Is Pulmonary Hypertension associated with Sickle Cell Anaemia?

This dissertation explores the association between Pulmonary Hypertension and Sickle Cell Anaemia and the contribution of one in the development of the other. It includes a literature review, methodology, and results.

Project Dissertation 1
Project Dissertation
Title: Is Pulmonary Hypertension associated with Sickle Cell Anaemia?
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ABSTRACT
Background: Sickle Cell Anaemia is a genetically inherited disorder which may cause extensive
organ damage. In sickle cell patients, Pulmonary Hypertension (PH) can complicate the acute
chest syndrome which is fatal. PH is known to occur in 6-11% of the sickle cell patients
contributing to increased risk of mortality. There is 40% mortality rate depicted in patients of
sickle cell anemia with pulmonary hypertension compared to sickle cell patients without PH .
Therefore, this field requires extensive research to identify their mutual impact.
Purpose of Study: To find out whether pulmonary hypertension is associated with Sickle Cell
Anaemia?
Method: The literature review explored four databases: Pubmed, CINAHL, Cochrane, Allied and
Contemporary medicine Database (AMED). 10 studies reflecting over the association of PH with
Sickle cell Anaemia were consulted.
Findings: Six studies proved the effective role of PH in Sickle Cell Disease (SCD) patients. Two
articles described the potential mechanism involved, and the two articles focused on the types of
PH and their prevalence in Sickle Cell Anaemia patients.
Conclusion: The analysis and evaluation of related articles reflects there are adequate evidences
to suggest that both diseases are interrelated.
Keywords: Sickle Cell Anaemia; Pulmonary Hypertension.

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CHAPTER 1- INTRODUCTION
1.1. Background
Sickle Cell Anemia is a blood disorder mainly occurring due to genetic inheritance of abnormal
protein in the RBCs which makes them distorted and sickle shaped (National Heart, Lung and
Blood Institute, 2018). It is characterized by the substitution of amino acids in beta globin chain
due to presence of homozygous hemoglobin SS (Klings and Farber,2019).
The disease is mostly prevalent in African Americans(National Heart, Lung and Blood Institute,
2018) . It is an autosomal recessive disorder in which the polymerization of Hemoglobin-S
occurs upon deoxygenation. The polymerization increases the sickling and rigidity of red blood
cells. It injures the RBCs and reduces the blood circulation in them. The resulting complications
cause microvascular occlusions leading to injury of several body organs like kidney, lungs,
spleen, liver, central nervous system and severe pain in abdomen, joints, back and chest. The
sickle cell anaemia when associated with pulmonary hypertension, results into elevated risk of
early deaths, elevated WBC count> 15000 cell/mm3, seizures and renal failures (Ataga and
Clinggs, 2014).
Pulmonary Hypertension (PH) refers to a condition of high blood pressure (where resting
Pulmonary artery pressure >25 mmHg) developed within the arteries in the lungs and the heart
(Pulmonary Hypertension Association, 2019). PH may occur due to any illness that obstructs the
normal blood flow in the lungs for sustained periods. For example: collagen vascular disease,
liver cirrhosis, chronic lung disease and thromboembolism. The clinical symptoms and signs
exhibited by the patients of PH are Chronic Dyspnea, Hypoxemia, elevated tricuspid
regurgitation, Syncope, Arrhythmias, Cor Pulmonale and early death.
The sickle cell disease (SCD) patients have enhanced cardiac output due to anaemia. It is
observed that pulmonary vascular resistance and pulmonary pressures are higher in patients of
Sickle cell disease with Pulmonary Hypertension. Their cardiac output is also higher than the
normal range. These patients exhibit high rate of fatigue on exertion.

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Haemodynamic
Measure
Normal Range Sickle Cell Patients
without PH
Sickle Cell Patients
with PH
Pulmonary Artery
Pressure
7 to 19 19+-45 36+-8
Cardiac Output 4.4 to 8.4 9+-3 8.6+-2
Pulmonary Vascular
Resistance
11-99 83+-46 205+-112
Table 1. Shows Comparison of Pulmonary Hemodynamic in Sickle Cell patients with PH
The SCD patients having PH have high mortality rate than the SCD patients without any PH. A
research by Castro colleagues in 2003 evaluated 34 adults who had undergone right heart
catheterization (Clarke, 2019). Initially, 20 of them had Pulmonary Hypertension. After a regular
follow up of 54 months, 11 out of 20 had died while only 3 patients died out of 14 having no
Pulmonary Hypertension (Clarke, 2019). The patients who died had a 10 mm Hg rise in their
mean Arterial pulmonary pressure leading to increase in rate of mortality.
Figure 1. Shows Kaplan Meier Survival in SCD patients with or without PH (Source: Clarke, 2019)
The upper red line in the graph shows the estimate survival of patients having Sickle cell disease,
without any PH. The blue line shows the estimate survival of the patients having Sickle Cell
Anaemia with PH. The time in months exhibited by X axis is the months of follow up post
catheterization of heart.

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The prevalence of Pulmonary Hypertension increases in the patients of Sickle Cell Anaemia
with age. The prevalence is nearly 40% in the patients aged 40-49 years, while it is 55-60% in
the patients with age 50 years or more. According to NIH Howard Research published in 2004,
the risk factors for Pulmonary Hypertension in Sickle Cell Anaemia are history of cardiac or
renal diseases, systemic blood pressure, age, degree of hemolysis, cholestasis and iron overload
(Clarke, 2019). Such evidences show that the frequency of PH is increasing in the patients of
Sickle Cell Anaemia.
1.2 . Pathophysiology of Pulmonary Hypertension in patients of Sickle Cell Anaemia
Pathogenesis of Pulmonary Hypertension can be elaborated in patients of Sickle Cell Disease in
terms of several mechanisms such as Intravascular Hemolysis resulting into Nitric Oxide (NO)
deficiency, vasculopathy due to intimal thickening and platelet activation, interstitial fibrosis due
to ACS, hypoperfusion of pulmonary blood vessels of the lungs, in-situ thrombosis and recurrent
thromboembolic disease.
Nitric Oxide is produced by the NO Synthase (NOS) Enzymes which convert Arginine into the
Cittruline, while releasing NO in the process. NO produces cyclic Guanosine 3’5’
monophosphate (cGMP) in myocytes which vasodilates the myocyte wall (Clarke, 2019). In
Sickle Cell Disease, intravascular deficiency of Nitric Oxide leads to vasoconstriction of
pulmonary vessels.
Figure 2. Shows the factors involved in the release and inhibition of NO Radical. (Source: Clarke, 2019)

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Low level of Arginine during the VOC, show depletion of substrates which further reduces the
production of Nitric Oxide (Clarke, 2019). All these factors contribute to the mechanism of
pulmonary hypertension.
Almost half of the patients of SCD having pulmonary hypertension exhibit: (1) a state of NO
deficiency; (2) Chronic pulmonary thrombo-embolism; (3) Microvascular obstruction, low
Oxygen Saturation, and hypoxic response to anaemia (Gordeuk, Castro and Machado, 2016).
The management of patients with SCD and PH is based on anticoagulation for the patients of
thromboembolism; treatment of failure of left ventricle in the patients of post capillary
pulmonary hypertension; oxygen therapy for the patients having low saturation level; and blood
transfusions to elevate the concentration of hemoglobin, to prevent the incidents of vaso-
occlusion and lower down the rate of hemolysis. These patients need to be sent to special centres
and should be treated with the therapies found effective in treating several other PH conditions.
Reports have found such treatments to be successful in several cases (Gordeuk, Castro and
Machado, 2016).
1.3. Significance of the Study
Not all the patients of sickle cell anaemia develop pulmonary hypertension however still the
people who are the patients of SCD are more likely to develop pulmonary hypertension. The
people who have both of these diseases are at high risk of death than the patients having only one
of them. According to Pulmonary Hypertension Studies (2019), about 75% of the SCD patients
develop changes in their lung tissues during death which indicates the presence of Pulmonary
Hypertension. Pulmonary Hypertension occurs in 6-11% of the SCD patients and is identified by
the WHO as having highly variable hemodynamics leading to premature deaths (Hayes, et al.
2014). The risk factors leading to the severity of disease are increasingly a concern for the
pulmonologists, cardiologists, hematologists and internists.
This study will explore the literature review less than 10 year old, to assess the potential
association between the two diseases and factors affecting the involvement of PH in contributing

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to the severity of Sickle Cell Anaemia and vice versa. It will also investigate the predictivity of
Pulmonary Hypertension in patients of Sickle Cell Anaemia.
The study also explores authentic literature to identify the potential signs and symptoms of both
the diseases and also suggests ongoing treatment options for Pulmonary Hypertension and Sickle
Cell Anaemia.
1.4. Research Question
Is Pulmonary Hypertension associated with Sickle Cell Anaemia?
1.5. Aim
The aim of the research is to analyze and evaluate the association between Pulmonary
Hypertension and Sickle Cell Anaemia and the contribution of one (PH) in development of the
other (SCD).
1.6. Objectives of the Study
2. To find out whether the pulmonary hypertension is a risk factor of death in sickle cell
anaemia.
3. To identify the signs and symptoms of SCD and PH.
4. To recommend possible ongoing treatments for SCD and PH.
CHAPTER 2- METHODOLOGY
A systematic Review was conducted to identify the quantitative and qualitative factors which
suits to the criteria for answering the research question. The peer reviewed literature journals less
than 10 year old were retrieved from the countries worldwide. There were prescribed inclusion
and exclusion criteria for the finding the appropriate answer to the research question.
Inclusion & Exclusion Criteria
1. Only peer reviewed academic journals published in English language were included in
the research. The articles in all other languages were excluded.

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2. The articles published between 2011 and 2019 are included in this research, beyond this
time frame were excluded.
3. The populations suffering from Sickle Cell Anaemia and Pulmonary Hypertension were
only included, all other diseases excluded.
4. The studies from across the world were included with no geographical exclusion.
5. All the studies having interventions involving Sickle Cell Anaemia or Sickle Cell Disease
were included.
Keyword Search
The keyword used for the search were “Sickle Cell Anaemia”,” Sickle Cell Disease”,
“Pulmonary Hypertension” with the Boolean operators AND and OR from the PubMed,
CINAHL, COCHRANE databases.
Search Strategy
The literature search used three databases namely PubMed, CINAHL, and Cochrane. The search
retrieved 32,435 articles from PubMed, 956 articles from CINAHL and 8,423 articles were
retrieved from Cochrane. Thus, total 41,814 articles were screened and selected from this search.
Screening of Relevant Studies
The selected articles were analyzed using PRISMA model. 39, 500 articles were found to be
duplicate hence they were removed from the process. 2000 were found to be unrelated and
irrelevant after matching against the keywords and after applying the limiters. After evaluating
the abstract of remaining articles for the population, comparisons, interventions and the
outcomes, only 25 articles were found to be authentic out of remaining 314. Thorough analysis
of the full text of 25 articles resulted into 10 meaningful articles matching to the inclusion
criteria.
Ethical Permission
The literature review involved only the peer reviewed articles published and composed by the
other scientists and researchers, thus did not include any human participation, survey or
interviews. This review is ethically approved by the Health research Ethics Committee under the
University of Bedfordshire, and signed Ethics form along with Research Proposal. The approval

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also ensures that the research should be free from plagiarism, misconduct, falsification or
fabrication of results. It should support research integrity and confidentiality.
The permission was granted to carry out this research through BREO Feedback.
CHAPTER 3- RESULTS
3.1 Summary of Findings
The findings of the literature review will be enlisted in this section in form of a table for effective
presentation of the explored facts.

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S.No
.
Reference Sample Interventions Findings
1 Bigna,J.J., Noubiap,J.J.,
Nansseu,J.R., and
Aminde,L.N.(2017).
Prevalence and
etiologies of pulmonary
hypertension in Africa: a
systematic review and
meta-analysis
N=79 Systematic Review and
Meta Analysis
Prevalence of PH is 36.9% in 79 SCD patients.
2 Oguanobi,N.I.,
Ejim,E.C.,
Anisiuba,B.C., and
Onwubere,B.J.(2012).
Clinical and
Electrocardiographic
Evaluation of Sickle-
Cell Anaemia Patients
with Pulmonary
Hypertension
N=124;
62 Sickle Cell
Patients and
62 controls
Clinical Evaluation Prevalence of PH in Nigerian Adult SCD patients is
41.9%
3 Patel,P.M.,
Sharma,S.M., Shah,N.,
and MAnglani,M.V.
(2016). Prevalence of
pulmonary hypertension
in children with sickle
cell disease.
N=50; 30
Males and 20
Females
Cross Sectional
Observational Study
High Pulmonary Pressure exists in subjects with
SCD, overall prevalence 38%.

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4 Colombatti, MAschietto,
Varotto, Grison (2010).
years of age
Pulmonary hypertension
in sickle cell disease
children under 10
N=75 Children Case Control
Observational Study
40% mortality during 22 months follow up after
identification with PH associated with Sickle Cell
Anaemia.
5 Parent F, Bachir D and
Inamo J.(2011). A
hemodynamic study of
pulmonary hypertension
in sickle cell disease
N=398 Prospective evaluation by
Doppler ECG
Prevalence of PH on catheterization was 6%. The
evaluation was done solely by ECG.
6 Mehari A, Gladwin MT,
Tian X, Machado RF
and Kato GJ.(2012).
Mortality in Adults with
sickle cell disease and
pulmonary hypertension
N=531; 84
undergone
Right Heart
Catheterization
Right Heart
Catheterization (RHC)at
National Institute of Health
55 out of 84 SCD patients had PH. They depicted
abnormal exercise capacity and abnormal
cardiopulmonary markers
7 Connes P.,
Lamarre Y., and
Waltz X. (2014).
Haemolysis and
abnormal
haemorheology in
sickle cell anaemia.
N=97 Comparative Study Haemolysis is characterized by reduced RBC
deformability and increased strength of RBC
aggregates
8 Nouraie M, Lee JS,
Zhang Y (2013).Walk-
PHASST Investigators
and Patients. The
relationship between the
N=415 PHASST Cohort
Observational study
High Hemolytic component is related to increased
mortality rate in SCD patients

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severity of hemolysis,
clinical manifestations
and risk of death in 415
patients with sickle cell
anemia in the US and
Europe
9 Gladwin MT.,
Barst RJ.,
and Gibbs JS.
(2014). Risk factors for
death in 632 patients
with sickle cell disease
in the United States and
United Kingdom.
N=632 PHASST Cohort
Observational study
TRV>3.0 is evident in 10% of deaths and imposes a
high risk. The role of PH in form of a cause of deaths
due to SCD in unclear and controversial.
10 Klinggs, Machado,
Barst, Morris, et.al.
(2014). An official
American Thoracic
Society clinical practice
guideline: diagnosis, risk
stratification, and
management of
pulmonary hypertension
of sickle cell disease.
Clinicians
taking care of
SCD patients
Question Answer Session TRV >2.5 and an RHC confirming Pulmonary
Hypertension signify elevated risk of mortality in
SCD patients.

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3.2. Thematic Analysis
According to World Symposium on Pulmonary Hypertension (2013), PH is clinically divided
into 5 main categories (Gordeuk, Castro and Machado, 2016) listed as follows:
1. Pulmonary Arterial Hypertension
2. PH due to Left Cardiac Disease
3. PH due to Hypoxia or Lung diseases
4. Chronic Thromboembolic PH
5. PH due to Multifactorial Mechanisms
SCD is kept in the Group 5 due to multifaceted reasons. Some people exhibit hemodynamics of
Pulmonary Arterial Hypertension, while in other cases PH is associated with thromboembolic
illness or left side cardiac disease.
No. of Adult
SCD patients
in Population
No.
Excluded
Population to
calculate
prevalence
Mean
Age
N % with
pulmonary
hypertension
References
79 0 79 34 36.9 2 (Africa)
124 0 124 32 41.9 5 (Nigeria)
50 12 38 35 38 16 (India)
398 18 380 33 6 17 (France)
531 0 531 31 65.4 13(US)
97 0 97 35 56 4 (France)
415 0 415 36 10 18 (US & Europe)
632 0 632 34 37 8 (US & UK)
Source: (Gordeuk, Castro & Machado, 2016) Showing Prevalence of Pulmonary Hypertension in
SCD patients as depicted in review studies
As per the findings of Gladwin et al. (2014), The TRV greater than 3 m/sec takes place in 10%
of the people and shows greatest risk of deaths due to elevated pulmonary artery systolic
pressure and corresponding mortality. According to the study of Mehari et al. (2012), the
estimated survival time limit for the patients with confirmed hypertension was 6.8 years. The

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patients who had SCD with pulmonary hypertension died earlier (at a young age) than the
general population.
It is evident from the collected data, that the cases of sickle cell anaemia with pulmonary
hypertension are higher in US followed by France. It is clear through the studies that the subjects
of sickle cell anemia have generally lower blood pressure than normal and the correlation varies
as per the BMI, age, and gender (Klings et al.,2014). The subjects having high BP were more
vulnerable to high risk of cardiac stroke and death.
Table. Hemodynamic profiles of SCD patients with and without PH
US PH (n=531)
CVP (mmHg) 11+-5
mPAP(mmHg) 36+-9
PCWP(mmHg) 16+-5
CO(L/min) 8+-3
PVR(dyne.sec/cm5) 229+-149
France PH (n=97)
CVP 10+-6
mPAP 30+-6
PCWP 16+-7
CO 8.7+-1.9
PVR 138+-58
Source: Mehari et al.(2012) and Connes et al.(2014)
The SCD patients who are suspected to have PH are evaluated in a way similar to non SCD
patients. Most of the patients of pulmonary hypertension have exhibited progressive exertional
dyspnea along with the symptoms of lightheadedness, chest pain. The initial symptoms of these
patients are not specific and may be same as the symptoms of SCD patients having no PH.
Dyspnea is depicted in 40% of the SCD patients and generally occurs without PH. Most of the
patients have been evaluated using transthoracic echocardiogram. The ECGs provide an exact
assessment of systolic and diastolic cardiac dysfunctions. The hypertrophy of the ventricle or
atrium may exhibit enhanced pressures and requires Right Heart Catheterization to clearly

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diagnose the Pulmonary Hypertension. The tests for electrolytes, complete blood count and liver
and renal functions are also done to evaluate the incidence of connective tissue diseases,
sarcoidosis and HIV disease because these diseases elevate the risk of Pulmonary Hypertension.
Several studies have showed that TRV>2.5 m/s depicted on Doppler ECG is related to high risk
of death in SCD patients. In the studies, Doppler ECG was done during the patients’ steady state.
A retrospective analysis by Parent et al (2011) evaluated the mean Pulmonary arterial pressures,
average systolic, diastolic pressures as 36 mmHg, 54.3 and 25.2 respectively among the 20 SCD
subjects also having PH in comparison to 17.8, 30.3 and 11.7 in 14 subjects of SCD and PH.
Every 10 mmHg increase in mPAP was found to be related to 1.7 times increase in hazard ratio
for the death. The prospective studies conducted more recently have confirmed the relationship
between increased mortality and RHC confirmed Pulmonary Hypertension in SCD patients.
In a study performed at multiple centers with 398 SCD subjects in France, the results described
clear relation between Pulmonary Hypertension and High risk of death (12.5%) (Parent et al.,
2011). The PH patients were compared with the patients having no PH, there was observed a
high mortality rate though the patients with renal inadequacy, restrictive lung disease and liver
disease were excluded. Thus different multivariate studies have also confirmed the association
between pulmonary vascular illness, mPAP, pulmonary pulse pressure, pulmonary arterial
systolic pressure and transpulmonary gradient to the increased risk of death.
The studies confirm that the prevalence of PH in SCD children in uncertain. In adults the PH is
associated with elevated risk of death in the patients.
Figure below showing Severity and Survival of PH patients with SCD

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_____ TRJV<2.5 m/s, ---- TRJV 2.5 to 2.9 m/s, _ _ _ TRJV >2.9 m/s
Source: Gladwin et al.(2014).
The graph shows, the rate of survival is higher in the patients with Tricuspid Regurgitant Jet
Velocity (TRJV) less than 2.5 m/s, when compared to the patients with TRJV greater than 2.5
m/s.
3.3. Signs and Symptoms
According to Gordeuk, Castro and Machado (2016) the signs and symptoms of the condition
involving presence of both the Sickle Cell Anaemia along with Pulmonary Hypertension may
vary from person to person and consistently change with time. The sickle cells break up
frequently and die leading to shortage of RBCs known as Anaemia. The body feels shortage of
oxygen and the patients generally feel fatigue. Periodic episodes of pain occur when the sickle
shaped RBCs block up the blood within the arteries inside the body organs and bones. The
patients may also develop chronic pain due to ulcers and bone damage. The patient develops
painful swelling of limbs due to sickle celled RBCs blocking the blood flow to the feet and
hands. The patient has recurrent infection rates, damaging the organs which fight the body
infection. Shortage of RBCs can hamper growth of the body in form of delayed growth and
delayed puberty in the children. Small blood vessels carrying blood to the sensory organs may

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get clogged and the patients may develop vision problems, ulcers, pulmonary hypertension, gall
stones, periapism and organ damage.
Figure.3. Cross Sectional Representation of Normal Pulmonary Artery and an Artery affected by Pulmonary
Hypertension (Source: Gordeuk, Castro and Machado, 2016)
Basically in Group I Pulmonary Hypertension, all the three layers of the arterial wall namely
intima, media and adventitia are influenced. The media layer encompasses a proliferation of
smooth muscle cells with an increase in the size and number of smooth muscle cells ultimately
leading to medial hypertrophy. Migration of these smooth muscle cells to the lumen lead to
proliferation. The proliferation of macrophages and fibroblasts into adventitia increase its
thickening. The group II pulmonary Hypertension is accompanied by the enlargement of
pulmonary capillaries and veins. The group 4 PH, the intima of pulmonary arteries is replaced by
the organized thrombi leading to complete occlusion of lumen.
3.4. Management & Treatment of disease
Limited evidences are available in the literature review about the management of patients with
PH related to SCD. Vasodilators are effective in treating these patients. However it is not known
whether these patients can tolerate the vasodilators due to lower systemic blood pressure. In
several randomized control trials, the medicines like inhaled iloprost, oral bosentin, treprostinil
and endothelin receptor antagonists have shown effectiveness (Pulmonary Hypertension

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Association, 2019). However, their therapeutic role has not been confirmed in SCD associated
with PH. Long Term Oxygen therapy is also used in hypoxemic patients. The patients who have
undergone cardiac failure should be provided cautious use of cardiac glycosides and diuretics. In
chronic conditions, pulmonary thromboendartectomy is performed (Hayes et al.2014). For
diagnosis of PH, right sided cardiac catheterization test can be used (Bijna et al. 2017).
Inhalation of NO can be effective in patients with SCD and PH due to its characteristic in
dilating the pulmonary blood vessels, increasing the oxygenation and reducing the pulmonary
pressure (Gordeuk, Castro and Machado, 2016).
Recently an oral drug ‘Riociguat’ is known to have proven effect in treatment of Chronic
Thrombo Embolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension
(PAH) (Sickle Cell Anaemia News, 2019). The drug activates the enzyme Guanylate Cyclase,
which initiates the cGMP after activation from Nitric Oxide. The cGMP relaxes the smooth
muscles and widens the arteries. It lowers down the blood pressure inside the lungs and enhances
the performance of heart. The Sickle Cell Anemia patients have disrupted NO signaling pathway.
Therefore therapies are mostly aimed to improve the functioning of blood vessels and relax this
pathway.

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Figure 4.Algorithm showing evaluation of PH associated with Sickle Cell Anaemia (Source: Gordeuk, Castro and
Machado, 2016).
The Ad Hoc Committee proposed the guidelines for the evaluation of the patients with Sickle
Cell Anaemia to assess the Pulmonary Hypertension (Gordeuk, Castro and Machado, 2016). It
involves screening of PH by ECG and the actions taken on the basis of the ECG results and the
results of Right Heart Catheterization.
In Sickle Cell Anaemia, the mutation at the beta globin chain makes the hemoglobin
polymerized during deoxygenation which alters the rheology of RBCs and makes them to lyse.
With increasing age, the patients develop complications of the different body organs such as
chronic kidney injury and cardiopulmonary dysfunction. These events influence the premature
mortality and morbidity in SCD patients. These factors increase chances of incepting pulmonary
hypertension, dysrhythmia and left ventricular heart disease ultimately contributing to early
death in SCD patients.
The screening of SCD patients for the PH with TRV and RHC has always showed variable
results. No reports have certainly confirmed the relation of increased TRV with increased
mortality. However, after a 22 months follow up, an elevated TRV is shown to be associated
with 10% reduced capacity for walking a 6 minute distance (Ataga and Clings, 2014). There are
limited evidences to confirm whether PH is progressive in the SCD patients. Even after
variability of data, the routine screening with Doppler ECG is an essential component to be
followed by the SCD patients due to the likeliness of progression of SCD in PH patients, and the
higher prevalence of this condition.
Chronic Intravascular Hemolysis releases the enzymes Arginase-I in plasma (Klings, Machado
and Barst, 2014). When the levels of cell free hemoglobin elevates in plasma,, the free
hemoglobin reacts with NO, giving rise to nitrate and methemoglobin. The nitrate has a
scavenging effect which leads to insufficiency and NO resistance known as Hemolysis
associated Endothelial Dysfunctioning. This chronic hemolysis exhibits a mechanical pathway
resulting into proliferative vasculopathy and ultimately results into Pulmonary Hypertension in
SCD patients.

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CHAPTER 4: DISCUSSION
The main objective of this research was to identify the association between Sickle Cell Anaemia
and Pulmonary Hypertension, through evaluation and analysis of different articles. The analyzed
comprehensive results of the whole research establish that there is prevalent influence of PH on
the SCD patients. 4 out of the 10 articles proved the association of PH with SCD (Bijna et al,
2017); (Oguanobi, 2012); (Colombatti et al.2010); (Parent et al.2011). Remaining six have
elaborated the factors associated with the complications, evaluation and identification of the risk
factors of PH in SCD patients. The research has consulted the articles from different countries
like Africa, US, France and Nigeria. All the articles consulted are peer reviewed authentic
journals.
The studies of Parent et al.(2011) screened 398 patients of SCD in France. The study confirmed
that there are certain risk factors associated with pulmonary Hypertension which include
Cholestatic liver dysfunction, hemolysis and renal insufficiency. The chronic hemolytic anaemia
gives rise to Pulmonary Hypertension in SCD patients. It is also related to dysfunction of liver
and renal organs. However it is not directly related to acute chest syndrome and recurrent vaso-
occlusions. The study by Mehari et al. (2012) demonstrated that mortality rate in SCD patients is
high. They used to die at an early age than the controls having no Pulmonary Hypertension. In
this study 65% of the RHCs were conducted with PH. The research of Nouraie et al(2013) found
that there is high relationship between the hemolytic component and the markers of intravascular
hemolysis in all the SCD patients.
Three research studies based on screening of Pulmonary Hypertension with ECG approved the
diagnosis with right heart catheterization exhibiting 6-10% minimum prevalence of pulmonary
Hypertension in the patients of sickle cell disease (SCD). In evaluating the minimum PH
prevalence, greater than 10% of the patients were excluded from the study due to creatinine
clearance less than 30 ml per minute and associated kidney disease. Though most of these people
had PH on right catheterization, all the subjects did not undergo the procedure leading to left out
of some of the people having PH. In various studies from France, Brazil and US, the mortality
rate is found to be significantly higher in patients of pulmonary hypertension with Sickle cell
disease. In a study from France, 3 out of 24 PH patients died within a time frame of 3 years while
only 3 out of 379 sickle cell patients died (Parent, Bachir and Inamo, 2011).

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Additionally, in Brazil, an evaluation and follow up of 8 patients for 3 years found 37.5 %
mortality rate in patients with SCD and PH compared to 5.6% mortality rate among the 72
patients without SCD (Fonseca, Souza, Salemi, Jardim and Gualandro, 2012). In a study from
US, the mortality rate of 37% was found in 55 patients of pulmonary hypertension while
compared to 17% mortality rate in 447 patients without pulmonary hypertension (Mehari,
Gladwin, Tian, Machado and Kato, 2012). A similar US study evaluated a follow up for 9 years
and found that 11 patients out of 20 PH patients died in 9 years while just 3 people died out of 14
SCD patients having no PH (Gordeuk, Castro and Machado, 2016). In most of these cases an
elevated pulmonary vascular resistance was responsible for the deaths. According to Ad Hoc
Committee on Pulmonary Hypertension and Sickle Cell Disease by American Thoracic Society,
It is possible to have both the post and pre capillary Pulmonary Hypertension in the same patient.
The mortality due to both types of PH is similarly high and primarily driven by the high intensity
of pre capillary pulmonary artery pressure, pulmonary vascular resistance and transpulmonary
pressure gradient (Mehari, Alam and Tian, 2013).
In more than half of the studies the SCD patients had pre-capillary Pulmonary Hypertension.
They had elevated cardiac outputs and lowered blood viscosity due to SCD which lead to lower
pulmonary resistance than the other non anemic patients. The patients of SCD having pre-
capillary PH generally do not have elevated pulmonary vascular resistance. In studies collected
worldwide from 2011 to 2014, the number of patients with precapillary pulmonary hypertension
were 52.6% while the number of patients with postcapillary pulmonary hypertension were 47.4%
(Gordeuk,Castro and Machado, 2016).
A large part of the literature reflects the contribution of abnormal NO signaling and intravascular
hemolysis in causing pre capillary pulmonary hypertension in the SCD patients. The hemolysis
releases of hemoglobin to the plasma which consist of arginase I and heme. These components
inhibit the signaling of NO and block their endothelial functioning. The plasma hemoglobin
combines with Nitric Oxide to form Nitrates while the arginase I restricts the availability of
arginine. The heme, released in plasma activates the inflammasome and TLR4 pathways. The
association of RBC microparticles and cell free hemoglobin along with dysfunctioning of
endothelium elevates the systolic pulmonary pressure in the artery thus increasing the pulmonary
hypertension (Nouraie, Lee and Zhang, 2013).

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The research has successfully described the causal factors, the outcomes, the pathogenesis and
clinical manifestations of the Pulmonary Hypertension in SCD patients. In patients of SCD, the
mortality and morbidity rates are associated with the mean pulmonary arterial pressures higher
than 30 mmHg (Hayes et al., 2014). The symptoms are also associated with slight increase in
pulmonary vascular resistance. In SCD patients with or without pulmonary hypertension, the
cardiac output is generally found to be greater than that observed in the normal people who are
non anemic. Thus the SCD patients having Pulmonary Hypertension may be expected to have
greater survival when compared to patients without any Sickle cell disease. However it is no
true. The complications in SCD patients like recurrent pain crisis and exceptionally high
pulmonary pressure results into Pulmonary Hypertension (Fonseca et al. 2012).
The research has significantly advanced in screening, diagnosis, identification and prognosis of
SCD related Pulmonary Hypertension however there are limited studies showing any specific
treatment options for the SCD associated PH. The Physicians generally use the interventions in
following order for treatment of disease (University of Pittsburg, 2019):
1. Identification of any symptom that impact functioning of lungs and pulmonary
hypertension like Asthma, Obstructive Sleep Apnea, and pulmonary embolism.
2. Management of SCD with Hydroxyurea through transfusion of blood to lower the
episodes of acute chest pain.
3. Vasodilator therapies in addition to pulmonary Hypertension medications.
4. Surgery for lung transplant.
Few studies elaborated over the Pathophysiology of SCD associated with Pulmonary
Hypertension (Gladwin et al, 2014) (Klinggs et al., 20014). The genetic mutation leading to
sickle cell anaemia occurs due to replacement of single amino acid (Glu to Val) in hemoglobin’s
beta-globin subunit. The inheritance occurs as an autosomal recessive trait. The vasoocclusion in
SCD patients take place due to combination of factors leading to abnormalities in the structure of
hemoglobin and its functional changes. The membrane integrity of RBC, density of RBC,
cellular adhesion and endothelial activation of smooth muscles, coagulation and inflammation is
also adversely affected. All these pathophysiological incidents result into complications of

Project Dissertation 23
hemolytic anaemia, infection, organ dysfunction, vasoocclusive crisis and fat embolization in
bone marrow. Further clinical manifestations involve retinopathy, stroke, splenic infarction,
necrosis in bone, hepatopathy and pulmonary hypertension.
CHAPTER 5: CONCLUSION
The Sickle Cell Anaemia is a primary cause of pulmonary hypertension. There are significant
differences in development of cardiac complications because of variations in cardiovascular
processes in response to hyperdynamic condition and haemolysis in SCD. The research approves
that PH is associated with low survival rate in SCD patients. The pulmonary Artery pressure
needs to be independently monitored in the SCD patients.The pathogenesis of PH is
heterogenous in patients of SCD and involves hemolysis along with its impact on chronic lung
disease and bioavailability of Nitric oxide. The subjects exhibiting increased levels of TRV may
undergo PH assessment by confirming the identification of causes, confirming the diagnosis and
elaborating hemodynamics, determining the prognosis and severity and may choose effective
therapy. The recommendations to undergo successful treatment of PH in SCD patients involve
intensification of therapies for sickle cell anaemia, effective supportive strategies, use of
medications for Pulmonary Hypertension and treatment of underlying causes. The research
conducted during the last decade has significantly expanded the knowledge about pathogenesis
and clinical manifestation of Pulmonary Hypertension in patients of Sickle Cell Disease.
However, the research needs further knowledge about Pathophysiology and clinical trials to
facilitate effective therapy for increasing the survival rate of the SCD patients in association with
Pulmonary Hypertension.

Project Dissertation 24
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