Therapeutic Erythrocytapheresis Is Effective in Treating High Altitude Polycythemia on the Qinghai-Tibet Plateau

Abstract

Introduction

High altitude polycythemia (HAPC) is a common chronic disease at high altitudes. It is characterized by excessive erythrocytosis (≥190 g·L^-1 in females or ≥210 g·L^-1 in males). HAPC severely jeopardizes the health status of plateau dwellers. The Qinghai-Tibet plateau, with an elevation above 4000 m, is the highest plateau in the world. Both Han and Tibetan populations residing there face the threat of HAPC. Therapeutic erythrocytapheresis (TE) was introduced to Tibet as an alternative to phlebotomy in 2015.

Methods

In this study, we retrospectively analyzed 155 patients with HAPC treated with TE in Tibet. Routine blood testing values before and after TE were compared to evaluate treatment efficacy. The efficiency rate, defined as the rate of increase in red blood cell depletion attained by TE compared with 450 mL whole blood phlebotomy, was calculated using whole blood volume and hematocrit before and after treatment and used to identify patients who maintained a normal hemoglobin level in the year after the TE procedure.

Results

On average, TE reduced red blood cell levels by 1.5×10¹²·L^-1, hemoglobin concentration by 52 g·L^-1, and hematocrit by 14% (P<0.001 for each). Patients who underwent TE with an efficiency rate ≥1.9 were more likely to maintain a normal hemoglobin level in the following year than those who underwent TE with an efficiency rate <1.9 (90 vs 28%, P<0.01).

Conclusions

TE is a feasible therapeutic method to treat HAPC on the Qinghai-Tibet plateau. The efficiency rate is a useful tool to predict the expected interval between TE procedures.

Keywords

efficiency rate excessive erythrocytosis hemoglobin level

Introduction

High altitude polycythemia (HAPC) is a common chronic altitude illness characterized by elevated hemoglobin concentration (≥190 g·L^-1 in females or ≥210 g·L^-1 in males).¹ Typical clinical manifestations include dyspnea, palpitations, sleep disorders, venous dilation, headache, and tinnitus. The increase in hemoglobin concentration is mainly caused by environmental hypoxia and is a crucial response in allowing the body to adapt to the high altitude. However, excessive erythrocytosis leads to significant increases in blood viscosity and microcirculation disturbances, which result in tissue hypoxia, stroke, sleep disorder, and myocardial infarction.^1,2

More than 140 million people worldwide reside at altitudes above 2500 m, most of them in the Andes, Ethiopian highlands, and Qinghai-Tibet plateau. The Qinghai-Tibet plateau, with an elevation above 4000 m, is the highest plateau in the world. It covers a vast area and has more than 12 million permanent residents.³ The prevalence of HAPC on the Qinghai-Tibet plateau is between 5 and 18%.⁴ Han people who have lived in a low-altitude environment for a long time are prone to development of HAPC after immigration to the Qinghai-Tibet plateau. Some Tibetans, despite their longer generational time residing at high altitudes, also present with HAPC.

Traditionally, patients with HAPC on the Qinghai-Tibet plateau are treated with phlebotomy. Side effects that commonly accompany this procedure include fatigue, fainting, hematomas, and anemia.^5,6 An alternative approach is therapeutic erythrocytapheresis (TE), an extracorporeal blood separation method in which whole blood is extracted from the patient, red blood cells (RBCs) are separated, and plasma is returned to the circulation. We aimed to assess the efficacy of TE since its introduction to the Qinghai-Tibet plateau in 2015. In addition, owing to the harsh weather conditions and remote settlements, longer intertreatment time intervals can offer great convenience to residents of the Qinghai-Tibet plateau. This calls for a tool to predict the prognosis of individual patients. Previously, the efficiency rate (ER) has been reported to be useful in selecting the appropriate treatment modality.⁷ We further optimized this model to predict when each patient would need another TE procedure.

Methods

Study Enrollment and Oversight

The study was approved by the human ethics committee of the Shigatse People’s Hospital and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients.

Adult patients with newly diagnosed HAPC from 2015 to 2019 at Shigatse People’s Hospital were included in the study. The condition was diagnosed according to published criteria.¹ For permanent residents at altitudes above 2500 m, men with hemoglobin concentrations >210 mg·dL^-1 and women with hemoglobin concentrations >190 mg·dL^-1 were considered to have HAPC. Patients with a history of malignant tumor, mutant JAK2 exon 12/14, MPL exon 10, CALR gene, or Bcr-Abl fusion gene were excluded. Patients who had previously been treated with phlebotomy were also excluded.

Treatment Protocol and Prevention of Adverse Effects

TE was performed using the COBE Spectra Apheresis System 6.1 (CaridianBCT) and disposable closed tubes. Blood (1000–1500 mL) was collected through a peripheral vein in each treatment cycle. The individual collection volume was calculated by the apheresis system according to the hematocrit. Continuous inlet flow was set at 40 to 60 mL·min^-1. On average, 350 mL anticoagulant citrate dextrose solution was used for each treatment cycle. During the TE procedure, 1 L of Ringer’s solution and 1 L of Dextran-40 were administrated to the patients.

Calcium gluconate (10 mL, 10%) was routinely administered via intravenous injection before treatment. After treatment, the treating physician determined for each patient whether further calcium gluconate was necessary to prevent hypocalcemia according to the severity of symptoms, the degree of hypocalcemia, and whether symptoms subsided spontaneously. Hypocalcemia was defined as serum calcium concentration lower than 2.25 mmol·L^-1 accompanied by numbness or cramps.

Data Collection

This was a retrospective study, and all data were collected at return visits. Demographic data (including age, sex, and ethnicity) were collected as per hospital protocol. Routine blood testing (including RBC count, hemoglobin concentration, hematocrit, white blood cell count, and platelet count) and coagulation tests (including activated partial thromboplastin time [APTT] and partial thromboplastin [PT]) were performed the same day as and 3 d after the TE procedure.

Routine blood testing was performed each month between TE treatments (except when heavy snow cut off the mountain roads and prevented patients from presenting for follow-up visits). A second TE procedure was performed when the hemoglobin level rose above 210 g·L^-1, and the time interval between the 2 procedures was documented. Clinical symptoms (splenomegaly, numbness/swelling/pain of limbs and face, itchy skin, hypertension, cerebral infarction, dysuria, and hyperuricemia) were monitored and documented between TE treatments. Systolic pressure ≥140 mm Hg or diastolic pressure ≥90 mm Hg was diagnosed as hypertension.⁸

Efficiency Rate and ER

The ER was first introduced as a mathematical model to evaluate the efficacy of a single TE procedure.⁷ It is calculated using estimated blood volume (calculated by the apheresis system), preprocedural hematocrit values (tested right before the procedure), and delta-hematocrit values (difference between the hematocrit the same day as and 3 d after the procedure). It is defined as the rate of increase in RBC depletion attained by TE when compared with 450 mL whole blood phlebotomy. We intended to optimize this mathematical model to predict the expected interval between TE procedures. Based on the ER of the individual procedure and whether the patient needed medical intervention in the following year, we plotted the receiver operating characteristic (ROC) curve. The cut-off value was determined according to Youden’s index, which is the difference between the true positive rate and the false positive rate. Maximizing this index allows one to find an optimal cut-off point from the ROC curve.

Statistical Analysis

Nominal data are presented as mean±SD and compared using a paired t test. Nonnominal data are presented as median (range) and compared using the Mann-Whitney U test. Categorical data are presented as n (%) and were compared using the Pearson χ² test. Results were considered statistically significant with a P-value <0.05. All statistical analyses were performed using SPSS 20.0 statistics software (SPSS Inc., Chicago, IL).

Results

Patient Characteristics

A total of 155 patients diagnosed with HAPC and treated with TE between 2015 and 2019 at Shigatse People’s Hospital were included in this retrospective analysis. Patient characteristics are presented in Table 1. The median age was 47 y (range 26–75); 151 (97%) were male and 4 (3%) were female. The majority (n=125, 81%) were Tibetan.

Table 1

Patient characteristics

Variables	Median (range) or n (%)
Age, y	47 (26–75)
Sex
Male	151 (97)
Female	4 (3)
Ethnic groups
Tibetan	30 (19)
Han	125 (81)
Clinical symptoms
Hyperuricemia	78 (50)
Numbness/Swelling and pain of limbs and face	72 (47)
Hypertension	28 (18)
Itchy skin	22 (14)
Splenomegaly	12 (8)
Cerebral infarction	4 (3)
Dysuria	3 (2)

Treatment Outcomes

The RBC collection time was 37±3 min (range 31–43), with a collection volume of 1252±145 mL (range: 937–1447). The RBC count, hemoglobin concentration, and hematocrit were significantly reduced after treatment (Table 2). The pre- and post-treatment RBC counts were 7.4±0.8×10¹²·L^-1 and 5.9±0.8×10¹²·L^-1 (P<0.001). The pre- and post-treatment hemoglobin concentrations were 230±18 g·L^-1 and 178±17 g·L^-1 (P<0.001). The pre- and post-treatment hematocrit level were 68±5% and 6±2% (P<0.001). In further analyses, there were no significant correlations between age, sex, ethnicity, or clinical symptoms and treatment outcomes (RBC count, hematocrit level, and hemoglobin concentration).

Table 2

Comparison of routine testing values before and after TE

Variables	Pretreatment	Post-treatment	P-value
RBC (×10¹²·L^-1)	7.4±0.8	5.9±0.8	<0.001
Hemoglobin (g·L^-1)	230±18	178±17	<0.001
HCT (%)	68±5	54±6	<0.001
WBC (×10⁹·L^-1)	5.7±1.6	5.7±1.6	0.798
PLT (×10⁹·L^-1)	137±46	164±52	0.217

HCT, hematocrit; PLC, platelet; RBC, red blood cell; TE, therapeutic erythrocytapheresis; WBC, white blood cell.

Of the 59 patients with coagulopathy before treatment, APTT was reduced from 48 to 36 s (P<0.001), and PT was reduced from 17 to 12 s (P<0.001). Of the 78 patients with hyperuricemia before treatment, uric acid level was significantly reduced after the TE procedure (566 μmol·L^-1 vs 432 μmol·L^-1, P<0.001).

Adverse Effects

Hypocalcemia was reported in 12 patients (8%) and was associated with slight numbness around the mouth, fingers, and toes. In all cases, symptoms subsided spontaneously without additional calcium supplementation.

Efficiency Rate and ER

The efficiency rate was 2.0±0.6 (0.7–3.9) for all the TE procedures. Based on the ROC curve, the cut-off value was 1.9. In patients who underwent TE procedures with an ER ≥1.9, the majority (90%) maintained a normal hemoglobin concentration (≤210 g·L^-1) for more than 1 y after treatment, whereas among patients with an ER <1.9, only 29% maintained a normal hemoglobin concentration in the same time period (P<0.01).

Discussion

Our study demonstrated that TE treatment significantly reduced the RBC count, hemoglobin concentration, and hematocrit level. Previous studies have established the advantages of TE compared with standard phlebotomy. TE requires less time per procedure and fewer treatments per patient⁹ and is therefore more economical¹⁰ and the method of preference for the majority of patients.¹¹ In addition, TE caused fewer hemodynamic changes than phlebotomy and preserved valuable blood components, such as plasma proteins, platelets, and white blood cells.^9,11

The ER is a mathematical model used to compare the outcome of individual TE procedures with standard phlebotomy and select the appropriate therapeutic method for individual patients.⁷ As originally described, ER >1.5 was an indication for choosing TE, with an intertreatment interval of 13 wk, rather than phlebotomy.⁷ Given the harsh geographical and transportation conditions on the Qinghai-Tibet plateau, frequent follow-up visits pose a great challenge for local people. Therefore, we aimed to realize a longer intertreatment time interval, ideally 1 y. In our study, the majority of patients with ER >1.9 did not need another TE procedure for at least 1 y, whereas only approximately a quarter of patients with ER <1.9 maintained a normal hemoglobin concentration for 1 y. This demonstrates that the ER can be used to predict intertreatment time intervals for individual patients. This is especially beneficial for residents on the Qinghai-Tibet plateau because the remote settlements and harsh weather conditions make it difficult to present for treatment frequently.

HAPC is often accompanied by bleeding and abnormal coagulation function (prolonged APTT and/or PT), which seriously affect the health status and quality of life of people in Tibet. After TE treatment, in most cases, symptoms were relieved and laboratory results returned to normal values.

There was an increased platelet count after the procedure compared to the testing value obtained just before the procedure. In further analysis, we identified that some of the patients had thrombocytopenia before treatment and recovered normal platelet levels after TE (see online Supplemental Table).

Among the 155 patients in our study, only 4 were female. Male predominance is expected because testosterone increases erythropoiesis.¹² The prevalence of tobacco smoking in male residents of the Qinghai-Tibet plateau may also account for the male predominance among patients with HAPC. Cigarette smoking is causally associated with increased hematocrit, hemoglobin concentration, and mean corpuscular volume.¹³ Carbon monoxide derived from tobacco smoking results in the formation of carboxyhemoglobin in erythrocytes, which lacks the ability to carry oxygen.¹⁴ Smoking-induced hypoxia could further increase hematocrit and hemoglobin concentration as a compensatory response. In addition, the increased mean corpuscular volume may be caused by alterations in protein and lipid composition in the cell membrane as a consequence of free radicals or toxic effects in the bone marrow caused by acetaldehyde from tobacco smoking.^15,16 The possible association between cigarette smoking and HAPC is worth further study because smoking is a potentially reversible risk factor.

Limitations

In this retrospective study, the blood volume drawn for the coagulation test was not corrected for hematocrit. Because hematocrit is increased in patients with HAPC, blood samples contain less plasma than blood samples of equal volume from healthy people, such that the anticoagulant agents in the test tube, pre-added according to the requirements of normal samples, are in relative excess.¹⁷ Therefore, the possibility of artifactual elevation of APTT and PT cannot be ruled out. Furthermore, the number of patients is small, and this is a retrospective, single-center study. A prospective, multicenter study with a larger sample size evaluating the clinical significance of the ER has been implemented. The results of this study should be interpreted with caution.

Conclusions

TE is an effective method to treat HAPC. An ER ≥1.9 indicates a higher possibility of maintaining normal hemoglobin concentration in the year following TE.

Footnotes

Acknowledgements

Acknowledgments: We thank the research assistants for their diligence and attentiveness to detail and the outstanding clinical care delivered by all staff members. We also thank the patients for participating in the study.

Author Contributions: All authors contributed to the study conception and design. Data collection and analysis (BD, PBWD, and XL); writing first draft of the manuscript (YD). All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding/Material Support: None.

Disclosures: None.

Supplementary data

Supplementary material associated with this article can be found in the online version at https://doi.org/10.1016/j.wem.2020.07.006.

Yuexin Dong, Ba Dun, and Pu Bu Wang Dui contributed equally to this work.

References

Leon-Velarde

Maggiorini

Reeves

J.T.

Aldashev

Asmus

Bernardi

et al. Consensus statement on chronic and subacute high altitude diseases. High Alt Med Biol 2005; 6(2), 147–157.

Guan

Bai

Z.Z.

Wuren

Wang

et al. Sleep disturbances in long-term immigrants with chronic mountain sickness: a comparison with healthy immigrants at high altitude. Respir Physiol Neurobiol 2015; 206, 4–10.

Kayser

High altitude adaptation in Tibetans. High Alt Med Biol 2006; 7(3), 193–208.

Windsor

J.S.

Rodway

G.W.

Heights and haematology: the story of haemoglobin at altitude. Postgrad Med J 2007; 83(977), 148–151.

Brissot

Ball

Rofail

Cannon

Jin

V.W.

Hereditary hemochromatosis: patient experiences of the disease and phlebotomy treatment. Transfusion 2011; 51(6), 1331–1338.

McDonnell

S.M.

Grindon

A.J.

Preston

B.L.

Barton

J.C.

Edwards

C.Q.

Adams

P.C.

A survey of phlebotomy among persons with hemochromatosis. Transfusion 1999; 39(6), 651–656.

Evers

Kerkhoffs

J.L.

Van Egmond

Wijermans

P.W.

The efficiency of therapeutic erythrocytapheresis compared to phlebotomy in relation to blood volume and delta-hematocrit: an evaluation in hereditary hemochromatosis polycythemia vera and secondary erythrocytosis. Transfus Apher Sci 2013; 48(2), 187.

Whelton

P.K.

Carey

R.M.

Aronow

W.S.

Casey

D.E.

Jr. Collins

K.J.

Dennison Himmelfarb

et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018; 71(6), e13–e115.

Adams

P.C.

Barton

J.C.

How I treat hemochromatosis. Blood 2010; 116(3), 317–325.

10.

Rombout-Sestrienkova

van Noord

P.A.

van Deursen

C.T.

Sybesma

B.J.

Nillesen-Meertens

A.E.

Koek

G.H.

Therapeutic erythrocytapheresis versus phlebotomy in the initial treatment of hereditary hemochromatosis - a pilot study. Transfus Apher Sci 2007; 36(3), 261–267.

11.

Rombout-Sestrienkova

Nieman

F.H.

Essers

B.A.

van Noord

P.A.

Janssen

M.C.

van Deursen

C.T.

et al. Erythrocytapheresis versus phlebotomy in the initial treatment of HFE hemochromatosis patients: results from a randomized trial. Transfusion 2012; 52(3), 470–477.

12.

Shahani

Braga-Basaria

Maggio

Basaria

Androgens and erythropoiesis: past and present. J Endocrinol Invest 2009; 32(8), 704–716.

13.

Pedersen

K.M.

Colak

Ellervik

Hasselbalch

H.C.

Bojesen

S.E.

Nordestgaard

B.G.

Smoking and increased white and red blood cell. Arterioscler Thromb Vasc Biol 2019; 39(5), 965–977.

14.

Blumenthal

Carbon monoxide poisoning. J R Soc Med 2001; 94(6), 270–272.

15.

Padmavathi

Reddy

V.D.

Kavitha

Paramahamsa

Varadacharyulu

Chronic cigarette smoking alters erythrocyte membrane lipid composition and properties in male human volunteers. Nitric Oxide 2010; 23(3), 181–186.

16.

Yanbaeva

D.G.

Dentener

M.A.

Creutzberg

E.C.

Wesseling

Wouters

E.F.

Systemic effects of smoking. Chest 2007; 131(5), 1557–1566.

17.

Marlar

R.A.

Potts

R.M.

Marlar

A.A.

Effect on routine and special coagulation testing values of citrate anticoagulant adjustment in patients with high hematocrit values. Am J Clin Pathol 2006; 126(3), 400–405.