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Hemolytic : Part 2 Kwesi Sackey in Review 1999;20;204 DOI: 10.1542/pir.20-6-204

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/20/6/204

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 1999 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.

Downloaded from http://pedsinreview.aappublications.org/ at Health Sciences Library State Univ Of New York on January 27, 2012 ARTICLE Hemolytic Anemia: Part 2* Kwesi Sackey, MD† ture, but precipitants may be OBJECTIVES unidentifiable. Upon completion of this article, readers should be able to: PAINFUL EPISODE 1. Describe the to which children who have are susceptible. This is the most frequent vaso- 2. Describe the complications of sickle cell disease. occlusive episode and results from 3. Describe the presentation of major. infarctions of the and cortical bone. It may occur early in the first year of life as “dactylitis” that involves the small of the associated with the formation of Sickle Cell Disease hands and feet (hand-foot syn- crystals of less soluble drome), but more commonly it DEFINITION S that align in a unique fashion, occurs later. No bone in the body is leading to the unusual shape of the Sickle cell disease is a hemoglobin- spared, but the spine, ribs, and long cell. Other precipitating factors opathy characterized by the inheri- bones are affected most frequently. include pH changes and temperature. tance of two abnormal hemoglobin Clinical features include pain of The rigid cells, in combination with genes, at least one of which is the acute or gradual onset with or with- the attendant increase in viscosity, sickle hemoglobin gene. The most out signs of local inflammation. result in sludging and organ common types are: hemoglobin SS Among systemic features are fever infarction. disease, hemoglobin SC disease, and and leukocytosis with neutrophilia hemoglobin S-thalassemia. The mimicking acute osteomyelitis. inheritance of one normal hemoglo- CLINICAL PRESENTATIONS Radiographs, bone scans, and bin gene (A) in association with gallium scans usually are of no help The clinical manifestations of sickle hemoglobin S leads to the formation in differentiating these episodes cell disease vary from patient to of hemoglobin AS, which also is from osteomyelitis; serial magnetic patient and from region to region, called sickle trait and is considered resonance imaging (MRI) appears to even among those who have appar- a carrier state, not a “disease.” be the most helpful modality. Useful ently similar phenotypes. The varia- differential features include the fact tion ranges from a complete lack of EPIDEMIOLOGY that long bone infarctions are symptoms even into adulthood to 50 times more common than osteo- The sickle gene is prevalent in West life-threatening complications begin- myelitis and that multifocal symp- Africa, Central Africa, the Mediter- ning in early infancy. Most affected toms are uncommon in osteomyeli- ranean, the Middle East, and certain patients, however, have long periods tis. A positive culture favors parts of India. It also is present in of “wellness” interspersed with the diagnosis of osteomyelitis; the other parts of the world where black recurrent symptomatic episodes. most common organisms are Salmo- immigrants from Africa comprise a Certain acute events, some of which nella sp, Staphylococcus aureus, and substantial portion of the population. are rather peculiar to sickle cell dis- Streptococcus pneumoniae. In the United States, the incidence ease, frequently may interrupt an of the sickle gene among African otherwise chronic course of the dis- Americans is 8%. ease. These events, which often are ACUTE CHEST SYNDROME referred to as “crises”, will be (EPISODE) , described in this article as “epi- Classically this is characterized by PATHOPHYSIOLOGY, AND sodes” because the word “crisis” an acute episode of chest pain in PATHOGENESIS denotes a situation hopelessly out of conjunction with the appearance of a In the sickle hemoglobin, a mutation control, which is not necessarily the new pulmonary infiltrate. Chest pain in codon 6 of the beta chain leads to case. may be absent initially or findings replacement of glutamic acid by on chest may be normal valine. This hemoglobin undergoes initially. The most common causes changes precipitated by many fac- VASO-OCCLUSIVE EPISODES are: 1) lung infarction, 2) pneumo- tors, with the classic one being These episodes, characterized by nia, 3) hypoventilation atelectasis, or deoxygenation. Deoxygenation is tissue infarction and often accompa- 4) a combination of these. It can nied by pain, can affect nearly all occur at any age. Features include organs or tissues (except probably chest pain, cough, fever, difficulty in the myocardium). The most common breathing, hypoxia, and leukocytosis. *Part 1 of this article appeared in the May 1999 issue. sites are the bones, lungs, spleen, Differentiating among the causes is †Associate Professor of Pediatrics, Division liver, penis, and brain. Precipitating difficult except with the use of a of /, The University of events can include , stress, ventilation-perfusion scan and the Texas Medical Branch, Galveston, TX. dehydration, or changes in tempera- presence of a positive blood culture.

204 Pediatrics in Review Vol. 20 No. 6 June 1999 Downloaded from http://pedsinreview.aappublications.org/ at Health Sciences Library State Univ Of New York on January 27, 2012 HEMATOLOGY Hemolytic Anemia

ACUTE ABDOMINAL EPISODE 2 years of transfusions, the recur- tions may produce the same effect. Causes of acute abdominal episodes rence rate for strokes is 70% within The aplasia usually lasts 10 to include acute cholecystitis, choleli- 3 years. Rarely, stroke may be from 14 days. thasis, acute intrahepatic sickling, hemorrhage rather than vaso-occlu- acute splenic infarction, and acute sion; the mortality in these cases is ACUTE SEQUESTRATION EPISODE mesenteric/lymph node infarction. If 50%. the pain is in the right upper quad- This is an acute trapping of blood in rant, the hepatobiliary tree is usually PRIAPISM the spleen and less frequently in the the source. Among the features are This sustained painful penile erec- liver caused by impaired egress of fever, chills, right upper quandrant tion occurs when drainage of blood blood out of these organs due to tenderness, enlarged liver, leukocy- out of the corpora cavernosa is clogging by sickled cells. It occurs commonly in preschool-age patients tosis, hyperbilirubinemia, and bio- impaired because of clogging by (before autosplenectomy) or in older chemical evidence of liver injury. sickled cells. It occurs at all ages and is estimated to occur in about children who have hemoglobin SC Ultrasonography usually identifies disease or hemoglobin S-beta thalas- the presence of gallstones. Splenic 50% of all patients into late adult- hood. There are two forms: 1) stut- semia with persistent splenomegaly. infarctions are associated with left tering, which lasts for fewer than The typical clinical picture is ane- upper quadrant pain and tenderness 24 hours per episode and is repeti- mia of rapid onset possibly with with “splinting” during inspiration. tive, and 2) prolonged, which lasts shock and a rapidly enlarging, pain- Mild pleural effusion with pleural for more than 24 hours. ful spleen. Precipitating factors are rub and segmental lower lobe atelec- The following is a recommended the same as for other acute vaso- tasis may be accompanying features. sequential approach to until occlusive episodes, but infections, The signs and symptoms of mesen- response is seen: 1) hydration and particularly upper respiratory tract teric/lymph node infarction are non- analgesia for the first 24 hours, infections and chest syndrome, have specific. Acute abdominal episodes 2) direct transfusion for the second been associated commonly with also may be a presenting feature of 24 hours, 3) exchange transfusion these episodes. The complete blood lower lobe pneumonia. A surgical for the third 24 hours, and 4) surgi- count reveals anemia, reticulocyto- abdomen always should be consid- cal intervention if there is no evi- sis, nucleated red blood cells, and ered in the differential diagnosis. dence of beginning detumescence . within a maximum of 48 hours fol- Transfusion invariably is needed lowing exchange transfusion. Pre- for treatment. Educating caregivers STROKE ferred surgical approaches are about palpation of an enlarged/ corporo-saphenous shunting or enlarging spleen and obtaining early This is usually a vaso-occlusive epi- medical attention can save lives. The sode resulting from occlusion of the corporo-glans shunting. Repeated priapism leads to sexual dysfunction. recurrence rate is nearly 50%. Elec- major arteries, such as the internal carotid, the anterior, and the middle Acute sequestration syndrome in patients who have sickle cerebral arteries usually at their bifurcation. Occlusion results from cell disease results from acute trapping of blood in the repeated progressive intimal fibrosis. spleen. Transfusion invariably is needed for treatment. It occurs in up to 7% of children and may be silent or overt. The TRANSIENT RED tive splenectomy following a maxi- spectrum of clinical features ranges APLASTIC EPISODE mum of two episodes is recom- from a decline in intelligence quo- This transient bone marrow arrest mended. Even though sequestration tient to hemiplegia, speech and affects primarily pre- may occur in the liver, the limited visual impairment, seizures, and cursors, but it also can affect white ability of this organ to expand coma. blood cells and to some results in less severe hematologic Transcranial Doppler is a good extent. The causative organism is and cardiovascular consequences. predictive screening tool for detect- parvovirus B19. Because the red INFECTIONS ing vasculopathy and altered blood blood cells in sickle cell disease flow, but MRI or magnetic reso- have a shortened life span (15 to Infections are common among nance angiography are the best diag- 50 days), the arrest may cause a fall patients who have sickle cell disease because functional asplenia resulting nostic tools for detecting stroke. in the hematocrit of up to 0.10 to from multiple infarcts leads to Treatment includes an initial 0.15 (10% to 15%) per day. The impaired production of antibodies exchange transfusion followed by hallmark is severe anemia with and opsonins and the absence of the regular direct transfusions for an reticulocytopenia. During the recov- splenic function of of indefinite period to keep levels of ery phase, nucleated red blood cells bacterial organisms. Infections are hemoglobin S at less than 0.30 Hb and reticulocytosis may be present. more frequent and more serious in fraction (Ͻ30%). Untreated strokes The virus produces the same clinical preschool-age children (15%) and are associated with a 20% mortality syndrome in other hemolytic ane- are associated with a 30% mortality rate. Following cessation of up to mias. Other viral and bacterial infec- rate. Fifty percent of those who have

Pediatrics in Review Vol. 20 No. 6 June 1999 205 Downloaded from http://pedsinreview.aappublications.org/ at Health Sciences Library State Univ Of New York on January 27, 2012 HEMATOLOGY Hemolytic Anemia hemoglobin SS disease are autosple- hemoglobin S in the anterior cham- ment put these patients at a psycho- nectomized by 2 years of age and ber following trauma may lead logical disadvantage. almost 100% are by 7 years of age. quickly to glaucoma. Sensorineural The risk of infection is highest with hearing loss may result from dam- encapsulated organisms such as age to the cochlea. Recurrent lung Other Sickle pneumococci (400 times greater infarctions and pneumonias can lead Hemoglobinopathies risk), Haemophilus influenzae (two to chronic lung disease. Resting HEMOGLOBIN SC DISEASE to four times increased risk), menin- arterial PO2 in steady-state may be gococci, and Salmonella sp. Infec- 65 to 85 mm Hg. There is evidence In this disease, glutamic acid in tions with organisms such as Myco- for increased shunting. Myocardial position 6 of the globin chain is plasma sp may present atypically infarctions are rare because of the replaced by lysine. The clinical with lobar consolidation. Clinically, rapid transit time of red blood cells manifestation is primarily chronic infection may present insidiously in coronary vessels. Left ventricular hemolytic anemia of lesser severity (eg, H influenzae) or as overwhelm- hypertrophy is common, but right than seen with sickle cell disease ing sepsis (eg, pneumococcus). ventricular hypertrophy and cor pul- (hemoglobin SS). Persistent painful A high index of suspicion and monale are seen only due to chronic vaso-occlusive episodes are less fre- proper use of antibiotics to cover the lung disease. quent. Splenomegaly is not uncom- three most common pathogens can Hyposthenuria leading to enuresis mon (60%). The complete blood be life-saving. Three cephalosporins is common. Hematuria that usually count reveals increased mean cor- provide adequate therapy; the choice is due to papillary necrosis involv- puscular hemoglobin concentration, is influenced by the patient’s clinical ing the left kidney occurs frequently microcytosis, and target cells in condition and by convenience. even in hemoglobin AS (sickle cell addition to anemia and reticulocyto- Ceftriaxone can be used on an out- trait), but it is more common in sis. The usual complications associ- patient basis once a day in patients hemoglobin SC disease. Gallstones ated with SS disease are found in who are not ill, cefotaxime has good develop in the first decade of life SC disease, but hematuria (from penetration of the central nervous and continue to progress. Repeated papillary necrosis), eye disease, system, and cefuroxime is available infarction leads to fibrosis (sickle aseptic necrosis of the femoral head, for both intravenous and oral admin- cell hepatopathy). Transfusion may and pregnancy-related complications istration. Parents and caregivers lead to hepatitis, and the gall blad- occur more frequently with hemo- should be taught to seek medical der may harbor Salmonella sp. globin SC. help as soon as possible after onset Sickle cell facies is characterized by of fever. It is recommended that frontal bossing and overgrowth of HEMOGLOBIN S THALASSEMIA children be given prophylactic anti- the maxilla from wide diploic This is usually a severe disease that biotics (penicillin, erythromycin, or spaces. Codfish vertebrae is a com- is characterized by many of the amoxicillin) at least for the first bination of flattened bones with manifestations of thalassemia as well as hemoglobin SS disease. It is recommended that children who have sickle cell disease be given prophylactic antibiotics at least for the HEMOGLOBIN SF DISEASE first 5 years of life. This is usually a mild disease.

5 years of life, starting as early as biconcave deformity. Aseptic necro- DIAGNOSIS 3 to 4 months of age. The optimum sis of the femoral head is more These diseases are diagnosed by duration of antibiotic administration common in hemoglobin SC disease. hemoglobin electrophoresis. Prenatal remains debatable. The use of Increases in both height and diagnosis may be made through cho- 24 valent pneumococcal, H influen- weight are affected negatively by rionic villi biopsy at 8 to 10 weeks’ zae, and meningococcal vaccines sickle cell disease, but the latter is gestation. Electrophoresis may be also is recommended. Children more so. Height catches up during performed on cord blood in the neo- receiving pneumococcal vaccine at adolescence. This growth delay may nate; ambiguous results require 2 years of age or younger require be evident as early as 2 years of repeat assessment at 3 months of reimmunization after that age. age. In females, menarche depends age and examination of family on weight as much as on age. Fertil- members. In late childhood, electro- LONG-TERM COMPLICATIONS ity is not affected in females, but phoresis may be performed on Nearly every organ system may be males have delayed sexual maturity peripheral blood. Family studies are affected by sickle cell disease. Silent as well as reduced fertility. Because always desirable. strokes may lead to a decrease in of recurrent hospital visits and hos- intelligence quotient and school per- pitalizations, it is not unusual for MANAGEMENT formance. Conjunctival vessel tortu- patients to fall behind their peers in Preventive management involves osity is common. Blindness may school work. In addition, the inabil- family studies, family counseling, result from retinopathy or central ity to keep up in sports and other and prenatal diagnosis to reduce retinal artery occlusion. The pres- activities combined with delayed propagation of the sickle gene. ence of any red blood cells with physical growth and sexual develop- Appropriate immunizations, penicil-

206 Pediatrics in Review Vol. 20 No. 6 June 1999 Downloaded from http://pedsinreview.aappublications.org/ at Health Sciences Library State Univ Of New York on January 27, 2012 HEMATOLOGY Hemolytic Anemia lin prophylaxis, and avoidance of rier) and deficiency of two genes have ascites due to heart failure that precipitating factors for acute epi- (alpha thalassemia trait) lead to no results from severe anemia. The sodes reduce the incidence of mor- symptoms; deficiency of three genes documents bidity and mortality. (hemoglobin H disease) and four hypochromic macrocytes and several Education of caregivers about the genes (hemoglobin Bart; hydrops nucleated red blood cells. Hemoglo- significance of fever, palpation of fetalis) leads to disease because of bin electrophoresis shows hemoglo- the spleen, and early medical inter- impaired synthesis of alpha globin bin H (beta4) and predominantly vention for affected patients can chains. hemoglobin Barts (gamma4). help to reduce the severity of com- There are two beta genes. Defi- plications. Medical interventions ciency of one leads to essentially no Beta Thalassemia Major include hydration, pain control, significant hemolysis (beta thalasse- The severity of this anemia results exchange transfusion, and chronic mia trait/thalassemia minor); defi- from a combination of ineffective transfusion therapy. Interventions at ciency of both genes leads to signif- and shortened sur- cellular and genetic levels include icant hemolytic anemia (thalassemia vival of the red blood cell in stimulation of increased hemoglobin major). Thalassemia intermedia is a circulation. F production (hydroxyurea), bone condition in which the degree of The complications of beta thalas- marrow transplant, and gene trans- hemolysis is milder even though the semia are those of increased iron fers (this is still experimental). patient may have a deficiency of absorption (a consequence of inef- both beta genes. Therefore, thalasse- fective erythropoiesis), hemolytic PROGNOSIS mia intermedia is essentially a anemia, and transfusions. Complica- Mortality is 2.6% in childhood for descriptive term that refers to mini- tions of hemolytic anemia include those who have hemoglobin SS dis- mal or no need for transfusions. ease, with the peak incidence of death occurring between ages 1 and Patients who have thalassemia should receive transfusion 3 years. The most frequent cause of therapy accompanied by chelation to reduce iron toxicity death is infection. For hemoglobin with deferoxamine. SS disease, the probability of surviv- ing until age 20 is 85%, and for CLINICAL PRESENTATIONS enlarged bone marrow cavity with hemoglobin SC disease it is 95%. Hemoglobin H Disease (Alpha thinning of cortex, specific facies, Thalassemia) gallstones, and chronic leg ulcers. Thalassemia This hemolytic anemia may present The complications of iron overload in the neonatal period as severe affect all organs of the body, includ- DEFINITION hypochromic anemia. Later in life ing the heart (arrhythmias, heart fail- ure), liver (cirrhosis), thyroid (hypo- This is a group of hereditary disor- the clinical features include anemia with and jaun- thyroidism), pancreas (diabetes), and ders of hemoglobin synthesis that hypothalamic-pituitary axis (delayed affects the globin chain and is char- dice. The hemoglobin level usually growth and sexual maturity). acterized in the more severe defi- is 1.09 to 1.55 mmol/L (7 to 10 g/ The aim of transfusion is to ciencies by mild-to-severe hemolytic dL), but it may be lower. Red blood maintain the pretransfusion hemo- anemia. They are classified accord- cells show hypochromia, microcyto- globin level at 1.55 mmol/L (10 g/ ing to the involved chain as alpha, sis, and fragmentation. Hemoglobin beta, or delta. electrophoresis reveals increased dL) or higher; the adequacy of hemoglobin H (beta4) of 0.5 to transfusion can be predicted by a count of EPIDEMIOLOGY 0.30 Hb fraction (5% to 30%) and increased hemoglobin Barts (gam- less than 5 nucleated red blood The milder forms of thalassemia are ma4) in the neonatal period. Hemo- cells/100 white blood cells. Transfu- among the most frequent genetic lysis may be precipitated by infec- sion is designed to suppress the defects in humans. Alpha thalasse- tions or oxidant drugs such as iron abnormal activity of the marrow, mia is found in people of African and sulfonamides. Treatment thereby allowing for normal growth descent and in Indochina, Malaysia, includes administration of folate, and development. Therefore, it and China. Beta thalassemia is avoidance of precipitating drugs, should be initiated as soon as possi- found largely in people of African transfusions as needed, and occa- ble (6 months to 1 year of age). and Mediterranean descent, but it sionally splenectomy for hyper- After the epiphyses are fused and also is widespread in the Far East, splenism. growth is complete, a lower pre- the Middle East, and the Asian transfusion hemoglobin level of subcontinent. 1.09 to 1.24 mmol/L (7 to 8 g/dL) Hydrops Fetalis (Alpha Thalassemia) may be adequate in some patients. PATHOLOGY, This is the most severe form of Transfusion therapy should be PATHOPHYSIOLOGY, AND alpha thalassemia. Because it is accompanied by chelation with PATHOGENESIS incompatible with life, affected deferoxamine to reduce iron toxicity. There are four alpha genes. Defi- patients are stillborn or die soon Most institutions prefer to start che- ciency of only one gene (silent car- after birth. They are edematous and lation at 3 to 4 years of age when

Pediatrics in Review Vol. 20 No. 6 June 1999 207 Downloaded from http://pedsinreview.aappublications.org/ at Health Sciences Library State Univ Of New York on January 27, 2012 HEMATOLOGY Hemolytic Anemia there usually is a sufficient amount of chelatable iron to make the risk: PIR QUIZ benefit ratio and cost effectiveness Quiz also available online at 12. Among the following, which is worthwhile. Chelation at a younger www.pedsinreview.org. most likely to be a long-term age is technically and socially more complication of hemoglobin SS 9. For patients who have hemoglobin disease? challenging, although some centers SS disease, osteomyelitis is differ- have embarked on chelation at the entiated from painful vaso-occlusive A. Cor pulmonale. time of initiating hypertransfusion. episodes in bone best by: B. Gallstones. C. Infertility in females. Complications associated with defer- A. Changes on serial magnetic D. Myocardial infarction. resonance imaging scans. oxamine therapy include deafness, E. Obesity. color and night blindness, visual B. Degree of leukocytosis. C. Early radiographic findings. 13. You are considering the initiation of field loss, predisposition to Yersenia D. Height of fever. infections, and mucormycosis. deferoxamine chelation therapy to E. Severity of pain. limit iron toxicity in a 4-year-old Splenectomy is indicated if: 10. The severe anemia that is produced girl who has beta thalassemia 1) the spleen is enlarged substan- by parvovirus B19 in many patients major. Among the following find- tially, 2) there is evidence of hyper- who have hemoglobin SS disease ings, which would be most likely in splenism with or without a massive reflects primarily: a patient who has iron overload? size leading to pancytopenia, or A. Accentuated intravascular A. Cirrhosis. 3) the requirements exceed sickling. B. Diabetes insipidus. 200 mL/kg per year. The success B. Deficient humoral immunity. C. Excessively tall stature. C. Dramatic decrease in production D. Hyperthyroidism. rate of curing thalassemia major by of mature red blood cells. E. Precocious puberty. bone marrow transplant is 75% to D. Impaired cellular immunity. 80%. E. Induced hypersplenism. 11. A 2-year-old boy who has hemo- Thalassemia Intermedia globin SS disease presents with a The definition of thalassemia inter- sudden onset of fever. In your office, his rectal temperature is media is the absence of chronic 39.2°C (102.6°F). Findings on phys- transfusion support in a patient who ical examination are otherwise unre- has the phenotype of thalassemia markable. Assuming that close major. These patients usually experi- follow-up is assured, the most appropriate choice of outpatient ence normal growth and develop- therapy is: ment and have low hemoglobin lev- A. Acetaminophen orally. els of 1.09 to 1.24 mmol/L (7 to B. Amoxicillin orally. 8 g/dL) that do not require C. Azithromycin orally. transfusions. D. Cefotaxime intramuscularly. E. Ceftriaxone intramuscularly.

SUGGESTED READING Embury SH, Hebbel RP, Mohandas N, Stein- bert MH. Sickle Cell Disease: Basic Prin- ciples and Clinical Practice. New York, NY: Raven Press; 1994 Lanzkowski P. Manual of Pediatric Hematol- ogy and Oncology. 2nd ed. New York, NY: Churchill Livingstone, Inc; 1995 Miller DR, Baehner RL, Miller LP. Blood Disease of Infancy and Childhood: In the Tradition of C.H. Smith. 7th ed. St. Louis, Mo: Mosby-Year Book; 1995 Nathan D, Orkin SH. Nathan and Oski’s Hematology of Infancy and Childhood. 5th ed. Philadelphia, Penn: WB Saunders; 1998 National Institutes of Health, National Heart, Lung, and Blood Institute. Management and Therapy of Sickle Cell Disease. 3rd ed. No 96–2117. Washington, DC: National Institutes of Health; 1995

208 Pediatrics in Review Vol. 20 No. 6 June 1999 Downloaded from http://pedsinreview.aappublications.org/ at Health Sciences Library State Univ Of New York on January 27, 2012 Hemolytic Anemia: Part 2 Kwesi Sackey Pediatrics in Review 1999;20;204 DOI: 10.1542/pir.20-6-204

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