Sickle Cell Anemia Clinical Presentation

Updated: Jul 27, 2017
  • Author: Joseph E Maakaron, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Presentation

History

Sickle cell disease (SCD) usually manifests early in childhood. For the first 6 months of life, infants are protected largely by elevated levels of Hb F; soon thereafter, the condition becomes evident.

The most common clinical manifestation of SCD is vaso-occlusive crisis. A vaso-occlusive crisis occurs when the microcirculation is obstructed by sickled RBCs, causing ischemic injury to the organ supplied and resultant pain. Pain crises constitute the most distinguishing clinical feature of sickle cell disease and are the leading cause of emergency department visits and hospitalizations for affected patients.

Approximately half the individuals with homozygous Hb S disease experience vaso-occlusive crisis. The frequency of crisis is extremely variable. Some have as many as 6 or more episodes annually, whereas others may have episodes only at great intervals or none at all. Each individual typically has a consistent pattern for crisis frequency.

Pain crises begin suddenly. The crisis may last several hours to several days and terminate as abruptly as it began.

The pain can affect any body part. It often involves the abdomen, bones, joints, and soft tissue, and it may present as dactylitis (bilateral painful and swollen hands and/or feet in children), acute joint necrosis or avascular necrosis, or acute abdomen. [24] With repeated episodes in the spleen, infarctions and autosplenectomy predisposing to life-threatening infection are usual. The liver also may infarct and progress to failure with time. Papillary necrosis is a common renal manifestation of vaso-occlusion, leading to isosthenuria (ie, inability to concentrate urine).

Severe deep pain is present in the extremities, involving long bones. Abdominal pain can be severe, resembling acute abdomen; it may result from referred pain from other sites or intra-abdominal solid organ or soft tissue infarction. Reactive ileus leads to intestinal distention and pain.

The face also may be involved. Pain may be accompanied by fever, malaise, and leukocytosis.

Bone pain is often due to bone marrow infarction. Certain patterns are predictable, since pain tends to involve bones with the most bone marrow activity and because marrow activity changes with age. During the first 18 months of life, the metatarsals and metacarpals can be involved, presenting as dactylitis or hand-foot syndrome.

As the child grows older, pain often involves the long bones of the extremities, sites that retain marrow activity during childhood. Proximity to the joints and occasional sympathetic effusions lead to the belief that the pain involves the joints. As marrow activity recedes further during adolescence, pain involves the vertebral bodies, especially in the lumbar region.

Although the above patterns describe commonly encountered presentations, any area with blood supply and sensory nerves can be affected.

Triggers of vaso-occlusive crisis

Often, no precipitating cause can be identified. However, because deoxygenated hemoglobin S (HbS) becomes semisolid, the most likely physiologic trigger of vaso-occlusive crises is hypoxemia. This may be due to acute chest syndrome or accompany respiratory complications.

Dehydration can precipitate pain, since acidosis results in a shift of the oxygen dissociation curve (Bohr effect), causing hemoglobin to desaturate more readily. Hemoconcentration also is a common mechanism.

Another common trigger is changes in body temperature—whether an increase due to fever or a decrease due to environmental temperature change. Lowered body temperature likely leads to crises as the result of peripheral vasoconstriction. Patients should wear proper clothing and avoid exposure to ensure normal core temperature.

Chronic pain in SCD

Many individuals with SCD experience chronic low-level pain, mainly in bones and joints. Intermittent vaso-occlusive crises may be superimposed, or chronic low-level pain may be the only expression of the disease.

Anemia

Anemia is universally present. It is chronic and hemolytic in nature and usually very well tolerated. While patients with an Hb level of 6-7 g/dL who are able to participate in the activities of daily life in a normal fashion are not uncommon, their tolerance for exercise and exertion tends to be very limited.

Anemia may be complicated with megaloblastic changes secondary to folate deficiency. These result from increased RBC turnover and folate utilization. Periodic bouts of hyperhemolysis may occur.

Children exhibit few manifestations of anemia because they readily adjust by increasing heart rate and stroke volume; however, they have decreased stamina, which may be noted on the playground or when participating in physical education class.

Aplastic crisis

A serious complication is the aplastic crisis. This is caused by infection with Parvovirus B-19 (B19V). This virus causes fifth disease, a normally benign childhood disorder associated with fever, malaise, and a mild rash. This virus infects RBC progenitors in bone marrow, resulting in impaired cell division for a few days. Healthy people experience, at most, a slight drop in hematocrit, since the half-life of normal erythrocytes in the circulation is 40-60 days. In people with SCD, however, the RBC lifespan is greatly shortened (usually 10-20 days), and a very rapid drop in Hb occurs. The condition is self-limited, with bone marrow recovery occurring in 7-10 days, followed by brisk reticulocytosis.

Splenic sequestration

Splenic sequestration occurs with highest frequency during the first 5 years of life in children with sickle cell anemia. Splenic sequestration can occur at any age in individuals with other sickle syndromes. This complication is characterized by the onset of life-threatening anemia with rapid enlargement of the spleen and high reticulocyte count.

Splenic sequestration is a medical emergency that demands prompt and appropriate treatment. Parents should be familiar with the signs and symptoms of splenic sequestration crises. Children should be seen as rapidly as possible in the emergency room. Treatment of the acute episode requires early recognition, careful monitoring, and aggressive transfusion support. Because these episodes tend to recur, many advocate long-term transfusion in young children and splenectomy in older children.

Infection

As HbS replaces HbF in the early months of life, problems associated with sickling and red cell membrane damage begin. The resulting rigid cells progressively obstruct and damage the spleen, which leads to functional asplenia. This, along with other abnormalities, results in extreme susceptibility to infection.

Organisms that pose the greatest danger include encapsulated respiratory bacteria, particularly Streptococcus pneumoniae. The mortality rate of such infections has been reported to be as high as 10-30%. Consider osteomyelitis when dealing with a combination of persistent pain and fever. Bone that is involved with infarct-related vaso-occlusive pain is prone to infection. Staphylococcus and Salmonella are the 2 most likely organisms responsible for osteomyelitis.

During adult life, infections with gram-negative organisms, especially Salmonella, predominate. Of special concern is the frequent occurrence of Salmonella osteomyelitis in areas of bone weakened by infarction.

Effects on growth and maturation

During childhood and adolescence, SCD is associated with growth retardation, delayed sexual maturation, and being underweight. Rhodes et al demonstrated that growth delays during puberty in adolescents with SCD is independently associated with decreased Hb concentration and increased total energy expenditure. [25]

Rhodes et al found that children with SCD progressed more slowly through puberty than healthy control children. Affected pubertal males were shorter and had significantly slower height growth than their unaffected counterparts, with a decline in height over time; however, their annual weight increases did not differ. In addition, the mean fat free mass increments in affected males and females were significantly less than those of the control children. [25]

Hand-foot syndrome

Infants with SCD may develop hand-foot syndrome, a dactylitis presenting as exquisite pain and soft tissue swelling of the dorsum of the hands and feet. The syndrome develops suddenly and lasts 1-2 weeks. Hand-foot syndrome occurs between age 6 months and 3 years; it is not seen after age 5 years because hematopoiesis in the small bones of the hands and feet ceases at this age. Osteomyelitis is the major differential diagnosis.

Cortical thinning and destruction of the metacarpal and metatarsal bones appear on radiographs 3-5 weeks after the swelling begins. Leukocytosis or erythema does not accompany the swelling.

Acute chest syndrome

In young children, the acute chest syndrome consists of chest pain, fever, cough, tachypnea, leukocytosis, and pulmonary infiltrates in the upper lobes. Adults are usually afebrile and dyspneic with severe chest pain and multilobar and lower lobe disease.

Acute chest syndrome is a medical emergency and must be treated immediately. Patients are otherwise at risk for developing acute respiratory distress syndrome.

Acute chest syndrome probably begins with infarction of ribs, leading to chest splinting and atelectasis. Because the appearance of radiographic changes may be delayed, the diagnosis may not be recognized immediately.

In children, acute chest syndrome is usually due to infection. Other etiologies include pulmonary infarction and fat embolism resulting from bone marrow infarction. Recognition of the specific cause is less critical than the ability to assess the management and pace of the lung injury.

Central nervous system involvement

Central nervous system involvement is one of the most devastating aspects of SCD. It is most prevalent in childhood and adolescence. The most severe manifestation is stroke, resulting in varying degrees of neurological deficit. Stroke affects 30% of children and 11% of patients by 20 years. It is usually ischemic in children and hemorrhagic in adults. [26]

Hemiparesis is the usual presentation. Other deficits may be found, depending on the location of the infarct.

Convulsions are frequently associated with stroke. Convulsions occur as an isolated event but also appear in the setting of evolving acute chest syndrome, pain crisis, aplastic crisis, and priapism. Rapid and excessive blood transfusion to a hemoglobin level of greater than 12 g/dL increases blood viscosity and can lead to stroke.

Children with sickle cell disease may have various anatomic and physiologic abnormalities that involve the CNS even if they appear to be neurologically healthy. These silent brain infarcts occur in 17% of patients and may be associated with deterioration in cognitive function, with effects on learning and behavior; these infarcts may increase the potential risk for clinical and subclinical damage to the CNS.

Hemorrhagic stroke is often caused by rupture of aneurysms that might be a result of vascular injury and tend to occur later in life. Moya moya, a proliferation of small fragile vessels found in patients with stenotic lesions, can also lead to cerebral hemorrhage. Hemorrhagic stroke is associated with a mortality rate of more than 29%.

Cardiac involvement

The heart is involved due to chronic anemia and microinfarcts. Hemolysis and blood transfusion lead to hemosiderin deposition in the myocardium. Both ventricles and the left atrium are all dilated.

A study by Nicholson et al also indicated that coronary artery dilation is common in children with SCD. The prevalence of coronary artery ectasia in patients with SCD was 17.7%, compared with 2.3% for the general population. [27] Furthermore, a systolic murmur is usually present, with wide radiation over the precordium.

Cholelithiasis

Cholelithiasis is common in children with SCD, as chronic hemolysis with hyperbilirubinemia is associated with the formation of bile stones. Cholelithiasis may be asymptomatic or result in acute cholecystitis, requiring surgical intervention. The liver may also become involved. Cholecystitis or common bile duct obstruction can occur.

Consider cholecystitis in a child who presents with right upper quadrant pain, especially if associated with fatty food. Consider common bile duct blockage when a child presents with right upper quadrant pain and dramatically elevated conjugated hyperbilirubinemia.

Renal involvement

The kidneys lose concentrating capacity. Isosthenuria results in a large loss of water, further contributing to dehydration in these patients. Renal failure may ensue, usually preceded by proteinuria. Nephrotic syndrome is uncommon but may occur.

Eye involvement

Paraorbital facial infarction may result in ptosis. Retinal vascular changes also occur. A proliferative retinitis is common in Hb SC disease and may lead to loss of vision. See Ophthalmic Manifestations of Sickle Cell Anemia for a complete discussion of this topic.

Leg ulcers

Leg ulcers are a chronic painful problem. They result from minor injury to the area around the malleoli. Because of relatively poor circulation, compounded by sickling and microinfarcts, healing is delayed and infection becomes established.

Priapism

Priapism, defined as a sustained, painful, and unwanted erection, is a well-recognized complication of SCD. Priapism tends to occur repeatedly. When it is prolonged, it may lead to impotence.

According to one study, the mean age at which priapism occurs is 12 years, and, by age 20 years, as many as 89% of males with sickle cell disease have experienced one or more episodes of priapism. Priapism can be classified as prolonged if it lasts for more than 3 hours or as stuttering if it lasts for more than a few minutes but less than 3 hours and resolves spontaneously. Stuttering episodes may recur or develop into more prolonged events.

Prolonged priapism is an emergency that requires urologic consultation. Recurrent episodes of priapism can result in fibrosis and impotence, even when adequate treatment is attempted.

Avascular necrosis

Vascular occlusion can result in avascular necrosis (AVN) of the femoral or humeral head and subsequent infarction and collapse at either site. AVN of the femoral head presents a greater problem because of weight bearing. Patients with high baseline hemoglobin levels are at increased risk. Approximately 30% of all patients with SCD have hip pathology by age 30 years.

The natural history of symptomatic hip disease in patients with sickle cell disease who are treated conservatively varies with the patient's age. In skeletally immature patients aged 12 years or younger, treatment with analgesics, NSAIDs, and protected weight bearing usually results in healing and remodeling of the involved capital epiphysis, similar to that observed in Legg-Calve-Perthes disease. This approach results in preservation of the joint despite the persistence of deformity, such as coxa magna and coxa plana.

In contrast, conservative management of osteonecrosis usually fails in older adolescents and adults. Progressive flattening and collapse of the femoral head results in painful secondary degenerative arthritis.

Pulmonary hypertension

Blood in the pulmonary circulation is deoxygenated, resulting in a high degree of polymer formation. The lungs develop areas of microinfarction and microthrombi that hinder the flow of blood. The resulting areas that lack oxygenation aggravate the sickling process. Pulmonary hypertension may develop. This may be due in part to the depletion of nitric oxide. Various studies have found that more than 40% of adults with SCD have pulmonary hypertension that worsens with age.

This is increasingly recognized as a serious complication of sickle cell disease, with an incidence as high as 31.8%. [28, 29] Familial clustering has also been recognized. Hemolysis, chronic hypoxia caused by sickle cell disease, and pulmonary disease (eg, recurrent acute chest syndrome, asthma, obstructive sleep apnea) are contributing factors.

Pulmonary hypertension is characterized by a regurgitant pulmonary (tricuspid) jet velocity of more than 2.5 m/s by echocardiography. Recently, there has been a lot of debate about the positive predictive value of measuring tricuspid regurgitant jet velocity. A recent study found that in a population of sickle cell patients, 25% had a tricuspid regurgitant jet of more than 2.5 m/s, but only 6% had actual pulmonary hypertension on right-sided heart catheterization. [30] It is associated with a high mortality rate in adult patients. Children with pulmonary hypertension have lower mortality, but the disease is associated with high morbidity.

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Physical Examination

Physical findings are not specific. Scleral icterus is present, and, upon ophthalmoscopic examination of the conjunctiva with the +40 lens, abnormal or corkscrew-shaped blood vessels may be seen. The mucous membranes are pale. A systolic murmur may be heard over the entire precordium.

Hypotension and tachycardia may be signs of septic shock or splenic sequestration crisis. With the severe anemia that accompanies aplastic crisis, patients may exhibit signs of high-output heart failure.

Orthostasis suggests hypovolemia. Tachypnea suggests pneumonia, heart failure, or acute chest syndrome. Dyspnea suggests acute chest syndrome, pulmonary hypertension, and/or heart failure.

Fever suggests infection in children; however, it is less significant in adults unless it is a high-grade fever. Examine the head and neck for meningeal signs or possible source of infection (eg, otitis, sinusitis).

Auscultate the heart to search for signs of congestive heart failure. Auscultate the lungs for signs of pneumonia, heart failure, or acute chest syndrome (similar to pulmonary embolism). Palpate for tenderness (abdomen, extremities, back, chest, femoral head) and hepatosplenomegaly.

In childhood, splenomegaly may be present, although this is not present in adults due to autosplenectomy. Spleen size should be measured, and parents should be made aware of it. A tongue blade may be used as a "spleen stick" in a small child, with the upper end of the blade corresponding to the nipple in the midclavicular line and a marking made on the stick corresponding to the edge of the spleen.

Growth parameters show patients falling below the growth isobars. This usually occurs around the prepubertal age because of delayed puberty.

Observe for pallor, icterus, and erythema or edema of the extremities or joints. In adults, leg ulcers may be found over the malleoli. Perform a neurological examination to search for focal neurological deficits.

Ocular manifestations

Go to Ophthalmic Manifestations of Sickle Cell Anemia for a complete discussion of this topic.

Meningitis

Meningitis is 200 times more common in children with HbSS. Consider lumbar puncture in children with fever who appear toxic and in those with neurologic findings such as neck stiffness, positive Brudzinski or Kernig signs, or focal deficits. Meningeal signs are not reliable if the children are irritable and inconsolable.

Skeletal manifestations

The characteristic appearance in children with sickle cell disease includes frontal and parietal bossing and prominent maxilla due to marrow hyperplasia expanding the bone. The extremities may appear proportionately longer than normal because there is often flattening of the vertebrae. Bone marrow expansion often causes maxillary hypertrophy with overbite; orthodontics consultations are recommended to prevent or correct this problem.

The physical findings of acute infarction include local effects from swelling of the affected bone, such as proptosis or ophthalmoplegia from orbital bone infarction. Also present is pain, swelling, and warmth of the involved extremity, such on the dorsa of the hands and feet in patients with dactylitis.

Sequelae of chronic infarction include structural and functional orthopedic abnormalities. Examples include an immobile or nonfunctional shoulder joint, abnormal hip growth and deformity, secondary osteoarthritis, shortened fingers and toes, and kyphoscoliosis.

Hand-foot syndrome

Hand-foot syndrome, or aseptic dactylitis, is a common presentation of sickle cell disease. This condition is caused by infarction of bone marrow and cortical bone in the metacarpals, metatarsals, and proximal phalanges. Hand-foot syndrome is usually one of the earliest manifestations of the disease.

Acute bone pain crisis

Acute bone pain crisis is caused by bone marrow ischemia or infarction. These crises usually start after age 2-3 years and occur as gnawing, progressive pain, most commonly in the humerus, tibia, and femur and less commonly in the facial bones. Periarticular pain and joint effusion, often associated with a sickle cell crisis, are considered a result of ischemia and infarction of the synovium and adjacent bone and bone marrow.

Patients with acute bone pain crisis usually present with fever, leukocytosis, and warmth and tenderness around the affected joints. This process tends to affect the knees and elbows, mimicking rheumatic fever and septic arthritis.

Osteonecrosis

In adolescence and adulthood, the most prominent complication is osteonecrosis of 1 or more epiphyses, usually of the femoral or humeral heads. Chronic pain is often associated with later stages of osteonecrosis, particularly in the femoral head. Pain due to avascular necrosis is most notable with weight bearing on the joint. Patients often have pain associated with functional limitation of the affected joint.

Osteomyelitis

Patients with sickle cell disease are prone to infection of the bone and bone marrow in areas of infarction and necrosis. Although Staphylococcus aureus is the most common cause of osteomyelitis in the general population, studies have shown that in patients with sickle cell disease, the relative incidence of Salmonella osteomyelitis is twice that of staphylococcal infection.

Nephrologic manifestations

See Nephrologic Manifestations of Sickle Cell Disease for more information on this topic.

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