The Relationship between Sickle Cell Disease and Pulmonary Hypertension in Adults - ssrg-journals
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
SSRG International Journal of Medical Science Volume 9 Issue 2, 1-7, Mar-Apr 2022
ISSN: 2393 – 9117 / https://doi.org/10.14445/23939117/IJMS-V9I2P101 © 2022 Seventh Sense Research Group®
Original Article
The Relationship between Sickle Cell Disease and
Pulmonary Hypertension in Adults
Mariam Alabdo1, Firas Hussein2, Basem Marouf 3
1,2
Hematology Department, Tishreen University Hospital, Lattakia, Syria
3
Cardiology Department, Tishreen University Hospital, Lattakia, Syria
Received Date: 25 January 2022
Revised Date: 01 March 2022
Accepted Date: 11 March 2022
Abstract - Sickle cell disease (SCD) is an inherited It is an inherited autosomal recessive disorder with the
hemoglobinopathy associated with high morbidity and presence of hemoglobin S in blood. Not all inherited
mortality. Pulmonary hypertension (PH) is reported to variants of hemoglobin are detrimental, a concept known
play a significant role. There is very limited literature on as genetic polymorphism. This disease has significant
PH in SCD in Syria. This study aimed to assess the morbidity and is a potentially fatal disease. Patients
prevalence of pulmonary hypertension and its relationship undergo painful crises and may have renal failure, heart
with clinical and laboratory parameters in sickle cell failure, infections, and other complications. in addition to
disease patients. This prospective case-control study its impact on patient's health, it causes a huge financial
included 50 patients with sickle cell disease and 50 burden because heavy expenses are required for frequent
controls matched for age and sex at Tishreen University hospitalization, medication, and blood transfusion. Sickle
Hospital at Lattakia between July 2019 – and July 2020. cell has a profound impact, not just on the patient but on
Both the patients and controls were subjected to the whole family dynamic. Regular follow-up and care
echocardiography. Pulmonary hypertension was may improve a patient's ability to lead productive life and
prospectively defined as a tricuspid regurgitant jet velocity reduction in acute care costs [1][21][25].
of at least 2.5 m per second. Sickle cell disease patients
had a greater mean TRV than controls. Doppler-defined Pulmonary hypertension (PH) is a relatively frequent
pulmonary hypertension occurred in 32% of patients. and severe complication of SCD and an independent risk
Using the dichotomous variable of a TRV < 2.5 m/s or factor for mortality [3]. Echocardiographic screening
TRV ≥ 2.5 m/s, multiple logistic regression analysis studies have identified evidence of elevated pulmonary
identified an increased age, high LDH, and indirect pressures, defined as a tricuspid regurgitant jet velocity
bilirubin levels (markers of hemolysis) as significant (TRV) ≥2.5 m/sec (equivalent to a pulmonary artery
correlates of pulmonary hypertension. The white-cell systolic pressure of approximately 36 mmHg), in 30 to 40
count, reticulocytes, sickle complications, clinical percent of hemoglobin SS (HbSS) and 10 to 28 percent of
measures, or hydroxyurea therapy were unrelated to hemoglobin SC (HbSC) adults [4][20]. Additionally, up to 22
pulmonary hypertension. In this study of adults with sickle percent of HbSS children and adolescents have this
cell disease, the prevalence of pulmonary hypertension, as echocardiographic finding [5], including children as young
confirmed by echocardiographic evaluation, was 32%. It as three years. However, echocardiographic estimates of
appears to be a complication of chronic hemolysis and is pulmonary pressures are substantially less accurate than
resistant to hydroxyurea therapy. Clinical assessment of right heart catheterization. Three prospective studies
adult patients with sickle cell disease should include utilizing right heart catheterization have defined the
echocardiography. prevalence of PH in SCD to be between 6 and 10.5 percent
[6] [7] [8]
. The exact pathogenesis of PH in SCD is not
Keywords - Pulmonary hypertension, Sickle cell disease, known. Still, a number of potential contributing factors
Echocardiography. have been implicated, including endothelial injury from
recurrent sickling, acute and chronic inflammation,
I. INTRODUCTION hypercoagulability, chronic intravascular hemolysis, and
Sickle cell disease (SCD) is a group of common altered bioavailability of the potent vasodilator nitric oxide
genetic disorders. The term "disease" is applied to this (NO) [9]. Vascular remodeling caused by chronically
condition because the inherited abnormality causes a elevated left heart pressures from diastolic dysfunction
pathological condition that can lead to death and severe may also contribute, similar to PH group 2, which is purely
complications [1][23]. SCD is one of the most common due to left heart disease [10][22].
inherited life-threatening disorders in humans, and it
predominantly affects people of African, Indiana, and Arab One theory is that hemolysis results in increased
ancestry [2]. plasma levels of cell-free hemoglobin (Hgb) more than the
binding capacity of the Hgb scavengers, haptoglobin, and
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Mariam Alabdo et al. / IJMS, 9(2), 1-7, 2022
hemopexin. This excess of cell-free Hgb may rapidly examination was performed on each subject. The weight,
deplete circulating NO, although there is continuing height, Body mass index (BMI), heart rate, and pulse
disagreement over the impact of this process on NO oxygen saturation were also recorded.
bioavailability [9]. Additionally, hemolysis releases Alanine transaminase (ALT), aspartate transaminase
arginase I from erythrocytes, limiting arginine availability (AST), bilirubin, lactate dehydrogenase, creatinine, and
for NO synthesis. in addition to these effects on complete blood count (CBC) tests were done.
endothelial regulation, increased cell-free Hgb may also
contribute to endothelial and vascular smooth muscle D. Echocardiography
dysfunction [11][24]. All Doppler Echocardiographic examinations were
done by the same cardiologist, who was blinded to all
Doppler echocardiography estimates pulmonary artery other patient data except the diagnosis of SCD, using a
and right ventricular systolic pressures via the TRV and Philips HD-11 Digital Ultrasound Machine and involved
assesses left and right ventricular size, thickness, and two-dimensional, M-mode, conventional Doppler (pulsed
function. in addition, echocardiography can evaluate the and continuous wave) and tissue Doppler studies to assess
right atrial size, left ventricular systolic and diastolic cardiac structure and function. All measurements were
function, and valve function. Although much attention has made as recommended by the American Society of
been given to the association of a TRV of ≥2.5 m/sec with Echocardiography [13]. Left ventricular wall and chamber
increased mortality risk in SCD [12], each echocardiogram dimensions, left atrial dimension, and ejection fraction
helps inform the clinician of PH risk. (EF) were measured using 2D-guided M-mode
echocardiography. Echocardiographic assessment of PH
This study was designed to determine the prevalence of was obtained using two methods:
pulmonary hypertension in sickle cell disease patients in
our sickle cell clinic and to correlate this with other • Determination of peak TRV by continuous-wave
clinical and laboratory parameters. Doppler by placing the cursor along the tricuspid
regurgitant jet in the apical four-chamber view after
II. PATIENT AND METHODS obtaining a color Doppler display of the tricuspid
A. Study Design and Settings regurgitation jet across the valve.
The study was carried out in the department of • Determination of the right ventricular acceleration
Hematology of Tishreen University Hospital, Lattakia, time (AT) and the ratio of right ventricular
Syria, between July 2019 and July 2020. Ethical acceleration time to right ventricular ejection time
Institutional ethical approval was obtained from the (AT/RVET) from the pulmonary ejection flow jet
hospital research and ethics committee. Informed written obtained by continuous-wave Doppler with sample
and verbal consent was obtained from participants. This volume just proximal to the pulmonary valve in the
was a cross-sectional case-controlled study. parasternal short-axis view. The acceleration time was
taken as the time interval from the onset of right
B. Participants ventricular ejection to peak ejection velocity. in
Fifty patients with sickle cell hemoglobinopathy contrast, the ejection time was taken as the time
documented by hemoglobin electrophoresis were eligible interval from the onset to the end of the ejection.
for the study. Only outpatients in stable condition were
included; patients who had had a Vaso-Occlusive crisis, an Pulmonary hypertension (PH) was defined as a peak
episode of acute chest syndrome, or received transfusions TRV of ≥2.5 m/s. Mean pulmonary arterial pressure
within the previous two weeks were excluded. (MPAP) was estimated using the regression equation
developed by Dabestani et al [14]: MPAP (mmHg) = 90 -
In addition, 50 control subjects with age and sex (0.62 × AT).
distributions similar to those of the patients were evaluated
for laboratory and echocardiographic data comparisons. E. Statistical Analysis
Analysis was done using SPSS version 16.0
C. Clinical Evaluation (Statistical Package for Social Sciences, Inc., Chicago, IL).
Baseline, clinical and demographic characteristics All data generated were entered into a standard pro forma.
were obtained from all the subjects. These include the date Continuous variables were expressed as mean (standard
of birth, gender, medical history, and treatment history deviation, SD), and categorical variables were expressed as
(hydroxyurea, blood transfusion). percentages. Normality was assessed with the Shapiro-
Wilks test. Differences in categorical variables were
Information about hemoglobin genotype was obtained assessed by chi-square analysis. The student's t-test
from existing records. All subjects' blood pressures were compared continuous variables between the two groups for
measured in the right arm with the subjects seated and independent groups. Where the assumption of normality
rested for at least 5 minutes before the procedure. was not satisfied, the Kruskal-Wallis test was used to
Measurements were taken using a mercury compare continuous variables. The critical level of
sphygmomanometer. Systolic and diastolic blood pressures significance was set at P < 0.05.
were measured at Korotkoff sounds V and I. A physical
2Mariam Alabdo et al. / IJMS, 9(2), 1-7, 2022
III. RESULT were significantly higher among the SCD subjects than in
A. Patient Characteristics the controls. on the other hand, hemoglobin and hematocrit
Table 1. shows the baseline characteristics of all 100 concentrations were significantly lower among the SCD
participants recruited for the study. The mean age of the subjects. There were no differences in creatinine and ALT
SCD subjects was 39 ± 10 years, while the mean age for levels between the SCD subjects and the control group.
the control group was 41 ± 10.5 years. The groups were of
Table 3 also shows the echocardiographic parameters
comparable age and sex distribution. There were 28 males
in SCD subjects and controls. The left atrial area, right
and 22 females in the SCD group, while the control group
atrial area, and left ventricular (LV) systolic and diastolic
had 25 males and 25 females. The BMI, systolic blood
diameters were significantly higher among the SCD
pressure, diastolic blood pressure, and oxygen saturation
subjects than in the controls. on the other hand, there was
were lower in the subjects with SCD than in normal
no difference in the left ventricular ejection fraction (EF)
controls. There were no differences in the heart rates
between the SCD subjects and the control group.
between the two groups.
There were significantly higher mean pulmonary pressure
Table 1. Clinical characteristics of sickle cell patients and controls and mean tricuspid regurgitant jet velocity (TRV) among
Variable SCD Normal P-value SCD subjects.
controls As assessed by a TRV of ≥ 2.5 m/s in this study, the
Age (years) 39 ± 10 41 ± 10.5 0.331 frequency of pulmonary hypertension was 32% among
Age groups SCD subjects; none of the controls had pulmonary
18 – 30 years 23 (46%) 18 (36%) hypertension.
31 – 50 years 20 (40%) 23 (46%) 0.585
> 50 years 7 (14%) 9 (18%) In this study, the patients with pulmonary
Gender hypertension had mild pulmonary hypertension, as
Male 28 (56%) 25 (50%) evidenced by the range of tricuspid regurgitant jet velocity
Female 22 (44%) 25 (50%) 0.54 of < 2.9 m/s. Only four (8%) subjects had a TRV ≥ 3 m/s.
BMI (Kg/m2) 22.4 ± 2.6 23.6 ± 2.5 0.02
Table 3. Laboratory and echocardiographic features of sickle cell
Systolic blood 122.5 ± 19 132 ± 18 0.008 patients and controls
pressure (mmHg) Variable SCD Normal P-
Diastolic blood 68 ± 15 75 ± 14 0.017 controls value
pressure (mmHg)
Heart rate 84 ± 12 82 ± 11 0.387 White blood cells 10.2 ± 7.5 ± 3.9Mariam Alabdo et al. / IJMS, 9(2), 1-7, 2022
(cm2) 3.3 2.7 older, had significantly lower hemoglobin and hematocrit
Left atrial area (cm2) 18.1 ± 15.4 ± 0.002 concentrations, and had higher levels of indirect bilirubin
4.2 4.3 and creatinine than SCD patients without pulmonary
LV systolic diameter 3 ± 0.5 2.7 ± 0.4 0.0013 hypertension.
(cm)
Ten SCD patients (62.5%) with pulmonary
LV diastolic 4.8 ± 4.5 ± 0.0001 hypertension (TRV ≥ 2.5 m/sec) had more than 10 Blood
diameter (cm) 0.4 0.35 transfusions during lifetime compared to 11 SCD patients
TRV (m/sec) (32.4%) without pulmonary hypertension (TRV < 2.5
< 2.5 34 50 m/sec) (P=0.04).
(68%) (100%)Mariam Alabdo et al. / IJMS, 9(2), 1-7, 2022
IV. DISCUSSION in our study, SCD patients with pulmonary hypertension
Sickle cell disease is a clinical condition characterized by (PH) were older than patients who did not have pulmonary
hemoglobin's qualitative or quantitative disorder. hypertension (P = 0.033), with no difference according to
Cardiopulmonary manifestations are prominent gender. Gladwin et al. [15], Fonseca et al. [8], and Amadi et
components of sickle cell hemoglobinopathy. Most al. [18] showed similar results.
patients show cardiac dysfunction manifested principally
as fatigue, dyspnea on exertion, cardiomegaly, Enakpene et al. [16] found no statistically significant
electrocardiographic and echocardiographic abnormalities. association with age, while they found that male gender is
Some patients develop acute chest syndrome and sickle an independent determinant of pulmonary hypertension in
cell chronic lung disease. With better medical SCD. They attributed the relatively lower frequency of
management, patients with SCD are living longer, and elevated pulmonary pressure (12.2%) compared with some
what was previously uncommon sequelae of sickle cell other studies and the absence of association between age
disease are now being seen, including pulmonary artery and pulmonary hypertension to the age of patients used in
hypertension (PH), which is a prime contributor to their study (mean age 24 ± 9 years).
mortality in young adult patients with sickle cell disease.
This study aimed to determine the prevalence of In our study, SCD patients with pulmonary
pulmonary hypertension among sickle cell disease patients hypertension (PH) had significantly lower hemoglobin and
attending Tishreen University Hospital and determine the hematocrit concentrations and higher indirect bilirubin and
characteristics of patients with pulmonary hypertension. creatinine levels compared to SCD patients without
pulmonary hypertension. The observation that markers of
The study included 50 patients with sickle cell disease hemolysis are associated with pulmonary hypertension
and 50 healthy controls. The groups were of comparable provides a link between sickle cell disease and other
age and sex distribution. The BMI, systolic blood pressure, chronic hemolytic disorders and suggests that there is a
diastolic blood pressure, and oxygen saturation were lower distinct syndrome of hemolysis-associated pulmonary
in the subjects with SCD than in normal controls. There hypertension. Thalassemia, for example, is another chronic
were no differences in the heart rates between the two hemolytic disease associated with secondary pulmonary
groups. Our results agree with Gladwin et al. [15] and hypertension; the prevalence of pulmonary hypertension
Enakpene et al. [16]. among patients with thalassemia ranges from 10% to 93%,
in our study, SCD patients had lower hemoglobin and depending on the patient population studied [15]. Hemolysis
hematocrit than controls and higher leukocytes, results in increased plasma levels of cell-free hemoglobin
reticulocytes, LDH, total bilirubin, direct bilirubin, and (Hgb) in excess of the binding capacity of the Hgb
AST. Our results are in agreement with Gladwin et al. [15], scavengers, haptoglobin, and hemopexin. This excess of
Enakpene et al. [16], and Aliyu et al. [17]. cell-free Hgb may rapidly deplete circulating NO, although
there is continuing disagreement over the impact of this
We found that the prevalence of pulmonary process on NO bioavailability [9].
hypertension, defined as TRV ≥ 2.5 m/s by transthoracic
echocardiography among patients with sickle cell disease Additionally, hemolysis releases arginase I from
was 32%. Twenty-four percent of them had mild PH (TRV erythrocytes, limiting arginine availability for NO
2.5-2.9 m/s), and 8% had severe PH (TRV ≥ 3 m/s). None synthesis. in addition to these effects on endothelial
of the controls had pulmonary hypertension. regulation, increased cell-free Hgb may also contribute to
endothelial and vascular smooth muscle dysfunction [11].
Previous studies have reported percentages as high as Our results agree with Gladwin et al. [15] and Fonseca et al.
12.5% to 40%. Defined as TRV ≥ 2.5 m/s in SCD patients [8]
.
by transthoracic echocardiography, Gladwin et al. [15]
reported pulmonary hypertension in 32%, Enakpene et al. Parent et al. reported that data regarding biologic
[16]
in 12.2%, Aliyu et al. [17] in 25%, and Amadi et al. [18] markers of hemolysis were discordant. Hemoglobin and
found pulmonary hypertension in 23.9%. indirect bilirubin levels were similar in patients with
Parent et al. [6] studied 398 patients with SCD who all confirmed pulmonary hypertension and those without
underwent transthoracic echocardiography; pulmonary pulmonary hypertension. in contrast, they observed in
hypertension, defined as TRV ≥ 2.5 m/s, was found in 27% patients with confirmed pulmonary hypertension
of patients. These patients (with TRV≥2.5 m/s) underwent significantly increased lactate dehydrogenase and aspartate
right heart catheterization, and only 6% were diagnosed aminotransferase levels, which may also be influenced by
with right heart catheter-confirmed pulmonary liver dysfunction. They concluded that the role of
hypertension. Fonseca et al. [8] studied 80 patients with hemolysis in the pathogenesis of pulmonary hypertension
SCD who all underwent transthoracic echocardiography; in patients with sickle cell disease remains controversial
pulmonary hypertension, defined as TRV ≥ 2.5 m/s, was and further studies are needed [6].
found in 40% of patients. These patients (with TRV≥2.5
m/s) underwent right heart catheterization, and only 10% Our study found no association between treatment
were diagnosed with right heart catheter-confirmed with hydroxyurea and the prevalence of pulmonary
pulmonary hypertension. hypertension in SCD patients (P = 0.565). More SCD
5Mariam Alabdo et al. / IJMS, 9(2), 1-7, 2022
patients with pulmonary hypertension received > 10 Blood patients with SCD, was 32%. Elevated serum markers of
transfusions during their lifetime compared to SCD hemolysis (LDH, indirect bilirubin) were associated with
patients without pulmonary hypertension (P=0.04). the prevalence of pulmonary hypertension.
Gladwin et al. [15] found no association between treatment
with hydroxyurea and pulmonary hypertension. Neither VI. RECOMMENDATIONS
Fonseca et al. [8] nor Parent et al. [6] found an association Further studies using right heart catheterization are
between treatment with hydroxyurea and pulmonary recommended, as it is the gold standard for pulmonary
hypertension. hypertension evaluation. Follow-up studies with a larger
number of patients would also be necessary to evaluate the
Treatment with hydroxyurea may not reduce the contribution of elevated pulmonary pressure to morbidity
incidence of pulmonary hypertension, but it may increase and mortality in SCD subjects.
survival. Hydroxyurea may be beneficial by decreasing
hemolysis and the frequency of painful episodes, acute Future studies with further laboratory evaluation
chest syndrome, and mortality associated with sickle cell (arginine, fibrinogen, ferritin, fetal hemoglobin) and
disease. Evidence favoring hydroxyurea comes from a clinical evaluation (six-minute walk test) are
longitudinal study of 299 SCD patients who were followed recommended.
up for 17.5 years [19]. in that study, 24% of deaths were due
to pulmonary complications; 87.1% occurred in patients AUTHOR'S CONTRIBUTIONS
who never took hydroxyurea or took it forMariam Alabdo et al. / IJMS, 9(2), 1-7, 2022
[13] Lang Rm, Bierig M, Devereux Rb, Et Al. Recommendations For [18] Valentine N Amadi, Michael O Balogun, Norah O Akinola, Rasaaq
Chamber Quantification: A Report from the American Society of A Adebayo, Anthony O Akintomide. Pulmonary Hypertension in
Echocardiography’s Guidelines and Standards Committee and The Nigerian Adults With Sickle Cell Anemia. Vascular Health and
Chamber Quantification Writing Group, Developed in Conjunction Risk Management 2017; 13 (2017)153–160.
With The European Association of Echocardiography, A Branch of [19] Steinberg Mh, Mccarthy Wf, Castro O, Et Al. The Risks and
The European Society of Cardiology. J Am Soc Benefits of Long-Term Use of Hydroxyurea in Sickle Cell Anemia:
Echocardiogr.18(12) (2005) 1440–1463. A 17.5-Year Follow-Up. Am J Hematol . 85 (2010) 403.
[14] Dabestani A, Mahan G, Gardin Jm, Et Al. Evaluation of Pulmonary [20] De Castro Lm, Jonassaint Jc, Graham Fl, Ashley-Koch A, Telen Mj.
Artery Pressure and Resistance by Pulsed Doppler Pulmonary Hypertension Associated With Sickle Cell Disease:
Echocardiography. Am J Cardiol. 59(6) (1987) 662–668. Clinical and Laboratory Endpoints and Disease Outcomes. Am J
[15] Gladwin M.T., Sachdev V., Jison M.L., Shizukuda Y., Plehn J.F., Hematol . 83 (2008) 19–25
Minter K., Brown B., Coles W.A., Nichols J.S., Ernst I., Hunter [21] Bunn Hf, Nathan Dg, Dover Gj, Et Al. Pulmonary Hypertension and
L.A., Blackwelder W.C., Schechter A.N., Rodgers G.P., Castro O., Nitric Oxide Depletion in Sickle Cell Disease. Blood. 116(5) (2010)
Ognibene F.P., Pulmonary Hypertension As A Risk Factor For 687- 692
Death in Patients With Sickle Cell Disease. N Engl J Med. 350(9) [22] Simonneau G, Gatzoulis Ma, Adatia I, Et Al. Updated Clinical
(2004)886-95. Classification of Pulmonary Hypertension. J Am Coll Cardiol.
[16] Evbu O. Enakpene, Adewole A. Adebiyi, Okechukwu S. Ogah, 2013;62(25 Suppl) (2013) D34-D41
John A. Olaniyi, Akinyemi Aje, Moshood A. Adeoye & Ayodele O. [23] Mcquillan Bm, Picard Mh, Leavitt M, Weyman Ae. there are
Falase. Non-Invasive Estimation of Pulmonary Artery Pressures in Clinical Correlations and Reference Intervals for Pulmonary Artery
Patients With Sickle Cell Anemia in Ibadan, Nigeria: an Systolic Pressure Among Echocardiographically Normal Subjects.
Echocardiographic Study, Acta Cardiologica. 69(5) (2014) 505-511 Circulation.104(23) (2001) 2797-2802
[17] Aliyu Z.Y., Gordeuk V., Sachdev V., Babadoko A., Mamman A.I., [24] Pyxaras Sa, Pinamonti B, Barbati G, Et Al. Echocardiographic
Akpanpe P., Attah E., Suleiman Y., Aliyu N., Yusuf J., Mendelsohn Evaluation of Systolic and Mean Pulmonary Artery Pressure in
L., Kato G.J., Gladwin M.T., Prevalence and Risk Factors For Follow-Up Patients with Pulmonary Hypertension. Eur J
Pulmonary Artery Systolic Hypertension Among Sickle Cell Echocardiogr.12(9) (2011) 696-701.
Disease Patients in Nigeria. Am J Hematol.83(6) (2008) 485-90. [25] Stuart Mj, Nagel Rl. Sickle Cell Disease. Lancet . 364 (9442)
(2004) 1343–1360 Pmid: 15474138.
7You can also read
