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Why don't individuals with sickle cell trait suffer from sickle cell anemia?

Why don't individuals with sickle cell trait suffer from sickle cell anemia?


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Ostensibly, in people with sickle cell trait, half of the hemoglobin in their body would be defective.

Is it actually the case that sickle cell hemoglobin is produced in equal amounts? If not, how is that regulated? If so, how does that still not cause anemia?


This could be a very long answer, but I'll try to keep it brief.

The first thing to understand is what causes the anaemia. I'm going to refer to defective haemoglobin found in a sickle cell patient as HbS and normal haemoglobin as HbA. Under certain circumstances (low O2 concentrations) the HbS protein is prone to aggregating into long filaments. Here is an image of a lysed erythrocyte releasing some of these filaments.

The presence of these filaments in the erythrocytes causes them to become misshapen (sickle-shaped) and this in turn causes them to get filtered out for destruction in the spleen which is continuously monitoring for defective erythrocytes (which could cause blockages in the circulation). This causes the anaemia (specifically a haemolytic anaemia, due to erythrocyte destruction, and nothing to do with a lack of iron).

The appearance of the ability to form filaments is due to a single Glu>Val mutation in the two β subunits of the haemoglobin tetramer. The new amino acid can fit into a pre-existing hydrophobic pocket on the surface of another subunit and so the molecules can daisy-chain to form the filaments.

The normal HbA can also bind on to a growing filament (it has the binding pocket) but that terminates the filament (because HbA doesn't have the Val residue). In this way people with sickle cell trait are protected from the anaemia by their normal haemoglobin.


How sickle-cell carriers fend off malaria

The elusive mechanism by which people carrying the gene for sickle-cell disease are protected from malaria has finally been identified. This could point to a treatment for malaria.

People develop sickle-cell disease, a condition in which the red blood cells are abnormally shaped, if they inherit two faulty copies of the gene for the oxygen-carrying protein haemoglobin. The faulty gene persists because even carrying one copy of it confers some resistance to malaria.

Now Miguel Soares and Ana Ferreira of the Gulbenkian Institute of Science in Oeiras, Portugal, and colleagues have discovered how mice that have been genetically modified to carry one version of the faulty gene are protected from malaria.

Their results show that the gene does not protect against infection by the malaria parasite, as was previously thought. Instead, it prevents the disease taking hold after the animal has been infected.

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Soares’s team found that haem – a component of haemoglobin – is present in a free form in the blood of mice with one faulty haemoglobin gene, but largely absent from normal mice. To find out whether this helped guard against malaria, the team injected haem into the blood of normal mice before infecting them with malaria. The mice did not develop the disease.


Sickle Cell Trait vs. Sickle Cell Disease

Millions of people worldwide are affected by the sickle cell blood disorder. About 100,000 people in the U.S. have sickle cell disease. It mostly affects African Americans, but it can also affect people from Hispanic, southern European, Middle Eastern and Asian Indian backgrounds.

Another 2.5 million people in the U.S. have sickle cell trait (SCT). But having sickle cell trait (SCT) is not the same as having sickle cell disease (SCD).

What is the difference between having sickle cell trait and sickle cell disease? Read on to find out—and learn the next steps to take if you or someone in your family is diagnosed with these conditions.

Sickle Cell Disease

People with sickle cell disease have red blood cells that are crescent (or sickle) shaped. This abnormal shape makes it difficult for the cells to travel through the blood vessels. As the sickle cells clog the blood vessel, they can block blood flow to various parts of the body, causing painful episodes (known as sickle cell crises) and raise the risk of infection. In addition, sickle cells die earlier than healthy cells, causing a contant shortage of red blood cells, also known as anemia.

SCD is diagnosed by a blood test. There are many forms of sickle cell disease, including sickle cell anemia, which is the most common and also the most severe. With all forms of SCD, symptoms can vary and severity from one person to another, but include serious pain, fatigue, shortness of breath, and dizziness.

People with SCD are at a higher risk for health complications such as infections, stroke, eye damage, and acute chest syndrome, a condition that causes chest pain, trouble breathing, fever, and coughing. It’s important that people with the condition work with their healthcare provider to manage their symptoms.

Currently, there is no widely available cure for sickle cell disease, but sickle cell research efforts are underway, including pain management and gene therapy. In late 2019, two new treatments were approved by the FDA to treat the condition.

Sickle Cell Trait

When someone has sickle cell trait (SCT), it means they have inherited one sickle cell gene and one normal gene. People with SCT have both normal red blood cells and some sickle-shaped red blood cells. Most people with SCT do not have any symptoms of sickle cell disease.

As carriers of the sickle cell gene, though, parents have a 50% chance of passing the gene on to their children. That means people with sickle cell trait can be at risk of having a child with SCT or SCD.


Reducing Health Care Disparities in Sickle Cell Disease: A Review

Sickle cell disease (SCD) is an inherited blood disorder most common among African American and Hispanic American persons. The disease can cause substantial, long-term, and costly health problems, including infections, stroke, and kidney failure, many of which can reduce life expectancy. Disparities in receiving health care among African Americans and other racial/ethnic minority groups in the United States are well known and directly related to poor outcomes associated with SCD. As an orphan disease-one that affects <200 000 persons nationwide-SCD does not receive the research funding and pharmaceutical investment directed to other orphan diseases. For example, cystic fibrosis affects fewer than half the number of persons but receives 3.5 times the funding from the National Institutes of Health and 440 times the funding from national foundations. In this review, we discuss the health inequities affecting persons with SCD, describe programs intended to improve their care, and identify actions that could be taken to further reduce these inequities, improve care, control treatment costs, and ease the burden of disease.

Keywords: Medicaid access to care community health centers health care disparities sickle cell disease.

Conflict of interest statement

Declaration of Conflicting Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Medical writing and editorial support were provided by Arjun Menon, PhD, Healthcare Consultancy Group, which was funded by Global Blood Therapeutics, Inc, South San Francisco, California.


Incidence of Sickle Cell Trait in the US

Although the occurrence of sickle cell trait (SCT) varies greatly from state-to-state and among different races and ethnicities, every state and racial/ethnic population includes people living with the condition and many are unaware of their personal sickle cell status. Because people with SCT are at risk of having a child with sickle cell disease if their partner also has SCT or one of several other abnormal hemoglobin genes, it is important to properly inform them of their status and educate them about possible health problems and reproductive considerations.

About this Study

To obtain up-to-date measures of the occurrence of SCT among newborns by race/ethnicity and state of birth, researchers from CDC examined data collected by newborn screening programs in 2010. On December 12, 2014, CDC published the results of this research study in the Morbidity and Mortality Weekly Report (MMWR). Key findings from this report are highlighted below and we invite you to read the abstract here.

Main Findings from this Study

  • In 2010, the total U.S. incidence estimate for sickle cell trait was 15.5 cases per 1,000 births, ranging from 0.8 cases per 1,000 births in Montana to 34.1 cases per 1,000 births in Mississippi.
  • The U.S. incidence estimate for sickle cell trait (based on information provided by 13 states) was 73.1 cases per 1,000 black newborns, 3.0 cases per 1,000 white newborns, and 2.2 cases per 1,000 Asian or Pacific Islander newborns. The incidence estimate for Hispanic ethnicity (within 13 states) was 6.9 cases per 1,000 Hispanic newborns.
  • The total number of babies born with sickle cell trait in 2010 was estimated to be greater than 60,000.
  • The incidence of sickle cell trait varies greatly from state-to-state and among different races and ethnicities however every state and racial/ethnic population has people living with the condition.

When a person has inherited the sickle hemoglobin gene from one parent and the gene for normal hemoglobin from their other parent, they have sickle cell trait (SCT). Their red blood cells make both normal and sickle hemoglobin. Hemoglobin (HEE-muh-glow-bin) is a protein in red blood cells which carries oxygen from the lungs to the rest of the body. People with SCT don&rsquot have sickle cell disease, and in most situations, they have no problems with how their red blood cells work. However, people with SCT can have children with sickle cell disease. To learn more about SCT and how it can lead to sickle cell disease (SCD) in the family, please visit the sickle cell trait section of our website.

What is Sickle Cell Disease (SCD)

People are born with SCD. It is an inherited life-long disease that can run in families. People with SCD inherited the gene (the instructions in the cell for making sickle hemoglobin) from both of their parents their red blood cells can make only sickle hemoglobin so they have SCD. SCD causes the red blood cells to change their shape from the usual donut shape to a C-shape. When the red blood cells are shaped like a donut, they can bounce off the walls of blood vessels like bumper cars, and they can squeeze through tiny blood vessels. However, when red blood cells are C-shaped, they get caught on the walls of tiny blood vessels, and stick to one another forming clumps inside the blood vessels. These clumps can cause severe pain and other serious problems, such as infections, organ damage, and blood vessels clogged with sickle cells in the lungs, called &ldquoacute chest syndrome.&rdquo

Critical Gaps & Future Directions

This study shows that as many as 1.5% of babies born in the United States have SCT. Based on previous studies, there are no standardized methods or protocols for alerting families or healthcare providers to this information, educating them about the potential health outcomes that might be associated with the condition, or counseling them about the impact that this might have on the family&rsquos future reproductive choices. By including educational materials and providing genetic counseling at the same time that families are given positive SCT results, the occurrence and public health burden of SCD might be reduced.


Complications and Treatments of Sickle Cell Disease

People with sickle cell disease (SCD) start to have signs of the disease during the first year of life, usually around 5 months of age. Symptoms and complications of SCD are different for each person and can range from mild to severe.

The reason that infants don&rsquot show symptoms at birth is because baby or fetal hemoglobin protects the red blood cells from sickling. When the infant is around 4 to 5 months of age, the baby or fetal hemoglobin is replaced by sickle hemoglobin and the cells begin to sickle.

SCD is a disease that worsens over time. Treatments are available that can prevent complications and lengthen the lives of those who have this condition. These treatment options can be different for each person depending on the symptoms and severity.

Hydroxyurea (pronounced hye droks ee yoor EE a) is a medicine that can decrease several complications of SCD. This treatment is very safe when given by medical specialists experienced in caring for patients with SCD. However, the side effects of taking hydroxyurea during pregnancy or for a long time are not completely known. The Food and Drug Administration has also approved a new medicine to reduce the number of sickle cell crises in adults and children older than age five it is called Endari (L-glutamine oral powder). Another treatment, which can actually cure SCD, is a stem cell transplant (also called a bone marrow transplant) this procedure infuses healthy cells, called stem cells, into the body to replace damaged or diseased bone marrow (bone marrow is the center of the bone where blood cells are made). Although transplants of bone marrow or blood from healthy donors are increasingly being used to successfully cure SCD, they require a matched donor (a person with similar, compatible bone marrow), and transplants can sometimes cause severe side effects, including occasional life-threatening illness or death. People with SCD and their families should ask their doctors about the benefits and risks of each treatment option.

Hand-Foot Syndrome

Swelling in the hands and feet usually is the first symptom of SCD. This swelling, often along with a fever, is caused by the sickle cells getting stuck in the blood vessels and blocking the flow of blood in and out of the hands and feet.

Treatment

The most common treatments for swelling in the hands and the feet are pain medicine and an increase in fluids, such as water.


Types - Sickle Cell Disease

People who have sickle cell disease have abnormal hemoglobin, called hemoglobin S or sickle hemoglobin, in their red blood cells . Hemoglobin is a protein in red blood cells that carries oxygen throughout the body. People who have sickle cell disease inherit two abnormal hemoglobin genes , one from each parent.

The types of sickle cell disease include the following:

  • Hemoglobin Sβ0 thalassemia
  • Hemoglobin Sβ+ thalassemia
  • Hemoglobin SC
  • Hemoglobin SD
  • Hemoglobin SE
  • Hemoglobin SS

In all types of sickle cell disease, at least one of the two abnormal genes causes a person’s body to make hemoglobin S. When a person has two hemoglobin S genes (hemoglobin SS), the disease is called sickle cell anemia. This is the most common and often most severe type of sickle cell disease. Hemoglobin SC disease and hemoglobin Sβ thalassemia are two other common types of sickle cell disease. Hemoglobin SD and hemoglobin SE are much less common.


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It was making this connection — that people with sickle cell trait can suffer from oxygen deprivation in some situations — that sparked the idea for the study now underway at Atlanta’s Grady Memorial Hospital. “Extreme, low oxygen conditions, like those at higher altitudes or during scuba diving, can trigger extreme pain, microinfarctions (tiny strokes), and even death in some people with sickle cell disease. Covid may be one of those triggering conditions,” said Deneen Vojta, a former pediatrician and executive vice president of global research and development at UnitedHealth Group who helped design the $600,000 study, which is being conducted by physicians at the Morehouse School of Medicine and funded by UnitedHealth, a managed health care and insurance company.

It is still not known whether patients with sickle cell disease fare worse when they contract Covid-19, though there are strong reasons to believe they would. Flu pandemics, for example, have led to higher death rates in patients with sickle cell disease. The Medical College of Wisconsin has created a national registry to track infected sickle cell patients, and while the data are not conclusive, they so far suggest having sickle cell disease may lead to worse outcomes and a higher risk of death. The average age of the 307 patients in the database is 25, and 16 of them, or 5%, have died. One in five has had a severe or critical case of Covid-19.

The case is less clear in patients with sickle cell trait, making the new Morehouse study of interest, said Kim Smith-Whitley, a pediatrician and hematologist who directs the Comprehensive Sickle Cell Center at Children’s Hospital of Philadelphia. “This could be really valuable,” she said.

Vojta, familiar with sickle cell disease from her training in hematology, said she saw many similarities between sickle cell and Covid. She noticed early on that X-rays of Covid-infected lungs resemble those of sickle cell patients with acute chest syndrome, a severe complication caused when sickling blocks oxygen flow in lungs. And many complications, like clotting and strokes, are common to both diseases.

“I thought, ‘Ding, ding, ding, doesn’t this sound familiar,’” Vojta said. Covid infections have triggered acute chest syndrome in some sickle cell patients.

The study is being co-led by Herman Taylor, a cardiologist who directs the cardiovascular research institute at Morehouse and was the longtime director of the Jackson Heart Study, which helped tease out why heart disease disproportionately kills African Americans. Taylor is now interested in finding out exactly why Black Americans who contract the coronavirus are dying at twice the rate of white people.


Having children

If you carry the sickle cell trait, you're at risk of having children with sickle cell disease, although this can only happen if your partner is also a carrier or has sickle cell disease themselves.

If you're planning to have a child and you know you're a carrier, it's a good idea for your partner to be tested.

If you and your partner both carry sickle cell, there's a:

  • 1 in 4 chance each child you have will not have sickle cell disease or be a carrier
  • 1 in 2 chance each child you have will be a carrier, but will not have sickle cell disease
  • 1 in 4 chance each child you have will be born with sickle cell disease

If both of you are carriers and you're planning to have a baby, talk to your GP about getting a referral to a genetic counsellor, who can explain the risks to your children and what your options are.

  • having tests during pregnancy to see if your baby will have sickle cell disease
  • adopting a child
  • trying IVF with a donor egg or sperm
  • trying pre-implantation genetic diagnosis (PGD)

PGD is similar to IVF, but the resulting embryos are tested to check that they do not have sickle cell disease before they're implanted in the womb.

The Human Fertilisation and Embryology Authority (HFEA) has more information about PGD.


Sickle-cell mystery solved

Researchers discover how carriers of the sickle-cell anaemia gene are protected from malaria.

It has been a medical mystery for 67 years, ever since the British geneticist Anthony Allison established that carriers of one mutated copy of the gene that causes sickle-cell anaemia are protected from malaria 1 . The finding wasn’t trivial: in equatorial Africa, where Allison did his work, up to 40% of people are carriers of this mutated gene. Since then, scientific sleuths have wondered how exactly the gene protects them.

With a paper published today in Science 2 , the answer — or a large part of it — seems to be at hand.

Michael Lanzer and his colleagues at Heidelberg University in Germany and the Biomedical Research Center Pietro Annigoni in Ouagadougou, Burkina Faso, used powerful electron microscopy techniques to compare healthy red blood cells both with 'normal' cells infected with the malaria parasite Plasmodium falciparum and with infected cells from people carrying the mutated “S” gene that causes sickle-cell disease, as well as another mutation, dubbed “C,” which occurs at the same spot. Both mutations lead to the substitution of a single amino acid in the hemoglobin molecule, causing the haemoglobin to aggregate abnormally inside the cell. In people with two copies of the S mutation, they deform into a half-moon shape — the 'sickle cells' that give the disease its name..

The researchers saw that in healthy red cells, very short pieces of actin filament — threads of protein crucial to maintaining the pliable internal 'skeleton' that lets the red blood cell squeeze through tiny blood vessels — are clustered just under the cell's outer membrane. But in infected cells, they observed that the malaria parasite steals this actin and uses it to construct an intracellular bridge to transport a parasite-made protein to the cell surface. This protein, called adhesin, makes the infected red blood cells 'sticky', causing them to adhere to each other and to the vessel wall to cause the widespread microvascular inflammation characteristic of malaria.

Evolution to the rescue

The parasite doesn't get everything its own way, however. Enter the sickle-cell factor. In red blood cells containing the aberrant sickle-cell haemoglobin, Lanzer and his team observed that the hijacking of actin filaments by the parasite was hobbled. The actin bridge was cut off from the intracellular depot of adhesin, and the vesicles that would normally transport the adhesin to the cell surface were floating free in the cytoplasm.

Further experiments led the team to hypothesize that ferryl haemoglobin, produced when the mutant haemoglobin reacts with oxygen, subverts the parasites’ efforts to reorganize their host cells' actin by preventing the actin proteins polymerizing to form long filaments.

The take-home message, says Lanzer, “is that the parasite, in order to survive within the red blood cell, has to remodel the host actin — and that evolutionary pressure has resulted in mutations in human haemoglobin that prevent this remodelling.” People who carry just one mutated copy of the sickle-cell gene still make enough normal haemoglobin and so are largely asymptomatic. So being a carrier confers a survival advantage in countries where malaria is endemic.

The finding is a big breakthrough, says David Sullivan, an associate professor at the Johns Hopkins Malaria Research Institute in Baltimore, Maryland. “This was a holy grail in the hunt for the pathogenesis of malaria.”

Sullivan notes that other recent work 3,4 has established that adhesin-containing 'knobs' on the surface of parasite-infected cells are abnormal in number and distribution when the cells have the mutated haemoglobin, and that the 'stickiness' of infected cells is diminished accordingly. “This kind of nails how that might happen,” he says.

Rick Fairhurst, a malaria expert at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, and an author on both of those papers, says the new study takes the work “a huge step forward". He says that Lanzer, with his “absolutely fabulous” images, “clearly beat us to the next step”.

In the meantime, Lanzer says, a logical next step will be to try to identify the factors in the parasite that allow it to coopt the host cell’s actin for its own ends. “If we can identify them,” he says, “one can envision developing inhibitors. But it is a very long shot.”