Sickle Cell Disease: Diagnosis, Complications and Management

Sickle cell disease is diagnosed with a peripheral blood smear and confirmed by haemoglobin analysis, ideally after a newborn heel-prick screen. Sickle cell disease complications and management are tightly linked, and care works in layers: preventive care and pain control, disease-modifying treatment with hydroxyurea and transfusion, and cure through stem cell transplant. Because the disease can damage almost every organ, effective management anticipates complications instead of only treating each crisis.

Dr. Divya Doval, Principal Consultant - Haemato Oncology & BMT, BLK-Max Super Speciality Hospital, New Delhi, India, set out this framework for an audience of doctors from across Africa. Her centre transplants patients with benign and malignant blood disorders, and her guidance reflects that vantage point: every acute crisis managed well protects the organs a patient will one day need to be eligible for cure. She is currently Principal Consultant - Haemato Oncology & BMT at the same hospital.

This guide covers the biology, inheritance, diagnosis and full complication profile of the disease, and the treatment ladder in outline. Three companion articles go deeper: managing sickle cell crises and acute emergencies, stroke prevention and chronic organ damage, and hydroxyurea, transfusion and newer therapies.

The history of sickle cell disease in three dates

Dr. Doval framed the history of the disease with three milestones. In 1910 the American physician James Herrick first described sickle-shaped red blood cells. The first stem cell transplant for sickle cell disease was performed in 1984. And hydroxyurea, which she calls "the wonder drug", arrived in 1995. The span between the first description and the first effective drug is a reminder of how long patients lived with nothing more than supportive care, and why the disease still carries a heavy burden where modern management is not consistently available.

What is sickle cell disease?

Sickle cell disease is a group of inherited haemolytic anaemias (conditions in which red cells are destroyed faster than normal) caused by haemoglobin S (HbS). It is a single-gene point mutation: valine replaces glutamic acid at the sixth position of the beta-globin chain. Every clinical problem in the disease traces back to the physical properties of this one abnormal haemoglobin.

Normal red blood cells survive 90 to 120 days in the circulation. Sickle red cells survive only about 15 to 20 days. Dr. Doval stressed that the short lifespan is only part of the problem: it is the shape and the stickiness of the sickled cell that cause it to be destroyed quickly and that cause many of the problems these patients face.

How sickling causes organ damage

HbS does not polymerise under favourable conditions. It polymerises when the cell is stressed: when oxygen saturation falls, in acidosis, dehydration, infection or fever. Once polymerisation starts, a chain of events follows:

• Haemolysis. Cells break down, raising the bilirubin and causing jaundice.
• Abnormal blood flow. Sickled cells become rigid and sticky, flow poorly through small vessels and adhere to the vessel lining (endothelium).
• Vasoconstriction. Nitric oxide availability falls, so vessels constrict.
• Tissue ischaemia. Together these starve tissue of oxygen, in repeated cycles of ischaemia and reperfusion.

Those cycles are what produce pain crises and end-organ damage: acute chest syndrome in the lungs, strokes in the brain, pulmonary hypertension, eye disease and skin ulcers. Asked during the discussion what "stress" means as a trigger, Dr. Doval was practical: fever is a stress, dehydration is a stress, and so is any hypoxic condition, such as being at high altitude where oxygen levels are lower.

How sickle cell disease is inherited

Sickle cell disease follows autosomal recessive inheritance: a child develops the disease only by inheriting the sickle gene from both parents. When both parents are carriers, each pregnancy carries:

• a 25% chance of a child with sickle cell disease;
• a 25% chance of a completely unaffected child;
• a 50% chance of a child who is a carrier, like the parents.

This is why consanguineous marriage matters. When partners are related, the chance that both carry the same gene is considerably higher because the gene may run in the family, and a carrier couple faces that one-in-four risk with every pregnancy. Dr. Doval made the point directly in the discussion: consanguinity raises the risk of autosomal recessive diseases such as sickle cell disease.

Why sickle cell disease is common in Africa

Sickle cell disease occurs worldwide, but its incidence and prevalence are highest in sub-Saharan Africa and the Caribbean. It also affects Latin America, the Mediterranean countries, the Middle East and the Indian subcontinent.

Asked why Africa is so heavily affected, Dr. Doval's answer was genetic: the geographical distribution reflects gene pools. Populations in certain regions carry the mutation more often, so they are more likely to carry the gene and to have children with the disease.

DNA analysis identifies distinct sickle haplotypes, which matter clinically. Four are prevalent in Africa, by region: Senegal, Benin, Bantu and Cameroon. In India and the Arabian Peninsula, the Arab-Indian haplotype predominates, and disease with this haplotype tends to be milder because these patients have higher levels of fetal haemoglobin (HbF), which protects against sickling.

Sickle cell trait vs sickle cell disease

People with sickle cell trait are carriers. HbS makes up approximately 40% of their haemoglobin, and their lifespan is normal. Dr. Doval noted a few situations where problems can arise: complications such as splenic infarction at high altitude, and a higher risk of renal medullary carcinoma, a rare kidney cancer associated with sickle cell trait whose prognosis is poor.

When a question in the discussion asked why sickle cell disease is "not a disease", she clarified that it was the trait she had described that way. Sickle cell disease itself has a whole spectrum of severity. Some patients have few manifestations for long periods, but once pain crises and other complications begin, the condition must be treated as a disease.

Other genotypes that cause sickling

Sickling complications are not limited to the homozygous HbSS state (sickle cell anaemia). HbS co-inherited with other abnormal haemoglobins also causes disease:

• HbSC disease;
• HbS beta-thalassaemia;
• HbS with HbO-Arab;
• HbS with HbD-Punjab.

Co-inherited alpha-globin gene deletions also shape the clinical picture. This variety is why laboratory confirmation of the exact genotype matters for management.

How sickle cell disease is diagnosed

Sickle cell disease is diagnosed with a peripheral blood smear and a sickle solubility screen, then confirmed by haemoglobin analysis with HPLC, isoelectric focusing or gel electrophoresis. Each test has a defined role.

Dr. Doval described the peripheral smear as very important in diagnosis. The solubility test is a useful screen, but because a positive result occurs in both carriers and patients, a confirmatory haemoglobin analysis is always needed.

To distinguish the different sickle cell phenotypes from sickle cell trait, clinicians combine six parameters: clinical severity, HbS percentage, HbA percentage, total haemoglobin, mean corpuscular volume (MCV, the average red cell size) and the reticulocyte count (a measure of new red cell production).

Newborn screening

Dr. Doval called neonatal screening very important for early diagnosis and for reducing the morbidity and mortality of the disease. A single spot of blood is taken from a heel prick at birth. This is a screening test only: if sickle cell disease is suspected, a confirmatory test is required. Early diagnosis allows penicillin prophylaxis, vaccination and family education to start before the first serious infection or crisis, which matters because the spleen loses its function in the first years of life.

Sickle cell disease complications, organ by organ

Sickle cell disease is defined by its complications. Dr. Doval walked through them from head to toe, dividing them into acute and chronic.

The acute emergencies, including pain crisis, acute chest syndrome, splenic sequestration, aplastic crisis and priapism, are covered in the companion guide to managing sickle cell crises. Stroke, silent cerebral infarcts and long-term damage to the kidneys, liver, eyes and bones are covered in the companion guide to stroke prevention and chronic organ damage.

Chronic jaundice

Many patients live with a persistently raised bilirubin. Dr. Doval explained that this jaundice reflects ongoing red cell breakdown, and that it does not in itself harm most patients. There is no specific treatment for the jaundice; hydroxyurea can reduce the underlying haemolysis. Persistent jaundice should still be investigated, however: hepatitis B and C and other infective causes need to be excluded before it is attributed to haemolysis alone.

Sickle cell disease management: four layers of care

Dr. Doval organises the management of sickle cell disease into four layers.

1. General medical care. Pneumococcal vaccination every 5 years, influenza vaccination every year and hepatitis A and B vaccination; an annual eye examination for retinopathy; attention to nutrition; and blood pressure control, because conventional vascular risk factors add to stroke risk.
2. Pain management, acute and chronic, together with screening for and managing every acute and chronic complication.
3. Disease-modifying therapy. Transfusion, hydroxyurea, L-glutamine, crizanlizumab and voxelotor, each with a defined place and, for the newer agents, important caveats.
4. Curative therapy. Haematopoietic stem cell transplant is the established cure; gene therapy is the newer option.

Hydroxyurea is the backbone of disease-modifying care. It raises fetal haemoglobin, reduces pain and chest crises, and cuts transfusion needs and hospital admissions. Its indications, dosing, monitoring and the newer drugs are covered in the companion guide to hydroxyurea, transfusion and newer therapies, together with transfusion thresholds, iron overload monitoring and pregnancy.

Hydration is first-line care

Asked what role hydration plays, Dr. Doval's answer was unequivocal: it is immense. Any patient who is about to have, or is having, a pain crisis benefits greatly from hydration. She added that, to her knowledge, there are no particular medications that people with sickle cell disease must specifically avoid.

Stem cell transplant and the case for cure

For Dr. Doval, the logic of management leads towards transplant. Medical management of sickle cell disease is an ongoing process, one complication after another. Even with careful care, silent cerebral infarcts accumulate and gradually erode cognitive function, a toll that is not obvious while the child is young. A stem cell transplant is a one-time treatment, and the cure is for life.

Her centre's threshold for recommending transplant in children is now low: a single episode of stroke, a single episode of acute chest syndrome, or repeated pain crises requiring hospital admission. Matched sibling transplants in published registry data achieve 5-year overall survival of 95% in children under 16, and Dr. Doval reported overall survival of 70% to 80% with half-matched (haploidentical) transplants. There is no upper age limit, but outcomes are best when transplant is done young, before strokes and liver and kidney damage reduce eligibility.

The transplant pathway is the subject of other Jivo haematology masterclasses. Dr. Dharma Choudhary's guide covers sickle cell transplant outcomes and how a transplant works, and Dr. Vikas Dua's covers bone marrow transplant for sickle cell anaemia, including donor registries for patients from Africa. Dr. Sukriti Gupta's guide follows sickle cell disease from screening to cure.

The questions doctors raised during the session, from transplant cost to urine alkalinisation and sickle cell disease in pregnancy, are answered in full on the Live Discussion page.