Review – Kaplan Pediatrics: Hematology

ANEMIAS OF INADEQUATE PRODUCTION

 

Physiologic Anemia of Infancy

• Intrauterine hypoxia stimulates erythropoietin → ↑ RBCs (Hb, Hct)
• High FiO2 at birth downregulates erythropoietin
• Progressive drop in Hb over first 2–3 months until tissue oxygen needs are greater than delivery (typically 8–12 weeks in term infants, to Hb of 9–11 g/dL)
• Exaggerated in preterm infants and earlier; nadir at 3–6 weeks to Hb of 7–9 g/dL
• In term infants—no problems, no treatment; preterm infants usually need transfu- sions depending on degree of illness and gestational age

 

Iron-Deficiency Anemia

An 18-month-old child of Mediterranean origin presents to the physician for routine well-child care. The mother states that the child is a “picky” eater and prefers milk to solids. In fact, the mother states that the patient, who still drinks from a bottle, consumes 64 ounces of cow milk per day. The child appears pale. Hemoglobin (Hb) and hematocrit (Hct) were measured; and the Hb is 6.5 g/dL and the Hct is 20 . The mean corpuscular volume (MCV) is 65 fL.

 

• Contributing factors/pathophysiology
  • More efficient iron absorption in proximal intestine in breast-fed versus cow milk or formula

−   Introducing iron-rich foods is effective in prevention.

• Infants with decreased dietary iron typically are anemic at 9–24 months of
  • Caused by consumption of large amounts of cow milk and foods not enriched with iron
  • Also creates abnormalities in mucosa of gastrointestinal tract → leakage of blood, further decrease in absorption
• Adolescents also susceptible → high requirements during growth spurt, dietary deficiencies, menstruation

• Clinical appearances—pallor most common; also irritability, lethargy, pagophagia, tachycardia, systolic murmurs; long-term with neurodevelopmental effects

 

 

• Laboratory findings
  • First decrease in bone marrow hemosiderin (iron tissue stores)
  • Then decrease in serum ferritin
  • Decrease in serum iron and transferrin saturation → increased total iron-bind- ing capacity (TIBC)
  • Increased free erythrocyte protoporhyrin (FEP)
  • Microcytosis, hypochromia, poikilocytosis
  • Decreased MCV, mean corpuscular hemoglobin (MCH), increase RDW, nucle- ated RBCs, low reticulocytes
  • Bone marrow—no stainable iron
• Treatment

−   Oral ferrous salts

• Limit milk, increase dietary iron
• Within 72–96 hours—peripheral reticulocytosis and increase in Hb over 4–30 days
• Continue iron for 8 weeks after blood values normalize; repletion of iron in 1–3 months after start of treatment

 

Lead Poisoning

• Blood lead level (BLL) up to 5 µg/dL is
• Increased risks
  • Preschool age
  • Low socioeconomic status

−   Older housing (before 1960)

• Urban dwellers
• African American
• Recent immigration from countries that use leaded gas and paint

• Clinical presentation
  • Behavioral changes (most common: hyperactivity in younger, aggression in older)
  • Cognitive/developmental dysfunction, especially long-term (also impaired growth)
  • Gastrointestinal—anorexia, pain, vomiting, constipation (starting at 20 µg/dL)
  • Central nervous system—related to increased cerebral edema, intracranial pres- sure (ICP [headache, change in mentation, lethargy, seizure, coma → death])
  • Gingival lead lines
• Diagnosis
  • Screening—targeted blood lead testing at 12 and 24 months in high-risk
  • Confirmatory venous sample—gold standard blood lead level
  • Indirect assessments—x-rays of long bones (dense lead lines); radiopaque flecks in intestinal tract (recent ingestion)
  • Microcytic, hypochromic anemia
  • Increased FEP
  • Basophilic stippling of RBC

•      Treatment—chelation (see Table 19-1)

 

 

Table 19-1. Treatment for Lead Poisoning

Lead Level (µg/dL)	Management
5–14	Evaluate source, provide education, repeat blood lead level in 3 months
15–19	Same plus health department referral, repeat BLL in 2 months
20–44	Same plus repeat blood lead level in 1 month
45–70	Same plus chelation: single drug, preferably DMSA (succimer, oral)
³70	Immediate hospitalization plus two-drug IV treatment: – EDTA plus dimercaprol

Definition of abbreviations: DMSA, dimercaptosuccinic acid; EDTA, ethylenediaminetetraacetic acid.

 

 

CONGENITAL ANEMIAS

 

Congenital Pure Red-Cell Anemia (Blackfan-Diamond)

A 2-week-old on routine physical examination is noted to have pallor. The birth history was uncomplicated. The patient has been doing well according to the mother.

 

•      Increased RBC programmed cell death → profound anemia by 2–6 months

• Congenital anomalies
  • Short stature
  • Craniofacial deformities
  • Defects of upper extremities; triphalangeal thumbs
• Labs
  • Macrocytosis
  • Increased HbF

−    Increased RBC adenosine deaminase (ADA)

• Very low reticulocyte count
• Increased serum iron

−   Marrow with significant decrease in RBC precursors

• Treatment

−   Corticosteroids

• Transfusions and deferoxamine
• Splenectomy; mean survival 40 years without stem cell transplant

• Definitive—stem cell transplant from related histocompatible donor

 

 

 

Note

Blackfan-Diamond Triphalangeal thumbs Pure RBC deficiency

 

Fanconi Absent/hypoplastic thumbs All cell lines depressed

Congenital Pancytopenia

A 2-year-old presents to the physician with aplastic anemia. The patient has microcephaly, microphthalmia, and absent radii and thumbs.

 

• Most common is Fanconi anemia—spontaneous chromosomal breaks
• Age of onset from infancy to adult
• Physical abnormalities
  • Hyperpigmentation and café-au-lait spots

−   Absent or hypoplastic thumbs

• Short stature
• Many other organ defects

• Labs
  • Decreased RBCs, WBCs, and platelets
  • Increased HbF

−   Bone-marrow hypoplasia

• Diagnosis—bone-marrow aspiration and cytogenetic studies for chromosome breaks
• Complications—increased risk of leukemia (AML) and other cancers, organ complications, and bone-marrow failure consequences (infection, bleeding, severe anemia)
• Treatment

−   Corticosteroids and androgens

• Bone marrow transplant definitive

 

ACQUIRED ANEMIAS

 

Transient Erythroblastopenia of Childhood (TEC)

• Transient hypoplastic anemia between 6 months–3 years
  • Transient immune suppression of erythropoiesis
  • Often after nonspecific viral infection (not parvovirus B19)
• Labs—decreased reticulocytes and bone-marrow precursors, normal MCV and HbF
• Recovery generally within 1–2 months
• Medication not helpful; may need one transfusion if symptomatic

 

Anemia of Chronic Disease and Renal Disease

• Mild decrease in RBC lifespan and relative failure of bone marrow to respond adequately
• Little or no increase in erythropoietin

 

 

• Labs
  • Hb typically 6–9 g/dL, most normochromic and normocytic (but may be mildly microcytic and hypochromic)
  • Reticulocytes normal or slightly decreased for degree of anemia
  • Iron low without increase in TIBC
  • Ferritin may be normal or slightly
  • Marrow with normal cells and normal to decreased RBC precursors
• Treatment—control underlying problem, may need erythropoietin; rarely need transfusions

 

 

MEGALOBLASTIC ANEMIAS

 

Background

• RBCs at every stage are larger than normal; there is an asynchrony between nuclear and cytoplasmic

•      Ineffective erythropoiesis

• Almost all are folate or vitamin B12 deficiency from malnutrition; uncommon in United States in children; more likely to be seen in adult
• Macrocytosis; nucleated RBCs; large, hypersegmented neutrophils; low serum folate; iron and vitamin B12 normal to decreased; marked increase in lactate dehy- drogenase; hypercellular bone marrow with megaloblastic changes

 

Folic Acid Deficiency

• Sources of folic acid—green vegetables, fruits, animal organs
• Peaks at 4–7 months of age—irritability, failure to thrive, chronic diarrhea
• Cause—inadequate intake (pregnancy, goat milk feeding, growth in infancy, chronic hemolysis), decreased absorption or congenital defects of folate metabolism
• Differentiating feature—low serum folate
• Treatment—daily folate; transfuse only if severe and symptomatic

 

Vitamin B12 (Cobalamin) Deficiency

• Only animal sources; produced by microorganisms (humans cannot synthesize)
• Sufficient stores in older children and adults for 3–5 years; but in infants born to mothers with deficiency, will see signs in first 4–5 months
• Inadequate production (extreme restriction [vegans]), lack of intrinsic factor (con- genital pernicious anemia [rare], autosomal recessive; also juvenile pernicious ane- mia [rare] or gastric surgery), impaired absorption (terminal ileum disease/removal)
• Clinical—weakness, fatigue, failure to thrive, irritability, pallor, glossitis, diarrhea, vomiting, jaundice, many neurologic symptoms
• Labs—normal serum folate and decreased vitamin B12
• Treatment—parenteral B12

 

 

 

 

 

 

 

 

 

 

Note

Hypersegmented neutrophils have >5 lobes in a peripheral smear.

 

 

 

 

Note

If autoimmune pernicious anemia is suspected, remember the Schilling test and antiparietal cell antibodies.

 

 

Table 19-2. Comparison of Folic Acid Versus Vitamin B12 Deficiencies

	Folic Acid Deficiency	Vitamin B12 (Cobalamin) Deficiency
Food sources	Green vegetables, fruits, animals	Only from animals, produced by microorganisms
Presentation	Peaks at 4−7 months	Older children and adults with sufficient stores for 3−5 years Infants born to mothers: first signs 4−6 months
Causes	Goat milk feeding Chronic hemolysis Decreased absorption Congenital defects of folate metabolism	Inadequate production (vegans) Congenital or juvenile pernicious anemia (autosomal recessive, rare) Gastric surgery Terminal ileum disease
Findings	Low serum folate with normal to increased iron and vitamin B12	Normal serum folate and decreased vitamin B12
Treatment	Daily folate	Parenteral vitamin B12

 

 

HEMOLYTIC ANEMIAS

 

Hereditary Spherocytosis and Elliptocytosis

• Most autosomal dominant
• Abnormal shape of RBC due to spectrin deficiency → decreased deformability →

early removal of cells by spleen

• Clinical presentation

−   Anemia and hyperbilirubinemia in newborn

• Hypersplenism, biliary gallstones
• Susceptible to aplastic crisis (parvovirus B19)

• Labs
  • Increased reticulocytes
  • Increased bilirubin
  • Hb 6–10 mg/dL
  • Normal MCV; increased mean cell Hb concentration (MCHC)

−   Smear—spherocytes or elliptocytes diagnostic

• Diagnosis
  • Blood smear, family history, increased spleen size
  • Confirmation—osmotic fragility test
• Treatment—transfusions, splenectomy (after 5–6 years), folate

 

 

Enzyme Defects

Pyruvate kinase (glycolytic enzyme)

• Wide range of presentation
  • Some degree of pallor, jaundice, and splenomegaly
  • Increased reticulocytes, mild macrocytosis, polychromatophilia
• Diagnosis—pyruvate kinase (PK) assay (decreased activity)
• Treatment—exchange transfusion for significant jaundice in neonate; transfusions (rarely needed), splenectomy

 

Glucose-6-phosphate dehydrogenase (G6PD)

A 2-year-old boy presents to the physician’s office for an ear check. The child had an ear infection that was treated with trimethaprim-sulfamethoxazole 3 weeks earlier. On physical examination, the patient is noted to be extremely pale. Hb and Hct were obtained and are noted to be 7.0 g/dL and 22 , respectively.

 

• Two syndromes
  • Episodic hemolytic anemia (most common)
  • Chronic nonspherocytic hemolytic anemia
• X-linked; a number of abnormal alleles
• Episodic common among Mediterranean, Middle Eastern, African, and Asian

ethnic groups; wide range of expression varies among ethnic groups

• Within 24–48 hours after ingestion of an oxidant (acetylsalicylic acid, sulfa drugs, antimalarials, fava beans) or infection and severe illness → rapid drop in Hb, hemoglobinuria and jaundice (if severe)
• Acute drop in Hb, saturated haptoglobin → free Hb and hemoglobinuria, Heinz bodies, increased reticulocytes
• Diagnosis—direct measurement of G6PD activity
• Treatment—prevention (avoid oxidants); supportive for anemia

 

 

HEMOGLOBIN DISORDERS

 

Sickle Cell Anemia (Homozygous Sickle Cell or S-Beta Thalassemia)

A 6-month-old, African-American infant presents to the pediatrician with painful swollen hands and swollen feet.

 

• Occurs in endemic malarial areas
• Single base pair change (thymine for adenine) at the sixth codon of the beta gene (valine instead of glutamic acid)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Note

Patients without a functioning spleen are predisposed to infection with encapsulated organisms. Pneumococcal vaccines 13 (PCV13) and 23 (PPSV23) are necessary.

• Clinical presentation
  • Newborn usually without symptoms; development of hemolytic anemia over first 2–4 months (replacement of HbF); as early as age 6 months; some children have functional asplenia; by age 5, all have functional asplenia
  • First presentation usually hand-foot syndrome (acute distal dactylitis)—sym- metric, painful swelling of hands and feet (ischemic necrosis of small bones)

−   Acute painful crises:

• Younger—mostly extremities
• With increasing age—head, chest, back, abdomen
• Precipitated by illness, fever, hypoxia, acidosis, or without any factors (older)

• More extensive vaso-occlusive crises → ischemic damage
  • Skin ulcers
  • Retinopathy
  • Avascular necrosis of hip and shoulder
  • Infarction of bone and marrow (increased risk of Salmonella osteomyelitis)

°      Splenic autoinfarction

• Pulmonary—acute chest syndrome (along with sepsis, are most common causes of mortality)
• Stroke (peak at 6–9 years of age)
• Priapism, especially in adolescence

• Acute splenic sequestration (peak age 6 mos to 3 yrs); can lead to rapid death
• Altered splenic function → increased susceptibility to infection, especially with

encapsulated bacteria (S. pneumococcus, H. influenzae, N. meningitidis)

• Aplastic crisis—after infection with parvovirus B19; absence of reticulocytes during acute anemia
• Cholelithiasis—symptomatic gallstones
• Kidneys—decreased renal function (proteinuria first sign); UTIs, papillary necrosis
• Labs
  • Increased reticulocytes
  • Mild to moderate anemia
  • Normal MCV
  • If severe anemia:

} Smear—target cells, poikilocytes, hypochromasia, sickle RBCs, nucleated RBCs, Howell-Jolly bodies (lack of splenic function)

} Bone marrow markedly hyperplastic

• Diagnosis
  • Confirm diagnosis with Hb electrophoresis (best test)
  • Newborn screen; use Hb electrophoresis
  • Prenatal diagnosis for parents with trait
• Treatment—Prevent complications:
• Immunize (pneumococcal regular plus 23-valent, meningococcal)
• Start penicillin prophylaxis at 2 months until age 5
• Educate family (assessing illness, palpating spleen, )
• Folate supplementation

 

 

• Aggressive antibiotic treatment of infections
• Pain control
• Transfusions as needed
• Monitor for risk of stroke with transcranial Doppler

−   Hydroxyurea

• Bone-marrow transplant in selected patients age <16 years

 

THALASSEMIAS

©2007 Kaplan Medical. Reproduced with permission from Dr. Philip Silberberg, University of California at San Diego.

 

Figure 19-1. X-Ray of the Skull Demonstrating “Hair on End” Appearance of Thallasemia

 

 

Alpha Thalassemia

• Alpha thalassemia trait: deletion of 2 genes
  • Common in African Americans and those of Mediterranean descent
  • Mild hypochromic, microcytic anemia (normal RDW) without clinical problems;
  • Often diagnosed as iron deficiency anemia; need molecular analysis for diagnosis
• HgB H disease: deletion of 3 genes; Hgb Barts >25% in newborn period and easily diagnosed with electrophoresis
  • At least one parent has alpha-thalassemia trait; later beta-tetramers develop (Hgb H—interact with RBC membrane to produce Heinz bodies) and can be identified electrophoretically; microcytosis and hypochromia with mild to mod- erate anemia; target cells present, mild splenomegaly, jaundice and cholelithiasis
  • Typically do not require transfusions or splenectomy; common in Southeast Asians
• Alpha-thalassemia major: deletion of 4 genes; severe fetal anemia resulting in hydrops fetalis

 

 

• Newborn has predominantly Hgb Barts with small amounts of other fetal Hgb; immediate exchange transfusions are required for any possibility of survival; transfusion-dependent with only chance of cure (bone marrow transplant)

 

Beta Thalassemia Major (Cooley Anemia)

A 9-year-old has a greenish-brown complexion, maxillary hyperplasia, splenomegaly, and gallstones. Her Hb level is 5.0 g/dL and MCV is 65 mL.

• Excess alpha globin chains → alpha tetramers form; increase in HbF (no problem with gamma-chain production)
• Presents in second month of life with progressive anemia, hypersplenism, and cardiac decompensation (Hb <4 mg/dL)
• Expanded medullary space with increased expansion of face and skull (hair-on- end); extramedullary hematopoiesis, hepatosplenomegaly
  • Labs
    • Infants born with HbF only (seen on Hgb electrophoresis)
    • Severe anemia, low reticulocytes, increased nucleated RBCs, hyperbilirubinemia microcytosis

−   No normal cells seen on smear

• Bone-marrow hyperplasia; iron accumulates → increased serum ferritin and transferrin saturation

• Treatment
  • Transfusions
  • Deferoxamine (assess iron overload with liver biopsy)
  • May need splenectomy
  • Bone-marrow transplant curative

 

 

Note

Minor bleeds = von Willebrand Deep bleeds = hemophilia

HEMORRHAGIC DISORDERS

 

Evaluation of Bleeding Disorders

• History provides the most useful

−   von Willebrand disease (vWD) or platelet dysfunction → mucous membrane bleeding, petechiae, small ecchymoses

• Clotting factors—deep bleeding with more extensive ecchymoses and hema- toma

• Laboratory studies
  • Obtain platelets, bleeding time, PT, PTT
    • If normal, von Willebrand factor (vWF) testing and thrombin time
    • If abnormal, further clotting factor workup
  • Bleeding time—platelet function and interaction with vessel walls; qualitative platelet defects or vWD (platelet function analyzer)
• Platelet count—thrombocytopenia is the most common acquired cause of bleeding disorders in children

 

 

• PTT—intrinsic pathway: from initiation of clotting at level of factor XII through the final clot (prolonged with factor VIII, IX, XI, XII deficiency)
• PT—measures extrinsic pathway after activation of clotting by thromboplastin in the presence of Ca2+; prolonged by deficiency of factors VII, XIII or antico- agulants; standardized values using the International Normalized Ratio (INR)
• Thrombin time—measures the final step: fibrinogen → fibrin; if prolonged: decreased fibrin or abnormal fibrin or substances that interfere with fibrin polymerization (heparin or fibrin split products)
• Mixing studies
  • If there is a prolongation of PT, PTT, or thrombin time, then add normal plasma to the patient’s and repeat labs:

} Correction of lab prolongation suggests deficiency of clotting factor.

} If not or only partially corrected, then it is due to an inhibitor (most common on inpatient basis is heparin).

} If it becomes more prolonged with clinical bleeding, there is an antibody directed against a clotting factor (mostly factors VIII, IX, or XI).

} If there is no clinical bleeding but both the PTT and mixing study are prolonged, consider lupus anticoagulant (predisposition to excessive clotting).

• Clotting factor assays—each can be measured; severe deficiency of factors VIII or IX = <1% of normal; moderate = 1–5%; mild = >5%
• Platelet aggregation studies—if suspect a qualitative platelet dysfunction, ristocetin

 

Table 19-3. Clinical Findings in Coagulopathies

	Factor VIII	Factor IX	vWF
Platelet	Normal	Normal	Normal
PT	Normal	Normal	Normal
PTT	↑	↑	↑
Bleeding time	Normal	Normal	↑
Factor VIII	↓	Normal	Normal
Factor IX	Normal	↓	Normal
vWF	Normal	Normal	↓
Sex	Male	Male	Male/female
Treatment	Factor VIII, DDAVP	Factor IX	Fresh frozen plasma, cryotherapy, DDAVP

Definition of abbreviations: DDAVP, Desmopressin; PT, prothrombin time; PTT, partial thromboplastin time; vWF, von Willebrand factor.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Note

There is no way to clinically differentiate factors VIII and IX deficiencies. You must get specific factor levels.

Hemophilia A (VIII) and B (IX)

• 85% are A and 15% B; no racial or ethnic predisposition

•      X-linked

• Clot formation is delayed and not robust → slowing of rate of clot formation
  • With crawling and walking—easy bruising
  • Hallmark is hemarthroses—earliest in ankles; in older child, knees and elbows
  • Large-volume blood loss into iliopsoas muscle (inability to extend hip)—vague groin pain and hypovolemic shock
  • Vital structure bleeding—life-threatening
• Labs
  • 2× to 3× increase in PTT (all others normal)

−   Correction with mixing studies

• Specific assay confirms:
  • Ratio of VIII:vWF sometimes used to diagnose carrier state
  • Normal platelets, PT, bleeding time, and vW Factor
• Treatment
  • Replace specific factor
  • Prophylaxis now recommended for young children with severe bleeding (intra- venous via a central line every 2–3 days); prevents chronic joint disease
  • For mild bleed—patient’s endogenous factor can be released with desmopressin

(may use intranasal form)

• Avoid antiplatelet and aspirin medications
• DDAVP increases factor VIII levels in mild disease

 

von Willebrand Disease (vWD)

• Most common hereditary bleeding disorder; autosomal dominant, but more females affected
• Normal situation—vWF adheres to subendothelial matrix, and platelets then adhere to this and become activated; also serves as carrier protein for factor VIII
• Clinical presentation—mucocutaneous bleeding (excessive bruising, epistaxis, menorrhagia, postoperative bleeding)

•      Labs—increased bleeding time and PTT

• Quantitative assay for vWFAg, vWF activity (ristocetin cofactor activity), plasma factor VIII, determination of vWF structure and platelet count
• Treatment—need to increase the level of vWF and factor VIII
  • Most with type 1 DDAVP induces release of vWF
  • For types 2 or 3 need replacement → plasma-derived vWF-containing concen- trates with factor VIII

 

Other Bleeding Disorders

Vitamin K deficiency

•      Newborn needs intramuscular administration of vitamin K or develops bleeding diathesis

 

 

• Postnatal deficiency—lack of oral intake, alteration in gut flora (long-term antibi- otic use), malabsorption
• Vitamin K is fat soluble so deficiency associated with a decrease in factors II, VII, IX, and X, and proteins C and S
• Increased PT and PTT with normal platelet count and bleeding time

 

Liver disease

•      All clotting factors produced exclusively in the liver, except for factor VIII

• Decreases proportional to extent of hepatocellular damage
• Treatment—fresh frozen plasma (supplies all clotting factors) and/or cryoprecipi- tate (supplies fibrinogen)

 

 

PLATELET DISORDERS

 

Immune Thrombocytopenic Purpura (ITP)

A 4-year-old child previously healthy presents with petechiae, purpura, and excessive bleeding after falling from his bicycle.

 

• Autoantibodies against platelet surface
• Clinical presentation
  • Typically 1–4 weeks after a nonspecific viral infection
  • Most 1–4 years of age → sudden onset of petechiae and purpura with or with- out mucous membrane bleeding
  • Most resolve within 6 months

−   <1% with intracranial hemorrhage

• 10–20% develop chronic ITP

• Labs

−   Platelets <20,000/mm3

• Platelet size normal to increased
• Other cell lines normal
• Bone marrow—normal to increased megakaryocytes

• Treatment
  • Transfusion contraindicated unless life-threatening bleeding (platelet antibod- ies will bind to transfused platelets as well)
  • No specific treatment if platelets >20,000 and no ongoing bleeding
  • If very low platelets, ongoing bleeding that is difficult to stop or life-threatening:
• Intravenous immunoglobulin for 1–2 days
  • If inadequate response, then prednisone
• Splenectomy reserved for older child with severe disease

 

Note

With ITP, the physical examination is otherwise normal; hepatosplenomegaly and lymphadenopathy should suggest another disease.