Pathophysiology

Haemoglobin S (HbS) is biochemically unstable and relatively insoluble. When deoxygenated, HbS polymerizes, damaging the erythrocyte and causing it to lose cations and water. The resulting polymer aligns into bundles, causing distortion of the red blood cells (RBCs) into a crescent or sickle shape, decreasing their half-life, and reducing flexibility and deformability. This impairs passage of the cells through narrow blood vessels. This results in vaso-occlusion and haemolytic anaemia, two characteristic features of SCA. Homozygous cells begin to sickle at much higher oxygen saturation, typically 85% (PaO ₂ 5.2–6.5 kPa) than heterozygous cells at 40% (PaO ₂ 3.2–4.0 kPa). Sickling with sickle cell trait is therefore rarely a problem without concomitant stasis and patients with sickle cell trait usually have no clinical consequences.

Traditionally, it was thought that a trigger such as hypoxia led to sickling which precipitates further flow impairment, stasis and acidosis leading to a ‘vicious cycle’ of further sickling ending in ischaemia, infarction, and end organ damage. Stress, hypothermia, alcohol abuse and dehydration are some other states which favour stasis and promote sickling. However, it has now been shown that several other pathological and interrelated processes simultaneously occur. These include vascular-endothelial dysfunction, functional nitric oxide deficiency, inflammation, oxidative stress, reperfusion injury, hypercoagulability, increased neutrophil adhesiveness and platelet activation. Any one of a variety of possible factors may cause endothelial activation leading to vaso-occlusion and sickling may occur as a secondary event rather than the initial trigger.

Infection remains a significant cause of morbidity and mortality, in particular bacterial infection. Those with SCA have a higher preponderance for infection due to splenic dysfunction, ischaemic environment created because of SCA, impaired phagocytic function of macrophages and cytokine release.

There is a high degree of clinical heterogeneity amongst patients with similar haemoglobin genotypes. The precipitants of SCA do not have uniform effects, the occurrence of vaso-occlusive episodes is unpredictable, the rate of haemolysis is variable, and the frequency of chronic complications is not always easy to explain.

Diagnosis

The diagnosis of SCA can take place in multiple settings including prenatally, newborn screening, testing of symptomatic individuals and incidental findings. Prenatally, diagnosis can be made from DNA obtained via chorionic villus sampling or amniocentesis. Heel prick testing is routinely carried out in the UK as part of the NHS neonatal blood spot-screening programme. Of note, testing may be unreliable in extreme prematurity or following blood transfusion. The sickledex test may be used as a rapid screening tool to identify the presence of HbS, however, it is unable to distinguish between sickle cell trait (HbAS) and SCA (HbSS). Haemoglobin analysis by electrophoresis remains the standard practice and DNA testing is the gold standard where there is uncertainty about the diagnosis. Other findings in SCD include: presence of crescent shaped cells on a peripheral blood smear, high mean cell volume and a low folate level.

Clinical features

The clinical features of SCA and the relevant investigations are highlighted in Table 1 .

See Table 1 . A significant number of these features are seen with the severe or homozygous form of the disease.

General principles

A haematologist at a specialist centre should follow up all patients with SCD regularly. General advice is to educate patients, together with parents where necessary, regarding avoidance of activities that may lead to dehydration, stress, exposure to extreme temperatures, exhaustion as well as the harmful effects of smoking and alcohol. Additionally, palpation for splenic size to encourage early presentation of splenic sequestration crisis has been suggested to be of benefit.

Routine blood tests are important to establish baseline values, which may be abnormal. Folate and vitamin D levels should be checked as supplementation may be required. Infection prevention is of vital importance. Oral penicillin prophylaxis is started at the time of diagnosis. All infants are prescribed and started on penicillin prophylaxis from 3 months to prevent an overwhelming pneumococcal infection. Routine childhood vaccinations including protection against Haemophilus influenza type B, Streptococcus pneumoniae , Neisseria meningitides, hepatitis B and seasonal influenza are given. From the age of two, unconjugated pneumococcal vaccination is needed, and malaria prophylaxis must also be considered when appropriate. There is an increased susceptibility to infections by encapsulated bacteria and as such, fever in a patient with SCA should be urgently assessed by a medical professional, cultures performed, and appropriate antibiotics started.

Pharmacotherapy, transfusion, haematopoietic stem cell transplant and gene editing treatment

Pharmacotherapy: hydroxycarbamide (hydroxyurea – HU) is currently one of the two oral agents approved for pharmacological treatment of SCA. This should be offered as base treatment for all eligible patients with SCD. Hydroxyurea is discussed and offered to all infants with Hb SS/HbAS from 9 months regardless of clinical severity to reduce sickle cell complications. This includes pain, dactylitis, anaemia and acute chest syndrome (ACS). It also reduces mortality in older children and adults. There is growing evidence that HU may prevent chronic organ damage in children with HbSS and preserve organ function in adults. This includes renal/splenic and retinopathy. It inhibits ribonucleotide reductase, which leads to inhibition of DNA synthesis, reduced cellular adhesion, vaso-occlusion, improved blood flow, and cellular cytotoxicity. It causes increased foetal haemoglobin (HbF) production thus, the overall effect is to dilute the concentration of HbS. The effects of HU on Hb F level can vary partly due to genetic variation. It is given as a once daily dose (15–35 mg/kg/day). The major side effect is myelosuppression, which must be monitored for. Other side effects include weight gain, hyperpigmentation, and azoospermia. Erythropoietin (EPO) has also been used alongside HU for management of anaemia.

Voxelotor is an oral agent recently approved by National Institute of Health and Care Excellence (NICE), UK in May 2024 for the treatment of haemolytic anaemia due to SCD in both adults and children above the age of 12 years. This can be used as monotherapy or in combination with Hydroxyurea. Voxelotor (Oxybryta) is a HbS polymerization inhibitor. It increases affinity of haemoglobin for oxygen and inhibits RBC sickling and improves deformability and stabilises the RBC. It is administered orally as a 1500 mg standard dose daily. The Haemoglobin Oxygen Affinity Modulation to Inhibit Hb S Polymerization (HOPE) study trial demonstrated an increase in haemoglobin levels (>1 g/dl) from baseline in patients with SCD. Other agents that have been utilized in patients with SCD include L-Glutamine (neutralises oxidative stress in SCD in patients >5 years of age) that was shown to decrease vaso-occlusive events by nearly 45% but is not used in the UK, and Crizanlizumab (an IgG2 monoclonal antibody) that decreased vaso-occlusive events but was only utilized in a small number of patients, was expensive, and not considered superior to a placebo, and was withdrawn by European Medicines Agency Committee for Medicinal Products for Human Use in 2023.

Transfusion: primary stroke prevention is addressed by annual transcranial doppler ultrasonography for all patients between two and 16 years of age. If there is concern then this is generally treated with blood transfusion, which could be a simple top up or an exchange transfusion where blood from the affected individual is taken and replaced by blood from a healthy donor. The aim of blood transfusion in SCA is to decrease the concentration of HbS to <30% and therefore reducing the amount of circulating sickled haemoglobin. Blood transfusion can be used in SCA for both therapy and prophylaxis. Prophylactically, it is given to children at risk of first stroke, in twin pregnancy or pregnancy with history of medical obstetric and foetal complications, and before high-risk cardio-thoracic, neurological, or abdominal surgery. Transfusion is readily used during sequestration crises, in multi-organ failure and in severe sepsis. During acute painful crisis anaemia should not be routinely treated with blood transfusion unless there is a haemoglobin drop greater than 2 g/dl or organ damage is worsening. For emergency surgery, the haemoglobin level, urgency, and complexity of procedure needs to be considered before transfusion. As a simple rule, transfusion can be given if Hb is <9 g/dl with the aim of achieving a haemoglobin of 10 g/dl. If simple transfusion (top up) is needed, patients with SCA must be given ABO-compatible, extended Rh- and Kell matched units. In all cases, the risks and benefits of blood transfusion must be carefully considered. Multiple transfusions in these patients can pose complications with alloimmunization, iron overload and limit the availability of appropriately cross matched blood. The red cell genotyping programme using DNA is currently looking at better matching of blood. This will help inform decisions on transfusion for patients living with inherited anaemias including sickle cell disease.

Haematopoietic stem cell transplant: haematopoietic stem cell transplantation (HSCT) is potentially curative treatment for SCD. HSCT is offered to all children and adults who have a human leukocyte antigen-matched sibling donor and meet the transplant criteria. In more severe disease in children, matched unrelated donor and haploidentical transplant is considered when a matched sibling donor is unavailable. There is currently an ongoing randomized controlled trial in adult patients looking at effectiveness of haploidentical transplant in patients with severe disease without a matched related donor.

Gene editing treatment: gene therapy technique using strands of DNA from stem cells to compensate for the affected individuals malfunctioning genes have now been approved by the US Food and Drug Administration and Medicines Healthcare Regulatory Agency representing the first cell-based gene therapies that is available for the treatment of sickle cell disease in patients greater than 12 years of age. This is the Casgevy Gene Editing Technique. The gene therapy technology can either increase production of HbF using Gene Editing CRISP-R technology or produce a modified HbA using lentiviral vector gene insertion technology that has a protective effect and prevents sickling.

Preoperative preparation

A multidisciplinary team (MDT) approach involving the anaesthetist, haematologist and surgeon is essential during the peri-operative period. Where possible, these procedures should only be carried out in centres where exchange transfusion is a possibility. Patients with SCA should have a detailed pre-operative assessment by a senior member of the anaesthetic team with focus on history and examination to assess disease severity. A variety of investigations are likely to be indicated depending on the type of surgery and end organ damage. These investigations include but are not limited to full blood count, renal function tests including electrolytes, baseline oxygen saturations, overnight sleep study if there is suspicion of sleep apnoea, an echocardiogram if there is suspicion of pulmonary hypertension or heart failure and a transcranial Doppler in children under 16 who have not had it performed in the last 12 months. A group and screen for antibody and a cross – match is essential for all patients. The need for preoperative transfusion should be discussed with an experienced haematologist. Pain management plans should be discussed with the patient and pain team preoperatively, with a multimodal approach likely to be most appropriate and effective. Venous access may prove to be difficult and central line may be necessary. Starvation time must be minimized, and preoperative hydration encouraged with oral and/or intravenous fluids as necessary. Prolonged starvation time in sickle cell patients is a common error in clinical practice. These patients should ideally be first on the operating list where possible and cancellations due to administrative reasons should be kept to a minimum especially if these patients have received a transfusion beforehand. A documented MDT care plan detailing various aspects of perioperative management is useful for high-risk surgery.

Intraoperative care

Meticulous attention must be paid to the avoidance of triggers that may lead to crisis with emphasis on maintaining good hydration, avoiding hypoxia, replacing blood loss, temperature monitoring to avoid hypothermia with use of active warming (noting that a spike in temperature could be an early sign of sickling) and preventing acidosis. Careful patient positioning intraoperatively should be maintained to reduce venous stasis and although arterial tourniquets are not absolutely contraindicated their use should be minimized whenever possible. If a tourniquet is required, then the patient’s oxygen levels, and acid base balance should be kept as normal as possible throughout and the limb should be exsanguinated before use of the tourniquet. Antibiotics should be used for surgical prophylaxis and aseptic techniques during invasive procedures to minimize the risk of infection are mandatory. Anaesthetic agents, sedatives, analgesics, and neuromuscular blockade along with anti-emetics should be titrated depending on the renal function of the individual. The choice of regional versus general anaesthetic depends on many considerations such as age, patient preference and type of surgery. Regional techniques may provide certain advantages such as excellent postoperative analgesia and increased blood flow to peripheries. Hypotension and hypoperfusion during an anaesthetic should be treated with vasopressors as necessary. Cell salvage is a relative contraindication in SCA but has been used in sickle cell trait.

Postoperative care

There should be a low threshold for admission to a critical care unit if necessary. Maintaining oxygen saturation greater than 95% (administering oxygen if necessary), effective pain relief, early mobilization, hydration, and thromboprophylaxis are essential strategies in the postoperative period. Patients with increased risk factors such as prolonged immobility or previous VTE should be discussed with a haematologist. Incentive spirometry and physiotherapy should be utilized if necessary for optimizing pulmonary outcomes. Cannulas or lines present should be inspected regularly for signs of thrombophlebitis. Close communication between all clinical teams is essential throughout the perioperative period.

Prognosis

The prognosis of those with SCD varies greatly. The current life expectancy of a person with SCA is around 60 years of age in a high-income country whilst in low-and-middle income countries, most children die before reaching adulthood. Better screening programmes, antibiotic prophylaxis, vaccination, and healthcare infrastructure contribute to this health disparity. Despite advances in management strategies, survival of those with SCA lags those unaffected and furthermore the quality of life is often poor due to chronic disease processes.

Pain

Many episodes of acute pain in SCD are managed in the community. Acute pain is caused by vaso-occlusion and resulting tissue ischaemia and inflammation. Detailed assessment is important to distinguish this from other sources of somatic and visceral pain. Use of appropriate terminology is necessary as patients and their relatives are likely to have significant experience in recognizing and managing their pain. Each step of the analgesic ladder should be followed, but it is important to bear in mind that those patients who present to hospital are likely to require intravenous opioids. Intravenous morphine (or fentanyl/oxycodone for those with renal impairment) is an appropriate choice but if repeated doses are required, patient-controlled analgesia (PCA) will be needed together with early referral to acute pain services. Attention should be paid to breakthrough pain, hydration status and potential side effects of opioids.

Acute chest syndrome

The acute chest syndrome (ACS) remains a leading cause of morbidity and mortality. It is defined as “an acute illness characterized by fever and/or respiratory symptoms, accompanied by a new pulmonary infiltrate on chest X-ray.” Severe hypoxia is a useful predictor of severity and outcome. The clinical features may be hard to distinguish and in many cases the patients present with a painful vaso-occlusive crisis and the acute chest syndrome develops within 24–72 hours. Abdominal surgery and caesarean section seem to be the common risk factors for ACS. Equally, it can also occur in the postoperative period. Early involvement of the critical care team to assess the need for respiratory support is vital. Appropriate pain relief, ventilator support to improve oxygenation, exchange transfusion, treatment of infection and thromboprophylaxis forms the mainstay of treatment.

Blood transfusion and hyperhaemolysis

There are both significant benefits and risks for blood transfusion in patients with SCD. These should be discussed with the MDT and ideally a plan should be made prior to the patient attending for surgery. The benefits include lower concentrations of HbS, increased oxygen carrying capacity and increased haemoglobin. The risks of transfusion include but are not limited to hyper-viscosity, sickling due to over transfusion, iron overload from repeated transfusion, infections and antibody formation resulting in haemolytic reactions.

Hyperhaemolysis syndrome is a rare type of haemolytic transfusion reaction that is most often seen in patients with SCA. Here, the posttransfusion haemoglobin levels are lower than the pretransfusion levels. This is due to the recognition of foreign surface antigens on transfused RBCs by antibodies produced by the recipient (alloimmunization). These patients are advised to carry a transfusion card which highlights information about their previous transfusions and antibodies. In patients who have had adverse reactions to blood transfusions previously, an MDT approach should be taken to optimize their haemoglobin pre-operatively. Erythroid-stimulating agents and HU can be used to increase Hb and reduce the chance of sickling in the perioperative period. Pre-treatment with intravenous immunoglobulins, and steroids or rituximab needs to be considered in these patients to prevent haemolytic transfusion reaction.

Pregnancy

Risks to both mother and fetus are significantly increased in SCD and as such preconceptual assessment and counselling should be performed whenever possible. The patient’s partner should be offered screening tests by 8–10 weeks to determine the risk to future offspring and subsequent genetic counselling. Hydroxyurea is usually stopped in preparation for pregnancy and conception. However, in an individual case with severe disease and no other alternative available, hydroxyurea may need to be continued in pregnancy. This will need to be shared decision making with the patient leading on this decision. Voxelotor and iron chelators should be discontinued. It is also wise to ensure that the patient’s immunisations are up to date.

High-risk women, those with severe disease or twin pregnancy should be considered and offered transfusion in pregnancy. The TAPS2 feasibility trial is the first randomized control trial looking at serial prophylactic exchange blood transfusion in pregnant women living with sickle cell disease. This proof-of-concept feasibility study has shown a trend towards lower incidence of vaso-occlusive crisis, preterm delivery, and improved birthweight in the regular transfusion arm.

Antenatally, pregnant women with SCD should be managed with an MDT approach in a specialist centre by a joint obstetric and haematology team. At the initial booking visit, folic acid, penicillin V prophylaxis, vitamin D and aspirin should be prescribed. Aspirin 75–150 mg daily is given from 12 to 36 weeks of gestation to reduce risk of pre-eclampsia. Women with SCD start thromboprophylaxis from 28 weeks until 6 weeks postpartum, however in some women this may be earlier if additional risk factors are present. Serial fetal growth scans commence from 24 weeks of gestation. If not done prenatally, assessment for evidence of end organ damage should be sought through blood tests (full blood count, electrolytes, liver function, ferritin, folate), and urinary protein to creatinine ratio should be completed. A baseline echocardiography, retinal screening, oxygen saturations to look for chronic lung disease and assess hips for avascular necrosis which may affect labour position. In women with high ferritin levels, MRI Iron assessment should be considered to assess and quantify liver and cardiac iron loading. Patient education is vitally important, as severe anaemia, urinary tract infections, vaso-occlusive crises and transfusion risks are more common in pregnancy. Hyperemesis during the first trimester can trigger dehydration and crises and needs to be dealt with aggressively. Finally, it is vital that blood samples including red cell genotyping are taken early at booking visit to ensure compatible and best matched blood is available.

The patient should be seen in clinic by an obstetric anaesthetist in third trimester. A delivery plan should be in place following MDT consultation, and it needs to include mode of delivery, place of labour and position for labour and any additional monitoring that may be needed. Woman are advised to give birth in a consultant-led delivery unit and delivery is ideally planned between 38 weeks and 40 weeks due to increased risk of placental insufficiencies and pre-eclampsia. Epidural analgesia is recommended whilst pethidine is avoided during labour. Regional anaesthesia is preferable for obstetric interventions (e.g. caesarean) in comparison to general anaesthesia where possible in view of its superior pain relief and lower blood transfusion requirements.

Mothers with SCA have been over-represented in the mortality reports with estimated mortality between 1% and 3%. Obstetric complications such as pre-eclampsia, intra-uterine growth restriction, preterm birth and antepartum haemorrhage are all increased in patients with SCA. Caesarean birth rates and maternal critical care admission rates are significant higher in women with SCA. (See Table 1 ).

Children

Many of the perioperative considerations are the same for adults and children with SCA. Adequate hydration, oxygenation and analgesia are of equal importance. It has become common practice for children presenting for lower risk surgeries to be transfused to a haemoglobin of 10 g/dl with a HbSS of less than 60%. This has been shown to reduce perioperative complications when compared with children that were not transfused. In high-risk surgeries or high-risk patients, it is common to aim for a preoperative Hb of 10 g/dl and a HbSS of less than 30%.

It is common for children with SCA to have adeno-tonsillar hypertrophy. If the child suffers from obstructive sleep apnoea and desaturation is seen during a sleep study, then they may be offered an adenotonsillectomy. These children should have a recent transcranial Doppler and special attention should be paid to those children at high risk of stroke. Perioperative desaturation should be avoided and an insertion of an nasopharyngeal airway by the ear, nose and throat surgeon may be required to aid oxygenation postoperatively. These children would normally be cared for in a critical care environment.

Coronavirus disease (COVID-19)

Patients with SCA are at an increased risk of severe infection with COVID-19. Patients with COVID-19 should still be assessed for bacterial infection in the usual manner if they were to develop a fever. Thromboprophylaxis and oxygen therapy should be administered as per local coronavirus guidelines. Any concerns should be discussed with the haematology and virology teams.