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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 43  |  Issue : 2  |  Page : 52-59

Pulmonary hypertension in adult Egyptian patients with b-thalassemia major: correlation with natural anticoagulant levels


1 Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
3 Department of Cardiology, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Submission13-Jan-2015
Date of Acceptance01-Mar-2015
Date of Web Publication3-Jun-2015

Correspondence Address:
Tamer A Elbedewy
Department of Internal Medicine, Faculty of Medicine, Tanta University, 31527 Tanta
Egypt
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DOI: 10.4103/1110-1415.158051

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  Abstract 

Background/aim
Thalassemia constitutes a heterogeneous group of inherited anemia. In Egypt, 1000/1.5 million live births per year suffer from thalassemia. b-Thalassemia major (b-TM) is characterized by absent or reduced synthesis of b hemoglobin chains. The incidence and pathophysiology of pulmonary hypertension (PH) in patients with b-TM is not clear. The hypercoagulable state in thalassemia enhances the risk of thrombosis, such as pulmonary embolism. The aim of the present study was to investigate the prevalence of PH in adults with b-TM and investigate the role of protein C, protein S, and antithrombin III deficiencies in the pathogenesis of PH in adults with b-TM.
Subjects and methods
Forty patients with b-TM (group I) were selected, along with 20 age-matched and sex-matched healthy individuals as controls (group II). Patients were subjected to full medical history and complete clinical examination. Plasma protein C, protein S, and antithrombin III assays were measured using ELISA. Doppler echocardiography was used for estimation of systolic pulmonary artery pressure (sPAP).
Results
PH was diagnosed in 16 (40%) patients. Significantly higher levels of sPAP were found in poorly chelated and inadequately transfused patients. Significantly lower levels of protein C, protein S, and antithrombin III were found in patients with PH. There was significant negative correlation between protein C, protein S, and antithrombin III and sPAP.
Conclusion
Significant decrease in protein C, protein S, and antithrombin III was found in b-TM, especially in patients with PH, which might suggest the role of the hypercoagulable state in the pathogenesis of PH in b-TM.

Keywords: b-thalassemia major; pulmonary hypertension; protein C; protein S; antithrombin III


How to cite this article:
Elbedewy TA, Elshweikh SA, Abd El-Naby AY, Elsheikh EA. Pulmonary hypertension in adult Egyptian patients with b-thalassemia major: correlation with natural anticoagulant levels. Tanta Med J 2015;43:52-9

How to cite this URL:
Elbedewy TA, Elshweikh SA, Abd El-Naby AY, Elsheikh EA. Pulmonary hypertension in adult Egyptian patients with b-thalassemia major: correlation with natural anticoagulant levels. Tanta Med J [serial online] 2015 [cited 2021 Mar 1];43:52-9. Available from: http://www.tdj.eg.net/text.asp?2015/43/2/52/158051


  Introduction Top


Thalassemia syndromes constitute a heterogeneous group of inherited anemias that collectively represent the most common recessive single gene disorder worldwide; about 3% of the world's population carries b-thalassemia genes [1] . In Egypt, it was estimated that 1000/1.5 million live births per year suffer from thalassemia; b-thalassemia is the most common type, with a carrier rate starting from 5.3%-9% [2] .

b-Thalassemia major (b-TM) is characterized by absent or reduced synthesis of b hemoglobin chains, which results in severe chronic hemolytic anemia from the first year of life, requiring regular lifelong blood transfusions for the patient's survival [3] .

Patients with thalassemia develop several complications, including cardiac, endocrinal, and hepatic dysfunctions [4] . In b-TM, cardiac disorders are responsible for more than half of the deaths in those patients and are thus the main determinants of survival [5] . Heart diseases may manifest as cardiomyopathy, heart failure, pulmonary hypertension (PH), or arrhythmias [6] .

Recently, it was suggested that PH is associated with a high mortality and morbidity rate [7] . The incidence and pathophysiology of PH in patients with b-TM is not clear but is thought to be due to chronic hypoxia, hemolysis, iron deposition, chronic high output state, and splenectomy [8],[9] . In recent years, the hypercoagulable state in thalassemia enhances the risk of thrombosis [10] . Pulmonary thromboembolism has also been documented by several investigators [11],[12] . Longstanding microembolization in the lungs can lead to PH [13],[14] . Several etiologic factors may play a role in the pathogenesis of the hypercoagulable state in thalassemia, such as decreased levels of naturally occurring anticoagulants such as protein C, protein S, and antithrombin III (AT-III) [15] .

Therefore, the aim of the present study was to investigate the prevalence of PH in adults with b-TM maintained on blood transfusion and iron-chelating agents and investigate the role of natural anticoagulants (protein C, protein S, and AT-III) deficiency in the pathogenesis of PH in adults with b-TM.


  Subjects and methods Top


Subjects

This cross-sectional study was carried out on 40 patients with b-TM (group I); they were randomly selected from among inpatients and outpatients of the Hematology Unit, Internal Medicine Department, Faculty of Medicine, Tanta University, from October 2013 to October 2014. Twenty age-matched and sex-matched healthy subjects were also included in the study as a control group (group II). This study was conducted in accordance with the guidelines of the Declaration of Helsinki (1975) and its subsequent amendments (1983). Participation in the study was voluntary after written informed consent was obtained from the subjects before the study after full explanation of the benefits and risks of the study.

The studied patients with b-TM fulfilled the following criteria in their history at the time of initial diagnosis (age at presentation was <2 years with mean hemoglobin level of 6-7 g/dl, HbF>50%, and HbA2 < 4%) [16] .

Patients with other hemoglobinopathies or other hemolytic anemia were excluded. Patients with clinically volume overload at the time of echocardiography, Chronic obstructive pulmonary disease (COPD), chest wall disease, parenchymal lung disease, previous pulmonary embolism, collagen vascular disease, mitral valve disease, aortic valve disease, left to right shunt, and primary PH were also excluded. Patients on treatment with warfarin or systemic sex hormone therapy such as oral contraceptive pills, pregnant women, and patients with chronic liver disease were also excluded.

None of the patients had cardiac symptoms or clinically apparent heart failure, and none of them were taking cardioactive medications at the time of examination.

All patients were on regular blood transfusion and iron chelation therapy with desferrioxamine (40 mg/kg/day administered subcutaneously through a battery-operated portable pump over a period of 8-12 h overnight, for 5-7 nights/week) [17] .

Mean pretransfusional hemoglobin level and mean serum ferritin level in each patient over the last year of follow-up were obtained to evaluate the transfusion therapy and the hemosiderosis level (hemoglobin was measured before each transfusion and serum ferritin was measured every 3 months).

According to the mean serum ferritin level, b-TM patients were subdivided into well-chelated group (with mean serum ferritin <2500 ng/ml) and poorly chelated group (with mean serum ferritin ≥2500 ng/ml) [18] . According to mean pretransfusional hemoglobin level, b-TM patients were subdivided into adequately transfused group (with mean pretransfusional hemoglobin ≥9 g/dl) and inadequately transfused group (with mean pretransfusional hemoglobin <9 g/dl) [17] .

Methods

All of the included patients were subjected to full medical history evaluation and complete clinical examination, including age, sex, weight, height, disease duration, first time of blood transfusion, number of blood transfusions/year, history of splenectomy, postsplenectomy duration, and type and duration of chelation therapy.

Laboratory assessment

Patients were instructed to fast overnight before attending the clinic in the morning and advised to abstain from taking any medications (including chelation) in the previous 24 h. Blood samples from patients were collected immediately before blood transfusion.

Fasting 10 ml venous blood was collected from all subjects for biochemical analysis. Serum samples were recovered and immediately aliquotted and frozen at −70°C until use. Citrated plasma was prepared as follows: blood samples were collected in tubes containing 3.2% sodium citrate as anticoagulant (9 : 1 ratio) and centrifuged at 2000g for 15 min to collect the plasma, and the samples were stored at −80°C until the time of assay.

Peripheral blood samples were collected on ethylenediaminetetraacetic acid (1.2 mg/ml) for complete blood count. Complete blood count was taken using SysmexXT-1800i (Sysmex, Hyogo, Japan).

Serum ferritin was evaluated using Cobas Integra 800 (Roche Diagnostics, Mannheim, Germany); plasma protein C assay was measured using the REAADS protein C antigen test Sandwich ELISA kit (Corginex Inc., Broomfield, Colorado, USA); plasma protein S assay was measured using the REAADS protein S antigen test Sandwich ELISA kit (Corginex Inc., Broomfield, Colorado, USA); and plasma AT-III assay was measured using the AT-III ELISA antigen kit (Affinity Biologicals, Hamilton, Ontario, Canada).

Doppler echocardiography

An experienced operator performed all echocardiographic studies before blood transfusion to avoid overestimation of systolic pulmonary artery pressure (sPAP) due to volume overload. Two-dimensional and M-mode Doppler echocardiographic images (Vivid 3, 7 machine) (GPS Medical 11730 Church Street Indianapolis, Indiana 46236 USA) were obtained from apical or parasternal windows in the left lateral recumbent position for each patient. In the presence of tricuspid valve regurgitation, sPAP was calculated using the modified Bernoulli equation and PH was defined as sPAP 35 mmHg or more at rest [19] .

Statistical analysis

The collected data were tabulated and analyzed using SPSS (version 17; SPSS Inc., Chicago, Illinois, USA) software. Categorical data were presented as number and percentages, whereas quantitative data were expressed as mean and standard deviation (SD). Comparison of continuous data between two groups was made using the unpaired t-test for parametric data and the Mann-Whitney test for nonparametric data. Fisher's exact test was used for comparison between categorical data. Spearman's and Pearson's tests for correlations between different parameters (nonparametric and parametric, respectively) were used. The accepted level of significance in this work was 0.05 (P < 0.05 was considered significant).


  Results Top


Our study included 40 adult patients with b-TM (group I) (26 men and 14 women); their ages ranged between 18 and 29 years (mean age 23.28 ± 3.595 years). The control group (group II) included 20 healthy participants (12 men and 8 women); their ages ranged between 19 and 27 years (mean age 22.5 ± 2.705 years). There were insignificant differences between group I and group II as regards age and sex [Table 1]. Sixteen (40%) patients had PH, 21 (52.5%) patients were poorly chelated, 17 (42.5%) patients were inadequately transfused, and all (100%) patients were splenectomized.
Table 1 Comparison between the two studied groups as regards different variables

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Our results showed significantly higher levels of platelet count, serum ferritin, and sPAP and lower levels of pretransfusional hemoglobin, protein C, protein S, and AT-III in b-TM patients in comparison with controls [Table 1] and [Figure 1].
Figure 1: Protein C, protein S, and antithrombin II I in the different groups.

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Our results showed significantly higher levels of sPAP in poorly chelated and inadequately transfused patients when compared with well-chelated and adequately transfused patients, respectively, and also showed an insignificant difference between poorly and well-chelated or inadequately and adequately transfused patients as regards protein C, protein S, and AT-III. Other comparisons between poorly and well-chelated or inadequately and adequately transfused patients are shown in [Table 2] and [Table 3].
Table 2 Comparison between well-chelated and poorly chelated patients as regards different variables in the thalassemic group

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Table 3 Comparison between adequately and inadequately transfused patients as regards different variables in the thalassemic group

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Significantly lower levels of protein C, protein S, and AT-III were found in patients with PH when compared with patients without PH [Figure 1]. Significantly higher levels of platelet counts were found in patients with PH when compared with patients without PH. Other comparisons between patients with PH and patients without PH are shown in [Table 4].
Table 4 Comparison between pulmonary hypertensive and nonpulmonary hypertensive patients as regards different variables in the thalassemic group

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Our results showed significant negative correlation between protein C, protein S, and AT-III on one hand and sPAP on the other hand [Figure 2]. Also, significant positive correlations were seen between protein C, protein S, and AT-III. Other correlations between protein C, protein S, and AT-III and other variables are shown in [Table 5].
Figure 2: Correlation between systolic pulmonary artery pressure and nat ural anticoagulant levels.

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Table 5 Correlation between plasma (protein C, protein S, and antithrombin III) and different variables in thalassemic patients

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  Discussion Top


PH has emerged as a major complication of several hematologic disorders and a common finding in patients with b-TM. The prevalence of PH is variable, depending on the method used for screening and the type of thalassemia. In most studies, the prevalence had been determined by echocardiography; however, the accuracy of echocardiography in the evaluation of PH in this entity is currently unknown [20] .

Our results showed that 16 (40%) patients had PH. Our results also showed highly significant levels of sPAP in poorly chelated and inadequately transfused patients when compared with well-chelated and adequately transfused patients, respectively.

In accordance with our results, Hagar et al. [21] reported that 44% of thalassemic patients had PH. In Egypt, El-Beshlawy et al. [22] reported that the prevalence of PH was 37.5% in 32 patients with b-TM, using echocardiography. Also, Hassan et al. [23] found that 40% of Egyptian thalassemic patients had PH, on Doppler echocardiogram.

In contrast to our results, striking rates of PH of 75 and 79% were reported in two previous studies in small populations of patients with thalassemia major [9],[24] , but those patients were generally poorly treated and had an increased prevalence of systolic left ventricular dysfunction. Also, Singer et al. [14] found that 68% of their thalassemic patients had PH on Doppler echocardiograms; their higher percentages can be explained by the older age of their patients and the higher percentage of splenectomized patients (94%). Different trials in optimally treated populations with b-TM showed that PH was rather rare and mild, with pulmonary artery pressure elevation, mostly borderline, encountered in ~10% of cases in different cohorts [25],[26],[27] .

Doppler echocardiography is an excellent screening tool for cardiovascular complications in patients with hemoglobinopathies, but it may overestimate pulmonary arterial pressure, resulting in false-positive results, especially in patients with hemoglobinopathies, in whom several factors lead to a high output state [28] . This fact was proven by Derchi et al. [29] who conducted a multicenter cross-sectional study of 1309 Italian b-thalassemia patients [mean age 36.4 ± 9.3 years, 46% men, 74.6% b-TM, 25.4% thalassemia intermedia (TI)]. The prevalence of PH in b-thalassemia patients as confirmed on right heart catheterization was 2.1%, with about five-fold higher prevalence in TI (4.8%) than in b-TM (1.1%). Advanced age and splenectomy are risk factors for PH in this patient population.

The higher incidence of PH in our study may be because 52.5% of patients were poorly chelated, 42.5% of patients were inadequately transfused, and all (100%) patients were splenectomized with significant increase in the platelet count. Also, we used Doppler echocardiography, not right heart catheterization, and we estimated sPAP, not the mean pulmonary pressure.

Although PH is being increasingly recognized as a part of the clinical spectrum for b-thalassemia, little is understood about the mechanisms and risk factors for its development. Risk factors for the development of PH in thalassemic patients include the severity of hemolysis, increasing age, splenectomy, iron overload, and prothrombotic state [14],[30],[31],[32] . Chronic transfusion therapy is commonly used in b-TM, together with iron-chelating therapy; it may prevent or ameliorate PH in these patients [33] .

A hypercoagulable state is another notable finding in thalassemia. Hypercoagulability results from a spectrum of abnormalities, including the native erythrocyte precoagulant surface, the frequently performed splenectomy, some coexistent genetic coagulation defects, and endothelial dysfunction and vasculopathy [10] . Several thromboembolic complications have been reported in thalassemic patients, including pulmonary embolism [34] .

Our results showed significantly high platelet counts and lower levels of protein C, protein S, and AT-III in b-TM patients in comparison with controls.

In accordance with our results, several investigators have reported profound changes in the levels of coagulation factor inhibitors. Low levels of the coagulation inhibitors protein C and protein S have been observed in patients with thalassemia from a variety of ethnic backgrounds [35],[36],[37],[38] . In Israel, Eldor et al. [35] found that protein C (antigen and activity) and free protein S were significantly decreased in both adults and children with thalassemia when compared with the control group. Similar results were obtained in studies of b-TI patients in Italy [36] and patients with a-TM or b-TM in Thailand and Turkey [37],[38] . Some thalassemic patients from Italy and Turkey had low AT-III levels in addition to protein C and protein S deficiencies, whereas no AT-III deficiency was found in Israeli patients [15],[35],[36] .

Also, Tripatara et al. [39] found that the average activity of protein C and protein S in thalassemic patients was statistically lower than those in the control group. Moafi et al. [40] found that 43% of thalassemic cases had protein C deficiency, 53% had protein S deficiency, and 30% had AT-III deficiency; 82% of all patients had at least one factor deficiency. The frequency of protein C, protein S, and AT-III deficiency was higher in patients with lower pretransfusion hemoglobin levels. High ferritin level was also significantly related to protein C and protein S deficiency. Hassan et al. [23] found that thalassemic patients had lower levels of proteins C and S compared with the control group and there was significant negative correlation between protein C level and serum ferritin. Mustafa et al. [41] found that the natural coagulation inhibitors protein C, protein S, and AT-III were significantly reduced in patients with b-TM. Rosnah et al. [42] showed that protein C and free protein S levels were significantly lower in thalassemia patients compared with age-matched normal controls, whereas mean total protein S and antithrombin levels were similar.

Explanations for decreased levels of protein C and protein S in thalassemic patients include vitamin K deficiency, liver dysfunction due to hemosiderosis, and the increased turnover rate of protein C and protein S [43] . One alternative explanation for the significant reduction in protein C may be that this type of protein binds to phosphatidylserine, or other negatively charged phospholipids, abnormally present in the external membrane of thalassemic erythrocytes [44] .

Our results showed that serum ferritin levels in patients were negatively correlated with protein C levels. Similar results were obtained in Italy by Musumeci et al. [15] on 74 thalassemic patients and in India by Naithani et al. [45] on 54 thalassemic patients. This can be explained by the fact that iron overload leads to a state of chronic oxidative stress in patients with b-thalassemia, as evidenced by higher reactive oxygen species and lower reduced glutathione levels in platelets [46] . This leads to platelet activation, protein C and protein S consumption, and susceptibility to the thromboembolic consequences [47] .

Our results showed significantly lower levels of protein C, protein S, and AT-III in patients with PH when compared with patients without PH. Further, our results showed significant negative correlation between protein C, protein S, and AT-III on one hand and sPAP on the other hand.

Moafi et al. [40] found that only two of 41 patients had evidence of PH with echocardiography, despite protein C deficiency, protein S deficiency, and AT-III deficiency. To our knowledge, there are no studies, to date, evaluating the levels of protein C, protein S, and AT-III and their impact on PH occurrence with b-TM.

Our study is not without limitation. We investigated patients using Doppler echocardiography, not right heart catheterization; however, we found that right heart catheterization is an invasive maneuver and it is unethical to expose patients to this aggressive technique without direct benefit to them.


  Conclusion Top


Significantly decreased levels of protein C, protein S, and AT-III were found in b-TM patients, especially in patients with PH, which might suggest the role of the hypercoagulable state in the pathogenesis of PH in b-TM patients.

Screening for probable presence of PH in thalassemic patients is recommended. A wider multicenter study on a large number of patients is also recommended to determine the exact prevalence of PH in thalassemic patients.


  Acknowledgements Top


Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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Abstract
Introduction
Subjects and methods
Results
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Acknowledgements
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