Sickle Cell Anemia

What is Sickle Cell Anemia?

Sickle cell disease (SCD) is a group of disorders that impact the blood’s hemoglobin – that’s the part of the blood that carries oxygen. These disorders happen because of changes or mutations in the genes responsible for hemoglobin. It was first recognized around the late 1800s, but it was not until the early 1900s that doctors actually noticed the unusually ‘sickle-shaped’ red blood cells that give the condition its name.

Researchers like Dr. James V Neel and Col. E. A. Beet in 1949 started to understand how the disease is passed down in families. In that same year, Dr. Linus Pauling described the disease on a molecular level. A few years later, in 1956, Vernon Ingram showed the specific chemical alteration that was causing the sickle shape.

There are several types of sickle cell disease, including sickle cell anemia, hemoglobin SC disease, and hemoglobin sickle-beta-thalassemia. There are also other minor variations of the disease and the sickle cell trait, which doesn’t usually show symptoms. Sickle cell anemia, characterized by a lifelong condition of anemia that often causes painful episodes and damages organs, is the most common version of SCD.

Since the discovery of this disease over a century ago, science has greatly expanded our understanding of it. In the past thirty years, we’ve seen significant progress in patient treatment, particularly in wealthier countries. In 1984, older treatments were enhanced by using hydroxyurea to boost hemoglobin levels. Today’s treatment options continue to evolve to include new drugs and the cutting-edge gene therapy.

What Causes Sickle Cell Anemia?

Hemoglobin is a crucial protein found in red blood cells. It is made up of four parts, two from a type called alpha-globin (found on chromosome 16) and two from a type called beta-globin (found on chromosome 11). There are many kinds of hemoglobin. In adults who don’t have blood disorders, the three most common types are:

* HbA1- It is composed of two alpha-globin chains and two beta-globin chains. This type makes up 95% of an adult’s total hemoglobin.
* HbA2- It is made up of two alpha-globin chains and two delta-globin chains. This type accounts for less than 4% of an adult’s total hemoglobin.
* HbF- It contains two alpha-globin chains and two gamma-globin chains. This type is more common in unborn babies, as its high oxygen-binding ability helps them extract oxygen from the mother’s bloodstream.

Sickle cell disease happens due to a mutation. Instead of having a negatively-charged glutamate at a specific spot in the beta-globin chain, there’s a neutral valine. This genetic change follows regular inheritance patterns. It’s possible to have two copies of the mutation, leading to the most severe form of sickle cell disease (SCA or HBSS disease). If someone has one copy of a sickle cell mutation and one copy of a beta-thalassemia mutation, they end up with a disease that behaves like HBSS disease, known as HBS-Beta-0 disease.

If you inherit one copy of the mutation, you will have Hemoglobin AS (HbAS). Most people with HbAS don’t show any typical symptoms of SCA, so they are usually not considered within the range of sickle cell disease. Doctors typically discover their HbAS status during childbirth, blood donation, or screening procedures.

There are other versions of sickle cell disease that happen because someone inherits one copy of the sickle cell mutation and one copy of a different mutation. The next most common version, after SCA, is the HbSC disease. This happens when one sickle cell mutation and one hemoglobin C mutation are inherited together. Hemoglobin C is formed when lysine replaces glutamine at the same specific spot on the beta-globin chain where the sickle cell mutation occurs. In the United States, HbSC disease is found in 30% of people who have a form of sickle cell disease.

Risk Factors and Frequency for Sickle Cell Anemia

Sickle Cell Disease (SCD) and its variant HbAS are prevalent in sub-Saharan Africa, with carriers of HbAS being naturally protected against severe malaria. In 2010, an estimated 230,000 babies were born with Sickle Cell Anemia (SCA), and more than 3.5 million were born with HbAS in this region. In fact, around 75% of all births with SCD are in sub-Saharan Africa, with West Africa hosting the largest population of those with another variant known as HbSC.

In the United States, an estimated 100,000 Americans have SCD, according to the Center for Disease Control (CDC). One in every 13 babies born to African-American parents have the sickle cell trait, and one in every 365 African-Americans have SCD. Hispanic Americans have a lower prevalence with an estimate of 1 in 16,300. About 40% of all SCD patients in the US are children and teenagers. These rates can vary by state and change due to migration and immigration, affecting the prevalence of SCD and HbAS. Similar patterns are found in many countries, including Brazil, which attributes the origin of their SCD and SCA patients to the West African slave trade. Projections estimate a rise in these figures with over 400,000 newborns predicted to have SCA annually by 2050 due to technological advancements and increased migration.

The care and outcomes for individuals with SCD or SCA also vary significantly between high-income and low-income countries. High-income countries have seen a substantial decrease in child mortality due to vaccination and screening (around a 68% drop from 1999 to 2002 compared to 1983 to 1986). However, in sub-Saharan Africa, about 50 to 90% of children born with SCD die before turning five. Although better care in high-income countries and focused training of healthcare providers have improved life expectancy, there is still a gap when compared with non-SCD individuals (54 years versus 76 years respectively).

Lastly, in the US, HbSC disease, a milder variant of SCD, affects 30% of all patients with SCD. Much like HbAS, most individuals with the Hb C trait (a heterozygous mutation) will live symptom-free for much of their lives. However, severe symptoms can arise with HbSC.

Signs and Symptoms of Sickle Cell Anemia

People with the sickle cell disease variant HbSS don’t usually experience the hallmark ‘sickle cell crises’ immediately after birth. This is because fetal hemoglobin (HbF) keeps oxygen levels in the tissue adequate, and it takes about 6-9 months for infants to lose this. However, not all sickle cell anemias are the same, and there are many forms of the disease that can exist together or as a spectrum.

There are several different subtypes of sickle cell disease:

• The vaso-occlusive subtype, which has higher levels of red blood cells (hematocrit) and can cause frequent vaso-occlusive crises and acute chest syndrome due to increased blood thickness.
• The hemolysis and vascular subtype, which has lower hematocrit but higher levels of lactate dehydrogenase (LDH) and bilirubin in the blood. This suggests more breakdown of red blood cells and severe anemia. This subtype also carries a higher risk of gallstones, high blood pressure in the lungs (pulmonary hypertension), strokes caused by lack of blood flow (ischemic stroke), priapism, and kidney disease (nephropathy).

Severe anemia can strain the heart and increase blood flow to organs, which can lead to damage. Certain individuals with sickle cell disease also have different pain sensitivities due to changes in their nervous system.

Those with sickle cell disease often end up dealing with short-term (acute) or long-term (chronic) complications. The most common acute complication is a vaso-occlusive crisis (VOC). Management strategies for these issues are discussed in the treatment section.

When taking the history of patients with sickle cell disease, doctors should take note of the following:

• All patients will go through VOCs at some point in their lives; the earliest sign is inflammation of fingers or toes (dactylitis) in babies as young as six months.
• VOCs can affect any part of the body but often affect the extremities and the chest.
• Understanding how the patient has been managing their pain, including details about their last crisis, how often they’ve been hospitalized due to pain, and their regular use of painkillers, is important.
• The doctor should know whether the patient has been taking medications that alter the course of the disease (like hydroxyurea, voxelotor, and crizanlizumab).
• Information on any substance misuse, mental health conditions, and the use of psychiatric medications is needed.
• If the patient has had blood or exchange transfusions, this will help assess the risk of iron overload and the presence of alloantibodies.
• Any history of other health problems, surgeries, or life-threatening crises should be discussed.

The physical examination should determine if the patient needs oxygen, pain management, or a blood transfusion. However, doctors should also pay attention to specific signs that might point to problems with particular organs. For example, a rapidly enlarging liver or spleen can be a sign of a sequestration crisis.

Testing for Sickle Cell Anemia

Patients with Sickle Cell Anemia (SCA) usually get their diagnosis during their childhood through a newborn screening program. These programs can detect this condition early on, particularly in developed countries. In the United States, such a screening for SCA is done universally and was implemented in all states by the year 2007. The screening methods include high-performance liquid chromatography and isoelectric focusing. However, in Europe, the screening is targeted and only done in areas where SCA is prevalent. Compared to sub-Saharan Africa, where no countries have adopted a screening program, India uses a solubility test as the first step of the screening process. If it’s positive, high-performance liquid chromatography is then used to confirm it at a reference center.

People with SCA can experience several complications. Some of these come on suddenly (acute) and others are ongoing (chronic). Acute ones include:

1. Acute Chest Syndrome (ACS): This is the most common complication and also the main cause of death and hospital admissions. Symptoms include sudden cough and shortness of breath. Fever might be present, suggesting an infection. A chest X-ray showing new lung infiltration helps define ACS.

2. Sequestration Crises: This presents as sudden liver or spleen enlargement with stretching of the capsule.

3. Stroke: This is a severe complication of SCA characterized by a severe headache, altered mental status, slurred speech, seizures, and paralysis.

4. Aplastic crises: This is usually triggered by parvovirus B-19 and causes severe fatigue, anemia, shortness of breath, and even fainting.

5. Acute intrahepatic cholestasis: This causes sudden right upper quadrant pain and an enlarging, tender liver.

6. Infections can occur in people with SCA and are usually from Streptococcus pneumoniae or osteomyelitis.

Some ongoing or chronic complications include iron overload due to repeated transfusions and chronic hemolysis, Avascular Necrosis (AVN) of joints, especially the hip joint, leg ulcers, Pulmonary Artery Hypertension (PAH), and chronic kidney disease (CKD).

Eye complications are common in people with Sickle Cell Anemia, e.g., Hyphema, where blood accumulates in the front chamber of the eye due to blunt trauma, and Central Retinal Artery Occlusion, where a clot forms in the retinal artery, damaging the retina. There’s also orbital infarction, where inflammation surrounds bone structures causing pain, and orbital compression syndrome. You can also have chronic complications, such as visual loss due to long-term high eye pressure, as well as kidney disease, blood clots in your lungs, and more.

Discussing these symptoms with your healthcare provider can help you manage them effectively. Treatment and care for Sickle Cell Anemia can help improve the quality of life for those affected by this condition.

Treatment Options for Sickle Cell Anemia

Patients with sickle cell anemia (SCA) can face both sudden and long-term complications.

Sudden Complications

The pain that comes with SCA needs to be managed early, ideally within half an hour of diagnosis. It’s essential to create long-term strategies for handling each person’s unique pain situation. Bouts of sudden pain are typically handled with a variety of drugs, including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. There’s concern about high opioid use, but it’s usually necessary for severe pain control. Chronic itching from opioids can be managed with antihistamines. Along with medication, patients should do deep-breathing exercises using a device, stay hydrated, and take extra oxygen if needed.

Sudden chest discomfort is a medical emergency. Patients need to be admitted to the hospital, be given antibiotics, and extra oxygen for best outcomes. They should regularly be checked for worsening signs, like breathing trouble and low blood oxygen levels. Patients with large amounts of blood in their abdomen or spleen might need a procedure called a splenectomy.

Stroke is also a risk for SCA patients. It needs urgent consultation from neurologists and transfusion medicine doctors to provide optimum care and prevent long-term damage.

Nosebleeds can potentially be a symptom of parvovirus infection, which might cause a temporary drop in hemoglobin levels. These patients should receive blood transfusion to keep their blood level safe. Patients should also be given antibiotics promptly when they have a fever.

The unwanted long-lasting erection males sometimes experience, called priapism, and eye damage in SCA patients should include consultation with urologists and ophthalmologists.

Long term Complications

SCA patients need to focus on the safe use of medications for chronic pain, especially opioids. Assessments of the patients’ conditions and consultations with various specialists like psychiatrists and social workers can help choose the right pain medicine and dosage.

Damaged joint tissue, especially in the hip, needs early treatment, like physical therapy, to manage the condition. Advanced cases might require a total hip replacement. Open sores on the skin, leg ulcers, receive wound care treatment and regular evaluation to track healing and prevent an infection.

Patients with mild to severe lung disease are referred to lung specialists for proper treatment. Kidney damage in SCA patients is assessed and monitored closely by kidney specialists, and they may recommend certain drugs.

Regular eye examinations can help catch slow vision changes in SCA patients. Eye specialists can recommend a variety of treatments that can help stop or slow down the loss of vision. The buildup of iron in the body resulting from blood transfusion, called iron overload, can be prevented or lessened with proper transfusion techniques.

Overall, blood transfusions can increase the blood’s ability to carry oxygen and decrease the levels of sickle hemoglobin, but they should be done judiciously, considering possible complications like reaction to the transfusion and iron overload.

What else can Sickle Cell Anemia be?

Globin gene mutations are quite common and affect 7% of the global population, leading to over 1000 types of hemoglobin. However, only a few of these variations are medically significant.

There are several variations of Sickle Cell Anemia (SCA) or HbSS Disease. These include:

• Hemoglobin S-beta-0 thalassemia, which behaves exactly like HbSS disease
• Hemoglobin SC, a milder form of Sickle Cell Disease (SCD) that can present with symptoms similar to sickle cell anemia
• Hemoglobin S-beta+ thalassemia, another milder version of SCD

Several other types of hemoglobin can mimic Sickle Cell Anemia if they are inherited along with HbS. These include:

• Hemoglobin Jamaica-Plain
• Hemoglobin Quebec-Chori
• Hemoglobin D-Punjab
• Hemoglobin O-Arab
• Hemoglobin E

Lastly, there are various conditions that might appear to involve the destruction of red blood cells (a process called hemolysis) like Sickle Cell Anemia, but can be differentiated based on the patient’s history, an exam, hemoglobin tests, and a study of a blood sample from the patient.

This list includes:

• Antibody-driven autoimmune hemolytic anemia
• Other types of hemoglobin diseases such as alpha or beta-thalassemia
• Paroxysmal nocturnal hemoglobinuria
• Red blood cell membrane defects
• Enzyme defects
• Drug-induced hemolysis
• Transfusion-related hemolysis
• Microangiopathic hemolytic anemia
• Infectious causes
• Vasculitis-induced hemolysis

What to expect with Sickle Cell Anemia

While examining survival rates in patients with Sickle Cell Anemia (SCA), many studies don’t include the potential impact of newly developed medications. A study conducted from 1978-88 revealed that the median age of death for women and men with SCA was 42 and 48 years respectively. The same study identified that suffering from an acute chest syndrome, kidney failure, seizures, high white blood cell count, and low levels of fetal hemoglobin increased the likelihood of an early death in patients with SCA.

More recent studies have highlighted other risk factors that contribute to an early death in patients with SCA. These include high velocity of blood flow in the heart’s tricuspid valve, prolonged heart electric activity intervals, high blood pressure in the arteries to your lungs, elevated levels of a heart disease indicator protein, a history of severe asthma, a history of severe kidney disease requiring dialysis, and severe red blood cell destruction.

A more recent study combined data from nine studies in Europe and North America, involving 3257 patients. They found that the following factors predicted early death:

• Increase in age (per 10-year increase)
• High velocity of blood flow through the heart’s tricuspid valve (2.5 m/s or more)
• A high count of young red blood cells
• Elevated levels of a specific heart disease indicator protein
• Presence of fetal hemoglobin

However, with the approval of new medicines and increased use of bone marrow transplants in recent years, along with ongoing investigation in gene therapy, it is likely that the survival rates and quality of life for SCA patients will continue to improve.

Possible Complications When Diagnosed with Sickle Cell Anemia

Sickle cell anemia (SCA) can cause both immediate (acute) and long-term (chronic) health issues.

Acute complications are often related to blocking of small to medium, and sometimes larger, blood vessels due to changes and breakdown of the sickle hemoglobin (HbS). Some of these include:

• Acute chest syndrome
• Sequestration crises: this may affect the liver or spleen
• Fat embolism: when fat particles enter the bloodstream
• Bone death or damage
• Coagulopathy: a condition that can increase the risk of clots in arteries and veins, leading to stroke or heart attack
• Eye issues: these can involve vitreous hemorrhage, retinal detachment, or blockages in the retina’s arteries or veins
• Decreased creation of new blood cells: this may happen in relation with a parvovirus infection
• Papillary necrosis: damage to kidney tissue

Chronic complications affect patients over a longer period of time and can disrupt growth and development. These complications include:

• Heart issues: enlarged heart, cardiomyopathy, left ventricular hypertrophy, abnormal heart rhythm, heart failure
• Lung problems: fluid in the lungs, sickle cell lung disease, high blood pressure in the lungs
• Liver and gallbladder problems: enlarged liver, cholestasis, gallstones, viral hepatitis
• Spleen issues: enlarged spleen, decreased or lack of spleen function
• Kidney issues: acute and chronic kidney failure, kidney infection, a particular type of kidney cancer
• Musculoskeletal issues: joint damage, bone infection, septic arthritis, necrosis of the bone, low bone density
• Nervous system problems: aneurysm, intellectual disability
• Eye issues: changes to the retina, vitreous hemorrhage, retinal detachment
• Endocrine problems: testosterone deficiency, pituitary gland dysfunction, hypothalamic dysfunction

SCA patients may also experience iron overload due to repeated blood transfusions and chronic breakdown of red blood cells.

Preventing Sickle Cell Anemia

SCA, or sickle cell anemia, is a tough illness that not only affects the body, but can also have a strong emotional and mental impact. People with SCA sometimes face negative judgement, often wrongly accused of being drug seekers because they require higher amounts of pain relieving medications than usual. Moreover, they often deal with different healthcare providers which can lead to inconsistent treatment. In circumstances like these, it’s important for these individuals to advocate for their own health. Here are some tips that might help.

Firstly, aim to be consistent with your medical appointments and regularly visit your health provider. This helps to strengthen trust within the healthcare system. Secondly, when discussing your needs for pain medications, be honest and open-minded with your healthcare provider. They may seem cautious when prescribing pain medications such as opioids, but they’re actually trying to safeguard you from overdosing.

Try to visit the same emergency room, or at least an ER within the same hospital system. This can aid in forming a bond with the emergency healthcare staff and provide easy retrieval of your personal care plan assembled by your provider for such situations. Following your prescribed treatment will aid in reducing painful episodes and preventing damage to organs in the long run.

Be open to alternative methods of managing pain, like music therapy, self-hypnosis, and deep muscle relaxation. Additionally, take measures to protect yourself – keep yourself cozy, avoid extreme temperatures, stay hydrated and practice breathing exercises.