidemia (NA=18)145 (46%)21 (37%)49 (53%)12 (44%)0.2

Summaries presented in median (IQR) or N (%)..

Abbreviations: BMI, body mass index; CLD, chronic lung disease; NA, not available; OSA, obstructive sleep apnea; PV, polycythemia vera..

Table 2 . Clinical findings when erythrocytosis was detected..

CharacteristicOverall (N=330)PV (N=61)OSA (N=96)CLD (N=31)P
Weight loss35 (11%)16 (26%)6 (6.2%)4 (13%)0.002
Fatigue111 (34%)18 (30%)41 (43%)10 (32%)0.2
Vasomotor symptoms132 (40%)32 (52%)46 (48%)11 (35%)0.3
Dyspnea75 (23%)3 (4.9%)29 (30%)16 (52%)<0.001
Snoring133 (40%)4 (6.6%)75 (78%)7 (23%)<0.001
Palpable splenomegaly54 (16%)28 (46%)13 (14%)0 (0%)<0.001
Palpable hepatomegaly31 (9.4%)15 (25%)7 (7.3%)0 (0%)<0.001
Arterial thrombosis25 (7.6%)5 (8.2%)2 (2.1%)1 (3.2%)0.2
Venous thrombosis31 (9.4%)13 (21%)5 (5.2%)4 (13%)0.007

Summaries presented in N (%)..

Abbreviations: CLD, chronic lung disease; OSA, obstructive sleep apnea; PV, polycythemia vera..

Table 3 . Laboratory findings during the diagnostic approach..

Laboratory featureOverall (N=330)PV (N=61)OSA (N=96)CLD (N=31)P
Hemoglobin (g/dL)19.0 (18.1, 20.0)19.0 (17.7, 20.6)19.5 (18.4, 20.6)19.2 (18.0, 20.3)0.5
Hematocrit (%)56 (54, 61)59 (54, 63)58 (55, 63)58 (53, 63)>0.9
Mean corpuscular volume (fL) (NA=2)90 (86, 93)87 (80, 91)91 (87, 94)91 (87, 95)0.2
Mean corpuscular hemoglobin (pg) (NA=2)30.4 (28.5, 31.7)28.7 (26.2, 30.6)30.5 (28.8, 31.9)30.6 (29.0, 31.5)0.003
Leukocyte count (×109L)7.3 (6.2, 9.1)10.2 (8.4, 13.9)7.0 (6.0, 8.5)7.4 (6.2, 9.0)<0.001
Platelet count (×109L)200 (157, 264)398 (236, 628)182 (143, 220)166 (140, 205)<0.001
EPO (mU/mL) (NA=70)10 (6, 16)2 (1, 6)13 (9, 18)16 (9, 36)0.002
Low EPO43 (16%)37 (63%)2 (2.9%)0 (0%)
High EPO61 (23%)3 (5.1%)25 (36%)9 (50%)
pO2 (mmHg) (NA=51)66 (57, 73)68 (58, 71)60 (54, 70)51 (47, 61)<0.001
SaO2 (%) (NA=51)93.2 (89.3, 95.0)93.4 (89.8, 95.0)91.9 (86.2, 94.3)83.7 (80.1, 91.8)<0.001
p50 (NA=168)27.0 (25.9, 28.1)27.0 (26.1, 27.8)27.3 (26.0, 28.1)27.6 (26.1, 29.1)0.8
Abnormal liver function test (NA=4)41 (13%)9 (15%)13 (14%)4 (13%)>0.9
Elevated LDH (NA=152)60 (34%)29 (57%)10 (21%)7 (41%)0.002
Glomerular filtration rate (mL/min/1.73 m2) (NA=1)93 (77, 108)82 (64, 102)98 (82, 113)95 (83, 104)0.003
Iron deficiency (NA=167)41 (25%)22 (43%)8 (17%)2 (17%)0.009

Summaries presented in median (IQR) or N (%)..

Abbreviations: CLD, chronic lung disease; EPO, erythropoietin; LDH, lactate dehydrogenase; NA, not available; OSA, obstructive sleep apnea; PV, polycythemia vera..

Table 4 . Complementary studies during the diagnostic approach..

Diagnostic studyOverall (N=330)PV (N=61)OSA (N=96)CLD (N=31)
JAK2 test performed166 (50%)54 (89%)38 (40%)8 (26%)
JAK2 V617F/exon12+52 (31%)48 (89%)2 (5.3%)a)1 (12%)a)
BMB performed98 (30%)58 (95%)16 (17%)3 (9.7%)
Panmyelosis64 (66%)55 (95%)5 (31%)1 (33%)
Chest image performed317 (96%)56 (92%)96 (100%)29 (94%)
Any alteration127 (40%)24 (43%)42 (44%)24 (83%)
Spirometry performed222 (67%)34 (56%)76 (79%)25 (81%)
Normal150 (68%)26 (76%)46 (61%)2 (8.0%)
Obstructive22 (9.9%)5 (15%)6 (7.9%)8 (32%)
Restrictive40 (18%)1 (2.9%)18 (24%)14 (56%)
Obstructive+restrictive10 (4.5%)2 (5.9%)6 (7.9%)1 (4.0%)
Polysomnography performed110 (33%)4 (6.5%)96 (100%)4 (13%)
Apnea-hypopnea index22 (9, 52)30 (7, 57)29 (10, 64)6 (2, 11)
Echocardiography performed145 (44%)16 (26%)56 (58%)21 (68%)
LVEF (%)65 (60, 70)67 (60, 70)66 (60, 70)68 (60, 70)

Summaries presented in median (IQR) or N (%)..

a)These three cases had the JAK2 V617F mutation but did not fulfill the diagnostic criteria for myeloproliferative neoplasm; they were classified as OSA or CLD during the diagnostic approach..

Abbreviations: CLD, chronic lung disease; LVEF, left ventricular ejection fraction; OSA, obstructive sleep apnea; PV, polycythemia vera..

Table 5 . Main outcomes during follow-up..

Overall (N=330) PV (N=61)OSA (N=96)CLD (N=31)P
Time to diagnosis (mo)9 (2, 32)3 (1, 12)14 (4, 44)4 (0, 18)<0.001
Time of follow up (mo)44 (20, 99)58 (26, 99)60 (28, 104)30 (11, 55)0.017
Cumulative incidence
Thrombosis38 (12%)13 (21%)8 (8.3%)7 (23%)0.029
Major bleeding23 (7.0%)6 (9.8%)9 (9.4%)2 (6.5%)>0.9
Death15 (4.5%)9 (15%)1 (1.0%)3 (9.7%)0.001
Incidence rate (cases/100 person-years)
Thrombosis2.324.511.466.240.009
Major bleeding1.361.931.621.690.9
Death0.862.720.172.430.003

Summaries presented in median (IQR) or N (%)..

Abbreviations: CLD, chronic lung disease; OSA, obstructive sleep apnea; PV, polycythemia vera..

Table 6 . Hazard ratios for the main outcomes during follow-up..

CovariateUnadjusted modelAdjusted model
HR95% CIPaHR95% CIP
Thrombosis
Etiologya)
OSA0.320.13–0.770.0120.160.05–0.510.002
CLD1.200.47–3.070.710.990.38–2.620.99
Age (1=1 yr)1.020.99–1.040.161.010.97–1.040.75
Male1.030.46–2.300.941.400.57–3.420.46
BMI (1=1 kg/m2)1.010.98–1.050.371.051.02–1.090.003
Hypertension1.090.51–2.330.820.870.36–2.100.75
Diabetes1.050.42–2.600.920.710.26–1.950.51
Smoking1.430.68–3.030.351.390.59–3.310.45
Bleeding
Etiologya)
OSA0.780.28–2.220.650.990.28–3.530.98
CLD0.800.16–4.010.790.790.15–4.130.78
Age (1=1 yr)1.000.97–1.040.791.000.96–1.050.85
Male1.160.40–3.300.791.340.40–4.450.64
BMI (1=1 kg/m2)0.970.91–1.030.340.960.89–1.040.34
Hypertension1.020.38–2.700.971.070.31–3.610.92
Diabetes1.210.39–3.710.751.590.44–5.750.48
Smoking0.840.31–2.280.730.750.25–2.240.60
All-cause mortality
Etiologya)
OSA0.060.01–0.510.0090.010.0002–0.550.024
CLD0.810.22–3.000.750.790.18–3.550.76
Age (1=1 yr)1.071.02–1.110.0031.061.01–1.120.025
Male0.410.14–1.210.111.250.30–5.160.76
BMI (1=1 kg/m2)1.010.97–1.060.631.111.03–1.200.009
Hypertension1.220.41–3.650.730.340.08–1.390.13
Diabetes1.280.35–4.680.711.110.24–5.110.90
Smoking1.030.34–3.150.960.810.16–4.040.79

a)Reference group is polycythemia vera..

Abbreviations: aHR, adjusted hazard ratio; BMI, body mass index; CI, confidence interval; CLD, chronic lung disease; HR, hazard ratio; OSA, obstructive sleep apnea..
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