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CHAPTER 144: Hematologic Emergencies in Infants and Children 949 30%, the possibility of a sickle crisis is minimized. Clearly, the known risks of infection and transfusion reaction that pertain to any transfu sion apply. Transfusion for sickle cell disease patients more frequently results in alloimmunization (5% to 36% of patients) compared to the general population. Alloimmunization is defined as immunization of the patient by donor red blood cell antigens. The risk can be minimized by using blood matched for minor red blood cell antigens such as C, E, and Kell. In these cases, patients experience a drop in hemoglobin to below pretransfusion levels, despite a negative direct antibody test, due to hemolytic anemia that can be life threatening. This phenomenon also increases the risk for future transfusion reactions in SCA patients. 4,14 Finally, chronic iron overload is another complication of frequent transfusions and may contribute to cardiomyopathy. Iron overload is treated with deferoxamine chelation therapy, a treatment that is also associated with risk: deferoxamine may increase the susceptibility for fungal infections (and other infections such as Yersinia) and lead to growth failure, allergic reactions, ophthalmic toxicity, or ototoxicity. Bone marrow or stem cell transplantation has been successfully used to cure SCA. However, due to the risks associated with transplantation, this is generally only considered in patients who have a human leukocyte antigen–matched sibling. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Hematologic Emergencies in Infants and Children Jessica A. Bailey Megan Mickley INTRODUCTION Bleeding in a child can be a diagnostic dilemma, because the causes range from benign to serious. Children with mild bleeding disorders may not experience an episode of bleeding until faced with a hemostatic challenge, such as an interventional procedure or trauma. On the other hand, children without an underlying bleeding disorder commonly present with complaints of bruising and bleeding such as epistaxis or menorrhagia. Red flags for a potential bleeding disorder include bleeding or bruising out of proportion to the injury, prolonged and/or recurrent bleeding (particularly with unknown cause or after a small injury or procedure), spontaneous bruising or bleeding, uncommon sites of bleeding (joints, GI) or bruising (proximal extremities, trunk), and a family history of a bleeding disorder. Consider nonaccidental trauma in the child with unusual bruising patterns (see Chapter 150, “Child Abuse and Neglect”). Figure 144-1 provides a basic approach for the initial ED assessment of a child with bleeding. The most common bleeding disor ders presenting in childhood are discussed below.  HEMOPHILIA A detailed discussion of hemophilia is provided in Chapter 235, “Hemophilias and von Willebrand’s Disease. ” Table 144-1 provides a summary of those bleeding disorders, which are also reviewed below. EPIDEMIOLOGY Factor VIII (hemophilia A) and factor IX (hemophilia B) deficiencies are X-linked recessive hematologic disorders and predominantly affect males. One third of cases arise from spontaneous mutations; thus, CHAPTER patients may have a negative family history of bleeding disorders.1 These disorders are clinically indistinguishable but differ in their treatment.

(hemophilia B) deficiencies are X-linked recessive hematologic disorders and predominantly affect males. One third of cases arise from spontaneous mutations; thus, CHAPTER patients may have a negative family history of bleeding disorders.1 These disorders are clinically indistinguishable but differ in their treatment. CLINICAL FEATURES The severity of disease, and thus risk of bleeding, is defined by the factor activity as a percentage of normal (which is defined as 50% to 100%). Patients with mild disease may never spontaneously bleed but have increased bleeding with trauma ( Figure 144-2), whereas individuals with severe disease have spontaneous bleeding into the joints (hemar throses; Figure 144-3) and soft tissue (hematomas) and may develop life-threatening hemorrhage. DIAGNOSIS Most children with hemophilia have already been identified before an ED visit because of a positive family history of bleeding disorder (prenatal testing is possible through chorionic villus sampling or amniocentesis), intracranial hemorrhage, significant hematoma after birth trauma, or prolonged and excessive bleeding after circumcision. However, some cases, especially mild hemophilia, may escape detection until the child is several years old, when symptoms are provoked by an injury or a small interventional procedure. The event precipitating initial presentation could be as minor as a trip and fall in a newly ambulatory toddler, a common age of diagnosis due to the increased activity level. Suspect hemophilia in a child who presents with spontaneous bleed ing, particularly in unusual locations (e.g., joints, areas not usually injured like the proximal extremities) or with bleeding that is out of proportion to the injury. Specific bleeding manifestations are listed in Tables 144-1 and 235-2. Hemarthroses are the hallmark of hemophilia, accounting for 80% of bleeding episodes in severe hemophiliacs. 2 Older children and adolescents describe a burning or tingling sensation pre ceding signs of hemarthrosis development.2 Differential diagnosis includes the spectrum of bleeding disorders. The screening test for hemophilia is an activated PTT, which will be prolonged in most patients. Platelet count, bleeding time, and pro thrombin time will be normal. Quantitative factor levels confirm a diagnosis of hemophilia. Mixing studies identify whether factor inhibi tors are present. TREATMENT The overall treatment goal is to increase levels of the deficient factor. Treatment of hemophilia depends on the specific factor deficiency, the baseline severity of the disease, and the nature and extent of the injury. In severe hemophiliacs, regular scheduled prophylactic administration of clotting factor concentrate is a well-established practice and signifi cantly reduces the incidence of bleeding. Even in the absence of physical findings, promptly order and initiate factor replacement for children with a presenting ED history that raises concern about high-risk sites for bleeding. A reliable adage in hemophilia is “When in doubt, treat, ” preferably within 2 hours. 3 In patients with known hemophilia, coagulation studies are not necessary upon presentation for a new bleeding episode. However, a level of factor VIII or IX or the presence of a factor inhibitor may be requested by the hematologist to assist in the patient’s evaluation and treatment. The dose of factor replacement and goal level of factor percentage are based on the clinical scenario. A good rule of thumb is to aim for a desired factor level of approximately 40% to 50% following replacement. For high-risk and/or life-threatening bleeds (CNS, retropharyngeal, ophthalmic, iliopsoas/retroperitoneal, intra-abdominal, intrathoracic, and GI), that goal doubles to 80% to 100%.

sed on the clinical scenario. A good rule of thumb is to aim for a desired factor level of approximately 40% to 50% following replacement. For high-risk and/or life-threatening bleeds (CNS, retropharyngeal, ophthalmic, iliopsoas/retroperitoneal, intra-abdominal, intrathoracic, and GI), that goal doubles to 80% to 100%. Specific factor replacement products are listed in Table 235-3, and factor replacement guidelines are listed in Table 235-4. Recombinant and human plasma-derived factors are available, and efforts should be made to use the patient’s home product. Treatment regimens will differ for factor VIII and factor IX products because they have different dosing requirements and different half-lives. In most patients, 1 unit/kg of factor VIII will increase the clotting activity of treated plasma by 2%; 1 unit/kg of Tintinalli_Sec12_p0669-0996.indd 949 8/2/19 7:59 PM

roduct. Treatment regimens will differ for factor VIII and factor IX products because they have different dosing requirements and different half-lives. In most patients, 1 unit/kg of factor VIII will increase the clotting activity of treated plasma by 2%; 1 unit/kg of Tintinalli_Sec12_p0669-0996.indd 949 8/2/19 7:59 PM 950 SECTION 12: Pediatrics Child with bleeding Family history of bleeding disorder? Bleeding history: prolonged, severe, recurrent, unusual locations? Neonatal history: intracranial hemorrhage, persistent bleeding after circumcision, delayed umbilical stump loss? Physical exam: hemodynamic instability, concerning size and/or location of bruising/bleeding, organomegaly, mass? Medications and/or supplements that may cause increased bleeding? YES NO If unconcerning history, vital signs and exam: Reassurance Close follow-up Education Screening Labs: CBC with differential Coagulation profile Peripheral smear Normal labs • If you have a high index of suspicion for a bleeding disorder: consult hematology and consider additional laboratory workup, including factor levels, vWD panel • Evaluate for other etiologies of bleeding: nonaccidental trauma, rheumatologic Abnormal PT/aPTT • Order mixing study to evaluate for presence of inhibitors • Consider other etiologies of bleeding: liver disease, disseminated intravascular coagulopathy, anticoagulant medications • Discuss bleeding disorder workup with hematology team, including factor levels, vWD panel Abnormal platelet count • Evaluate for other cytopenias • Confirm CBC results with peripheral smear • Discuss thrombocytopenia workup with hematology team • See section “Thrombocytopenia” FIGURE 144-1. Algorithm for the approach to a child with undiagnosed bleeding. aPTT = activated partial thromboplastin time; PT = prothrombin time; vWD = von Willebrand’s disease. factor IX will raise factor activity level by only 1%. 3 Given the cost of these products, an effort should be made to use the whole unit dose. In the rare case in which factor replacement products are not immediately available, administer cryoprecipitate for factor VIII deficiency or fresh frozen plasma for factor IX deficiency. Patients with mild hemophilia A who have been pretested to docu ment a response may be treated with desmopressin instead of factor replacement. Desmopressin releases stored factor VIII from the sub endothelial compartment. The use of desmopressin is particularly advantageous for pediatric patients, due to its lower cost, availability in intranasal form, and the elimination of viral transmission risk as com pared to frequent factor replacement. 3 See Table 235-5 for desmopressin dosing. Of note, desmopressin is an antidiuretic; patients must be monitored for water retention and hyponatremia. For hemophilia patients requiring surgery and scheduled to go to the operating room from the ED, factor replacement must be given before hand to optimize factor levels. Adjunctive management for bleeding in joints and muscles should also include rest, ice, compression, elevation, and splinting. Minimal oral bleeding (e.g., after dental procedures) may be treated with topical thrombin or antifibrinolytic drugs such as tranexamic acid or aminocaproic acid. 3 Minimal anterior epistaxis may respond to conservative therapies, such as direct pressure and phenylephrine, without factor replacement. Patients, usually with severe hemophilia A, who have factor inhibitors (antibodies) may require very high doses of standard factor products to overwhelm the inhibitors present. However, some patients will need to be treated with products that bypass factor VIII and factor IX in the clotting cascade (see Table 235-6). These include activated prothrombin complex concentrates (FEIBA ® ) and recombinant activated factor VIIa (NovoSeven® ).

dard factor products to overwhelm the inhibitors present. However, some patients will need to be treated with products that bypass factor VIII and factor IX in the clotting cascade (see Table 235-6). These include activated prothrombin complex concentrates (FEIBA ® ) and recombinant activated factor VIIa (NovoSeven® ). COMPLICATIONS Hemarthrosis is the most common hemorrhagic complication of hemophilia and most commonly affects the knee, ankle, elbow, and shoulder. Minor, often unrecognized, trauma may precipitate spontaneous intraarticular hemorrhage with pain, swelling, and decreased range of motion. Unfortunately, the presence of blood in the joint precipitates a cascade of inflammation and synovial neovascularization. This increases vulnerability to bleeding and leads to synovium fibrosis, irreversible cartilage destruction, and hemophilic arthropathy ( Figure 144-4). 2 Aggressive measures must be taken to limit the number and extent of these events. Spontaneous muscle hematomas account for 10% to 25% of hemophilia bleeds and can also present with severe pain and limited range of motion.4 Complications from ongoing bleeding include compartment syndrome and nerve compression. Particularly concerning are iliopsoas bleeds, which may mimic acute appendicitis or hip pathology, with radiation of pain to the back, groin, and hip. The hip is often held in flexion. Such bleeds can be particularly uncomfortable if there is compression of the femoral nerve or sacral plexus. They require aggressive factor replacement, given the potential for blood accumulation in the retroperitoneal space. The leading cause of death in children with hemophilia is intracranial hemorrhage, which can be spontaneous or occur after even mild head trauma. 4 Because bleeding can progress slowly, patients may not yet have clinical manifestations of hemorrhage upon presentation. Maintain a Tintinalli_Sec12_p0669-0996.indd 950 8/2/19 7:59 PM CHAPTER 144: Hematologic Emergencies in Infants and Children 951 TABLE 144-1 Coagulation Disorders Disease Inheritance Defect Incidence Distribution Subtypes Inhibitors Diagnostics Symptoms Treatment Hemophilia A Factor VIII deficiency X-linked recessive Defect in factor VIII procoagulant activity Quantitative and qualitative 1:5000 live male births Males

CHAPTER 144: Hematologic Emergencies in Infants and Children 951 TABLE 144-1 Coagulation Disorders Disease Inheritance Defect Incidence Distribution Subtypes Inhibitors Diagnostics Symptoms Treatment Hemophilia A Factor VIII deficiency X-linked recessive Defect in factor VIII procoagulant activity Quantitative and qualitative 1:5000 live male births Males Severe: <1% factor VIII activity Frequency: 50%–70% Bleeding spontaneously into joints or soft tissue Moderate: 1%–5% factor VIII activity Frequency: 10% Bleeding with minor trauma or surgery Mild: >5% factor VIII activity Frequency: 30%–40% Bleeding with major trauma or surgery 30% of those with severe subtype have inhibitors Platelet count, PT, bleeding time—WNL PTT— prolonged Factor VIII assay—low or absent amount Intracranial hemorrhage Hemarthroses (large joints) Bleeding after neonatal circumcision Muscle and soft tissue hematomas Retroperitoneal bleeds Epistaxis and mucosal bleeding from oral trauma Pharyngeal bleeding (posttussive and after emesis) Hematochezia and melena from GI bleeding Hematuria Menorrhagia Factor VIII replacement Desmopressin (in pretested mild hemophiliacs) Activated prothrombin complex concentrates (FEIBA ® ) Recombinant activated factor VIIa (NovoSeven ® ) Cryoprecipitate* Hemophilia B (Christmas disease) Factor IX deficiency X-linked recessive Defect in factor IX procoagulant activity Quantitative and qualitative 1:30,000 live male births Males Severe: <1% factor IX activity Bleeding spontaneously into joints or soft tissue Moderate: <1% factor IX activity Bleeding with minor trauma or surgery Mild: >5% factor IX activity Bleeding with major trauma or surgery 1%–3% with inhibitors Platelet count, PT, bleeding time—WNL PTT— prolonged Factor IX assay—low or absent amount Symptoms same as for factor VIII deficiency Factor IX replacement Activated prothrombin complex concentrates (FEIBA ® ) Recombinant activated factor VIIa (NovoSeven ® ) Fresh frozen plasma* von Willebrand’s disease vWF deficiency Autosomal dominant (type 1 and subtypes of 2); autosomal recessive (subtypes of 2 and type 3) Defect in vWF Quantitative and qualitative Variable factor VIII activity 1%–2% of general population Males = females

Factor IX replacement Activated prothrombin complex concentrates (FEIBA ® ) Recombinant activated factor VIIa (NovoSeven ® ) Fresh frozen plasma* von Willebrand’s disease vWF deficiency Autosomal dominant (type 1 and subtypes of 2); autosomal recessive (subtypes of 2 and type 3) Defect in vWF Quantitative and qualitative Variable factor VIII activity 1%–2% of general population Males = females Type 1 von Willebrand’s (classic) disease: Mild quantitative deficiency of vWF Most common form (80%) Type 2 von Willebrand’s disease: Variable qualitative abnormalities of vWF Type 3 von Willebrand’s disease: Severe quantitative deficiency of vWF Rare (1–3 per million) Inhibitors rare PT—WNL PTT— prolonged or WNL Factor VIII— borderline or decreased vWF activity, antigen and multimer evaluation Types 1 and 2 (mild): Mucocutaneous bleeding Recurrent or prolonged epistaxis Bleeding after surgery or trauma, e.g., dental procedures GI bleeding Menorrhagia Type 3: Spontaneous hemarthroses Muscle hematomas Severe bleeding vWF replacement Desmopressin for type 1 and some type 2 Antifibrinolytic agents (ε-aminocaproic acid) Abbreviations: PT = prothrombin time; PTT = partial thromboplastin time; vWF = von Willebrand factor; WNL = within normal limits. *If concentrated factor products unavailable. Tintinalli_Sec12_p0669-0996.indd 951 8/2/19 7:59 PM

Types 1 and 2 (mild): Mucocutaneous bleeding Recurrent or prolonged epistaxis Bleeding after surgery or trauma, e.g., dental procedures GI bleeding Menorrhagia Type 3: Spontaneous hemarthroses Muscle hematomas Severe bleeding vWF replacement Desmopressin for type 1 and some type 2 Antifibrinolytic agents (ε-aminocaproic acid) Abbreviations: PT = prothrombin time; PTT = partial thromboplastin time; vWF = von Willebrand factor; WNL = within normal limits. *If concentrated factor products unavailable. Tintinalli_Sec12_p0669-0996.indd 951 8/2/19 7:59 PM 952 SECTION 12: Pediatrics high index of suspicion. Unless directed otherwise by the hematology consultant, treat all reports of head injuries, neurologic symptoms, or visible head trauma presumptively with 100% factor correction. Obtain immediate head CT imaging to identify intracranial hemorrhage. Bleeding from the GI tract is rarely severe unless a specific anatomic lesion is present. Gross hematuria may require factor replacement. Obtain urinalysis to rule out infection and renal ultrasonography to identify a serious anatomic lesion. Other uncommon but critical lesions that require aggressive factor replacement (100%) and specialist inter vention to avoid massive hemorrhage or permanent injury include tonsillar bleeding, solid organ bleeding from blunt abdominal or thoracic trauma, spinal hematoma, and intraocular hemorrhage. DISPOSITION Consult a hematologist for all children with hemophilia and active bleeding prior to disposition. Pediatric hemophilia patients and their families are often comfortable participating in that decision, because they may receive some treatments at home. Children with mild bleeding episodes may be discharged home with careful instructions and a concrete hematology follow-up appointment. Patients with moderate or severe bleeding and those with high-risk bleeds require hospital admission, because close monitoring and documentation of adequate response to factor replacement are necessary and repeat doses are frequently required.  VON WILLEBRAND’S DISEASE A detailed discussion of von Willebrand’s disease (vWD) is provided in Chapter 235; vWD classification and basic treatment are outlined in Table 235-7. CLINICAL FEATURES vWD type 1 is usually associated with mild mucocutaneous bleeding, including easy bruising, recurrent or prolonged epistaxis, and prolonged postprocedural bleeding (e.g., gingival bleeding after dental work). Menorrhagia may be the sole presenting complaint in young women. In type 3 vWD, clinical features can closely resemble those of hemophilia, because significantly reduced amounts of von Willebrand factor (vWF) allow increased clearance of factor VIII. In general, the severity of bleeding correlates with the degree of reduction of factor VIII. DIAGNOSIS A high index of suspicion is necessary for the diagnosis of vWD because clinical features are mild in most patients, and mucocutaneous bleeding (e.g., bruising, epistaxis) is common in childhood. History should include frequency, duration, severity, and location of bleeding, as well as concurrent medications. Note any family history of “easy” bleeding. ED screening labs for vWD usually reveal a normal CBC and prothrombin time, a normal or prolonged activated PTT (if factor VIII is sufficiently reduced), and low vWF levels. More specific testing includes vWF antigen, vWF ristocetin cofactor activity, vWF multimers, and factor VIII level. 6,7 Bleeding time, once the gold standard for vWD diagnosis, has difficulties with reproducibility and poor sensitivity and specificity. 7,8 Levels of vWF can be affected by a variety of normal (e.g., stress) and medical (e.g., active bleeding) conditions.8 Repeat testing should be done if clinical suspicion is high. TREATMENT Treatment of active bleeding in a known vWD patient consists initially of localized measures to achieve hemostasis, including direct pressure on bleeding sites, packing dental extraction sites and nasal passages, and the application of topical hemostatic agents.

g should be done if clinical suspicion is high. TREATMENT Treatment of active bleeding in a known vWD patient consists initially of localized measures to achieve hemostasis, including direct pressure on bleeding sites, packing dental extraction sites and nasal passages, and the application of topical hemostatic agents. Antifibrinolytic agents can be used to treat oral trauma. Oral contraceptive pills or an intrauterine device helps to control menorrhagia. Desmopressin (see earlier section on hemophilia treatment), which releases stored vWF from the endothelium, is the preferred initial treatment of bleeding in patients with type 1 vWD. It has no effect in those with type 3 vWD and variable effect in those with type 2. 5 Pay attention to the fluid status of patients receiving desmopressin, because dilutional hyponatremia is a rare side effect due to its antidiuretic properties. Children with type 2 or 3 vWD or type 1 with inadequate response to desmopressin usually require treat ment with purified plasma-derived vWF replacement. Other emerging therapies, such as recombinant vWF concentrate, have been approved for adults but are not yet routinely used in children. 9 In emergencies only, administer cryoprecipitate if no vWF:factor VIII replacement is available. Cryoprecipitate is not recommended as standard therapy because it has a low concentration of vWF and carries infectious risks because it does not undergo viral inactivation. 5 Advise all patients with vWD to avoid medications with known antiplatelet effects (e.g., aspirin, NSAIDs).  VITAMIN K DEFICIENCY BLEEDING Vitamin K deficiency bleeding, formerly known as hemorrhagic disease of the newborn , is a neonatal bleeding coagulopathy resulting from vitamin K deficiency. Although the American Academy of Pediatrics FIGURE 144-2. Hemophilia A. Extensive bruising in a child with factor VIII deficiency. [Photo contributed by Ralph A. Gruppo, MD. Reproduced with permission from Knoop K, Stack L, Storrow A, Thurman RJ: Atlas of Emergency Medicine, 3rd ed. © 2010, McGraw-Hill, Inc., New York.] FIGURE 144-3. Hemarthrosis. A child with hemophilia A who presented with bilateral knee hemarthroses. [Reproduced with permission from Shah BR, Lucchesi M: Atlas of Pediatric Emergency Medicine, © 2006, McGraw-Hill, Inc., New York.] Tintinalli_Sec12_p0669-0996.indd 952 8/2/19 7:59 PM

2010, McGraw-Hill, Inc., New York.] FIGURE 144-3. Hemarthrosis. A child with hemophilia A who presented with bilateral knee hemarthroses. [Reproduced with permission from Shah BR, Lucchesi M: Atlas of Pediatric Emergency Medicine, © 2006, McGraw-Hill, Inc., New York.] Tintinalli_Sec12_p0669-0996.indd 952 8/2/19 7:59 PM CHAPTER 144: Hematologic Emergencies in Infants and Children 953 FIGURE 144-4. Hemophilic arthropathy. Note the extensive degenerative changes. [Image used with permission of J. Fitzpatrick, MD, Cook County Hospital. Reproduced with permission from Simon RR, Koenigsknecht SJ: Emergency Orthopedics: The Extremities, 5th ed. Copyright © 2007 by The McGraw-Hill Companies, Inc. All rights reserved.] has recommended intramuscular vitamin K prophylaxis as standard of care in newborns since 1961, there has been an increasing rate of parental refusal in the past decade. 10 Risk factors include breastfed infants (because breast milk contains less vitamin K content than cow’s milk formulas), infants with malabsorption or hepatobiliary disorders, and maternal medications (e.g., phenytoin, isoniazid). In classic cases, bleeding occurs 2 to 14 days after birth; however, there are reports of cases <24 hours after birth and up to 12 weeks after birth. Bleeding can present as mild oozing from the umbilicus or circumcision site or as life-threatening pulmonary and intracranial hemorrhage. Although vitamin K deficiency bleeding is rare in developed countries, 30% to 60% of reported cases are associated with intracranial hemor rhage. 10 Labs reveal a decreased hematocrit, depending upon the severity and duration of the bleed, and prolonged prothrombin time and activated PTT. Treatment is the immediate administration of 1 milligram of SC, IM, or IV vitamin K (phytonadione). The IM route places the patient at risk for a significant hematoma, whereas the IV route carries a greater risk of an anaphylactoid reaction. Given the risk of intracranial bleeding, do not wait for laboratory results if your clinical suspicion is high. Life-threatening hemorrhage may require a transfusion of 10 to 20 mL/kg of fresh frozen plasma to increase serum procoagulant levels.  ANEMIA Children may develop profoundly low hemoglobin levels (e.g., 3 to 4 grams/dL) before coming to medical attention. Patients may be asymptomatic or present with symptoms ranging from pallor and decreased activity to congestive heart failure in an infant. This section reviews the ED diagnosis and management of some important types of anemia in children. The management of anemia due to hemorrhage is discussed in Chapters 13, “ Approach to Traumatic Shock” and 110, “Pediatric Trauma. ” Hemoglobin levels vary with a child’s age, peaking at approximately 14 to 15 grams/dL in the full-term newborn period and at approximately 13 grams/dL (females) and approximately 15 grams/dL (males) in the teenage years. The dramatic increase in oxygen availabil ity after birth briefly shuts down erythropoietin production, resulting in a physiologic nadir, or “physiologic anemia, ” of about 9 to 11 grams/dL at approximately 2 months of age. Hemoglobin levels then rise steadily throughout childhood. After the first year of life, the normal reticulocyte count is 1% to 2% of circulating red blood cells, assuming normal red blood cell physiology. 8 Refer to normal hemoglobin and red blood cell values when evaluating pediatric anemia. ED TREATMENT OF SEVERE ANEMIA Children with anemia unrelated to acute blood loss rarely require blood transfusion in the ED. Some children with very low hemoglobin levels and a presentation highly consistent with iron deficiency ane mia, for example, may be managed as outpatients if close follow-up is ensured.

anemia. ED TREATMENT OF SEVERE ANEMIA Children with anemia unrelated to acute blood loss rarely require blood transfusion in the ED. Some children with very low hemoglobin levels and a presentation highly consistent with iron deficiency ane mia, for example, may be managed as outpatients if close follow-up is ensured. Exceptions include hemolytic anemias, bone marrow failure, hemodynamic instability, congestive heart failure, or other symptoms due to severe anemia. Obtain a hematology consultation to assist with transfusion management. The decision to transfuse must take into account whether the child has a chronic or acute anemia; those with chronic anemias are at risk for volume overload. For children with hemoglobin ≤8 grams/dL and Tintinalli_Sec12_p0669-0996.indd 953 8/2/19 7:59 PM

a hematology consultation to assist with transfusion management. The decision to transfuse must take into account whether the child has a chronic or acute anemia; those with chronic anemias are at risk for volume overload. For children with hemoglobin ≤8 grams/dL and Tintinalli_Sec12_p0669-0996.indd 953 8/2/19 7:59 PM 954 SECTION 12: Pediatrics signs of hemodynamic compromise, active bleeding, or consumptive coagulopathy, consider an initial transfusion of packed red blood cells in 10 to 15 mL/kg aliquots. With extremely low hemoglobin levels (<5 grams/dL) due to chronic anemia, the transfusion should be small (2 to 3 mL/kg packed red blood cells) and slow (1 mL/kg/h), with continuous monitoring and frequent reassessment. In cases of volume overload, diuretics can be considered, or an exchange transfusion can be performed in severe cases. CLASSIFICATION OF ANEMIA As with adults, a differential diagnosis for anemia in childhood can be broken down into microcytic, normocytic, and macrocytic categories (see Figures 231-2, 231-3, and 231-4). The pathologic causes can be classified as those that decrease red blood cell production and those that increase red blood cell destruction, in addition to blood loss and iatro genic dilutional anemia from fluid administration. To help with those differentiations, a peripheral smear and reticulocyte count should always be sent with the CBC. A more detailed differential diagnosis of anemia is provided in Table 144-2. Selected common pediatric anemias are discussed below. For a more thorough discussion of specific etiologies, see Chapters 231, “ Anemia and Polycythemia”; 233, “ Acquired Bleeding Disorders”; 236, “Sickle Cell Disease and Hereditary Hemolytic Anemias”; and 237, “ Acquired Hemolytic Anemia. ” Hemolytic-uremic syndrome is discussed in detail in Chapter 137, “Renal Emergencies in Children. ” IRON DEFICIENCY ANEMIA Iron deficiency anemia is the leading cause of anemia in childhood and can be profound. Healthy term infants have adequate iron storage for the first 4 to 6 months of life. After this, iron stores are depleted. Decreas ing prevalence of iron deficiency anemia may be attributable, in part, to the American Academy of Pediatrics recommendations regarding iron supplementation in breastfed infants, iron-fortified formulas and infant foods, delayed use of cow’s milk until after 1 year of age, and universal hemoglobin screening at 1 year of age. 12 However, excessive whole-milk feeding and poor dietary intake of iron make iron deficiency anemia a diagnosis common in the toddler years. Milk proteins may also cause a low-grade colitis with occult GI bleeding. Nutritional iron deficiency anemia is uncommon in children >3 to 4 years of age and is suspi cious for occult bleeding. 8 Iron deficiency anemia is diagnosed based on clinical suspicion, with labs demonstrating a hypochromic micro cytic anemia and low reticulocyte count. Iron studies help to confirm the diagnosis. For hemodynamically stable children, treatment is outpatient oral ferrous sulfate supplementation and primary care follow-up. For children with severe anemia and/or evidence of hemodynamic com promise, inpatient care may be necessary, and hematology should be consulted regarding transfusion guidelines. PARVOVIRUS B19 INFECTION Parvovirus, a common virus in childhood, replicates in erythroid progenitor cells and can cause transient red cell aplasia. In the normal host, parvovirus infection may go unrecognized or be identified by its characteristic reticular rash and slapped cheek appearance (erythema infectiosum, or fifth disease); see “Erythema Infectiosum” in Chapter 142, “Rashes in Infants and Children. ” The red cell aplasia is so short lived that concomitant anemia is usually not discovered.

fection may go unrecognized or be identified by its characteristic reticular rash and slapped cheek appearance (erythema infectiosum, or fifth disease); see “Erythema Infectiosum” in Chapter 142, “Rashes in Infants and Children. ” The red cell aplasia is so short lived that concomitant anemia is usually not discovered. However, in patients with hemoglobinopathy or hemolytic anemias such as sickle cell disease, in whom the life span of a red cell is decreased, even brief periods of red cell aplasia may result in severe anemia and aplastic crisis, often requiring transfusion. TRANSIENT ERYTHROBLASTOPENIA OF CHILDHOOD Transient erythroblastopenia of childhood is a gradually developing, self-resolving normocytic anemia caused by a temporary decrease in red blood cell precursors. The cause is unknown. It is most common in the toddlers and preschool age groups, but can be diagnosed in children 6 months to 10 years of age. 13 Other cell lines should not be affected, and iron studies are normal. Bone marrow recovery usually occurs in 1 to 2 months, and transfusions are rarely needed. AUTOIMMUNE HEMOLYTIC ANEMIA Autoimmune hemolytic anemia is caused by the production of autoantibodies to red blood cells. In primary autoimmune hemolytic anemia (most common in infants and young children), there is no evidence of an underlying disorder; the disease may manifest after a simple viral illness. Older children are more likely to experience autoimmune hemolytic anemia secondary to an underlying systemic illness, such as malignancy, human immunodeficiency virus, or an autoimmune disorder. The clinical presentation may be abrupt and the anemia severe. White cells and platelets are unaffected, and reticulocytes are increased unless the hemolysis is sudden and recent. Labs reveal spherocytes and schistocytes on peripheral blood smear, an indirect hyperbilirubinemia, elevated lactate dehydrogenase, and urine bilirubin metabolites (hemoglobinuria in the absence of red blood cells on urine microscopy). Definitive diagnosis is made by a direct Coombs test. These patients should be hospital ized, and treatment usually begins with corticosteroids. If transfusion is required, the most compatible packed red blood cells are used. THROMBOCYTOPENIA A platelet count <150,000/mm 3 should be considered abnormal, and patients with a count <20,000/mm 3 are at high risk for spontaneous bleeding. Consider thrombocytopenia in patients with petechiae (see Figure 233-1A), easy bruising, epistaxis, gingival bleeding, menorrha gia, hematuria, and GI bleeding. Perform a thorough physical exam to assess for signs of systemic disease. Refer to Figure 144-1 for the general TABLE 144-2 Classification of Anemia Decreased red blood cell (RBC) production Impaired RBC proliferation •   Parvovirus B19 infection •   Aplastic anemia (congenital or acquired) •   Isolated pure red cell aplasia (Diamond-Blackfan syndrome) •   Transient erythroblastopenia of childhood (TEC) •   Bone marrow infiltration (e.g., leukemia) Impaired erythropoietin production •   Anemia of chronic disease •   Chronic renal disease •   Malnutrition Abnormal hemoglobin synthesis •   Lead poisoning •   Iron deficiency •   Thalassemia •   Vitamin B12 or folate deficiency •   Sideroblastic anemia Increased RBC destruction Hemoglobinopathy •   Thalassemia •   Sickle cell disease •   Membrane defect (e.g., hereditary spherocytosis) Extrinsic disease •   Autoimmune hemolytic anemia •   Glucose-6-dehydrogenase deficiency •   Disseminated intravascular coagulopathy •   Microangiopathic process (e.g., hemolytic-uremic syndrome) •   Paroxysmal nocturnal hemoglobinuria Tintinalli_Sec12_p0669-0996.indd 954 8/2/19 7:59 PM