Pediatric Hematologic Emergencies
May 1, 2024 41 minutes read
AUTHORS
Tess Munoz, MD, Resident Physician, Department of Emergency Medicine, University of North Carolina at Chapel Hill
Daniel Migliaccio, MD, FPD, FAAEM, Clinical Associate Professor, Division Director of Emergency Ultrasound, Ultrasound Fellowship Director, Department of Emergency Medicine, University of North Carolina at Chapel Hill
Peer Reviewer
Steven M. Winograd, MD, FACEP, Attending Emergency Physician, Trinity Health Care, Samaritan, Troy, NY
Executive Summary
- To diagnose anemia in children, providers must reference hemoglobin values based on their age.
- The most common cause of iron deficiency anemia is nutritional deficiency.
- The most common sources of elevated lead levels in children in the United States are lead-based paints and soil contaminated with lead. Some other sources include contaminated drinking water and imported goods, such as candies, spices, and pottery. Houses built before 1978 pose a larger risk of lead exposure.
- Additional tests that assist in detecting lead toxicity include a complete blood count, which can uncover instances of microcytic hypochromic anemia and, in some cases, basophilic stippling on a blood smear.
- Frequently observed symptoms at the initial presentation of immune thrombocytopenic purpura (ITP) include mucosal bleeding, petechiae, and purpura. Some patients with ITP may not display any symptoms, and their low platelet count may be detected incidentally.
- Hemolytic uremic syndrome (HUS) is characterized by the simultaneous presence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. It predominantly manifests in rural areas following episodes of acute gastroenteritis triggered by enterohemorrhagic Escherichia coli or Shigella dysenteriae infections. HUS also can be triggered by other infections, such as Streptococcus pneumoniae and human immunodeficiency virus.
- Splenic sequestration is a rare complication of sickle cell disease (SCD) and occurs when there is a drop in hemoglobin associated with an enlarged spleen caused by intrasplenic sickling. The typical clinical manifestation involves abdominal pain and splenomegaly, yet patients might exhibit a nonspecific presentation, such as fussiness or general discomfort.
- Infection remains the most common cause of death in children with SCD, which is why it is important to evaluate these patients early and thoroughly. The most common cause of fever in children with SCD is acute chest syndrome, but other infections to be aware of are urinary tract infections; viral infections, which tend to be more severe in SCD; and noninfectious causes, such as pulmonary embolism and vaso-occlusive crises
Hematology is a challenging area in pediatrics, with unique diseases that do not occur commonly. The authors review critical pediatric hematologic conditions that the acute care provider may encounter and provide a concise guide to diagnosis, stabilization, and management.
— Ann M. Dietrich, MD, FAAP, FACEP, Editor
Introduction
Hematologic disorders typically can be characterized by a decreased or increased amount of a certain cell line or multiple cell lines. The basic cell lines include erythrocytes, platelets, and leukocytes. Furthermore, these disorders can be characterized by decreased production, increased destruction, or abnormally functioning cells. It is important for emergency medicine physicians to understand how these different disorders present and how to stabilize and treat these patients.
Anemia
Anemia is characterized as having a hemoglobin level less than the fifth percentile corresponding to an individual’s age. Physiologic anemia of infancy occurs at about 6 weeks to 9 weeks of age, and the hemoglobin is typically 10 g/dL to 11 g/dL as the infant starts producing their own hemoglobin. Anemia affects an estimated 20% of children in the United States. Many of these children are found to be anemic based on screening laboratory testing and are asymptomatic.1 Anemia can furthermore be broken down in the microcytic, normocytic, and macrocytic based on the size of the red blood cells, which can be determined by the mean corpuscular volume (MCV).2
History and Physical
The initial step when a pediatric patient comes into the emergency department should be to determine whether the patient is stable. Patients should be examined for mottling, hypoxia, and signs of hypoperfusion, including altered mental status, poor perfusion and hypotension (a very late finding). The first steps always should be obtaining a full set of vital signs and intravenous (IV) access. In the acutely anemic patient presenting to the emergency department who ultimately requires blood products, type- and cross-matched blood products are preferred. However, in more emergent situations, it is appropriate to administer O-negative blood.
In a stable patient, it is paramount to get a thorough history and physical exam to help aid proper diagnosis and treatment. In younger infants and neonates, birth history also is important, including previous jaundice, phototherapy, or blood transfusions. Some key components that should be elicited in all children are other medical issues, new medications, trauma, potential sources of blood loss, travel, diet, and infections. Additionally, a detailed family history should be obtained regarding bleeding disorders, splenectomies, and autoimmune diseases.
A thorough physical exam can help determine the chronicity and severity of anemia. In cases of severe and sudden onset anemia, such as in cases of hemorrhaging, patients present with significant tachycardia, tachypnea, and signs of poor perfusion — altered mentation and delayed capillary refill. However, in more chronic cases of hemolytic anemia, they can present with jaundice, splenomegaly, scleral icterus, and conjunctival pallor.
Laboratory Evaluation
The initial laboratory evaluation to determine if a child has anemia is a complete blood count (CBC), with an eye on hemoglobin, hematocrit, white blood count, platelet count, and red blood cell indices. The red blood cell indices include MCV, red cell distribution width (RDW), and mean corpuscular hemoglobin concentration (MCHC). It is important to look at the platelet and white blood cell counts to see if the disease is affecting multiple cell lines. It also is important to evaluate reticulocyte count. As young and immature red blood cells, an indication of whether they are elevated or decreased can determine if the disease process is caused by decreased production or increased destruction. Another useful laboratory study is a peripheral blood smear because it can aid in identifying spherocytes, elliptocytes, schistocytes, target cells, helmet cells, and intracellular inclusions. There also have been studies that showed increasing accuracy of deoxyribonucleic acid (DNA) sequencing techniques to diagnose inherited anemias.4 Although not likely to be useful in the emergency department because of time and cost, they could be useful in the future with more advances in technology as well as in initiating workups for admitted patients.
To diagnose anemia in children, providers must reference hemoglobin values based on their age. A reference for hemoglobin levels by patient age can be found at https://bit.ly/3xBQPzl (Table 1 at the source). One of the main criteria used to differentiate anemias is based on the MCV, which categorizes anemias into three areas: microcytic, normocytic, and macrocytic. (See Figure 1.) The MCV for each of these anemias is < 80 fL, 80 fL to 100 fL, and > 100 fL, respectively.
Figure 1. Classification of Types of Anemias Based on Mean Corpuscular Volume |
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It is recommended that symptomatic and critically ill patients receive blood transfusions when their hemoglobin falls below 7 g/dL.5 However, children with more complicated comorbidities, such as sickle cell anemia and leukemia, may benefit from transfusions at higher hemoglobin levels. The standard transfusion volume usually is 10 mL/kg administered at a rate not exceeding 5 mL/kg/hour.1
Continuous monitoring for signs of heart failure is essential during the transfusion process. The risks of blood transfusions can be divided into infectious and noninfectious causes. Fortunately, because of the extensive screening done on donated blood, the risk of infection has dropped significantly.
About 1% of children who receive red blood cell transfusions experience a transfusion reaction.6 These transfusion reactions include hemolytic reactions, febrile nonhemolytic reactions, allergic reactions, transfusion-related acute lung injuries, and transfusion-associated lung overload. For these reactions, the most important initial treatment is to discontinue the transfusion. Transfusions also can lead to metabolic derangements, including hypothermia, hyperkalemia, and citrate toxicity, leading to hypocalcemia.7 Therefore, it is important to monitor for signs such as hypotension, tetany, arrhythmias, and changing electrolyte levels with frequent basic metabolic panels BMP(s), especially if patients are receiving multiple units of blood.
Iron Deficiency Anemia
Iron deficiency anemia stands as one of the most prevalent hematologic conditions in childhood and adolescence. The occurrence of iron deficiency anemia among children aged 1 to 5 years in the United States is approximately 1% to 2%.8 There are multiple factors that can lead to iron deficiency anemia. It can be broken down into four main categories: decreased dietary iron, increased iron requirements, loss of blood, and ineffective intestinal absorption of iron. (See Table 1.)
Table 1. Causes of Iron Deficiency Anemia9 |
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Low dietary iron |
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Increased demand for iron |
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Reduced iron absorption |
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Blood loss |
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Adapted with permission of CC BY 4.0 DEED https://creativecommons.org/licenses/by/4.0/ |
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The most common cause of iron deficiency anemia is nutritional deficiency. (often excessive intake of cow’s milk). This can be prevented with thorough parental counseling on dietary supplementation. One of the high-risk populations for iron deficiency anemia is preterm infants because 80% of iron acquisition occurs during the final trimester of pregnancy — and they also undergo rapid growth in the initial months of their lives.9 Depending on their age and what they eat, infants may require different amounts of iron supplementation:2
- Preterm (< 37 weeks’ gestation) infants aged 1 month to 12 months: 2 mg/kg/day supplementation if exclusively breastfed or 1 mg/kg/day supplementation if using iron-fortified formula;
- Term infants aged 4 to 12 months: 1 mg/kg/day supplementation if exclusively breastfed or not needed if they are using iron-fortified formula;
- Toddlers aged 1 to 3 years: 7 mg/day; modify diet and/or supplement if anemic; and
- Children aged 4 to 8 years: 10 mg/day; modify diet and/or supplement if they are anemic.
Most children present asymptomatically with iron deficiency anemia, which may be identified during American Academy of Pediatrics-recommended universal screening at 12 months of age. When there is an acute illness, sometimes these children will present with pallor and fatigue. Another sign to beware of is pica, or the intense craving for nonfood items, including clay, dirt, ice, and raw rice, which has been associated with iron deficiency anemia. Iron deficiency anemia also is associated with many other conditions, including febrile seizures, thrombosis, breath-holding spells, impaired cognitive development, and impaired cell-mediated immunity.10 It is much less common for infants to present with severe anemia, but when they do, they exhibit signs like lethargy, pallor, cardiomegaly, feeding difficulties, and tachypnea.
In terms of diagnosing iron deficiency anemia, the CBC will show microcytic-hypochromic anemia with reduced reticulocyte count (reduced hemoglobin, MCV, MCHC, and elevated RDW). Additional studies can be used for confirmation, including decreased ferritin and normal to increased total iron-binding capacity. The most sensitive test is ferritin level, since it serves as a reliable indicator of overall iron storage and is the first laboratory parameter to decrease in response to iron deficiency. However, its precision might be reduced in cases involving children with infectious or inflammatory disorders because it also acts as an acute phase reactant.11
First-line treatment for iron deficiency anemia is oral supplementation, typically with ferrous sulfate or gluconate because of their high oral bioavailability and cost effectiveness.12
For most well-appearing children, oral supplementation will suffice as long as they have close outpatient follow-up. Cases where emergency medicine physicians should consider admitting these children for parenteral treatment usually would be those with severe symptoms and failed oral therapy, malabsorption issues caused by gastrointestinal disorders, ongoing controlled blood loss, and anemia caused by chronic inflammation.3 The most commonly used formula is IV iron sucrose, with the recommended maximum individual dose to prevent adverse effects being 300 mg total or 7 mg iron/kg.13
Lead Poisoning
In 2012, the Centers for Disease Control and Prevention’s Advisory Committee on Childhood Lead Poisoning Prevention decreased the threshold for blood lead level to 5 mcg/dL (0.24 μmol/L). This number is based on the 97.5th percentile of the previous two National Health and Nutrition Examination blood lead level distributions in 1- to 5-year-olds.14 More than 500,000 children in the United States were found to have elevated lead levels in 2017.15 The most common sources of elevated lead levels in children in the United States are lead-based paints and soil contaminated with lead. Some other sources include contaminated drinking water as well as imported goods, such as candies, spices, and pottery.14 Houses built before 1978 pose a larger risk of lead exposure. In addition, individuals living in a high-poverty areas have a greater risk because those houses tend to be older and less well-maintained.16 Children with iron deficiency anemia are at a four- to five-fold increased risk for lead toxicity caused by increased absorption of lead.17
The manifestations of lead poisoning show considerable diversity and hinge on the duration of exposure as well as the total quantity of lead accumulated in the body. Many times, children are asymptomatic. Because children are in their developmental stages, they are especially vulnerable to lead exposure due to an underdeveloped blood-brain barrier, a heightened absorption, and a tendency to place objects in their mouth that are not safe. Symptoms of lead poisoning can be very nonspecific, including gastrointestinal symptoms like vomiting and abdominal pain to vague neurologic symptoms like headache, ataxia, seizures, encephalopathy, weakness, and peripheral neuropathy. That is why, if lead toxicity is suspected, a thorough history to discover these exposures and risk factors is essential to identify the source.
Screening and diagnosing lead poisoning rely on measuring lead levels in venous blood. Confirmatory venous testing is necessary if capillary samples are used. Additional tests include a CBC, which can uncover instances of microcytic hypochromic anemia and, in some cases, basophilic stippling on a blood smear.18 If there is a suspicion for ingestion of a lead-containing object, radiographs should be obtained immediately to determine the location of the object in the gastrointestinal tract and guide the correct specialists to remove the item.
For children without symptoms and whose blood lead levels reach 5 mcg/dL or higher, healthcare providers should formally seek an environmental lead inquiry from the local or state health department. These children should be closely monitored as outpatients for frequent rechecks until levels return to a normal range. In cases where children have blood lead levels ranging from 20 mcg/dL to 45 mcg/dL, the basic medical approach involves reducing their contact with any lead sources, addressing iron deficiency if present, ensuring sufficient calcium intake, and close monitoring, which can all be done outpatient.19 Supplementary iron therapy typically is started as a dosage of 3 mg/kg/day to 6 mg/kg/day of elemental iron to address any deficiencies in iron.17
If a child is symptomatic with known lead toxicity, clinicians should strongly consider admitting them to the hospital for further care and management. Chelation therapy is advised when blood lead levels surpass 45 mcg/dL, regardless of whether the lead exposure is acute or chronic.20 Before starting chelation therapy, baseline laboratory tests should be obtained to ensure no contraindications to this therapy. These tests include free erythrocyte protoporphyrin, comprehensive metabolic panel (CMP), magnesium, iron, total iron-binding capacity, transferrin levels, and urinalysis.
Healthcare professionals need to get in touch with a poison control center prior to initiating chelation therapy. Those children who present with encephalopathy or seizures should first be stabilized with airway management if needed along with neuroimaging. Benzodiazepines are still first-line treatment for seizures in children with lead toxicity. Adequate fluid administration also is essential to ensure chelation is appropriately functioning and excretion of blood and tissue lead. This can be obtained using 5% dextrose with normal saline running at a maintenance rate for daily urine output between 300 mL/m2 and 350 mL/m2.21
There are four frequently used chelating agents: dimercaprol and edetate calcium disodium edetate, which are given through injections, while dimercaptosuccinic acid (succimer) and D-penicillamine are taken orally. In asymptomatic children with levels of 45 mcg/dL to 69 mcg/dL, the agent of choice is succimer.19 An alternative would be D-penicillamine however it is associated with more severe side effects.19 Dimercaprol is given intramuscularly and is essential for children with encephalopathy because it crosses the blood-brain barrier. It is often recommended that children who receive dimercaprol be pretreated with diphenhydramine to prevent adverse effects that are associated with histamine release.19 Calcium disodium edetate is an intravenous chelating agent that does not cross the blood-brain barrier, so must be used in combination with dimercaprol when levels reach 70 mcg/dL to 99 mcg/dL and there are features of encephalopathy.19
Children displaying symptoms and having blood lead levels ranging from 45 mcg/dL to 69 mcg/dL should undergo combined therapy using calcium disodium edetate along with dimercaprol. If lead levels reach above 100 mcg/dL regardless of symptoms, a combination of intramuscular dimercaprol and intravenous calcium disodium edetate should be administered.19 Table 2 has the recommended doses for these chelating agents with indications and side effects. With chronic lead exposures, lead can be incorporated into bones and, therefore, chelation therapy may not be as successful.
Table 2. Recommended Doses for Chelating Agents19,21 |
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| Medication | Dose | Indications | Side Effects |
Dimercaptosuccinic acid (succimer) |
10 mg/kg or 350 mg/m2 three times per day |
Asymptomatic children with lead levels 45 mcg/dL to 69 mcg/dL (first-line) |
Rash, neutropenia, elevated LFTs, GI upset, hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency |
D-penicillamine |
10 mg/kg/day initial dose divided twice daily for two weeks, then increase to 25 mg/kg/day to 40 mg/kg/day |
Asymptomatic children with lead levels 45 mcg/dL to 69 mcg/dL (second-line because of side effects) |
Leukopenia, thrombocytopenia, Stevens-Johnson syndrome, liver dysfunction, nephritic syndrome, and angioedema |
Dimercaprol |
3 mg/kg to 4 mg/kg every four hours |
Encephalopathy because it crosses the blood-brain barrier; used in combination with calcium disodium edetate if lead levels > 100 mcg/dL |
Tightness sensation in the chest, jaw, limbs, and abdomen; injection site reaction; GI upset; paresthesias; tremors; hypertension; tachycardia; fever |
Calcium disodium edetate |
35 mg/kg/day to 50 mg/kg/day or 1,000 mg/m2/day to 1,500 mg/m2/day; should be administered after dimercaprol because of risk of increasing lead concentration in the CNS |
Used in combination with dimercaprol in symptomatic children with lead levels 45 mcg/dL to 99 mcg/dL; used in combination with dimercaprol if lead levels > 100 mcg/dL |
Possible elevation of lead concentration in the CNS, injection site reaction, fever, hypocalcemia, renal dysfunction |
LFTs: liver function tests; GI: gastrointestinal; CNS: central nervous system |
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Neonatal Polycythemia
Polycythemia is defined as a hemoglobin or hematocrit that is greater than two standard deviations above normal. In term newborns, these values are hemoglobin values more than 22 g/dL and hematocrit greater than 65%.22 The reported incidence of neonatal polycythemia ranges between 0.4% and 12% and varies because of many factors, including altitude, maternal health, time to cord clamping, and gestational characteristics.23 Most of these newborns tend to be asymptomatic. However, if they do present with symptoms, they typically are gastrointestinal (vomiting or poor feeding) and cyanosis or apnea. These symptoms typically also present within two hours of birth. In these patients, it is important to rule out other abnormalities, including dehydration and hypoglycemia.22
For asymptomatic neonates with hematocrit between 60% and 70%, the recommendation typically is conservative management — IV hydration with normal saline and repeat hematocrit checks every four to six hours for at least 24 hours and until the hematocrit begins to decrease.22 A partial exchange transfusion should be considered in asymptomatic patients with hematocrit greater than 75%. However, in symptomatic patients with hematocrit greater than 70%, it is recommended to initiate partial exchange transfusion with normal saline to reduce the risk of organ dysfunction.22
Platelet Disorders
Immune Thrombocytopenic Purpura
Immune thrombocytopenic purpura (ITP) stands as the most frequently diagnosed bleeding disorder in children. ITP is characterized by isolated platelets less than 100,000/mL. Primary ITP is believed to result from the immune system’s destruction of platelets, while secondary ITP is linked to underlying medical conditions. Additionally, there is a growing body of evidence indicating that platelet production also is compromised in individuals with ITP.24
ITP can be brought on by viral infections or other environmental triggers. It peaks during childhood, young adulthood, and the geriatric years. Between 2011 and 2016, the rate of ITP incidence among children younger than 18 years of age in the United States was 8.8 per 100,000 person-years.25 In children, ITP typically resolves on its own. However, approximately 20% to 30% of newly diagnosed ITP patients become refractory to common treatments.26
Frequently observed symptoms at the initial presentation of ITP include mucosal bleeding, petechiae, and purpura. Some patients with ITP may not display any symptoms, and their low platelet count may be detected incidentally. Life-threatening bleeding is a rare but concerning manifestation of ITP. One study also found that the weighted proportion of intracerebral hemorrhage (ICH) in children with acute or chronic ITP is 0.4%. In the same study, the weighted proportion for all other forms of severe bleeding, excluding ICH, was 20.8% in children.27 In terms of diagnosis, it always is important to obtain a CBC in any patient who presents with signs of bleeding. Other useful laboratory tests include reticulocyte count, peripheral blood smear, and coagulation studies, including prothrombin time (PT)/partial thromboplastin time. Another test that would be helpful to obtain for the long term and to assist with diagnosis would be serum quantitative immunoglobulin panels for use by the hematologists.28 In children with ITP who present with head trauma or atraumatic headache, it is important to obtain a rapid head computed tomography (CT) scan.
The American Society of Hematology (ASH) recommends treatment of ITP based on symptoms rather than platelet counts.29 As soon as the diagnosis of ITP is suspected, it is important to consult a hematologist for further recommendations. In terms of life-threatening bleeding, ASH recommends platelet transfusion, corticosteroids, and intravenous immunoglobulin (IVIG). Platelet transfusions should be administered as an initial bolus dose ranging from 10 mL/kg to 30 mL/kg and followed by a continuous infusion.30 It is crucial to assess the platelet count immediately after the bolus transfusion to monitor its effectiveness. In terms of steroids, methylprednisolone is administered intravenously typically at a dosage of 30 mg/kg/day, with a maximum limit of 1 g, for three to four days.30 The dose of IVIG is 1 g/kg/day for one to three days.30
For non-life-threatening bleeding, the first-line treatment is a short course of steroids, with common regimens being prednisone 2 mg/kg to 4 mg/kg/day with a maximum dose of 120 mg/day orally for five to seven days or dexamethasone 0.6 mg/kg/day with a maximum dose of 40 mg/day orally for four days.29 Second-line treatment is thrombopoietin receptor agonist but are generally reserved for individuals who are expected to require extended maintenance of their platelet count and who have either recently used or are currently taking glucocorticoids.29
In asymptomatic children with newly diagnosed ITP who have no bleeding or minor bleeding, the ASH recommends outpatient management if it can be obtained promptly.29 When these children are discharged, parents should be aware of signs of bleeding to look out for and should advise these children to avoid sports that have high risk of head trauma.30 Children with severe bleeding or who have a high risk for bleeding should be admitted to the hospital.30
Hemolytic Uremic Syndrome
Hemolytic uremic syndrome (HUS) is characterized by the simultaneous presence of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. It is a type of thrombotic microangiopathy that primarily affects the kidneys. It predominantly manifests in rural areas following episodes of acute gastroenteritis triggered by enterohemorrhagic Escherichia coli (EHEC) or Shigella dysenteriae infections. HUS also can be triggered by other infections, such as Streptococcus pneumoniae and human immunodeficiency virus (HIV).
Additionally, other causes of HUS include hereditary factors primarily linked to variations in complement genes, drug-related toxicity, and autoimmune disorders. This condition is most commonly observed in children aged younger than 3 years to 5 years.31 Shiga toxin-producing E. coli-associated hemolytic uremic syndrome (STEC-HUS) is the most prevalent type of HUS in children, comprising 90% of all cases. HUS develops in around 15% of children who contract STEC infections.32 The pathogenesis of HUS induced by STEC is rooted in the injury to vascular endothelial cells, which affect kidneys and brain. This damage primarily is caused by the potent cytotoxins produced by the bacteria, which are released in the gut and subsequently enter the bloodstream, leading to endothelial injury.33
In terms of clinical presentation, children typically complain of diarrhea but can have associated abdominal pain, vomiting, and fever. Symptoms tend to occur about three to eight days after the consumption of the contaminated food. The symptoms of HUS tend to occur about two to 14 days after the onset of diarrhea.34 Regarding renal involvement, patients commonly have hypertension as well as hematuria or proteinuria. They also can develop severe kidney injury causing oliguria and anuria as well as renal failure, which can lead to the requirement of temporary dialysis. These children tend have favorable long-term renal outcomes.
Although the kidneys typically are the organs affected, HUS can affect the central nervous system (CNS) as well as the cardiovascular, gastrointestinal, and musculoskeletal systems. Some signs that would suggest CNS involvement include lethargy, altered mental status, seizure, stroke, coma, and (rarely) cortical blindness, diplopia, facial nerve palsy, and hemiplegia.35 Other signs of extrarenal involvement include bowel ischemia, bowel perforation, pancreatitis, insulin-dependent diabetes mellitus, pericardial effusion, ischemic cardiomyopathy, and rhabdomyolysis.35
Laboratory testing that can be helpful in making the diagnosis of HUS includes CBC, BMP, peripheral blood smear, and urinalysis. Laboratory findings that typically are present in HUS include:36
- hemoglobin: < 8 g/dL;
- Coomb’s test: negative;
- peripheral blood smear: schistocytes and helmet cells;
- platelets: < 140,000/ mm³, typically around 40,000/mm³;
- reticulocyte count: elevated;
- lactate dehydrogenase: elevated;
- haptoglobin: decreased;
- creatinine: elevated; and
- urinalysis: hematuria or proteinuria.
The CBC would show evidence of microangiopathic hemolytic anemia. Even though thrombocytopenia is present, children typically do not present with active bleeding or purpura. When working with children presenting with diarrhea, it may be helpful to send a stool sample for analysis to look for Shiga toxin.
One of the first things to identify in these children when they present to the emergency department is volume status. Patients can present dehydrated or volume overloaded because of renal failure. If a child is dehydrated, it is important to start immediate rehydration with normal saline, but ensure frequent reassessment to avoid overcorrecting. For children displaying signs of volume overload and reduced urine output, IV furosemide can be administered, often requiring doses of up to 5 mg/kg, to stimulate diuresis.
After achieving a euvolemic state, the management strategy should focus on maintaining a neutral fluid balance.31 A study demonstrated that administering fluid infusions early in the treatment process can reduce the need for dialysis, hospitalization, and the development of both renal and extrarenal complications.37 It is important to involve the pediatric nephrologists early in case these patients decompensate and need to be evaluated for dialysis. In the event of a hypertensive emergency, the preferred treatment agent in the acute setting is calcium channel blockers. Angiotensin-converting enzyme inhibitors should be avoided in the acute setting out of concern for decreased renal perfusion.31
The ECUSTEC trial has provided guidelines for transfusion based on the following criteria: a hemoglobin level below 7 g/dL or below 7.5 g/dL accompanied by a decrease greater than 2 g/dL compared to the previous 24-hour level. It is crucial to involve the nephrologist in the decision-making process for transfusions because of the associated risks of hyperkalemia and hypervolemia.38
Unless bleeding is present, routine platelet transfusions are not recommended, but they can be given prophylactically for insertion of hemodialysis catheters.36 During the acute phase, the mortality rate is around 5%, but it tends to be even higher in patients with extrarenal complications. In the long term, nearly 25% of survivors experience some renal sequelae.34
Hemophilia
Hemophilia typically is an X-linked recessive disorder that causes a deficiency of either factor VIII (hemophilia A) or factor IX (hemophilia B). In the United States, there are an estimated 12 cases of hemophilia A per 100,000 males and 3.7 cases of hemophilia B per 100,000 males.39 Hemophilia’s severity is classified based on factor levels in the blood. Mild cases have factor levels > 5% but < 40%, moderate cases range from 1% to 5%, and severe cases have factor levels < 1%. In individuals without hemophilia, factor VIII levels usually fall between 50% and 150%.40
Individuals with hemophilia typically present to the emergency department because of active bleeding, consequences of bleeding, or reactions to factor infusions. The most frequent type of bleeding in individuals with hemophilia is hemarthrosis, accounting for approximately 70% to 80% of cases, followed by intramuscular bleeding, and then involvement of the CNS.41 These individuals can present with catastrophic bleeds with minimal or no trauma. The leading cause of death in people with hemophilia is intracranial hemorrhage.41
Individuals with severe forms of the condition typically are diagnosed with hemophilia early in life, whereas those with milder forms might not receive an immediate diagnosis. In cases of patients, especially males, who have a history of spontaneous bleeding or bleed easily with minor trauma and who have not had their bleeding system tested (no circumcision, etc.), emergency department providers should consider the possibility of hemophilia. It is essential to get a thorough history, including a family history for bleeding disorders or families that require treatment before surgery, of not only the events that led to an emergency department visit but also their hemophilia history, with key questions to ask listed in Table 3.
Table 3. Hemophilia History: Questions to Ask |
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Reprinted with permission from Alblaihed L, Dubbs SB, Koyfman A, Long B. High risk and low prevalence diseases: Hemophilia emergencies. Am J Emerg Med 2022;56:21-27. |
In addition to history, an extensive physical exam is important, but keep in mind that the exam can be normal early on. It is important to look for any signs of bleeding, bruising, or swelling, but bleeds in areas like the retroperitoneal space can be difficult to identify. These individuals usually present with vague back or groin pain that is worse when externally rotating their hip.
Another cannot-miss diagnosis is intracranial hemorrhage, which may present with altered mental status, neurological deficits, emesis, or other signs of increased intracranial pressure. When there is evidence of hemarthrosis or intramuscular hematomas, it is important to conduct a thorough neurologic exam. If there is evidence of compartment syndrome, it typically is a surgical emergency. The signs of compartment syndrome can be remembered by the Five Ps: pain, pallor, paresthesia, pulselessness, and paralysis. If any of these signs are present, it is important to get a surgeon involved as soon as possible for consideration of a fasciotomy. In the emergency department, laboratory testing should never delay the necessary coagulation correction.41
Nevertheless, if feasible, it is advisable to obtain a CBC, coagulation panel, and measurement of factor activity levels because they are valuable to hematologists in determining any required adjustments in dosing. Individuals with severe hemophilia typically exhibit an extended activated partial thromboplastin time, while their PT, bleeding time, and platelet count remain within normal ranges.42 The decision to obtain imaging is based on the patient history and physical exam. Any individual with hemophilia who presents with concerning neurologic findings should obtain an emergent CT scan. In addition, a CT scan can aid in the diagnosis of a retroperitoneal hematoma.
Although hemarthrosis typically is a clinical diagnosis, it is best identified on ultrasound rather than X-ray.43 Of note, the typical clinical rules like the Pediatric Emergency Care Applied Research Network, Canadian CT Head rule, and Ottawa Ankle and Knee Rules do not apply to people with hemophilia.41
When a child with hemophilia arrives to the emergency department, it is key to resuscitate and evaluate for any life-threatening injuries. It is important to remember the basics of airway, breathing, and circulation. However, it also is imperative to control the bleeding, initiate factor replacement, and involve hematology as soon as possible. Intramuscular injections should be avoided because of the increased risk of hematoma formations.42
Anticoagulants and antiplatelets should also be avoided due to their increased bleeding risk. In terms of nonsteroidal anti-inflammatory drugs (NSAIDs), there are limited data available for people with hemophilia, but a systematic review showed that there was no statistically significant increased risk of hemorrhage with the use of NSAIDs vs. a placebo in people with hemophilia. However, the review noted several limitations in these studies, including generalizability.44 Table 4 provides additional medications and dosing to aid in caring for patients with hemophilia with bleeds. Typically, the standard dose of factor VIII for severe bleeding is 50 U/kg and attempts to raise factor VIII levels to a range of 80% to 100% of normal.42 Dosing also can be calculated based on the desired increase in factor concentration multiplied by the patient’s weight in kilograms and 0.5.45
Table 4. Adjuncts to Hemophilia Management |
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| Medication | Dose | Mechanism |
Dimercaptosuccinic desmopressin (DDAVP) |
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Tranexamic acid (TXA) |
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Aminocaproic acid |
For oral bleeds, providers can use aminocaproic acid mouthwash: may crush tablet and mix with water, use elixir, or intravenous preparation 2.5 mg/10 mL OR Swish 10 mL over site gently for two minutes, repeat four times per day, then nothing by mouth for one hour |
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Reprinted with permission from Alblaihed L, Dubbs SB, Koyfman A, Long B. High risk and low prevalence diseases: Hemophilia emergencies. Am J Emerg Med 2022;56:21-27. |
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If factor VIII is not easily available, cryoprecipitate can be used instead because of its high concentration of factor VIII and von Willebrand factor. However, it does not contain factor IX, so it is not useful for hemophilia B. The dosing for children is 1 unit per 6 kg body weight every 12 hours.42 In minor bleeds, the typical dosing is 25 IU/kg of factor VIII.41 For hemophilia B, the typical dosing for major bleeds is 100 U/kg of factor IX concentrate and 50 U/kg for minor bleeds.41 For individuals requiring surgical intervention, it is preferred that these patients reach the targeted factor levels prior to the procedure. Table 5 summarizes typical major and minor bleeding presentations of patients with hemophilia.
Table 5. Major vs. Minor Bleeds46 |
|
| Major Bleeds | Minor Bleeds |
|
|
Hemoglobinopathies
Sickle Cell Disease
Sickle cell disease (SCD) is the most prevalent blood disorder in the United States, affecting approximately 100,000 people.47 It is caused by a genetic mutation in the hemoglobin, creating hemoglobin S (HbS). HbS forms sickled hemoglobin when in a deoxygenated state, which ultimately leads to the complications that are seen with this disease, including hemolysis, chronic anemia, and damage to endothelium.47 The most extreme variant, hemoglobin SS (HbSS), represents the homozygous form of SCD, but other variations exist and involve the presence of HbS combined with variant hemoglobins, such as hemoglobin C or thalassemia.48
A study conducted in California from 2005 to 2014 found that there were 90,904 emergency department visits for SCD, with an average of 2.1 visits per person annually.49 More specifically, when looking at the pediatric data, those researchers found that about 5% of patients younger than 20 years of age had between four and 10 emergency department visits within a single year.49
For any child who comes into the emergency department with SCD, it is important to obtain some basic laboratory tests, which should include a CBC, reticulocyte count, and any other relevant laboratory tests pertinent to the chief complaint. It is useful to compare patients’ laboratory results to prior and baseline levels.
Baseline hemoglobin is dependent on the genotype of the disease, but it typically falls within the range of 6 g/dL to 8 g/dL for individuals with HbSS, 10 g/dL to 15 g/dL for those with HbSC, and 9 g/dL to 12 g/dL for individuals with HbSBeta+ thalassemia.48 The reticulocyte count serves as a valuable indicator of the body’s capacity to produce new red blood cells and typically is elevated in individuals with SCD because there is chronic hemolysis.
Pain Crises
The most common acute complication of SCD is vaso-occlusive crisis. They account for between 79% and 91% of emergency department visits for those with SCD and also for a large number of hospitalizations.50 The pain typically involves the extremities but can affect various parts of the body. These episodes can last days to weeks.
The National Heart, Lung, and Blood Institute expert panel emphasizes the importance of urgent evaluation and the commencement of pain medications ideally within 30 minutes of arrival, careful selection and appropriate dosing of analgesic medications, and frequent reassessments.51 A study demonstrated that incorporating intranasal fentanyl with typical IV opioids greatly reduced the time it took for patients to receive their first dose of analgesia by up to 56 minutes.52 The study used intranasal fentanyl in children weighing 10 kg or more and administered two doses of 1.5 mcg/kg with a five- to 10-minute gap between each dose (with a maximum single dose of 100 mcg).52
Common IV opioids include morphine, with a dose of 0.1 mg/kg to 0.15 mg/kg and maximum initial dose 10 mg, or hydromorphone, with a dose of 0.02 mg/kg to 0.05 mg/kg and maximum initial dose of 1.5 mg. A small study also showed the utility of low-dose ketamine infusions of 1 mcg/kg/min to 10 mcg/kg/min in adolescents to be effective in reducing pain during these crises.53 Rapid reassessment, optimally after 30 minutes of analgesia administration, is recommended. If there is inadequate pain relief, providers should redose their patients with the medications given. Typically, when at least three rounds of analgesia have been attempted with minimal relief, the patient requires admission for continuous opioids or patient-controlled analgesia.
Acute Chest Syndrome
Acute chest syndrome ranks as the second most prevalent complication of SCD and is the primary factor contributing to mortality in these individuals.48 In the first decade of life, more than 50% of children with homozygous SCD experience at least one episode of acute chest syndrome.54 The pathophysiology involves a cycle of lung infarction, inflammation, and atelectasis.55 Pulmonary infections have been linked to acute chest syndrome, especially in children.56 Common infections that are seen in children include Chlamydia pneumoniae, Mycoplasma pneumoniae, respiratory syncytial virus, Staphylococcus aureus, and S. pneumoniae.54
In addition to infection, other more prevalent etiologies of acute chest syndrome are pulmonary fat embolism from necrotic bone marrow as well as pulmonary infarction.57 Patients with acute chest syndrome can present with cough, shortness of breath, chest pain, tachypnea, respiratory distress, hypoxemia, and fever. If any of these signs are present, obtain a chest X-ray. The diagnostic criteria for acute chest syndrome include the presence of a new infiltrate on chest imaging along with accompanying fever, chest pain, or respiratory distress. However, it is important to note that the findings on chest X-rays may lag behind, so maintaining a high level of suspicion is advisable.48
In terms of management in the emergency department, these patients’ oxygen status should be monitored closely, with the goal of reaching above 95% oxygen saturation and with supplementation as needed. These individual ideally should be treated for community-acquired pneumonia and atypical bacteria, with a common regimen being ceftriaxone and azithromycin.48 Involve a hematologist early to discuss the utility of simple or exchange transfusion. Existing evidence suggests that there should be a low threshold for transfusion to improve oxygen-carrying capacity.48 Because of the high mortality risk, it is imperative that all patients with acute chest syndrome be admitted to the hospital.
Stroke
SCD patients tend to experience more ischemic strokes than hemorrhagic strokes.58 Children with SCD experienced a 221-fold increase in the incidence of all strokes, a 41-fold increase for ischemic strokes, and a seven-fold increase for hemorrhagic strokes, so it is essential to keep stroke on the differential for these patients with any kind of neurologic complaint.59 In children with SCD between 2 years and 10 years of age, it is common for them to experience an overt ischemic stroke, and they tend to present with hemiparesis.58 Strokes also tend to recur if no prophylaxis is initiated. In the emergency department, the evaluation of a child presenting with concerns of a stroke should include a thorough neurologic exam, including using the National Institutes of Health Stroke Scale as well as laboratory tests, including blood glucose, CBC, and reticulocyte count, and imaging. Typically, a non-contrast CT head is the initial imaging choice because it is quick and can rule out hemorrhage. However, magnetic resonance imaging and angiography are preferred because they are the most sensitive for ischemic stroke.
If a stroke is identified, it is important to get a hematologist and neurologist involved early. These patients should be admitted, and the standard treatment is exchange transfusion with a goal of hemoglobin S < 30%.60 As for long-term prognosis, children with SCD who have a stroke tend to function more poorly on a majority of neuropsychological measures, including full scale intelligence quotient, verbal intelligence quotient (IQ), performance IQ, and math achievement.60
Splenic Sequestration
Splenic sequestration is a rare complication of SCD and occurs when there is a drop in hemoglobin associated with an enlarged spleen caused by intrasplenic sickling.61 The typical clinical manifestation involves abdominal pain and splenomegaly, yet patients might exhibit a nonspecific presentation, such as fussiness or general discomfort. Infants and toddlers often present without abdominal pain and with either fever or lethargy. These patients also can present with hypovolemic shock. In addition to worsening anemia, thrombocytopenia and leukopenia also usually are present.48 Treatment for these individuals includes volume resuscitation, ideally with blood transfusions. However, if that is not readily available, it is appropriate to initially use crystalloids.48 Because there is about a 50% chance for recurrence, it is important to involve the hematologist to consider splenectomy.62
Aplastic Crisis
An aplastic crisis is defined by a sudden decrease in reticulocytes and red cell precursors in the bone marrow.63 This is prompted by various types of infections, including S. pneumoniae, Salmonella, and Epstein-Barr virus, but the most common cause of aplastic crisis in SCD patients is parvovirus B19, which infects the erythrocyte precursors in the bone marrow.64,65 These children typically present with signs of severe anemia, including pallor, lethargy, and shortness of breath. Lab work also will reveal low reticulocyte count, thrombocytopenia, and leukopenia.64 Treatment includes blood transfusion and inpatient monitoring to ensure the normalization of bone marrow function, which can be seen with increasing reticulocyte count.64
Fever
Infection remains the most common cause of death in children with SCD, which is why it is important to evaluate these patients early and thoroughly. The most common cause of fever in children with SCD is acute chest syndrome, but other infections to be aware of are urinary tract infections; viral infections, which tend to be more severe in SCD; and noninfectious causes, such as pulmonary embolism and vaso-occlusive crises.66 A majority of individuals with SCD will develop functional asplenia at a young age. Thus, they have a high risk of infection with encapsulated bacteria, especially S. pneumoniae, so it generally is standard practice for these pediatric patients to receive pneumococcal vaccines early on and penicillin prophylaxis.48
The work-up in the emergency department should include a CBC with differential, bilirubin, blood cultures, reticulocyte count, urinalysis, and urine cultures. If patients appear very ill, consider a type and screen in case they might need a transfusion. If they are having respiratory symptoms or chest pain, it is important to obtain a chest X-ray and respiratory pathogen panel. Based on their symptoms and clinical presentation, additional testing can be done to rule out other sources of infection, such as osteomyelitis, meningitis, or viral illnesses. Initiation of empiric antibiotics is recommended and typically consist of ceftriaxone. If a severe beta-lactam allergy is present, levofloxacin can be used instead. If the patient appears very ill, vancomycin can be used for methicillin-resistant S. aureus (MRSA) infection.64 If children are at a low risk, they generally can be discharged home after a dose of ceftriaxone and ensuring that they have a daily follow-up with their pediatrician. Otherwise, these children should be admitted.
Low-risk criteria for sepsis include:64
- well-appearing, hemodynamically stable;
- age ≥ 6 months;
- white blood cell count 5 to 30 × 109/L, platelet count ≥ 100 × 109/L and not significantly lower than baseline, hemoglobin ≥ 60 g/L and not > 20 g/L lower than baseline (admit when baseline is unknown);
- no respiratory distress or chest X-ray abnormality;
- no clinical findings suggestive of meningitis, osteomyelitis, septic arthritis, acute coronary syndrome, or splenic sequestration;
- no history of pneumococcal sepsis or meningitis;
- no significant pain or dehydration;
- initial visit for the episode; and
- safe for discharge, ability for close follow-up.
Thalassemia
Thalassemia is a hereditary disorder that occurs when there is a reduction or absence in the synthesis of normal alpha- or beta-globin subunits of hemoglobin. The disease is characterized by chronic hemolysis, ineffective erythropoiesis, and excess iron. The estimated mutation carrier rate worldwide is 1% to 5%.67 Alpha thalassemia and beta thalassemia represent the two main categories, with their occurrence determined by four and two genes, respectively. The number of missing genes correlates to the severity of the disease.68 The four types of alpha thalassemias (from most severe clinical features to least) are hemoglobin Bart’s, hemoglobin H disease, alpha thalassemia minor, and alpha thalassemia minima. The types of beta thalassemias (from most severe clinical features to least) are beta thalassemia major (or transfusion-dependent), beta thalassemia intermidia (or transfusion-independent), and beta thalassemia minor.
Individuals with thalassemia can present asymptomatically as a carrier or with a variety of clinical features, including severe anemia, iron overload from recurrent transfusions, skeletal abnormalities, growth impairments, and extramedullary hematopoiesis.69 In hemoglobin Bart’s and hemoglobin H disease, anemia can present in utero. However, for beta thalassemias, newborns are asymptomatic, and symptoms typically present within the first year of life. In addition to signs of anemia, these children can present with signs of hemolysis, including jaundice, gallstones, and hepatosplenomegaly. Some signs of extramedullary hematopoiesis include facial deformities, rib cage and limb deformities, osteopenia, osteoporosis, pain, and bone masses.69 Iron overload can cause various endocrine and metabolic abnormalities, including hypogonadism, hypothyroidism, diabetes, and hypoparathyroidism.69 Thalassemia also can lead to hypercoagulability and pulmonary hypertension.69
The most useful initial screening laboratory tests include CBC, peripheral blood smear, and iron studies. Results typically will reveal microcytic, hypochromic anemia with an elevated red blood cell count.69 A peripheral blood smear also will show bizarre red blood cell morphology, with red blood cell inclusion bodies that are best visualized with supravital staining.69 Iron studies are important to ensure there also is not a component of iron deficiency anemia. The definitive diagnostic testing for thalassemia is DNA testing to detect the mutations in the genes, but it is highly unlikely to be conducted in the emergency department.68
For stable patients who present to the emergency department with thalassemia, it is important to obtain a thorough history, including transfusion history, iron load, iron chelation regimen, splenectomy status, surgical history, medication history, and vaccination status.70 For those with a history of a splenectomy, it is important to keep infections with encapsulated organisms on the differential. If patients present with hemodynamic instability or with trauma, they should be resuscitated and stabilized like any other patient.
Patients with thalassemia tend to require routine transfusions with a goal hemoglobin between 9.5 g/dL to 10 g/dL.71 If patients fall below their steady state hemoglobin, they should receive a blood transfusion. Patients also may present with symptoms of delayed transfusion hemolytic reaction from a recent blood transfusion. Common symptoms of these reactions include fever, dark urine, and pain.
Laboratory values associated with these reactions include new red blood cell allo- or autoantibody, low hemoglobin, elevated indirect bilirubin, and hemoglobinuria.71 These should be treated with immunosuppressive therapies, including steroids, IVIG, and rituximab.72 In patients with thalassemia, infection stands out as a primary contributor to mortality.70 If a patient appears septic, it is important to provide fluid resuscitation and initiate broad-spectrum antibiotics early including coverage for gram-negative pathogens, including Klebsiella and encapsulated organisms, such as S. pneumoniae, Haemophilus influenzae, and Neisseria meningitides.70
Individuals with thalassemia also are at an increased risk of venous thromboembolism, heart failure, and dysrhythmias, which can present with dyspnea. In addition to obtaining the initial screening laboratory tests, it also is important to test electrolytes, renal function, liver enzymes, bilirubin, brain natriuretic peptide, and troponin and obtain an electrocardiogram and chest X-ray. It also may be beneficial to perform point-of-care ultrasonography of the heart to assess for any evidence of heart failure or right ventricular strain. If patients are found to be in decompensated heart failure, early diuresis is key, and they should be admitted. Iron deposition in the myocardium is the most common cause of heart failure in these patients, especially in those who are transfusion-dependent.70 In patients with a high suspicion for iron overload as the cause of heart failure, iron chelation therapy with deferoxamine should be initiated.70 If a patient with thalassemia presents with an arrhythmia, they should be treated in the same fashion as someone without the disease.
Bone Marrow Failure
Aplastic Anemia
Aplastic anemia is a condition that is characterized by the absence or decreased number of hematopoietic precursor cells caused by bone marrow failure, which leads to pancytopenia. It is a rare condition, with an incidence of about two to three cases per million.73 Aplastic anemia can be caused by acquired or inherited instigators.
Acquired causes include viral infections (hepatitis, HIV, parvovirus, Epstein-Barr virus, cytomegalovirus); drug-induced (chloramphenicol, carbamazepine, valproic acid, phenytoin); nutritional deficiencies (zinc, copper, vitamin B12, folate); myelodysplastic syndrome; rheumatologic disorders; and paroxysmal nocturnal hemoglobinuria. Meanwhile, inherited causes of aplastic anemia include congenital syndromes (Fanconi syndrome, Shwachman-Diamond syndrome, telomere biology disorders, congenital amegakaryocytic thrombocytopenia) and hematopoietic malignancy predisposition syndrome.73
As with all hematologic disorders, it is important to obtain a thorough history and physical exam. Since these patients have pancytopenia, they may present with signs of anemia, thrombocytopenia, neutropenia, or a combination of the three. These symptoms can include fatigue, pallor, weakness, mucosal bleeding, bruising, fever, and recurrent infections. Important laboratory tests to obtain in the emergency department include CBC, reticulocyte count, CMP, lactate dehydrogenase, serum folate and B12, viral serologies, and peripheral blood smear.73 It also is beneficial to obtain coagulation studies for liver function evaluation. Once the patient is admitted, they likely will need a bone marrow sample.
When treating children with known or suspected aplastic anemia, it is important to provide supportive care with restricted transfusions to ensure hemoglobin > 7 g/dL and platelets > 10,000 cells/μL to try to minimize the risks of alloimmunization and iron overload.74 These transfusions should be irradiated to reduce the risk of graft-vs.-host disease.75
Because of their leukopenia, these patients also are prone to infections, so it is imperative to diagnose them promptly and get antibiotics started early if there is any concern for infection. These individuals typically are admitted to consider for long-term therapy, including stem cell transplantation or immunosuppressive therapy.
Conclusion
Hematologic disorders in the pediatric population can be difficult to diagnose and treat in the emergency department. They can present with an array of symptoms that range from asymptomatic to life-threatening bleeds. In addition, these children often do not have a known diagnosis of a hematologic disorder and are presenting for the first time. Emergency medicine physicians must be able to conduct thorough histories and physical exams, determine the necessary work-up, and promptly interpret laboratory results to ultimately devise a treatment plan for these patients.
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Hematology is a challenging area in pediatrics, with unique diseases that do not occur commonly. The authors review critical pediatric hematologic conditions that the acute care provider may encounter and provide a concise guide to diagnosis, stabilization, and management.
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