Overview of the clinical manifestations of sickle cell disease

INTRODUCTION — The sickle point mutation in the beta globin gene results in the production of sickle hemoglobin, which is less soluble than normal fetal or adult hemoglobin. Sickle cell disease (SCD) refers to any one of the syndromes in which the sickle mutation is co-inherited with a mutation at the other beta globin allele that reduces or abolishes normal beta globin production. These include sickle cell anemia (homozygous sickle mutation), sickle-beta thalassemia, hemoglobin SC disease, and others.

The clinical manifestations of SCD are protean. The major features are related to hemolytic anemia and vaso-occlusion, which can lead to acute and chronic pain and tissue ischemia or infarction. Splenic infarction leads to functional hyposplenism early in life, which in turn increases the risk of infection. These complications have a major impact on morbidity and mortality.

This topic review presents an overview of the major clinical manifestations of SCD. Each of these is discussed in more detail in separate topic reviews mentioned herein.

General overviews of the pathophysiology, diagnosis, and management of SCD are also presented separately.

●Pathophysiology – (See "Pathophysiology of sickle cell disease".)

●Diagnosis – (See "Diagnosis of sickle cell disorders" and "Methods for hemoglobin analysis and hemoglobinopathy testing" and "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

●Management – (See "Overview of the management and prognosis of sickle cell disease" and "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance" and "Hydroxyurea use in sickle cell disease".)

GENERAL OVERVIEW — The clinical manifestations of SCD are protean, but their severity may vary markedly among the major genotypes and even among patients with the same genotype. As a general rule, individuals with sickle cell anemia (homozygous Hb S) and sickle-beta⁰-thalassemia have more severe manifestations than those with Hb SC disease or sickle-beta⁺-thalassemia [1]. One exception is retinopathy, which occurs most frequently in individuals with Hb SC disease. (See 'Retinopathy' below.)

The Centers for Disease Control and Prevention has a website that provides additional information concerning sickle cell trait and SCD. It is available at: www.cdc.gov/ncbddd/sicklecell/index.html [2].

Acute complications — The major acute complications of SCD include the following (table 1):

●Infections – (See 'Infection' below.)

●Severe anemia (due to splenic sequestration, aplastic crisis, or hyperhemolysis) – (See 'Anemia' below.)

●Vaso-occlusive phenomena

•Acute vaso-occlusive pain – (See 'Acute painful episodes' below.)

•Stroke – (See 'Stroke and TIA' below.)

•Acute chest syndrome – (See 'Acute chest syndrome' below.)

•Kidney infarction or medication toxicity – (See 'Kidney complications' below.)

•Dactylitis or bone infarction – (See 'Dactylitis and vaso-occlusive pain' below.)

•Myocardial infarction – (See 'Myocardial infarction, dysrhythmia, and sudden death' below.)

•Complications related to pregnancy – (See 'Pregnancy complications' below.)

•Priapism – (See 'Priapism' below.)

•Venous thromboembolism – (See 'Venous thromboembolism' below.)

Chronic complications — Many organ systems can develop chronic manifestations (table 1):

●Pain – (See 'Chronic pain' below.)

●Anemia – (See 'Chronic compensated hemolytic anemia' below.)

●Neurologic deficits or seizure disorder – (See 'Neurologic complications' below.)

●Pulmonary conditions – (See 'Asthma' below and 'Pulmonary hypertension' below and 'Sleep disordered breathing and nocturnal hypoxemia' below.)

●Impaired kidney function and hypertension – (See 'Kidney complications' below.)

●Osteoporosis and complications of bone infarction – (See 'Osteoporosis' below and 'Avascular necrosis and osteomyelitis' below.)

●Cardiomyopathy with diastolic dysfunction – (See 'Cardiomyopathy and heart failure' below.)

●Hepatotoxicity (transfusional iron overload or medications) and pigmented gallstones (chronic hemolysis) – (See 'Hepatobiliary complications' below.)

●Delayed puberty and reduced growth – (See 'Growth and development' below.)

●Chronic leg ulcers – (See 'Leg ulcers' below.)

●Proliferative retinopathy – (See 'Retinopathy' below.)

Complications of therapy also can be a significant cause of morbidity, especially complications related to chronic transfusion and iron chelation therapy, and side effects of chronic opioid pain medication. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Opioid side effects' and "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

The amount of time investment for the multiple appointments and specialists, and adverse attitudes of some providers who are not familiar with SCD, can also produce a large burden on patients, families, and other caregivers. (See 'Psychosocial issues' below.)

Transition from pediatric to adult care — The transition from pediatric to adult care is an especially vulnerable period and a critical prognostic factor for individuals with SCD, and is often associated with a worsening of complications. The majority of patients do not have successful transitions to an adult provider and as a result lack appropriate preventative care. The causes of this lapse in care are multifactorial and include lack of adult providers with expertise in SCD, lack of effective communication between pediatric and adult providers, and inadequate insurance coverage. Another major problem is the lack of skill development in the adolescent to become independent. There are validated self-efficacy and readiness tools that predict the success of transfer. An approach to pediatric-to-adult transfer using appropriate training and self-efficacy tools must be established during the early years before patients are transferred to adult care [3,4]. This important subject is discussed in detail separately. (See "Sickle cell disease (SCD) in adolescents and young adults (AYA): Transition from pediatric to adult care".)

Morbidity and mortality — People with SCD have a lifespan that is shortened by at least 20 years. Chronic organ failure is a common problem in older patients; acute sudden death is a major cause of fatality throughout life [5]. This subject is discussed separately. (See "Overview of the management and prognosis of sickle cell disease", section on 'Survival and prognosis'.)

VASO-OCCLUSIVE PAIN — Sickled red blood cells (RBCs) have a marked reduction in deformability as well as other effects including increased adhesion to vascular endothelial cells, inflammation, and activation of hemostatic mechanisms; all of these changes synergize to cause vascular obstruction and vaso-occlusion. Pain is one of the major consequences. Patients may have intermittent episodes of acute pain, which in some cases is accompanied by underlying chronic pain [6].

Acute painful episodes — Episodes of acute pain are one of the most common types of vaso-occlusive events in SCD [7,8]. While these episodes were previously called "sickle cell crises" we prefer to use the term painful episodes because not all patients are in true crisis, and pain should not be allowed to progress to the point of crisis for patients. (See "Pathophysiology of sickle cell disease".)

Pain can co-occur with (and mask) other potentially life-threatening complications of SCD. Treatment of pain should be accompanied by additional evaluations as appropriate for these complications, as discussed below. (See 'Potentially serious complications associated with acute pain' below.)

Vaso-occlusive pain in SCD is intense, although there is significant variability in the severity and frequency of acute painful episodes [9-11]. The majority of pain episodes are managed by the patient at home [6,9,12]. Many patients have specific triggers for pain such as cold, wind, low humidity, dehydration, stress, alcohol, and menses, which they develop strategies to minimize or avoid [13-18].

Pain episodes can begin as early as six months of age and typically last throughout life. In a series of children diagnosed with SCD at birth, one-third had experienced pain by the age of one year, two-thirds by the age of two years [7]. The sites of pain can include the back, chest, extremities, and abdomen. In young children, dactylitis (acute pain in the hands or feet) is a common site of pain.

Acute pain should be assessed rapidly so as not to delay analgesia (see "Evaluation of acute pain in sickle cell disease", section on 'Clinical assessment of pain'):

The gold standard for the assessment of pain is the patient’s report. There is no combination of physical findings or laboratory tests that can be used to determine (or confirm) whether an individual with SCD is in pain. The stability of the hemoglobin level cannot be used to justify withholding or underdosing of pain medication [19]. Placebo should never be used as it undermines the physician-patient relationship and lengthens the duration of pain.

Management of acute pain is individualized. A study emphasized that the implementation of an individual pain protocol that was reviewed with the family prior to implementation markedly decreased treatment delays and improved patient outcomes [20]. Most patients only present to the hospital or emergency department when their pain has exceeded what they can manage at home with oral opioids. Provider misconceptions about the nature and severity of SCD pain that interfere with adequate pain assessment and treatment should be addressed. In addition to hydroxyurea, there are US Food and Drug Administration (FDA)-approved therapies that decrease painful events and should be discussed with the patient, family, and other caregivers [21]. (See "Acute vaso-occlusive pain management in sickle cell disease" and "Disease-modifying therapies to prevent pain and other complications of sickle cell disease".)

Potentially serious complications associated with acute pain — Vaso-occlusive events may mask other life-threatening complications [22-32]. These complications may present with pain, but they require additional evaluations and treatments in addition to analgesia for pain, to avoid missing a potentially serious complication (table 2) [33].

The following are often present in the setting of acute pain:

●Acute chest syndrome (over 50 percent of ACS episodes are preceded by or occur in the setting of acute pain [24]).

●Acute multi-organ failure [22,27]

●Sudden death syndrome

●Acute surgical abdomen (eg, cholecystitis)

●Acute papillary necrosis

●Delayed hemolytic transfusion reaction [29,34]

●Acute splenic or hepatic sequestration crises [26]

●Opioid withdrawal [25]

Less commonly seen events that may be initially misdiagnosed as an acute painful event include:

●Acute coronary syndrome [35]

●Osteomyelitis [36,37]

●Gout [28]

●Arthritis

●Acute synovitis with avascular necrosis

●Autoimmune Disease [38]

●Deep vein thrombosis and/or pulmonary embolism [31]

Distinguishing characteristics of these conditions are described in the table (table 2), and our approach to evaluating for these in the setting of acute pain is discussed in detail separately. (See "Evaluation of acute pain in sickle cell disease", section on 'Clinical assessment of pain'.)

Chronic pain — Chronic pain is experienced by a large percentage of patients with SCD. Mechanisms of chronic pain differ from acute pain and may include bone and joint damage, chronic ulcers, central sensitization and hyperalgesia, and altered opioid metabolism, among others.

Frequent pain may generate feelings of despair, depression, and apathy that interfere with daily life and promote an existence that revolves around pain. A comprehensive approach to pain with an understanding of each patient’s management plan is indicated. (See "Overview of the management and prognosis of sickle cell disease", section on 'Routine evaluations and treatments'.)

INFECTION — Infection is a major cause of morbidity and mortality in patients with SCD. Mechanisms include functional hyposplenism or asplenism, altered humoral and cellular immunity, reduced tissue perfusion, presence of an indwelling catheter (eg, for chronic transfusion), splinting, and hypoventilation [39]. (See "Clinical features, evaluation, and management of fever in patients with impaired splenic function".)

Functional hyposplenism develops in early childhood (often starting as early as four months of age), and infants and young children are at greatest risk of certain infections. Splenic infarction typically renders patients functionally asplenic by two to four years of age, which greatly increases the risk of serious infection with encapsulated organisms [40]. Viral infections may also be more virulent in individuals with SCD (eg, parvovirus, H1N1 influenza, Zika virus, SARS-CoV-2 [the virus that causes COVID-19]), possibly due to increased sickling and an enhanced inflammatory response [41-44]. SCD patients with COVID-19 have increased morbidity and mortality compared with the general population. Individuals with COVID-19 may initially present with vaso-occlusive pain, followed by an increased risk of hospitalization, acute chest syndrome, with pulmonary thrombotic complications and bacterial infection, and multi-organ failure [45-48]. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'COVID-19'.)

Worldwide, malaria is a common cause of morbidity and mortality in children with SCD [49]. (See "Sickle cell disease in sub-Saharan Africa", section on 'Malaria'.)

Common sites/common organisms — Common sites of infection include bacteremia, meningitis, and pulmonary infections (pneumonia, acute chest syndrome [ACS]). These may present with fever and leukocytosis, and in some cases with focal findings (fever, headache, meningismus, seizures in meningitis; or fever, chest pain, cough, wheezing, and/or hypoxemia in ACS). Some patients also may have pancytopenia from bone marrow suppression, or signs of disseminated intravascular coagulation such as prolonged prothrombin time (PT) or activated partial thromboplastin time (aPTT), decreased fibrinogen, or increased D-dimer [50].

Common organisms include:

●Bacteremia – Encapsulated organisms, especially Streptococcus pneumoniae and Haemophilus influenzae [50-57].With adequate preventative measures for pneumococcus, other organisms predominate, including Escherichia coli, Staphylococcus aureus, and Salmonella species [56,58,59]. These and other frequently seen or especially concerning organisms are discussed in more detail separately. (See "Evaluation and management of fever in children and adults with sickle cell disease", section on 'Empiric antibiotic therapy'.)

●Meningitis – Encapsulated organisms, especially S. pneumoniae. H. influenzae is also seen but has become less common following institution of the vaccine. Meningitis is often seen in the setting of bacteremia and must be distinguished from other acute neurologic events such as ischemic stroke or intracerebral hemorrhage. (See "Bacterial meningitis in children older than one month: Clinical features and diagnosis", section on 'Epidemiology' and 'Neurologic complications' below.)

●Pneumonia/ACS – Mycoplasma pneumoniae, Chlamydia pneumoniae (which together account for approximately 20 percent of cases), and Legionella. Respiratory viruses are also common causes of pulmonary infection, while S. pneumoniae and H. influenza type b are uncommon. Some studies suggest Staphylococcus aureus may need to be considered in adults [60]. Patients may present with any combination of dyspnea, cough, chest pain, fever, tachypnea, and leukocytosis, and may develop the acute chest syndrome (ACS). (See "Overview of the pulmonary complications of sickle cell disease" and "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

Impact of preventive care — The routine use of prophylactic penicillin and vaccination against pneumococci and H. influenzae has reduced the frequency of these infections greatly but has not eliminated them. Reasons include infection with pneumococcal serotypes not included in the vaccines, and infection in those not vaccinated has continued to occur [50,61]. (See "Overview of the management and prognosis of sickle cell disease", section on 'Infection prevention'.)

Important preventive care includes comprehensive vaccination and prophylactic penicillin during early childhood; parent, caregiver, and patient education regarding the importance of seeking medical attention for fever or other signs of infection; and prompt initiation of appropriate antimicrobial therapy. These issues are discussed in detail separately:

●Prevention – (See "Overview of the management and prognosis of sickle cell disease", section on 'Infection prevention' and "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

●Education – (See "Overview of the management and prognosis of sickle cell disease", section on 'Routine evaluations and treatments'.)

●Fever – (See "Evaluation and management of fever in children and adults with sickle cell disease".)

●Acute chest syndrome – (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

MULTIORGAN FAILURE — Acute multiorgan failure is a life-threatening complication of SCD in which multiple organ systems are affected by ischemia and/or infarction. It is typically seen in the setting of an acute painful episode [22].

The mechanism is incompletely understood. Complement and other factors have been implicated. Some patients may present with a thrombotic microangiopathy (TMA, such as thrombotic thrombocytopenic purpura [TTP] or complement-mediated hemolytic uremic syndrome [CM-HUS] picture), which has led to anecdotal use of plasmapheresis and complement therapy. (See "Sepsis syndromes in adults: Epidemiology, definitions, clinical presentation, diagnosis, and prognosis".)

Management of multiorgan failure involves prompt and aggressive exchange transfusion therapy [62]. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Multiorgan failure'.)

ANEMIA — SCD produces a chronic, compensated hemolytic anemia that may be punctuated with episodes of acute worsening. Other contributing factors to chronic anemia include inappropriately low serum erythropoietin (EPO) concentration (eg, due to kidney disease or increased plasma viscosity) and/or folate or iron deficiency [63-65]. The major causes of an acute drop in hemoglobin level are aplastic crisis, splenic sequestration crisis, and hyperhemolytic crisis, all of which are potentially life-threatening. In addition, a sudden fall in hemoglobin is often associated with the early presentation of acute chest syndrome and other complications [62,66].

Iron deficiency can occur but is relatively uncommon.

Chronic compensated hemolytic anemia — Sickled cells undergo hemolysis, with a typical red blood cell (RBC) lifespan of approximately 17 days (one-seventh that of normal RBCs), leading to chronic hemolytic anemia [63]. Compensatory increases in RBC production and adaptation to a lower hemoglobin level typically are sufficient to prevent major symptoms of anemia.

The baseline complete blood count (CBC) and peripheral blood smear in individuals with SCD typically shows the following findings [63,67]:

●Hemoglobin level approximately 8 to 10 g/dL

●Hematocrit approximately 20 to 30 percent

●Polychromasia and reticulocytosis (typical reticulocyte count approximately 3 to 15 percent)

●Sickled cells (picture 1 and picture 2)

●Howell Jolly bodies (nuclear remnants that have not been phagocytosed, due to reduced splenic function) (picture 1)

●Mildly increased white blood cell (WBC) count in some cases

The RBC indices typically show normochromic, normocytic cells, unless there is coexistent thalassemia or iron deficiency, in which case microcytosis and hypochromia may be present. A high percentage of reticulocytes may cause mild macrocytosis. (See "Microcytosis/Microcytic anemia" and "Macrocytosis/Macrocytic anemia".)

Other findings typical of hemolysis may also be seen, including unconjugated hyperbilirubinemia, elevated serum lactate dehydrogenase (LDH), and low serum haptoglobin. (See "Approach to the child with anemia", section on 'Reticulocyte response' and "Diagnosis of hemolytic anemia in adults".)

Pigment gallstones may also develop. (See 'Pigment gallstones' below.)

The anemia and markers of hemolysis may be less severe in some individuals, including those with concomitant alpha thalassemia, those undergoing chronic transfusion therapy, and those receiving hydroxyurea [68]. Individuals with hemoglobin SC disease may have target cells and canoe-shaped RBCs (picture 3). Individuals with hemoglobin SC disease may retain splenic function until later in childhood, but up to half of children with hemoglobin SC disease become functionally asplenic by 12 years of age [69].

Fetal hemoglobin (Hb F) is mildly to moderately elevated (typical range, 1 to 4 percent), especially in individuals receiving hydroxyurea (typically 15 percent or greater). Other beta globin haplotypes also affect the percentage of Hb F, and greater percentage of Hb F often correlates with reduced disease severity [68]. (See "Fetal hemoglobin (Hb F) in health and disease", section on 'Impact of Hb F on sickle cell disease severity' and "Hydroxyurea use in sickle cell disease".)

Important aspects of routine management include:

●Supplementation with a multivitamin without iron containing folic acid, vitamin D, and other vitamins and minerals. (See "Overview of the management and prognosis of sickle cell disease", section on 'Nutrition'.)

●Establishment and monitoring of the patient’s baseline values so that it is readily apparent when these decline in the setting of suspected aplastic, splenic sequestration, or hyperhemolytic crises. (See 'Aplastic crisis' below and 'Splenic sequestration crisis' below and 'Hyperhemolytic crisis' below.)

●Baseline determination of the patient's red blood cell phenotype is appropriate, using serology or genotyping. Monitoring for alloimmunization can be helpful in patients receiving chronic or recurrent transfusions. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Alloimmunization and hemolysis'.)

●Evaluation for possible iron deficiency or other causes of worsening anemia or inappropriately low reticulocyte count. The diagnosis of iron deficiency may be obscured by the elevated serum iron concentration associated with chronic hemolysis and the normal to increased mean corpuscular volume (MCV). A serum ferritin <25 ng/mL or an elevated serum transferrin should be used to make this diagnosis [65]. Additional details regarding the evaluation of iron deficiency and SCD-specific management issues are presented separately. (See "Overview of the management and prognosis of sickle cell disease", section on 'Nutrition' and "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

●Assessment of the role of chronic transfusions; disease-modifying drugs including hydroxyurea, voxelotor, glutamine, crizanlizumab; and hematopoietic stem cell transplantation to reduce the frequency of complications. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques" and "Hydroxyurea use in sickle cell disease" and "Hematopoietic stem cell transplantation in sickle cell disease".)

●Attention to excess iron stores. Despite limiting transfusion to appropriate indications, many patients with SCD will develop excessive iron stores if chelation therapy is not used. Excess iron is a cause of significant morbidity, especially as the longevity of individuals with SCD continues to increase. Hepatic fibrosis and death from hemosiderosis-related cirrhosis of the liver can occur. Patients can also accumulate cardiac iron, albeit at a lower rate than patients with thalassemia. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

Aplastic crisis — Aplastic crisis is characterized by an acute drop in hemoglobin level caused by a transient arrest of erythropoiesis, leading to abrupt reductions in red cell precursors in the bone marrow and a markedly reduced number of reticulocytes in the peripheral blood (typically, reticulocytes <1.0 percent, absolute reticulocyte count <10,000 per microL). (See 'Anemia' above and "Acquired pure red cell aplasia in adults", section on 'Clinical features'.)

Infection is the typical cause. Most cases in children follow infection with human parvovirus B19, which specifically invades proliferating erythroid progenitors. (See "Clinical manifestations and diagnosis of parvovirus B19 infection", section on 'Transient aplastic crisis'.)

Other reported causes of transient aplasia are infections by Streptococcus pneumoniae, Salmonella, other streptococci, and Epstein-Barr virus.

Patients with transient aplastic crisis typically have restoration of erythropoiesis and reappearance of reticulocytes in the peripheral blood within 2 to 14 days. Recurrent aplasia from parvovirus is rare, presumably due to persistent immunity. However, recurrence due to other causes is not uncommon.

Aplastic crisis can result in a rapid and life-threatening drop in hemoglobin level caused by chronic hemolysis without the ability of the bone marrow to compensate. Management is with transfusion. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Symptomatic or severe anemia'.)

Splenic sequestration crisis — Splenic sequestration crisis is a potentially life-threatening complication of SCD characterized by an acute drop in hemoglobin level, typically two g/dL below baseline. This occurs when RBCs are captured and pool within the spleen. A large percentage of the total blood volume can become sequestered in the spleen, leading to hypovolemic shock and death.

Splenic sequestration typically occurs in individuals whose spleens have not yet become fibrotic due to repeated splenic infarction. Infants with homozygous sickle mutation (Hb SS) or sickle beta⁰ thalassemia are most often affected, as well as children or adults with some residual splenic function in the setting of variant sickle cell syndromes such as Hb SC disease or sickle beta⁺ thalassemia [70,71]. Splenic sequestration has been reported to occur in as many as 30 percent of young children with SCD and to be the presenting symptom in up to 20 percent of patients overall [7,72]. Parvovirus B19 infection may be a risk factor for splenic sequestration, although parvovirus infection is more commonly associated with aplastic crisis [73]. (See 'Aplastic crisis' above.)

Patients with splenic sequestration crisis present with a rapidly enlarging spleen and a marked decrease in hemoglobin level despite persistent reticulocytosis [7,72,74,75]. The mortality rate is as high as 10 to 15 percent, and patients often die before transfusions can be given [72,74]. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Symptomatic or severe anemia'.)

Up to half of individuals who survive a splenic sequestration crisis are reported to have recurrent sequestration, and splenectomy is often used after the first acute event to prevent recurrence [72]. In a report of 15 children who underwent elective splenectomy for recurrent acute splenic sequestration crisis, the median age at splenectomy was five years (range: 13 months to 15 years) [76]. No postsurgical complications were noted, and, at a median follow-up of 12 months, no child had developed bacterial infection.

A large retrospective cohort study evaluated the incidence of splenic sequestration in 423 pediatric patients with SCD (Hb SS in 240, Hb S-beta⁰-thalassemia in 128, Hb S-beta⁺-thalassemia in 30, Hb S-O(Arab) in 14, and Hb SC in 11) [77]. At least one episode of splenic sequestration was reported in 150 children (35 percent), at an average age of slightly over 4 years (range, 2 months to 14 years). Of those who had a splenic sequestration episode, recurrent splenic sequestration occurred in 117 (78 percent). In a multivariate analysis, four baseline risk factors were associated with initial splenic sequestration:

●Age at first symptoms <24 months (hazard ratio [HR] 1.60; 95% CI 1.10-2.33)

●Chronic pallor as a revealing sign (HR 1.69; 95% CI 1.12-2.53)

●Spleen size ≥3 cm (HR 7.27; 95% CI 4.01-13.20)

●Absolute reticulocyte count (ARC) ≥300,000/microL (HR 1.63; 95% CI 1.18-2.56)

Among the 117 children with recurrent splenic sequestration, the strongest risk factor for recurrence was spleen size ≥3 cm (HR 6.37; 95% CI 1.46-27.83) [77]. Of importance to management, regular blood transfusion therapy did not decrease the risk of splenic sequestration recurrence; 24 children (36 percent) had splenic sequestration recurrence while being transfused to prevent such events. Based on these data and data from a prior case series, we do not recommend regular blood transfusion therapy as a strategy to decrease splenic sequestration [78]. Our approach to managing splenic sequestration involves individualized decision-making that incorporates patient age and immune function, with splenectomy at an appropriate point in time for the majority of individuals. This approach is presented in detail separately. (See "Overview of the management and prognosis of sickle cell disease", section on 'Splenic and hepatic sequestration'.)

Hyperhemolytic crisis — Hyperhemolytic crisis refers to the sudden exacerbation of hemolysis with worsening anemia despite ongoing reticulocyte production. This complication is rare, and some experts doubt its existence. The causes and mechanisms of hyperhemolytic crisis are unknown. The following have been proposed:

●Complement activation, free heme activating Toll-like receptors and P-selectin expression [62,66].

●Macrophage activation [79].

●Many cases of hyperhemolytic crisis probably reflect occult splenic sequestration or aplastic crisis detected during a period of resolving reticulocytosis [80].

●Some episodes have been documented in multiply-transfused patients, consistent with a delayed hemolytic transfusion reaction in which transfused cells as well as the patient's own cells are hemolyzed ("bystander hemolysis") [81-83]. The mechanism of bystander hemolysis is unclear [84-88]. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Alloimmunization and hemolysis'.)

●Accelerated hemolysis has been associated with acute vaso-occlusive events including acute chest syndrome and acute painful episodes.

●Infections and/or drug exposure may be responsible for increased hemolysis in some cases. In one report, seven of eight children with increased hemolysis had associated glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is seen in as many as 10 to 20 percent of individuals of African descent [89]. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Epidemiology'.)

Hyperhemolytic crisis is potentially fatal if the cause of hemolysis is not addressed and transfusion with compatible blood is not administered rapidly. Anecdotal reports have noted improvement with plasmapheresis [90]. Immunosuppressive therapies have been used including intravenous immune globulin (IVIG; eg, 0.4 g/kg daily for five days) plus glucocorticoids (eg, intravenous methylprednisolone 500 mg/day for two days) [83,84,91,92]. Rituximab and tocilizumab also have been used [62,93]. (See "Overview of intravenous immune globulin (IVIG) therapy".)

Iron deficiency — Iron deficiency is relatively uncommon in SCD overall. Its occurrence is affected by hemoglobin genotype, age, geography, and concurrent risk factors. Iron deficiency is more common in individuals with hemoglobin SC disease and other sickle variants, with evidence of ongoing iron deficiency in up to 20 percent of non-transfused infants with these genotypes. This is particularly true in less developed regions. Up to 10 percent of young adult women with SCD from resource-limited regions may have iron deficiency [94-97]. The management of iron deficiency and the subject of a possible deleterious effect of iron repletion in adults are presented separately.

NEUROLOGIC COMPLICATIONS — SCD is associated with a number of cerebrovascular and other neurologic complications (figure 1). Standardized guidelines for the prevention, diagnosis, and treatment of cerebrovascular disease have been developed by the American Society of Hematology (ASH) [98]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease".)

The risk of dementia is likely higher in SCD and requires prevention and early treatment of neurologic events [99].

Stroke and TIA — Individuals with SCD are at risk of ischemic as well as hemorrhagic stroke. Without intervention, up to 11 percent patients with SCD will have a clinically apparent stroke by 20 years of age and one-fourth will have a stroke by age 45 (figure 2). Ischemic stroke is more common than hemorrhagic stroke in children and adolescents with SCD; hemorrhagic stroke is more common in adults. Other neurovascular events including transient ischemic attacks (TIAs) and silent cerebral infarctions (SCIs; infarction seen on neuroimaging that lacks a clinical correlate) can also occur and cause serious morbidity including neurocognitive and behavioral deficits. SCI is associated with a 14-fold increased risk of overt stroke [100,101]. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease" and "Prevention of stroke (initial or recurrent) in sickle cell disease".)

Primary prevention to reduce the risk of a first stroke is based on the use of regular transcranial Doppler measurements for risk stratification and selective screening with magnetic resonance angiography. Extracranial internal carotid artery (eICA) stenosis is relatively common and requires close monitoring. eICA may be responsible for progressive ischemic lesions (figure 3). (See "Overview of the management and prognosis of sickle cell disease", section on 'Routine evaluations and treatments'.)

At-risk children are treated with chronic prophylactic transfusion (figure 4). In some cases, a switch to hydroxyurea or evaluation for hematopoietic cell transplantation may be appropriate, as discussed in detail separately. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of a first ischemic stroke (primary stroke prophylaxis)'.)

Individuals who have had a stroke are treated with chronic prophylactic transfusions to prevent recurrent stroke. As many as 41 percent of patients with SCD experience recurrent stroke despite chronic transfusions; the risk of recurrence is significantly higher for those who have moyamoya collaterals [102]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Prevention of recurrent ischemic stroke (secondary stroke prophylaxis)'.)

Seizures — Seizures and epilepsy are two to three times more common in individuals with SCD compared with other populations. This was shown in an examination of all records of the 543 persons in the Jamaica sickle cell cohort, in which the five-year cumulative incidence of febrile convulsions was 2.2 percent and the incidence of epilepsy was 100 per 100,000 person-years [103]. Male sex and dactylitis in childhood were associated with an increased risk of epilepsy (odds ratios [ORs] 4.0 and 17, respectively).

Posterior reversible encephalopathy — Posterior reversible encephalopathy syndrome (PRES) is a syndrome of confusion headache, visual symptoms, and seizures that may accompany a number of medical conditions including hypertension and endothelial dysfunction. The etiology is unknown. PRES is less common than stroke in individuals with SCD, but it can occur, and when it does, it can present with acute neurologic changes that initially may mimic stroke [104]. The pathogenesis, diagnosis, and management of PRES is discussed separately. (See "Reversible posterior leukoencephalopathy syndrome".)

PULMONARY COMPLICATIONS — The pulmonary arterial circulation has low oxygen tension and low flow, both of which facilitate sickling. A number of acute and chronic complications are seen, including acute chest syndrome (ACS), asthma, sleep disordered breathing, pulmonary fibrosis, pulmonary fat embolism, thromboembolic disease, and pulmonary hypertension (PH). Pulmonary function test abnormalities and/or low oxygen saturation may also be seen. (See "Overview of the pulmonary complications of sickle cell disease".)

Standardized guidelines for the diagnosis and treatment of cardiopulmonary disease have been developed by the American Society of Hematology (ASH) [105]. (See "Pulmonary hypertension associated with sickle cell disease" and "Sickle cell disease effects on the kidney".)

There is much overlap in the symptoms of these conditions, and patients should have a baseline assessment of respiratory symptoms, as well as comprehensive evaluation for symptoms of dyspnea or chest pain, which may include assessments for ACS, asthma, pulmonary embolism, and/or PH, depending on the clinical features and degree of concern. (See "Overview of the management and prognosis of sickle cell disease", section on 'Routine evaluations and treatments'.)

Acute chest syndrome — Acute chest syndrome (ACS) refers to a syndrome of fever, chest pain, hypoxemia, wheezing, cough, or respiratory distress in the setting of a new pulmonary infiltrate. ACS occurs in as many as half of patients with SCD and is one of the major reasons for hospitalization and a major cause of mortality. The cause is often multifactorial and includes infection, vaso-occlusion, hypoventilation, atelectasis, thrombosis or thromboembolism, and in some cases fat embolism. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

ACS can lead to other vaso-occlusive phenomena, chronic lung disease, and PH. ACS is also associated with reactive airways disease. (See 'Pulmonary hypertension' below and 'Asthma' below.)

Management of ACS in the acute setting includes analgesia, oxygen, incentive spirometry, bronchodilators, antibiotics, and transfusion. As patients age, volume overload becomes a major complicating factor, especially in patients with diastolic dysfunction and other cardiopulmonary disease [106]. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Acute interventions'.)

Preventive approaches to reducing the risk of ACS include one or more of the following:

●Prophylactic antibiotics and immunizations, especially during early childhood. (See "Overview of the management and prognosis of sickle cell disease", section on 'Infection prevention' and "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

●Hydroxyurea. (See "Hydroxyurea use in sickle cell disease", section on 'Indications and evidence for efficacy'.)

●Transfusions for those who continue to have ACS episodes despite hydroxyurea therapy. (See "Red blood cell transfusion in sickle cell disease: Indications and transfusion techniques", section on 'Acute chest syndrome treatment and prevention'.)

●Consideration of hematopoietic cell transplantation for those with an available donor. (See "Hematopoietic stem cell transplantation in sickle cell disease".)

Asthma — Airway hyperreactivity or asthma is much more common in individuals with SCD than in control populations. Up to 70 percent of children with SCD have airway hyperresponsiveness, and a history of wheezing is ten-fold more common in individuals with SCD compared to controls [107].

As noted above, asthma is more common in children with SCD who have a history of ACS compared with those who do not have a history of ACS [108]. Conversely, children with asthma have an increased incidence of ACS, painful events, and the early onset of the first ACS event [109]. In addition, asthma is associated with early death in SCD compared to patients without asthma. (See 'Acute chest syndrome' above.)

Mechanistically, airway hyperresponsiveness appears to be causally related to hemolysis and the pathophysiology of SCD. In transgenic animal models with SCD, the lung demonstrates a histologic and biochemical picture consistent with asthma and airway inflammation with increased eosinophil count, IgE, and interleukin elevations. It appears that individuals with SCD have multiple risk factors for broncho-reactive lung disease that result in an increased frequency and severity of pulmonary events and SCD complications.

As in other settings, the diagnosis of asthma is based on the demonstration of variable airflow limitation, preferably by spirometry before and after bronchodilator administration, and exclusion of other causes of wheezing. (See "Overview of the pulmonary complications of sickle cell disease" and "Asthma in children younger than 12 years: Initial evaluation and diagnosis" and "Asthma in adolescents and adults: Evaluation and diagnosis".)

Management of asthma in individuals with SCD should follow established guidelines, which are discussed in detail separately. (See "An overview of asthma management" and "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control" and "Acute asthma exacerbations in children younger than 12 years: Emergency department management".)

Sleep disordered breathing and nocturnal hypoxemia — Most studies indicate that individuals with SCD have an increased rate and severity of sleep disordered breathing syndromes. This is usually recognized as a pediatric problem, but it is also increased in adults with SCD; as many as 79 percent of children and 44 percent of adults with SCD have evidence of sleep disordered breathing [107,110-113]. The degree of hypoxia is significantly greater in SCD than controls and is associated with a more severe and longer period of nocturnal desaturation. (See "Overview of the pulmonary complications of sickle cell disease", section on 'Sleep-disordered breathing'.)

The cause of nocturnal hypoxemia in SCD is multifactorial. In addition to anatomical narrowing, patients have an altered oxygen disassociation curve, decreased oxygen-carrying capacity due to anemia, and ventilation perfusion abnormalities that contribute to nocturnal oxygen desaturation.

Sleep-disordered breathing and nocturnal hypoxemia have potentially serious long-term consequences, including an increased risk for vaso-occlusive events, cardiovascular complications, and neurologic disease. Epidemiologic studies suggest that correction of obstructive sleep apnea decreases the rate of vaso-occlusive events, ACS, and cerebrovascular disease [114].

Evaluation with polysomnography is usually performed in patients with snoring, non-restorative sleep, nocturnal gasping, choking, observed apneas during sleep, or daytime hypersomnolence, and perhaps other symptoms such as enuresis, recurrent ACS, or recurrent painful episodes. (See "Evaluation of suspected obstructive sleep apnea in children" and "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

Management of sleep disordered breathing in individuals with SCD is similar to that in other patients. (See "Management of obstructive sleep apnea in children" and "Obstructive sleep apnea: Overview of management in adults".)

Pulmonary hypertension — Pulmonary hypertension (PH) refers to elevated pulmonary artery pressures, which may be due to isolated changes in the pulmonary arterial vasculature or too elevated pressures in the pulmonary capillary or venous systems (eg, from heart failure or pulmonary emboli). (See "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)

PH occurs in approximately 6 to 10 percent of individuals with SCD. However, symptoms are variable and non-specific (chronic dyspnea, chest pain, presyncope, reduced exercise tolerance, or merely reduction of daily activities without specific symptoms). (See "Overview of the management and prognosis of sickle cell disease".)

We take a thorough history of respiratory symptoms in all patients and have a low threshold for evaluating PH risk in symptomatic patients. Exercise testing is a helpful, non-invasive examination that complements screening with tricuspid jet regurgitant velocity [115,116]. For individuals with SCD who have no respiratory symptoms, we generally initiate screening for PH by measuring tricuspid jet regurgitant velocity using transthoracic Doppler echocardiography in late adolescence or adulthood. (See "Overview of the management and prognosis of sickle cell disease", section on 'Routine evaluations and treatments'.)

Some experts obtain a baseline transthoracic Doppler echocardiogram in all children ≥8 years old and perform routine screening echocardiograms every one to three years in adults. (See "Pulmonary hypertension associated with sickle cell disease", section on 'Screening and risk stratification'.)

The distinction between PH and other conditions such as cardiomyopathy, venous thromboembolic disease, and disordered sleep breathing; and the management of PH in individuals with SCD, are discussed separately. (See "Pulmonary hypertension associated with sickle cell disease", section on 'Diagnosis' and "Pulmonary hypertension associated with sickle cell disease", section on 'Management'.)

KIDNEY COMPLICATIONS — Kidney involvement is common in SCD, with up to one-fifth of patients eventually developing chronic kidney disease.

Manifestations include the following (see "Sickle cell disease effects on the kidney"):

●In young patients, hyperfiltration results in the GFR (glomerular filtration rate) underestimating the magnitude of kidney dysfunction

●Urinary concentrating defect with hyposthenuria; this may cause enuresis and may lead to overestimation of the glomerular filtration rate and dehydration

●Abnormalities in urinary acidification and potassium excretion associated with distal renal tubular acidosis

●Acute kidney injury (AKI, rapid increase in serum creatinine; associated with hospitalization)

●Painless hematuria due to papillary infarcts and very rarely renal medullary carcinoma

●Proteinuria from albuminuria, which is often a precursor of progressive kidney disease

●Contrast-induced nephropathy associated with intravenous iodinated contrast material used for imaging studies, although this may be less of a concern with second-generation low- and iso-osmolar contrast agents

●Medication toxicities, especially if glomerular filtration rate is overestimated

●Hypertension

●Kidney infarction, papillary necrosis, and renal colic

●Arginine vasopressin resistance (previously called nephrogenic diabetes insipidus) with polyuria

●Focal segmental glomerulosclerosis that can lead to end-stage kidney disease

●Renal medullary carcinoma (found almost exclusively in Black patients with Hb SC disease or sickle cell trait) [117]

It is important to avoid unnecessary exposure to nephrotoxic medications. We avoid chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), treat hypertension with agents other than diuretics (which may cause volume depletion and precipitate vaso-occlusion), and maintain adequate hydration during acute hospitalizations or imaging studies that require contrast agents.

High-quality data regarding routine screening for the complications of SCD affecting the kidney are lacking [105]. A reasonable approach to screening includes a chemistry panel including creatinine and a urine for protein and albumin, typically done by age three to five years and no later than 10 years of age. Adults are monitored at regular visits, typically four to six times per year. Individuals receiving an iron chelator or other nephrotoxic medication or those with known chronic kidney disease may require more frequent monitoring. Abnormal findings should be evaluated further and treated [118]. This evaluation, and management of specific complications of SCD affecting the kidney, are discussed separately. (See "Sickle cell disease effects on the kidney" and "Evaluation of proteinuria in children" and "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults" and "Evaluation of microscopic hematuria in children" and "Evaluation of gross hematuria in children" and "Etiology and evaluation of hematuria in adults".)

Of note, hemodialysis and/or kidney transplantation are both reasonable options for individuals with SCD who develop kidney failure, although these patients are at increased mortality risk. (See "Overview of the management and prognosis of sickle cell disease", section on 'Predictors of morbidity and mortality'.)

SKELETAL COMPLICATIONS — The skeletal system is frequently affected by SCD. Common findings include dactylitis in infants and younger children, and osteoporosis and/or avascular necrosis in older individuals. (See "Acute and chronic bone complications of sickle cell disease".)

Dactylitis and vaso-occlusive pain — Dactylitis is vaso-occlusive pain in the small bones of the hands and feet that typically occurs in infants with SCD and children with SCD up to approximately four years of age. Pain may be severe. As many as 45 percent of infants and toddlers will have dactylitis by the age of two years. The diagnosis is generally made by history and physical examination, as radiography typically does not show any changes, although repeated episodes of dactylitis will lead to a mottled appearance of the small bones. Older children and adults may experience vaso-occlusive pain episodes affecting the bones and joints as well. It is important to distinguish dactylitis and vaso-occlusive pain from osteomyelitis, although this may be challenging. (See "Acute and chronic bone complications of sickle cell disease", section on 'Acute vaso-occlusive pain'.)

Management of dactylitis and vaso-occlusive bone pain involves hydration, analgesics, and warm packs. Initiation of hydroxyurea therapy is usually appropriate. Other therapies may be appropriate in individuals for whom hydroxyurea is ineffective. Hematopoietic stem cell transplantation may be indicated. (See "Hydroxyurea use in sickle cell disease" and "Disease-modifying therapies to prevent pain and other complications of sickle cell disease" and "Hematopoietic stem cell transplantation in sickle cell disease".)

Osteoporosis — Chronic hemolytic anemia in SCD leads to a compensatory increase in erythropoietic activity. The extension of hematopoietic bone marrow can lead to a number of skeletal changes including chronic tower skull, bossing of the forehead, and fish-mouth deformity of vertebrae. These effects in turn cause widening of the medullary space, thinning of the trabeculae and cortices, and osteoporosis. As a result, individuals with SCD have a high rate of vitamin D deficiency and osteoporosis [119]. Orbital compression syndrome may occur in the setting of vaso-occlusion in the periorbital bone marrow space, with subperiosteal hemorrhage. Patients with this syndrome present with headache, fever, and palpebral edema. Compression of the optic nerve may also occur and may require surgical decompression. (See "Congenital and acquired abnormalities of the optic nerve", section on 'Compression'.)

We generally assess bone health including calcium and vitamin D intake, vitamin D status at every visit, and measure bone density at 12 years of age. We repeat vitamin D screening annually and bone density testing every one to three years. (See "Overview of the management and prognosis of sickle cell disease", section on 'Routine evaluations and treatments'.)

Information about calcium requirements and management of osteoporosis is presented separately. (See "Bone health and calcium requirements in adolescents" and "Screening for osteoporosis in postmenopausal women and men" and "Calcium and vitamin D supplementation in osteoporosis".)

Avascular necrosis and osteomyelitis — Avascular necrosis of bone, also called osteonecrosis, ischemic necrosis, or aseptic necrosis, results from infarction of bone trabeculae. The femoral and humeral heads may be affected. The femoral heads more commonly undergo progressive joint destruction as a result of chronic weight bearing. Avascular necrosis may be an underlying cause of chronic pain. The changes are best detected by magnetic resonance imaging (MRI) (image 1). (See "Acute and chronic bone complications of sickle cell disease", section on 'Osteonecrosis (avascular necrosis)' and "Treatment of nontraumatic hip osteonecrosis (avascular necrosis of the femoral head) in adults".)

Bone marrow infarction involving death of hematopoietic cells can also occur, leading to reduced red blood cell (RBC) production and anemia with reduced reticulocyte response. Some patients may have a leukoerythroblastic blood picture or pancytopenia. Bone marrow infarction may be associated with life-threatening pulmonary fat embolism. (See "Evaluation of bone marrow aspirate smears", section on 'Bone marrow necrosis' and "Fat embolism syndrome" and "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Adults'.)

The incidence of osteomyelitis is also increased in individuals with SCD. Long bones are usually affected, often at multiple sites, resulting from infection of infarcted bone. The most common organisms are Salmonella species. Staphylococcus aureus, the most common organism in patients without SCD, accounts for less than a quarter of cases. Articular infection is less common and is often due to Streptococcus pneumoniae [120].

It may be difficult to distinguish osteomyelitis from vaso-occlusive events involving bone. Bone imaging studies may be helpful, and cultures are essential. (See "Acute and chronic bone complications of sickle cell disease", section on 'Osteomyelitis and septic arthritis'.)

CARDIAC COMPLICATIONS — Cardiac complications are a common, often unrecognized cause of morbidity and mortality in SCD and are a major cause of death in adult patients [23,121-123].

Cardiomyopathy and heart failure — Cardiomyopathy is increasingly being identified in individuals with SCD, especially left-sided diastolic dysfunction, both with and without concomitant pulmonary hypertension (PH) [68,122,124-127]. Potential contributing factors may include:

●PH (see 'Pulmonary hypertension' above)

●Chronic anemia and hypoxemia with increased cardiac output, increased left ventricular stroke volume, and dilation of the left ventricle [121,128-131]

●Transfusional iron overload, especially in older individuals [132,133]

●Hypertension

●Alterations in intravascular volume associated with vasculopathy and chronic kidney disease

Left-sided diastolic dysfunction is increasingly being identified in patients with pulmonary hypertension and early cor pulmonale [124,134]. Diastolic abnormalities also increase with aging, and older individuals with SCD may have both right and left heart failure, with both systolic and diastolic dysfunction. Diastolic abnormalities also increase with aging, and older individuals with SCD may have both right and left heart failure, with both systolic and diastolic dysfunction.

Diffuse myocardial fibrosis is common in individuals with SCD and is associated with left atrial dysfunction, increased tricuspid regurgitant velocity, reduced exercise capacity, and risk of arrhythmia [135].

In a 2016 series of individuals with SCD (median age, 11 years) who underwent screening echocardiography at a single institution, more than half had evidence of restrictive cardiomyopathy with diastolic dysfunction and left atrial enlargement [124]. This suggests that elevated tricuspid regurgitant jet velocity (TRV) and possibly secondary PH may be due to a primary cardiac defect. The authors also performed a meta-analysis of published studies that found a high proportion of similar echocardiographic findings.

A 2013 meta-analysis of left ventricular systolic function in 841 individuals with SCD compared with 554 controls found an association of SCD with higher cardiac index and left ventricular end-systolic stress volume index but no difference in ejection fraction [125]. End-systolic and end-diastolic left ventricular dimensions were higher in individuals with SCD and increased with age.

Exercise capacity is often diminished in SCD, but overt systolic heart failure is uncommon and restriction of activity is seldom necessary [136,137]. However, an age-dependent loss of cardiac reserve may predispose to heart failure in adulthood following fluid overload, transfusion, reduced oxygen carrying capacity, or hypertension [138]. Exercise performance may be improved by transfusion therapy [139].

Myocardial infarction, dysrhythmia, and sudden death — Acute myocardial infarction in the absence of epicardial coronary artery disease has been described in patients with SCD, and is often misdiagnosed [35,121,122,140]. In one autopsy series, 7 of 72 consecutive patients with SCD (10 percent) had evidence of myocardial infarction, despite the absence of obstructive or atherosclerotic lesions [140]. In a case-control study involving approximately 500 individuals with SCD and 500 controls presenting with acute myocardial infarction (MI), those with SCD were more likely to lack risk factors for MI and to have a higher rate of complications and mortality [141]. Cardiac magnetic resonance is a useful test in assessing microvascular disease. MI in individuals with SCD may reflect increased oxygen demand exceeding limited oxygen-carrying capacity of abnormal myocardial microvasculature [142].

Individuals with SCD are also reported to have conduction abnormalities such as QT prolongation, ventricular arrhythmias, first-degree AV block, and nonspecific ST-T wave changes [121]. Certain medications such as methadone used in individuals with chronic pain may also increase the QT interval [143,144].

Sudden death is often multifactorial due to a combination of cardiopulmonary dysfunction, pulmonary fat embolism, sudden pulmonary hypertension, unexpected acute sequestration crisis, and/or intracranial hemorrhage. Cardiopulmonary causes are increasingly recognized as primary or contributing factors [5,121,145]. Restrictive cardiomyopathy, which may be associated with heart chamber enlargement, diastolic dysfunction, and mild pulmonary hypertension, places patients at high risk for sudden death [124]. During cardiovascular stressors such as vaso-occlusive events or exercise, dramatic increases in pulmonary pressures have been noted that suggest these events may be fatal in patients with underlying cardiomyopathy risks [146]. In adults, microvascular occlusion resulting in acute myocardial ischemia is underdiagnosed. Individuals with SCD often lack atherosclerotic lesions, but they may have chest pain, with cardiac microvascular obstruction detected on cardiac magnetic resonance imaging (MRI). More aggressive evaluation of chest pain and underlying cardiovascular disease will provide risk assessment information that may decrease the incidence of sudden cardiac death in SCD [147].

HEPATOBILIARY COMPLICATIONS — Diagnosis and management of hepatobiliary complications are discussed in detail separately. (See "Hepatic manifestations of sickle cell disease".)

Hepatic dysfunction — There are multiple causes of hepatic dysfunction in patients with SCD ("sickle cell hepatopathy"). These include but are not limited to the following [148,149]:

●Acute ischemia

●Cholestasis

●Hepatic sequestration crisis

●Transfusional iron overload

●Pigment gallstones due to chronic hemolytic anemia

●Drug toxicity from iron chelators or other medications

●Hepatitis C virus (HCV) infection

●Autoimmune liver disease

●Fibrosis

HCV infection — The risk of HCV in SCD is higher than the general population, with a reported prevalence among adults with SCD from 10 to 30 percent [150-156]. The risk is influenced by transfusion practices in different regions of the world. Individuals with SCD may have increased morbidity from HCV because of the interaction between viral hepatitis, hemosiderosis, and sickle hepatic injury [150].

●In the United States, immigration patterns have increased the number of patients exposed to HCV or to possible transfusion-transmitted HCV in high-risk areas [157]. The risk of HCV infection as a complication of blood transfusion has dramatically decreased with universal screening, and generally applies to transfusions received before 1990. Additional issues regarding blood donor screening are discussed separately. (See "Blood donor screening: Laboratory testing", section on 'Hepatitis C virus'.)

●In Africa, HCV remains a major health problem.

Since most adults with SCD receive repeated intermittent transfusions, annual HCV screening is warranted, along with monitoring iron overload [158]. (See "Screening and diagnosis of chronic hepatitis C virus infection".)

Pigment gallstones — Pigment gallstones eventually develop in most individuals with SCD. Though they can be initially noted during pain events or acute complications, gallstones are often asymptomatic. Over time, as individuals age, the percentage of patients with gallstones increases along with the development of symptoms.

Gallstones can present with cholecystitis, pancreatitis, biliary colic, or acute abdominal pain, which can be incorrectly attributed to vaso-occlusion. Ultrasonography is generally an effective screening test for gallstones. However, evaluation of the overall bile system is necessary for complete assessment and surgical planning. Endoscopic retrograde cholangiopancreatography (ERCP) and/or magnetic resonance cholangiopancreatography (MRCP) are required to identify common duct stones. (See "Choledocholithiasis: Clinical manifestations, diagnosis, and management" and "Overview of endoscopic retrograde cholangiopancreatography (ERCP) in adults".)

The management of gallstones requires a multidisciplinary approach. There is controversy concerning whether asymptomatic gallstones can be followed indefinitely or should be electively removed. Overall, the morbidity and mortality rate for elective laparoscopic cholecystectomy is low. The French National Authority for Health recommends elective laparoscopic cholecystectomy for children with SCD who have asymptomatic cholelithiasis [158-160]. (See "Hepatic manifestations of sickle cell disease", section on 'Cholelithiasis' and "Approach to the management of gallstones", section on 'Cholecystectomy in selected patients'.)

OTHER MANIFESTATIONS

Leg ulcers — Vaso-occlusion in the skin can produce leg ulcers and myofascial syndromes in patients with SCD. The mechanism is incompletely characterized, but compromised blood flow, endothelial dysfunction, thrombosis, inflammation, and delayed healing are thought to contribute [161]. These symptoms can cause significant pain, physical disability, and negative psychologic and social impacts.

When they occur, leg ulcers usually present after the age of 10 years and are more common in males than females [162-165]. Ulcers may develop spontaneously or after trauma. Their development appears to correlate with trauma and the degree of hemolysis and/or anemia, and individuals in tropical regions of the world are most likely to be affected. Prevalence from 30 to 70 percent has been reported in Jamaica [10,166]. Typical sites include the medial and lateral malleolus [165]. Bilateral involvement is common.

Leg ulcers in SCD may become superinfected. Staphylococcus aureus, Pseudomonas species, streptococci, or Bacteroides species may be cultured. Rarely, they may lead to systemic infection, osteomyelitis, or tetanus [167]. The lesions can be slow to heal and often recur. In a series of 225 patients with SCD from Jamaica, 53 (24 percent) had chronic leg ulcers [166]. The median age of ulcer onset was 17 years, and 32 (60 percent) occurred in the setting of trauma such as insect bite, animal bite, bicycle injury, barbed wire, or nails. The likelihood of developing chronic ulcers was greater in those with greater degrees of hemolysis, Doppler evidence of venous incompetence, and poverty.

Preventive strategies include well-fitting shoes and early, aggressive treatment if signs of skin injury appear. Additional aspects of management including indications for antibiotics and other local and systemic therapies are discussed separately. (See "Overview of the management and prognosis of sickle cell disease", section on 'Leg ulcers'.)

Retinopathy — SCD can cause retinopathy from retinal artery occlusion and ischemia, with associated proliferative retinopathy, vitreal hemorrhage, severe vision impairment, and retinal detachment [168-171]. These changes may be observed in older children and adolescents and tend to progress throughout adulthood. Unlike other complications, which tend to occur with greater frequency in individuals with homozygous Hb S or sickle-beta⁰ thalassemia, proliferative retinopathy is more common in hemoglobin SC disease than in other SCD genotypes [168,169,172].

The greater frequency of proliferative retinopathy in individuals with Hb SC disease was illustrated in cohort that included 307 children with homozygous Hb S and 166 children with Hb SC disease who were followed longitudinally for over 20 years [168]. Retinopathy developed in 14 with Hb SS and 45 with Hb SC (5 and 27 percent, respectively). Similar results were seen when comparing two series that quantified the frequency of retinopathy for individuals of a single genotype. Retinopathy was seen in 29 of 260 (11 percent) individuals with homozygous Hb S disease, and in 90 of 243 (37 percent) with Hb SC disease [169,172]. In a series of 182 individuals with SCD, Hb SC disease had a stronger association with retinopathy than patient age (odds ratios [ORs] for Hb SC genotype and age >35 years: 4.0 and 2.0, respectively) [173].

Infarction and ischemia typically begin in the peripheral retina, followed by neovascularization, which may be facilitated by autocrine production of angiogenic factors such as basic fibroblast growth factor and vascular endothelial growth factor [174]. Macular perfusion abnormalities are an important component in the pathophysiology of sickle retinopathy [175].

The elaborate neovascular structures that form are referred to as "sea fans" because of their resemblance to a marine invertebrate. Postmortem studies suggest that autoinfarction occurs at the preretinal capillary and that sea fans tend to develop at the site of arteriovenous crossings [176]. Superficial hemorrhages have a pink "salmon patch" appearance that resolves into an iridescent "schisis cavity," whereas deeper retinal hemorrhages have a black "sunburst" appearance, which is the most common abnormality [177]. Blindness is uncommon but loss of visual acuity may occur. In one series, spontaneous regression of retinal lesions was reported in up to a third of patients, and permanent visual loss was uncommon in younger adults. However, with increasing age, up to 5 to 10 percent of individuals may lose sight [178].

We evaluate children with an ophthalmologic examination (eg, dilated examination), typically starting around age 10 years and continuing annually through adulthood. (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance", section on 'Age five years to adolescence' and "Overview of the management and prognosis of sickle cell disease", section on 'Routine evaluations and treatments'.)

Management may involve laser photocoagulation, similar to that used in other forms of proliferative retinopathy in other settings such as diabetes (see "Diabetic retinopathy: Prevention and treatment", section on 'Treatment'). Two randomized trials that compared laser photocoagulation with no treatment in individuals with SCD-associated retinopathy both found a protective effect of treatment, with reduction in the incidence of vitreous hemorrhage, greater preservation of vision, and a trend towards regression of the lesions, although it was not able to prevent new lesions from developing [179-181]. The role of antiangiogenic therapy, hydroxyurea, and chronic transfusion in preventing or treating SCD-associated retinopathy remain to be established.

Pregnancy complications — Pregnancy is associated with both fetal and maternal complications in individuals with SCD, including intrauterine growth restriction, fetal death, and low birth weight; and acute chest syndrome, infections, preeclampsia, and thromboembolic events, respectively. (See "Sickle cell disease: Obstetric considerations".)

Components of reproductive and pregnancy care include the following:

●Access to birth control and reproductive planning. (See "Overview of the management and prognosis of sickle cell disease", section on 'Routine evaluations and treatments'.)

●Preconception counseling with medication management, alloantibody screening, hemoglobinopathy testing of the partner. (See "Sickle cell disease: Obstetric considerations", section on 'Before conception' and "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

●Supplementation with additional folic acid and screening for asymptomatic bacteriuria and fetal growth restriction; and discussion of the possible harvesting of cord blood for future hematopoietic cell transplant for first-degree relatives with SCD. (See "Sickle cell disease: Obstetric considerations", section on 'During pregnancy'.)

●Appropriate management of SCD complications during pregnancy by a team of clinicians with expertise in SCD and high-risk pregnancy; prophylactic transfusion for those at high risk of complications; and postpartum anticoagulation for those who undergo cesarean delivery. (See "Sickle cell disease: Obstetric considerations", section on 'Management of other complications of SCD' and "Sickle cell disease: Obstetric considerations", section on 'Transfusion therapy' and "Sickle cell disease: Obstetric considerations", section on 'Postpartum care'.)

Priapism — Priapism (unwanted erection in the absence of sexual desire or stimulation) is a common, serious, and often underdiagnosed problem in SCD. Priapism may be an early risk factor for developing other complications [182]. Prolonged episodes may lead to irreversible changes including tissue necrosis, fibrosis, and erectile dysfunction. Priapism lasting more than two to four hours is considered a medical emergency that requires immediate attention. Patients should be educated about this complication of SCD and possible interventions that can be used at home before seeking medical attention. Pathophysiology, evaluation, and management are discussed in detail separately. (See "Priapism and erectile dysfunction in sickle cell disease".)

Venous thromboembolism — SCD is considered a hypercoagulable state, and patients are considered to be at increased risk of venous thrombosis and pulmonary embolism (PE), especially adults in the setting of an indwelling catheter, immobility, infection, surgery, or pregnancy. We use thromboprophylaxis in hospitalized adults with SCD, and we have a low threshold for evaluating adults and children for thromboembolism if they develop symptoms. (See "Overview of the management and prognosis of sickle cell disease", section on 'Thromboembolism prophylaxis'.)

Growth and development — Impaired growth and delayed puberty are common in children with SCD. Most have detectable growth reduction that affects weight more than height by the age of two years [183,184]. Normal height is often achieved by adulthood but weight remains lower than that of individuals without SCD. The pathogenesis is uncertain and may include primary hypogonadism, hypopituitarism, and hypothalamic insufficiency [185].

Children may have delayed sexual maturation and delayed menarche [183,186]. In a report from the Jamaican Cohort Study, 8 of 52 boys (15 percent) did not have an adolescent growth spurt or age-appropriate prepubertal sexual development [185]. (See "Approach to the patient with delayed puberty".)

We monitor growth in children and adolescents with SCD and evaluate nutritional, endocrine, and environmental factors in those with decreased growth trajectories. (See "Overview of the management and prognosis of sickle cell disease", section on 'Routine evaluations and treatments'.)

Psychosocial issues — Most individuals with SCD are well adjusted [187]. However, the stress of living with a chronic medical condition may raise issues involving low self-esteem, social isolation, poor relationships, and withdrawal from normal daily living [187]. In a series of 58 children with SCD who were treated in the emergency department or inpatient unit, experiencing three or more prior painful events was associated with an increased risk of functional impairment and/or of a caregiver missing work or school [188]. Specific problem areas may include inappropriate pain coping strategies, reduced quality of life, anxiety, depression, and neurocognitive impairment [189-192]. These may be compounded by silent cerebral infarctions due to neurovascular vaso-occlusion with delayed neurodevelopmental maturation [193]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Individuals with silent cerebral infarctions'.)

The development of active coping strategies and support for the patient, family, and other caregivers should be encouraged [194]. Individuals with neurocognitive delay should have age-appropriate evaluations, educational resources, and other supports. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Management of cognitive and behavioral dysfunction' and "Specific learning disorders in children: Educational management".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Sickle cell disease (The Basics)" and "Patient education: When your child has sickle cell disease (The Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Sickle cell disease".)

SUMMARY

●Acute manifestations – The major acute manifestations of sickle cell disease (SCD) are related to infection (due to functional asplenia), anemia, and vaso-occlusion (table 1). Many of these complications are potentially life-threatening.

•Infection – (See 'Infection' above.)

•Anemia – (See 'Aplastic crisis' above and 'Hyperhemolytic crisis' above.)

•Splenic sequestration – (See 'Splenic sequestration crisis' above.)

•Acute vaso-occlusive pain, which may be accompanied by other complications (table 2) – (See 'Acute painful episodes' above.)

•Stroke – (See 'Stroke and TIA' above.)

•Acute chest syndrome – (See 'Acute chest syndrome' above.)

•Kidney infarction or medication toxicity – (See 'Kidney complications' above.)

•Dactylitis or bone infarction – (See 'Dactylitis and vaso-occlusive pain' above.)

•Myocardial infarction – (See 'Myocardial infarction, dysrhythmia, and sudden death' above.)

•Complications related to pregnancy – (See 'Pregnancy complications' above.)

•Priapism – (See 'Priapism' above.)

•Venous thromboembolism – (See 'Venous thromboembolism' above.)

●Chronic manifestations – The major chronic manifestations of SCD are related to chronic organ ischemia and infarction, exacerbated in some cases by the toxicities of therapy (table 1):

•Pain – (See 'Chronic pain' above.)

•Anemia, with transfusional iron overload – (See 'Chronic compensated hemolytic anemia' above.)

•Neurologic deficits or seizure disorder – (See 'Neurologic complications' above.)

•Pulmonary conditions including pulmonary hypertension – (See 'Asthma' above and 'Sleep disordered breathing and nocturnal hypoxemia' above and 'Pulmonary hypertension' above.)

•Impaired kidney function and hypertension – (See 'Kidney complications' above.)

•Osteoporosis and complications of bone infarction – (See 'Osteoporosis' above and 'Avascular necrosis and osteomyelitis' above.)

•Cardiomyopathy with diastolic dysfunction and heart failure – (See 'Cardiomyopathy and heart failure' above.)

•Liver injury and pigmented gallstones – (See 'Hepatobiliary complications' above.)

•Delayed puberty and reduced growth – (See 'Growth and development' above.)

•Chronic leg ulcers – (See 'Leg ulcers' above.)

•Proliferative retinopathy – (See 'Retinopathy' above.)

•Psychosocial stress – (See 'Psychosocial issues' above.)

●Screening, evaluation, and management – Infection prophylaxis and routine screenings and evaluations are discussed separately. (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance" and "Sickle cell disease (SCD) in adolescents and young adults (AYA): Transition from pediatric to adult care" and "Overview of the management and prognosis of sickle cell disease".)

●Evaluation and treatment of pain – (See "Evaluation of acute pain in sickle cell disease" and "Evaluation of acute pain in sickle cell disease", section on 'Clinical assessment of pain'.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.