Complications
Presents with chronic symptoms such as excessive tiredness, fatigability, breathlessness on exertion, pallor, and decreased exercise tolerance.
Opioid use disorder can occur in any patient taking opioids for a prolonged period of time. Patients receiving opioids for chronic pain should be made aware of this complication, but it should not influence whether opioid analgesia is offered to a patient. Due to dependence and tolerance, changing opioid or increasing the dose may be necessary to maintain adequate pain management.
Chronic exposure to blood transfusions can lead to end-organ damage in people with sickle cell disease. Patients who are on a chronic transfusion programme should be monitored for iron overload. Those patients who have had more than 50 units of red cells should be assessed for iron overload. Recommendations for evaluation of iron overload in chronically transfused patients include serum ferritin, hepatic iron assessment by quantitative magnetic resonance imaging, or liver biopsy annually and a yearly echocardiogram.[70][146][147]
Treatment of iron overload can be with desferrioxamine, deferiprone, or deferasirox. Deferiprone has been approved by the US Food and Drug Administration specifically for the treatment of transfusional iron overload due to sickle cell disease.[148] Deferasirox has been shown to be as effective as desferrioxamine. Deferasirox and deferiprone are available orally, which may lead to improved adherence.[149][150]
Jaundice and hepatomegaly are common, as is iron overload.[123][124]
The chronic haemolysis experienced by patients with sickle cell disease leads to high incidence of gallstones; 50% to 70% of patients may have bilirubin stones.[125]
Laparoscopic cholecystectomy has been shown to be safe and effective for treating symptomatic gallstones in children and adults.[126][127]
Caused by thrombosis of the endarterial vessels, often resulting in severe pain and gait disturbance. Because of the resulting progressive degenerative joint disease, these patients require chronic pain treatment, physiotherapy, and surgical management.[92] Occurs in 10% to 50% of adults with sickle cell anaemia or HbSC.
Limited to infants and young children.
Caused by hypoxia of the bone marrow in the hands and feet.
Treatment focuses on supportive care including analgesia and hydration. Hydroxycarbamide has been shown to reduce the frequency of dactylitis in infants.[49]
Can range from mild and small to large and severe. Typically occur in children aged older than 10 years. Other risk factors include male sex, alpha gene deletion, high total haemoglobin level, and high levels of haemoglobin F (HbF).[35]
Management is similar to that for other leg ulcers, including elevation and zinc sulfate pressure dressings.[134]
Because of recurrent fever and chronic anaemia, cardiomegaly, hyperdynamic precordium, and a flow murmur may occur in some patients. Standard treatments are used for hypertension and congestive heart failure.
Between the ages of 12-20 years, nearly 90% of male sickle cell disease patients will experience one or more episodes of priapism, often resulting in permanent impotence.[142][143] Episodes lasting 4 hours or more are considered medical emergencies, and urological evaluation is indicated. Analgesia, hydration, and local measures (urological aspiration, decompression) are the mainstays of therapy.
Randomised controlled trials of treatments for detumescence are lacking.[144]
Presents with splenomegaly, pallor, tachycardia, lethargy, and shock, caused by intrasplenic trapping of red blood cells and the resultant drop in haemoglobin levels.
Treated with emergent transfusions.[35]
Repeated episodes (sequestration crises) in the spleen result in fibrosis and autosplenectomy.
Splenectomy can be considered for patients with recurrent splenic sequestration or symptomatic hypersplenism, although evidence is lacking.[35][128]
In older children and adults, abdominal sonogram may be used to document spleen size and the presence of biliary stones.
Patients with autosplenectomy or splenectomy should be vaccinated with influenza, pneumococcal, and meningococcal vaccines. CDC: immunization schedules Opens in new window
Patients with sickle cell disease other than HbSS commonly have splenomegaly.
Echocardiographic evidence of increased pulmonary pressure occurs in 30% to 40% of adults with sickle cell disease.[135] Long-standing intravascular haemolytic anaemia results in a relative deficiency of nitrous oxide (NO) caused by release of haemoglobin and arginase from lysed red blood cells, which scavenge NO. The relative NO deficiency causes pulmonary vasoconstriction, endothelial dysfunction, pulmonary hypertension, and potential thrombosis.[13] The diagnosis of true pulmonary arterial hypertension should be confirmed with right heart catheterisation prior to any treatment.[136]
Standard treatment is similar to that given to other patients with pulmonary hypertension and includes continuous infusion of prostacyclin.[137][138][139]
Blood vessels in the renal medulla are highly susceptible to damage from sickling because of the medulla's anoxic and acidaemic environment. Recurrent crises can result in renal failure. Because patients hypersecrete creatinine, it is a poor measure of renal disease. Patients should have yearly screenings for the presence of increased urinary albumin excretion. If there is proteinuria, treatment with ACE inhibitors is suggested.[141]
Patients with advanced chronic kidney disease or end-stage renal failure should be referred for renal transplant consideration.[141]
Sickle cell trait is associated with an increased risk of haematuria, proteinuria, chronic kidney disease and end stage renal disease.[14]
An analysis of growth trends showed that children fall further off the growth curve as they get older, with boys more severely affected than girls. Growth velocity curves for a series of 13 adolescents showed a delay in the onset of the pubertal growth spurt.[145]
Sudden neurological deficits include: difficulty with language, writing, and/or reading; seizures; motor and sensory deficits; and altered consciousness. Chances of having a first stroke at age 20-45 years are 11% and 14%, respectively, for HbSS patients, and 2% and 10% for HbSC patients.[114]
Doppler flow studies conducted via transcranial Doppler (TCD) ultrasound of intracranial vessels help assess the risk of stroke caused by lesions of major vessels (internal carotid and anterior and middle cerebral arteries).[115] TCD screening of children with HbSS is recommended for primary stroke prevention, starting at 2 years of age and continued annually if TCD is normal, or every 4 to 6 months if TCD is marginal.[31] Children with abnormal results are tested again within 2 to 4 weeks.[32][33] Children with abnormal TCD velocities have traditionally been maintained on chronic transfusion therapy, which reduces the risk of stroke. The TWiTCH trial demonstrated that children with sickle cell anaemia who had received at least 1 year of transfusions for an elevated TCD, and had no magnetic resonance angiography-defined high-risk severe vasculopathy, could be safely switched to hydroxycarbamide treatment.[116] The American Society of Hematology recommends surveillance for cognitive impairment using simplified signalling questions (strong recommendation) and screening with MRI brain without sedation to detect silent cerebral infarcts at least once in early-school-age children and adults with HbSS and Hb0 thalassaemia (conditional recommendation).[31]
In children with overt stroke, chronic transfusion therapy is recommended.[117][118]
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However, one study demonstrated that children with prior stroke placed on chronic transfusion therapy remained at risk for progressive cerebral infarcts (both overt and silent cerebral infarcts), which occurred in 45% of the 40 children studied.[119] In adults, few data are available to guide management, and treatment for acute stroke is similar to that of any other stroke patient.
Prevention involving the use of regular blood transfusions to maintain the HbS at or below 30% should be considered.
Children and adults with acute neurological deficits, including transient ischaemic attack, should receive transfusion immediately on recognition of symptoms. Exchange transfusion is preferred, but simple transfusion should be performed if Hb is ≤8.5g/dL and exchange transfusion is not available within 2 hours of presentation for medical care.[31]
The most common neurological injury in children is silent cerebral infarcts. Children with silent strokes are at increased risk of overt stroke and poor academic achievement. There is evidence that chronic transfusion therapy can significantly decrease the risk of clinical stroke and other sickle cell disease-related complications (acute chest syndrome and painful crises) in high-risk children (e.g., those with abnormal TCD velocities or previous silent cerebral infarct).[120][121]
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Adults with sickle cell anaemia may have significant, unrecognised neurocognitive dysfunction. In a study of 149 adults with sickle cell anaemia, mean WAIS-III performance IQ score of patients with sickle cell anaemia was significantly lower than that of controls. Poorer cognitive function was associated with anaemia and age.[122]
One systematic review reported that the prevalence of invasive pneumococcal disease in children with sickle cell disease is 1.9%. The most common presentation was septicaemia, followed by lower respiratory tract infection, and meningitis. Most cases were caused by pneumococcal serotypes not included in the 13-valent pneumococcal conjugate vaccine (PCV13); risk can be mitigated by strict adherence to penicillin prophylaxis.[129]
Chronic infarction may be accompanied by vitreous haemorrhages and blindness due to neovascularisation.
Patients complaining of acute onset of floaters or acute loss of vision require an immediate evaluation by an ophthalmologist to check for signs of retinal haemorrhage or retinal artery occlusion.[130]
Patients require yearly retinal exams to screen for proliferative retinopathy. Screening for retinopathy with a dilated eye exam begins at age 10 years. 45% of patients have maculopathy detectable with optical coherence tomography angiography; prevalence increases with age.[131]
Nifedipine has been shown to improve perfusion and colour vision.[132]
Laser treatment should be considered as a therapeutic option for patients with evidence of proliferative retinopathy or visual loss and vitreous haemorrhage.[133] Other therapies such as intravitreal injection of anti-vascular endothelial growth factors have not been extensively studied.
One systematic review found that sickle cell trait is associated with an increased risk of pulmonary embolism. Hazard ratio for pulmonary embolism with or without deep vein thrombosis in people with sickle cell trait was 2.24 (confidence interval 1.28 to 3.95).[14]
Transient cessation of red cell production, often triggered by a viral infection, is characterised by pallor, tachypnoea, and tachycardia without splenomegaly. It is most commonly associated with parvovirus infection. Reticulocyte counts are usually <1%. Treated with red blood cell transfusions.[35]
The incidence of Plasmodium falciparum infection in people living in Africa with sickle cell anaemia has been found to be lower than in those without. However, the manifestations of malaria may be more severe in those with sickle cell disease.
One randomised controlled trial demonstrated that intermittent preventative treatment with mefloquine-artesunate was more effective in preventing malaria than daily prophylaxis with proguanil.[140]
Sickle cell trait is associated with increased risk of exertional rhabdomyolysis.
A study of active military personnel reported a hazard ratio of 1.54 (confidence interval 1.12 to 2.12) for exertional rhabdomyolysis in people with sickle cell trait.[151]
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