Sickle Cell Treatment: Hydroxyurea, Transfusion, Pregnancy

Sickle cell treatment rests on supportive care that prevents crises and protects the organs: regular check-ups, penicillin prophylaxis and vaccines, generous hydration, blood transfusion or red cell exchange when needed, and hydroxyurea, one of the most widely used drugs, which raises fetal haemoglobin. Pregnancy needs a separate, closely monitored plan. A cure requires a transplant or, in future, gene therapy.

Dr. Sukriti Gupta, Sr. Consultant, BMT, Haematopoietic Stem Cell Transplant, Hematology, Oncology, Paediatric Haemato-Oncology & BMT, Artemis Hospitals, Gurugram, India, describes the goal of initial treatment as avoiding crises and relieving symptoms and complications, through a calculated balance of supportive care and, for the right patients, a definitive approach. This article covers the supportive and drug treatment she uses, her assessment of the newer drugs, and how she manages pregnancy. The complete guide to sickle cell disease explains the disease itself, and the testing article covers diagnosis and stroke screening.

Sickle cell treatment starts with supportive care

Supportive care is the foundation of sickle cell treatment: regular review, infection prevention, hydration and pain relief.

Regular review, even without symptoms

Every child with known sickle cell disease should see a general practitioner or paediatrician every two to three months, Dr. Gupta advises, even when there are no symptoms. These visits are the backbone of everything else: they are where prophylaxis is reinforced, vaccinations checked, transcranial Doppler scans scheduled and early organ damage detected.

Penicillin prophylaxis and vaccination

Because the spleen stops working early in sickle cell disease, children are highly vulnerable to encapsulated bacteria such as Streptococcus pneumoniae. The protective measures are:

• Penicillin prophylaxis, recommended up to five years of age and, in high-risk cases, continued beyond it.
• Routine childhood vaccinations, which should be stressed with every family.
• Additional vaccines: the pneumococcal vaccine and an annual influenza vaccine for all patients with sickle cell disease.

Hydration

Adequate hydration is, in Dr. Gupta's words, a must for every child with sickle cell disease. Dehydration concentrates the blood and promotes sickling, so she recommends a daily fluid intake about 10 to 20% above what is normally required for the child's age and weight.

Pain relief

Painkillers are the first-line treatment for vaso-occlusive pain crises (episodes in which sickled cells block small vessels), given alongside fluids. Frequent crises that need hospital care are a signal that supportive care alone is no longer enough.

Blood transfusion and red cell exchange in sickle cell disease

Transfusion works by dilution. When red cells from a donor without sickle cell disease are given, the proportion of HbS in the patient's blood falls and the proportion of normal haemoglobin rises. That lowers the risk of the complications driven by a high HbS level, above all stroke and painful vaso-occlusive crises.

The choice between simple transfusion and exchange depends on the patient's haemoglobin.

The reason for the exchange is viscosity. Pushing the haemoglobin of a patient with sickle cell disease too high thickens the blood and can itself provoke vessel blockage. In a red cell exchange, an equal volume of the patient's blood is removed as donor red cells are given, so the patient gains healthy red cells without the haemoglobin rising. Like transfusion, it reduces vaso-occlusive crises.

Hydroxyurea for sickle cell disease

Hydroxyurea (also called hydroxycarbamide) is, in Dr. Gupta's description, one of the most commonly used drugs for all patients with sickle cell disease.

How hydroxyurea works

It acts in two ways:

1. It raises fetal haemoglobin (HbF). HbF does not polymerise with HbS, so the more HbF a red cell contains, the less it sickles. Sickling crises fall significantly as the HbF percentage rises.
2. It increases nitric oxide in the blood vessels, which dilates them and helps red cells flow more smoothly.

What to expect

Dr. Gupta's assessment was balanced. Theoretically, hydroxyurea is a very helpful drug. In practice, how much it helps over the long term varies considerably from one patient to another, which is why a patient who continues to have significant symptoms on hydroxyurea should be assessed for a transplant.

When to start hydroxyurea

Asked by a paediatrician from Nigeria at what age hydroxyurea should start, Dr. Gupta replied that it should begin as early as possible after the disease is detected. United States NHLBI guidance recommends offering hydroxyurea to all infants with HbSS from nine months of age, whether or not they have symptoms.

Newer sickle cell drugs: approval, then retreat

None of the newer drugs has displaced hydroxyurea: nitric oxide drugs have not reached the market, and voxelotor and crizanlizumab lost ground after approval. Research into new drugs has followed the biology of sickling closely, and Dr. Gupta reviewed what has and has not reached patients.

Nitric oxide pathways

Depletion of L-arginine, the amino acid from which the body makes nitric oxide, and impaired endothelial nitric oxide synthase both limit the ability of vessels to dilate in sickle cell disease. Drugs that maintain nitric oxide levels have been studied at an experimental level, but none has come to market.

Voxelotor and crizanlizumab

Two drugs reached the market with considerable expectations.

• Voxelotor, an oral drug, inhibits the polymerisation of sickle haemoglobin, which should reduce red cell damage and vessel blockage. It received accelerated approval from the US Food and Drug Administration (FDA) in 2019.
• Crizanlizumab, given intravenously, blocks P-selectin, an adhesion molecule that makes red cells stick to vessel walls and aggregate. It was also approved by the FDA in 2019.

Both looked very useful in early studies. In practical use, Dr. Gupta noted, they fell short. Voxelotor was withdrawn from all markets in 2024 because of safety concerns, and the European marketing authorisation for crizanlizumab was revoked in 2023 after a confirmatory trial did not show benefit. For now, hydroxyurea and transfusion remain the foundation of care.

When supportive care is not enough

Dr. Gupta draws a clear line. When symptoms remain significant despite hydroxyurea and red cell exchange, compromise organ function or leave the patient with a debilitated life, the definitive options should come into play. Specific triggers, including any stroke, repeated acute chest syndrome, transfusion dependence and more than three hospital visits a year for pain, are examined in bone marrow transplant versus gene therapy for sickle cell disease. The question of when to refer is also the focus of Dr. Dharma Choudhary's article on when to refer sickle cell disease for bone marrow transplant.

Sickle cell disease in pregnancy

Sickle cell disease in pregnancy calls for a distinct plan: hydroxyurea can be held, monitoring intensifies in the third trimester, and delivery is planned. Two of the session's questions concerned pregnancy.

Hydroxyurea during pregnancy

A doctor from Zambia asked about hydroxyurea in pregnancy and the alternatives. Women with sickle cell disease who have done well up to childbearing age and conceived usually have less frequent pain crises, Dr. Gupta observed. In these women, hydroxyurea can be held for a while during pregnancy, because it is not a good option for fetal development. In its place she advises:

• better hydration
• avoiding other stressful conditions
• continuing folic acid supplements, which must not stop

UK guidance from the Royal College of Obstetricians and Gynaecologists advises stopping hydroxyurea at least three months before a planned conception, and stopping it as soon as pregnancy is confirmed in a woman who conceives while taking it.

Monitoring in the third trimester

Women with sickle cell disease are monitored much more frequently in the third trimester. Dr. Gupta prefers visits to the gynaecologist twice a month, with close attention to any abnormal blood flow to the baby.

Timing and mode of delivery

Asked about the best mode of delivery given the combined burden of sickle cell pain and labour pain, Dr. Gupta said her team prefers a timely, planned caesarean section, usually electively at 36 to 37 weeks of gestation, to minimise the stress of labour. Steroids (betamethasone or dexamethasone) are given earlier to mature the baby's lungs, so that delivery can be brought forward whenever needed. If blood flow becomes compromised at any point, delivery is planned earlier still.

Practice differs internationally. UK guidance from the Royal College of Obstetricians and Gynaecologists advises offering planned birth, by induction of labour or by caesarean section, between 38 and 40 weeks, and does not regard sickle cell disease alone as a reason for caesarean section. The decision rests with the obstetric and haematology team caring for each woman.

The doctors' full questions on pregnancy, hydroxyurea and sickling tests are in the Live Discussion.