Aplastic Anemia

Aplastic Anemia (AA)

• Likely cause of normocytic anemia, leukopenia, and thrombocytopenia with normal serum iron after hepatitis A infection
• AA can be inherited or acquired
• Common causes of acquired AA:
  • Viruses like hepatitis, Epstein-Barr, or HIV
  • Chemicals like benzene
  • Medications like methimazole, sulfa antibiotics, or chloramphenicol
  • Sometimes, it's idiopathic
• The destruction of bone marrow progenitors is thought to be autoimmune
• Patients with AA after viral infection often show pancytopenia within 6 months, but symptoms like fatigue and petechiae can appear sooner
• Diagnosis includes a bone marrow biopsy and aspiration:
  • Profoundly hypocellular bone marrow
  • Paucity of progenitor cells of all lineages
  • Replacement by fat and stroma
  • Absence of malignant cells and fibrosis
• Treatments for AA:
  • Immunosuppressive medications
  • Hematopoietic stem cell transplant from a matched sibling

Anemia Types (Incorrect Answers)

• Acute hemorrhagic anemia arises from massive blood loss
  • Common in trauma
  • Presents with anemia and absence of leukopenia or thrombocytopenia
• Autoimmune hemolytic anemia occurs when autoantibodies bind to red blood cell surface antigens
  • Leads to removal via the reticuloendothelial system or intravascular hemolysis
  • Diagnosed via a positive Coombs test
  • See unconjugated hyperbilirubinemia, decreased haptoglobin, spherocytes, and reticulocytes on the peripheral smear
• Anemia of chronic disease relates to autoimmune and inflammatory diseases, chronic infections, and malignancy
  • Increased hepcidin concentrations decrease iron absorption and increase iron storage in the bone marrow
  • Prevents iron use by erythrocyte precursors and results in anemia
• Glucose 6-phosphate dehydrogenase deficiency results in hemolysis
  • Occurs with exposure to medications like sulfa drugs and oxidants
  • Does not cause marked leukopenia or thrombocytopenia
• Hereditary spherocytosis arises from autosomal dominant mutations in ankyrin, spectrin, and band erythrocyte membrane proteins
  • Leads to a loss of connection between the inner membrane skeleton and the outer lipid bilayer
  • Clinical symptoms include jaundice, splenomegaly, and anemia
  • A peripheral smear shows spherocytes
• Sickle cell disease occurs from mutations in both β-globin alleles, resulting in abnormal hemoglobin S
  • Hemoglobin S polymerizes in hypoxia, causing sickling of erythrocytes
  • Anemia and sickle forms are present on peripheral blood smear
• Sickle cell trait is caused by a mutation in one β-globin allele
  • Symptoms associated with sickle cell disease are rare
  • Anemia, if present, is mild, and other cell lines have no abnormalities
• Thalassemia minor is due to mutations or deletions in α- or β-globin alleles
  • Impaired production of hemoglobin A
  • Mild microcytic anemia with normal leukocyte and platelet concentrations
  • Hemoglobin electrophoresis distinguishes this condition

Educational Objective: Aplastic Anemia

• Can be acquired following a viral infection
• Presents with normocytic, normochromic anemia, thrombocytopenia, and leukopenia
• A bone marrow biopsy and aspirate will show a paucity of progenitor cells with marrow replacement by fat in the absence of fibrosis or malignant infiltration

Hereditary Spherocytosis (HS)

• Likely in patients with hemolytic anemia, increased reticulocyte count, and a family history of similar symptoms requiring splenectomy
• HS arises from mutations in proteins that link the erythrocyte inner membrane skeleton to the outer lipid bilayer
  • Mutations in spectrin, ankyrin, band 3, and band 4.2 are common
  • Inherited in an autosomal dominant pattern
• Spherocytosis occurs from progressive loss of erythrocyte membrane, giving erythrocytes a spherical shape
  • Surface area decreases, and volume remains unchanged
  • Impairs erythrocyte's ability to confirm in small vessels of the microcirculation
• Patients present with splenomegaly, hemolytic anemia, and pigmented gallstones
• Peripheral smear will show normocytic, normochromic erythrocytes and reticulocytes if there's a high degree of hemolysis
  • Reticulocytes appear as larger, pale blue erythrocytes
• Treatment involves splenectomy

Erythrocyte Findings in Other Conditions

• Macrocytic and hyperchromic erythrocytes are found in vitamin B12 or folate deficiency
  • Can occur in pediatric patients with malabsorptive conditions such as celiac disease
  • Can occur in older patients and adults with gastric bypass, chronic alcohol use, and pernicious anemia
• Macrocytic and hypochromic erythrocytes occur from a combination of diseases
  • Vitamin B12 deficiency
  • Folate deficiency (macrocytosis)
  • Iron deficiency
  • Anemia of chronic disease
  • Thalassemia (hypochromia)
• Microcytic and hypochromic erythrocytes are seen in iron deficiency
  • Often the result of chronic blood loss
  • Uncommon in young patients without gastrointestinal bleeding
• Normocytic and hypochromic erythrocytes are commonly observed in thalassemia
  • Target cells are often present on peripheral smear

Educational Objective: Hereditary Spherocytosis

• Autosomal dominant mutations in ankyrin, spectrin, and band erythrocyte membrane proteins cause hereditary spherocytosis through loss of the normal connection between the inner membrane skeleton and the outer lipid bilayer.
• Symptoms: jaundice, splenomegaly, and anemia
• Peripheral blood smear shows normocytic, normochromic anemia with presence of spherocytes
• Treatment: splenectomy

Fetal Alcohol Syndrome (FAS)

• A proven teratogen
• Alcohol use in pregnancy can lead to neurological effects and physical malformations
• Characterized by:
  • Microcephaly
  • Facial abnormalities like small palpebral fissures, maxillary hypoplasia, thin vermilion border, cleft lip/palate
  • Limb deformities
  • Congenital heart disease
• Leading cause of intellectual disability in the United States
• Muscular abnormalities like gross motor delays and hypotonia
• Abnormal bone development like cervical spine fusion and delayed bone growth

Other Conditions

• Congenital toxoplasmosis typically presents with chorioretinitis, hepatosplenomegaly, jaundice, convulsions, cerebral calcifications, and hydrocephalus
• Down Syndrome presents with hypotonia:
  • Downturned palpebral fissures
  • Prominent epicanthal folds
  • Flat facies
  • Single palmar creases
  • Intellectual developmental disorder
  • Increased risk for congenital cardiac and gastrointestinal malformations
• Fragile X syndrome presents with intellectual developmental disorder:
  • Elongated face with a prominent jaw
  • a high-arched palate
  • Large ears
  • Hyperextensible joints
  • Postpubertal macroorchidism
• Seminiferous tubule dysgenesis (Klinefelter syndrome)
  • XXY karyotype
  • Dysgenesis of the seminiferous tubules and testicular atrophy
  • Leads to decreased spermatogenesis
  • Dysmorphic body features include a eunuchoid body shape, long extremities, and gynecomastia
• Trisomy 13 (Patau syndrome) presents with intellectual developmental disorder:
  • Cleft lip and palate
  • Holoprosencephaly
  • Microphthalmia
  • Cutis aplasia
  • Feet with a prominent calcaneus and convexly rounded soles
  • Polydactyly

Educational Objective: Fetal Alcohol Syndrome

• Alcohol is a known teratogen that causes fetal alcohol syndrome when used during pregnancy
• Symptoms: intellectual developmental disorder along with physical malformations
  • Facial dysmorphia like small palpebral fissures, thin vermillion border, smooth philtrum
  • Limb and muscular deformities
  • Congenital heart disease

Neonatal Jaundice

• Defined as increased bilirubin (>5 mg/dL)
• Due to increased hemolysis or decreased bilirubin conjugation/excretion
• Presents as:
  • Direct (conjugated) hyperbilirubinemia: the conjugated bilirubin levels are increased
  • Indirect (unconjugated) hyperbilirubinemia: the unconjugated bilirubin levels are increased
  • Physiologic
  • Pathologic
• Anemia and unconjugated hyperbilirubinemia presenting in the first few days of life indicates a pathologic hemolytic process
• Includes immune-mediated hemolysis, inherited erythrocyte membrane defects, and erythrocyte enzyme deficiencies
• Most likely cause: glucose-6-phosphate dehydrogenase (G6PD) deficiency in patients with a negative Coombs test and Mediterranean background
• G6PD is an enzyme in erythrocytes
• G6PD makes NADPH from NADP+
• Inadequate NADPH leads to decreased glutathione, a critical scavenger of reactive oxygen species within erythrocytes
• Increased oxidative stress, from exposure to sulfa-containing compounds, results in hemolysis

Other Conditions

• Dehydration can result in jaundice in newborns due to increased enterohepatic circulation, renal resorption, and concentration of bilirubin in the serum
• Milk protein allergy may occur in infants fed with cow’s milk formula and breast milk in the first year of life
  • IgE-mediated manifestations: anaphylaxis, urticaria, and angioedema
  • Non-IgE-mediated symptoms: reflux, enterocolitis, or enteropathy
• Physiologic jaundice arises from increased red blood cell breakdown, immature liver metabolism of bilirubin, and increased enterohepatic circulation of bilirubin
  • Onset: after 24 hours of life
  • Rate of bilirubin increase: less than 0.5 mg/dL daily
  • Maximum peak: 14 to 15 mg/dL
  • Predominance of indirect bilirubin (>90%) A sepsis diagnosis should be suspected if bilirubin is over 20mg/dL and low hematocrit should prompt evaluation for pathologic causes
• Sepsis may manifest as a range from asymptomatic to hemodynamic collapse
  • Early symptoms can include irritability lethargy and poor feeding

Educational Objective: NADPH

• NADPH is produced from NADP+ by G6PD
• NADPH is required for the reduction of glutathione
• Glutathione helps scavenge reactive oxygen species in erythrocytes
• Absence of G6PD results in increased oxidative stress that can lead to hemolysis when patients are exposed to medications such as trimethoprim-sulfamethoxazole and other sulfa drugs

Cyclic Neutropenia

• Rare, inherited immunodeficiency syndrome
• Characterized by periodic episodes of neutropenia and infection
• Most cases follow a cyclic pattern that reoccurs every 21 days and lasts for 3 to 6 days
• Classic symptoms: fever, malaise, and ulcers
  • Affect oral mucous membranes
• Can cause pharyngitis and chronic periodontal disease that results in early tooth loss
• During episodes of neutropenia, patients have an increased risk for bacterial infections:
  • Respiratory
  • Gastrointestinal
  • Urinary
  • Skin
• Pathophysiology is not well understood, but the disease is associated with mutations in the gene encoding neutrophil elastase
• Confirmed via monitoring a patient’s neutrophil count several times weekly for at least 6 weeks
• Genetic testing for mutations in the neutrophil elastase gene is also recommended
• Acute management involves treating the current infection
• Long-term therapy with human granulocyte-colony stimulating factor

Other Conditions

• Chédiak-Higashi syndrome arises from mutations in the lysosomal trafficking regulator gene (LYST)
  • Essential for normal formation and transport of lysosomes
  • Presents with frequent bacterial infections, oculocutaneous albinism, peripheral neuropathy, and progressive neurologic dysfunction
• Dyskeratosis congenita is a rare genetic condition associated with bone marrow failure
  • Triad of skin abnormalities: reticular hyperpigmentation pattern, pale-gray macules, areas of atrophy, dystrophic nails, and oral leukoplakia
• Fanconi syndrome
  • Inherited or acquired
  • Causes malabsorption of solutes in the renal proximal tubule
  • Fanconi anemia causes bone marrow suppression, pancytopenia, and recurrent infections
  • Characterized by short stature, microcephaly, developmental delay, and café-au-lait skin lesions
• Hypersplenism involves splenomegaly and cytopenias of all three cell lines (anemia, leukopenia, thrombocytopenia)
• Leukemia, especially acute lymphoblastic leukemia
  • Common pediatric malignancy of B- or T-lymphocytes
  • Can present with malaise, fatigue, weight loss, splenomegaly, lymphadenopathy, anemia, and thrombocytopenia, with circulating leukemic blasts on peripheral blood smear
• Severe congenital neutropenia (SCN)
  • Characterized by low concentrations of circulating neutrophils and recurrent bacterial infections
  • More severe than cyclic neutropenia
  • Presents with infections in the first few months of life
  • High risk for transformation into acute myeloid leukemia
• Viral illness (parvovirus B19, Epstein-Barr virus, cytomegalovirus, HIV, and dengue)
  • Bone marrow suppression with cytopenias of varying degrees
  • Viral illnesses often present with additional characteristic symptoms
  • Viral illnesses do not follow a cyclic pattern
• Vitamin B12 (cobalamin) deficiency
  • Results in megaloblastic anemia
  • Macro cytosis and segmented neutrophils
  • Common in patients who chronically abuse alcohol or in patients with a Roux-en-Y gastric bypass, Crohn disease, or malabsorptive disorders

Educational Objective: Cyclic Neutropenia

• Rare, inherited immunodeficiency syndrome associated with dysfunctional neutrophil elastase
• Characterized by periodic episodes of neutropenia and infection
• Most cases reoccur every 21 days and last for 3 to 6 days

Thalassemia Minor

• Can occur as a result of mutations or deletions in one of the β-globin alleles or in one or two of the α-globin alleles
• Leads to the impaired production of globin chains
• Patients typically demonstrate a mild microcytic anemia with a low RDW and normal concentrations of leukocytes and platelets
• Hemoglobin electrophoresis can be used to distinguish between these two entities
• Treatment is often not necessary

Other Potential Conditions

• Antibiotic-induced autoimmune hemolysis
  • Can occur after exposure to penicillins and cephalosporins
  • Onset is typically acute
  • Occurs within hours to days
  • Patients would be expected to present with normocytic anemia and unconjugated hyperbilirubinemia with low haptoglobin concentrations
• Iron deficiency
  • Common cause of anemia in menstruating women, strict vegans or vegetarians, and those with chronic gastrointestinal bleeding or celiac disease
• Presents with microcytosis with a higher MCV than what is seen in thalassemia
  • Increased RDW, indicating the release of premature erythrocytes from the bone marrow
• Transient postinfectious bone marrow suppression
  • May occur following viral infections
  • Presents with leukopenia
• Vitamin B12 (cobalamin) deficiency
  • Results in megaloblastic anemia
  • Presents with macrocytosis and hypersegmented neutrophils
  • Common in patients who chronically abuse alcohol or in patients with a Roux-en-Y gastric bypass, Crohn disease, or malabsorptive disorders

Educational Objective: Thalassemia Minor

• Arises from mutations or deletions in one of the β-globin alleles or in one or two of the α-globin alleles
• Leads to the impaired production of globin chains
• Patients typically demonstrate a mild microcytic anemia with a low RDW and normal concentrations of leukocytes and platelets
• Hemoglobin electrophoresis can be used to distinguish between these two entities
• Treatment is often not necessary

Autism Spectrum Disorder (ASD)

• Formerly classified as pervasive developmental disorder
• Includes a group of syndromes:
  • Autism
  • Asperger syndrome
  • Childhood disintegrative disorder
  • Pervasive developmental disorder not otherwise specified
• Refers to a range of neurodevelopmental/neurodivergent syndromes characterized by atypical forms of social communication and interaction
• Includes restricted and repetitive patterns of behavior or activities
• Manifestations:
  • Decreased interest in socializing
  • Challenging behaviors conflicting with established societal norms
  • Decreased nonverbal communication like eye contact and facial expressions
• Diagnosed via behavioral, neuro, and genetic features
• Management of ASD is individualized depending on the clinical manifestations
  • Therapy involves behavioral, developmental, social, and educational interventions to improve social functioning, communication skills, and academic functioning

Other Conditions

• Learning disorders are characterized by a persistent impairment in reading, written expression, or mathematical ability
• Patients may have difficulty with specific skills relating to these subjects
• Learning disorders may coexist with ASD
• Mild intellectual developmental disorder refers to mild impairment related to abstract or theoretical thinking
  • Patients have decreased social and daily functional skills
  • They are typically able to adapt to living in society with life-skills training in specific areas
• Oppositional defiant disorder manifests as a persistent pattern of angry mood, defiant behavior, and vindictiveness that can cause impaired functioning in the child and distress to their caretakers
• Parent-child relational problem is diagnosed by the presence of pervasive dissatisfaction with the relationship, persistent thoughts of running away, and a perception that professional help is needed for maintaining the relationship

Educational Objective: Autism Spectrum Disorder

• Characterized by atypical forms of social communication and interaction that involve external manifestations
  • Avoidance of eye contact
  • Narrow and focused interests
  • Disinterest in typical forms of socialization and play
• Reliance on predictable routine

Initial Management of Alcohol Intoxication

• Airway protection, including endotracheal intubation, is indicated for patients with altered mental status, obtundation, respiratory distress, and hypoxia
• Patients often show signs of chronic excessive alcohol abuse (enlarged liver palpated below the costal margin and scleral icterus), consistent with alcoholic hepatitis

Other Considerations

• Determining the exact amount and type of alcohol ingested and measurement of blood alcohol concentration may be helpful
• Nebulized acetylcysteine therapy is a mucolytic agent that is not indicated
• Hemodialysis is typically not used in the treatment of alcohol intoxication, as the liver is usually able to metabolize alcohol -Dialysis may be helpful in patients with ethylene glycol poisoning and metabolic acidosis

Educational Objective:

• The initial management of an obtunded patient showing signs of respiratory distress include airway protection, including endotracheal intubation to support the patient's ventilation and oxygenation.

Opioid Overdose

• Opioid receptors are often located throughout the central nervous system (CNS) and peripheral nervous system (PNS).
• Opioid intoxication signs and symptoms include euphoria, altered mental status, sedation, bradycardia and hypotension, depressed respiratory drive or apnea, and constricted pupils.
• Miosis is a distinctive finding caused by direct opioid receptor activity Opioids also decrease gut motility, causing constipation
• Opioid overdoses are characterized by patients with respiratory depression, apnea and hypoxia

Treatment Considerations

• Naloxone should be administered to patients presenting with respiratory depression in the setting of potential opioid overdose -Focus on the primary survey and management of the patient’s airway, breathing, and circulation
• Transient ventilation is often achieved using a bag-valve mask
• Emergent intubation and mechanical ventilation may be needed if the patient doesn't respond to the antidote or has further decompensation or airway compromise

Additional Information

• Administration of activated charcoal would be harmful to the pulmonary parenchyma and cause aspiration pneumonitis
• 5% glucose would be helpful for patients with hypoglycemia
• Methadone would be helpful for patients in with opioid overdose
• 0.9% saline is helpful for patients who may be dehydrated in the setting of substance use

Educational Objective:

• Opioid overdoses include miosis, altered mental status, and respiratory depression -Naloxone should be administered emergently to patients presenting with altered mental status and respiratory depression

Immune Thrombocytopenic Purpura (ITP)

• Caused by antiplatelet antibodies that bind platelets -Leads to opsonization and destruction -Macrophages within the spleen phagocytose the platelet-antibody complex, resulting in thrombocytopenia
• ITP is diagnosed in the setting of a low platelet count and absence of other explanatory causes for thrombocytopenia
  • Bone marrow biopsy = increased number of megakaryocytes
• Presents with petechiae, purpura, and prolonged bleeding time on laboratory analysis
• Acute ITP is often seen in pediatric patients and may follow an infection
  • Generallly self-limited
  • Managed conservatively in the absence of life-threatening bleeds

Other Conditions

• Abnormal platelet function presents with a defect in the Gpllb/Illa protein, preventing both platelet aggregation and formation of a platelet plug
• Child abuse presents with unexplained ecchymosis and bone fractures at different stages of healing, as well as cerebral hematomas
• Decreased platelet production results from conditions including aplastic anemia
• Typically presents with anemia, thrombocytopenia, and leukopenia
  • Associated with parvovirus B19 infection in children with underlying sickle cell anemia
• Disseminated intravascular coagulation is a systemic disorder that spreads by the widespread activation of the clotting cascade
• Results in microthrombi formation, thrombocytopenia, and bleeding complications due to consumption of platelets and clotting factors

Educational Objective:

• ITP is associated to the development of antibodies that bind platelets, leading to opsonization and phagocytosis by macrophages in the spleen
• ITP is diagnosed in patients with a low platelet count with petechiae and purpura