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Sickle cell life span

Sickle cell life span


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How long do sickle red blood cells "live" before being broken down in phagocytosis?

I had trouble doing a normal search as it brings up life span of those inflicted with the disease. Also, I have been doing a semester long assignment, where we are delving into all aspects of this disease, and I have 20 sources so far and still haven't come across the answer.


Sickle cells usually die after about 10 to 20 days, compared to normal red blood cells, which live an average of 120 days. The bone marrow can't make new red blood cells fast enough to replace all the dying ones which causes anemia,low blood count that results in fatigue,shortness of breath and related symptoms.As the cells are made normally but die too rapidly,this is termed as haemolytic.


E. Jason Wambsgans/Chicago Tribune/TNS/Sipa USA

Sickle cell disease is red blood cell disorder that mostly affects people of African or Hispanic descent. About 100,000 Americans are currently living with it. Above, Terrance Hill, 40, is examined by Dr. Santosh Saraf, a hematologist-oncologist, during a checkup at University of Illinois Hospital on Nov. 27, 2019. Hill received a successful stem cell transplant in 2016 to combat his sickle cell disease.

Treatment for sickle cell disease has come a long way since the 1970s when the life expectancy of people living with it was less than 20 years.

People with sickle cell disease are not only living longer – life expectancy is now 42 to 47 years of age – but are enjoying a better quality of life, too.

"In the Philadelphia area, there has been great pediatric care for sickle cells disease and because of that people who have it are living very well," said Dr. Farzana Sayani, a hematologist at Penn Medicine.

Sayani is the director of a comprehensive sickle cell program focusing on adults living with the disease. Penn also has an active transition program for youth transitioning from a pediatric institution to adult care.

WHAT IS SICKLE CELL DISEASE?

Sickle cell disease is an inherited red blood cell disorder that affects about 100,000 Americans. It is most often found in people of African or Hispanic descent. About 1 in 365 African-American babies are born with sickle cell disease, according to Sayani.

People who have the disease inherit an abnormal type of hemoglobin in their red blood cells, called Hemoglobin S, from both their mother and father. When only one parent has the hemoglobin S gene, a child will have the sickle cell trait, but usually does not develop the disease. But they may pass it on to their children.

Hemoglobin is the protein in the blood responsible for carrying oxygen to the rest of the body. Hemoglobin S causes red blood cells to become stiff and sickle-shaped. Instead of being round in shape, they look like crescent moons.

Sickle cells are sticky and can bind together, blocking the flow of blood and preventing oxygen from getting where it needs to go in the body. This causes sudden attacks of pain referred to as a pain crisis.

There are several different types of sickle cell disease. Hemoglobin SS, also known as sickle cell anemia, is the most common and most severe type of sickle cell disease.

Anemia occurs when red blood cells die at a rate faster than the body can replace them. Normal red blood cells generally live for 90 to 120 days. Sickled cells only live for 10 to 20 days. This shorter life-to-death cycle is harder for the body to sustain.

Another form, Hemoglobin SC, is not as severe as sickle cell anemia, but it can still cause significant complications, Sayani said. Other forms include Hemoglobin Sβ0 thalassemia, Hemoglobin Sβ+ thalassemia, Hemoglobin SD and Hemoglobin SE.

DIAGNOSING SICKLE CELL DISEASE

Sickle cell disease screening is a mandatory part of newborn screenings in Pennsylvania.

If the screening is positive, the family is informed and plugged into the health care system in order to receive the proper care.

If the disease is not diagnosed at birth, a blood test can confirm it at any age in which symptoms start to surface.

SICKLE CELL SYMPTOMS

The severity of sickle cell disease can vary.

Each individual is affected differently, making it difficult to predict who will get what complications, Sayani said. That is why a comprehensive sickle cell program is so important.

Early signs include a yellowish tint to the skin or jaundice, fatigue and a painful swelling of the hands and feet.

"Young children with sickle cell disease may be tired, not eat very well and have delayed growth," Sayani said. "They may also develop anemia, be at greater risk of infection and start to experience pain crises."

Acute pain crises, also known as vaso-occlusive crises, can lead to long stays in the hospital to manage the crippling pain. Children with sickle cell disease also tend to experience delayed growth and puberty.

As a person with sickle cell disease grows older, the sickled red blood cells start to affect various organs, bones and joints.

This can lead to acute chest syndrome, which occurs when damaged lung tissues makes it difficult to breathe. Brain complications, including stroke, are possible. People with sickle cell disease are also prone to heart damage, eye problems, and infections like chlamydia, salmonella and staphylococcus. Chronic and acute pain is common.

ADVANCEMENTS IN TREATMENT

There are different types of medicine that can help manage sickle cell disease.

Last year, an oral medicine was approved that makes sickle cells less likely to sickle. So was an intravenous medicine that has been shown to reduce pain crises and hospitalizations by 50%. Some people living with sickle cell disease also may need regular blood transfusions.

Hydroxyurea has also been used successfully for many years to reduce pain crises and the need for blood transfusions and hospitalizations.

Currently, blood and bone marrow transplant is the only way to cure the disease. But it is not an option for everyone because of the difficulty of finding a well-matched stem cell donor.

A related donor is best but only about a third of sickle cell patients have a donor that is related and fully-matched, Sayani said.

While these transplants have a 85% or more success rate, they also are associated with significant risks, including organ dysfunction, infection and graft vs. host disease – which can be quite debilitating.

Transplants completed in children have the best results, Sayani said. But because of the risks involved, doctors only suggest it for patients with severe forms of the disease.

Early clinical trials with gene therapy are also showing promise, she added.

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Sickle Cell Anemia Life Expectancy

The life expectancy of sickle cell anemia can be extended with good treatment and care. The subject is examined in some detail below. Have a look.

The life expectancy of sickle cell anemia can be extended with good treatment and care. The subject is examined in some detail below. Have a look…

Sickle cell anemia is an inherited disease that more than 70,000 Americans suffer from. While the condition cannot be cured in a majority of cases, it can be effectively managed. Treatment is meted out to relieve pain and help prevent further problems associated with the condition.

Causes

A sickle is a farming tool with a semicircular blade. This illness shares the name of the tool as it is defined as a condition where the body produces sickle-shaped red blood cells. Normal red blood cells are circular with slight depressions in the center, and travel with ease through the blood vessels. The protein hemoglobin contained in red blood cells is what gives blood its rich red color, and carries oxygen from the lungs to the rest of the body. When this protein is not normal, it causes the red blood cells to take on this crescent shape. These cells are stiff and sticky, and have the tendency of bunching together and getting stuck in the blood vessels, often blocking blood flow.

Symptoms

As sickle cell anemia is an inherited disease, it is present from birth, but signs of the condition are usually seen after 4 months. Anemia is one of the most common symptoms of the disease, which is shortage of red blood cells. People with anemia are unusually pale and experience constant fatigue. People with sickle cell anemia also suffer from periodic episodes of pain. Called crises, they are caused by the sickle-shaped red blood cells blocking blood flow through blood vessels. The pain may be severe or mild, and may last from anywhere between a few hours to a few weeks. Often, swelling of hands and feet of infants is the first sign of this condition. Other symptoms are jaundice, frequent infections, delayed growth, and vision problems.

Life Expectancy

As the illness can result in serious health problems, the life expectancy for patients is obviously lesser than those who don’t have the condition. However, treatment and care for the disease is getting better, which means improved life expectancy. In the US, on an average, men with this condition live for about 42 years, while women live for 48 years.

Treatment

The only possible cure lies in bone marrow transplant. However, the procedure is very risky, and finding a donor is difficult. Usually, treatment is given with the aim of avoiding crises, relieving the symptoms, and preventing complications. This can include medications to reduce pain and prevent complications, blood transfusions, and supplemental oxygen, and in cases where it is possible, a bone marrow transplant. The treatment options are likely to widen as ongoing researches into the condition yield results. The patient needs consistent medical attention, and frequent visits to the doctor to check the red blood cell count and overall health.

In the past, people with sickle cell anemia often died between the ages 20 and 40 from organ failure. However, thanks to a better understanding and management of the disease, the expectancy has increased, and patients can live into their 50s. This illness places a lot of stress on the patient as well as his/her family, which can be dealt with (one of the ways) by joining a support group.


Sickle Cell Disease QoL and Life Expectancy

Biree Andemariam, MD: Michael, what you just informed our audience about, particularly those who may not have a lot of experience taking care of individuals with sickle cell disease, is heartbreaking and devastating. It really does align with what our panelists have described about the path of physiology, what Julie called a blood vessel disease in the background of a blood disease.

Some of the statistics that you cited: 11% stroke risk, 10% pregnancy-related mortality in low-income settings, 30% depression, the amount of suffering related to priapism, end-stage renal disease mortality. What about quality of life in these individuals? Wally, what does the impact of what Michael explained to us have on the individual living with sickle cell disease?

Wally Smith, MD: Health-related quality of life in sickle cell disease is poor, even in young adults. It might even be age dependent, meaning that the transition age group may have the worst health-related quality of life with their suffering and the shock of leaving home. There’s the shock of often not having insurance as adults when they had them as children. There’s the shock of having to fend for themselves now and managing all those complications that Mike and others have talked about.

Then the organic problem of organ failure starts to take a toll on their physical health-related quality of life. If you add up depression, PTSD [post-traumatic stress disorder], organ failure, worsening cognitive function together, the health-related quality of life in patients with sickle cell disease is somewhere around that of dialysis patients—or maybe a little better—according to 1 of the comparative studies we did.

Biree Andemariam, MD: Somewhere around that of being someone on dialysis. Julie, in light of everything Michael and Wally told us about the acute and chronic manifestations and the impact on quality of life, where are we with sickle cell and life expectancy in this country or even globally?

Julie Kanter, MD: I’ll answer your question in 1 minute. I want to first respond to my colleagues because, while this disease is incredibly serious and has multiple complications, there are also people who are living very well and very strong with sickle cell disease. Sometimes we neglect to talk about how if individuals are taught how to take care of themselves and are seeing a sickle cell specialist, this disease can be managed.

We see many affected individuals who are doctors, nurses, lawyers, and other able-bodied individuals. There are a lot of complications and a lot of unmet needs, but there are also a lot of wins. We do know that if you’re seeing a specialist, you can have better outcomes, and that’s really important when you look at our overall life expectancies. When you compare life expectancies, in different countries but also among different institutions, a lot of what predicts outcomes is what type of specialist you’re seeing and access to care you have.

What I harp on is access to care. The most important thing we can do is to make sure everybody with a sickle cell disease diagnosis is able to see a specialist, whether they’re here or in sub-Saharan Africa, and that we can get the very best options for those individuals.

In the United States and other high-income countries, we’ve seen a couple of studies that show us a range in life expectancy. From the lower end we saw out of the Sickle Cell Data Collection [program] and really important data out of the CDC project in California, where we’re seeing an average life expectancy of 41 to 44 years of age. There are more recent data that we’ve seen out of Tennessee that put that age of life expectancy a bit higher. Then we have some information out of England that suggests perhaps even a higher life expectancy.

We can compare that with sub-Saharan Africa, where unfortunately, we still have more than half our kids dying before they’re 10. That is really neglectful on our parts because we can make a huge difference with newborn screening, early diagnosis, and early treatment. The range really depends on what type of access to care you have.

Biree Andemariam, MD: Elliott and Michael, I’d like you to both chime in because Julie did mention your states of California and Tennessee, so unpack that for us a little.

Michael DeBaun, MD, MPH: Go ahead, Elliott.

Elliott Vichinsky, MD: Thank you, Michael. I just wanted to comment that after practicing for many years, I would say that the ethical challenge in this country has been taking care of chronically ill people. The health inequities and disparity are best illustrated in sickle cell disease. The real problem for sickle cell in this country has been lack of access to getting the minimum standard of care available. I would say that in working in a community and with many universities, the majority of patients don’t get appropriate care or access to appropriate care.

In my region this is the No. 1 cause of death. It’s the lack of getting access to well-established standard-of-care practices that could prevent or minimize outcomes. It’s a tragedy. Sickle cell is the best and worst of health care. As we develop these new treatments, we really have to get at this incredible disparity in survival, which in my opinion is because of a lack of access. It can’t be kept in the closet.

Michael DeBaun, MD, MPH: I just wanted to comment quickly about 2 studies that Julie mentioned. The first 1 was out of the United Kingdom, where they have a life span in the mid-60s for sickle cell disease. The initial attribution was that they have the National Health Service with a social service network, and anybody who needs medical care will receive medical care. It turns out that there was a statistical approach that they used to make an assumption. We repeated that analysis with who my peers would say are 2 reasonably knowledgeable hematologists, Dr Kenneth Ataga [at the University of Tennessee Health Science Center] and Dr Adetola Kassim [at Vanderbilt-Ingram Cancer Center].

These are adults who were treated with optimal medical therapy. Sixty percent were on hydroxyurea, and as you all know, that’s a much higher rate than you would expect in the general population. Among those who were not on hydroxyurea, they either did not want it because they were trying to get pregnant, they were on transfusions, or they had SC [sickle–hemoglobin C] disease. It’s really a high percentage.

In that group, the median survival was age 48. Among those patients, there was no statistically significant difference between those with SC and SS [sickle cell anemia]. Although there was a numerical difference, patients with SC were still dying earlier than you would’ve expected. I don’t want to ignore this population, because we often tend to focus on the complications as it relates to SS and sickle beta zero thalassemia and not SC.

Julie Kanter, MD: That’s so true. That’s an area where we all need to improve our outcomes. One of the things we found in some of our research, especially with our kids with SC disease, is that they often don’t feel poorly or have a lot of these complications. By the time they get to adult care, often in their early 20s, it’s really a failure not so much of transition. It’s that they weren’t seen in their late teens to transition, so by the time they get to us, sometimes they have organ complications or other issues. We need to do a better job of taking care of those patients when they’re younger to get them in steady hands when they’re older too.

Biree Andemariam, MD: I agree with you 100%, having taken care of adults with sickle cell disease my whole professional life. I was always astounded by the labeling of children with SC as having a mild phenotype. Michael and Julie, you’re absolutely right. By the time they get to adulthood, all bets are off, and the statistics that both of you outlined for us tell that same story.


Results

Figure 1. Figure 1. Survival of Patients in the Cooperative Study of Sickle Cell Disease.

Panel A shows male and female patients with sickle cell anemia (SS), as compared with black males and females in the general population (data are from the National Center for Health Statistics 12 ). Panel B shows male and female patients with sickle cell-hemoglobin C disease (SC), and Panel C patients with sickle cell anemia more than five years of age who had fetal hemoglobin (Hb F) levels at or below the 75th percentile (8.6 percent).

Kaplan-Meier survival curves for children and adults with sickle cell anemia (1313 females and 1229 males) or sickle cell-hemoglobin C disease (427 females and 417 males) are shown in Figure 1 . Among patients with each phenotype, females survived longer than males (P = 0.004 by Cox regression), and patients with sickle cell-hemoglobin C disease survived longer than those with sickle cell anemia (P<0.001 by Cox regression). The median age at death among patients with sickle cell anemia was 42 years for males and 48 years for females. Among patients with sickle cell-hemoglobin C disease, the corresponding ages were 60 and 68 years the data on age at death among patients with sickle cell-hemoglobin C disease should be interpreted with some caution, however, since the number of deaths was relatively low in this group. The corresponding survival curves for blacks in the general population 12 are included for comparison and show that life expectancy among patients with sickle cell anemia was decreased by 25 to 30 years. The improved survival of patients with sickle cell anemia who had fetal hemoglobin levels above the 75th percentile (>8.6 percent) is illustrated in Figure 1C .

Figure 2. Figure 2. Probability of Surviving for the Next 10 Years, According to Age, among Males and Females with Sickle Cell Anemia (SS), as Compared with Black Males and Females in the General Population.

Data are from the National Center for Health Statistics 12 .

To investigate the relation between age and the risk of death in sickle cell disease, we analyzed the data according to decade of age and calculated the probability of surviving each decade ( Figure 2 ). The probability of surviving for 10 years dropped dramatically with age, particularly after the age of 20 years, when compared with similar data for blacks in the general population.


Causes of sickle-cell anemia

Individuals with sickle-cell disease have inherited from each parent a gene &mdash &beta S &mdash encoding the beta chain of hemoglobin. Individuals who inherit only one &beta S gene along with the &beta A allele have both Hb A and Hb S in their red cells. In the malaria-free United States, these heterozygotes are well. In regions where malaria is common, having one of each beta chain gene (&beta A and &beta S) confers resistance to one of the most dangerous types of malaria (falciparum). This would explain why the Hb S gene is so prevalent in those regions.

The amino acid sequences of the beta chains of Hb A and Hb S have been determined. The beta chains are identical except for the amino acid at position 6 (counting, as always, from the amino terminal). This position is occupied by glutamic acid in Hb A chains, but in Hb S beta chains, valine is found there instead.

Figure (PageIndex<2>): Sequence alignment between Hb A and Hb S

Why does this single amino acid change in a chain of 146 amino acids so drastically alter the properties of deoxygenated hemoglobin? In switching from glutamic acid to valine, a strongly hydrophilic molecule has been replaced by a strongly hydrophobic one. Position 6 is located at the surface of the beta chain, where it would normally be exposed to water. This switch from a hydrophilic to a hydrophobic region on the surface reduces the solubility of the molecule and promotes the formation of large insoluble aggregates.

The mutation that produces Hb S is a single-base substitution in which the substitution of a T for an A at the 17th nucleotide of the sense strand of the first exon of the beta chain gene converts a codon for glutamic acid (GAG) to a codon for valine (GTG). Although this change might at first appear trivial, the resulting substitution of valine for glutamic acid so alters the physical properties of hemoglobin that a serious disease is produced in people carrying both genes for the trait.


Life expectancy

Several studies in past years have assessed the average life expectancy of a patient with sickle cell anemia, but new treatments are changing expectations and new studies are needed. One often used as a baseline is the Cooperative Study of Sickle Cell Disease, published in the New England Journal of Medicine in 1994. This study monitored patients in the U.S. between 1978 and 1988, and estimated the median life expectancy of women with sickle cell anemia to 48 years and men 42 years. However, it authors noted that 50 percent of deaths were seen in patients ages 45 or older.

Another study, conducted between 1979 and 2005 in the U.S, estimated the average life expectancy for a woman with sickle cell anemia to be 42 years, and 38 years for a man. The results were published in Public Health Reports, based on death certificates listing sickle cell anemia as the underlying or contributing cause of death.

Both studies are now somewhat dated, and it is possible for sickle cell anemia patients to live well beyond the average life expectancy, as demonstrated in a case series of four women with the disease — three in the U.S. and one in Brazil — who lived well into their eighties. This study was published in the journal Blood in 2016.


SCD in the United States

SCD is more common in Americans whose ancestors lived in Africa, South and Central America, and India. The U.S. Centers for Disease Control and Prevention (CDC) projects that: 1

  • About 100,000 Americans have SCD
  • About 1 in every 13 Blacks have sickle cell trait
  • About 1 in every 365 Blacks have SCD
  • About 1 in every 16,300 Hispanics have SCD

Health outcomes for people with SCD in the United States have improved because of better diagnosis and treatments. For example: 8

  • In the 1970s, life expectancy was less than 20 years old. Now, most people live past 50 years old.
  • Until the 1990s, up to 30 percent of children with sickle cell anemia died from infections. Early diagnosis, antibiotics, and education have reduced this to below 3 percent.
  • More than 90 percent of Americans with SCD live into adulthood

Despite these improvements, many people with SCD suffer from severe pain, depression, discrimination, and stigma. As health outcomes continue to improve, the number of Americans with SCD will increase. It is important to keep expanding access to care and reducing treatment costs. 2


Effects of Sickle Cell Disease on Daily Life, Symptoms, and Disease Management

The Sickle Cell World Assessment Survey (SWAY) asked patients about the effects of the disease on their daily lives.

Sickle cell disease (SCD) has a significant effect on patient quality of life, with a global commonality in unmet treatment needs, disease burden, and effects on daily life, according to results from an international survey published in American Journal of Hematology.

SCD is an inherited disorder that affects millions of people around the world. Patients with SCD experience anemia, organ damage and painful vaso-occlusive crises (VOCs). Previous surveys have found that SCD contributes to poor health-related quality of life, but most of those surveys were generic and limited to 1 country.

The Sickle Cell World Assessment Survey (SWAY) surveyed patients on the impact of the disease on their daily lives. A total of 2145 patients from 16 countries completed the survey from April 3 to October 4, 2019. The survey included patients from high-income (HI) and low-middle-income (LMI) countries, and used a 7-point Likert scale, with scores of 5, 6, or 7 indicating high impact or high severity.

Of the participants surveyed, the majority indicated that SCD affected their emotional wellbeing (60%). Many patients also reported feeling frustrated with putting ip with symptoms (58%), and worries about worsening disease (58%). In addition, the majority of patients reported avoidance of intense physical activity (62%).

A total of 53% of patients felt that SCD limited them to certain careers, 44% reported that SCD has prevented them from attending work, and 46% reported that SCD reduced attendance at school.

Fatigue, bone aches, and headaches were the 3 most commonly reported symptoms (41%, 38%, and 25%, respectively). Patients who experienced these symptoms were more likely to respond that the disease had a high impact on their lives or wellbeing. Fatigue was the most common symptom in patients before the survey (65%). Almost all patients experienced at least 1 VOC in the 12 months before the survey. Usually, VOCs were managed by an overnight hospital stay.

Survey results confirm previous studies finding that patients with SCD experience poorer quality of life across the globe and that VOCs are highly debilitating. The results also suggested the need for improvement in VOC management. Nearly 25% of patients reported managing their VOCs at home, and 94% of patients were receiving ongoing treatment for SCD, with folic acid being the most common. The majority of patients saw an SCD specialist and felt confident in the care they received by their healthcare provider.

The burden of SCD seemed to be greater for patients in HI countries, which may be due to older patient age in these countries. Disease burden worsens with age, and patients in HI countries have a longer life expectancy than those in LMI nations. SWAY results can help providers understand how SCD affects patients to tailor management strategies to their unique needs.

“Further analyses of SWAY will also fully explore how patient demographic factors (eg, age, gender), VOC and symptom/complication frequency, and treatment use (eg, opioids) influence self-reported impact of SCD on patients’ daily lives.”

Disclosure: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Sickle cell life span - Biology

The final product of this mutation, hemoglobin S (HbS), is a protein whose quaternary structure is a tetramer made up of two normal alpha-polypeptide chains and two aberrant ß s -polypeptide chains. The primary pathological process leading ultimately to sickle shaped red blood cells involves this molecule. After deoxygenation of hemoglobin S molecules, long helical polymers of HbS form through hydrophobic interactions between the ß s -6 valine of one tetramer and the ß-85 phenylalanine and ß-88 leucine of an adjacent tetramer (Schechter, 1978).

Deformed, sickled red cells can occlude the microvascular circulation, producing vascular damage, organ infarcts, painful crises and other such symptoms associated with sickle cell disease. Although everyone with sickle cell disease shares a specific, invariant genotypic mutation, the clinical variability in the pattern and severity of disease manifestations is astounding. In other genetic disorders such as cystic fibrosis, phenotypic variability between patients can be traced genotypic variability (Powars and Hiti, 1993). Such is not the case, however, with sickle cell disease. Physicians and researchers have sought explanations of the variability associated with the clinical expression of this disease. The most likely causes of this inconstancy are disease modifying factors. I have reviewed the role of some of these factors, and tried to ascertain the clinical importance of each.

Fetal Hemoglobin

Fetal hemoglobin binds oxygen more tightly than does adult hemoglobin A. The characteristic allows the developing fetus to extract oxygen from the mother's blood supply (Powars and Hiti, 1993). After birth, this trait is no longer necessary and the production of the gamma-subunit decreases as the production of the ß-globin subunit increases. The ß-globin subunit replaces the gamma-globin subunit in the hemoglobin tetramer so that eventually adult hemoglobin, HbA, replaces fetal hemoglobin as the primary component red cells.

HbF levels stabilize during the first year of life at less than 1% of the total hemoglobin. In cases of hereditary persistence of fetal hemoglobin, that percentage is much higher. This persistence substantially ameliorates sickle cell disease severity (Personal Communication, Dr. Ken Bridges, April 1996).

Mechanism of Protection

Hemoglobin F Levels and Amelioration of Sickle Cell Disease

Platt et al. (1994) examined predictive factors for life expectancy and risk factors for early death (among Black Americans). In their study, a high level of fetal hemoglobin (>8.6%) augured improved survival. Koshy et al. (1989) reported that fetal hemoglobin levels above 10% were associated with fewer chronic leg ulcers in American children with sickle cell disease.

Other studies, however, suggest that protection from the ravages of sickle cell diesease occurs only with higher levels of HbF. In a comparison of data from Saudi Arabs and information from Jamaicans and Black Americans, Perrine et al. (1978) found that serious complications (i.e. jaundice, splenectomy, hematuria) occurred only 6% to 25% as frequently in Saudi Arabs as North American Blacks. In addition mortality under the age of 15 was 10% as great among Saudi Arabs. Further, these patients experienced no leg ulcers, reticulocyte counts were lower and hemoglobin levels were higher on average.

The average a fetal hemoglobin level in the Saudi patients ranged between 22-26.8%. This is more than twice that reported in studies mentioned above. Kar et al. (1986) compared patients from Orissa State, India to Jamaican patients with sickle cell. These patients also had a more benign course when compared with Jamaican patients. The reported protective level of fetal hemoglobin in this study was on average 16.64%, with a range of 4.6% to 31.5%. Interestingly, ß-globin locus haplotype analysis shows that the Saudi HbS gene and that in India have a common origin (see below).

These studies suggest that the level of fetal hemoglobin that protects against the complications of sickle cell disease depends strongly on the population group in question. Among North American blacks, fetal hemoglobin levels in the 10% range ameliorate disease severity. The higher average level of fetal hemoglobin could contribute to the generally less severe disease in Indians and Arabs.

Fetal hemoglobin levels have correlated with specific clinical complications of sickle cell disease in several studies. Emond et al. (1980) examined fetal hemoglobin levels, priapism and consequent impotence. Priapism is a prolonged painful erection. The problem develops when sickled cells obstruct the drainage of blood from the corpora cavernosa.

Emond et al (1980) characterized two types of priapism. Stuttering episodes of priapism occured in 59% of patients studied while major episodes affected 38%. Stuttering priapism was characterized by multiple attacks of less than three hours duration occuring in bursts two to three times per week for several months. Major episodes were manifested by a single severe attack exceeding 24 hours duration and most often requiring hospitalization. In 10% of the patients, major episodes of priapism produced complete impotence.

Of the patients afflicted by stuttering priapism, 28% subsequently suffered a major attack. The investigators found that patients with less severe stuttering attack also had higher levels of fetal hemoglobin than did those who suffered major attacks. While this study provides some information useful for treatment and prevention, important pieces of information are absent.

Although a table provided hematological indices for the overall patient population, specific information on the group with priapism was lacking. While the sample size of 61 young men who suffered from attacks of priapism was reasonable, the study was based on a questionnaire. All data are retrospective. As with all retrospective analyzes, the completeness of the information is unknown. Also, no way exists to ascertain whether observational bias occurred in the initial recording of the data.

The results of Koshy et al (1989), on the other hand can be accepted greater assurance. Data on patients were collected prospectively. Consequently, patients were observed under study conditions (e.g. patients were at steady-state at the time of blood collection patients were regularly monitored). Unfortunately, this study failed to include patients with sickle cell disease who had not suffered from leg ulcers.

Several studies showed little or no correlation between fetal hemoglobin levels and certain aspects of severity. Seltzer et al. (1992) reported on five black families with abnormally high levels of fetal hemoglobin (19-45% HbF). Of the eight patients observed in this study, two suffered from moderately severe disease. These two patients had HbF levels of 25% and 31%. Two other patients had HbF levels of 19%. One of these patients had mild disease while the other suffered from severe symptoms.

The investigators attributed the variability to uneven distribution of fetal hemoglobin in erythrocytes (mature red blood cells). Other observations generally supported this line of reasoning. Patients who were asymptomatic or virtually asymptomatic patients had HbF in most of their erythrocytes. In contrast, the patients with markedly uneven distributions of HbF tended to be more symptomatic.

The mean level of fetal hemoglobin in the circulation is important. However, the distribution of fetal hemoglobin between the cells is also significant. Heterogeneity of HbF distribution means that some cells will have none of the protective fetal hemoglobin. These cells would be prone to sickling, and could occlude the microcirculation, blocking the flow of cells that normally might have made it across the circulatory narrows. Such a "logjam" would nullify the anti-sickling effect of HbF in the other red cells.

However, even accounting for heterogeneous HbF distribution, not all of the clinical heteroneniety could be explained. For instance, one moderately symptomatic patient had HbF value of 25% and a F cell percentage of 79% (namely, 79% of his red cells contained some fetal hemoglobin). Another patient with mild symptoms had a fetal hemoglobin level of 19% and an F cell percentage of 17%. More than 80% of the patient's cells lacked fetal hemoglobin, despite a high mean fetal hemogloin level. Seltzer et al. concluded that F-cell percentages and fetal hemoglobin levels, while important, are not the only variables that affect disease severity.

Acquaye et al. (1984) studied two groups of patients in western Saudi Arabia totaling seventy-one individuals. One group had HbF levels above 10% and was designated SSHF. The other group had levels of HbF below 10%, and was designated SSLF. Many patients of both groups suffered clinically severe sickle cell disease, including urinary and respiratory tract infections, bone pain or infarcts and severe anemia. Some even had rare complications such as retinal hemorrhages, epistaxis, hepatic crisis, acute chest syndrome, and thrombotic stroke.

No significant difference existed in several "severity factors" in these two groups. These factors included, hemoglobin levels, red cell count, mean cell volume, mean cell hemoglobin, reticulocyte count, and serum bilirubin levels. The only clinically significant difference between the two groups was a higher tendency toward infections and more frequent hepatomegaly in SSLF patients. Like Seltzer et al., these investigators concluded that additional factors to fetal hemoglobin levels modulate the severity of sickle cell disease.

Another study that suggests only a small role at best for fetal hemoglobin as a modifier of sickle cell disease severity was reported by El-Hazmi (1992). The subjects were Saudi Arabs in whom a variety of symptoms associated with sickle cell disease were assessed to form a "severity" index. The author concluded that among his patients , no correlation existed between HbF and the severity index.

However, his analysis has a fundamental flaw. El-Hazmi failed to examine the effect of HbF on each of these symptoms individually. There important information and an association between fetal hemoglobin levels specific disease manifestations could be concealed in his data. However, the study reinforces the conclusion that fetal hemoglobin levels most likely work in conjunction with other moderating factors to determine clinical severity in patients with sickle cell disease.

Alpha-Thalassemia

Embury et al. (1984) examined the effect of concurrent alpha-thalassemia and sickle cell disease. Based on prior studies, they proposed that alpha-thalassemia reduces intraerythrocyte HbS concentration, with a consequent reduction in polymerization of deoxyHbS and hemolysis. They investigated the effect of alpha gene number on properties of sickle erythrocytes important to the hemolytic and rheological consequences of sickle cell disease. Specifically they looked for correlations between the alpha gene number and irreversibly sickled cells, the fraction of red cells with a high hemoglobin concentration (dense cells), and red cells with reduced deformabilty.

The investigators found a direct correlation between the number of alpha-globin genes and each of these indices. A primary effect of alpha-thalassemia was reduction in the fraction of red blood cells (RBCs) that attained a high hemoglobin concentration. These dense cells result from potassium loss due to acquired membrane leaks. The overall deformability of dense RBCs is substantially lower than normal.

This property of alpha-thalassemia was confirmed by comparison of red cells in people with or without 2-gene deletion alpha-thalassemia (and no sickle cell genes). The cells in the nonthalassemic individuals were more dense than those from people with 2-gene deletion alpha-thalassemia. The difference in median red cell density produced by alpha-thalassemia was much greater in patients sickle cell disease.

Reduction in overall hemoglobin concentration due to absent alpha genes is not the only mechanism by which alpha-thalassemia reduces the formation of dense and irreversibly sickled cells. In reviewing the available literature, Embry and Steinburg (1986) suggested that alpha-thalassemia moderates red cell damage by increasing cell membrane redundancy (morphologically seen as target cells). This protect against sickling-induced stretching of the cell membrane. Potassium leakage and cell dehydration would thereby be minimized.

These two papers by Embury et al. give some insight into the moderation of sickle cell disease severity by alpha thalassemia. Some deficiencies exist, nonetheless. The first paper makes no mention of the patient pool. Unspecified are the number of patients used, their ethnicity, or their state of health when blood samples were taken.This information would help establish the statistical reliablility of the data, and its applicability across patient groups. Despite these limitation, the work provides important insight into the mechanisms by which alpha-thalassemia ameliorates sickle cell disease severity.

Ballas et al. (1988) reached different conclusions regarding alpha thalassemia and sickle cell disease than did Embury et al . They reported that decreased red blood cell deformability was associated with reduced clinical severity of sickle cell disease. Patients with more highly deformabile red cells had more frequent crises. They also found that fewer dense cells and irreversible sickle cells correlated inversely with the severity of painful crises. Like Embury et al., Ballas and colleagues found alpha thalassemia was associated with fewer dense red cells.

In addition, Ballas' group found that alpha thalassemia was associated with less severe hemolysis. However they reached no clear conclusion concerning alpha gene number and deformability of RBC except to note that the alpha thalassemia was associated with less red cell dehydration.

The two studies are not completely at odds. Both state that concurrent alpha-thalassemia reduces hemolytic anemia. They agree that this occurs through reduction in the number of dense cells, a number directly related to the fraction of irreversibly sickled cells. Embury et al. conclude that through this mechanism red blood cell deformability is increased.

The investigators diverge, however, on the relationship to clinical severity of dense cells and rigid cells. Ballas et al. assert that both the reduction of dense cells and rigid cells contribute to disease severity. They advance three possible mechanisms. The most interesting holds that the higher the deformability of cells, the greater their adherence to the endothelium lining the blood vessels. Red cell adhesion to endothelial cells is believed to contribute to vaso-occlusion by retarding erythrocytes in the microcirculation sufficiently long for sickling to occur there (Fabry, et al., 1992). Rigid erythrocytes may or may not enter microvasculature. If they do they are less likely to adhere to the endothelium and cause vaso-occlusion or compromise the blood flow. In contrast, deformable cells have a higher probability of entering the microvasculature, adhering to endothelium and causing vaso-occlusion.

Ballas (1991) described a pair of patient groups with sickle cell disease in which the fetal hemoglobin level was less than 15%. The first group had a significantly fewer painful crises and more leg ulcers. However, the mortality in this group was 0%, while the second group had 33% mortality rate. The red cells of the first group were more rigid, and 22% were dense cells. The second group had fewer rigid red cells and about 10% dense cells.

The reports of Ballas et al. (1988) and Embury et al. (1982, 1984 and 1986) agree that concurrent alpha-thalassemia and sickle cell disease produces less severe hemolytic anemia through the action of alpha gene number on HbS concentration, HbS polymer formation, and the frequency of dense cells and ISC. The effect of alpha-thalassemia on other manifestations of sickle cell disease such as painful crises and vaso-occlusion are unresolved.

Hemoglobin Haplotype

The final potential modulator of sickle cell disease now known is haplotype. Of the three modulating factors discussed in this review, the role of sickle cell haplotype is least well characterized.
Figure 1. Restriction Endonuclease Sites in the ß-globin Gene Locus. The ß-globin gene locus or cluster has in series the "ß-like" genes expressed in humans, including those expressed in embryonic (episilon) and fetal (gamma) development. After birth, two "ß-like" genes predominate: beta (98% gene product, hemoglobin A) and delta (about 2% gene product hemoglobin A2). The blue dots indicate the locations of the informative restriction endonuclease sites used in sickle haplotype analysis (the specific restriction enzymes used at each site are not indicated). The pattern of restriction sites for the sickle haplotypes is shown (a "+ " indicates susceptible to restriction enzyme digestion, while a "- " indicates resistance to restriction endonuclease digestion.)

Haplotypes of sickle cell disease can be described as polymorphic restriction endonuclease sites in and around the mutant ß-globin gene (Figure 1 and Powars and Hiti, 1993). Although the haplotypes have numeric identifiers, they are most commonly designated by the geographic areas in which they were first identified (Figures 2 and 3): Senegal, Benin, Central African Republic (or Bantu), Cameroon and Arabo-Indian (or Asian) (Oner, et al., 1992). The haplotypes were identified by investigators working with groups of people in various countries primarily in west Afria (Adekile, et al., 1992). By focusing on people in limited geographic areas, the investigators were able to limit the confusion which would have resulted from investigations in areas with a heterogenous population of patients with sickle cell disease (e.g., the US.)

The Senegal haplotype is represented most prominently in Senegal and in the most westerly regions of Africa above the Niger River. The Benin haplotype designates those found in Nigeria, Benin, and countries in the Bight of Benin. The Bantu or CAR haplotype encompasses those haplotypes discovered in the Central African Republic and countries in south central Africa. The Cameroon haplotype has been found in only one ethnic group in the Cameroons. The Arabo-Indian haplotype usually refers to those haplotypes found in the Persian gulf and India. Sickle cell disease in India has been poorly investigated, relative to that in west Africa and the Middle East. Sickle cell disease is quite prevalent among tribal peoples in India. Unfortunately, the tribal peoples continue to have limited access to health care, in part due to their largely rural location.

The existence of haplotypes specific to certain regions of the world suggests that the mutant ß-globin gene arose separately in these locations (Oner et al., 1992). All of the areas in question are now or have been endemic loactions of malarial infestation. This observation is consistent with the idea that the high incidence of the sickle mutation in these areas derived from natural selection (Carlson, et al.,1994). The mutation that produces sickle hemoglobin occurs spontaneously at a low rate. People with one sickle hemoglobin gene and one normal hemoglobin gene (sickle cell trait) are somewhat more resistant to malaria than people with two normal hemoglobin genes. People with sickle cell trait would have a better chance of surviving an outbreak of malaria and passing their genes (for sickle and normal hemoglobin) to the next generation when they have children.

The independent origin of the sickle mutation opens the possibility that haplotypes could differ in associated sickle cell disease severity. The three most common haplotypes in the Americas are Senegal, Benin, and Bantu/CAR (Hattori et al., 1989)(Powars et al. 1994). In African populations, each is associated with different degrees of disease severity. People with the Senegal haplotype, on average, have the least severe clinical course, while those with the CAR/Bantu haplotype, on average, have the most severe disease. People with the Benin haplotype usually have disease of intermediate severity (Powars et al , 1994).

Sickle cell disease in India and the Persian Gulf region apparently follows a more benign course than it does in Africa and the Americas. The cause of the discrepancy in clinical manifestations is not clear. Leg ulcers are uncommon in India, for instance. In contrast, this complication is frequent in Africa and the Americas (Koshy, et al., Blood 1989). Priapism, which is a debilitating problem for many patients in the Americas, likewise is uncommon in India. In contrast, splenomegaly is common in patients with sickle cell disease in India, while the spleens of most patients in the Americas are small and poorly functional (due to recurrent splenic infarctions). Endemic malaria in much of the Indian subcontinent may account for the splenomegaly. This view is mere supposition, however.

Figure 2. Sickle Hemoglobin Haplotype Distribution in Africa. The three major ß s -globin haplotypes found in Africa are shown. The distributions represent the highest concentrations. The genes are expressed at lower frequency outside the highlighted zones.

Unfortunately, the dearth of data on sickle cell disease in India allows nothing more than educated guesses. Although the mutation is identical in the sixth position of the ß s -globin in both the African and Asian varieties of the sickle cell disease, the surrounding genetic environment of the two probably differ. The expression of a gene not currently recognized as a modifier of sickle cell disease expression, for instance, could differ between the African and Asian varieties of the condition. If we knew more about these "epigenetic" factors, new treatment strategies for severe sickle cell disease might become apparent.

The existence of identical haplotypes in India and in the Persian Gulf region lacks an obvious explanation. Sickle cell disease in India exists mainly in the tribal populations, who to this day remain relatively isolated from the country's mainstream society. The likelihood is low that an influx of a sickle cell gene from outside India occurred to a degree to account for rates of heterozygosity that reach 35% in some tribes. Although current information precludes a conclusive answer, gene flow from from India to the Persia Gulf area through commerce and migration seems the more likely scenario. Interestingly, there are small pockets of sickle genes of the African haplotypes in regions along India's western coast. Sickle cell disease here exists in the decendants of African peoples who came to India during the Moghul period, often as "praetorian" guards for Indian princes.

Figure 3. Sickle Hemoglobin Haplotype Distribution in the Middle East and India. The ß s -globin haplotype found in the Middle East and India are shown. The haplotypes are identical in the two areas. The gene probably originated in India and was carried to the Persian Gulf area by trade and migration. This point is unproven, however.

The mechanism by which haplotypes influence sickle cell disease severity remains a mystery. Individual haplotypes have varying levels of fetal hemoglobin. Patients with the Senegal haplotype often preserve fetal hemoglobin levels of 20% or more. In contrast, patients with the Bantu/Car haplotype generally express the lowest fetal hemoglobin levels. The Benin haplotype is associated with intermediate fetal hemoglobin levels (Powars and Hiti, 1994).

Powars and Hiti (1994) content that a mutation in the 5' promoter region of the fetal globin gene, "G-gamma", maintains the high production of fetal hemoglobin in people with the Senegal haplotype. Economou et al. (1991) earlier reported that variation in hemoglobin F levels was not due to nucleotide substitution in the promoter region of either the "G-gamma" or "A-gamma" fetal globin genes. Irrespective of the cause, the observation remains higher levels of fetal hemoglobin are seen in patients with the Senegal haplotype

Most people native to an area indigenous for a particular haplotype are homozygous for that haplotype. In the Americas, mixing among slave populations left most patients with sickle cell disease heterozygous for the two of the three common haplotypes (Nagel et al, 1991) .

Several investigators have examined the effect of heterozygous sickle haplotype on clinical severity. Nagel et al. (1991) found that the presence of one Senegal haplotype still results in high fetal hemoglobin levels, higher overall hemoglobin levels, lower reticulocyte counts and lower bilirubin levels. In general, patients with at least one Senegal haplotype had milder disease than those who had none.

In a study conducted by Steinburg et al. (1995), Benin/CAR heterozygotes trended toward lower fetal hemoglobin levels as well as greater disease severity, while Senegal/CAR haplotypes tended toward intermediate characteristics with respect to fetal hemoglobin level and disease severity (this observation was made by Nagel et al. as well).

In addition to haplotype, Steinberg et al. examined the effect of at gender in patients with sickle cell disease. Females tended to have higher levels of fetal hemoglobin than did males, irrespective of haplotype. The investigators suggested that the higher level of fetal hemoglobin could reflect hormonal factors that interact with a haplotype-specific DNA gene regulatory region. Another possibility is a relative peristence of HbF related to genes located on the X chromosome. Further insight into this phenomena possibly could be gained by examining post-menopausal patients with sickle cell disease in whom hormonal patterns differ from those of younger women.

Although the mechanism by which haplotype is coupled to disease severity is unknown, a correlation clearly exists. Fetal hemoglobin levels vary generally by haplotype. A correlation appears also to exist between between gender, haplotype and HbF levels. This is a relatively new area of investigation with respect to the variability in sickle cell disease and has not been as fully characterized as alpha-thalassemia and fetal hemoglobin effects. Further investigation could shed additional light on the interplay of haplotypes and disease severity.

Conclusions

The need for disease severity prognosis factors is even greater when bone marrow transplantation is considered as a treatment. Bone marrow transplantation can cure patients with sickle cell disease (Walters et al., 1996). Transplantation, however, carries significant intrinsic risks, including death. Reliable selection criteria for patients most likely to benefit would make transplantation a more attractive treatment alternative for many patients.

Fetal hemoglobin level is constant throughout life (after stabilization during infancy) and is a relatively good predictor of disease severity. Its ability to augur future clinical course is insufficiently fine, however, for use as the sole arbiter for high risk treatments such as bone marrow transplantation.

Concurrent alpha thalassemia also provides some prognostic information about sickle cell disease severity. Alpha thalassemia is a less powerful predictor than is hemoglobin F level, however. Treatment decisions for individuals cannot be made on the basis of this parameter.

Haplotypes provide useful population data. Haplotype analysis has been used by anthropologists to trace the migration of African sickle cell genes into the Mediterranean basin. As a predictor of disease severity, however, haplotype analysis is far tos crude for clinical utility.

Multivariant analysis has been used to enhance the predictive value of independent parameters of disease. By combining several weak predictors, a more compelling set of forecast data often can be generated. The interrelationship between fetal hemoglobin levels and haplotype means that these may not be independent variables in considerations of disease severity. Therefore, multivariant analysis may be of limited utility.

With rare exception, clinical prediction in medicine is at best a chancy matter. In sickle cell disease, the point was made dramatically by Amin et al (1991) who examined many parameters in a monozygotic twin pair living in the same environment. The sickle cell disease severity was strikingly different in the children. No measured parameter differed between the two, however. We must continue to explore the biological basis of sickle cell disease and its severity. We must at the same time remember that we only scratch the surface of nature's complexity.



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