Sections

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.^[31]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.^[32]

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.^[32]

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.^[33]

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.^[34]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. Kidney 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%.^{[35, 36]}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.^[37]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.

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

Sickle cell vasoocclusive events can affect every vascular bed in the eye, often with visually devastating consequences in advanced stages of the disease.

Anterior segment abnormalities include the following:

Segmentation "corkscrew" conjunctival vessel, more commonly seen in the inferior bulbar conjunctiva
Iris infarct and atrophy
Cataracts
Phthisis bulbi
Hyphema

The abnormalities of the posterior segment can be divided into 6 categories, as follows^{[38, 39, 40, 41]}:

Optic disc changes
Posterior retinal and macular vascular occlusionChronic macular changes (sickling maculopathy)
Choroidal vascular occlusions
Nonproliferative retinal changes
Proliferative retinal changes

Optic disc changes

Intravascular occlusions on the surface of the optic disc appear ophthalmoscopically as dark-red intravascular spots. These occlusions are transient and do not produce any clinical impairment.^[42]These changes are most common in hemoglobin SS disease but can also occur in patients with hemoglobin SC and hemoglobin S.

Posterior retinal and macular vascular occlusions

Retinal artery occlusions are either central or branch. Peripapillary or macular arteriolar occlusions are rare. Retinal vein occlusions also are rare with SCD.

Chronic macular changes

Chronic macular vascular occlusions occur in SCD. These are manifested by microaneurysms resembling dots, hairpin-shaped vascular loops, and abnormal foveal avascular zone (FAZ).

Choroidal vascular occlusions

This is an extremely rare manifestation of SCD. Only 3 cases have been reported thus far in the literature.

Nonproliferative retinal changes

Nonproliferative or background sickle retinopathy includes the following manifestations:

Venous tortuosity
Salmon-patch hemorrhage
Schisis cavity
The black sunburst

Venous tortuosity probably is due to arteriovenous shunting from the retinal periphery. It can occur in many patients with hemoglobin SS and hemoglobin SC disease.

Salmon-patch hemorrhages are superficial intraretinal hemorrhages. They are usually seen in the mid periphery of the retina adjacent to a retinal arteriole.

The schisis cavity is a space caused by the disappearance of the intraretinal hemorrhage. Nonproliferative sickle retinopathy features iridescent spots and glistening refractive bodies in the schisis cavity.

The black sunburst consists of round chorioretinal scars usually located in the equatorial fundus. These lesions result from pigment accumulated around the vessels. They do not cause any visual symptoms.

Proliferative sickle retinopathy

Proliferative sickle retinopathy (PSR) is the most severe ocular change in SCD. This is a peripheral retinal change most frequent in patients with hemoglobin SC but also can be present in patients with hemoglobin S–thalassemia disease, homozygous hemoglobin SS, and hemoglobin AS and hemoglobin AC disease.^{[43, 44]}

PSR is progressive. A desirable objective is to treat the neovascular tissue before a vitreous hemorrhage occurs.

Goldberg classified PSR into the following 5 stages:

Peripheral arteriolar occlusions
Arteriolar-venular anastomosis
Neovascular proliferation
Vitreous hemorrhage
Retinal detachment

In stage I, the peripheral arteriolar vessels occlude, with anteriorly located avascular vessels evident. Early in the process, the occluded arterioles are dark-red lines, but eventually they turn into silver-wire–appearing vessels.

In stage II, peripheral arteriolar-venular anastomosis occurs as the eye adjusts to peripheral arteriolar occlusion, and blood is diverted from the occluded arterioles into the adjacent venules. Peripheral to these anastomoses, no perfusion is present.

In stage III, new vessel formation occurs at the junction of the vascular and avascular retina. These neovascular tufts resemble sea fans. Initially, the sea fans can be fed by a single arteriole and draining vessel.

Later, as the sea fan grows in size, it is difficult to distinguish the major feeding and draining vessels. The sea fans may acquire a glial and fibrotic tissue envelope. This envelope may pull on the vitreous. A full-thickness retinal break, which may lead to total rhegmatogenous retinal detachment, may occur.

For more information, see Ophthalmologic Manifestations of Sickle Cell Disease (SCD).

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.

Differential Diagnoses

Pecker LH, Lanzkron S. Sickle Cell Disease. Ann Intern Med. 2021 Jan. 174 (1):ITC1-ITC16. [QxMD MEDLINE Link].
Sedrak A, Kondamudi NP. Sickle Cell Disease. 2021 Jan. [QxMD MEDLINE Link]. [Full Text].
Shatat IF, Jakson SM, Blue AE, Johnson MA, Orak JK, Kalpatthi R. Masked hypertension is prevalent in children with sickle cell disease: a Midwest Pediatric Nephrology Consortium study. Pediatr Nephrol. 2013 Jan. 28(1):115-20. [QxMD MEDLINE Link].
Linguraru MG, Orandi BJ, Van Uitert RL, Mukherjee N, Summers RM, Gladwin MT, et al. CT and image processing non-invasive indicators of sickle cell secondary pulmonary hypertension. Conf Proc IEEE Eng Med Biol Soc. 2008. 2008:859-62. [QxMD MEDLINE Link]. [Full Text].
Olujohungbe A, Howard J. The clinical care of adult patients with sickle cell disease. Br J Hosp Med (Lond). 2008 Nov. 69(11):616-9. [QxMD MEDLINE Link].
Johnson L, Carmona-Bayonas A, Tick L. Management of pain due to sickle cell disease. J Pain Palliat Care Pharmacother. 2008. 22(1):51-4. [QxMD MEDLINE Link].
De D. Acute nursing care and management of patients with sickle cell. Br J Nurs. 2008 Jul 10-23. 17(13):818-23. [QxMD MEDLINE Link].
Teixeira RS, Terse-Ramos R, Ferreira TA, Machado VR, Perdiz MI, Lyra IM, et al. Associations between endothelial dysfunction and clinical and laboratory parameters in children and adolescents with sickle cell anemia. PLoS One. 2017. 12 (9):e0184076. [QxMD MEDLINE Link]. [Full Text].
Manwani D, Frenette PS. Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies. Blood. 2013 Dec 5. 122 (24):3892-8. [QxMD MEDLINE Link]. [Full Text].
Zen Q, Batchvarova M, Twyman CA, Eyler CE, Qiu H, De Castro LM, et al. B-CAM/LU expression and the role of B-CAM/LU activation in binding of low- and high-density red cells to laminin in sickle cell disease. Am J Hematol. 2004 Feb. 75(2):63-72. [QxMD MEDLINE Link].
Ford AL, Ragan DK, Fellah S, Binkley MM, Fields ME, Guilliams KP, et al. Silent infarcts in sickle cell anemia occur in the borderzone region and are associated with low cerebral blood flow. Blood. 2018 Jul 30. [QxMD MEDLINE Link].
Stotesbury H, Kirkham FJ, Kölbel M, Balfour P, Clayden JD, Sahota S, et al. White matter integrity and processing speed in sickle cell anemia. Neurology. 2018 Jun 5. 90 (23):e2042-e2050. [QxMD MEDLINE Link]. [Full Text].
Merlet AN, Chatel B, Hourdé C, Ravelojaona M, Bendahan D, Féasson L, et al. How Sickle Cell Disease Impairs Skeletal Muscle Function: Implications in Daily Life. Med Sci Sports Exerc. 2018 Aug 8. [QxMD MEDLINE Link].
Silva PO, Ferreira AS, Lima CMA, Guimarães FS, Lopes AJ. Balance control is impaired in adults with sickle cell anaemia. Somatosens Mot Res. 2018 Jul 16. 1-10. [QxMD MEDLINE Link].
Morris CR. Asthma management: reinventing the wheel in sickle cell disease. Am J Hematol. 2009 Apr. 84(4):234-41. [QxMD MEDLINE Link].
National Institutes of Health. Introduction to Genes and Disease: Anemia, Sickle Cell. National Center for Biotechnology Information. Available at http://www.ncbi.nlm.nih.gov/books/NBK22238/. Accessed: October 14, 2015.
Centers for Disease Control and Prevention. Sickle Cell Disease: Health Care Professionals: Data & Statistics. Centers for Disease Control and Prevention. Department of Health and Human Services. Available at http://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed: September 28, 2016.
Abbott KC, Hypolite IO, Agodoa LY. Sickle cell nephropathy at end-stage renal disease in the United States: patient characteristics and survival. Clin Nephrol. 2002 Jul. 58(1):9-15. [QxMD MEDLINE Link].
Powars DR, Elliott-Mills DD, Chan L, Niland J, Hiti AL, Opas LM, et al. Chronic renal failure in sickle cell disease: risk factors, clinical course, and mortality. Ann Intern Med. 1991 Oct 15. 115(8):614-20. [QxMD MEDLINE Link].
Derebail VK, Nachman PH, Key NS, Ansede H, Falk RJ, Kshirsagar AV. High prevalence of sickle cell trait in African Americans with ESRD. J Am Soc Nephrol. 2010 Mar. 21(3):413-7. [QxMD MEDLINE Link]. [Full Text].
Audard V, Homs S, Habibi A, Galacteros F, Bartolucci P, Godeau B, et al. Acute kidney injury in sickle patients with painful crisis or acute chest syndrome and its relation to pulmonary hypertension. Nephrol Dial Transplant. 2010 Aug. 25(8):2524-9. [QxMD MEDLINE Link].
Scheinman JI. In: Holliday M, Barratt TM, Avner ED (Eds.). Sickle cell nephropathy. Baltimore: Williams and Wilkins; 1994. Pediatric Nephrology: 908.
Nissenson AR, Port FK. Outcome of end-stage renal disease in patients with rare causes of renal failure. I. Inherited and metabolic disorders. Q J Med. 1989 Nov. 73(271):1055-62. [QxMD MEDLINE Link].
Saborio P, Scheinman JI. Disease of the month - Sickle cell nephropathy. J Amm Soc Nephrol. 1999. 10:187.
Miller ST, Sleeper LA, Pegelow CH, Enos LE, Wang WC, Weiner SJ, et al. Prediction of adverse outcomes in children with sickle cell disease. N Engl J Med. 2000 Jan 13. 342(2):83-9. [QxMD MEDLINE Link].
Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, et al. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med. 1994 Jun 9. 330(23):1639-44. [QxMD MEDLINE Link].
Quinn CT, Rogers ZR, Buchanan GR. Survival of children with sickle cell disease. Blood. 2004 Jun 1. 103(11):4023-7. [QxMD MEDLINE Link]. [Full Text].
Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, et al. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004 Feb 26. 350(9):886-95. [QxMD MEDLINE Link].
Parent F, Bachir D, Inamo J, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med. 2011 Jul 7. 365(1):44-53. [QxMD MEDLINE Link].
Wright SW, Zeldin MH, Wrenn K, Miller O. Screening for sickle-cell trait in the emergency department. J Gen Intern Med. 1994 Aug. 9(8):421-4. [QxMD MEDLINE Link].
Chiang EY, Frenette PS. Sickle cell vaso-occlusion. Hematol Oncol Clin North Am. 2005 Oct. 19(5):771-84, v. [QxMD MEDLINE Link].
Rhodes M, Akohoue SA, Shankar SM, Fleming I, Qi An A, Yu C, et al. Growth patterns in children with sickle cell anemia during puberty. Pediatr Blood Cancer. 2009 Oct. 53(4):635-41. [QxMD MEDLINE Link]. [Full Text].
Telfer P, Coen P, Chakravorty S, Wilkey O, Evans J, Newell H, et al. Clinical outcomes in children with sickle cell disease living in England: a neonatal cohort in East London. Haematologica. 2007 Jul. 92(7):905-12. [QxMD MEDLINE Link].
Nicholson GT, Hsu DT, Colan SD, et al. Coronary artery dilation in sickle cell disease. J Pediatr. 2011 Nov. 159(5):789-794.e1-2. [QxMD MEDLINE Link].
Dahoui HA, Hayek MN, Nietert PJ, et al. Pulmonary hypertension in children and young adults with sickle cell disease: evidence for familial clustering. Pediatr Blood Cancer. 2010. 54(3):398-402.
Onyekwere OC, Campbell A, Teshome M, Onyeagoro S, Sylvan C, Akintilo A, et al. Pulmonary hypertension in children and adolescents with sickle cell disease. Pediatr Cardiol. 2008 Mar. 29(2):309-12. [QxMD MEDLINE Link].
Parent F, Bachir D, Inamo J, et al. A hemodynamic study of pulmonary hypertension in sickle cell disease. N Engl J Med. 2011 Jul 7. 365(1):44-53. [QxMD MEDLINE Link].
Akinsola FB, Kehinde MO. Ocular findings in sickle cell disease patients in Lagos. Niger Postgrad Med J. 2004 Sep. 11 (3):203-6. [QxMD MEDLINE Link].
Hingorani M, Bentley CR, Jackson H, Betancourt F, Arya R, Aclimandos WA, et al. Retinopathy in haemoglobin C trait. Eye (Lond). 1996. 10 ( Pt 3):338-42. [QxMD MEDLINE Link].
Sokol JA, Baron E, Lantos G, Kazim M. Orbital compression syndrome in sickle cell disease. Ophthalmic Plast Reconstr Surg. 2008 May-Jun. 24 (3):181-4. [QxMD MEDLINE Link].
Wisotsky BJ, Tesser PM, Schultz JS. Trabecular meshwork hemorrhage in a patient with sickle cell trait. Arch Ophthalmol. 1995 Mar. 113 (3):381. [QxMD MEDLINE Link].
Goldbaum MH, Jampol LM, Goldberg MF. The disc sign in sickling hemoglobinopathies. Arch Ophthalmol. 1978 Sep. 96 (9):1597-600. [QxMD MEDLINE Link].
Babalola OE, Wambebe CO. When should children and young adults with sickle cell disease be referred for eye assessment?. Afr J Med Med Sci. 2001 Dec. 30 (4):261-3. [QxMD MEDLINE Link].
Gill HS, Lam WC. A screening strategy for the detection of sickle cell retinopathy in pediatric patients. Can J Ophthalmol. 2008 Apr. 43 (2):188-91. [QxMD MEDLINE Link].
[Guideline] Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014 Dec. 45 (12):3754-832. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Centre for Clinical Practice at NICE (UK). Guidelines for the management of the acute painful crisis in sickle cell disease. Br J Haematol. 2012 Jun. 120(5):744-52. [QxMD MEDLINE Link]. [Full Text].
[Guideline] US Preventive Services Task Force. Screening for sickle cell disease in newborns: U.S. Preventive Services Task Force recommendation statement. Agency for Healthcare Research and Quality (AHRQ). Sep 2007. [Full Text].
Bernard AW, Venkat A, Lyons MS. Best evidence topic report. Full blood count and reticulocyte count in painful sickle crisis. Emerg Med J. 2006 Apr. 23(4):302-3. [QxMD MEDLINE Link]. [Full Text].
Cerci SS, Suslu H, Cerci C, Yildiz M, Ozbek FM, Balci TA, et al. Different findings in Tc-99m MDP bone scintigraphy of patients with sickle cell disease: report of three cases. Ann Nucl Med. 2007 Jul. 21(5):311-4. [QxMD MEDLINE Link].
[Guideline] Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014. National Heart, Lung and Blood Institute. Available at https://www.nhlbi.nih.gov/sites/default/files/media/docs/Evd-Bsd_SickleCellDis_Rep2014.pdf. September 8, 2014; Accessed: August 31, 2018.
Lee MT, Piomelli S, Granger S, Miller ST, Harkness S, Brambilla DJ, et al. Stroke Prevention Trial in Sickle Cell Anemia (STOP): extended follow-up and final results. Blood. 2006 Aug 1. 108(3):847-52. [QxMD MEDLINE Link]. [Full Text].
Adams RJ, Brambilla D. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med. 2005 Dec 29. 353(26):2769-78. [QxMD MEDLINE Link]. [Full Text].
Hammoudi N, Lionnet F, Redheuil A, Montalescot G. Cardiovascular manifestations of sickle cell disease. Eur Heart J. 2020 Apr 1. 41 (13):1365-1373. [QxMD MEDLINE Link].
[Guideline] Brawley OW, Cornelius LJ, Edwards LR, Gamble VN, Green BL, Inturrisi C, et al. National Institutes of Health Consensus Development Conference statement: hydroxyurea treatment for sickle cell disease. Ann Intern Med. 2008 Jun 17. 148(12):932-8. [QxMD MEDLINE Link]. [Full Text].
Payne J, Aban I, Hilliard LM, Madison J, Bemrich-Stolz C, Howard TH, et al. Impact of early analgesia on hospitalization outcomes for sickle cell pain crisis. Pediatr Blood Cancer. 2018 Aug 27. e27420. [QxMD MEDLINE Link].
Hand L. Sickle Cell Treatment Guideline Released. Medscape Medical News. Available at http://www.medscape.com/viewarticle/831603. Accessed: September 14, 2014.
Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, et al. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014 Sep 10. 312(10):1033-48. [QxMD MEDLINE Link].
Brown T. FDA OKs First New Treatment for Sickle Cell in Almost 20 Years. Medscape Medical News. Available at http://www.medscape.com/viewarticle/882617. July 7, 2017; Accessed: July 10, 2017.
FDA approves new treatment for sickle cell disease. U.S. Food & Drug Administration. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm566084.htm. July 7, 2017; Accessed: July 10, 2017.
Niihara Y, et al; Investigators of the Phase 3 Trial of l-Glutamine in Sickle Cell Disease. A Phase 3 Trial of l-Glutamine in Sickle Cell Disease. N Engl J Med. 2018 Jul 19. 379 (3):226-235. [QxMD MEDLINE Link].
Ataga KI, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2017 Feb 2. 376 (5):429-439. [QxMD MEDLINE Link]. [Full Text].
Kutlar A, Kanter J, Liles DK, Alvarez OA, Cançado RD, Friedrisch JR, et al. Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis. Am J Hematol. 2019 Jan. 94 (1):55-61. [QxMD MEDLINE Link].
Vichinsky E, Hoppe CC, Ataga KI, et al and the, HOPE Trial Investigators. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med. 2019 Aug 8. 381 (6):509-519. [QxMD MEDLINE Link].
Gluckman E, Cappelli B, Bernaudin F, et al, behalf of Eurocord, the Pediatric Working Party of the European Society for Blood and Marrow Transplantation, et al. Sickle cell disease: an international survey of results of HLA-identical sibling hematopoietic stem cell transplantation. Blood. 2017 Mar 16. 129 (11):1548-1556. [QxMD MEDLINE Link]. [Full Text].
Curtis SA, Shah NC. Gene therapy in sickle cell disease: Possible utility and impact. Cleve Clin J Med. 2020 Jan. 87 (1):28-29. [QxMD MEDLINE Link]. [Full Text].
Orkin SH, Bauer DE. Emerging Genetic Therapy for Sickle Cell Disease. Annu Rev Med. 2018 Oct 24. [QxMD MEDLINE Link].
Ribeil JA, Hacein-Bey-Abina S, Payen E, et al. Gene Therapy in a Patient with Sickle Cell Disease. N Engl J Med. 2017 Mar 2. 376 (9):848-855. [QxMD MEDLINE Link]. [Full Text].
bluebird bio Presents New Data for LentiGlobin Gene Therapy in Sickle Cell Disease at 60th Annual Meeting of the American Society of Hematology. bluebirdbio. Available at http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-presents-new-data-lentiglobin-gene-therapy-sickle. December 3, 2018; Accessed: January 29. 2019.
Esrick EB, Lehmann LE, Biffi A, et al. Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease. N Engl J Med. 2021 Jan 21. 384 (3):205-215. [QxMD MEDLINE Link].
McGann PT, Ware RE. Hydroxyurea therapy for sickle cell anemia. Expert Opin Drug Saf. 2015 Sep 14. 1-10. [QxMD MEDLINE Link].
Heeney MM, Ware RE. Hydroxyurea for children with sickle cell disease. Pediatr Clin North Am. 2008 Apr. 55(2):483-501, x. [QxMD MEDLINE Link].
Strouse JJ, Lanzkron S, Beach MC, Haywood C, Park H, Witkop C, et al. Hydroxyurea for sickle cell disease: a systematic review for efficacy and toxicity in children. Pediatrics. 2008 Dec. 122(6):1332-42. [QxMD MEDLINE Link].
Hankins JS, McCarville MB, Rankine-Mullings A, Reid ME, Lobo CL, et al. Prevention of conversion to abnormal TCD with hydroxyurea in sickle cell anemia: A phase III international randomized clinical trial. Am J Hematol. 2015 Sep 28. [QxMD MEDLINE Link].
Siklos (hydroxyurea) Prescribing Information [package insert]. Bryn Mawr, Pennsylvania: Medunik USA, Inc. 12/2017. Available at [Full Text].
Hilliard LM, Kulkarni V, Sen B, Caldwell C, Bemrich-Stolz C, Howard TH, et al. Red blood cell transfusion therapy for sickle cell patients with frequent painful events. Pediatr Blood Cancer. 2018 Aug 27. e27423. [QxMD MEDLINE Link].
Firth PG, Head CA. Sickle cell disease and anesthesia. Anesthesiology. 2004 Sep. 101(3):766-85. [QxMD MEDLINE Link].
Cappellini MD, Piga A. Current status in iron chelation in hemoglobinopathies. Curr Mol Med. 2008 Nov. 8(7):663-74. [QxMD MEDLINE Link].
Rienhoff HY Jr, Viprakasit V, Tay L, et al. A phase 1 dose-escalation study: safety, tolerability, and pharmacokinetics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload. Haematologica. 2011 Apr. 96(4):521-5. [QxMD MEDLINE Link]. [Full Text].
Das BB, Sobczyk W, Bertolone S, Raj A. Cardiopulmonary stress testing in children with sickle cell disease who are on long-term erythrocytapheresis. J Pediatr Hematol Oncol. 2008 May. 30(5):373-7. [QxMD MEDLINE Link].
Leen JS, Ratnakaram R, Del Priore LV, Bhagat N, Zarbin MA. Anterior segment ischemia after vitrectomy in sickle cell disease. Retina. 2002 Apr. 22 (2):216-9. [QxMD MEDLINE Link].
Karim A, Laghmari M, Dahreddine M, Guedira K, Ibrahimy W, Essakali N, et al. [Hyphema with secondary hemorrhage: think about sickle cell disease]. J Fr Ophtalmol. 2004 Apr. 27 (4):397-400. [QxMD MEDLINE Link].
Nasrullah A, Kerr NC. Sickle cell trait as a risk factor for secondary hemorrhage in children with traumatic hyphema. Am J Ophthalmol. 1997 Jun. 123 (6):783-90. [QxMD MEDLINE Link].
Rogovik AL, Li Y, Kirby MA, Friedman JN, Goldman RD. Admission and length of stay due to painful vasoocclusive crisis in children. Am J Emerg Med. 2009 Sep. 27(7):797-801. [QxMD MEDLINE Link].
Wang WC, Ware RE, Miller ST, et al. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY HUG). Lancet. 2011 May 14. 377(9778):1663-72. [QxMD MEDLINE Link].
Gladwin MT, Kato GJ, Weiner D, et al. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA. 2011 Mar 2. 305(9):893-902. [QxMD MEDLINE Link].
[Guideline] Howard J, Hart N, Roberts-Harewood M, Cummins M, Awogbade M, Davis B, et al. Guideline on the management of acute chest syndrome in sickle cell disease. Br J Haematol. 2015 May. 169 (4):492-505. [QxMD MEDLINE Link]. [Full Text].
Styles L, Wager CG, Labotka RJ, Smith-Whitley K, Thompson AA, Lane PA, et al. Refining the value of secretory phospholipase A2 as a predictor of acute chest syndrome in sickle cell disease: results of a feasibility study (PROACTIVE). Br J Haematol. 2012 Jun. 157 (5):627-36. [QxMD MEDLINE Link]. [Full Text].
Ogunlesi F, Heeney MM, Koumbourlis AC. Systemic corticosteroids in acute chest syndrome: friend or foe?. Paediatr Respir Rev. 2014 Mar. 15 (1):24-7. [QxMD MEDLINE Link].
[Guideline] Brandow AM, Carroll CP, Creary S, Edwards-Elliott R, Glassberg J, Hurley RW, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020 Jun 23. 4 (12):2656-2701. [QxMD MEDLINE Link]. [Full Text].
Goodwin EF, Partain PI, Lebensburger JD, Fineberg NS, Howard TH. Elective cholecystectomy reduces morbidity of cholelithiasis in pediatric sickle cell disease. Pediatr Blood Cancer. 2016 Sep 19. [QxMD MEDLINE Link].
Rogers ZR. Priapism in sickle cell disease. Hematol Oncol Clin North Am. 2005 Oct. 19(5):917-28, viii. [QxMD MEDLINE Link].
Burnett AL, Bivalacqua TJ, Champion HC, Musicki B. Long-term oral phosphodiesterase 5 inhibitor therapy alleviates recurrent priapism. Urology. 2006 May. 67(5):1043-8. [QxMD MEDLINE Link].
Burnett AL, Anele UA, Trueheart IN, Strouse JJ, Casella JF. Randomized controlled trial of sildenafil for preventing recurrent ischemic priapism in sickle cell disease. Am J Med. 2014 Jul. 127 (7):664-8. [QxMD MEDLINE Link]. [Full Text].
Chinegwundoh FI, Smith S, Anie KA. Treatments for priapism in boys and men with sickle cell disease. Cochrane Database Syst Rev. 2020 Apr 6. 4:CD004198. [QxMD MEDLINE Link].
[Guideline] Furie KL, Kasner SE, Adams RJ, Albers GW, Bush RL, Fagan SC, et al. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association. Stroke. 2011 Jan. 42(1):227-76. [QxMD MEDLINE Link]. [Full Text].
Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998 Jul 2. 339(1):5-11. [QxMD MEDLINE Link].
DeBaun MR, Gordon M, McKinstry RC,et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med. 2014 Aug 21. 371(8):699-710. [QxMD MEDLINE Link].
[Guideline] Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011 Feb. 42(2):517-84. [QxMD MEDLINE Link]. [Full Text].
Freed J, Talano J, Small T, Ricci A, Cairo MS. Allogeneic cellular and autologous stem cell therapy for sickle cell disease: 'whom, when and how'. Bone Marrow Transplant. 2012 Dec. 47 (12):1489-98. [QxMD MEDLINE Link]. [Full Text].
Ware RE, Helms RW, SWiTCH Investigators. Stroke With Transfusions Changing to Hydroxyurea (SWiTCH). Blood. 2012 Apr 26. 119 (17):3925-32. [QxMD MEDLINE Link].
Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet. 2016 Feb 13. 387 (10019):661-70. [QxMD MEDLINE Link].
Walters MC, De Castro LM, Sullivan KM, Krishnamurti L, Kamani N, Bredeson C, et al. Indications and Results of HLA-Identical Sibling Hematopoietic Cell Transplantation for Sickle Cell Disease. Biol Blood Marrow Transplant. 2016 Feb. 22 (2):207-211. [QxMD MEDLINE Link]. [Full Text].
Tanhehco YC, Bhatia M. Hematopoietic stem cell transplantation and cellular therapy in sickle cell disease: where are we now?. Curr Opin Hematol. 2019 Nov. 26 (6):448-452. [QxMD MEDLINE Link].
Krishnamurti L, Neuberg DS, Sullivan KM, et al. Bone marrow transplantation for adolescents and young adults with sickle cell disease: Results of a prospective multicenter pilot study. Am J Hematol. 2019 Apr. 94 (4):446-454. [QxMD MEDLINE Link]. [Full Text].
Kar BC. Splenectomy in sickle cell disease. J Assoc Physicians India. 1999 Sep. 47(9):890-3. [QxMD MEDLINE Link].
Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1997 Apr 4. 46:1-24. [QxMD MEDLINE Link].
Kazancioglu R, Sever MS, Yüksel-Onel D, Eraksoy H, Yildiz A, Celik AV, et al. Immunization of renal transplant recipients with pneumococcal polysaccharide vaccine. Clin Transplant. 2000 Feb. 14(1):61-5. [QxMD MEDLINE Link].
Fiore AE, Shay DK, Broder K, Iskander JK, Uyeki TM, Mootrey G, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep. 2009 Jul 31. 58:1-52. [QxMD MEDLINE Link].
[Guideline] Liem RI, Lanzkron S, D Coates T, DeCastro L, Desai AA, Ataga KI, et al. American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease. Blood Adv. 2019 Dec 10. 3 (23):3867-3897. [QxMD MEDLINE Link]. [Full Text].
[Guideline] DeBaun MR, Jordan LC, King AA, Schatz J, Vichinsky E, Fox CK, et al. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv. 2020 Apr 28. 4 (8):1554-1588. [QxMD MEDLINE Link]. [Full Text].
[Guideline] Chou ST, Alsawas M, Fasano RM, Field JJ, Hendrickson JE, Howard J, et al. American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support. Blood Adv. 2020 Jan 28. 4 (2):327-355. [QxMD MEDLINE Link]. [Full Text].
Kanter J, Liem RI, Bernaudin F, Bolaños-Meade J, Fitzhugh CD, Hankins JS, et al. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 2021 Sep 28. 5 (18):3668-3689. [QxMD MEDLINE Link]. [Full Text].

Media Gallery

Molecular and cellular changes of hemoglobin S.
Skeletal sickle cell anemia. H vertebrae. Lateral view of the spine shows angular depression of the central portion of each upper and lower endplate.
Peripheral blood with sickled cells at 400X magnification. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Peripheral blood smear with sickled cells at 1000X magnification. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Peripheral blood smear with Howell-Jolly body, indicating functional asplenism. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Effects of therapy with hydroxyurea.
Skeletal sickle cell anemia. Bone-within-bone appearance. Following multiple infarctions of the long bones, sclerosis may assume the appearance of a bone within a bone, reflecting the old cortex within the new cortex.
A 12-year-old boy with HgbSS disease presents to the pediatric emergency department after his mother tried to wake him for school this morning and noted altered mental status, left-sided gaze paralysis with his head tilted to the left, and flaccid paralysis of the right arm and leg. A CT scan of the brain was obtained immediately.
Embolic stroke of the left middle cerebral artery. SCD is the most common cause of stroke in children and one of the most devastating complications of SCD. Clinically overt strokes are typically due to embolism of the intracranial internal carotid artery and proximal middle cerebral artery (MCA), while "silent strokes" more typically occur in the smaller lacunar and penetrating arteries. As RBCs undergo sickling and hemolysis within the cerebral circulation, they adhere to the vascular endothelium and promote a hypercoaguable state and fuel thromboembolism formation. Treatment options include prophylactic therapy with hydroxyurea to promote HgbF concentrations and monitoring via transcranial Doppler to evaluate MCA blood flow velocity. Children found to have high velocities are at increased risk for stroke and commonly receive RBC transfusions to decrease the concentration of HgbS.
The spleen enlarges during the first year of life in SCD, as it becomes congested with trapped slow-flowing sickled cells within the splenic sinuses and reticuloendothelial system. The histology image shown demonstrates splenic congestion from sequestered sickled RBCs (arrows). Microvascular occlusions produce chronic tissue hypoxia and microinfarctions. Over time, fibrosis induces autosplenectomy. With functional asplenia, patients are particularly susceptible to infection by the encapsulated organisms Streptococcus pneumoniae and Haemophilus influenzae. Vaccination and prophylactic daily penicillin throughout childhood are mainstays of treatment to prevent sepsis and meningitis
Splenic sequestration is an important cause of morbidity that occurs when sudden splenic pooling of blood within the reticuloendothelial system causes an acute drop in circulatory volume and shock-like symptoms (hypotension, tachycardia) with a rigid distended abdomen. It is an acute emergency and can be fatal in 1-2 hours secondary to circulatory hypovolemia. Treatment is with volume resuscitation and blood transfusion. The CT image shown demonstrates splenomegaly with a mass-like process (arrows) from splenic sequestration.
Patients with SCD are also at increased risk of developing pulmonary arterial hypertension (PAH). The etiology is most likely multifactorial but likely related to increased cardiac output secondary to underlying chronic anemia. Impedance to the elevated blood flow will cause further dilation and increase in pulmonary pressures. Postsickling changes including interstitial fibrosis secondary to vaso-occlusive crisis of ACS and hypoperfusion with resultant hypoxia of the pulmonary vascular beds are both proposed offenders inciting further dilation and elevation of pulmonary pressures. A pulmonary arteriogram depicting the markedly dilated vascular supply of the lungs seen in PAH is shown.
Proliferative sickle cell retinopathy. Sickle cell retinopathy is believed to be vaso-occlusion of peripheral arterioles of the retina leading to retinal hypoxia, ischemia, and infarction. New vessels then form at the junction of the vascular and avascular areas of retina. This neovascularization of retinal tissue and resultant traction of fibrovascularization places patients at risk for vitreous hemorrhage (arrows) and retinal detachment. Another common ocular manifestation is hyphema. Anterior chamber bleeding occurs spontaneously, but sickled erythrocytes obstruct the trabecular meshwork leading to significant elevations of intraocular pressure. Patients are particularly susceptible to glaucomatous optic nerve damage from even mildly elevated intraocular pressures. Pressures greater than 36 mm Hg for 24 hours are an indication for surgical drainage in both SCD and sickle cell trait, regardless of the size of hyphema. Image courtesy of the National Eye Institute, National Institutes of Health (NEI/NIH).
A 19-year-old man with known HgbSS disease presents because his girlfriend reports his eyes are yellow. He has no complaints. Physical exam is notable for mild abdominal pain, but is otherwise within normal limits. What imaging test is warranted for this work-up? The image shown is of a male child with similar symptoms. Image courtesy of Wikimedia Commons.
Right upper quadrant ultrasoundChronic hemolysis of sickled cells in HgbSS disease and high heme turnover yields hyperbilirubinemia and is associated with increased formation of bile stones. Stone formation occurs as substances in bile reach concentrations that approach the limits of their solubility. As saturation levels are reached, crystals precipitate, become trapped in mucus, and produce sludge (shown). Over time, the crystals aggregate and form stones. Occlusion of the biliary tree by sludge and/or stones produces clinical disease, typically right upper quadrant pain. The scleral icterus seen in the image of the previous slide is most likely secondary to the elevated circulating levels of bilirubin as a result of an acute hemolytic event (such as an acute vaso-occlusive crisis).
Renal papillary necrosisThe microvascular beds of the renal parenchyma are susceptible to sickling and vaso-occlusive crisis because of their inherent low-oxygen and high-osmolarity state. Depending on the location of occlusion, symptoms vary from a decreased ability to concentrate urine (yielding nocturia and polyuria), a disruption of exchange mechanisms (yielding hyperkalemia) or hematuria, which further damages renal tubules. In renal papillary necrosis, repeated vascular occlusion infarcts the renal medullary pyramids and papillae. This causes sloughing of papillae, which obstructs the urinary tract. Treatment options include hydration, high-dose antibiotics for resulting pyelonephritis, and possible percutaneous nephrostomy tube or invasive retrieval of sloughed papillae in acute urinary obstruction. The intravenous pyelogram demonstrates the "egg-in-a-cup" appearance of sloughed renal papillae (arrows) secondary to renal papillary necrosis.
Skeletal sickle cell anemia. Hand-foot syndrome. Soft tissue swelling with periosteal new-bone formation and a moth-eaten lytic process at the proximal aspect of the fourth phalanx.
Skeletal sickle cell anemia. Advanced dactylitis. Lytic processes are present at the first and fifth metacarpals, along with periostitis, which is most prominent in the third metacarpal.
Skeletal sickle cell anemia. Expanded medullary cavity. The diploic space is markedly widened due to marrow hyperplasia. Trabeculae are oriented perpendicular to the inner table, giving a hair-on-end appearance.
Skeletal sickle cell anemia. Detailed view of the expanded medullary cavity in the same patient as in the previous image.
Skeletal sickle cell anemia. Osteonecrosis. Image shows flattening of the femoral heads with a mixture of sclerosis and lucency characteristic of osteonecrosis.
Skeletal sickle cell anemia. Osteonecrosis. Detail of the right hip.
Skeletal sickle cell anemia. Osteonecrosis. Detail of the left hip.
Skeletal sickle cell anemia. Bone infarct. Image shows patchy sclerosis of the humeral head and shaft representing multiple prior bone infarcts.
Skeletal sickle cell anemia. Chronic infarcts and secondary osteoarthritis. Image shows advanced changes of irregular sclerosis and lucency on both sides of the knee joint reflecting numerous prior infarcts. The joint surfaces are irregular and the cartilages are narrowed due to secondary osteoarthritis.
Skeletal sickle cell anemia. Osteonecrosis. Coronal T1-weighted MRI shows a slightly flattened femoral head with a serpentine margin of low signal intensity around an area of ischemic marrow with signal intensity similar to that of fat.
Skeletal sickle cell anemia. Osteonecrosis in the same patient as in the previous image. Coronal T2-weighted MRI shows a serpentine area of low signal intensity and additional focal areas of abnormal low signal intensity in the femoral head; these findings reflect collapse of bone and sclerosis.
Skeletal sickle cell anemia. Osteomyelitis. CT scan in a soft tissue window demonstrates a large abscess in the left thigh encircling the femur, with hypoattenuating pus surrounded by a rim of vivid enhancement.
Skeletal sickle cell anemia. Osteomyelitis and bone-within-bone. Bone-window CT scan in the same patient as in the previous image shows a bone-within-bone appearance (concentric rings of cortical bone) in the right femur. On the left, a sinus tract (cloaca) traverses the lateral aspect of the femoral cortex, and a small, shardlike sequestrum is present deep to the sinus tract.
Skeletal sickle cell anemia. Bone scan of bone infarct shows an area of increased uptake in the distal femoral metaphysis corresponding to the infarct demonstrated on the previous plain radiograph.

of 30

Author

Joseph E Maakaron, MD Research Fellow, Department of Internal Medicine, Division of Hematology/Oncology, American University of Beirut Medical Center, Lebanon

Disclosure: Nothing to disclose.

Coauthor(s)

Ali T Taher, MD, PhD, FRCP Professor of Medicine, Associate Chair of Research, Department of Internal Medicine, Division of Hematology/Oncology, Director of Research, NK Basile Cancer Center, American University of Beirut Medical Center, Lebanon

Disclosure: Nothing to disclose.

Specialty Editor Board

Jeanne Yu, PharmD

Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Mark Ventocilla, OD, FAAO Chief Executive Officer, Elder Eye Care Group, PLC; Chief Executive Officer, Mark Ventocilla, OD, Inc; President, California Eye Wear, Oakwood Optical

Mark Ventocilla, OD, FAAO is a member of the following medical societies: American Academy of Optometry, American Optometric Association

Disclosure: Nothing to disclose.

Acknowledgements

Roy Alson, MD, PhD, FACEP, FAAEM Associate Professor, Department of Emergency Medicine, Wake Forest University School of Medicine; Medical Director, Forsyth County EMS; Deputy Medical Advisor, North Carolina Office of EMS; Associate Medical Director, North Carolina Baptist AirCare

Roy Alson, MD, PhD, FACEP, FAAEM is a member of the following medical societies: Air Medical Physician Association, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, National Association of EMS Physicians, North Carolina Medical Society, Society for Academic Emergency Medicine, and World Association for Disaster and Emergency Medicine