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Hemoglobin is present in erythrocytes and is important for normal oxygen delivery to tissues. Hemoglobinopathies are disorders affecting the structure, function or production of hemoglobin.
Different hemoglobins are produced during embryonic, fetal and adult life. Each consists of a tetramer of globin polypeptide chains: a pair of ”-like chains 141 amino acids long and a pair of ”-like chains 146 amino acids long. The major adult hemoglobin, HbA has the structure ”2”2. HbF (”2”2) predominates during most of gestation and HbA2 (”2”2) is the minor adult hemoglobin.

Each globin chain surrounds a single heme moiety, consisting of a protoporphyrin IX ring complexed with a single iron atom in the ferrous state (Fe2+). Each heme moiety can bind a single oxygen molecule; a molecule of hemoglobin can transport up to four oxygen molecules as each hemoglobin contains four heme moieties.
The amino acid sequences of various globins are highly homologous to one another and each has a highly helical secondary structure. Their globular tertiary structures cause the exterior surfaces to be rich in polar (hydrophilic) amino acids that enhance solubility and the interior to be lined with nonpolar groups, forming a hydrophobic pocket into which heme is inserted Numerous tight interactions (i.e.,”1”1 contacts) hold the ” and ” chains together. The complete tetramer is held together by interfaces (i.e., ”1”2 contacts) between the ”-like
chain of one dimer and the non-” chain of the other dimer. The hemoglobin tetramer is highly soluble, but individual globin chains are insoluble. (Unpaired globin precipitates, forming inclusions that damage the cell and can trigger apoptosis. Normal globin chain synthesis is balanced so that each newly synthesized ” or non-” globin chain will have an available partner with which to pair.)

Solubility and reversible oxygen binding are the two important functions which were deranged in hemoglobinopathies. Both depend mostly on the hydrophilic surface amino acids, the hydrophobic amino acids lining the heme pocket, a key histidine in the F helix and the amino acids forming the ”1”1 and ”1”2 contact points. Mutations in these strategic
regions alter oxygen affinity or solubility.
Principal function of Hb is to transport oxygen and delivery to tissue which is represented most appropriately by oxygen dissociation curve (ODC).

Fig: The well-known sigmoid shape of the oxygen dissociation curve (ODC), which reflects the allosteric properties of haemoglobin.
Hemoglobin binds with O2 efficiently at the partial pressure of oxygen (Po2) of the alveolus, retains it in the circulation and releases it to tissues at the Po2 of tissue capillary beds. The shape of the curve is due to co-operativity between the four haem molecules. When one takes up oxygen, the affinity for oxygen of the remaining haems of the tetramer increases dramatically. This is because haemoglobin can exist in two configurations – deoxy (T) and oxy (R). The T form has a lower affinity than the R form for ligands such as oxygen.
Oxygen affinity is controlled by several factors. The Bohr effect (e.g. oxygen affinity is decreased with increasing CO2 tension) is the ability of hemoglobin to deliver more oxygen to tissues at low Ph. The major small molecule that alters oxygen affinity in humans is 2,3-bisphosphoglycerate (2,3-BPG; formerly 2,3-DPG) which lowers oxygen affinity when bound to hemoglobin. HbA has a reasonably high affinity for 2,3-BPG. HbF does not bind 2,3-BPG, so it tends to have a higher oxygen affinity in vivo. Increased levels of DPG, with an associated decrease in P50 (partial pressure at which haemoglobin is 50 per cent saturated), occur in anaemia, alkalosis, hyperphosphataemia, hypoxic states and in association with a number of red cell enzyme deficiencies.
Thus proper oxygen transport depends on the tetrameric structure of the proteins, the proper arrangement of hydrophilic and hydrophobic amino acids and interaction with protons or 2,3-BPG.

The human hemoglobins are encoded in two tightly linked gene clusters; the ”-like globin genes are clustered on chromosome 16, and the ”-like genes on chromosome 11. The ”-like cluster consists of two ”-globin genes and a single copy of the ” gene. The non-” gene cluster consists of a single ” gene, the G” and A” fetal globin genes, and the adult ” and ” genes. The ”-like cluster consists of two ”-globin genes and a single copy of the ” gene. The non-” gene cluster consists of a single ” gene, the G” and A” fetal globin genes, and the adult ” and ” genes.
Red cells first appearing at about 6 weeks after conception contain the embryonic hemoglobins Hb Portland (”2”2), Hb Gower I (”2”2) and Hb Gower II (”2”2). At 10’11 weeks, fetal hemoglobin (HbF; ”2”2) becomes predominant and synthesis of adult hemoglobin (HbA; ”2”2) occurs at about 38 weeks. Fetuses and newborns therefore require ”-globin but not ”-globin for normal gestation. Small amounts of HbF are produced during postnatal life. A few red cell clones called F cells are progeny of a small pool of immature committed erythroid precursors (BFU-e) that retain the ability to produce HbF. Profound erythroid stresses, such as severe hemolytic anemias, bone marrow transplantation, or cancer chemotherapy, cause more of the F-potent BFU-e to be recruited. HbF levels thus tend to rise in some patients with sickle cell anemia or thalassemia. This phenomenon probably explains the ability of hydroxyurea to increase levels of HbF in adult and agents such as butyrate and histone deacetylase inhibitors can also activate fetal globin genes partially after birth.
Hemoglobinopathies are disorders affecting the structure, function or production of hemoglobin. These conditions are usually inherited and range in severity from asymptomatic laboratory abnormalities to death in utero. Different forms may present as hemolytic anemia, erythrocytosis, cyanosis or vaso-occlusive stigmata.
Structural hemoglobinopathies occur when mutations alter the amino acid sequence of a globin chain, altering the physiologic properties of the variant hemoglobins and producing the characteristic clinical abnormalities. The most clinically relevant variant hemoglobins polymerize abnormally as in sickle cell anemia or exhibit altered solubility or oxygen-binding affinity.
Thalassemia syndromes arise from mutations that impair production or translation of globin mRNA leading to deficient globin chain biosynthesis. Clinical abnormalities are attributable to the inadequate supply of hemoglobin and imbalances in the production of individual globin chains, leading to premature destruction of erythroblasts and RBC. Thalassemic hemoglobin
variants combine features of thalassemia (e.g., abnormal globin biosynthesis) and of structural hemoglobinopathies (e.g., an abnormal amino acid sequence).
Hereditary persistence of fetal hemoglobin (HPFH) is characterized by synthesis of high levels of fetal hemoglobin in adult life. Acquired hemoglobinopathies include modifications of the hemoglobin molecule by toxins (e.g., acquired methemoglobinemia) and clonal abnormalities of hemoglobin synthesis (e.g., high levels of HbF production in preleukemia and ” thalassemia in myeloproliferative disorders).

There are five major classes of hemoglobinopathies.
Classification of hemoglobinopathies:
1 Structural hemoglobinopathies’hemoglobins with altered amino acid sequences that result in deranged function or altered physical or chemical properties

A. Abnormal hemoglobin polymerization’HbS, hemoglobin sickling

B. Altered O2 affinity

1. High affinity’polycythemia

2. Low affinity’cyanosis, pseudoanemia

C. Hemoglobins that oxidize readily

1. Unstable hemoglobins’hemolytic anemia, jaundice

2. M hemoglobins’methemoglobinemia, cyanosis
2 Thalassemias’defective biosynthesis of globin chains

A. ” Thalassemias

B. ” Thalassemias

C. ”, ”, ” Thalassemias
3 Thalassemic hemoglobin variants’structurally abnormal Hb associated
with coinherited thalassemic phenotype

A. HbE

B. Hb Constant Spring

C. Hb Lepore
4 Hereditary persistence of fetal hemoglobin’persistence of high levels of
HbF into adult life
5 Acquired hemoglobinopathies

A. Methemoglobin due to toxic exposures

B. Sulfhemoglobin due to toxic exposures

C. Carboxyhemoglobin

D. HbH in erythroleukemia

E. Elevated HbF in states of erythroid stress and bone marrow dysplasia

This genetic disorder is due to the mutation of a single nucleotide, from a GAG to GTG codon on the coding strand, which is transcribed from the template strand into a GUG codon. Based on genetic code, GAG codon translates to glutamic acid while GUG codon translates to valine amino acid at position 6. This is normally a benign mutation, causing no apparent effects on the secondary, tertiary, or quaternary structures of hemoglobin in conditions of normal oxygen concentration. But under conditions of low oxygen concentration, the deoxy form of hemoglobin exposes a hydrophobic patch on the protein between the E and F helices. The hydrophobic side chain of the valine residue at position 6 of the beta chain in hemoglobin is able to associate with the hydrophobic patch, causing hemoglobin S molecules to aggregate and form fibrous precipitates. It also exhibits changes in solubility and molecular stability.
These properties are responsible for the profound clinical expressions of the sickling syndromes.
‘ HbSS disease or sickle cell anemia (the most common form) – Homozygote for the S globin with usually a severe or moderately severe phenotype and with the shortest survival
‘ HbS/”0 thalassemia – Double heterozygote for HbS and b-0 thalassemia; clinically indistinguishable from sickle cell anemia (SCA)
‘ HbS/”+ thalassemia – Mild-to-moderate severity with variability in different ethnicities
‘ HbSC disease – Double heterozygote for HbS and HbC characterized by moderate clinical severity
‘ HbS/hereditary persistence of fetal Hb (S/HPHP) – Very mild or asymptomatic phenotype
‘ HbS/HbE syndrome – Very rare with a phenotype usually similar to HbS/b+ thalassemia
‘ Rare combinations of HbS with other abnormal hemoglobins such as HbD Los Angeles, G-Philadelphia and HbO Arab
Sickle-cell conditions have an autosomal recessive pattern of inheritance from parents. The types of hemoglobin a person makes in the red blood cells depends on what hemoglobin genes are inherited from her or his parents. If one parent has sickle-cell anaemia and the other has sickle-cell trait, then the child has a 50% chance of having sickle-cell disease and a 50% chance of having sickle-cell trait. When both parents have sickle-cell trait, a child has a 25% chance of sickle-cell disease, 25% do not carry any sickle-cell alleles, and 50% have the heterozygous condition.
The allele responsible for sickle-cell anemia can be found on the short arm of chromosome 11, more specifically 11p15.5. A person who receives the defective gene from both father and mother develops the disease; a person who receives one defective and one healthy allele remains healthy, but can pass on the disease and is known as a carrier or heterozygote. Several sickle syndromes occur as the result of inheritance of HbS from one parent and another hemoglobinopathy, such as ” thalassemia or HbC (”2”2 6 Glu’Lys), from the other parent. The prototype disease, sickle cell anemia, is the homozygous state for HbS.

The sickle cell syndromes are caused by mutation in the ”-globin gene that changes the sixth amino acid from glutamic acid to valine. HbS (”2”2 6 Glu’Val) polymerizes reversibly when deoxygenated to form a gelatinous network of fibrous polymers that stiffen the RBC membrane, increase viscosity, and cause dehydration due to potassium leakage and calcium influx. These changes also produce the sickle shape. The loss of red blood cell elasticity is central to the pathophysiology of sickle-cell disease. Sickled cells lose the flexibility needed to traverse small capillaries. They possess altered ‘sticky’ membranes that are abnormally adherent to the endothelium of small venules.
Repeated episodes of sickling damage the cell membrane and decrease the cell’s elasticity. These cells fail to return to normal shape when normal oxygen tension is restored. As a consequence, these rigid blood cells are unable to deform as they pass through narrow capillaries, leading to vessel occlusion and ischaemia.

These abnormalities stimulate unpredictable episodes of microvascular vasoocclusion and premature RBC destruction (hemolytic anemia). The rigid adherent cells clog small capillaries and venules, causing tissue ischemia, acute pain, and gradual end-organ damage. This venoocclusive component usually influences the clinical course.
The actual anaemia of the illness is caused by hemolysis which occurs because the spleen destroys the abnormal RBCs detecting the altered shape of red cells. Although the bone marrow attempts to compensate by creating new red cells, it does not match the rate of destruction. Healthy red blood cells typically function for 90’120 days, but sickled cells only last 10’20 days.

Clinical Manifestations of Sickle Cell Anemia:
Patients with sickling syndromes suffer from hemolytic anemia, with hematocrits from 15 to 30%, and significant reticulocytosis. Anemia was once thought to exert protective effects against vasoocclusion by reducing blood viscosity. The role of adhesive reticulocytes in vasoocclusion might account for these paradoxical effects.
Granulocytosis is common. The white count can fluctuate substantially and unpredictably during and between painful crises, infectious episodes, and other intercurrent illnesses.
Vasoocclusion causes protean manifestations and cause episodes of ischemic pain (i.e., painful crises) and ischemic malfunction or frank infarction in the spleen, central nervous system, bones, joints, liver, kidneys and lungs.

Syndromes cause by sickle hemoglobinopathy:

Painful crises: Intermittent episodes of vasoocclusion in connective and musculoskeletal structures produce ischemia manifested by acute pain and tenderness, fever, tachycardia and anxiety. These episodes are recurrent and it is the most common clinical manifestation of sickle cell anemia. Their frequency and severity vary greatly. Pain can develop almost anywhere in the body and may last from a few hours to 2 weeks.
Repeated crises requiring hospitalization (>3 episodes per year) correlate with reduced survival in adult life, suggesting that these episodes are associated with accumulation of chronic end-organ damage. Provocative factors include infection, fever, excessive exercise, anxiety, abrupt changes in temperature, hypoxia, or hypertonic dyes.

Acute chest syndrome: Distinctive manifestation characterized by chest pain, tachypnea, fever, cough, and arterial oxygen desaturation. It can mimic pneumonia, pulmonary emboli, bone
marrow infarction and embolism, myocardial ischemia, or lung infarction. Acute chest syndrome is thought to reflect in situ sickling within the lung, producing pain and temporary pulmonary dysfunction. Pulmonary infarction and pneumonia are the most common underlying or concomitant conditions in patients with this syndrome. Repeated episodes of acute chest pain correlate with reduced survival. Acutely, reduction in arterial oxygen saturation is especially ominous because it promotes sickling on a massive scale. Chronic acute or subacute pulmonary crises lead to pulmonary hypertension and cor pulmonale, an increasingly common cause of
death in patients.

Aplastic crisis: A serious complication is the aplastic crisis. This is caused by infection with Parvovirus B-19 (B19V). This virus causes fifth disease, a normally benign childhood disorder associated with fever, malaise, and a mild rash. This virus infects RBC progenitors in bone marrow, resulting in impaired cell division for a few days. Healthy people experience, at most, a slight drop in hematocrit, since the half-life of normal erythrocytes in the circulation is 40-60 days. In people with SCD however, the RBC lifespan is greatly shortened (usually 10-20 days), and a very rapid drop in Hb occurs. The condition is self-limited, with bone marrow recovery occurring in 7-10 days, followed by brisk reticulocytosis.

CNS sickle vasculopathy: Chronic subacute central nervous system damage in the absence of an overt stroke is a distressingly common phenomenon beginning in early childhood. Stroke is especially common in children and may reoccur, but is less common in adults and is often hemorrhagic. Stroke affects 30% of children and 11% of patients by 20 years. It is usually ischemic in children and hemorrhagic in adults.
Modern functional imaging techniques have indicated circulatory dysfunction of the CNS; these changes correlate with display of cognitive and behavioral abnormalities in children and young adults. It is important to be aware of these changes because they can complicate clinical management or be misinterpreted as ‘difficult patient’ behaviors.
Splenic sequestration crisis: The spleen enlarges in the latter part of the first year of life in children with SCD. Occasionally, the spleen undergoes a sudden very painful enlargement due to pooling of large numbers of sickled cells. This phenomenon is known as splenic sequestration crisis. Over time, the spleen becomes fibrotic and shrinks causing autosplenectomy. In cases of SC trait, the spleenomegaly may persist upto adulthood due to ongoing hemolysis under the influence of persistent fetal hemoglobin.
Acute venous obstruction of the spleen a rare occurrence in early childhood, may require emergency transfusion and/or splenectomy to prevent trapping of the entire arterial output in the obstructed spleen. Repeated microinfarction can destroy tissues having microvascular beds, thus, splenic function is frequently lost within the first 18’36 months of life, causing susceptibility to infection, particularly by pneumococci.

Infections: Life-threatening bacterial infections are a major cause of morbidity and mortality in patients with SCD. Recurrent vaso-occlusion induces splenic infarctions and consequent autosplenectomy, predisposing to severe infections with encapsulated organisms (eg, Haemophilus influenzae, Streptococcus pneumoniae).
Cholelithiasis: Cholelithiasis is common in children with SCD as chronic hemolysis with hyperbilirubinemia is associated with the formation of bile stones. Cholelithiasis may be asymptomatic or result in acute cholecystitis, requiring surgical intervention. The liver may also become involved. Cholecystitis or common bile duct obstruction can occur. Child with cholecystitis presents with right upper quadrant pain, especially if associated with fatty food. Common bile duct blockage suspected when a child presents with right upper quadrant pain and dramatically elevated conjugated hyperbilirubinemia.

Leg ulcers: Leg ulcers are a chronic painful problem. They result from minor injury to the area around the malleoli. Because of relatively poor circulation, compounded by sickling and microinfarcts, healing is delayed and infection occurs frequently.
Eye manifestation: Occlusion of retinal vessels can produce hemorrhage, neovascularization, and eventual detachments.

Renal manifestation: Renal menifestations include impaired urinary concentrating ability, defects of urinary acidification, defects of potassium excretion and progressive decrease in glome”rular filtration rate with advancing age. Recurrent hematuria, proteinuria, renal papillary necrosis and end-stage renal disease (ESRD) are all well recognized.
Renal papillary necrosis invariably produces isosthenuria. More widespread renal necrosis leads to renal failure in adults, a common late cause of death.

Bone manifestation: Bone and joint ischemia can lead to aseptic necrosis, common in the femoral or humeral heads; chronic arthropathy; and unusual susceptibility to osteomyelitis, which may be caused by organisms, such as Salmonella, rarely encountered in other settings.
-The hand-foot syndrome is caused by painful infarcts of the digits and dactylitis.

Pregnancy in SCD: Pregnancy represents a special area of concern. The high rate of fetal loss is due to spontaneous abortion. Placenta previa and abruption are common due to hypoxia and placental infarction. At birth, the infant often is premature or has low birth weight.

Other features: Particularly painful complication in males is priapism, due to infarction of the penile venous outflow tracts; permanent impotence may also occur. Chronic lower leg ulcers probably arise from ischemia and superinfection in the distal circulation.

Sickle cell syndromes are remarkable for their clinical heterogeneity. Some patients remain virtually asymptomatic into or even through adult life, while others suffer repeated crises requiring hospitalization from early childhood. Patients with sickle thalassemia and sickle-HbE
tend to have similar, slightly milder symptoms, perhaps because of the bad effects of production of other hemoglobins within the RBC.

Clinical Manifestations of Sickle Cell Trait:
Sickle cell trait is often asymptomatic. Anemia and painful crises are rare. An uncommon but highly distinctive symptom is painless hematuria often occurring in adolescent males, probably due to papillary necrosis. Isosthenuria is a more common manifestation of the same process. Sloughing of papillae with urethral obstruction has been also seen, due to massive sickling or sudden death due to exposure to high altitudes or extremes of exercise and dehydration.

Pulmonary hypertension in sickle hemoglobinopathy:
In recent years, PAH a proliferative vascular disease of the lung, has been recognized as a major complication and an independent correlate with death among adults with SCD. Pulmonary hypertension is defined as a mean pulmonary artery pressure >25mmHg, and includes pulmonary artery hypertension, pulmonary venous hypertension or a combination of both. The etiology is multifactorial, including hemolysis, hypoxemia, thromboembolism, chronic high CO, and chronic liver disease. Clinical presentation is characterized by symptoms of dyspnea, chest pain, and syncope. It is important to note that high cardiac output can also elevate pulmonary artery pressure adding to the complex and multifactorial pathophysiology of PHT in sickle cell disease. Thus, if left untreated, the disease carries a high mortality rate, with the most common cause of death being decompensated right heart failure.

Prevalance and prognosis:
Echocardiographic screening studies have suggested that the prevalence of hemoglobinopathy-associated PAH is much higher than previously known. In SCD, approximately one-third of adult patients have an elevated tricuspid regurgitant jet velocity (TRV) of 2.5 m/s or higher, a threshold that correlates in right heart catheterization studies to a pulmonary artery systolic pressure of at least 30 mm Hg. Even though this threshold represents quite mild pulmonary hypertension, SCD patients with TRV above this threshold have a 9- to 10- fold higher risk for early mortality than those with a lower TRV. It appears that the baseline compromised oxygen delivery and co-morbid organ dysfunction of SCD diminishes the physiological reserve to tolerate even modest pulmonary arterial pressures.
Different hemolytic anemias seem to involve common mechanisms for development of PAH. These processes probably include hemolysis, causing endothelial dysfunction, oxidative and inflammatory stress, chronic hypoxemia, chronic thromboembolism, chronic liver disease, iron overload, and asplenia.
Hemolysis results in the release of hemoglobin into plasma, where it reacts and consumes nitric oxide (NO) causing a state of resistance to NO-dependent vasodilatory effects. Hemolysis also causes the release of arginase into plasma, which decreases the concentration of arginine, substrate for the synthesis of NO. Other effects associated with hemolysis that can contribute to the pathogenesis of pulmonary hypertension are increased cellular expression of endothelin, production of free radicals, platelet activation, and increased expression of endothelial adhesion mediating molecules.
Previous studies suggest that splenectomy (surgical or functional) is a risk factor for the development of pulmonary hypertension, especially in patients with hemolytic anemias. It is speculated that the loss of the spleen increases the circulation of platelet mediators and senescent erythrocytes that result in platelet activation (promoting endothelial adhesion and thrombosis in the pulmonary vascular bed), and possibly stimulates the increase in the intravascular hemolysis rate.
Vasoconstriction, vascular proliferation, thrombosis, and inflammation appear to underlie the development of PAH. In long-standing PH, intimal proliferation and fibrosis, medial hypertrophy, and in situ thrombosis characterize the pathologic findings in the pulmonary vasculature. Vascular remodeling at earlier stages may be confined to the small pulmonary arteries. As the disease advances, intimal proliferation and pathologic remodeling progress, resulting in decreased compliance and increased elastance of the pulmonary vasculature.
The outcome is a progressive increase in the right ventricular afterload or total pulmonary vascular resistance (PVR) and, thus, right ventricular work.
Chronic pulmonary involvement due to repeated episodes of acute thoracic syndrome can lead to pulmonary fibrosis and chronic hypoxemia, which can eventually lead to the development of pulmonary hypertension.
Coagulation disorders, such as low levels of protein C, low levels of protein S, high levels of D-dimers and increased activity of the tissue factor, occur in patients with sickle cell anemia.This hypercoagulable state can cause thrombosis in situ or pulmonary thromboembolism, which occurs in patients with sickle cell anemia and other hemolytic anemias.
Clinical manifestations:
On examination, there may be evidence of right ventricular failure with elevated jugular venous pressure, lower extremity edema, and ascites. The cardiovascular examination may reveal an accentuated P2 component of the second heart sound, a right-sided S3 or S4, and a holosystolic tricuspid regurgitant murmur. It is also important to seek signs of the diseases that are often concurrent with PH: clubbing may be seen in some chronic lung diseases, sclerodactyly and telangiectasia may signify scleroderma, and crackles and systemic hypertension may be clues to left-sided systolic or diastolic heart failure.
Diagnostic evaluation:
The diagnosis of pulmonary hypertension in patients with sickle cell anemia is typically difficult. Dyspnea on exertion, the symptom most typically associated with pulmonary hypertension, is also very common in anemic patients. Other disorders with similar symptomatology, such as left heart failure or pulmonary fibrosis, frequently occur in patients with sickle cell anemia. Patients with pulmonary hypertension are often older, have higher systemic blood pressure, more severe hemolytic anemia, lower peripheral oxygen saturation, worse renal function, impaired liver function and a higher number of red blood cell transfusions than do patients with sickle cell anemia and normal pulmonary pressure.
The diagnostic evaluation of patients with hemoglobinopathies and suspected of having pulmonary hypertension should follow the same guidelines established for the investigation of patients with other causes of pulmonary hypertension.
Echocardiography: Echocardiography is important for the diagnosis of PAH and often essential for determining the cause. All forms of PAH may demonstrate a hypertrophied and dilated right ventricle with elevated estimated pulmonary artery systolic pressure. Important additional information can be obtained about specific etiologies such as valvular disease, left ventricular systolic and diastolic function, intracardiac shunts, and other cardiac diseases.
An echocardiogram is a screening test, whereas invasive hemodynamic monitoring is the gold standard for diagnosis and assessment of disease severity.
Pulmonary artery (PA) systolic pressure (PASP) can be estimated by Doppler echocardiography, utilizing the tricuspid regurgitant velocity (TRV). Increased TRV is estimated to be present in approximately one-third of adults with SCD and is associated with early mortality. In the more severe cases, increased TRV is associated with histopathologic changes similar to atherosclerosis such as plexogenic changes and hyperplasia of the pulmonary arterial intima and media.

The cardiopulmonary exercise test (CPET): This test may help to identify a true physiologic limitation as well as differentiate between cardiac and pulmonary causes of dyspnea but test can only be performed if patient has reasonable functional capacity. If this test is normal, there is no indication for a right heart catheterization.

Right Heart Catheterization: If patient has cardiovascular limitation to exercise, a right heart catheterization should be inserted. Right heart catheterization with pulmonary vasodilator testing
remains the gold standard both to establish the diagnosis of PH and to enable selection of appropriate medical therapy. The definition of precapillary PH or PAH requires (1) an increased mean pulmonary artery pressure (mPAP ’25 mmHg); (2) a pulmonary capillary wedge pressure (PCWP), left atrial pressure, or left ventricular end-diastolic pressure ’15 mmHg; and (3) PVR >3 Wood units. Postcapillary PH is differentiated from precapillary PH by a PCWP of ’15 mmHg; this is further differentiated into passive, based on a transpulmonary gradient <12 mmHg, or reactive, based on a transpulmonary gradient >12 mmHg and an increased PVR. In either case, the CO may be normal or reduced. If the echocardiogram or cardiopulmonary exercise test (CPET) suggests PH and the diagnosis is confirmed by catheterization.

Chest imaging and lung function tests: These are essential because lung disease is an important cause of PH. A sign of PH that may be evident on chest x-ray include enlargement of the central pulmonary arteries associated with ‘vascular pruning,’ a relative paucity of peripheral vessels. Cardiomegaly, with specific evidence of right atrial and ventricular enlargement may present. The chest x-ray may also demonstrate significant interstitial lung disease or suggest hyperinflation from obstructive lung disease, which may be the underlying cause or contributor to the development of PH.

High-resolution computed tomography (CT): Classic findings of PH on CT include those found on chest x-ray: enlarged pulmonary arteries, peripheral pruning of the small vessels, and enlarged right ventricle and atrium. High-resolution CT may also show signs of venous congestion including centrilobular ground-glass infiltrate and thickened septal lines. In the absence of left heart disease, these findings suggest pulmonary veno-occlusive disease, a rare cause of PAH that can be quite challenging to diagnose.

CT angiograms: Commonly used to evaluate acute thromboembolic disease and have demonstrated excellent sensitivity and specificity for that purpose.

Ventilation-perfusion Ratio: Scanning done for screening because of its high sensitivity and
its role in qualifying patients for surgical intervention. Negative ratio virtually rules out CTEPH, some cases may be missed through the use of CT angiograms.

Pulmonary function test: Isolated reduction in DLco is the classic finding in PAH,
results of pulmonary function tests may also suggest restrictive or obstructive
lung diseases as the cause of dyspnea or PH.
Evaluation of symptoms and functional capacity (6 Min walk test): Although the 6-minute walk test has not been validated in patients with hemoglobinopathies, preliminary data suggest that this test correlates well with maximal oxygen uptake and with the severity of pulmonary hypertension in patients with sickle cell anemia. In addition, in these patients, the distance covered on the 6-minute walk test significantly improves with the treatment of pulmonary hypertension, which suggests that it can be used in this population.
Disorders of lipoprotein metabolism are known as ‘dyslipidemias.’ Dyslipidemias are generally characterized clinically by increased plasma levels of cholesterol, triglycerides, or both, accompanied by reduced levels of HDL cholesterol. Mostly all patients with dyslipidemia are at increased risk for ASCVD, the primary reason for making the diagnosis, as intervention may reduce this risk. Patients with elevated levels of triglycerides may be at risk for acute pancreatitis and require intervention to reduce this risk.
Hundreds of proteins affect lipoprotein metabolism and may interact to produce dyslipidemia
in an individual patient, there are a limited number of discrete ‘nodes’ that regulate lipoprotein metabolism. These include: (1) assembly and secretion of triglyceriderich VLDLs by the liver; (2) lipolysis of triglyceride-rich lipoproteins by LPL;
(3) receptor-mediated uptake of apoB-containing lipoproteins by the liver;
(4) cellular cholesterol metabolism in the hepatocyte and the enterocyte; and
(5) neutral lipid transfer and phospholipid hydrolysis in the plasma.
Hypocholesterolemia and, to a lesser extent, hypertriglyceridemia have been documented in
SCD cohorts worldwide for over 40 years, yet the mechanistic basis and physiological
ramifications of these altered lipid levels have yet to be fully elucidated. Cholesterol (TC, HDL-C and LDL-C) levels decreased and triglyceride levels increased in relation to severity of anemia. While not true for cholesterol levels, triglyceride levels show a strong correlation with markers of severity of hemolysis, endothelial activation, and pulmonary hypertension.
Decreased TC and LDL-C in SCD has been documented in virtually every study that
examined lipids in SCD adults (el-Hazmi, et al 1987, el-Hazmi, et al 1995, Marzouki and
Khoja 2003, Sasaki, et al 1983, Shores, et al 2003, Stone, et al 1990, Westerman 1975),
with slightly more variable results in SCD children. Although it might be hypothesized that SCD hypocholesterolemia results from increased cholesterol utilization during the increased
erythropoiesis of SCD, cholesterol is largely conserved through the enterohepatic
circulation, at least in healthy individuals, and biogenesis of new RBC membranes would
likely use recycled cholesterol from the hemolyzed RBCs. Westerman demonstrated that
hypocholesterolemia was not due merely to increased RBC synthesis by showing that it is
present in both hemolytic and non-hemolytic anemia (Westerman 1975). He also reports that serum cholesterol was proportional to the hematocrit, suggesting serum cholesterol may be in equilibrium with the cholesterol reservoir of the total red cell mass (Westerman 1975). Consistent with such equilibration, tritiated cholesterol incorporated into sickled erythrocytes is rapidly exchanged with plasma lipoproteins (Ngogang, et al 1989). Thus, low plasma cholesterol
appears to be a consequence of anemia itself rather than increased RBC production (Westerman 1975).
Total cholesterol, in particular LDL-C, has a well-established role in atherosclerosis. The
low levels of LDL-C in SCD are consistent with the low levels of total cholesterol and the
virtual absence of atherosclerosis among SCD patients. Decreased HDL-C in SCD has also been documented in some previous studies(Sasaki, et al 1983, Stone, et al 1990). As in lipid studies
for other disorders in which HDL-C is variably low, potential reasons for inconsistencies
between studies include differences in age, diet, weight, smoking, gender, small sample
sizes, different ranges of disease severity, and other diseases and treatments(Choy and Sattar
2009, Gotto A 2003). Decreased HDL-C and apoA-I is a known risk factor for endothelial
dysfunction in the general population and in SCD, a potential contributor in SCD to PH,
although the latter effect size might be small(Yuditskaya, et al 2009).
In addition, triglyceride levels have been reported to increase during crisis.
Why is increased triglyceride but not cholesterol in serum associated with vascular
dysfunction and pulmonary hypertension? Studies in atherosclerosis have firmly established
that lipolysis of oxidized LDL in particular results in vascular dysfunction. Lipolysis of
triglycerides present in triglyceride-rich lipoproteins releases neutral and oxidized free fatty
acids that induce endothelial cell inflammation (Wang, et al 2009). Many oxidized fatty
acids are more damaging to the endothelium than their non-oxidized precursors; for
example, 13-hydroxy octadecadienoic acid (13-HODE) is a more potent inducer of ROS
activity in HAECs than linoleate, the nonoxidized precursor of 13-HODE(Wang, et al
2009). Lipolytic generation of arachidonic acid, eicosanoids, and inflammatory molecules
leading to vascular dysfunction is a well-established phenomenon (Boyanovsky and Webb
2009). Although LDL-C levels are decreased in SCD patients, LDL from SCD patients is
more susceptible to oxidation and cytotoxicity to endothelium (Belcher, et al 1999) and an
unfavorable plasma fatty acid composition has been associated with clinical severity of
SCD (Ren, et al 2006). Lipolysis of phospholipids in lipoproteins or cell membranes by
secretory phospholipase A2 (sPLA2) family members releases similarly harmful fatty acids,
particularly in an oxidative environment (Boyanovsky and Webb 2009 ) and in fact selective
PLA2 inhibitors are currently under development as potential therapeutic agents for
atherosclerotic cardiovascular disease(Rosenson 2009). Finally, sPLA2 activity has been
linked to lung disease in SCD. sPLA2 is elevated in acute chest syndrome of SCD and in
conjunction with fever preliminarily appears to be a good biomarker for diagnosis,
prediction and prevention of acute chest syndrome(Styles, et al 2000). The deleterious
effects of phospholipid hydrolysis on lung vasculature predicts similar deleterious effects of
triglyceride hydrolysis, particularly in the oxidatively stressed environment of SCD.
Elevated triglycerides have been documented in autoimmune inflammatory diseases with
increased risk of vascular dysfunction and pulmonary hypertension, including systemic lupus erythematosus, scleroderma, rheumatoid arthritis, and mixed connective tissue diseases(Choy and Sattar 2009, Galie, et al 2005). In fact, triglyceride concentration is a stronger predictor of stroke than LDL-C or TC(Amarenco and Labreuche 2009). Even in healthy control subjects, a high-fat meal induces oxidative stress and inflammation, resulting in endothelial dysfunction and vasoconstriction(O’Keefe, et al 2008). Perhaps having high levels of plasma triglycerides promotes vascular dysfunction, with the clinical outcome of vasculopathy mainly in the coronary and cerebral arteries in the general population, and with more targeting to the pulmonary vascular bed in SCD and autoimmune diseases.
The mechanisms leading to hypocholesterolemia and hypertriglyceridemia in plasma or
serum of SCD patients are not completely understood. In normal individuals, triglyceride
levels are determined to a significant degree by body weight, diet and physical exercise, as
well as concurrent diabetes. Diet and physical exercise very likely impact body weight and triglyceride levels in SCD patients also. These findings indicate that standard risk factors for high triglycerides are also relevant to SCD patients. Mechanisms of SCD-specific risk factors for elevated plasma triglycerides are not as clear. RBCs do not have de novo lipid synthesis (Kuypers 2008). In SCD the rate of triglyceride synthesis from glycerol is elevated up to 4-fold in sickled reticulocytes (Lane, et al 1976), but SCD patients have defects in post absorptive plasma homeostasis of fatty acids (Buchowski, et al 2007). Lipoproteins and albumin in plasma can contribute fatty acids to red blood cells for incorporation into membrane phospholipids
(Kuypers 2008), but RBC membranes are not triglyceride-rich and contributions of RBCs to
plasma triglyceride levels have not been described. Interestingly, chronic intermittent or stable hypoxia just by exposure to high altitudes, with no underlying disease, is sufficient to increase triglyceride levels in healthy subjects (Siques, et al 2007). Thus, it has also been suggested that hypoxia in SCD may contribute at least partially to the observed increase in serum triglyceride. Finally, there is a known link of low cholesterol and increased triglycerides that occurs in any primate acute phase response, such as infection and inflammation (Khovidhunkit, et al 2004). Perhaps because of their chronic hemolysis, SCD patients have a low level of acute phase response, which is also consistent with the other inflammatory markers. Further studies are required to elucidate the mechanisms leading to hypocholesterolemia and hypertriglyceridemia in SCD.
Pulmonary hypertension is a disease of the vasculature that shows many similarities with the vascular dysfunction that occurs in coronary atherosclerosis (Kato and Gladwin 2008). The similarities and differences are: They both have proliferative vascular smooth muscle cells ‘ just in different vascular beds. They both have an impaired nitric oxide axis, increased oxidant stress, and vascular dysfunction. Most importantly, serum triglyceride levels, previously linked to vascular dysfunction, are definitely shown to correlate with NT-proBNP and TRV and thus, with
pulmonary hypertension. Moreover, triglyceride levels are predictive of TRV independent of
systolic blood pressure, low transferrin or increased lactate dehydrogenase.
PAH in SCD is also characterized by oxidant stress but in SCD patients plasma total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) are low. There have been some reports of low HDL cholesterol (HDL-C)17,18 and increased triglyceride in SCD patients ‘ features widely recognized as important contributory factors in cardiovascular disease. These findings and the therapeutic potential to modulate serum lipids with several commonly used drugs prompted us to investigate in greater detail the serum lipid profile in patients with sickle hemoglobinopathy (SH) coming to our hospital and its possible relationship to vasculopathic complications such as PAH.

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