Sickle Cell Anemia
Sickle cell anemia is a hereditary hemoglobinopathy. It is caused by a point mutation in the gene encoding for the beta-globin chain that results in changing the sixth amino acid from glutamic acid to valine. (So glutamine is ousted by valine). HbS (Alpha2Beta1 6 glu > val) polymerizes reversibly when deoxygenated to form a gelatinous network of fibrous polymers that stiffen the RBC membrane, increase viscosity. Also results in dehydration due to potassium leakage and calcium influx. RBC and especially reticuloctyes membranes are altered. They become sticky and stick to vascular endothelium. In the capillary venule it causes occlusion and microinfarction, ischemic tissue pain, malfunction, and autoinfarction of spleen. Shortened RBC survival due to hemolytic anemia leads to anemia, jaundice, gallstones, leg ulcers.
Most common d/o from production of a variant Hb.
Worldwide sickle cell anemia is the most common form of familial hemolytic anema.
AA are commonly affected.
Venocclusive crisis dominates the clinical course.
Homozygous recessive (Hb SS) is most common. It is a d/o in individuals who have inherited two mutant genes (one from each parent) that code for the synthesis for the beta-chains of the globin molecules. The resulting, referred to HB SS. The presence of disease is not evident in an infant until sufficient HbF has been replaced by HbS, so that sickling can occur. Painful crises, lifelong hemolytic anemia, increased susceptibility to infection and poor circulation.
Heterozygotes have one normal and one sickle-cell gene. 40% of HbS. Contain both HbA and HbS. These are said to have sickle cell trait.
Hb SC disease have more severe disease than sickle cell trait. HB S-beta thalassemia is another common heterozygous sickle cell disorder.
Pathophysiology:
Glutamate in position six is replaced with valine. Glutamate is usually charged and hydrophilic, and valine is nonpolar - not charged, and hydrophobic. So HBS is less soluble in its deoxygenated form. Molecules tend to aggregate to form fibers that deform red cells into a crescent or sickle shape. Such sickle cell block the flow of blood in the small diameter capillaries. Interruption in the supply of oxygen leads to localized anoxia, which causes pain and eventually death of cells in the vicinity. Other triggers: increased O2 tension due ot high altitude.
Prevention:
Dehydration and hypoxia must be avoided. Give IVF, hydration, O2.
Virgorous oral hydration during or in anticipation of periods of extreme exercise, exposure to heat or cold, emotional stress, or infection.
Folic acid, 1 mg PO daily because of chronic hemolysis.
Antimicrobial prophylaxis with PCN VK, 125 mg PO bid up to age 3 years and then 250 mg PO bid until 5 years, is effective at reducing the risk of infection. Those allergic to PCN should received erythromycin, 10 mg/kg PO bid. In most patients ABx prophylaxis should be discontinued after 5 years of age to decrease the risk of resistant organisms. ABx prophylaxis is appropriate for splenectomized patients during dental or other invasive procedures.
Immunizations against the usual childhood illness is necessary. Include HBV vaccine. After 2 years of age, a polyvalent pneumococcal vaccine should be administered. Yearly influenza vaccine is recommended.
Pneumococcal and H. influenzae vaccines are less effective in splenectomized patients. Thus, patients with sickle cell anemia should be vaccinated early in life.
Ophthalmologic examinations are recommended yearly in adults because of the high incidence of proliferative retinopathy, which leads to vitreous H'ge and retinal detachment.
Surgery and anesthesia. Local anesthesia can be used without special precautions. With GA, measures to avoid volume depletion, hypoxia, and hypernatremia are crucial. For major surgery, RBC transfusions to increase the Hb concentration to 10 g/dL seem to be be as effective as more aggressive regimens in most circumstances.
No hematologic findings are associated with sickle cell trait, which is a benign hereditary condition. Some risks have been reported in patients with sickle cell trait:
High altitude hypoxia → splenic infarction, CVA.
Basic training of military recruits associated with increased incidence of sudden death related to extreme exertion and dehydration.
Clinical presentation
Heterogenous presentations. Some Pts are asx some have repeated crisis needing hospitalization form early childhood.
Complications from chronic hemolysis with Hct 15-30%, and significant reticulocytosis, and/or vascular occlusion.
Trials suggest if Hct is ▲, reticulocytosis may be inhibited by negative feedback, at the expense of blood viscosity, however.
Granulocytosis is common, and fluctuates unpredictably during and between painful crisis, infectious episodes, and other intercurrent illnesses.
Vaso-occlusive complications, called painful crises include pain crises, fever, tachycardia, anxiety, avascular necrosis, priapism, and acute chest syndrome.
Pain can develop anywhere, can last few hrs - 2 wks.
Triggers: infection, fever, excessive exercise, anxiety, sudden changes in temp, hyoxia, or hypertonic dyes.
Hemolytic complications include pulmonary HTN, cholelithiasis, and leg ulcers. Strokes and renal medullary infarctions are complications of both.
Delayed growth and development occur in the pediatric years.
Acute intermittent complications:
Acute painful episodes ("sickle cell crisis")
Vaso-occlusive crisis are the most common manifestations of sickle cell disease.
Pain in long bones, back, chest, and abdomen.
Crises are precipitated by stress, including vasoreactivity of the microvascular system along with dehydration or infection or both, and generally last for 2 to 6 days. May last to 2 weeks.
Individual patients have a consistent pattern of presentation, but wide variability is found among patients depending on individual coping level to stress and illness.
Spleen is typically lost in first 18-36 month of life, causing susceptibility to infection, particulary by pneumococci.
Acute venous obstruction of spleen (splenic sequestration crisis), a rare occurrence in early childhood, may need emergency transfusion and/or splenectomy to prevent trapping of the entire arterial output in the obstructed spleen.
Acute chest syndrome occurs when hypoxia (SpO2 <90%) leads to an increase in intravascular sickling and irreversible occlusion of the microvasculature (predominantly pulmonary) circulation. Patients with lung pathology, such as pneumonia, are particularly at risk.
Characterized by CP, tachypnea, fever, cough, and arterial oxygen desaturation. It can mimic pneumonia, PE, bone marrow infarction and embolism, MI, or in situ lung infarction. Pulmonary infarction and pneumonia are the most frequent underlying or concomitant conditions in patients with this syndrome. It may require management in the ICU. Acute reduction of arterial O2 is especially ominous because it can promote sickling on a massive scale.
Needs ICU admission. It is a medical emergency.
Aplastic "crisis" presents with a sudden decrease in Hb level. The RI is inappropriately low, reflecting suppression of erythropoiesis. The most common etiology in pediatric patients is infection with parvovirus B19; folate deficiency should also be suspected because of the chronic increased requirements for erythropoiesis.
Priapism. Painful erection due to infarction of the venous outflow. Often presents in adolescence and may persists into adulthood. Lead to permanent impotence.
Cerebrovascular events: Stroke may occur at any age but is most common in children younger than 10 years and is usually caused by cerebral infarction. Less common in adults, and tends to be H'gic.
Neurologic complications of Hb SS disease include: ischemic stroke, intracranial hemorrhage, cranial neuropathies, spinal cord infarction (although rare), intracranial aneurysm formation with subarachnoid hemorrhage, ischemic optic neuropathy, optic atrophy, seizures, and headaches.
Ischemic stroke is more common in children with Hb SS disease than in adults.
In children, transcranial Doppler ultrasonography should be periodically performed, and when elevated velocities are detected, blood transfusions have been shown to reduce the risk of ischemic stroke.
Patients with Hb SS disease are more likely than those with hemoglobin SC (Hb SC) disease to suffer from neurologic complications.
Infections in adults typically occur in tissues that are susceptible to vasocclusive infarcts (bone, kidney, lung). Staphylococcus spp., Salmonella spp., and enteric organisms are the most common. Pneumonia is most likely to be caused by Mycoplasma pneumoniae, Staphylococcus aureus, or H. influenzae and must be distinguished from acute chest syndrome.
Renal medullary infarction results in chronic polyruia due to impaired urinary concentration, leading to a chronic risk of dehydration.
Renal tubular defects caused by sickling in the anoxic hyperosmolar environment of the renal medulla may lead to isosthenuria (inability to concentrate urine) and hematuria in both sickle cell trait and disease. These conditions predispose patients to dehydration, which increases the risk of vaso-occlusive events.
Cholelithiasis is present in more than 80% of patients, primarily due to bilirubin stones.
Osteonecrosis (AVN) of the femoral heads occurs in up to 50% of patients and is a cause of severe pain in adults. Sickle cell chronic arthropathy, and usual susceptibility to osteomyelitis from organisms like Salmonella.
Hand-foot syndrome is caused by painful infarcts of the digits and dactylitis.
Leg ulceration occurring at the ankle is often chronic and recurring. Occurs due to ischemia and superinfection of the distal circulation.
Pregnancy in a patient with sickle cell anemia should be considered high risk and is associated with increased spontaneous abortions or premature delivery, along with increased vaso-occlusive crisis.
Ophthalmological complications: rentinal infarcts in HbSC due to retinal vessel occlusion and H'ge, neovascularization, and eventual detachments.
Factors associated with increased morbidity and reduced survival are more than three crises requiring hospitalization per year, chronic neutrophilia, history of splenic sequestration or hand-foot syndrome and second episodes of acute chest syndrome.
Diagnostic Testing:
HbEP is used to diagnose sickle cell disease (Hb SS) from other hemoglobinopathies and distinguishes abnormal Hb types like sickle thalassemia, and Hb SC disease.
Mean Hb in Hb SS disease is about 8 g/dL (range 5 - 10 g/dL). MCV is slightly elevated due to reticulocytosis but is low in Hb S-beta thalassemia
Leukocytosis (10,000 - 20,000/mm3) and thrombocytes (>450,000/mm3) are common due to enhanced stimulation of the marrow compartment and to autosplenectomy.
Peripheral smear shows sickle-shaped RBCs, target cells (particulary in Hb SC and Hb S-beta thalassemia), and Howell-Jolly bodies, indicative of functional asplenism.
The degree of anemia and reticulocytosis is generally milder in Hb SC disease.
Treatment:
Acute vaso-occlusive complications, >3 time/year needs hospitalization. Chronic neutrophilia, history of splenic sequestration of hand-foot syndrome, and second episodes of acute chest syndrome.
http://www.nhlbi.nih.gov/health/prof/blood/sickle/sc_mngt.pdf
Most crisis resolves in 1-7 days.
IVF fluids, oral fluids (3 - 4 L/day)
Analgesia
PCA Morphine 2 mg/hr basal rate with boluses of 2 - 10 mg q6 -10 mintue is the drug of choice for moderate to severe pain.
Morphine 0.1 - 0.5 mg/kg IV q3- 4h OR
Hydromorphone, 0.02 - 0.04 mg/kg IV q2 - 3h is recommended OR
Meperidine, 0.75 - 1.5 mg/kg q2 - 4hr, used only for acute short-term pain control.
Ketorolac 30 - 60 mg initial dose, then 15 - 30 mg q6 - 8h for bone pain is effective.
Treat underlying cause that precipitated the crisis.
Transfusion therapy has no role in the treatment of uncomplicated vaso-occlusive crises.
Supplemental oxygen does not benefit acute pain crisis unless hypoxia is present.
Hydroxyurea therapy (10 - 30 mg/kg PO daily), ▲ by 5 mg/kg q2 weeks to a max of 35 mg/kg has been shown to increase levels of Hb F and significantly decreases the frequency of vaso-occlusive crises and acute chest syndrome in adults with sickle cell disease. Also suppresses granulocyte count and reticulocytosis. Dosage is adjusted to maintain a WBC 5000-8000/uL.
Considered in patients with crisis >3/year.
In acute chest syndrome require aggressive transfusion therapy, including red cell exchange. The presentation of acute chest syndrome is clinically indistinguishable from pneumonia; thus, empiric broad-spectrum antibiotics should be administered.
Iron chelation therapy can be used as dictated by transfusion frequency.
Priapism is initially treated with hydration and analgesia. Persistent erections for more than 24 hours may require transfusion therapy or surgical drainage.
Management of infections.
Antipyretic and empiric ABx therapy
Pt. suspected with aplastic crisis require hospitalization. Therapy included folic acid, 5 mg/d, as well as RBC transfusions.
Cholelithiasis may lead to acute cholecystitis or biliary colic. Acute cholecystitis should be treated medically with ABx and cholecystectomy should be performed when the attack subsides. Elective cholecystectomy for asymptomatic gallstones is controversial.
Treatment of osteonecrosis consists of local heat, analgesics, and avoidance of weight bearing. Hip and shoulder arthroplasty may be effective in decreasing symptoms and improving function.
Pts with history of stroke, long-term transfusions to maintain the Hb S concentration to <50% for at least 5 years significantly reduce the incidence of recurrence.
Leg ulcers should be treated with rest, leg elevation, and intensive local care. Wet to dry dressings should be applied three to four times per day. A zinc oxide-impregnated bandage (Unna boot), changed weekly for 3 - 4 weeks, can be used for nonhealing or more extensive ulcers.
Diagnostic evaluation of pneumonia, and PE must be thorough.
If arterial SpO2 <90%, may need PRBCs to maintain Hct >30. Emergency exchange transfusion needed.
As patients with sickle cell survive into their 50s-60s, ESRD and pulmonary HTN are becoming more prominent causes of end-stage morbidity.
Cardiomyopathy/ premature CAD may compromise cardiac function.
Bone marrow transplantation can provide definitive cures but is known to be effective and safe only in children.
Children who do suffer a stroke should be maintained for at least 3-5 years on a program of vigorous exchange transfusion, as the risk of second strokes is very high.
Agents blocking RBC dehydration or vascular adhesion, such as clotrimazole or magnesium is being evaluated for efficacy.