Overview of the clinical manifestations of sickle cell disease

INTRODUCTION — 

The sickle point mutation (sickle cell variant) in the beta-globin gene produces sickle hemoglobin (Hb S), which is less soluble than fetal or adult hemoglobins.

Sickle cell disease (SCD) refers to any syndrome in which the sickle mutation is coinherited with a pathogenic variant at the other beta-globin allele that reduces or abolishes normal beta-globin production. These include sickle cell anemia (homozygous sickle mutation [Hb SS]), sickle-beta thalassemia, hemoglobin SC disease, and others. The key feature of all types of SCD is that the Hb S proportion is typically >50 percent, and Hb S is the predominant hemoglobin.

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, increasing 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, which are discussed in more detail in the linked topic reviews.

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

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

●Other compound SCD syndromes such as Hb SC – (See "Overview of compound sickle cell syndromes".)

●Diagnosis – (See "Diagnosis of sickle cell disorders" and "Methods for hemoglobin analysis and hemoglobinopathy testing".)

●Reproductive testing – (See "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

●Management

•Pediatrician – (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance".)

•Outpatient care – (See "Overview of preventive/outpatient care in sickle cell disease".)

•Inpatient care – (See "Sickle cell disease: Overview of management during hospital admission".)

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's website provides additional information concerning sickle cell trait and SCD. It is available at: www.cdc.gov/ncbddd/sicklecell/index.html [2].

Education and the physician relationship with the patient — SCD is a lifelong illness. Each age group has specific health needs. Patient outcome is greatly influenced by the family and patient's trust in their medical team. The importance of building a trusting relationship and details of these discussions are presented separately. (See "Overview of preventive/outpatient care in sickle cell disease" and "Sickle cell disease: Overview of management during hospital admission".)

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

●Infections (due to functional asplenism caused by splenic infarction in early childhood) – (See 'Infection' below.)

●Severe anemia (due to splenic or hepatic sequestration, aplastic crisis, or hyperhemolysis, all of which can reduce hemoglobin below the baseline anemic level) – (See 'Anemia' below.)

●Vaso-occlusive phenomena (due to numerous vascular effects beyond simple obstruction):

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

•Stroke – (See 'Neurologic' below.)

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

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

•Dactylitis or bone infarction – (See 'Skeletal' below.)

•Myocardial infarction – (See 'Cardiac' below.)

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

●Pulmonary conditions including acute chest syndrome, asthma, sleep-disordered breathing, thromboembolic disease, and pulmonary hypertension – (See 'Pulmonary' below.)

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

●Osteoporosis and complications of bone infarction – (See 'Skeletal' below.)

●Cardiomyopathy with diastolic dysfunction – (See 'Cardiac' below.)

●Hepatotoxicity – (See 'Hepatobiliary' below.)

●Pigment gallstones – (See 'Hepatobiliary' 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 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. Most adolescents do not have successful transitions to an adult provider and lack appropriate preventive care resulting in an increase in clinical complications and an increase in hospitalization rates during this period. 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 [3]. Heart, lung, and kidney disease remain the major cause of morbidity and mortality. (See "Sickle cell disease: Overview of management during hospital admission", section on 'Survival and prognosis'.)

MULTI-ORGAN FAILURE — 

Acute multi-organ failure is a life-threatening complication of SCD in which multiple organ systems are affected by ischemia and/or infarction. It is typically accompanied by, and may present as, an acute vaso-occlusive pain episode [4]. Rapidly progressive acute chest syndrome may trigger multi-organ failure, or acute chest syndrome may develop later in the course of multi-organ failure. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Clinical features'.)

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 "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Management involves prompt and aggressive exchange transfusion therapy [5]. The decision to use exchange transfusion and the details of how to perform exchange transfusions are presented separately. (See "Sickle cell disease: Overview of management during hospital admission", section on 'Multi-organ failure' and "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications", section on 'Multi-organ failure'.)

VASO-OCCLUSIVE PAIN — 

Sickled red blood cells (RBCs) have a marked reduction in deformability and other effects, including increased adhesion to vascular endothelial cells, resulting in an inflammatory state and activation of hemostatic mechanisms. Collectively 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; they can begin as early as six months of age [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 a true crisis that denotes helplessness and limited self-determination. (See "Pathophysiology of sickle cell disease".)

Details are summarized briefly here and discussed separately in the linked reviews.

●Pain assessment – Vaso-occlusive pain in SCD is intense, although there is significant variability in the severity and frequency of acute painful episodes [9-11].

Acute pain should be assessed rapidly so as not to delay analgesia. The gold standard for pain assessment 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 [12]. (See "Evaluation of acute pain in sickle cell disease", section on 'Clinical assessment of pain'.)

Pain can co-occur with (and mask) other potentially life-threatening complications of SCD. Pain treatment should be accompanied by additional evaluations as appropriate for these complications. (See 'Other conditions misdiagnosed as vaso-occlusive pain' below.)

●Pain treatment and prevention – These subjects are discussed in detail separately:

•Individualized management, management at home, and use of pain protocols. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Care outside of the emergency department'.)

•Provider misconceptions about the nature and severity of SCD pain that interfere with adequate pain treatment. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Provider misperceptions that interfere with the assessment'.)

•(See "Approach to the management of chronic non-cancer pain in adults".)

•Optimal use of SCD therapies that can reduce pain episodes. (See "Hydroxyurea use in sickle cell disease" and "Disease-modifying therapies to prevent pain and other complications of sickle cell disease" and "Curative therapies in sickle cell disease including hematopoietic stem cell transplantation and gene therapy".)

Other conditions misdiagnosed as vaso-occlusive pain — Other complications requiring attention (table 2) may be misdiagnosed as vaso-occlusive pain, and vaso-occlusive pain may mask other life-threatening complications [4,13-23]. Analgesia should not be withheld while evaluating for these other conditions.

The following can co-occur with or be misdiagnosed as acute vaso-occlusive pain:

●Acute chest syndrome (over 50 percent of ACS episodes are preceded by or occur in the setting of acute vaso-occlusive pain [14])

●Acute multi-organ failure [4,17]

●Sudden death syndrome

●Acute surgical abdomen (eg, cholecystitis)

●Acute papillary necrosis

●Delayed hemolytic transfusion reaction [19,24]

●Acute splenic or hepatic sequestration [16]

●Opioid withdrawal [15]

Less common conditions that may be initially misdiagnosed as acute vaso-occlusive pain include:

●Acute coronary syndrome [25]

●Gynecologic conditions (dysmenorrhea, pelvic inflammatory disease, pregnancy)

●Physical or sexual abuse

●Acute stroke

●Osteomyelitis [26,27]

●Gout [18]

●Arthritis

●Acute synovitis with avascular necrosis

●Autoimmune disease such as systemic lupus erythematosus or rheumatoid arthritis [28]

●Deep vein thrombosis and/or pulmonary embolism [21]

Distinguishing characteristics of these conditions are described in the table (table 2); an approach to evaluation is discussed separately. (See "Evaluation of acute pain in sickle cell disease", section on 'Clinical assessment of pain'.)

Chronic pain — Chronic pain in SCD is defined by self-reported ongoing pain present on most days over the past six months in either a single location or multiple locations [29].

Chronic pain occurs in a significant proportion of adults with SCD and, to a lesser extent, adolescents and infrequently in children. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Chronic pain'.)

Chronic pain can either be due to an identifiable SCD cause such as avascular necrosis of a joint, or it may be due to an unidentifiable cause. In patients with chronic pain but without an identifiable SCD cause, the etiology is often related to central sensitization and ongoing vaso-occlusion [30,31].

Frequent or chronic pain may generate feelings of despair, depression, and apathy that interfere with daily life and promote an existence that revolves around pain. Untreated depression increases pain events and the risk of opioid misuse [32]. A comprehensive approach to pain with an understanding of each patient's management plan is indicated. (See "Overview of preventive/outpatient care in sickle cell disease", section on 'Routine evaluations and preventive interventions'.)

Management of chronic pain is discussed separately. (See "Disease-modifying therapies to prevent pain and other complications of sickle cell disease", section on 'Chronic pain'.)

INFECTION

Increased infectious risk from hyposplenia — Infection is a major cause of morbidity and mortality for children and, to a lesser extent, adults with SCD. Mechanisms include functional hyposplenism or asplenism (often starting as early as four to six months of age), altered humoral and cellular immunity, reduced tissue perfusion, indwelling catheters (eg, for chronic transfusion), splinting, and hypoventilation [33]. 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 [34].

Individuals with Hb SC disease may retain splenic function until later in childhood, but up to half of children with Hb SC disease become functionally asplenic by 12 years of age [35]. (See "Overview of compound sickle cell syndromes", section on 'Hb SC disease'.)

Viral illnesses may be more severe in individuals with SCD, possibly due to increased sickling and an enhanced inflammatory response [36-39].

Additional details and implications for management are discussed separately. (See "Clinical features, evaluation, and management of fever in patients with impaired splenic function" and "Evaluation and management of fever in children and adults with sickle cell disease".)

Common sites/common organisms — Common sites of infection include bacteremia, meningitis, pulmonary infections (pneumonia, acute chest syndrome [ACS]), and bone infections. These may present with fever and leukocytosis and, in some cases, with focal findings (fever, headache, meningismus, and/or seizures in meningitis or fever, chest pain, cough, wheezing, and/or hypoxemia in ACS). Globally, up to 7.5 percent of children develop a bone infection, often initially misdiagnosed as an infarction. Central line infections have become a major source of bacteremia [40].

Common organisms include:

●Bacteremia – Encapsulated organisms, especially Streptococcus pneumoniae and Haemophilus influenzae [41-48]. With adequate preventive measures for pneumococcus, other organisms predominate, including Escherichia coli, Staphylococcus aureus, and Salmonella species [47,49-51]. 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 'Rates of bacteremia and specific organisms'.)

●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' 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. influenzae type b are uncommon. Some studies suggest S. aureus may need to be considered in adults [52]. Patients may present with any combination of dyspnea, cough, chest pain, fever, tachypnea, and leukocytosis and may develop 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)".)

●Osteoarticular infection – Bone infections account for a high proportion of invasive bacterial infections [53]. Multifocal osteomyelitis is relatively common. The most common organisms in a 2023 study were Salmonella species and S. aureus, comprising 61 and 22 percent of bone infections, respectively [54]. The diagnosis of osteomyelitis in this population is often difficult because its clinical presentation is often similar vaso-occlusive pain, which is much more common.

The diagnosis of osteomyelitis is also often initially missed or delayed because of the similarity to vaso-occlusive pain. Clinical findings, including symptoms, fever, tenderness, swelling, and decreased range of motion are common in both diseases. Diagnosis and management are discussed separately. (See "Acute and chronic bone complications of sickle cell disease", section on 'Osteomyelitis and septic arthritis' and "Evaluation of acute pain in sickle cell disease", section on 'Potentially serious conditions associated with pain'.)

●Viral infections – These infections, including parvovirus, H1N1 influenza, Zika virus, respiratory syncytial virus (RSV), and coronavirus disease 2019 (COVID-19), may be more severe in patients with SCD [55].

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 (ACS), pulmonary thrombotic complications and bacterial infection, and multi-organ failure [56-59].

●Malaria – Worldwide, malaria is a common cause of morbidity and mortality in children with SCD [60]. (See "Sickle cell disease in sub-Saharan Africa", section on 'Malaria'.)

Impact of preventive care — Routine use of prophylactic penicillin and vaccination against pneumococci and H. influenzae has reduced the frequency of these infections but has not eliminated them. Reasons include infection with pneumococcal serotypes not included in the vaccines and lack of vaccination [41,61]. (See "Overview of preventive/outpatient care in 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 separately:

●Prevention – (See "Overview of preventive/outpatient care in 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 preventive/outpatient care in sickle cell disease", section on 'Routine evaluations and preventive interventions'.)

●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)".)

ANEMIA — 

Documentation of the individual's baseline hemoglobin, percent Hb S, reticulocyte count, and, for children, measurement of spleen size, are important so that changes can be appreciated during an acute illness or if anemia worsens. (See "Sickle cell disease: Overview of management during hospital admission", section on 'Splenic and hepatic sequestration' and "Overview of preventive/outpatient care in sickle cell disease", section on 'Anemia'.)

Chronic compensated hemolytic anemia — SCD causes chronic compensated hemolytic anemia. The typical red blood cell (RBC) lifespan in patients with homozygous Hb SS is approximately 17 days (compared to 140 days in controls) [62]. (See "Diagnosis of hemolytic anemia in adults", section on 'RBC turnover'.)

Compensatory increases in RBC production and adaptation to a lower hemoglobin level are typically sufficient to prevent major symptoms of chronic anemia. However, the severity of chronic anemia is an independent predictor of overall mortality [63]. An acute decline in hemoglobin may occur due to concomitant conditions and may cause symptoms or life-threatening complications. (See 'Aplastic crisis' below and 'Splenic or hepatic sequestration crisis' below and 'Hyperhemolytic crisis' below.)

The following features of chronic compensated hemolysis are seen:

●CBC and blood smear – The baseline complete blood count (CBC) and peripheral blood smear in individuals vary with the SCD phenotype (such as Hb SS, Hb SC, Hb SB⁰-thalassemia). Typical findings for Hb SS include [62,64]:

•Hemoglobin level approximately 7 to 10 g/dL

•Hematocrit approximately 20 to 30 percent

•Polychromasia, indicating reticulocytosis

•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

•Individuals with Hb SC disease may have target cells and canoe-shaped RBCs (picture 3)

●RBC indices – 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".)

In hemoglobin SC disease, the mean corpuscular hemoglobin concentration (MCHC) is high, reflecting dense, dehydrated RBCs. A small percentage of Hb SC RBCs have dense crystals [65]. (See "Overview of compound sickle cell syndromes", section on 'Hb SC disease'.)

●Other findings of hemolysis – There may be 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".)

Hemolysis generates increased exposure to phosphoserine and RBC-derived particles that can catalyze endothelial dysfunction, inflammation, microthrombi, and chronic vasculopathy. (See 'Other manifestations' below.)

●Reticulocyte count – Consistent with hemolysis, the reticulocyte count is increased (typical reticulocyte count approximately 3 to 15 percent).

Reduction in reticulocyte count from the patient's baseline raises the concern for parvovirus B19 infection. While this rarely causes significant anemia in people without SCD, in SCD the bone marrow cannot rebound as rapidly, and severe anemia or aplastic crisis may occur. (See "Clinical manifestations and diagnosis of parvovirus B19 infection" and 'Aplastic crisis' below.)

●Gallstones – Chronic hemolytic anemia may also cause pigment gallstones to develop. (See 'Hepatobiliary' below.)

●Hb F – 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 a greater percentage of Hb F may correlate with reduced disease severity [66]. (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".)

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 [66].

Hyperhemolytic crisis refers to the sudden exacerbation of hemolysis with worsening anemia despite ongoing reticulocyte production. (See 'Hyperhemolytic crisis' below.)

Other causes of anemia

●Acute drop in hemoglobin – Major causes of an acute drop in hemoglobin concentration include aplastic crisis, splenic or hepatic sequestration, and hyperhemolysis, all of which are potentially life-threatening. (See 'Aplastic crisis' below and 'Splenic or hepatic sequestration crisis' below and 'Hyperhemolytic crisis' below.)

Additional causes of an acute drop in hemoglobin may include acute chest syndrome and other complications. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

●Chronic decline in hemoglobin – Additional causes of chronic anemia may include:

•Vitamin B12 or folate deficiencies – These can contribute to anemia. (See "Overview of preventive/outpatient care in sickle cell disease", section on 'Nutrition' and "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

•Iron deficiency – Iron deficiency is relatively uncommon, except in infancy [67]. Iron deficiency is more common in individuals with Hb 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 resource-limited regions of the world. Up to 10 percent of young adult females with SCD from resource-limited regions may have iron deficiency [68-71].

Diagnosis and treatment of iron deficiency are discussed separately:

-Diagnosis – (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Diagnosis of iron deficiency and iron deficiency anemia in adults".)

-Treatment – (See "Iron deficiency in infants and children <12 years: Treatment" and "Iron requirements and iron deficiency in adolescents" and "Treatment of iron deficiency anemia in adults".)

•Chronic kidney disease (CKD) – Chronic kidney disease can cause inappropriately low erythropoietin (EPO) concentration (eg, due to kidney disease or increased plasma viscosity) and/or folate or iron deficiency [72].

•Hydroxyurea – Hydroxyurea is titrated to ensure that it does not suppress reticulocytosis. However, suppression may occur. (See "Hydroxyurea use in sickle cell disease", section on 'Myelosuppression'.)

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 'Chronic compensated hemolytic anemia' above and "Acquired pure red cell aplasia in adults", section on 'Clinical features'.)

This can cause a rapid, life-threatening drop in hemoglobin, since chronic hemolysis dramatically reduces RBC lifespan that requires bone marrow compensation. Management is with transfusion. (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications", section on 'Symptomatic or severe anemia'.)

Infection is the typical cause. Most cases in children follow infection with 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 S. pneumoniae, Salmonella, other streptococci, and Epstein-Barr virus. (See 'Common sites/common organisms' above.)

Erythropoiesis is typically restored and reticulocytosis typically resumes within 2 to 14 days following transient aplastic crisis. Recurrent aplasia from parvovirus is rare, presumably due to persistent immunity. However, recurrence due to other causes is not uncommon.

Splenic or hepatic sequestration crisis

●Definition – 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 due to RBC pooling in the spleen. A large percentage of the total blood volume can become sequestered in the spleen, leading to hypovolemic shock and death. A similar process can occur in the liver. (See "Hepatic manifestations of sickle cell disease", section on 'Acute hepatic sequestration'.)

●Risk factors – Splenic sequestration typically occurs in individuals whose spleens have not yet become fibrotic due to repeated splenic infarction. This typically applies to infants with homozygous sickle mutation (Hb SS) or sickle beta⁰ thalassemia, as well as children or adults with some residual splenic function (eg, Hb SC disease or sickle beta⁺ thalassemia) [73,74]. Splenic sequestration is also very common in individuals with SCD in India.

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 [7,75]. Parvovirus B19 infection may be a risk factor for splenic sequestration, although parvovirus infection is more commonly associated with aplastic crisis [76]. (See 'Aplastic crisis' above.)

●Presentation – Patients with splenic sequestration crisis present with a rapidly enlarging spleen and a marked decrease in hemoglobin level despite persistent reticulocytosis [7,75,77,78]. The mortality rate is as high as 10 to 15 percent, and patients often die before transfusions can be given [75,77].

●Treatment – The main treatment is transfusion; transfusion volume needs to be kept low enough that autotransfusion (when blood pooled in the spleen re-enters the circulation) does not have hyperviscosity and volume overload, as discussed separately. (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications", section on 'Symptomatic or severe anemia' and "Hepatic manifestations of sickle cell disease", section on 'Acute sickle cell hepatic vaso-occlusive episode'.)

●Prevention – 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 [75]. Our approach to preventing recurrent 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 "Sickle cell disease: Overview of management during hospital admission", section on 'Splenic and hepatic sequestration'.)

●Supporting data – The incidence of splenic sequestration was evaluated in a retrospective cohort study 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) [79]. At least one episode of splenic sequestration was reported in 150 children (35 percent) at an average age of slightly over four years (range 2 months to 14 years). Of those with a splenic sequestration episode, recurrent splenic sequestration occurred in 117 (78 percent). In 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) [79]. Regular blood transfusion therapy did not decrease the risk of recurrent splenic sequestration [80].

Hyperhemolytic crisis

●Definition – Hyperhemolytic crisis refers to the sudden exacerbation of hemolysis with worsening anemia despite ongoing reticulocyte production.

This complication can occur after transfusion or following an acute vaso-occlusive event. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Hyperhemolysis'.)

●Risk factors and mechanism – The causes and mechanisms of hyperhemolytic crisis are multifactorial and are thought to include:

•Delayed hemolytic transfusion reaction with bystander hemolysis [81-87].

•Activation of complement and macrophages [5,88-90].

•Infections.

•Drug exposure, especially with concomitant glucose-6-phosphate dehydrogenase (G6PD) deficiency, which is seen in as many as 10 to 20 percent of individuals of African descent [91]. (See "Glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Epidemiology'.)

●Presentation – Patients may present with acute drop in hemoglobin and markers of increased hemolysis. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Alloimmunization and hemolysis'.)

●Treatment – Hyperhemolytic crisis is potentially fatal if the cause of hemolysis is not addressed and transfusion is not administered rapidly. Management and discussion of investigational treatments are discussed separately. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Hyperhemolysis'.)

COMPLICATIONS AFFECTING SPECIFIC ORGAN SYSTEMS

Retinopathy — SCD can cause retinopathy from retinal vessel occlusion, which can ultimately lead to proliferative retinopathy, vitreal hemorrhage, severe vision impairment, and retinal detachment [92-95]. These changes may be observed in older children and adolescents and tend to progress throughout adulthood.

●Mechanism – 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 [96]. Macular perfusion abnormalities are an important component in the pathophysiology of sickle retinopathy [97]. 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 [98].

●Increased risk in Hb SC disease – 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 [92,93,99]. (See "Overview of compound sickle cell syndromes", section on 'Hb SC disease'.)

The greater frequency of proliferative retinopathy in individuals with Hb SC disease was illustrated in a cohort that included 307 children with homozygous Hb S and 166 children with Hb SC disease who were followed longitudinally for over 20 years [92]. 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 [93,99]. 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) [100].

●Surveillance – 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 preventive/outpatient care in sickle cell disease", section on 'Routine evaluations and preventive interventions'.)

●Ophthalmologic appearance – 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 [101].

●Clinical course – Loss of visual acuity may occur, although blindness is uncommon. 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 [102].

●Treatment – 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 versus 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 development of new lesions was not fully prevented [103-105].

The roles of antiangiogenic therapy, hydroxyurea, and chronic transfusion in preventing or treating SCD-associated retinopathy remain to be established.

Neurologic — SCD is associated with a number of cerebrovascular and other neurologic complications (figure 1).

●Stroke and silent cerebral infarcts

•Risk factors – Individuals with SCD are at risk of ischemic as well as hemorrhagic stroke. Without intervention, up to 11 percent of 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). (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Incidence'.)

Ischemic stroke is more common than hemorrhagic stroke in children and adolescents with SCD; hemorrhagic stroke is more common in adults. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Pathophysiology and risk factors'.)

Other neurovascular events include silent cerebral infarct (SCI; infarction seen on neuroimaging that lacks a clinical correlate) and transient ischemic attack (TIA). These can also occur and cause serious morbidity including neurocognitive and behavioral deficits. By the age of 30 years, almost 50 percent of individuals with SCD have had an SCI [106]. SCI is associated with a 14-fold increased risk of overt stroke [107,108]. As patients age, the number and size of SCIs increase, and the areas as well as regions affected [106,109,110]. (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".)

•Surveillance and primary prevention – 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; it may be responsible for progressive ischemic lesions (figure 3). American Society of Hematology Guidelines suggest obtaining one MRI in childhood and one MRI in adulthood to assess for SCI [111]. Close monitoring and control of hypertension should be part of standard care [111]. (See "Overview of preventive/outpatient care in sickle cell disease", section on 'Routine evaluations and preventive interventions'.)

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

•Presentation – Patients with acute stroke may present with headache or acute neurologic changes. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease", section on 'Presentation'.)

SCI may manifest as a decline in cognitive function and increased school/educational-related difficulties. [112]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'Individuals with silent cerebral infarctions'.)

Rapid evaluation and distinction among meningitis, stroke, and other neurologic complications are essential. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease", section on 'Immediate evaluation and management'.)

•Treatment and secondary prevention – Standardized guidelines for the prevention, diagnosis, and treatment of cerebrovascular disease have been developed by the American Society of Hematology (ASH) [111]. (See "Prevention of stroke (initial or recurrent) in sickle cell disease".)

Treatment is discussed separately. (See "Acute stroke (ischemic and hemorrhagic) in children and adults with sickle cell disease".)

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 [113]. (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 [114]. Male sex and dactylitis in childhood were associated with an increased risk of epilepsy (odds ratios [ORs] 4.0 and 17, respectively).

Treatment of epilepsy is similar to individuals without SCD. (See "Seizures and epilepsy in children: Initial treatment and monitoring" and "Evaluation and management of the first seizure in adults".)

Additional attention to stroke and silent cerebral infarction prevention is warranted. (See "Prevention of stroke (initial or recurrent) in sickle cell disease", section on 'MRI screening for silent infarcts'.)

●Dementia – The risk of dementia is likely higher in SCD and requires prevention and early treatment of neurologic events [115]. (See "Overview of preventive/outpatient care in sickle cell disease", section on 'Routine evaluations and preventive interventions'.)

Neurocognitive decline may be prevented by early use of hydroxyurea in childhood [116]. (See "Hydroxyurea use in sickle cell disease".)

●PRES – 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. In children with SCD, an association has been observed between PRES and recent transfusion or hematopoietic stem cell transplantation. The etiology is unknown. (See "Reversible posterior leukoencephalopathy syndrome".)

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 [117].

Pulmonary — 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) – ACS refers to a syndrome of fever, chest pain, hypoxemia, wheezing, cough, or respiratory distress in the setting of a new pulmonary infiltrate; it cannot be distinguished from pneumonia. 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. Evaluation and management are discussed separately. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)".)

●Asthma – Airway hyperreactivity or asthma is much more common in individuals with SCD than in controls. Up to 70 percent of children with SCD have airway hyperresponsiveness, and a history of wheezing is 10-fold more common in individuals with SCD compared with controls [118]. A history of ACS increases the risk of asthma, and asthma increases the risk of ACS [119,120]. Additional details and management guidelines are presented separately. (See "Overview of the pulmonary complications of sickle cell disease", section on 'Asthma' and "An overview of asthma management in children and adults" and "Acute asthma exacerbations in children younger than 12 years: Emergency department management" and "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control".)

●Sleep-disordered breathing – Individuals with SCD have increased rates 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 [118,121-124]. The degree of hypoxia is significantly greater in individuals with SCD than in 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'.)

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 [125]. Epidemiologic studies suggest that correction of obstructive sleep apnea decreases the rate of vaso-occlusive events, ACS, and cerebrovascular disease [126].

Evaluation with polysomnography is usually performed in patients with snoring, nonrestorative 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 similar to patients without SCD. (See "Management of obstructive sleep apnea in children" and "Obstructive sleep apnea: Overview of management in adults".)

●Pulmonary fibrosis – Pulmonary function test abnormalities and/or low oxygen saturation may also be seen. (See "Overview of the pulmonary complications of sickle cell disease", section on 'Pulmonary function test abnormalities'.)

●Pulmonary fat embolism – Fat embolism can accompany bone infarction or other vaso-occlusive complications. It can cause ACS, especially in adults. It may be associated with nonfocal neurologic symptoms and/or liver dysfunction. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Common triggers' and "Acute and chronic bone complications of sickle cell disease", section on 'Osteonecrosis (avascular necrosis)'.)

●Thromboembolic disease – (See 'Venous thromboembolism' below.)

●Pulmonary hypertension (PH) – PH refers to elevated pulmonary artery pressures, which may be due to isolated changes in the pulmonary arterial vasculature or 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 nonspecific (chronic dyspnea, chest pain, presyncope, reduced exercise tolerance, or merely reduction of daily activities without specific symptoms). (See "Overview of preventive/outpatient care in sickle cell disease".)

PH is an independent predictor of mortality in SCD. (See "Sickle cell disease: Overview of management during hospital admission", section on 'Predictors of morbidity and mortality'.)

Screening, evaluation of symptoms, and management are discussed separately. (See "Overview of preventive/outpatient care in sickle cell disease", section on 'Routine evaluations and preventive interventions' and "Pulmonary hypertension associated with sickle cell disease".)

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 preventive/outpatient care in sickle cell disease", section on 'Routine evaluations and preventive interventions'.)

Kidney — Kidney involvement is common in SCD, with injury to the glomeruli, tubules, and renal vasculature. Young children develop impairment in urine concentrating function, causing enuresis. With aging, albuminuria, proximal renal tubular acidosis, and acute kidney injury are frequently observed. In adults, chronic kidney disease may occur in up to one-fifth of patients, progressing in many older adults to end-stage kidney disease, with up to one-fifth of patients eventually developing chronic kidney disease. Hypertension is also common and may be missed because baseline blood pressures are lower in sickle cell disease than in the general population. Clinical manifestations, prevention, and treatment are discussed separately. (See "Sickle cell disease effects on the kidney".)

Unnecessary exposure to nephrotoxic medications, including chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), should be avoided. (See "Acute vaso-occlusive pain management in sickle cell disease", section on 'Therapies we do not use'.)

The National Heart Lung and Blood Institute (NHLBI) expert panel recommends screening all patients with SCD for proteinuria annually beginning at age 10 years, as discussed separately. (See "Sickle cell disease effects on the kidney", section on 'Routine surveillance and early detection' and "Overview of preventive/outpatient care in sickle cell disease", section on 'Interventions and monitoring done by the medical team'.)

Adequate hydration should be maintained during hospitalizations or with imaging studies that require contrast agents. (See "Sickle cell disease: Overview of management during hospital admission", section on 'Hydration' and "Sickle cell disease: Overview of management during hospital admission", section on 'Monitoring pulmonary, hematologic status and liver and kidney function'.)

Skeletal — The skeletal system is frequently affected by SCD, including the following:

●Dactylitis – 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'.)

●Avascular necrosis – Avascular necrosis of bone, also called osteonecrosis, ischemic necrosis, or aseptic necrosis, results from infarction of bone trabeculae. This is more common in older individuals. 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, and the individual may initially have back or leg pain rather than hip 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 – This can reduce hematopoietic reserve and decrease red blood cell (RBC) production. 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'.)

●Osteomyelitis – Osteomyelitis is 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. S. 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 S. pneumoniae [54]. Evaluation and distinction from vaso-occlusive pain are discussed separately. (See "Acute and chronic bone complications of sickle cell disease", section on 'Osteomyelitis and septic arthritis'.)

●Osteoporosis – Osteoporosis is increased due to several factors including hemolysis-induced bony changes and vitamin D deficiency [127].

Chronic hemolysis causes compensatory increase in erythropoietic activity and extension of hematopoietic bone marrow, leading to widening of the medullary space, thinning of the trabeculae and cortices, and osteoporosis. This can lead to a number of skeletal changes, including chronic tower skull, bossing of the forehead, and fish-mouth deformity of vertebrae.

Orbital compression syndrome may occur with vaso-occlusion in the periorbital bone marrow space and 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'.)

Assessment of bone health, bone density, and calcium and vitamin D intake are discussed separately. (See "Overview of preventive/outpatient care in sickle cell disease", section on 'Routine evaluations and preventive interventions' and "Bone health and calcium requirements in adolescents" and "Screening for osteoporosis in postmenopausal women and men" and "Calcium and vitamin D supplementation in osteoporosis" and "Acute and chronic bone complications of sickle cell disease".)

●Gout – The incidence of gout is higher in patients with SCD (18 percent, versus 4 percent in the general population) [18]. Acute gout may present similarly to an acute vaso-occlusive pain event.

Cardiac — Cardiac complications are a common, often unrecognized cause of morbidity and mortality in SCD and are a major cause of death in adult patients [13,128-130].

These may include:

●Acute MI – Acute myocardial infarction (MI) in the absence of coronary artery disease has been described in patients with SCD and is often misdiagnosed [25,128,129,131]. Individuals with SCD often lack atherosclerotic lesions, but they may have chest pain, with cardiac microvascular obstruction detected on cardiac MRI; microvascular occlusion resulting in acute myocardial ischemia in adults is underdiagnosed.

In a case-control study involving approximately 500 individuals with SCD and 500 controls presenting with acute myocardial infarction, those with SCD were more likely to lack risk factors for MI and to have a higher rate of complications and mortality [132]. 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 [133].

In an autopsy series, 7 of 72 consecutive patients with SCD (10 percent) had evidence of myocardial infarction despite the absence of obstructive or atherosclerotic lesions [131].

●Arrythmias – Conduction abnormalities including QT prolongation, ventricular arrhythmias, first-degree AV block, and nonspecific ST-T wave changes have been reported [128]. Certain medications such as methadone used in individuals with chronic pain may also increase the QT interval [134,135].

●Cardiomyopathy and heart failure – Cardiomyopathy is increasingly identified in individuals with SCD, especially left-sided diastolic dysfunction, with or without concomitant pulmonary hypertension (PH) [66,129,136-140]. Older individuals with SCD may have both right and left heart failure, with both systolic and diastolic dysfunction. Potential contributing factors may include:

•Pulmonary hypertension and early cor pulmonale [136,140]. (See 'Pulmonary' above.)

•Chronic anemia and hypoxemia with increased cardiac output, increased left ventricular stroke volume, and left ventricular dilatation [128,141-144]. (See 'Chronic compensated hemolytic anemia' above.)

•Transfusional iron overload, especially in older individuals [145,146]. (See "Transfusion in sickle cell disease: Management of complications including iron overload", section on 'Excessive iron stores'.)

•Hypertension. (See "Sickle cell disease effects on the kidney", section on 'Hypertension'.)

•Alterations in intravascular volume associated with vasculopathy and chronic kidney disease. (See "Sickle cell disease effects on the kidney", section on 'Sickle cell nephropathy'.)

•Myocardial fibrosis, which can be associated with left atrial dysfunction, increased tricuspid regurgitant velocity, reduced exercise capacity, and risk of arrhythmia [147].

•Age-related changes leading to loss of cardiac reserve, especially with fluid overload, hypertension, following transfusion, or during periods of hypoxemia [148].

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 [136]. This suggests that elevated tricuspid regurgitant jet velocity (TRV) and possibly secondary PH may be due to a primary cardiac condition. 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 [137]. End-systolic and end-diastolic left ventricular dimensions were higher in individuals with SCD and increased with age.

Exercise capacity is often diminished, but overt systolic heart failure is uncommon and restriction of activity is seldom necessary [149,150]. However, exercise performance may be improved by transfusion therapy [151]. (See "Red blood cell transfusion in sickle cell disease: Indications, RBC matching, and modifications".)

●Sudden death – Acute sudden death accounts for over 20 percent of deaths in patients with SCD, and cardiopulmonary causes are increasingly recognized as primary or contributing factors to sudden death [3,128,136,152,153]. Causes are often multifactorial, including a combination of cardiopulmonary dysfunction, restrictive cardiomyopathy, diastolic dysfunction, pulmonary fat embolism, pulmonary hypertension, sudden acute increases in pulmonary pressure, unexpected acute sequestration crisis, and/or intracranial hemorrhage. More aggressive evaluation of chest pain and underlying cardiovascular disease will provide risk assessment information that may decrease the incidence of sudden death in SCD [154,155].

Hepatobiliary — Approximately 10 to 40 percent of individuals with SCD have liver involvement, with a 7 percent mortality rate [156]. Diagnosis and management of hepatobiliary complications are discussed in detail separately. (See "Hepatic manifestations of sickle cell disease".)

●Sickle cell hepatopathy – This refers to hepatic dysfunction in individuals with SCD that may be due to several causes, including but not limited to the following [157-159]:

•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

•Hepatic fibrosis

●HCV infection – 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 [160].

•United States – The risk of HCV as a complication of blood transfusion has dramatically decreased with universal screening. (See "Blood donor screening: Laboratory testing", section on 'Hepatitis C virus'.)

•Sub-Saharan Africa – HCV remains a major health problem. (See "Sickle cell disease in sub-Saharan Africa", section on 'HIV'.)

Screening recommendations differ depending on the country of residence and its transfusion practices, presence of underlying liver disease, and other risk factors, as discussed separately. (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. Children with asymptomatic gallstones have much lower complication rates than children who are symptomatic [161]. Over time, as individuals age, the percentage of patients with gallstones increases along with the development of symptoms. (See "Hepatic manifestations of sickle cell disease", section on 'Cholelithiasis'.)

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

Management of gallstones requires a multidisciplinary approach, as there is controversy concerning whether asymptomatic gallstones can be followed indefinitely or should be removed electively. The associated risks increase in adults with comorbidities. We review the risk factors of individual adults in a multidisciplinary meeting with specialists from anesthesia, surgery, radiology, and hematology. 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 [159,162,163]. (See "Hepatic manifestations of sickle cell disease", section on 'Cholelithiasis' and "Approach to the management of gallstones", section on 'Cholecystectomy in selected patients'.)

Pregnancy — Pregnancy is associated with both fetal and maternal complications in individuals with SCD. (See "Sickle cell disease: Obstetric considerations", section on 'During pregnancy' and "Sickle cell disease: Obstetric considerations", section on 'Postpartum care'.)

●Fetal – Intrauterine growth restriction, low birth weight, and fetal death

●Maternal – Acute chest syndrome, infections, preeclampsia, and thromboembolic events

Reproductive and pregnancy care are discussed separately:

●Birth control and reproductive planning – (See "Overview of preventive/outpatient care in sickle cell disease", section on 'Routine evaluations and preventive interventions'.)

●Preconception counseling – With additional folic acid, medication management, alloantibody screening, and partner testing for hemoglobinopathies. (See "Sickle cell disease: Obstetric considerations", section on 'Before conception' and "Hemoglobinopathy: Screening and counseling in the reproductive setting and fetal diagnosis".)

●Pregnancy management – Requires a team of clinicians with expertise in SCD and high-risk pregnancy who can manage prophylactic transfusion if needed. Additional considerations include screening for asymptomatic bacteriuria and fetal growth restriction, discussion of the possible harvesting of cord blood for future hematopoietic cell transplant for first-degree relatives with SCD, and postpartum anticoagulation for those who have a 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 [164]. 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".)

OTHER MANIFESTATIONS

Growth and development — Impaired growth and delayed puberty are common in children with SCD. Most have growth reduction that affects weight more than height by the age of two years [165,166].

Height is often within the normal range 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 [167].

Children may have delayed sexual maturation and delayed menarche [165,168]. 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 [167]. (See "Delayed puberty: Approach to evaluation and management".)

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 preventive/outpatient care in sickle cell disease", section on 'Routine evaluations and preventive interventions'.)

Leg ulcers — Vaso-occlusion in the skin can produce leg ulcers and myofascial syndromes in patients with SCD.

●Mechanism – The mechanism is incompletely characterized. Development appears to correlate with trauma and the degree of hemolysis and/or anemia; compromised blood flow, endothelial dysfunction, thrombosis, inflammation, and delayed healing are thought to contribute [169].

In a series of 225 patients with SCD from Jamaica, 60 percent of leg ulcers 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 adverse social determinants of health, greater degrees of hemolysis, and Doppler evidence of venous insufficiency.

●Epidemiology – Individuals in tropical regions of the world are most likely to be affected. In Jamaica, prevalence from 30 to 70 percent has been reported [10,170].

●Presentation – Leg ulcers usually present after the age of 10 years and are more common in males than females [171-174]. Ulcers may develop spontaneously or after trauma. Typical sites include the medial and lateral malleolus [174]. Bilateral involvement is common.

Leg ulcers can cause significant pain, physical disability, and negative psychologic and social impacts.

●Clinical course – Leg ulcers in SCD may become superinfected. S. aureus, Pseudomonas species, streptococci, or Bacteroides species may be cultured. Rarely, they may lead to systemic infection, osteomyelitis, or tetanus [175].

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 [170].

●Treatment – Debridement, antibiotics, and other local and systemic therapies are discussed separately. (See "Overview of the care of adult patients with nonhealable wounds".)

●Prevention – Preventive strategies include well-fitting shoes and early, aggressive treatment if signs of skin injury appear. (See "Overview of preventive/outpatient care in sickle cell disease", section on 'Leg ulcers'.)

Venous thromboembolism — SCD is considered a hypercoagulable state, and patients are considered to be at increased risk of venous thrombosis and pulmonary thrombi or pulmonary embolism (PE), especially adults who have an indwelling catheter, immobility, infection, surgery, or pregnancy. Acute chest syndrome is associated with in situ pulmonary thrombi, which are often segmental or subsegmental thrombi in the site of an infiltrate on imaging [21,176]. Anticoagulation is indicated, but consideration of additional interventions for acute chest syndrome such as transfusions may also be warranted. (See "Acute chest syndrome (ACS) in sickle cell disease (adults and children)", section on 'Acute interventions'.)

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 "Sickle cell disease: Overview of management during hospital admission", section on 'Thromboembolism prophylaxis'.)

Psychosocial issues — The stress of living with a chronic medical condition may raise issues involving low self-esteem, social isolation, relationship difficulties, and withdrawal from normal daily living, although most individuals with SCD manage these stresses well [177].

●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 [178].

●Specific problem areas may include inappropriate pain coping strategies, reduced quality of life, anxiety, depression, and neurocognitive impairment [179-182].

●These may be compounded by silent cerebral infarctions due to neurovascular vaso-occlusion with delayed neurodevelopmental maturation [183]. (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 [184]. (See "Overview of preventive/outpatient care in sickle cell disease", section on 'Routine evaluations and preventive interventions'.)

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), hemolytic 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 or hepatic sequestration crisis' above.)

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

•Stroke – (See 'Neurologic' above.)

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

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

•Dactylitis or bone infarction – (See 'Skeletal' above.)

•Myocardial infarction – (See 'Cardiac' above.)

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

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

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

•Pulmonary conditions including asthma and pulmonary hypertension – (See 'Pulmonary' above.)

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

•Osteoporosis and complications of bone infarction – (See 'Skeletal' above.)

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

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

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

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

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

●Management – Separate topics discuss:

•Infection prophylaxis and routine screenings and evaluations. (See "Sickle cell disease in infancy and childhood: Routine health care maintenance and anticipatory guidance" and "Overview of preventive/outpatient care in sickle cell disease".)

•Transition from pediatric to adult care. (See "Sickle cell disease (SCD) in adolescents and young adults (AYA): Transition from pediatric to adult care".)

•Inpatient considerations. (See "Sickle cell disease: Overview of management during hospital admission".)

•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, who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.