Sickle Cell Disease: Symptoms, Diagnosis and Treatment

Sickle cell disease is the most common inherited red blood cell disorder, which happens due to a genetic defect in the haemoglobin gene. This defect causes the shape of red blood cells to change from a normal round shape to a sickle shape. These sickle-shaped red blood cells are rigid and sticky. Thus, they get stuck in the small blood vessels of our body, where they get destroyed, thereby leading to a reduction of haemoglobin or anaemia. When both beta haemoglobin genes have the sickle mutation, it is called sickle cell anaemia (SCA).

Since it is a genetic disorder, its occurrence varies from region to region. Its occurrence is high in Sub-Saharan Africa, in the Middle East, in Mediterranean countries, and the central part of India. 

In fact, among South Asian countries, the highest number of patients is found in India itself, with about 40,000 newborns being born in India with sickle cell anaemia every year.

Sickle Cell Disease Symptoms

The symptoms of sickle cell disease usually start after six months of age. Symptoms vary with the severity of the genetic defect in the haemoglobin gene, which in turn varies with the geographical region or ethnicity to which the patient belongs. Generally, sickle cell variants in Africa are considered to be severe compared to milder variants in some of the Indian population. Common triggers include dehydration, reduction in oxygen saturation, oxidative stress, and acute illness leading to a reduction in the pH of blood (acidosis). These factors cause the polymerisation of less soluble sickle haemoglobin in RBCs, causing a change in the shape of RBCs to sickle-shaped (half-moon-shaped). This phenomenon is called 'sickling '.

Symptoms are dependent on the amount of sickle haemoglobin in the blood. 

Major types of acute symptoms seen in sickle cell disease are as follows:

• Anaemia: This happens due to the destruction of abnormally shaped sickle red blood cells, leading to a fall in haemoglobin and jaundice. In certain chronic cases, this chronic destruction of RBCs may lead to gall bladder stones due to the accumulation of waste products of haemoglobin in the bile fluid of the gall bladder.

• Vaso-occlusive/Pain crisis: This refers to frequent episodes of pain due to the occlusion of small blood vessels with less flexible sickle cells. This leads to pain; and infarction/ischemic damage to the organ involved by compromising. Pain crisis can affect any part of the body, but most commonly, it affects hands and feet (called dactylitis), causing pain and swelling of fingers and toes.

• Infections: Frequent fever due to infections; most commonly, infections affect lungs, bones and blood-stream. The spleen is an abdominal organ of our body which is rich in a network of small blood vessels. Sickle cells, owing to their shape, are not able to pass freely through these vessels, and get stuck, causing a compromise in the blood supply of the spleen. The spleen acts as a reservoir of immune cells in our body, and thus slow destruction of the spleen due to vascular occlusion leads to immune system deficiency, making the body prone to certain bacterial infections.

• Stroke: Due to the blockade of blood vessels of the brain, there is a risk of brain damage or stroke in certain severe cases. Signs of a stroke include seizures, weakness or numbness of the arms and legs, sudden speech difficulties, and loss of consciousness.

• Acute Chest Syndrome (ACS): It is the most common cause of death in patients with SCD. ACS presents with cough or breathlessness with or without fever. Fever may indicate pneumonia (infection).

Apart from the above acute complications, patients with SCA can have some chronic complications as well:

• Iron overload: Due to repeated blood transfusions in anaemia, iron may get accumulated in certain organs like the heart, lungs, and hormonal glands, affecting their function.

• Avascular necrosis of joints: The capillaries of bones, most commonly the hip joint, get occluded by sickle RBCs leading to bone death. It is a common cause of pain and disability in SCA.

• Leg ulcers: Mostly affects ankles. Severe anaemia, infections, and trauma increase the risk.

• Pulmonary artery hypertension: It is multifactorial, and presenting symptoms include breathlessness on exertion and swelling in the legs.

• Chronic kidney disease: This affects 30% of adult patients with SCA. It is caused by slow damage to the kidneys due to repeated obstruction of blood vessels in the kidneys with sickle RBCs.

• Sickle retinopathy: Repeated occlusion of retinal vessels of the eye causes the formation of new blood vessels and bleeding from fragile new blood vessels.

Sickle Cell Disease Diagnosis

Diagnosis is suspected in children based on symptoms and family history. The diagnosis is confirmed by doing simple blood tests like Complete blood count (normocytic normochromic anaemia), peripheral smear, which may reveal sickle-shaped cells, and High-pressure liquid chromatography (HPLC), which detects the abnormal sickle haemoglobin. In high-income countries, SCA patients are identified with the help of intensive newborn screening tests.

Sickle Cell Disease Treatment

Hematopoeitic stem cell transplant: The only cure for SCD can be provided by replacement of the genetic defect in the stem cells, and this can be achieved either through hematopoietic stem cell transplant (HSCT), also called bone marrow transplant (BMT) or through gene therapy.

Gene therapy is in the experimental stages and is not yet available in India. And thus, in India, the usual curative option is BMT. The results of BMT in sickle cell anaemia have been refined with time, and the cure rates are high, approaching 80 - 90%, irrespective of the availability of matched donors.

Patients not undergoing BMT continue on supportive care to manage pain crises and infections:

• General supportive measures: Oxygen supplementation in hypoxic patients and adequate hydration are crucial aspects of managing acute complications in SCA. This prevents further sickling of RBCs, thus relieving symptoms.

• Analgesics: To manage painful crises, patients are admitted and given oral or intravenous painkillers, like NSAIDS, initially. Often, patients with severe pain need the administration of opioid analgesics with dose titration under supervision.

• Antibiotics: Every fever in SCA is an emergency due to underlying immune deficiency (due to splenic damage) and should be promptly treated with IV antibiotics.

• Blood transfusion: Simple or exchange blood transfusion is indicated in cases of anaemia and acute complications like ACS or stroke. It acts by reducing the percentage of sickle haemoglobin in the blood.

• Hydroxyurea: It is an oral drug which increases the quantity of fetal haemoglobin in the blood, thus reducing the relative quantity of sickle haemoglobin. It helps to reduce the frequency of complications in SCA. All infants >9 months of age, children and adolescents, should be offered hydroxyurea. The clinical response may take 3 to 6 months. Regular monitoring of blood counts is important during hydroxyurea administration.

• Newer drugs: Voxelotor, an oral drug given daily, and Crizanlizumab, an injectable drug given every four weeks, have shown clinical benefits in trials. However, due to prohibitive cost, and difficult availability, these drugs are not routinely being used in India.

• Also, antibiotics prophylaxis (like Penicillin) and vaccination (especially pneumococcal, meningococcal, and H. influenza vaccines) should be given to these patients to reduce the frequency of life-threatening bacterial infections.

In patients with sickle cell disease, if there is pain, fever, cough, breathing difficulty, sudden weakness or numbness, you should immediately consult your haematologist to prevent life-threatening complications. For the prevention of acute complications, patients with SCA should ensure adequate hydration. Every patient with sickle cell anaemia should be vaccinated and should be on antibiotics for the prevention of infections. In case of frequent or severe symptoms, BMT is indicated for a long-term cure.