Hematologic emergencies in the pediatric emergency room

Hematologic emergencies in the pediatric emergency room


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HEMATOLOGIC EMERGENCIES IN THE PEDIATRIC EMERGENCY ROOM Peter D. Sadowitz, MD, Siraj Amanullah, MD, and Abdul-Kader Souid, MD, PhD

Children with various hematologic problems frequently present to the emergency department (ED) and require a careful physical examination, appropriate diagnostic testing, and prompt initiation of therapy. In this brief review, the common causes and treatment for children with anemia, neutropenia, thrombocytopenia, and abnormal hemostasis are discussed. ANEMIA Introduction to the Pediatric Hemogram Hemoglobin (Hgb) concentration varies with age, with higher values being present in the newborn and adolescent male (Table 1).17, 23, 36, 40 The high Hgb level at birth occurs in response to the low fetal ambient oxygen tension (PO2 ⬃30 mm Hg). Immediately after birth, the rise in arterial PO2 (⬃90 mm Hg) decreases erythropoietin production, producing the ‘‘physiologic anemia’’ seen in the first 2 months of life (i.e., Hgb concentration of ⬃10 g/dL at ⬃2 months of age). This period is followed by a steady rise in Hgb, reaching a maximum at about 14 years of age.

From the Departments of Pediatrics (PDS, SA, AS) and Emergency Medicine (PDS, SA), State University of New York, Upstate Medical University, Syracuse, New York





Table 1. THE PEDIATRIC HEMOGRAM Lower Limits (2 SD) of the Hemoglobin Concentrations (g/dL) Birth: 14.5 2 wk: 12.5 1 mo: 11.0 2–6 mo: 10.0 0.5–2 yr: 10.5 2–6 yr: 11.0 6–12 yr: 11.5 12–18 yr (males): 14.0 12–18 yr (females): 12.3 Normal Reticulocyte Counts (% and Absolute) Birth: 3–7% (100–500103/mm3) 1 week–2 months: 0.1–1.0% (10–50103/mm3) ⬎12 months 1–2% (50–100103/mm3) Normal MCV (fl) Values Birth: 98–116 ⬎one month to ⱕ9 years: 70  age in years–96 ⬎9 years to adults: 80–96

Adolescent male children have higher Hgb levels in response to androgen production. Normal red blood cell (RBC) counts average ⬃5.0  106 mm3 (mm3  ␮l). In adults and children older than 1 year, reticulocytes (immature, non-nucleated RBC containing ribonucleic acid) constitute 1% to 2% of the circulating RBC (i.e., ⬃ 50–100  103/mm3); (Table 1). Mean cell volume (MCV), the average volume of RBC, is expressed in femtoliter (fl) or cubic micrometer (fl  10–15 L). The RBCs are macrocytic at birth, ranging from 98 to 116 fl.17, 36 After 1 month of age, the lowest normal MCV is 70 fl; thereafter ‘‘70 fl plus years of age until the age of 9.’’ Normal MCV values for adults are 80 fl to 96 fl (see Table 1). The red cell distribution width (RDW) measures the variation of individual RBC volume from the mean value (the more variation the larger the RDW). Most instruments calculate RDW by dividing standard deviation by MCV. Normal RDW values are 11.5% to 14.5%. Review of the blood smear is instructive and can be diagnostic. For example, the presence of spherocytes or fragmented RBC reflects hemolysis; whereas small RBC with large areas of central pallor (hypochromia) suggest iron deficiency or thalassemia. Figures 1 and 2 summarize the differential diagnosis of anemia. The most common entities are discussed below. Iron Deficiency This deficiency is the leading cause of anemia in early childhood and can be severe (e.g., Hgb ⬍4 g/dL). The anemia is characterized by



Figure 1. Differential diagnosis of anemia. *Resulting from inadequate iron or impaired protoporphyrin or globin-chain synthesis;† resulting from increased RBC destruction commonly associated with jaundice, reticulocytosis, and splenomegaly.

Figure 2. Pathology of anemia.



a low Hgb, RBC count, MCV, and reticulocyte count, with elevated free erythrocyte protoporphyrin (FEP) and RDW. During the first 4 to 6 months of life, most full-term infants are iron sufficient owing to transplacental passage of iron during the last trimester of pregnancy. Thereafter, in the absence of adequate iron intake, most children become iron depleted. Iron deficiency is most common in the first 3 years of life, resulting from inadequate iron intake during this period of rapid growth. Iron deficiency is also common in young children consuming whole cow’s milk, because excessive milk ingestion can cause colitis and gastrointestinal bleeding. In addition, children ingesting large quantities of milk often eat little meat, further aggravating the iron-deficient state.4 Children older than 3 years with iron deficiency require gastrointestinal evaluation to rule out occult blood loss because nutritional iron deficiency is uncommon in this period.39 The most conclusive evidence of iron deficiency anemia is the incremental rise in Hgb concentration during therapeutic iron supplementation (i.e., iron-responsive anemia). Optimal response is obtained with 3 to 6 mg/kg/day of elemental iron; ferrous sulfate is the preferred form. Typically, the reticulocyte count increases within 1 week, and gradual correction of Hgb occurs over 4 weeks. In most patients, the treatment should continue for about 3 months. Iron studies are rarely necessary in young children with a typical history and characteristic blood count findings. Recommendations to prevent iron deficiency anemia include iron supplementation (1–2 mg/kg/day) for all breastfed infants after 3 months of age, use of iron-fortified formulas (containing 12-mg iron as ferrous sulfate per liter) and cereals, iron supplement (2–3 mg/kg/ day) to preterm infants after the first month of life, and delaying the introduction of cow’s milk until after 1 year of age.4 Sickle Cell Anemia Sickle cell anemia is an inherited disorder affecting about 1 in 500 African Americans and to a lesser extent other ethnic groups. The mutation (GAG to GTG) involves the beta-chain gene, replacing the sixth amino acid glutamate (hydrophilic) with valine (hydrophobic). The presence of HgbS in sickle cell disease and trait is detected by the characteristic pattern on Hgb electrophoresis. This substitution produces an unstable Hgb (termed Hgb S), which polymerizes to form rigid, nondeformable, sickle-shaped RBCs that are trapped in the reticuloendothelial (RE) system. The deformed cells also occlude capillary beds throughout the body, causing tissue anoxic injury, organ dysfunction, and severe pain. These vaso-occlusive events (painful crises) represent the most frequently encountered complication in patients with sickle cell disease who present to the ED.11 In addition, splenic sequestration, increased risk for sepsis, and marrow hypoplastic episodes are potential complications in patients with sickle cell disease. These complications and treatment strategies are discussed in detail here.



Vaso-occlusive or pain crises are common manifestation of this disease. Ischemic pain occurs as a result of occlusion of small vessels of various organs, most commonly the skeletal system. Precipitating causes include physical exhaustion, fever, infection, dehydration, cold exposure, alcohol consumption, pregnancy, hypoxia, and emotional stress. Patients may present with pain, fever, and joint swelling if the occluded vessels are present in the joint region. Treatment includes hydration and analgesics, such as the nonsteroidal anti-inflammatory drug (NSAID) ketorolac (oral or parenteral) and the mixed agonist-antagonist narcotic agent Nubain (e.g., IV loading dose for Nubain of 0.3 mg/kg [maximum 20 mg] followed by a continuous infusion of 0.075 mg/kg/h [maximum 0.15 mg/kg/hour]). When age permits, patient-controlled analgesia (PCA) is preferred. Patients who do not respond to Ketorolac and Nubain (nalbuphine) should receive morphine. Meperidine (Demerol) should be avoided, because its metabolite (normeperidine) can accumulate in the serum and cause seizures. Hydroxyurea (20 mg/kg/day PO, titrated to maintain WBC counts ⬃5  103/mm3), promotes Hgb F synthesis, which decreases Hgb S polymerization and prevents many vasoocclusive events.27 Both adult and pediatric trials demonstrated the effectiveness of hydroxyurea in decreasing the incidence and severity of vaso-occlusive crises, decreasing the number of hospitalizations needed to treat these painful crises, and reducing the amount of analgesics used in patients who achieved a Hgb F level ⱖ 10%.8, 15 Hand-foot syndrome (acute dactylitis) is common in infants. Bilateral swelling of the hands and feet occurs as a result of symmetric infarction of the metacarpal and metatarsal bones. The occurrence of this complication can predict an increased risk for repeated, severe vasoocclusive events in the patient. These episodes should be treated with IV hydration and analgesics. Splenic sequestration occurs in about 10% of the children between 5 months and 2 years of age (i.e., before the occurrence of splenic infarction). These patients usually present with left upper quadrant pain, massive splenomegaly, and hypovolemic shock. Rapid recognition is essential with immediate restoration of systemic perfusion using IV fluids until blood is available. Exchange transfusion represents the treatment of choice. Splenectomy should be considered following any lifethreatening sequestration event, because the incidence of recurrence is high (⬃50%). Susceptibility to bacterial infections is increased as the result of impaired splenic function (asplenia or autosplenectomy), leading to inadequate clearance of bacteria from the circulation (e.g., Streptococcus pneumoniae, Hemophilus influenzae, and Mycoplasma pneumoniae). The presence of Howell-Jelly bodies (nuclear remnants in the red cells) on the smear confirms the absence of the spleen. Thus, children with sickle cell disease and fever should be evaluated immediately (i.e., physical examination, CBC, white cell differential, reticulocyte count, blood culture, and appropriate radiographic studies) and treated with an appro-



priate antibiotic. Children 3 years of age and older with normal physical examination, CBC, and chest X-ray can be discharged to home after receiving one dose of parenteral antibiotic (e.g., ceftriaxone) with a close follow-up within 24 hours. Children younger than 3 years of age invariably require hospitalization, parenteral antibiotic, and careful observation. Immunization with the polyvalent pneumococcal polysaccharide vaccine at 6 months of age, 2 years of age, and every 5 years thereafter substantially reduces the risk of pneumococcal sepsis. Amoxicillin prophylaxis should be considered for children less than 5 years of age. Acute chest syndrome results from vaso-occlusion involving the lung vasculature. Initially, the patient is asymptomatic but soon develops fever, cough, tachypnea, shortness of breath, chest pain, and hypoxia. The clinical and radiographic findings are indistinguishable from pneumonia. Hospitalization and careful observation are mandatory. Treatment involves oxygen supplementation (to maintain Hgb saturation ⱖ95%), antibiotics to cover Pneumococcus, Hemophilus influenzae B, and Mycoplasma (e.g., azithromycin), IV hydration, and analgesics. Transfusions, and often exchange transfusion, are required for patients with clinical deterioration or worsening hypoxia. Vancomycin, to cover penicillin-resistant Pneumococci, should be considered for patients deteriorating on appropriate therapy. Stroke is an acute vasoocclusive event that involves the cerebral vasculature in about 5% of children with this disease and can cause death or devastating neurologic impairment. Subclinical strokes can account for declining academic performance that is observed in some children with sickle cell anemia. Seizure, hemiplegia, visual disturbance, and unresponsiveness are the most common presenting signs. Diagnostic evaluation includes CT scan, MR imaging, and MR angiography of the brain (MRA). Immediate exchange transfusion is essential, and it should not be delayed if the initial CT scan is negative. Many patients experience complete neurologic recovery with prompt therapy. Following an initial episode of a CNS vaso-occlusive event, the risk of subsequent events approaches 50%. Monthly transfusions designed to reduce the Hgb S concentration to below 30% reduces the risk of recurrent stroke to about 10%. Patients at increased risk for a CNS vaso-occlusive event can be identified by abnormal blood flow in the carotid system (by Doppler).1 Patients with an increased gradient (i.e., exhibiting turbulent flow in the carotid system) can be placed on prophylactic transfusions to prevent strokes.19 Complications of chronic transfusions include iron overload, alloimmunization, hepatitis, and HIV infection. Extended red cell phenotyping (e.g., Kell and Duffy antigens) minimizes the risk of alloimmunization. Abdominal pain presents a diagnostic challenge and results from vaso-occlusion of vessels in the abdominal wall or intra-abdominal organs. Patients often present with severe pain, fever, and absent bowel sounds and may require multiple radiologic studies (e.g., abdominal films, CT scan, and ultrasonography) in conjunction with a CBC and



liver function tests to role out cholecystitis and appendicitis. If the results of these studies are normal, careful observation, IV hydration, analgesics, and oxygen supplementation for patients with impaired respiration are the major components of therapy. Hypoplastic episodes manifest themselves by increased pallor, tachycardia, declining Hgb concentration, and reticulocytopenia. These episodes are precipitated by acute infection (e.g., B19 parvovirus), which suppresses RBC production.26 Because cells containing Hgb S have a lifespan of only 10 to 12 days, profound anemia can develop. Treatment involves careful observation and, when necessary, RBC transfusion until marrow recovery occurs. Priapism (painful erection) affects about two/three of male children. Engorgement typically involves the corpora cavernosa (bicorporal), sparing the glans penis and corpora spongiosum. Recurrent attacks eventuate in impotence in 50% of the patients. IV hydration and analgesics are used to treat this entity. Exchange transfusion is necessary if symptoms persist for 12 hours, and if no resolution ensues, corporal aspiration (irrigation) is then recommended. Surgery (creating a fistula between the glans penis and the corpora cavernosum) is indicated if priapism continues 12 hours after irrigation.14 Chronic complications include cardiomegaly, hepatomegaly, obstructive lung disease, nephropathy, retinopathy, impaired growth and development, aseptic necrosis of the femoral and humeral heads, compression fractures of the spine, gallbladder stones, and skin ulcers. Because some of these complications are present early in life, it is vital to obtain baseline studies in children with sickle cell disease to include CBC and reticulocyte count, bilirubin, pulse oximetry, blood pressure, carotid Doppler study, eye (retina) examination, growth and development, academic performance, biliary ultrasonography, and renal and pulmonary function studies. Glucose-6-phosphate Dehydrogenase Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an Xlinked trait common in the African-American population, having an incidence of about 10%. The ability of RBC to detoxify oxidants depends on the activity of G6PD. G6PD catalyzes the reduction of nicotinamide adenine dinucleotide phosphate (NADP) to NADPH in the hexosemonophosphate shunt. NADPH converts glutathione disulfide (GSSG) to reduced glutathione (GSH). GSH, in return, inactivates hydrogen peroxides (H2O2) and protects protein sulfhydryl groups from oxidation. In the absence of G6PD, the red cell membrane and hemoglobin can be damaged by oxidant exposure, leading to rapid hemolysis. Avoidance of oxidants (e.g., sulfa drugs) and careful observation during stress (e.g., infection and surgery) are necessary. Patients with severe pallor or abdominal pain need immediate evaluation. RBC transfusion is sometimes necessary during episodes of severe hemolysis.



Hereditary Spherocytosis This disorder is autosomal dominant (sporadic in ⬃ 10%) and characterized by an abnormal RBC cytoskeleton, commonly involving the protein spectrin. This defect is associated with membrane loss producing nondeformable spherocytes that are prematurely trapped and destroyed in the spleen. The presence of spherocytes on the smear is diagnostic. Hemolysis can begin in the first 24 hours of life, causing early jaundice. Hypoplastic episodes are also common following viral infection. RBC transfusion is sometimes necessary during episodes of acute hemolysis or prolonged hypoplasia. Splenectomy is necessary if the Hgb concentration is persistently below 10 g/dL and the reticulocyte count above 10%. Splenectomy is usually deferred until after 5 years of age to minimize the risk of postsplenectomy sepsis. Autoimmune Hemolytic Anemia This disease manifests itself with sudden pallor and fatigue, often following a viral illness. Because of the rapid onset, jaundice, hyperbilirubinemia, and reticulocytosis might not be present initially. The laboratory findings reveal a rapidly falling Hgb, increased bilirubin metabolites in the urine, positive Coombs’ tests, and abundant spherocytes on the smear. The direct Coombs’ test confirms the diagnosis (the presence of antibodies or complements C3 and C4 on the RBC). The antibody specificity is detected by the indirect Coombs’ test. Hemolysis occurs with either IgG or IgM antibodies. IgG antibodies react at 37C and do not agglutinate RBC in vitro, thus, are termed warm or incomplete antibodies. In contrast, IgM antibodies cause in vitro agglutination at less than or equal to 20C; thus, they are termed cold or complete antibodies. The antibody-coated RBCs are destroyed primarily in the RE system; intravascular hemolysis is rare. The treatment involves hospitalization, careful observation, high-dose steroids, and if necessary, RBC transfusion using the most compatible blood. Transient Erythrocytopenia of Childhood Transient erythrocytopenia of childhood (TEC) is characterized by gradual onset of a normocytic anemia and reticulocytopenia caused by temporary suppression of erythropoiesis. TEC usually occurs in children between 1 month and 6 years of age and is commonly proceeded by a viral illness. Full recovery usually occurs in 4 to 6 weeks. Blood transfusions are necessary if Hgb concentration is less than ⬃5 g/dL. Followup studies are necessary until the Hgb concentration and reticulocyte count recover. In about 25% of patients, the anemia is associated with mild neutropenia. TEC needs to be distinguished from a rare disease, termed pure red cell aplasia or Diamond-Blackfan syndrome (DBS). These patients typically



have macrocytic red cells. Fifty percent of patients with DBS have short stature, poor growth, and at least one congenital anomaly. Bone marrow recovery is the hallmark of TEC and rules out DBS. Bone Marrow Infiltration Marrow infiltration by malignant cells or as the result of inherited metabolic disorders produces an anemia that is normocytic. These patients can have lymphadenopathy, hepatomegaly, and splenomegaly on physical examination, although laboratory abnormalities can include reticulocytopenia, neutropenia, thrombocytopenia, and circulating immature cells (e.g., nucleated RBC, promyelocytes, metamyelocytes, and myelocytes). Bone marrow examination is essential in this setting to establish the correct diagnosis. NEUTROPENIA Neutropenia is defined as a decreased number of circulating neutrophils in the peripheral blood. An absolute neutrophil count (ANC) less than 1500/␮L is defined as neutropenia. The lower limit for AfricanAmerican patients can be 200 to 600/␮L less than the figure cited for caucasians.22, 32 Increased risk for a life-threatening infection occurs when the ANC is ⬍ 500/␮L.34, 35 This susceptibility varies from patient to patient, depending on the clinical state. Patients with an underlying malignancy and neutropenia tend to have more infections than do those patients with congenital defects in neutrophil production. Children with fever and neutropenia require prompt evaluation and institution of appropriate antibiotic therapy. A careful physical examination is needed, with special attention to examination of the regions most susceptible to bacterial infection in the neutropenic patients, that is, the oral mucosa, skin, ears, lungs, and perianal area. Digital rectal examination and rectal temperatures should never be done in a patient with neutropenia to avoid inducing gram-negative sepsis, although visual inspection of the anus and gentle examination of the area is acceptable. In addition, phenotypic abnormalities (i.e., cartilage-hair hypoplasia syndrome) associated with neutropenia should be noted (Table 2). A brief review of neutropenia in children and the treatment strategies in these children is summarized below. Neutropenia in Patients with Cancer Patients with oncologic disorders are at increased risk for infectious complications because of a weakened host defense system. The type and pattern of infection vary according to the degree of immune suppression. Most infections are caused by organisms that are found as part of the normal flora in healthy subjects, including gram negative bacteria, Can-



Table 2. DIFFERENTIAL DIAGNOSIS OF NEUTROPENIA* Congenital Neutropenic Disorders Kostmann’s Agranulocytosis–severe congenital neutropenia Reticular dysgenesis (absence of thymus, lymphocytes, and neutrophils) Cyclic neutropenia (autosomal dominant in 1⁄3 of patients) Schwachman syndrome (neutropenia, pancreatic insufficiency, growth failure, and skeletal anomalies) Neutropenia with abnormal B or T lymphocytes (e.g., X-linked agammaglobulinemia) Transient Neonatal Neutropenia Prematurity/sepsis/asphyxia Pregnancy-induced maternal hypertension Periventricular hemorrhage Congenital cytomegalovirus infection Maternal antineutrophil antibodies (alloimmune-isoimmune neutropenia) Immune-Mediated Destruction Autoimmune neutropenia Postinfectious Influenza A, varicella Hepatitis A and B Respiratory syncytial virus, Epstein-Barr Virus, cytomegalovirus (counts recover spontaneously over several days) Drug-Induced Chemotherapy, anticonvulsants, cimetidine, ranitidine, phenothiazines, semisynthetic penicillins, cephalosporins, NSAID Acquired Decreased Production Aplastic anemia Marrow infiltration (malignant cells, inborn metabolic errors) Sequestration Splenomegaly Data from refs.33, 34, 35.

dida albicans, varicella, and pneumocystis. When the host immune system is weakened, these organisms proliferate and produce life-threatening infections. Other agents such as Pseudomonas or Aspergillus spp. are acquired from exogenous sources. Most infections in immunocompromised children result from bacterial pathogens. Escherichia coli, Pseudomonas and Klebsiella spp. represent the most common gram-negative organisms producing infections in immunocompromised children, whereas coagulase-negative staphylococci represent the predominant gram-positive organism causing infection, especially in patients who have central venous access. Anaerobic infections are uncommon in children with cancer. Candida and Aspergillus spp. compose the majority of fungal infections. The most common viral pathogens include herpes simplex, varicella zoster, cytomegalovirus, adenovirus, and Epstein-Barr virus. Pneumocystis and toxoplasmosis represent the major protozoan infections in this group of patients. The standard approach for managing a neutropenic patient with no discernable focus of infection has been combination therapy to cover gram-positive and gram-negative infections. Ceftazidime and vancomy-



cin are often used as initial therapy in patients with central venous access in view of increased risk of coagulase-negative staphylococcal infection. Other centers choose to use an aminoglycoside in combination with a beta-lactam antibiotic. Children with pneumonia or perirectal infections sometimes require antibiotics designed to cover pathogens such as pneumocystis and clostridium, respectively. Each hospital can have a unique and specific profile of documented infections and antibiotic susceptibility that must be considered in selecting appropriate therapy in these settings. Management of Infected Catheters Although coagulase-negative staphylococcal infections represent most catheter infections, other infectious agents can be encountered, specifically gram-negative organisms, fungi, Bacteroides sp., and corynebacterium. Most simple catheter infections can be cleared with antibiotics without catheter removal. Tunnel site infections (i.e., infections where the catheter enters the skin) represent a more difficult problem. Despite appropriate antibiotics, many catheters must be removed to clear the infection. Prophylactic Antibiotics Surveillance cultures and prophylactic antibiotic administration have been studied in an attempt to predict the agent responsible for infections when they develop and to prevent infection in the neutropenic patient. To date, these studies have not proved successful in reducing the incidence of infection or in selecting appropriate antibiotic therapy. Neupogen (Filgrastim) Colony Stimulating Factor (G-CSF) stimulates the production of neutrophils from committed progenitor cells in the marrow. The dose is 5 to 10 ␮g/kg (maximal dose 480 ␮g) administered subcutaneously. This medication is started immediately following a cycle of intensive chemotherapy, and within 10 to 14 days the patient generally has an ANC above 1500/mm3. Autoimmune Neutropenia Autoimmune neutropenia is caused by the production of antibodies against neutrophil antigens. The physical examination and laboratory findings are normal, except for isolated neutropenia. The bone marrow shows a normal myeloid proliferation and maturation. This entity is usually self-limiting, with recovery of a normal neutrophil count occurring over a several-week period. Appropriate antibiotics and Neupogen are given to febrile, neutropenic patients. The length of treatment



depends on the site and nature of the infection. Corticosteroids (e.g., prednisone, 1–2 mg/kg/day for 1 week) and intravenous immunoglobulin (IVIgG) (e.g., a single dose of 1 g/kg over 3 hours) can hasten ANC recovery; however, the decision to use these therapeutic modalities should be individualized. Congenital Cyclical Neutropenia Congenital cyclic neutropenia is characterized by chronic periodic oscillations in the neutrophil count from normal to profound neutropenia.33 The disease is caused by a defect in stem cell development, more pronounced in the late myeloid precursors. The duration of each cycle is usually 21 days (range, from 14–36 days). The nadir of neutrophil counts ranges from low normal to zero and usually lasts 3 to 10 days. The most common manifestations of this entity are oral ulcers, stomatitis, pharyngitis, tonsillitis, lymphadenitis, cellulitis, otitis media, and sinusitis. All infectious episodes should be treated promptly with appropriate antibiotics and Neupogen (e.g., 5 mg/kg daily SC injections until WBC count is ⱖ 10,000/mm3).13, 41

Figure 3. Differential diagnosis of thrombocytopenia. *Pseudothrombocytopenia occurs with spontaneous or EDTA- or citrate-mediated platelet clumping.



THROMBOCYTOPENIA Patients with a platelet count of ⬍20,000/mm3 can experience spontaneous bleeding (e.g., petechiae, bruising, epistaxis, menorrhagia, and gastrointestinal hemorrhage) and therefore require prompt evaluation and treatment. The differential diagnosis of thrombocytopenia is summarized in Figure 3, and the common entities are discussed below. Acute Childhood Immune Thrombocytopenic Purpura ITP is caused by the production of antibodies against platelet antigens. The antibody-coated platelets are trapped and destroyed in the RE system (primarily the spleen) causing thrombocytopenia. The typical history is sudden onset of petechiae and bruising in a previously healthy child; often there is a history of a preceding viral illness. Fever, bone or joint pain, weight loss, pallor, fatigue, weakness, and other complaints are typically lacking; their presence suggests a different entity. Similarly, the physical examination is entirely normal except for mucocutaneous bleeding. Any abnormal physical findings such as lymphadenopathy and hepatosplenomegaly strongly suggests a marrow infiltrative process and requires bone marrow examination. In ITP, the hemogram and blood smear are normal except for isolated thrombocytopenia.37 In older children, antinuclear antibody, anti-DNA antibody and human immunodeficiency virus tests are sometimes necessary because these entities can present initially with isolated thrombocytopenia. The need for bone marrow examination to confirm the diagnosis is controversial; many specialists perform this test before initiating prednisone therapy. Typically, the bone marrow shows a normal hematopoietic system with increased number of megakaryocytes. In many children, the thrombocytopenia resolves within 6 weeks. Although the incidence of life-threatening hemorrhages is low (⬃1%), intracranial, pulmonary, upper airway, and GI bleedings have all been observed in children with acute ITP.31 Patients with excessive skin and mucosal bleeding or with a platelet count ⬍10,000/mm3 are especially at risk for life-threatening bleeding. A careful evaluation and appropriate treatment is essential in the child with newly diagnosed ITP. Treatment options include corticosteroids, immunoglobulin G (IgG) concentrates, and Anti-Rh (D) immunoglobulin (WinRho-SD); (Table 3). Corticosteroids (e.g., prednisone 2 mg/kg/day) remain the treatment of choice for most patients. Corticosteroids increase vascular stability, enhance platelet production, decrease antibody production, and impair clearance of antibody-coated platelets, thus, immediately reducing the risk of bleeding before any rise in the platelet count occurs. Intravenous IgG (e.g., 1 g/kg/day for 2 consecutive days over 3 hours) binds to receptors in the RE system, preventing platelet destruction; a rise in the platelet count is usually observed in 1 to 2 days. Intravenous anti-D (WinRho-SD, a single dose of 40–80 mg/kg over 5 minutes) is effective in Rh-positive patients. The anti-D antibodies saturate the RE sites with anti-D–coated RBC, preventing platelet destruction. Side effects associ-



Table 3. TREATMENT OF ACUTE CHILDHOOD ITP* Corticosteroids Prednisone, 1–5 mg/kg/day in 3 divided doses for 1–2 weeks, followed by tapering and discontinuation by day 21. Methylprednisolone (Solu-Medrol), 30 mg/kg (maximum, 1 g) IV over 30 minutes every 24 hours for 3 doses. This option is reserved for hospitalized patients with severe bleeding. IgG Concentrates Intravenous IgG, 1 g/kg/day for 2 consecutive days. Anti-D Intravenous anti-D (WinRho-SD, single dose of 40–80 ␮g/kg over 5 minutes) for Rhpositive patients. Combined Therapy Corticosteroids in combination with either IgG or anti-D (using the previously cited dosages). This option is used for patients with significant mucocutaneous bleeding. Hospitalization (24–48) is sometimes necessary. *Data from refs.31, 37.

ated with intravenous anti-D (WinRho-SD) include chills and a slight drop in Hgb concentration by 1 to 2 g/dL (i.e., mild hemolytic anemia). These symptoms can be ameliorated by using acetaminophen, diphenhydramine, and a single dose of prednisone.6 Emergency splenectomy and platelet transfusion are reserved for severe and refractory ITP with lifethreatening bleeding. Acute Leukemia Acute leukemia is frequently associated with thrombocytopenia. These patients usually have symptoms and signs of a marrow infiltrative process (e.g., bone pain, anemia, neutropenia, and circulating blasts) and an abnormal physical examination (e.g., lymphadenopathy and hepatomegaly). The diagnosis is confirmed by bone marrow examination. Hemolytic Uremic Syndrome Hemolytic uremic syndrome (HUS) is characterized by intravascular platelet and RBC consumption with RBC fragments on the smear (microangiopathic process) as the result of intravascular thrombi in the renal vasculature, hemoglobinuria (positive Hgb and negative RBCs in the urine), renal failure, and a preceding history of diarrhea. Disseminated Intravascular Coagulation Disseminated intravascular coagulation (DIC) is characterized by a severely ill child with thrombocytopenia, consumption of coagulation



factors (e.g., hypofibrinogenemia, and prolonged partial thromboplastin time [PTT], prothrombin time [PT], and thrombin time [TT]), and hemolytic anemia (i.e., RBC fragments, hemoglobinemia, and hemoglobinuria). Thrombocytopenia from Chemotherapy This complication requires a platelet transfusion (0.2 units/kg, maximum 6 units) if the count is less than 20,000/mm3. Immune compromised patients should receive irradiated (removes lymphocytes that can produce graft-versus-host disease), leuko-depleted platelets (using thirdgeneration filters that remove approx. 99% of the granulocytes). The transfusion should be stopped immediately if the patient develops chills, urticaria, or dyspnea. Premedication with acetaminophen, diphenhydramine (e.g., 0.5 mg/kg), cimetidine, and a single dose of SoluMedrol (methylprednisolone) (e.g., 1 mg/kg) are effective in treating and preventing most of the previously noted transfusion reactions. Aspirin and NSAID should be avoided in all thrombocytopenic patients. BLEEDING The child presenting to the ED with bruising and bleeding represents a diagnostic challenge. A key element in the diagnostic evaluation of the child with abnormal bleeding is the type of bleeding experienced by the patient. Mucocutaneous bleeding, petechiae, and bruises are common in primary hemostatic disorders (i.e., thrombocytopenia, von Willebrand disease, or conditions with abnormal platelet function), whereas hemarthroses, hematomas, and delayed bleeding from lacerations are seen in secondary hemostatic disorders (e.g., hemophilia). The medical history, intercurrent or chronic illness, current medications, physical examination, and screening tests (e.g., hemogram, including platelet count, PT, PTT, TT, examination of the blood smear, and urinalysis) are essential components in determining the diagnosis.38 The hemostatic mechanism and its commonly encountered disorders are reviewed below. The term primary hemostasis refers to processes that lead to immediate formation of platelet plugs (i.e., clumps of activated platelets bound to von Willebrand factor (VWF) and fibrinogen) at sites of injury. Platelets also provide the phospholipids and biochemical mediators needed for secondary hemostasis. Thus, the hemostatic process is severely impaired in the presence of thrombocytopenia or dysfunctional platelets.25 Von Willebrand Disease Von Willebrand disease (VWF) is a multimeric glycoprotein that mediates platelet adhesion to the subendothelial collagen.30 In its ab-



sence, the ability to form platelet plugs and, subsequently, fibrin clots, is severely impaired. VWF is synthesized by endothelial cells and megakaryocytes. It circulates in the blood and is stored in the subendothelial space and platelet alpha-granules. Moreover, vWF binds factor VIII, protecting it from degradation. Thus, in the absence of vWF, factor VIII decays rapidly. VWF antigen is measured by an immunoassay and activity by a functional assay termed ristocetin cofactor activity. The latter test is based on the fact that ristocetin mediates in vitro binding of vWF to platelets.25 The term secondary hemostasis refers to the processes that lead to formation of an insoluble fibrin clot from soluble fibrinogen and is evaluated by the PTT, prothrombin time PT, and TT. A prolonged PTT is associated with factor deficiency (e.g., high-molecular-weight kininogen, prekallekrein, factor XII, XI, IX, VIII, X, V, II, or I), the presence of heparin, or the presence of interfering antibodies. Deficiency of highmolecular-weight kininogen, prekallekrein, or factor XII is not associated with increased bleeding, reflecting one limitation of the PTT test. A prolonged PT is associated with factor deficiency (e.g., VII, X, V, II, or I), the presence of heparin, or the presence of interfering antibodies. A prolonged TT is associated with low or abnormal fibrinogen, the presence of heparin, or in the presence of fibrin(ogen) degradation products. The PT and PTT are prolonged if a clotting factor diminishes 50% or less of its normal value. Thus, diluting (1:1) patient’s plasma with normal plasma should correct a prolonged PT or PTT resulting from a factor deficiency. In contrast, the 1:1 dilution test does not correct a prolongation resulting from antiphospholipid or antiphospholipoprotein antibodies (termed lupus-like anticoagulants). These transient inhibitors are not associated with abnormal bleeding, reflecting another limitation of the coagulation tests.24 Von Willebrand disease (vWD) is the most common hereditary disorder of primary hemostasis, affecting about 1 in 100 persons. The prevalence of the severe form (i.e., complete absence of vWF) is about 1 in 1,000,000, however. The disease usually is transmitted as an autosomal dominant trait.12 Affected persons typically have frequent episodes of mucosal bleeding (e.g., recurrent epistaxis, menorrhagia, and excessive bleeding following tonsillectomy and tooth extraction). The diagnostic findings include low vWF antigen and activity and, in the severe forms, a prolonged PTT due to decreased factor VIII.7 Type I vWD (about 80% of the patients) involves only quantitative abnormality of vWF, type II (about 20% of patients) both quantitative (decreased large multimers) and qualitative abnormalities, and type III complete absence of vWF.29 Guidelines for treatment of vWD are summarized in Table 4. Patients with type I vWD, and some patients with type II vWD, can be successfully treated with DDAVP (Stimate, desmopressin acetate, 1 deamino-8-arginine vasopressin) and amicar (aminocaproic acid).3, 29 DDAVP releases stored vWF and factor VIII from the subendothelial compartment The average rise of vWF after a DDAVP dose is ⬃two to



Table 4. EVALUATION AND TREATMENT VWD AND HEMOPHILIA Evaluation Inquire about the missing factor (e.g., von Willebrand factor, VIII, or IX) Type of bleeding (e.g., nosebleeds, joint bleeding) Previous surgery or bleeding Severity of disease (i.e., mild, moderate, or severe) Prior exposure to blood products Prior response to DDAVP (for patients with vWD and mild hemophilia A) Type and availability of factor product History and titer of inhibitors History of poor response requiring larger or more frequent dosing ‘‘Target’’ sites (e.g., a joint with frequent bleeds) Compliance Treatment of vWD 1. DDAVP: intravenous (0.3 mg/kg over 30 minutes) or intranasal (one spray in each nostril, 150 ␮g/spray). One spray only for children less than 8 yrs. 2. Amicar: 50–100 mg/kg PO every 6–8 hours for 1 week in patients with mucosal bleeding. 3. Factor VIII concentrate containing adequate vWF (e.g., Humate P): For patients with severe disease (vWF ⬍10%), using the guidelines outlined here for hemophilia A. Treatment of Hemophilia 1. Infuse the missing factor intravenously over 2–3 minutes as soon as possible (usually within 15 minutes from arriving to the ED). 2. Head injury, major trauma, or psoas muscle bleeding: Replace to 100% (i.e., 50 U/kg factor VIII or 100 U/kg factor IX). 3. Joint, soft tissue, or muscle bleeding: Replace to 50% (i.e., 25 units/kg factor VIII or 50 U/kg factor IX). 4. Oral mucosal or dental bleeding: Replace to 50% and give amicar (as noted before). 5. Peak level and half-life determinations are necessary in the presence of severe bleeding, history of poor response, or inhibitor. 6. Subsequent replacements sometimes necessary in the presence of persistent pain and swelling, delayed replacement, ‘‘target’’ joint, and severe bleeding. 7. Consider DDAVP (as earlier) for patients with mild hemophilia A.

three times baseline value, and adequate hemostatic levels usually are sustained for approximately 6 to 8 hours.9, 21, 42 DDAVP is available in IV and intranasal (1.5 mg/mL solution) forms. The IV dose is 0.3 ␮g/kg over 30 minutes and the intranasal dose one spray (150 ␮g) in each nostril.28, 42 These doses can be given once (or at most twice) a day for a total of 3 days to stop an acute bleeding episode (e.g., epistaxis, menorrhagia, or prior to a short surgical or dental procedure).18, 42 More frequent dosing causes depletion of endothelial stores (tachyphylaxis).20 Following administration of DDAVP, fluid intake should be minimized for 4 to 6 hours to avoid water retention, a common side effect of DDAVP.43 Amicar, an antifibrinolytic agent that inhibits plasminogen activity, is used to prevent and treat oral bleeding following injury or surgery. Plasminogen, normally present at a high concentration in the saliva, rapidly lyses fibrin clots in the mouth. Patients with impaired coagulation (e.g., vWD and mild hemophilia A) frequently have recurrent oral mucosal bleeding as a result of this high plasminogen activity. Amicar



is available in 500-mg tablets and oral solution; the dosage is 50 to 100 mg/kg orally every 6 to 8 hours (maximum, 6 g q6h) for 1 week (until the wound is healed). Patients with severe vWD (vWF ⬍ 10%) do not respond to DDAVP; they require replacement with a factor VIII concentrate containing adequate amounts of vWF (e.g., Humate P and Koate HP).7

Hemophilia (factor VIII or IX deficiency) Hemophilia A (factor VIII deficiency) is the most common inherited (sex-linked recessive) disorder of secondary hemostasis, affecting about 1 in 10,000 male children. One third of the patients have a negative family history for the disease (i.e., new mutations), however. The laboratory findings are prolonged PTT, normal PT and TT, and a markedly decreased factor VIII level (measured by mixing test plasma with specific factor VIII–deficient plasma and plotting fibrin generation times). Patients with factor VIII activity less than 1% (normal, 50 to 100%) have severe hemophilia (about 60% of the patients); patients with moderate hemophilia have levels of 1% to 5%, and mild hemophiliacs have levels greater than 5%. Patients with severe disease can experience spontaneous bleeding, whereas patients with mild or moderate disease usually bleed following trauma or surgery (e.g., circumcision). Guidelines for treatment of hemophilia are summarized in Table 4. Hemophilia A is treated with intravenous infusion of factor VIII concentrate; fresh-frozen plasma does not produce adequate hemostasis in most patients. To minimize the risk of HIV, hepatitis, and other infectious agents, the preferred products are those prepared by recombinant technology (e.g., Recombinate). In theory, 1 U/kg (1 unit is defined as the amount of clotting activity found in 1 mL of normal fresh plasma) of factor VIII raises the measured plasma activity 1% to 2%, with a halflife of about 8 hours. Thus, a patient receiving 50 U/kg should have a measured activity of 50% to 100%, with levels decaying by ⬃50% every 4 to 8 hours. Both peak activity and decay rate can vary remarkably among patients and among different products. Thus, an adequate response (i.e., increment per dose and half-life) should be verified in each patient with any new product, especially with any poor response to replacement. Because the PTT is prolonged only if factor VIII level is less than 50%, this test cannot be used to monitor replacement aiming to achieve activities above 50% (e.g., major procedures in the ED, orthopedic surgical procedures, extensive dental procedures, and pre- and postoperative replacements). Thus, adequate response is monitored by peak and trough factor VIII activities. In most situations, DDAVP and amicar (as discussed earlier for vWD) are sufficient in most patients with mild hemophilia.18, 20, 21, 42 Common bleeding sites are outlined here.



Joints and Muscle Bleeding Ninety percent of bleeding episodes involve the joints and muscles. The knee accounts for 50% of the observed bleeds. Other common targets include the elbow, ankle, and shoulder. In the presence of hemarthrosis, an inflammatory reaction occurs in the synovium, leading to neovascularization with resultant increased risk for recurrent bleeding. This cycle ultimately leads to fibrosis of the synovium and damage of the articular cartilage, leaving a stiff, contracted joint (chronic arthropathy).5 Prompt factor replacement is essential to prevent this complication. Factor VIII should be administered as soon as possible (at the time of premonitory symptoms, such as warmth, tingling, and burning sensation) to correct the level to 50%. Repeated replacements are necessary in the presence of severe pain and swelling, if the episode progressed more than 4 hours before treatment, and when treating a target joint. Children with a muscle bleeding (e.g., flexor muscles in the arm and in the posterior leg) present with pain, swelling, and limitation of movements. Repetitive replacements to 60% is required until the patient is asymptomatic. Inadequate or delayed replacements can lead to muscle fibrosis (contracture) and nerve compression (entrapment). Patients with a psoas muscle bleeding present with groin pain and painful hip joint movements, simulating appendicitis. This site requires prompt correction to about 100% (confirmed by peak and trough factor activities), followed by confirmation by CT scan or MR imaging. The replacement should continue for several days until adequate healing occurs. Oral bleeding Examples include a split frenulum, gum and tongue lacerations, and oozing from an erupting tooth, all common in young children. These episodes are usually managed by one replacement (less 50%) and amicar (5–7 days as discussed previously).16 CNS bleeding Patients usually present with sudden onset of severe headache with or without other neurologic findings. The bleeding can be spontaneous or following trauma, and can occur in patients with even mild disease. Patients must be corrected to 100% immediately followed by CT scan or MR imaging to document the site and extent of bleeding. Continued replacement (confirmed by peak and trough activities) and neurosurgical consultation are mandatory. CNS bleeding is the major cause of death in these patients. Inhibitors Approximately 10% of patients with severe hemophilia develop alloantibodies (IgG4) to factor VIII (termed inhibitors).2 The inhibitors are



expressed in Bethesda units; 1 Bethesda corresponds to the ability of patient’s plasma to inactivate 50% of factor VIII of an equal volume of normal plasma following a 2-hour incubation at 37C. This complication should be suspected with any poor clinical response or inadequate activity increment following replacement, and can be confirmed by detecting and titrating the inhibitor in the plasma. The bleeding in patients with inhibitors can be treated adequately using massive quantities of factor VIII (sometimes by continuous infusion). Alternatively, activated factor IX concentrate (FEIBA or Autoplex, containing the vitamin K–dependent factors II, VII, IX, and X), porcine factor VIII (HyateC), or recombinant factor VII is used. For long term therapy, an immune tolerance can be induced by infusing large amounts of factor VIII over several months. Hemophilia B (factor IX deficiency) is also an X-linked disease, affecting male children with a frequency of 1 per 50,000 (i.e., 20% of hemophilia A). The clinical findings are similar to those of hemophilia A. One U/kg of a factors IX concentrate (e.g., Alphanine [ultrapure product], Mononine [ultrapure product]), and Benefix [albumin-free, recombinant product]) produces a rise of about 1%, with a half-life of approximately 12 hours.

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43. Weinstein RE, Bona RD, Altman AJ, et al: Severe hyponatremia after repeated intravenous administration of desmopressin. Am J Hematol 32:258, 1989 Address reprint requests to Peter D. Sadowitz, MD Departments of Pediatrics and Emergency Medicine State University of New York Upstate Medical University 750 East Adams Street Syracuse, NY 13210 e-mail: [email protected]