Hematology

Question 1

Normal ferritin <5yo: less than __ mcg/L;5yo: less than ___

Answer 1

Normal ferritin <5yo: <12 mcg/L; >5yo: <15mcg/L

Question 2

Normal PTT: ____
Normal PT: _____
Normal MPV (mean platelet volume): ____
A general rule is that: Normal MCV (in a noninfant child) = ____ + _____

Answer 2

Normal PTT: 25-35
Normal PT: 11-13.5
Normal MPV (mean platelet volume): 8-12
A general rule is that: Normal MCV (in a noninfant child) = approximately 72 + age in years (Until age 10yo)

Question 3

Fetus

• RBC formation in the yolk sac begins at 2 weeks gestation. By the 8th week, RBC formation shifts to the liver, increases, peaks at 5 months, and then decreases thereafter. At 5 months, the bone marrow takes over and remains the predominant site for RBC production.
• Production of RBCs is regulated by erythropoietin EPO, which is produced by the liver in the fetus. Production switches from liver to kidney soon after birth. EPO production is regulated by tissue oxygenation.

Answer 3

Fetus

• RBC formation in the yolk sac begins at 2 weeks gestation. By the 8th week, RBC formation shifts to the liver, increases, peaks at 5 months, and then decreases thereafter. At 5 months, the bone marrow takes over and remains the predominant site for RBC production.
• Production of RBCs is regulated by erythropoietin EPO, which is produced by the liver in the fetus. Production switches from liver to kidney soon after birth. EPO production is regulated by tissue oxygenation.

Question 4

Newborn

• At birth, hemoglobin averages ___ g/dL
  
  • At birth, term neonates have a higher hematocrit than preterm neonates.
• Red cell lifespan during the first 6-8 weeks of life is around ___ days instead of the usual 120 days. This results in the “physiologic anemia of infancy,” which reaches its nadir around ____ mo of age, with an average hemoglobin level ___ g/dL.

Answer 4

Newborn

• At birth, hemoglobin averages 17 g/dL
  
  • At birth, term neonates have a higher hematocrit than preterm neonates.
• Red cell lifespan during the first 6-8 weeks of life is around 90 days instead of the usual 120 days. This results in the “physiologic anemia of infancy,” which reaches its nadir around 2 mo of age, with an average hemoglobin level 9-11 g/dL.

Question 5

Hemoglobin

• By 8-12 weeks of gestation, the Gower and Portland hemoglobins disappear and fetal hemoglobin (HbF) predominates. HbF contains alpha and gamma chains and is alpha2gamma2.
• Normal adult hemoglobin HbA contains 2 pairs of alpha and beta chains and is designated alpha2beta2
• HbA2 (alpha2delta2), or minor adult hemoglobin, is produced in late gestation and account for 2-3% of total hemoglobin after the first few months of life.
  
  • HbA2 is elevated in ____.

Answer 5

Hemoglobin

• By 8-12 weeks of gestation, the Gower and Portland hemoglobins disappear and fetal hemoglobin (HbF) predominates. HbF contains alpha and gamma chains and is alpha2gamma2.
• Normal adult hemoglobin HbA contains 2 pairs of alpha and beta chains and is designated alpha2beta2
• HbA2 (alpha2delta2), or minor adult hemoglobin, is produced in late gestation and account for 2-3% of total hemoglobin after the first few months of life.
  
  • HbA2 is elevated in beta-thalassemia trait.

Question 6

HgbF = \_\_\_\_
HgbA1 = \_\_\_\_
HgbA2 = \_\_\_\_
HbH = \_\_\_\_
Hb Bart = \_\_\_\_

Answer 6

HgbF = Alpha2gamma2 
HgbA1 = Alpha2beta2 
HgbA2 = Alpha2delta2 
HbH = beta 4
Hb Bart = gamma 4

Question 7

At birth: Hgb__ 75-80%, Hgb__ 20-25%, Hgb__ 0.5%

Normal: Hgb__ 95%, Hgb__ 3.5%, Hgb__ <1%

Beta thalassemia minor: Hgb__ 80-90%, Hgb__ 5-10%, Hgb__ 2% (diagnosed on hgb electrophoresis)

Beta thalassemia major: absent Hgb__, variable/increased Hb__, Hb__ 10-99% (diagnosed on NBS)

Alpha thalassemia carrier (3 genes, aa/-1)

Alpha thalassemia trait (-a/-a or aa/–)

HbH (1 gene, -a/–): Hb__ 15-20%, Hb__ 15-25%

Hydrop fetalis (0 genes –/–): Hb___ 100%

Sickle cell disease: Hgb__ 0%, Hgb__ 85-95%, Hgb__ 5-15%

Sickle cell trait: Hgb__ 50-60%, Hgb__ 35-45%, Hgb__ <2%

Answer 7

At birth: HgbF 75-80%, HgbA1 20-25%, HgbA2 0.5%

Normal: HgbA1 95%, HgbA2 3.5%, HgbF <1%

Beta thalassemia minor: HgbA1 80-90%, HgbA2 5-10%, HgbF 2% (diagnosed on hgb electrophoresis)

Beta thalassemia major: absent HgbA1, variable/increased HbA2, HbF 10-98% (diagnosed on NBS)

Alpha thalassemia carrier (3 genes, aa/-1)

Alpha thalassemia trait (-a/-a or aa/–)

HbH (1 gene, -a/–): HbH 15-20%, HbBart 15-25%

Hydrop fetalis (0 genes –/–): Hb Bart 100%

Sickle cell disease: HgbA 0%, HgbS 85-95%, HgbF 5-15%

Sickle cell trait: HgbA 50-60%, HgbS 35-45%, HgbF <2%

Question 8

Newborn screen → Disease
HbFS → Hb\_\_, Hb\_\_\_, or Hb\_\_\_
HbFSA → Hb\_\_\_
HbFSC → Hb\_\_
HbFAS → Hb\_\_\_\_
AFS → \_\_\_

Answer 8

Newborn screen → Disease
HbFS → HbSS, HbSHPFH, or HbSB0-thal
HbFSA → HbSB+thal
HbFSC → HbSC
HbFAS → HbAS (sickle cell trait)
AFS → newborn transfused with RBCs or there has been an error

Question 9

Iron Deficiency Anemia
- The diagnosis of early iron deficiency requires testing iron indices, including serum ferritin and transferrin saturation

• Low MCV (<80, microcytic), Low iron, High TIBC, low transferrin saturation, low _____ (iron stores) (__%), Mentzer index (__/__)>___
• Hepcidin can help distinguish IDA from anemia of chronic disease. Hepcidin blocks iron transport.
  
  • When levels are high, iron absorption is low. In IDA, hepcidin levels _____ in response to low iron stores and iron absorption increases.
  • In contrast, in anemia of chronic disease, iron stores are normal-high, but the cytokine-mediated production of hepcidin inhibits their use and causes anemia.
• Tx:
  
  • Trial ___ mg/kg elemental ferrous sulfate daily for __ months with ____ (NOT ____) (also not with calcium (like tums is calcium carbonate))
  • AND dietary changes
  • RTC in 1 month. Follow up CBC __ weeks after begin iron for mild anemia
  • If Hgb increases by 1g/dl, therapy continues. CBC should be retested ___ mo after initiation
• To prevent:
  
  • 1) iron supplementation for breastfed infants begin at __mo age for term and at __ weeks for premature, continued until infant taking sufficient quantities of iron rich foods.
    
    • Provide elemental iron supplementation of 1mg/kg/day for infants who are exclusively breastfed beyond 4 months of age.
  • 2) Introduce iron rich foods (cereals, puréed meats) at 6mo.
  • 3) Avoid cows milk until 12mo.
    
    • Do not give cow’s milk during the 1st year of life to prevent occult GI bleeding.
  • 4) After 12 mo, milk intake limit <20oz/600ml.

Answer 9

Iron Deficiency Anemia
- The diagnosis of early iron deficiency requires testing iron indices, including serum ferritin and transferrin saturation

• Low MCV (<80, microcytic), Low iron, High TIBC, low transferrin saturation, low ferritin (iron stores) (<12), elevated RDW (>17%), Mentzer index (MCV/RBC)>13
• Hepcidin can help distinguish IDA from anemia of chronic disease. Hepcidin blocks iron transport.
  
  • When levels are high, iron absorption is low. In IDA, hepcidin levels decrease in response to low iron stores and iron absorption increases.
  • In contrast, in anemia of chronic disease, iron stores are normal-high, but the cytokine-mediated production of hepcidin inhibits their use and causes anemia.
• Tx:
  
  • Trial 3- 6 mg/kg elemental ferrous sulfate daily for 3 months with juice/water (NOT milk) (also not with calcium (like tums is calcium carbonate))
  • AND dietary changes
  • RTC in 1 month. Follow up CBC 4 weeks after begin iron for mild anemia
  • If Hgb increases by 1g/dl, therapy continues. CBC should be retested 3 mo after initiation
• To prevent:
  
  • 1) iron supplementation for breastfed infants begin at 4mo age for term and at 2 weeks for premature, continued until infant taking sufficient quantities of iron rich foods.
    
    • Provide elemental iron supplementation of 1mg/kg/day for infants who are exclusively breastfed beyond 4 months of age.
  • 2) Introduce iron rich foods (cereals, puréed meats) at 6mo.
  • 3) Avoid cows milk until 12mo.
    
    • Do not give cow’s milk during the 1st year of life to prevent occult GI bleeding.
  • 4) After 12 mo, milk intake limit <20oz/600ml.

Question 10

Thalassemias

• Inherited disorders in which there is unbalanced globin chain synthesis due to absence or decreased production of either the beta chain (beta-thalassemia) or the alpha chain (alpha-thalassemia)
• Each chromosome ___ contains 2 alleles coding for the alpha-globin chain (4 alleles total), and each chromosome ___ contains 1 allele for the beta-globin chain (2 alleles total)

Answer 10

Thalassemias

• Inherited disorders in which there is unbalanced globin chain synthesis due to absence or decreased production of either the beta chain (beta-thalassemia) or the alpha chain (alpha-thalassemia)
• Each chromosome 16 contains 2 alleles coding for the alpha-globin chain (4 alleles total), and each chromosome 11 contains 1 allele for the beta-globin chain (2 alleles total)

Question 11

See alpha thalassemia table

Answer 11

See alpha thalassemia table

Question 12

Beta thalassemia
- Screening: Beta-thalassemia major (B0/B0) is diagnosed on newborn screening (Hb__ only). Other B-thalassemias have the normal newborn hemoglobin pattern of fetal hemoglobin and adult hemoglobin (FA).

Answer 12

Beta thalassemia
- Screening: Beta-thalassemia major (B0/B0) is diagnosed on newborn screening (HbF only). Other B-thalassemias have the normal newborn hemoglobin pattern of fetal hemoglobin and adult hemoglobin (FA).

Question 13

Beta-thalassemia has 3 categories.

• Beta-thalassemia minor or trait (Heterozygous; one normal Beta and 1 thalassemic allele: B/B0 or B/B+
  
  • Is usually asymptomatic but may be diagnosed when a suspected iron deficiency anemia does not respond to treatment.
  • Dx: Finding of Hb__ >___% is diagnostic!
  • No tx

Answer 13

Beta-thalassemia has 3 categories.

• Beta-thalassemia minor or trait (Heterozygous; one normal Beta and 1 thalassemic allele: B/B0 or B/B+
  
  • Is usually asymptomatic but may be diagnosed when a suspected iron deficiency anemia does not respond to treatment.
  • Dx: Finding of HbA2 >3.5% is diagnostic!
  • No tx

Question 14

• Beta-thalassemia intermedia (Homozygous B+/B+; with some normal B-globin production)
  
  • Moderate microcytic anemia
  • Dx: Quantitative hemoglobin electrophoresis shows increased HbA2 (alpha2delta2) and HbF (alpha2gamma2)
  • Tx: Requires intermittent RBC transfusions

Answer 14

• Beta-thalassemia intermedia (Homozygous B+/B+; with some normal B-globin production)
  
  • Moderate microcytic anemia
  • Dx: Quantitative hemoglobin electrophoresis shows increased HbA2 (alpha2delta2) and HbF (alpha2gamma2)
  • Tx: Requires intermittent RBC transfusions

Question 15

• Beta-thalassemia major (Cooley anemia; homozygous B0/B0 or compound heterozygous B0/B+)
  
  • Hb__ and Hb__ levels will be high on hemoglobin electrophoresis
  • Homozygosity for impaired gene synthesis with essentially no B-globin production. The remaining highly insoluble alpha-globin precipitates into inclusion bodies (Heinz bodies)
  • Pt: Severe hemolysis
    
    • At 4-6mo: Anemia, failure to thrive, feeding problems, pallor, jaundice, irritability, recurrent fevers, splenomegaly, bone abnormalities
    • Expansion of the bone marrow space (due to extramedullary hematopoiesis) in facial bones leads to characteristic changes such as frontal bossing and prominent malar eminences (ie “_____ facies” in children).
  • Labs: Anemia is microcytic. But 2 differences from iron deficiency: 1) ____ ferritin level, 2) Mentzer index (MCV/RBC) less than ___
    
    • Vs IDA: RDW <17%, MCV<70
• Dx: Hemoglobin electrophoresis shows almost all HbF.
  - 100% Hb__ at birth is B thalassemia major until proven otherwise.
  • Tx: Patients are ____ dependent and often develop iron overload, requiring ___ therapy.
    
    • TOC: ___
    • Avg life expectancy is ___yo, may die by 30yo. If no tx, death by 4yo.

Answer 15

• Beta-thalassemia major (Cooley anemia; homozygous B0/B0 or compound heterozygous B0/B+)
  
  • HbF and HbA2 levels will be high on hemoglobin electrophoresis
  • Homozygosity for impaired gene synthesis with essentially no B-globin production. The remaining highly insoluble alpha-globin precipitates into inclusion bodies (Heinz bodies)
  • Pt: Severe hemolysis
    
    • At 4-6mo: Anemia, failure to thrive, feeding problems, pallor, jaundice, irritability, recurrent fevers, splenomegaly, bone abnormalities
    • Expansion of the bone marrow space (due to extramedullary hematopoiesis) in facial bones leads to characteristic changes such as frontal bossing and prominent malar eminences (ie “chipmunk facies” in children).
  • Labs: Anemia is microcytic. But 2 differences from iron deficiency: 1) Normal ferritin level, 2) Mentzer index (MCV/RBC) <13
    
    • Vs IDA: RDW <17%, MCV<70
  • Dx: Hemoglobin electrophoresis shows almost all HbF.
    
    • 100% HbF at birth is B thalassemia major until proven otherwise.
  • Tx: Patients are transfusion dependent and often develop iron overload, requiring chelation therapy.
    
    • TOC: Bone marrow transplant
    • Avg life expectancy is 17yo, may die by 30yo. If no tx, death by 4yo.

Question 16

Sideroblastic Anemia
- Path: Drugs, alcohol, lead, B6 deficiency, myelodysplastic syndrome

• Iron studies: increased Fe/iron (ONLY form of microcytic anemia ass with ____ circulating IRON level)
• Peripheral blood smear
  
  • Blood smear shows _____ bodies, which are often at the periphery of the cell (these are dark blue cytoplasmic inclusions of iron occurring as small single or multiple blue granules)
  • Usually has 2 populations or erythrocytes, including normal-appearing cells along with hypochromic microcytes cells (low MCV; low MCH). This variation in size and shape is reflected in the CBC with a large RBC volume distribution width (RDW).
• Bone marrow biopsy shows _______ (normoblasts with iron-laden mitochondria surrounding the nucleus)

Answer 16

Sideroblastic Anemia
- Path: Drugs, alcohol, lead, B6 deficiency, myelodysplastic syndrome

• Iron studies: increased Fe/iron (ONLY form of microcytic anemia ass with HIGH circulating IRON level)
• Peripheral blood smear
  
  • Blood smear shows Pappenheimer bodies, which are often at the periphery of the cell (these are dark blue cytoplasmic inclusions of iron occurring as small single or multiple blue granules)
  • Usually has 2 populations or erythrocytes, including normal-appearing cells along with hypochromic microcytes cells (low MCV; low MCH). This variation in size and shape is reflected in the CBC with a large RBC volume distribution width (RDW).
• Bone marrow biopsy shows ringed sideroblasts (normoblasts with iron-laden mitochondria surrounding the nucleus)

Question 17

Anemia of Chronic Disease

• Low iron, low TIBC, low-normal transferrin saturation, normal-high ferritin
• In contrast to IDA, in ACD, iron stores are normal-high, but the cytokine-mediated production of _______ inhibits their use and causes anemia.

Answer 17

Anemia of Chronic Disease

• Low iron, low TIBC, low-normal transferrin saturation, normal-high ferritin
• In contrast to IDA, in ACD, iron stores are normal-high, but the cytokine-mediated production of hepcidin inhibits their use and causes anemia.

Question 18

Vitamin B12 (cobalamin) deficiency

• Path: Disruption of vitamin B12 absorption.
  
  • Absence of terminal ileum (surgical or congenital)
  • Deficiency of intrinsic factor (Pernicious Anemia)
    
    • Congenital pernicious anemia- genetic defect resulting in hypofunctional or absent intrinsic factor
    • Juvenile pernicious anemia in adolescents- results from gastric atrophy and achlorhydria caused by antibodies to the parietal cell and intrinsic factor.
• RFs: Small bowel resection and maternal vegan diet in a child who is exclusively breastfed
• Pt:
  
  • In contrast to folate deficiency, leads to ________, including paresthesias, ataxia, and gait abnormalities. Eventually to irreversible neurologic damage, including bilateral paresthesias, decreased proprioception and vibration sense (dorsolateral column “dropout”), spastic ataxia, central scotoma, and dementia. These neurologic defects can occur even in the absence of anemia or macrocytosis.
• Dx: Peripheral smear reveals basophilic stippling of RBCs and Howell-Jolly bodies
• Tx: Parenteral administration of vitamin B12 for life: Monthly subcutaneous injections of 1mg of cyanocobalamin or hydroxocobalamin.

Answer 18

Vitamin B12 (cobalamin) deficiency

• Path: Disruption of vitamin B12 absorption.
  
  • Absence of terminal ileum (surgical or congenital)
  • Deficiency of intrinsic factor (Pernicious Anemia)
    
    • Congenital pernicious anemia- genetic defect resulting in hypofunctional or absent intrinsic factor
    • Juvenile pernicious anemia in adolescents- results from gastric atrophy and achlorhydria caused by antibodies to the parietal cell and intrinsic factor.
• RFs: Small bowel resection and maternal vegan diet in a child who is exclusively breastfed
• Pt:
  
  • In contrast to folate deficiency, leads to neurologic symptoms, including paresthesias, ataxia, and gait abnormalities. Eventually to irreversible neurologic damage, including bilateral paresthesias, decreased proprioception and vibration sense (dorsolateral column “dropout”), spastic ataxia, central scotoma, and dementia. These neurologic defects can occur even in the absence of anemia or macrocytosis.
• Dx: Peripheral smear reveals basophilic stippling of RBCs and Howell-Jolly bodies
• Tx: Parenteral administration of vitamin B12 for life: Monthly subcutaneous injections of 1mg of cyanocobalamin or hydroxocobalamin.

Question 19

Folate deficiency

• Path:
  
  • Can result from inadequate dietary intake, increased metabolic demand (eg infancy, pregnancy, lactation), malabsorption, or metabolic interference (eg methotrexate, sulfonamide).
  • Consumption of a diet high in ______, which is low in folic acid
    
    • Goat milk is a poor source of folate and results in megaloblastic anemia in unsupplemented infants if used as the sole food.
• Tx: 1-5 mg daily.
  
  • If patient has concomitant vitamin B12 deficiency, use high-dose folate can correct RBC problems but worsen neurologic manifestations of B12 deficiency. It is therefore important to determine if B12 deficiency is also present.

Answer 19

Folate deficiency

• Path:
  
  • Can result from inadequate dietary intake, increased metabolic demand (eg infancy, pregnancy, lactation), malabsorption, or metabolic interference (eg methotrexate, sulfonamide).
  • Consumption of a diet high in goat milk, which is low in folic acid
    
    • Goat milk is a poor source of folate and results in megaloblastic anemia in unsupplemented infants if used as the sole food.
• Tx: 1-5 mg daily.
  
  • If patient has concomitant vitamin B12 deficiency, use high-dose folate can correct RBC problems but worsen neurologic manifestations of B12 deficiency. It is therefore important to determine if B12 deficiency is also present.

Question 20

Hereditary Spherocytosis
- Path: ___inheritance? defect in gene encoding RBC membrane protein ____. Results in fragile RBC membranes and shortened RBC lifespan (10-30 days, about 1 month).

• Pt: Increasing pallor in a child with HS is a sign of aplastic crisis, with decreased hemoglobin and retic count typically caused by parvovirus B19 infection.
• Dx: Finding the presence of anemia (of varying degrees), reticulocytosis, increased MCHC, spherocytes in the peripheral smear, and a positive osmotic fragility test.
• Management:
  
  • ______ should be recommended for patients with hereditary spherocytosis (hemoglobin level chronically <11g/dl). Splenectomy is sometimes required to prolong RBC survival.
    
    • Prior to splenectomy, administer pneumococcal, H influenzae, and meningococcal vaccinations to minimize the risk of postsplenectomy sepsis. Postsplenectomy _____ prophylaxis is also necessary, and urgent medical eval is necessary for splenectomized children with fever.
  • Pts are at higher risk for bacteremia with encapsulated organisms and should be vaccinated appropriately. If not previously vaccinated, pts should receive PCV13 followed by PPSV23 after 8 weeks, and a 2nd dose of PPSV23 after 5 years

Answer 20

Hereditary Spherocytosis
- Path: AD defect in gene encoding RBC membrane protein ankyrin. Results in fragile RBC membranes and shortened RBC lifespan (10-30 days, about 1 month).

• Pt: Increasing pallor in a child with HS is a sign of aplastic crisis, with decreased hemoglobin and retic count typically caused by parvovirus B19 infection.
• Dx: Finding the presence of anemia (of varying degrees), reticulocytosis, increased MCHC, spherocytes in the peripheral smear, and a positive osmotic fragility test.
• Management:
  
  • Splenectomy should be recommended for patients with hereditary spherocytosis (hemoglobin level chronically <11g/dl). Splenectomy is sometimes required to prolong RBC survival.
    
    • Prior to splenectomy, administer pneumococcal, H influenzae, and meningococcal vaccinations to minimize the risk of postsplenectomy sepsis. Postsplenectomy penicillin prophylaxis is also necessary, and urgent medical eval is necessary for splenectomized children with fever.
  • Pts are at higher risk for bacteremia with encapsulated organisms and should be vaccinated appropriately. If not previously vaccinated, pts should receive PCV13 followed by PPSV23 after 8 weeks, and a 2nd dose of PPSV23 after 5 years

Question 21

Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Rare disorder of hematopoietic stem cells resulting in the production of RBCs which lack a critical surface protein, rendering them vulnerable to hemolysis by the _____ system.

• Rare, acquired clonal stem cell disorder involving
  
  • Glycophosphatidylinositol (GPI)-linked membrane proteins
  • Decay-accelerating factor (____, aka CD___), and
  • Homologous restriction factor 9HRF aka CD___ of the ____ gene on the X chromosome
• Deficiency of these proteins makes cells more susceptible to complement-mediated lysis.
• Pt:
  
  • Triad: ___, ____, ____
    
    • Pancytopenia may be the 1st detected lab abnormality
  • ¼ of patients with the disorder have the classic 1st morning red urine
  • Pts often present with otherwise unexplained hemolytic anemia
  • One rare yet distinguishing factor is that pts are more prone to thrombosis
• Labs
  
  • Negative ______ test (since hemolysis is mediated by complement instead of antibodies. All cells that active complement are promptly lysed and therefore do not agglutinate in the assay.)
  • Deficiency or absence of CD55 and CD59 on RBCs and WBCs
• Dx: Flow cytometry, which detects specific _____
• Management:
  
  • Supportive with correction of anemia and tx of any thromboses
  • ____ is a drug that blocks complement-mediated lysis
  • ____ may be considered in severe cases. Bone marrow transplant (BMT) is curative and is indicated for patients with severe refractory pancytopenia or life-threatening thrombosis.

Answer 21

Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Rare disorder of hematopoietic stem cells resulting in the production of RBCs which lack a critical surface protein, rendering them vulnerable to hemolysis by the complement system.

• Rare, acquired clonal stem cell disorder involving
  
  • Glycophosphatidylinositol (GPI)-linked membrane proteins
  • Decay-accelerating factor (DAF, aka CD55), and
  • Homologous restriction factor 9HRF aka CD59 of the PIG-A gene on the X chromosome
• Deficiency of these proteins makes cells more susceptible to complement-mediated lysis.
• Pt:
  
  • Triad: Hemolytic anemia, Pancytopenia, Arterial and venous thromboses
    
    • Pancytopenia may be the 1st detected lab abnormality
  • ¼ of patients with the disorder have the classic 1st morning red urine
  • Pts often present with otherwise unexplained hemolytic anemia
  • One rare yet distinguishing factor is that pts are more prone to thrombosis
• Labs
  
  • Negative direct antibody test (since hemolysis is mediated by complement instead of antibodies. All cells that active complement are promptly lysed and therefore do not agglutinate in the assay.)
  • Deficiency or absence of CD55 and CD59 on RBCs and WBCs
• Dx: Flow cytometry, which detects specific GPI-linked proteins
• Management:
  
  • Supportive with correction of anemia and tx of any thromboses
  • Eculizumab (Soliris) is a drug that blocks complement-mediated lysis
  • Bone marrow transplant may be considered in severe cases. Bone marrow transplant (BMT) is curative and is indicated for patients with severe refractory pancytopenia or life-threatening thrombosis.

Question 22

Glucose-6-phosphate dehydrogenase (G6PD) Deficiency

• Epidemiology: ______inheritance? red cell enzymopathy
• Deficiency results in decreased amounts of reduced _____. Reduced glutathione is an antioxidant required to protect RBCs from oxidative stress. When an oxidant stress is present (eg systemic infection, sulfa drugs, dapsone, primaquine, fava beans), there is an inadequate reserve of reduced glutathione, and RBCs hemolyze.
  
  • _____ is a drug that is known to cause oxidative stress.
• G6PD disease is typically more significant in those of Mediterranean origin.
• Pt:
  
  • Symptoms of hemolytic crisis include sudden onset of pallor, fatigue, and dark urine.
  • Neonatal unconjugated hyperbilirubinemia: jaundice and anemia day of life 2-3
• Lab
  
  • Normocytic hemolytic anemia. Elevated reticulocyte count.
  • Peripheral smear shows ___ cells with ____ bodies (consist of denatured globin)
    
    • Bite cells are RBCs cells that have irregularly shaped and rigid portions of their periphery due to the breakdown of denatured hemoglobin by macrophages.
• Dx:
  
  • Except during an acute hemolytic crisis (when all the affected RBCs have hemolyzed and the remaining RBCs have normal or near-normal G6PD levels), measurement of G6PD is diagnostic.
    
    • Low _____ assay (may be artificially normal during attack, make sure to check 6-8 weeks after attack)
• Tx: Supportive, avoid stress and substances that can trigger. Packed RBC support as needed for severe, life-threatening anemia.

Answer 22

Glucose-6-phosphate dehydrogenase (G6PD) Deficiency

• Epidemiology: X-linked recessive red cell enzymopathy
• Deficiency results in decreased amounts of reduced glutathione. Reduced glutathione is an antioxidant required to protect RBCs from oxidative stress. When an oxidant stress is present (eg systemic infection, sulfa drugs, dapsone, primaquine, fava beans), there is an inadequate reserve of reduced glutathione, and RBCs hemolyze.
  
  • Nitrofurantoin is a drug that is known to cause oxidative stress.
• G6PD disease is typically more significant in those of Mediterranean origin.
• Pt:
  
  • Symptoms of hemolytic crisis include sudden onset of pallor, fatigue, and dark urine.
  • Neonatal unconjugated hyperbilirubinemia: jaundice and anemia day of life 2-3
• Lab
  
  • Normocytic hemolytic anemia. Elevated reticulocyte count.
  • Peripheral smear shows bite cells with Heinz bodies (consist of denatured globin)
    
    • Bite cells are RBCs cells that have irregularly shaped and rigid portions of their periphery due to the breakdown of denatured hemoglobin by macrophages.
• Dx:
  
  • Except during an acute hemolytic crisis (when all the affected RBCs have hemolyzed and the remaining RBCs have normal or near-normal G6PD levels), measurement of G6PD is diagnostic.
    
    • Low G6PD assay (may be artificially normal during attack, make sure to check 6-8 weeks after attack)
• Tx: Supportive, avoid stress and substances that can trigger. Packed RBC support as needed for severe, life-threatening anemia.

Question 23

Sickle Cell Disease

• Path:
  
  • HbS is caused by a point mutation in the 6th codon of the B-globin gene, which is located on the short arm of chromosome 11. _____ being encoded instead of glutamic acid.
  • Average lifespan of a RBC in HbSS is only 15-50 days (normal =120 days).
• At birth, infants have high levels of HbF, which interferes with sickling. Therefore, newborns are not anemic. Symptoms generally occur at 6 months of age, as HbF decreases.
• Tx:
  
  • ______ (Droxia, Hydrea) is the only disease modifying medication shown to reduce acute and chronic complications.
  • _____ is increasingly utilized as a curative therapy for high-risk patients.

Answer 23

Sickle Cell Disease

• Path:
  
  • HbS is caused by a point mutation in the 6th codon of the B-globin gene, which is located on the short arm of chromosome 11. Valine being encoded instead of glutamic acid.
  • Average lifespan of a RBC in HbSS is only 15-50 days (normal =120 days).
• At birth, infants have high levels of HbF, which interferes with sickling. Therefore, newborns are not anemic. Symptoms generally occur at 6 months of age, as HbF decreases.
• Tx:
  
  • Hydroxyurea (Droxia, Hydrea) is the only disease modifying medication shown to reduce acute and chronic complications.
  • BMT is increasingly utilized as a curative therapy for high-risk patients.

Question 24

Sickle Cell Disease

Risk of infection with encapsulated organisms (Strep pneumoniae, Neisseria meningitidis, H influenzae)

• Risk is high due to functional “asplenia,” which is a result of autoinfarction from repeated sickling of RBCs within the spleen
• Prescribe _____ prophylaxis to infants diagnosed with SCD by newborn screening bc it dramatically decreases invasive pneumococcal infections in children

Answer 24

Sickle Cell Disease

Risk of infection with encapsulated organisms (Strep pneumoniae, Neisseria meningitidis, H influenzae)

• Risk is high due to functional “asplenia,” which is a result of autoinfarction from repeated sickling of RBCs within the spleen
• Prescribe penicillin prophylaxis to infants diagnosed with SCD by newborn screening bc it dramatically decreases invasive pneumococcal infections in children <5 yo with SCD.
• Children with SCD require immunizations against encapsulated organisms. Pneumococcal conjugate and polysaccharide vaccines are recommended for all children with SCD.

Question 25

Sickle Cell Disease

Splenic sequestration
- Dx: ___megaly and ______ suggest the diagnosis of acute splenic sequestration.

• Tx: IV ____ and ____ decrease sequestration in the spleen and alleviate symptoms.

Answer 25

Sickle Cell Disease

Splenic sequestration
- Dx: Splenomegaly and thrombocytopenia suggest the diagnosis of acute splenic sequestration.

• Tx: IV hydration and RBC transfusion decrease sequestration in the spleen and alleviate symptoms.

Question 26

Sickle Cell Disease

Acute chest syndrome (ACS)

• Development of new pulmonary infiltrate with fever, chest pain, tachypnea, and/or hypoxia.
• It is the leading cause of death in adolescents and adults with SCD.
• Tx: Respiratory support, hydration (if necessary), and antibiotics that cover pneumococcus, Mycoplasma, and Chlamydia. ______ are administered to pts with significant hypoxia and respiratory distress and to those who do not improve with appropriate respiratory support, hydration, and antibiotic therapy.

Answer 26

Sickle Cell Disease

Acute chest syndrome (ACS)

• Development of new pulmonary infiltrate with fever, chest pain, tachypnea, and/or hypoxia.
• It is the leading cause of death in adolescents and adults with SCD.
• Tx: Respiratory support, hydration (if necessary), and antibiotics that cover pneumococcus, Mycoplasma, and Chlamydia. Exchange transfusions are administered to pts with significant hypoxia and respiratory distress and to those who do not improve with appropriate respiratory support, hydration, and antibiotic therapy.

Question 27

Sickle Cell Disease

Aplastic crisis (red cell aplasia)
- Path: Occurs bc of infection with \_\_\_\_\_. 

• Characterized by a falling hemoglobin (over 1-3 days) and reticulocytopenia. The low retic count differentiates aplastic crisis from other causes of worsening anemia.

Answer 27

Sickle Cell Disease

Aplastic crisis (red cell aplasia)
- Path: Occurs bc of infection with parvovirus B19. 

• Characterized by a falling hemoglobin (over 1-3 days) and reticulocytopenia. The low retic count differentiates aplastic crisis from other causes of worsening anemia.

Question 28

Sickle Cell Disease

Stroke

• Acute tx:
  
  • Emergent ________, which should be done even before an MRI in pts with sickle cell who are diagnosed with a stroke on the basis of the physical examination.
  • In addition, pts with SCD who have had a stroke require chronic RBC transfusion to keep the HbS

Answer 28

Sickle Cell Disease

Stroke

• Acute tx:
  
  • Emergent exchange transfusion, which should be done even before an MRI in pts with sickle cell who are diagnosed with a stroke on the basis of the physical examination.
  • In addition, pts with SCD who have had a stroke require chronic RBC transfusion to keep the HbS <30% to reduce the risk of recurrence.
• Screening:
  
  • Use transcranial Doppler ultrasound to screen children with HbSS and HbSB0, starting at 2yo. To prevent strokes, chronic RBC transfusions are recommended for children with abnormally high TCD velocities.

Question 29

Sickle Cell Disease

Moyamoya disease

• Occurs in some pts with SCD and is the collateral formation of vessels due to vascular occlusion. The vessels on angiography appear to be a cluster of vessels with a smoky appearance
• Risk factor for stroke

Answer 29

Sickle Cell Disease

Moyamoya disease

• Occurs in some pts with SCD and is the collateral formation of vessels due to vascular occlusion. The vessels on angiography appear to be a cluster of vessels with a smoky appearance
• Risk factor for stroke

Question 30

Sickle Cell Disease

Priapism

• Prolonged, painful erection.
• Management include hydration and pain control. In many cases, aspiration of the corpora cavernosa and irrigation with a dilute solution of epinephrine rapidly alleviates the condition.

Answer 30

Sickle Cell Disease

Priapism

• Prolonged, painful erection.
• Management include hydration and pain control. In many cases, aspiration of the corpora cavernosa and irrigation with a dilute solution of epinephrine rapidly alleviates the condition.

Question 31

Sickle cell trait (HbAS)

• Pt
  
  • Unusual to have any sickle cell-related complications, except in cases of extreme physical exertion or low oxygen tension (eg unpressurized aircraft, high altitude).
  • ______ (inability to concentrate urine) and ____ with gross hematuria are the most common complications.

Answer 31

Sickle cell trait (HbAS)

• Pt
  
  • Unusual to have any sickle cell-related complications, except in cases of extreme physical exertion or low oxygen tension (eg unpressurized aircraft, high altitude).
  • Hyposthenuria (inability to concentrate urine) and renal papillary necrosis with gross hematuria are the most common complications.

Question 32

Hemoglobin SC disease (HbSC)
- HbC occurs bc of the substitution of ____ for the glutamic acid residue in the 6th position of the B-globin chain.

• Pt
  
  • Usually less anemia and have less severe hemolysis than those with HbSS.
  • ______ remains throughout adolescence and adulthood.
  • Adolescents are at risk for ___ disease and ___ of the hips.
• Peripheral smears show microcytosis and target cells but not irreversibly sickled cells.

Answer 32

Hemoglobin SC disease (HbSC)
- HbC occurs bc of the substitution of lysine for the glutamic acid residue in the 6th position of the B-globin chain.

• Pt
  
  • Usually less anemia and have less severe hemolysis than those with HbSS.
  • Splenomegaly remains throughout adolescence and adulthood.
  • Adolescents are at risk for retinal disease and avascular necrosis of the hips.
• Peripheral smears show microcytosis and target cells but not irreversibly sickled cells.

Question 33

Hemoglobin C disease (HbCC)

• Pt: Mild hemolytic anemia and splenomegaly but do not have vaso-occlusive problems.
• RBCs are microcytic with large number of target cells on peripheral smear.

Answer 33

Hemoglobin C disease (HbCC)

• Pt: Mild hemolytic anemia and splenomegaly but do not have vaso-occlusive problems.
• RBCs are microcytic with large number of target cells on peripheral smear.

Question 34

Hemoglobin E disease (HbEE)

- Pt: Mild hemolytic anemia with significant microcytosis, hypochromia, and target cells.

Answer 34

Hemoglobin E disease (HbEE)

- Pt: Mild hemolytic anemia with significant microcytosis, hypochromia, and target cells.

Question 35

Autoimmune hemolytic anemia (AIHA; warm, cold, or paroxysmal)

• Labs: Severe, normocytic anemia with a marked _____, suggesting destructive process (rather than RBC production failure)
• Management - it is a true hematologic emergency
  • Emergent ____ of a “least-incompatible” unit of packed RBCs
  • Rapid initiation of immune suppression with ____
  • Other immunosuppressive agents, including rituximab, are used when systemic corticosteroids fail.

Answer 35

Autoimmune hemolytic anemia (AIHA; warm, cold, or paroxysmal)

• Labs: Severe, normocytic anemia with a marked reticulocytosis, suggesting destructive process (rather than RBC production failure)
• Management - it is a true hematologic emergency
  • Emergent transfusion of a “least-incompatible” unit of packed RBCs
  • Rapid initiation of immune suppression with corticosteroids
  • Other immunosuppressive agents, including rituximab, are used when systemic corticosteroids fail.

Question 36

1) Warm AIHA
- IgG antibodies specific for the Rh group of RBC antigens can bind to these antigens at body temperature.

• IgG-coated RBCs and spherocytes are sequestered by the spleen.
• Positive _____ test findings for _____ is diagnostic of a warm AIHA
  • The direct Coombs test reveals what components (IgG or C3) are “directly” attached to the patient’s RBCs, suggesting an autoimmune reaction.
  • The indirect Coombs test reveals antibodies in the pt’s serum that have the potential to bind to RBCs.

Answer 36

1) Warm AIHA
- IgG antibodies specific for the Rh group of RBC antigens can bind to these antigens at body temperature.

• IgG-coated RBCs and spherocytes are sequestered by the spleen.
• Positive direct antibody test findings for IgG is diagnostic of a warm AIHA
  • The direct Coombs test reveals what components (IgG or C3) are “directly” attached to the patient’s RBCs, suggesting an autoimmune reaction.
  • The indirect Coombs test reveals antibodies in the pt’s serum that have the potential to bind to RBCs.

Question 37

2) Cold agglutinin disease
- Can occur with Mycoplasma and Epstien-Barr virus. IgM-RBC complexes lyse complement and cause intravascular hemolysis.
- ____ disease is Coombs ____
- Positive Coombs test for complement ___ only and negative with IgG

Answer 37

2) Cold agglutinin disease
- Can occur with Mycoplasma and Epstien-Barr virus. IgM-RBC complexes lyse complement and cause intravascular hemolysis.
- IgM disease is Coombs negative
- Positive Coombs test for complement C3d only and negative with IgG

Question 38

3) Paroxysmal cold hemoglobinuria
- Caused by cold-reacting IgG (Donath-Landsteiner antibody). This antibody binds at cold temperatures and causes RBC lysis at warm temperatures. PCH is common after viral illness, and tx is supportive.

• Positive direct antibody test for complement but negative for IgG
• Tx: Keep the pt warm and use a blood warmer for transfusions. Consider plasmapheresis for severe disease. Steroids are less helpful than with warm AIHA.

Answer 38

3) Paroxysmal cold hemoglobinuria
- Caused by cold-reacting IgG (Donath-Landsteiner antibody). This antibody binds at cold temperatures and causes RBC lysis at warm temperatures. PCH is common after viral illness, and tx is supportive.

• Positive direct antibody test for complement but negative for IgG
• Tx: Keep the pt warm and use a blood warmer for transfusions. Consider plasmapheresis for severe disease. Steroids are less helpful than with warm AIHA.

Question 39

NEUTROPENIA
Very severe: less than ___ neutrophils/uL
Severe neutropenia = ANC less than __ cells/uL
Moderate neutropenia = ___-__ cells/uL
Mild neutropenia = __-___ cells/uL

Answer 39

NEUTROPENIA
Very severe: <200 neutrophils/uL
Severe neutropenia = ANC <500 cells/uL
Moderate neutropenia = 500-1000 cells/uL
Mild neutropenia = 1000-1500 cells/uL

Question 40

Cyclic Neutropenia

• In ⅓ of patients, the disorder is inherited in an ___inheritance? pattern.
• Neutropenia occurs at regular interval every ___ +/- 3 days.
• Mutations involve the ELANE/ELA2 gene.
• Pt:
  
  • During 3-5 day periods of neutropenia, which usually have an ANC <200 cells/uL, pt usually presents with fever, aphthous stomatitis, cervical lymphadenitis, and/or rectal and vaginal ulcers.
• Management: ___ and antibiotics for infections. Oral hygiene is important.

Answer 40

Cyclic Neutropenia

• In ⅓ of patients, the disorder is inherited in an AD pattern.
• Neutropenia occurs at regular interval every 21 +/- 3 days.
• Mutations involve the ELANE/ELA2 gene.
• Pt:
  
  • During 3-5 day periods of neutropenia, which usually have an ANC <200 cells/uL, pt usually presents with fever, aphthous stomatitis, cervical lymphadenitis, and/or rectal and vaginal ulcers.
• Management: G-CSF and antibiotics for infections. Oral hygiene is important.

Question 41

Severe Congenital Neutropenia (___ Syndrome)

• Rare __inheritance? disorder.
• Pt: ANC is typically <200 cells/uL.
• Management: ____ (often at high dose). ___ is curative.

Answer 41

Severe Congenital Neutropenia (Kostmann Syndrome)

• Rare AR disorder.
• Pt: ANC is typically <200 cells/uL.
• Management: G-CSF (often at high dose). BMT is curative.

Question 42

Severe Chronic Neutropenia

• AD neutropenia
• Pt: Neutropenia is often the only presenting signs.
• Tx: G-CSF

Answer 42

Severe Chronic Neutropenia

• AD neutropenia
• Pt: Neutropenia is often the only presenting signs.
• Tx: G-CSF

Question 43

Shwachman-Diamond Syndrome
- ____inheritance? disorder resulting from mutations in the SBDS gene.

• 2nd most common cause of _____ in children (after CF)
• Pt: Characterized by multisystem involvement.
  
  • Children present with features similar to those of children with ______, including failure to thrive, steatorrhea due to pancreatic exocrine insufficiency, and recurrent infections.
  • Unique features include neutropenia and metaphyseal dysostoses.
  • Exocrine pancreatic insufficiency (EPI): Foul-smelling diarrhea, steatorrhea, sx of fat malabsorption. Fecal pancreatic _____ will be low (indicative of EPI)
  • Hematologic abnormalities/Bone marrow dysfunction: Intermittent or persistent ______ is universal finding. Anemia and thrombocytopenia are commonly present as well
  • Short stature is a consistent feature for more than half of individuals
  • Skeletal abnormalities including ______, thoracic dystrophy with rib cage abnormalities, and costochondral thickening
• Diagnostic:
  
  • It is recommended that pts suspected of having SDS undergo ______ analysis for SBDS, DNAJC21, and EFL1 genes, which are definitive causes of SDS.
  • Sweat test is _____
• Tx:
  
  • Supportive care with _____ and, depending on frequency and severity of infections, ____ administration of BMT.
  • _____ can cure the hematologic abnormalities of SDS but does not improve the remainder of the disease phenotype
  • Pts are predisposed to myelodysplastic syndrome and _____

Answer 43

Shwachman-Diamond Syndrome
- AR disorder resulting from mutations in the SBDS gene.

• 2nd most common cause of exocrine pancreatic insufficiency in children (after CF)
• Pt: Characterized by multisystem involvement.
  
  • Children present with features similar to those of children with cystic fibrosis, including failure to thrive, steatorrhea due to pancreatic exocrine insufficiency, and recurrent infections.
  • Unique features include neutropenia and metaphyseal dysostoses.
  • Exocrine pancreatic insufficiency (EPI): Foul-smelling diarrhea, steatorrhea, sx of fat malabsorption. Fecal pancreatic elastase will be low (indicative of EPI)
  • Hematologic abnormalities/Bone marrow dysfunction: Intermittent or persistent Neutropenia is universal finding. Anemia and thrombocytopenia are commonly present as well
  • Short stature is a consistent feature for more than half of individuals
  • Skeletal abnormalities including metaphyseal dysostosis, thoracic dystrophy with rib cage abnormalities, and costochondral thickening
• Diagnostic:
  
  • It is recommended that pts suspected of having SDS undergo genetic mutational analysis for SBDS, DNAJC21, and EFL1 genes, which are definitive causes of SDS.
  • Sweat test is normal
• Tx:
  
  • Supportive care with pancreatic enzyme replacement (PERT) and, depending on frequency and severity of infections, G-CSF administration of BMT.
  • Hematopoietic stem cell transplant can cure the hematologic abnormalities of SDS but does not improve the remainder of the disease phenotype
  • Pts are predisposed to myelodysplastic syndrome and AML/leukemia.

Question 44

Cartilage-Hair Hypoplasia
- ____inheritance? form of short-limb dysostosis.

• Pt:
  
  • Characterized by sparse or fine hair.
  • Pts are at high risk for autoimmune disease
• Tx: ___ is the TOC for those with recurrent severe infections.

Answer 44

Cartilage-Hair Hypoplasia
- Autosomal recessive form of short-limb dysostosis.

• Pt:
  
  • Characterized by sparse or fine hair.
  • Pts are at high risk for autoimmune disease
• Tx: BMT is the TOC for those with recurrent severe infections.

Question 45

Neonatal Isoimmune Neutropenia
- Self-limited disease that occurs in 1/1000 newborns

• Path:
  
  • Similar to Rh disease except maternal antibodies result from maternal sensitization to neutrophil antigens that are shared by the fetus and the father but are absent from the mother’s neutrophils.
• Infant’s neutrophil count recovers in ____ weeks.
• Any infection requires quick, appropriate antibiotic therapy. Subsequent siblings are at risk for the same condition.

Answer 45

Neonatal Isoimmune Neutropenia
- Self-limited disease that occurs in 1/1000 newborns

• Path:
  
  • Similar to Rh disease except maternal antibodies result from maternal sensitization to neutrophil antigens that are shared by the fetus and the father but are absent from the mother’s neutrophils.
• Infant’s neutrophil count recovers in 6-12 weeks.
• Any infection requires quick, appropriate antibiotic therapy. Subsequent siblings are at risk for the same condition.

Question 46

Chronic Benign Neutropenia / Autoimmune neutropenia (AIN)
- The most common cause of neutropenia in “healthy” children and must be differentiated from more serious forms of neutropenia. It can be AD or sporadic.

• Path: Autoantibodies to granulocytes
• Pt:
  
  • Characterized by persistently low ANC <1000 cells/uL
  • Median age of diagnosis of 8-11 months and typically lasts about 2 years.
• Dx: ______ antibody usually positive.
• Tx:_____

Answer 46

Chronic Benign Neutropenia / Autoimmune neutropenia (AIN)
- The most common cause of neutropenia in “healthy” children and must be differentiated from more serious forms of neutropenia. It can be AD or sporadic.

• Path: Autoantibodies to granulocytes
• Pt:
  
  • Characterized by persistently low ANC <1000 cells/uL
  • Median age of diagnosis of 8-11 months and typically lasts about 2 years.
• Dx: Antineutrophil antibody usually positive.
• Tx: Disease is mild and usually does not require treatment. G-CSF is given for severe infections.

Question 47

Virus-Induced Immune-Related Neutropenia
- Most common etiology of neutropenia in children is viral infection resulting in transient bone marrow suppression.

• Tx: Viral-induced neutropenia is very common and does not require specific treatment

Answer 47

Virus-Induced Immune-Related Neutropenia
- Most common etiology of neutropenia in children is viral infection resulting in transient bone marrow suppression.

• Tx: Viral-induced neutropenia is very common and does not require specific treatment

Question 48

Myeloperoxidase deficiency
- AR disorder

• The absence of myeloperoxidase from azurophilic granules in neutrophils is the most common neutrophil disorder.
• Pt: Recurrent mild infections but usually is completely asymptomatic due to variable expression of the defect.
• Dx: Confirmed by finding the absence of neutrophil myeloperoxidase.

Answer 48

Myeloperoxidase deficiency
- AR disorder

• The absence of myeloperoxidase from azurophilic granules in neutrophils is the most common neutrophil disorder.
• Pt: Recurrent mild infections but usually is completely asymptomatic due to variable expression of the defect.
• Dx: Confirmed by finding the absence of neutrophil myeloperoxidase.

Question 49

Dyskeratosis congenita (aka Zinsser-Cole-Engman syndrome):
- Congenital \_\_\_ syndrome

• ___, ___, and ____
  
  • Disease initially mainly affects the skin, but a major consequence is progressive bone marrow failure, which occurs in over 80% of patients. The abnormal skin pigmentation includes changes in cutaneous pigmentation and premature graying.
  • Pts can have continuous lacrimation due to atresia of the lacrimal ducts as well.

Answer 49

Dyskeratosis congenita (aka Zinsser-Cole-Engman syndrome):
- Congenital neutropenia syndrome

• Abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa
  
  • Disease initially mainly affects the skin, but a major consequence is progressive bone marrow failure, which occurs in over 80% of patients. The abnormal skin pigmentation includes changes in cutaneous pigmentation and premature graying.
  • Pts can have continuous lacrimation due to atresia of the lacrimal ducts as well.

Question 50

Loffler syndrome

• ___, ___, and ___.
• Tx: Corticosteroids, vinca alkaloids, hydroxyurea, and if necessary BMT.

Answer 50

Loffler syndrome

• Hypereosinophilia, endocardial fibrosis, and mural thrombi.
• Tx: Corticosteroids, vinca alkaloids, hydroxyurea, and if necessary BMT.

Question 51

4 inherited platelet disorders cause abnormal platelet morphology:

1) Bernard-Soulier syndrome (___ platelets)
2) Wiskott-Aldrich syndrome (___ platelets)
3) MYH9-related disorders, including May-Hegglin anomaly (___ platelets; white cell inclusions called Dohle bodies)
4) Gray platelet syndrome (pale platelets)

Answer 51

4 inherited platelet disorders cause abnormal platelet morphology:

1) Bernard-Soulier syndrome (large platelets)
2) Wiskott-Aldrich syndrome (small platelets)
3) MYH9-related disorders, including May-Hegglin anomaly (large platelets; white cell inclusions called Dohle bodies)
4) Gray platelet syndrome (pale platelets)

Question 52

Wiskott-Aldrich syndrome
- Extremely rare X-linked disorder that presents with thrombocytopenia with very ___ platelets (in contrast to ITP in which platelets are large), eczema, and an immune deficiency

Answer 52

Wiskott-Aldrich syndrome
- Extremely rare X-linked disorder that presents with thrombocytopenia with very small platelets (in contrast to ITP in which platelets are large), eczema, and an immune deficiency

Question 53

Myosin heavy chain 9 (MYH9) disorders

• AD mutations
• Pt: Bleeding tendency and renal failure, sensorineural hearing loss, and/or cataracts.
• Characteristics on the blood smear include ____ and ___ bodies in WBCs.

Answer 53

Myosin heavy chain 9 (MYH9) disorders

• AD mutations
• Pt: Bleeding tendency and renal failure, sensorineural hearing loss, and/or cataracts.
• Characteristics on the blood smear include macrothrombocytes and Dohle bodies in WBCs.

Question 54

Thrombocytopenia with absent radius (TAR) syndrome
- ____inheritance? disoder

• Pt:
  
  • Thrombocytopenia is severe
    
    • Thrombocytopenia in the 1st year can be life-threatening, but severe bleeding can be prevented through the use of prophylactic transfusions of single-donor platelets
  • Bilateral absent radii with shortened forearms with flexion at the elbow, resulting in appearance of clubbed arms but with sparing of the thumb.
    
    • Absent radii are a hallmark that distinguishes TAR from other congenital thrombocytopenia
    • The ______ helps to distinguish this disorder from Fanconi anemia or diamond-blackfin or Trisomy 18, in which thumbs are abnormal
  • Other defects of the upper extremities, cardiac defects (like ToF), a persistently elevated WBC count, and anemia
    
    • ______disease (most often ASD, isolated VSD, or ToF) occurs in 30-35% of patients with TAR syndrome.
• Tx: If necessary for clinically significant bleeding, is best accomplished with platelet transfusion

Answer 54

Thrombocytopenia with absent radius (TAR) syndrome
- AR disoder

• Pt:
  
  • Thrombocytopenia is severe
    
    • Thrombocytopenia in the 1st year can be life-threatening, but severe bleeding can be prevented through the use of prophylactic transfusions of single-donor platelets
  • Bilateral absent radii with shortened forearms with flexion at the elbow, resulting in appearance of clubbed arms but with sparing of the thumb.
    
    • Absent radii are a hallmark that distinguishes TAR from other congenital thrombocytopenia
    • The NORMAL thumb helps to distinguish this disorder from Fanconi anemia or diamond-blackfin or Trisomy 18, in which thumbs are abnormal
  • Other defects of the upper extremities, cardiac defects (like ToF), a persistently elevated WBC count, and anemia
    
    • Congenital heart disease (most often ASD, isolated VSD, or ToF) occurs in 30-35% of patients with TAR syndrome.
• Tx: If necessary for clinically significant bleeding, is best accomplished with platelet transfusion

Question 55

Pseudothrombocytopenia
- If pt has an unexpected thrombocytopenia, then review the blood smear. In some cases, platelet clumping results in a factitiously low platelet count on the automated reader.

Answer 55

Pseudothrombocytopenia
- If pt has an unexpected thrombocytopenia, then review the blood smear. In some cases, platelet clumping results in a factitiously low platelet count on the automated reader.

Question 56

Immune (Idiopathic) thrombocytopenic Purpura (ITP)
- Path: Type _____ hypersensitivity reaction: Autoimmune platelet-specific antibodies against platelet membrane glycoproteins result in destruction of platelets in spleen

• Pt: 1st sign is usually acute petechiae and ecchymosis most common, mucocutaneous bleeding (epistaxis, hematuria, GI bleeding). Antecedent viral infection (in preceding 1-6 weeks) or immunization is found in a large percentage of those affected.
  
  • 1. Thrombocytopenia (platelet count <150,000)
       - Platelet counts normalize in nearly 80% of children with ITP within 12mo of diagnosis
  • 2. A classic purpuric rash
  • 3. Normal bone marrow proven by biopsy
  • 4. The absence of signs of other causes of thrombocytopenia
• Work up: Peripheral smear. Peripheral smear with ____ platelets (but not as large as RBCs; vs giant platelets indicated inherited platelet disorder Bernard-Soulier vs small platelets in Wiskott Aldrich)
  
  • Bottom line: The bone marrow is cranking out the platelets as fast as it can, but the destructive process is eliminating them just as fast.
• Dx: Diagnosis of exclusion.
• Tx:
  
  • ___ and platelet count >___/uL: _____
  • Bleeding (petechia does not count) or platelet count less than __
    
    • 1) ___
    • 2) ____
    • 3) ___
  • If ITP becomes chronic, splenectomy, immunosuppressive agents, or thrombopoietin mimetics are treatment options.

Answer 56

Immune (Idiopathic) thrombocytopenic Purpura (ITP)
- Path: Type II hypersensitivity reaction: Autoimmune platelet-specific antibodies against platelet membrane glycoproteins result in destruction of platelets in spleen

• Pt: 1st sign is usually acute petechiae and ecchymosis most common, mucocutaneous bleeding (epistaxis, hematuria, GI bleeding). Antecedent viral infection (in preceding 1-6 weeks) or immunization is found in a large percentage of those affected.
  
  • 1. Thrombocytopenia (platelet count <150,000)
       - Platelet counts normalize in nearly 80% of children with ITP within 12mo of diagnosis
  • 2. A classic purpuric rash
  • 3. Normal bone marrow proven by biopsy
  • 4. The absence of signs of other causes of thrombocytopenia
• Work up: Peripheral smear. Peripheral smear with megathrombocytes / megakaryocytes (large platelets but not as large as RBCs; vs giant platelets indicated inherited platelet disorder Bernard-Soulier vs small platelets in Wiskott Aldrich)
  
  • Bottom line: The bone marrow is cranking out the platelets as fast as it can, but the destructive process is eliminating them just as fast.
• Dx: Diagnosis of exclusion.
• Tx:
  
  • No bleeding (Skin manifestations only) and platelet count >10,000/uL: observe and monitor platelet count over time
  • Bleeding (petechia does not count) or platelet count <10,000/uL
    
    • 1) IVIG
    • 2) Glucocorticoids
    • 3) Anti-Rh(D) immunoglobulin
  • If ITP becomes chronic, splenectomy, immunosuppressive agents, or thrombopoietin mimetics are treatment options.

Question 57

Evans syndrome

- ____ is found in association with ____.

Answer 57

Evans syndrome

- ITP is found in association with AIHA.

Question 58

Thrombotic Thrombocytopenic Purpura (TTP)
- Antibodies against ____, a protease that breaks down ultra-large von Willebrand factor (vWF) multimers.

• Pt: Anemia, thrombocytopenia
• Lab findings: Elevated LDH, hyperbilirubinemia, and azotemia.
• Dx based on classic pentad:
  
  • 1) ____ (usually profound, little/no bleeding)
  • 2) ____ (may be mild, few schistocytes)
  • 3) ____ (typically fluctuating)
  • 4) ___ (mild azotemia, rarely overt renal failure)
  • 5) ____ (in about 80%)
• Condition is life-threatening bc of the risk of thrombosis in small arteries supplying the heart and CNS
• Tx: Emergent plasmapheresis and corticosteroids

Answer 58

Thrombotic Thrombocytopenic Purpura (TTP)
- Antibodies against ADAMTS13, a protease that breaks down ultra-large von Willebrand factor (vWF) multimers.

• Pt: Anemia, thrombocytopenia
• Lab findings: Elevated LDH, hyperbilirubinemia, and azotemia.
• Dx based on classic pentad:
  
  • 1) Thrombocytopenia (usually profound, little/no bleeding)
  • 2) Microangiopathic hemolytic anemia (may be mild, few schistocytes)
  • 3) Neurologic dysfunction (typically fluctuating)
  • 4) Renal dysfunction (mild azotemia, rarely overt renal failure)
  • 5) Fever (in about 80%)
• Condition is life-threatening bc of the risk of thrombosis in small arteries supplying the heart and CNS
• Tx: Emergent plasmapheresis and corticosteroids

Question 59

Neonatal autoimmune thrombocytopenia due to Maternal idiopathic thrombocytopenic purpura or maternal systemic lupus erythematosus
- Path: Maternal IgG antiplatelet antibodies cross the placenta and result in increased destruction of fetal platelets

• Tx:
  
  • Administer _____.
    
    • IVIG is given during the 3rd trimester to mothers who have ITP, esp if there is maternal bleeding.
    • IVIG is also given to the newborn with a platelet count <20,000.
  • If the newborn also has intracranial hemorrhage (<1% risk), give steroids and platelet transfusions as well.

Answer 59

Neonatal autoimmune thrombocytopenia due to Maternal idiopathic thrombocytopenic purpura or maternal systemic lupus erythematosus
- Path: Maternal IgG antiplatelet antibodies cross the placenta and result in increased destruction of fetal platelets

• Tx:
  
  • Administer IVIG.
    
    • IVIG is given during the 3rd trimester to mothers who have ITP, esp if there is maternal bleeding.
    • IVIG is also given to the newborn with a platelet count <20,000.
  • If the newborn also has intracranial hemorrhage (<1% risk), give steroids and platelet transfusions as well.

Question 60

Neonatal alloimmune thrombocytopenia (NAIT)
- Path: Maternal antibody production to an antigen expressed on fetal platelets that is not expressed on maternal platelets. Fetal platelets express a paternally inherited antigen

• Tx: ____

Answer 60

Neonatal alloimmune thrombocytopenia (NAIT)
- Path: Maternal antibody production to an antigen expressed on fetal platelets that is not expressed on maternal platelets. Fetal platelets express a paternally inherited antigen

• Tx: Self-limiting, requiring only temporary support.

Question 61

Kasabach-Merritt syndrome
- Destruction of platelets in certain vascular tumors of the skin, liver, or spleen. These tumors include tufted angiomas and kaposiform hemangioendotheliomas.

• Pt:
  
  • Usually presents early in life.
  • Clinical syndrome characterized by _____ and severe _____.
• Dx: Diagnostic criteria include:
  
  • 1. Documented hemangioma of the skin or internal organs
  • 2. Thrombocytopenia and consumptive coagulopathy
  • 3. Other causes for the abnormalities have been excluded, such as hypersplenism or idiopathic thrombocytopenic purpura
• Management:
  
  • Medications (steroids, vincristine, propranolol, and interferon-alpha) and supportive care.

Answer 61

Kasabach-Merritt syndrome
- Destruction of platelets in certain vascular tumors of the skin, liver, or spleen. These tumors include tufted angiomas and kaposiform hemangioendotheliomas.

• Pt:
  
  • Usually presents early in life.
  • Clinical syndrome characterized by giant hemangiomas and severe thrombocytopenia.
• Dx: Diagnostic criteria include:
  
  • 1. Documented hemangioma of the skin or internal organs
  • 2. Thrombocytopenia and consumptive coagulopathy
  • 3. Other causes for the abnormalities have been excluded, such as hypersplenism or idiopathic thrombocytopenic purpura
• Management:
  
  • Medications (steroids, vincristine, propranolol, and interferon-alpha) and supportive care.

Question 62

Von Willebrand disease
- Usually _____inheritance?.

• Path: Decreased function or absence of von Willebrand factor due to mutations.
  
  • Von Willebrand factor is a linking factor that allows functional platelets to bind to exposed subendothelium / connective tissue proteins/collagen/fibrin to form a clot.
• Pt: ______ is a frequent 1st manifestation of vWD
• Labs:
  
  • Normal PT, normal/prolonged ___. Normal platelet count (except mild thrombocytopenia in type 2b vwd)
  • ____ is usually normal but is prolonged in severe subtypes (due to decreased Factor 8), whereas PT is always normal.
• Initial screening tests: Decreased (less than ___ IU/dL) Plasma _____(vwF:Ag, measures total amount of vwf protein present), decreased (less than __ IU/dL) Plasma _____ (Ristocetin cofactor activity (vwf:RCo) and vwf collagen binding (vwf:CB), decreased/normal factor 8 activity.
• Classification determined by Ristocetin:vwF antigen ratio
  
  • Type 1 (ratio >0.5-0.7):
    
    • AD, most common
    • Partial _____ deficiency (due to a decrease in the amount of vWF)
  • Type 2 (4 subtypes: 2A, 2B, 2M, 2N): Results from _____ problem
    
    • Type 2A - decreased binding of vWF to platelets
    • Type 2B - increased binding of vWF to platelets, but it is a bleeding disorder.
    • Type 2M - decreased binding of vWF to platelets
    • Type 2N - decreased binding of vWF to Factor 8
  • Type 3:
    
    • AR
    • Total deficiency of vWF with undetectable vWF levels and low Factor 8 levels
    • Very serious bleeding phenotype
• Dx: A family history of either VWD or bleeding symptoms is required for the diagnosis of VWD.
• Diagnosis of Type 1 vWD is confirmed with the combination of all of the following:
  
  • Decreased vWF antigen
  • Proportional decrease in Factor 8 activity (vWF protein is a cofactor of Factor 8)
  • Proportional decrease in biologic activity, as measured by the ristocetin cofactor (rCoF) assay)
• Tx:
  
  • ____ causes a release of stored vWF and Factor 8 from endothelial cells. DDAVP may be used to treat and prevent bleeding in most patients with Type 1 vWD and some patients with Type 2A.
    
    • Trial of DDAVP (Stimate) by looking at if Ristocetin cofactor and Factor 8 increase in response to DDAVP.
  • Patients with Type 1 and Type 2A who do not respond to DDAVP or have major bleeding or surgery are treated with vWF/Factor 8 concentrates.
  • For type 2B, 2N, type 3 are required to be treated with _______.

Answer 62

Von Willebrand disease
- Usually autosomal dominant.

• Path: Decreased function or absence of von Willebrand factor due to mutations.
  
  • Von Willebrand factor is a linking factor that allows functional platelets to bind to exposed subendothelium / connective tissue proteins/collagen/fibrin to form a clot.
• Pt: Menorrhagia is a frequent 1st manifestation of vWD
• Labs:
  
  • Normal PT, normal/prolonged PTT. Normal platelet count (except mild thrombocytopenia in type 2b vwd)
  • PTT is usually normal but is prolonged in severe subtypes (due to decreased Factor 8), whereas PT is always normal.
• Initial screening tests: Decreased (<30 IU/dL) Plasma von willebrand factor antigen (vwF:Ag, measures total amount of vwf protein present), decreased (<30 IU/dL) Plasma vwf activity (Ristocetin cofactor activity (vwf:RCo) and vwf collagen binding (vwf:CB), decreased/normal factor 8 activity.
• Classification determined by Ristocetin:vwF antigen ratio
  
  • Type 1 (ratio >0.5-0.7):
    
    • AD, most common
    • Partial quantitative deficiency (due to a decrease in the amount of vWF)
  • Type 2 (4 subtypes: 2A, 2B, 2M, 2N): Results from qualitative problem
    
    • Type 2A - decreased binding of vWF to platelets
    • Type 2B - increased binding of vWF to platelets, but it is a bleeding disorder.
    • Type 2M - decreased binding of vWF to platelets
    • Type 2N - decreased binding of vWF to Factor 8
  • Type 3:
    
    • AR
    • Total deficiency of vWF with undetectable vWF levels and low Factor 8 levels
    • Very serious bleeding phenotype
• Dx: A family history of either VWD or bleeding symptoms is required for the diagnosis of VWD.
• Diagnosis of Type 1 vWD is confirmed with the combination of all of the following:
  
  • Decreased vWF antigen
  • Proportional decrease in Factor 8 activity (vWF protein is a cofactor of Factor 8)
  • Proportional decrease in biologic activity, as measured by the ristocetin cofactor (rCoF) assay)
• Tx:
  
  • DDAVP causes a release of stored vWF and Factor 8 from endothelial cells. DDAVP may be used to treat and prevent bleeding in most patients with Type 1 vWD and some patients with Type 2A.
    
    • Trial of DDAVP (Stimate) by looking at if Ristocetin cofactor and Factor 8 increase in response to DDAVP.
  • Patients with Type 1 and Type 2A who do not respond to DDAVP or have major bleeding or surgery are treated with vWF/Factor 8 concentrates.
  • For type 2B, 2N, type 3 are required to be treated with vWF/Factor 8.

Question 63

Bernard-Soulier syndrome
- Disorder of platelet function.

• ___inheritance? disorder with mild thrombocytopenia and giant, abnormal platelets that do not aggregate in response to ____ but do aggregate in response to ___, ___, or ____.
• Path: Abnormality is a deficiency of platelet ____ in the platelet membrane, which results in the inability of the platelets to aggregate properly.
• Normal PT, PTT, and platelet count.
• Dx: Reduced platelet aggregation response to _____

Answer 63

Bernard-Soulier syndrome
- Disorder of platelet function.

• AR disorder with mild thrombocytopenia and giant, abnormal platelets that do not aggregate in response to ristocetin but do aggregate in response to ADP, epinephrine, or collagen.
• Path: Abnormality is a deficiency of platelet glycoprotein 1b (GP1b) in the platelet membrane, which results in the inability of the platelets to aggregate properly.
• Normal PT, PTT, and platelet count.
• Dx: Reduced platelet aggregation response to ristocetin

Question 64

Glanzmann Thrombasthenia
- Deficiency in the _____complex. Pts are unable to aggregate platelets.

• _____inheritance? disorder with normal platelet counts and poor platelet aggregation in response to ADP, epinephrine, and collagen.
• Path: Due to an abnormality in the genes encoding the alphaIIb-beta3 integrin fibrinogen receptor. This results in the inability of platelets to bind fibrinogen and aggregate.
• Pt: Severe mucocutaneous bleeding starting in infancy
• _____ aggregation test helps to diagnose Glanzmann thrombasthenia.

Answer 64

Glanzmann Thrombasthenia
- Deficiency in the GP2b/3a complex. Pts are unable to aggregate platelets.

• Autosomal recessive disorder with normal platelet counts and poor platelet aggregation in response to ADP, epinephrine, and collagen.
• Path: Due to an abnormality in the genes encoding the alphaIIb-beta3 integrin fibrinogen receptor. This results in the inability of platelets to bind fibrinogen and aggregate.
• Pt: Severe mucocutaneous bleeding starting in infancy
• Epinephrine aggregation test helps to diagnose Glanzmann thrombasthenia.

Question 65

Drug-induced platelet dysfunction

• Aspirin irreversibly inactivates platelet cyclooxygenase, which alters platelet function for the entire lifespan of the platelet.
• NSAIDs reversibly inhibit platelet function.

Answer 65

Drug-induced platelet dysfunction

• Aspirin irreversibly inactivates platelet cyclooxygenase, which alters platelet function for the entire lifespan of the platelet.
• NSAIDs reversibly inhibit platelet function.

Question 66

Platelets are an acute phase reactant.
Thrombocytosis in children is usually due to a reaction to some secondary cause: acute or chronic infection, iron deficiency anemia, inflammatory disorders, or acute blood loss. It is a benign condition and does not require specific therapy.

Answer 66

Platelets are an acute phase reactant.
Thrombocytosis in children is usually due to a reaction to some secondary cause: acute or chronic infection, iron deficiency anemia, inflammatory disorders, or acute blood loss. It is a benign condition and does not require specific therapy.

Question 67

Essential thrombocythemia
- Rare myeloproliferative disorder with persistent platelet counts >1,000,000

• Thrombosis and bleeding commonly occur bc platelet function is abnormal
• Pts who are not bleeding are treated with a platelet aggregation inhibitor, such as aspirin.

Answer 67

Essential thrombocythemia
- Rare myeloproliferative disorder with persistent platelet counts >1,000,000

• Thrombosis and bleeding commonly occur bc platelet function is abnormal
• Pts who are not bleeding are treated with a platelet aggregation inhibitor, such as aspirin.

Question 68

PANCYTOPENIA
Decrease in more than 1 blood cell line (leukocytes, erythrocytes, or thrombocytes)
- Pancytopenia with reticulocytopenia raises concern about bone marrow failure or leukemia.
- Any time a child exhibits multiple cytopenias, a bone marrow evaluation should be considered.

Answer 68

PANCYTOPENIA
Decrease in more than 1 blood cell line (leukocytes, erythrocytes, or thrombocytes)
- Pancytopenia with reticulocytopenia raises concern about bone marrow failure or leukemia.
- Any time a child exhibits multiple cytopenias, a bone marrow evaluation should be considered.

Question 69

Aplastic Anemia
- Aplastic anemia is a stem cell disorder with the clinical presentation of _______, rather than anemia, and therefore is a misnomer. Aplastic anemia involves all cell lines, whereas aplastic crisis involves the red cell line only.

• Path:
  
  • Cause is unknown in >50% of cases, with the remainder due to certain drugs, toxins, infections, or radiation exposure.
  • Idiosyncratic causes are sulfa drugs, gold, chloramphenicol, and insecticides.
  • Include hepatitis, CMV, EBV, HIV, and parvovirus testing in the initial evaluation of aplastic anemia.
  • In addition, evaluate children with aplastic anemia for inherited bone marrow failure syndromes (IBMFS).
• Pt:
  
  • Combination of bruising and pallor suggests a marrow disorder affecting >1 cell line.
• Lab: Normocytic/macrocytic anemia (_____ MCV), leukopenia, reticulocyto____ (hallmark is inappropriately low reticulocyte count), thrombocytopenia
• Evaluation:
  
  • Bone marrow biopsy evaluation for percent cellularity is necessary in evaluation with pancytopenia
    
    • Pts have hypocellularity with decrease in all cell lines and fatty infiltration of marrow or acellular bone marrow
    • While acute leukemia most often presents with hypercellular bone marrow, aplastic anemia presents with markedly hypocellular marrow
• Diagnostic criteria for severe aplastic anemia: At least ____ severe cytopenias (ANC <500, plt <20,000, or retic <60,000) and bone marrow cellularity of less than 25%
• Treatment:
  
  • Immunosuppressive therapy with antithymocyte globulin (ATG), cyclosporine, and prednisone offers a complete response rate of 65%, although relapses are common.
  • Matched BMT, is available, has a 10-year survival rate of >80%
  • A patient treatment medically is at risk for a secondary malignancy if the pt has an underlying IBMFS.

Answer 69

Aplastic Anemia
- Aplastic anemia is a stem cell disorder with the clinical presentation of pancytopenia, rather than anemia, and therefore is a misnomer. Aplastic anemia involves all cell lines, whereas aplastic crisis involves the red cell line only.

• Path:
  
  • Cause is unknown in >50% of cases, with the remainder due to certain drugs, toxins, infections, or radiation exposure.
  • Idiosyncratic causes are sulfa drugs, gold, chloramphenicol, and insecticides.
  • Include hepatitis, CMV, EBV, HIV, and parvovirus testing in the initial evaluation of aplastic anemia.
  • In addition, evaluate children with aplastic anemia for inherited bone marrow failure syndromes (IBMFS).
• Pt:
  
  • Combination of bruising and pallor suggests a marrow disorder affecting >1 cell line.
• Lab: Normocytic/macrocytic anemia (INCREASED MCV), leukopenia, reticulocytopenia (hallmark is inappropriately low reticulocyte count), thrombocytopenia
• Evaluation:
  
  • Bone marrow biopsy evaluation for percent cellularity is necessary in evaluation with pancytopenia
    
    • Pts have hypocellularity with decrease in all cell lines and fatty infiltration of marrow or acellular bone marrow
    • While acute leukemia most often presents with hypercellular bone marrow, aplastic anemia presents with markedly hypocellular marrow
• Diagnostic criteria for severe aplastic anemia: At least 2 severe cytopenias (ANC <500, plt <20,000, or retic <60,000) and bone marrow cellularity of <25%
• Treatment:
  
  • Immunosuppressive therapy with antithymocyte globulin (ATG), cyclosporine, and prednisone offers a complete response rate of 65%, although relapses are common.
  • Matched BMT, is available, has a 10-year survival rate of >80%
  • A patient treatment medically is at risk for a secondary malignancy if the pt has an underlying IBMFS.

Question 70

Fanconi Anemia - most common congenital cause of aplastic anemia
- AR or XLD.

• Path: Poor DNA repair mechanisms.
• Pt:
  
  • Presents with _____.
  • Classically, present with short stature, absent or abnormal thumbs, abnormal _____, microcephaly, cafe-au-lait spots, dark pigmentation, and renal anomalies
  • THUMB _____ is a common clinical feature
• Patients have a 15% risk of developing ____.
• Can present as macrocytic anemia with or without other cytopenias
• Tx: ____ is the only known cure for aplasia, but it does not decrease risks of other cancers.
  Do not confuse with Fanconi Syndrome, which is a renal condition characterized by generalized proximal tubular dysfunction.

Answer 70

Fanconi Anemia - most common congenital cause of aplastic anemia
- AR or XLD.

• Path: Poor DNA repair mechanisms.
• Pt:
  
  • Presents with pancytopenia.
  • Classically, present with short stature, absent or abnormal thumbs, abnormal radii, microcephaly, cafe-au-lait spots, dark pigmentation, and renal anomalies
  • THUMB HYPOPLASIA is a common clinical feature
• Patients have a 15% risk of developing AML.
• Can present as macrocytic anemia with or without other cytopenias
• Tx: BMT is the only known cure for aplasia, but it does not decrease risks of other cancers.
  Do not confuse with Fanconi Syndrome, which is a renal condition characterized by generalized proximal tubular dysfunction.

Question 71

Red Cell Aplasia
- Defined by ____ in the setting of reticulocyto_____

• Differentiating the 3 red cell aplasias below
  
  • Parvovirus B19 usually occurs in ___-aged children and has associated fever, rash, and arthropathy
  • TEC typically occurs in children___ yo and has ___ RBCs and no rash, fever, or arthropathy
  • DBA is most often diagnosed in children less than __yo and has macrocytic RBCs. Pts also often have congenital deformities.

Answer 71

Red Cell Aplasia
- Defined by anemia in the setting of reticulocytopenia.

• Differentiating the 3 red cell aplasias below
  
  • Parvovirus B19 usually occurs in school-aged children and has associated fever, rash, and arthropathy
  • TEC typically occurs in children 1-4 yo and has normocytic RBCs and no rash, fever, or arthropathy
  • DBA is most often diagnosed in children <1yo and has macrocytic RBCs. Pts also often have congenital deformities.

Question 72

Parvovirus B19

• Pt:
  
  • In an otherwise healthy pt, this is a transient phenomenon and is often asymptomatic.
  • However, chronic infection with red cell aplasia can be seen in the immunocompromised
  • Remember: In patients with hemolytic anemias such as sickle cell disease, parvovirus B19 infection can cause an aplastic crisis.
• Pt:
  
  • Suspect in patients presenting with red cell aplasia in the setting of fever, rash, and/or arthropathy.
  • The rash can have a “_________” presentation of erythema infectiosum, one of the presentations or parvovirus B19 seen in otherwise healthy children.
• Tx: ______. IVIG is prescribed for complicated cases in immunosuppressed patients

Answer 72

Parvovirus B19

• Pt:
  
  • In an otherwise healthy pt, this is a transient phenomenon and is often asymptomatic.
  • However, chronic infection with red cell aplasia can be seen in the immunocompromised
  • Remember: In patients with hemolytic anemias such as sickle cell disease, parvovirus B19 infection can cause an aplastic crisis.
• Pt:
  
  • Suspect in patients presenting with red cell aplasia in the setting of fever, rash, and/or arthropathy.
  • The rash can have a “slapped cheek” presentation of erythema infectiosum, one of the presentations or parvovirus B19 seen in otherwise healthy children.
• Tx: Supportive. IVIG is prescribed for complicated cases in immunosuppressed patients

Question 73

Transient erythroblastopenia of childhood
- Acquired, self-limited condition seen in previously healthy children between 1-3 yo (under ____ years old)

• Path: Unknown.
• Labs: _____ anemia, absolute reticulocytopenia. Normal MCV
• New-onset isolated normocytic anemia with reticulocytopenia in a healthy toddler (no congenital anomalies) should raise suspicion for transient erythroblastopenia of childhood.
• Management:
  
  • Idiopathic, self-limited anemia. In most cases, anemia resolves in 1-2 months without transfusions, and does not recur.
  • Supportive care with transfusion for symptomatic anemia while waiting for the bone marrow to start producing red cells again.
  • Pts should be followed with serial ______ insure the expected full erythropoietic recovery.

Answer 73

Transient erythroblastopenia of childhood
- Acquired, self-limited condition seen in previously healthy children between 1-3 yo (under 4 years old)

• Path: Unknown.
• Labs: NORMOCYTIC anemia, absolute reticulocytopenia. Normal MCV
• New-onset isolated normocytic anemia with reticulocytopenia in a healthy toddler (no congenital anomalies) should raise suspicion for transient erythroblastopenia of childhood.
• Management:
  
  • Idiopathic, self-limited anemia. In most cases, anemia resolves in 1-2 months without transfusions, and does not recur.
  • Supportive care with transfusion for symptomatic anemia while waiting for the bone marrow to start producing red cells again.
  • Pts should be followed with serial CBC and reticulocyte counts to insure the expected full erythropoietic recovery.

Question 74

Congenital Hypoplasia Anemia (Diamond-Blackfan Anemia)
- ______inheritance??

• Path: Intrinsic defect of erythroid progenitor cells which results in increased apoptosis
  
  • Problem making RBCs
• Most are diagnosed at less than ___yo.
• Pt:
  
  • Presents in infancy with profound ____ anemia and _____ by 2-6 months.
  • Pallor.
  • ⅓ have various congenital deformities: craniofacial defects, short stature, and limb abnormalities, thumb anomalies, glaucoma, renal anomalies, hypogonadism, short, webbed necks, congenital heart disease, and intellectual disability
  • _____ thumbs.
  • Presence of congenital anomalies
• Labs:
  
  • MACROCYTIC anemia (NO hypersegmentation). Increased MCV
  • Elevated erythrocyte ADA activity
• Tx:
  
  • Manage with ____ until 6-12 months of age, then try corticosteroids.

Answer 74

Congenital Hypoplasia Anemia (Diamond-Blackfan Anemia)
- AD

• Path: Intrinsic defect of erythroid progenitor cells which results in increased apoptosis
  
  • Problem making RBCs
• Most are diagnosed at <1yo.
• Pt:
  
  • Presents in infancy with profound MACROCYTIC anemia and reticulocytopenia by 2-6 months.
  • Pallor.
  • ⅓ have various congenital deformities: craniofacial defects, short stature, and limb abnormalities, thumb anomalies, glaucoma, renal anomalies, hypogonadism, short, webbed necks, congenital heart disease, and intellectual disability
  • Triphalangeal thumbs.
  • Presence of congenital anomalies
• Labs:
  
  • MACROCYTIC anemia (NO hypersegmentation). Increased MCV
  • Elevated erythrocyte ADA activity
• Tx:
  
  • Manage with transfusions until 6-12 months of age, then try corticosteroids.

Question 75

HEMOSTASIS

• Primary hemostatic problems (90% involve low platelets or platelet dysfunction) result in multiple, tiny, superficial hemorrhages. Pts present with petechiae, ecchymosis, and mucocutaneous bleeding. Remember that vasculitis disorders are a cause of bruising or palpable purpura in a child with a normal platelet count.
• Patients with a coagulation disorder, such as hemophilia, develop deep tissue bleeding, including hematomas or hemarthroses.

Answer 75

HEMOSTASIS

• Primary hemostatic problems (90% involve low platelets or platelet dysfunction) result in multiple, tiny, superficial hemorrhages. Pts present with petechiae, ecchymosis, and mucocutaneous bleeding. Remember that vasculitis disorders are a cause of bruising or palpable purpura in a child with a normal platelet count.
• Patients with a coagulation disorder, such as hemophilia, develop deep tissue bleeding, including hematomas or hemarthroses.

Question 76

5 tests which are usually done to assess coagulation and platelets status
- 1) Prothrombin time (PT) measure the function of extrinsic and common pathways.

• 2) Activated PTT measures the function of the intrinsic and the common pathways.
• 3) The thrombin time measures the time of conversion of fibrinogen to fibrin; it is abnormal only if there is a problem with this process. An increased thrombin time reflects decreased or defective fibrinogen, elevated fibrin degradation products (FDPs), or the presence of heparin or heparin-like anticoagulants.
• 4) Platelet count
• 5) Bleeding time (<10 minutes is normal) reflects the effectiveness of platelet aggregation. In other words, it is a measure of both adequate platelet number and adequate platelet function. Bc this test is difficult, it is not often used. Instead, rapid platelet function analysis (PFA) is performed.

Answer 76

5 tests which are usually done to assess coagulation and platelets status
- 1) Prothrombin time (PT) measure the function of extrinsic and common pathways.

• 2) Activated PTT measures the function of the intrinsic and the common pathways.
• 3) The thrombin time measures the time of conversion of fibrinogen to fibrin; it is abnormal only if there is a problem with this process. An increased thrombin time reflects decreased or defective fibrinogen, elevated fibrin degradation products (FDPs), or the presence of heparin or heparin-like anticoagulants.
• 4) Platelet count
• 5) Bleeding time (<10 minutes is normal) reflects the effectiveness of platelet aggregation. In other words, it is a measure of both adequate platelet number and adequate platelet function. Bc this test is difficult, it is not often used. Instead, rapid platelet function analysis (PFA) is performed.

Question 77

If there is a greatly increased PTT with a normal PT and normal platelet count, check to see if the PT normalizes when the patient’s plasma is mixed 1:1 with normal plasma (a “mixing study”). If it does correct, the platelet has a clotting factor deficiency; if it does not correct, the pt has developed an inhibitor to a clotting factor protein, usually a lupus anticoagulant or Factor 8 inhibitor.

Answer 77

If there is a greatly increased PTT with a normal PT and normal platelet count, check to see if the PT normalizes when the patient’s plasma is mixed 1:1 with normal plasma (a “mixing study”). If it does correct, the platelet has a clotting factor deficiency; if it does not correct, the pt has developed an inhibitor to a clotting factor protein, usually a lupus anticoagulant or Factor 8 inhibitor.

Question 78

____ stabilizes factor 8

- The one factor not made in the liver is Factor 8. Factor 8 is made in endothelial cells

Answer 78

Vwf stabilizes factor 8

- The one factor not made in the liver is Factor 8. Factor 8 is made in endothelial cells

Question 79

Heparin binds to the enzyme inhibitor ____, causing a conformational change that results in its activation.

Answer 79

Heparin binds to the enzyme inhibitor antithrombin III (AT), causing a conformational change that results in its activation.

Question 80

Warfarin is an anticoagulant inhibits the vitamin K-dependent synthesis of calcium-dependent clotting factors II, VII, IX and X, as well as the regulatory factors protein C, protein S, and protein Z.

Answer 80

Warfarin is an anticoagulant inhibits the vitamin K-dependent synthesis of calcium-dependent clotting factors II, VII, IX and X, as well as the regulatory factors protein C, protein S, and protein Z.

Question 81

Antithrombin and proteins C and S are naturally occurring anticoagulants.

Answer 81

Antithrombin and proteins C and S are naturally occurring anticoagulants.

Question 82

Hemophilia A (Factor 8 deficiency)
- Due to a deficiency of Factor 8

• Inheritance: ______inheritance? (more likely in males). ⅓ of cases are sporadic and have no family hx of bleeding.
  
  • Family hx of might be positive for bleeding in males on the maternal side of the family.
• Pt:
  
  • Easy bruising, muscle and joint hemorrhages, and prolonged hemorrhage after surgery or trauma - but typically no mucosal bleeding or excessive bleeding after minor cuts.
  • _____ is a classic presentation of hemophilia.
• Labs: Prolonged _____. PT unaffected.
• Tx:
  
  • It is important to begin the treatment of bleeding episode with the onset of symptoms and not wait until it is clinically established.
  • DDAVP is a treatment option for some patients with mild Factor 8 deficiency. DDAVP challenge is done to prove response.
    
    • ____ causes a release of vWF and Factor 8 stores from endothelial cells.
    • If a patient has an adequate response to DDAVP, it can be used as treatment for an acute bleed and prophylactically for a tooth extraction in pts with mild disease (ie Factor 8 levels >5%).
    • DDAVP is not effective in pts with moderate or severe hemophilia.
  • Patients with moderate or severe Factor 8 deficiency who have acute bleeding are treated with _____.
• It is important to know when to suspect intracranial hemorrhage and how to manage it.
  
  • A new or worsening headache in a pt with hemophilia is very concerning for a possible intracranial bleed. Symptoms of intracranial bleeding in infants include lethargy and poor feeding.
  • Start _____ immediately for hemophilia patients with serious head trauma, even in the absence of LOC or an abnormal neurologic exam.
  • Consider emergent CT of the head without contrast after factor is administered.
• It is important to recognize and aggressively treat bleeding into the forearm.
  
  • Bleeding in the forearm of a person with hemophilia is an emergency bc of the risk of hemophilia is an emergency because of the risk of compartment syndrome and nerve damage and long-term risk of contractures.

Answer 82

Hemophilia A (Factor 8 deficiency)
- Due to a deficiency of Factor 8

• Inheritance: X-linked recessive (more likely in males). ⅓ of cases are sporadic and have no family hx of bleeding.
  
  • Family hx of might be positive for bleeding in males on the maternal side of the family.
• Pt:
  
  • Easy bruising, muscle and joint hemorrhages, and prolonged hemorrhage after surgery or trauma - but typically no mucosal bleeding or excessive bleeding after minor cuts.
  • Excessive bleeding following neonatal elective circumcision is a classic presentation of hemophilia.
• Labs: Prolonged PTT. PT unaffected.
• Tx:
  
  • It is important to begin the treatment of bleeding episode with the onset of symptoms and not wait until it is clinically established.
  • DDAVP is a treatment option for some patients with mild Factor 8 deficiency. DDAVP challenge is done to prove response.
    
    • DDAVP causes a release of vWF and Factor 8 stores from endothelial cells.
    • If a patient has an adequate response to DDAVP, it can be used as treatment for an acute bleed and prophylactically for a tooth extraction in pts with mild disease (ie Factor 8 levels >5%).
    • DDAVP is not effective in pts with moderate or severe hemophilia.
  • Patients with moderate or severe Factor 8 deficiency who have acute bleeding are treated with Factor 8 concentrate.
• It is important to know when to suspect intracranial hemorrhage and how to manage it.
  
  • A new or worsening headache in a pt with hemophilia is very concerning for a possible intracranial bleed. Symptoms of intracranial bleeding in infants include lethargy and poor feeding.
  • Start factor therapy immediately for hemophilia patients with serious head trauma, even in the absence of LOC or an abnormal neurologic exam.
  • Consider emergent CT of the head without contrast after factor is administered.
• It is important to recognize and aggressively treat bleeding into the forearm.
  
  • Bleeding in the forearm of a person with hemophilia is an emergency bc of the risk of hemophilia is an emergency because of the risk of compartment syndrome and nerve damage and long-term risk of contractures.

Question 83

Hemophilia B (Factor 9 deficiency) (“Christmas disease”)

• _____inheritance? (more likely in males)
• Labs: Prolonged PTT.
• Tx: Treat an acute bleed with a Factor 9 concentrate.

Answer 83

Hemophilia B (Factor 9 deficiency) (“Christmas disease”)

• X-linked recessive (more likely in males)
• Labs: Prolonged PTT.
• Tx: Treat an acute bleed with a Factor 9 concentrate.

Question 84

Factor 11 Deficiency (Hemophilia C)
-____inheritance?

• Pt:
  
  • These pts usually do not get hemarthroses.
  • For some reason, these patients tend to have more ______ bleeding, such as epistaxis and menorrhagia.
• The risk of bleeding does not correlate with the level of Factor 11.
• Tx:
  
  • Tranexamic acid and e-aminocaproic acid are useful for mucosal bleeding.
  • For severe bleeding episodes, use fresh frozen plasma.

Answer 84

Factor 11 Deficiency (Hemophilia C)
- Autosomal recessive.

• Pt:
  
  • These pts usually do not get hemarthroses.
  • For some reason, these patients tend to have more mucosal bleeding, such as epistaxis and menorrhagia.
• The risk of bleeding does not correlate with the level of Factor 11.
• Tx:
  
  • Tranexamic acid and e-aminocaproic acid are useful for mucosal bleeding.
  • For severe bleeding episodes, use fresh frozen plasma.

Question 85

Factor 5, 7, and 10 Deficiencies

• Rare ____inheritance? bleeding disorders.
• Know that acquired Factor 10 deficiency can be seen in pts with _____.

Answer 85

Factor 5, 7, and 10 Deficiencies

• Rare autosomal recessive bleeding disorders.
• Know that acquired Factor 10 deficiency can be seen in pts with amyloidosis.

Question 86

Factor 12 (Hageman factor) Deficiency
- \_\_\_\_\_inheritance? disorder. 

• Pt: Do NOT have a clinical bleeding disorder and can even undergo surgery without worry of bleeding. Do NOT cause bleeding
• Decreased factor 12. Normal PT and very prolonged ____

Answer 86

Factor 12 (Hageman factor) Deficiency
- Autosomal recessive disorder. 

• Pt: Do NOT have a clinical bleeding disorder and can even undergo surgery without worry of bleeding. Do NOT cause bleeding
• Decreased factor 12. Normal PT and very prolonged PTT

Question 87

Factor 13 Deficiency
- Rare _____inheritance? disorder.

• Factor XIII (13) is responsible for clot formation. Since it plays a role after the formation of a clot, an absence of factor 13 would not prolong the PT or PTT (which are measures of time to clot formation, not clot stabilization)
• Ask about ______ bc offspring of consanguineous parents are at higher risk for rare disorders.
• Pt: Severe bleeding problems and severe scarring with superficial wounds and yet have a ____ PT and PTT

Answer 87

Factor 13 Deficiency
- Rare autosomal recessive disorder.

• Factor XIII (13) is responsible for clot formation. Since it plays a role after the formation of a clot, an absence of factor 13 would not prolong the PT or PTT (which are measures of time to clot formation, not clot stabilization)
• Ask about consanguinity bc offspring of consanguineous parents are at higher risk for rare disorders.
• Pt: Severe bleeding problems and severe scarring with superficial wounds and yet have a normal PT and PTT

Question 88

Disseminated Intravascular Coagulation (DIC)
- DIC is the most common acquired coagulopathy.

• Path: It is always a secondary condition, so the underlying disease must be treated for the DIC to resolve. DIC occurs in diseases that promote tissue-factor release. These include:
  
  • Massive direct tissue trauma
  • Production of tumor necrosis factor (esp seen in solid tumors)
  • Sepsis
  • Endotoxin production in certain infections
  • Placental tissue substances in obstetric patients with placental abruption, dead fetus, or amniotic fluid embolism
  • Acute promyelocytic leukemia
  • Rattlesnake or viper envenomation
• Lab results reflect the abnormalities with
  
  • _____ PT and PTT
  • Thrombocyto___
  • ____ fibrinogen
  • ____ D-dimer (This is an FDP specifically produced by the action of plasmin on fibrin.)
  • Increased thrombin time (due to both decreased fibrinogen and increased FDPs)
• Tx: Treat underlying disorder. With severe bleeding, give _____ and platelets. Give ____ if fibrinogen is low.

Answer 88

Disseminated Intravascular Coagulation (DIC)
- DIC is the most common acquired coagulopathy.

• Path: It is always a secondary condition, so the underlying disease must be treated for the DIC to resolve. DIC occurs in diseases that promote tissue-factor release. These include:
  
  • Massive direct tissue trauma
  • Production of tumor necrosis factor (esp seen in solid tumors)
  • Sepsis
  • Endotoxin production in certain infections
  • Placental tissue substances in obstetric patients with placental abruption, dead fetus, or amniotic fluid embolism
  • Acute promyelocytic leukemia
  • Rattlesnake or viper envenomation
• Lab results reflect the abnormalities with
  
  • Prolonged PT and PTT
  • Thrombocytopenia
  • Decreased fibrinogen
  • Elevated D-dimer (This is an FDP specifically produced by the action of plasmin on fibrin.)
  • Increased thrombin time (due to both decreased fibrinogen and increased FDPs)
• Tx: Treat underlying disorder. With severe bleeding, give fresh frozen plasma and platelets. Give cryoprecipitate if fibrinogen is low.

Question 89

Vitamin K Deficiency
- Vitamin K deficiency results in decreased production of factors 2, 7, 9, and 10 and of proteins C and S

• Path:
  
  • Newborn infants are functionally vitamin K deficient and require vitamin K supplements soon after birth. Newborns who don’t receive vitamin K at birth are at risk for vitamin K deficiency bleeding (VKDB)
• Tx:
  
  • Administer ___ vitamin K to patients with vitamin K deficiency if the pt is bleeding. Fresh frozen plasma or nonactivated prothrombin complex concentrate can be used while waiting for the vitamin K to take effect (8 hours).
  • Likewise, the effect of warfarin can be reversed with vitamin K. However, if a pt on warfarin has significant bleeding, give fresh frozen plasma or nonactivated prothrombin complex concentrate for immediate factor replacement.

Answer 89

Vitamin K Deficiency
- Vitamin K deficiency results in decreased production of factors 2, 7, 9, and 10 and of proteins C and S

• Path:
  
  • Newborn infants are functionally vitamin K deficient and require vitamin K supplements soon after birth. Newborns who don’t receive vitamin K at birth are at risk for vitamin K deficiency bleeding (VKDB)
• Tx:
  
  • Administer IV vitamin K to patients with vitamin K deficiency if the pt is bleeding. Fresh frozen plasma or nonactivated prothrombin complex concentrate can be used while waiting for the vitamin K to take effect (8 hours).
  • Likewise, the effect of warfarin can be reversed with vitamin K. However, if a pt on warfarin has significant bleeding, give fresh frozen plasma or nonactivated prothrombin complex concentrate for immediate factor replacement.

Question 90

Lupus Anticoagulants
- LACs are common in young children in the setting of viral infection. They are not pathogenic and resolve spontaneously.

• Pt: In most cases, a pt with LAC does not present with bleeding. It is associated with _____.
• Lupus anticoagulants (LACs) result in a prolonged ____.
• Use a PTT mixing study to differentiate congenital factor deficiency from an LAC.
  
  • A pt with a deficiency of a clotting factor corrects completely when mixed with normal plasma (ie with normal factor levels). On the other hand, the PTT of pts with inhibitors remains abnormally prolonged after the mix. In these cases, a 1:1 dilution of the patient’s plasma is not sufficient to eliminate the full effect of the inhibitor of the PTT.

Answer 90

Lupus Anticoagulants
- LACs are common in young children in the setting of viral infection. They are not pathogenic and resolve spontaneously.

• Pt: In most cases, a pt with LAC does not present with bleeding. It is associated with thrombosis.
• Lupus anticoagulants (LACs) result in a prolonged PTT.
• Use a PTT mixing study to differentiate congenital factor deficiency from an LAC.
  
  • A pt with a deficiency of a clotting factor corrects completely when mixed with normal plasma (ie with normal factor levels). On the other hand, the PTT of pts with inhibitors remains abnormally prolonged after the mix. In these cases, a 1:1 dilution of the patient’s plasma is not sufficient to eliminate the full effect of the inhibitor of the PTT.

Question 91

Bleeding disorders that appear with a normal platelet count, PT, PTT, and bleeding time

• Mild __
• Mild ___
• Factor __ deficiency (rare)

Answer 91

Bleeding disorders that appear with a normal platelet count, PT, PTT, and bleeding time

• Mild vWD
• Mild hemophilia
• Factor 13 deficiency (rare)

Question 92

Venous thrombosis

- RF: Most common cause of DVT in children is a central venous catheter.

Answer 92

Venous thrombosis

- RF: Most common cause of DVT in children is a central venous catheter.

Question 93

Renal vein thrombosis
- Infants with hx of birth asphyxia, shock, and/or sepsis are at increased risk of developing endothelial cell injury leading to renal vein thrombus formation.

• It is also more common in infants of diabetic mothers and in those with congenital hypercoagulable states.
• Pt:
  • Sudden onset of _____ and a unilateral or bilateral _____.
  • Almost all pts have at least 1 of the following: Gross hematuria, unilateral or bilateral flank mass, and/or _____.

Answer 93

Renal vein thrombosis
- Infants with hx of birth asphyxia, shock, and/or sepsis are at increased risk of developing endothelial cell injury leading to renal vein thrombus formation.

• It is also more common in infants of diabetic mothers and in those with congenital hypercoagulable states.
• Pt:
  • Sudden onset of gross hematuria and a unilateral or bilateral flank mass.
  • Almost all pts have at least 1 of the following: Gross hematuria, unilateral or bilateral flank mass, and/or thrombocytopenia.

Question 94

Protein S or C deficiency
- Infants who are homozygous for protein S or C deficiency have neonatal purpura fulminans with life-threatening thrombosis.

Answer 94

Protein S or C deficiency
- Infants who are homozygous for protein S or C deficiency have neonatal purpura fulminans with life-threatening thrombosis.

Question 95

Protein C is an anticoagulant protein. A deficiency of protein C would result in an increased risk of thrombosis, not an increased risk of bleeding.

Answer 95

Protein C is an anticoagulant protein. A deficiency of protein C would result in an increased risk of thrombosis, not an increased risk of bleeding.

Question 96

Factor 5 Leiden (____ resistance)

- Path: Mutation in factor __ where protein ___ cannot bind to, leading to ____ state

Answer 96

Factor 5 Leiden (Activated protein C (APC) resistance)

- Path: Mutation in factor V where protein C cannot bind to, leading to hypercoagulable state

Question 97

RBC transfusions

• A transfusion of __ml/kg typically raises the hemoglobin by ___ g/dL.
• A transfusion of 5 ml/kg will increase the hemoglobin 1g/dl.

Answer 97

RBC transfusions

• A transfusion of 10ml/kg typically raises the hemoglobin by 2.5-3 g/dL.
• A transfusion of 5 ml/kg will increase the hemoglobin 1g/dl.

Question 98

Complications of RBC transfusions

• Hemolytic reaction (life-threatening with fever, chills, flank pain, and oozing from IV sites)
  
  • Path:
    
    • ____ in the recipients’ plasma to antigens on the transfused RBCs.
    • Hemolysis caused by ABO incompatibility would only occur in the case of a clerical error, but it would be severe.
    • Delayed hemolytic transfusion reaction can occur due to incompatibility with minor RBC antigens and tend to be less severe.
• Febrile nonhemolytic reaction (___ and ___ only)
  
  • Caused by the passive infusion of ___ on leukocytes in the donor’s plasma or the presence of antibodies in the recipient’s plasma to antigens on donor leukocytes.
  • This is usually defined as a temperature increase >___C
  • Risk for febrile transfusion reactions can be reduced by ____ of the blood product (filtering) prior to infusion.
• Allergic transfusion reactions
  
  • Caused by antibodies in the recipient to plasma proteins in the donor
  • Range from mild reactions to full anaphylaxis.
• Transfusion-associated graft-vs-host disease
  
  • Occurs when donor lymphocytes in the transfused product recognize the host (recipient) as foreign and cause immunological rejection.
  • Skin (rash), liver (elevated liver function test results and bilirubin levels), and intestines (diarrhea).
  • The risk for this complication can be completely ameliorated by ____ the blood product prior to infusion.
• Transfusion-associated lung injury
  
  • Presents within 6 hours of a transfusion and manifests with significant ____ symptoms, pulmonary edema, and sometimes accompanying severe systemic findings, such as hypotension.
• Chronic transfusions result in iron overload.

Answer 98

Complications of RBC transfusions

• Hemolytic reaction (life-threatening with fever, chills, flank pain, and oozing from IV sites)
  
  • Path:
    
    • Antibodies in the recipients’ plasma to antigens on the transfused RBCs.
    • Hemolysis caused by ABO incompatibility would only occur in the case of a clerical error, but it would be severe.
    • Delayed hemolytic transfusion reaction can occur due to incompatibility with minor RBC antigens and tend to be less severe.
• Febrile nonhemolytic reaction (fever and chills only)
  
  • Caused by the passive infusion of cytokines on leukocytes in the donor’s plasma or the presence of antibodies in the recipient’s plasma to antigens on donor leukocytes.
  • This is usually defined as a temperature increase >1C
  • Risk for febrile transfusion reactions can be reduced by leukoreduction of the blood product (filtering) prior to infusion.
• Allergic transfusion reactions
  
  • Caused by antibodies in the recipient to plasma proteins in the donor
  • Range from mild reactions to full anaphylaxis.
• Transfusion-associated graft-vs-host disease
  
  • Occurs when donor lymphocytes in the transfused product recognize the host (recipient) as foreign and cause immunological rejection.
  • Skin (rash), liver (elevated liver function test results and bilirubin levels), and intestines (diarrhea).
  • The risk for this complication can be completely ameliorated by irradiating the blood product prior to infusion.
• Transfusion-associated lung injury
  
  • Presents within 6 hours of a transfusion and manifests with significant respiratory symptoms, pulmonary edema, and sometimes accompanying severe systemic findings, such as hypotension.
• Chronic transfusions result in iron overload.

Question 99

Management of transfusion reactions

• Always begins with stopping the infusion of the blood product followed by providing supportive care directed at the specific transfusion reaction.
  
  • Administer IV fluids to support BP if the pt becomes hypotensive.
  • Signs of anaphylaxis require IM epinephrine for treatment. Prepare for emergent airway intervention.

Answer 99

Management of transfusion reactions

• Always begins with stopping the infusion of the blood product followed by providing supportive care directed at the specific transfusion reaction.
  
  • Administer IV fluids to support BP if the pt becomes hypotensive.
  • Signs of anaphylaxis require IM epinephrine for treatment. Prepare for emergent airway intervention.

Question 100

Leukoreduction
- Involves reducing the number of transfused _____. It also removes the risk of human leukocyte antigen alloimmunization and transmission of CMV (which typically resides in leukocytes).

• 1) Prevents ____ reaction
• 2) Removes risk of ____
• 3) Reduces risk of ___ that resides in leukocytes
• Good for _____

Answer 100

Leukoreduction
- Involves reducing the number of transfused leukocytes. It also removes the risk of human leukocyte antigen alloimmunization and transmission of CMV (which typically resides in leukocytes).

• 1) Prevents febrile nonhemolytic transfusion reaction
• 2) Removes risk of HLA alloimmunization
• 3) Reduces risk of CMV that resides in leukocytes
• Good for sickle cell

Question 101

Irradiation
- Inactivates ____, rending replication incompetent, to prevent ___

• Good for ___ patients

Answer 101

Irradiation
- Inactivates DNA of leftover donor T lymphocyte, rending replication incompetent, to prevent GVHD

• Good for cancer patients

Question 102

Platelet Transfusion

- 1 unit of random-donor platelets/kg raises the platelet count by ~__ x 10^9/L.

Answer 102

Platelet Transfusion

- 1 unit of random-donor platelets/kg raises the platelet count by ~50 x 10^9/L.

Question 103

Fresh frozen plasma
- Contains all clotting factors except ____

• Indications: life threatening bleeding in pt who has received warfarin, severe liver disease, DIC, massive transfusion, isolated congenital factor deficiency that does not have safer product

Answer 103

Fresh frozen plasma
- Contains all clotting factors except platelets

• Indications: life threatening bleeding in pt who has received warfarin, severe liver disease, DIC, massive transfusion, isolated congenital factor deficiency that does not have safer product

Question 104

Cryoprecipitate
- Enriched for __, ____, and factor __

• Indications: severe liver disease, DIC, afibrinogenemia or significant hypofibrinogenemia, von willebrand dx, factor 8 deficiency

Answer 104

Cryoprecipitate
- Enriched for vWF, fibrinogen, and factor 8

• Indications: severe liver disease, DIC, afibrinogenemia or significant hypofibrinogenemia, von willebrand dx, factor 8 deficiency

Question 105

PORPHYRIAS
- Disorders are caused by an enzyme defect in the heme synthesis pathway

• Pt:
  
  • Hepatic - Neuropathy, mental disturbances, abdominal pain
  • Erythropoietic group - Cutaneous photosensitivity

Answer 105

PORPHYRIAS
- Disorders are caused by an enzyme defect in the heme synthesis pathway

• Pt:
  
  • Hepatic - Neuropathy, mental disturbances, abdominal pain
  • Erythropoietic group - Cutaneous photosensitivity

Question 106

Acute Intermittent Porphyria (AIP)
- ____inheritance? disorder

• Path: Due to deficiency (usually 50% of normal) of _____
• Most common drugs that precipitate attacks:
  
  • Barbiturates (eg phenobarbital)
  • Sulfonamide antibiotics
  • Antiseizure medications (eg carbamazepine, valproic acid)
  • Griseofulvin
  • Synthetic estrogen (birth control pills)
  • Note: Aspirin, phenothiazines, glucocorticoids, insulin, and acetaminophen are not likely to cause problems
• Pt: Expression is variable
  
  • Most heterozygous children are asymptomatic, unless some factor increases the production of pyrogens.
  • ____ is the most common symptom, along with ileus, abdominal distention, and decreased bowel sounds.
  • Peripheral neuropathy
  • Progressive weakness without effective tx can lead to respiratory and bulbar paralysis.
• Initial screening: Testing ___ for elevated ____.
• Dx: Measure _____ activity of approx 50% in ___.
  
  • A normal ___ level in the ___ rules out AIP.
• Tx:
  
  • Acute attacks:
    
    • Narcotic analgesics for abdominal pain
    • Phenothiazines for nausea and vomiting
    • IV glucose (300g/day) can be helpful with continuous parenteral infusion if the pt cannot maintain oral intake.
    • IV ____ is probably the most effective therapy if given early.
  • Some women have cyclical attacks, which can be prevented with a LH-release hormone analog.

Answer 106

Acute Intermittent Porphyria (AIP)
- AD disorder

• Path: Due to deficiency (usually 50% of normal) of porphobilinogen (PBG) deaminase
• Most common drugs that precipitate attacks:
  
  • Barbiturates (eg phenobarbital)
  • Sulfonamide antibiotics
  • Antiseizure medications (eg carbamazepine, valproic acid)
  • Griseofulvin
  • Synthetic estrogen (birth control pills)
  • Note: Aspirin, phenothiazines, glucocorticoids, insulin, and acetaminophen are not likely to cause problems
• Pt: Expression is variable
  
  • Most heterozygous children are asymptomatic, unless some factor increases the production of pyrogens.
  • Abdominal pain is the most common symptom, along with ileus, abdominal distention, and decreased bowel sounds.
  • Peripheral neuropathy
  • Progressive weakness without effective tx can lead to respiratory and bulbar paralysis.
• Initial screening: Testing urine for elevated PBG.
• Dx: Measure PBG deaminase activity of approx 50% in RBCs.
  
  • A normal PBG level in the stool rules out AIP.
• Tx:
  
  • Acute attacks:
    
    • Narcotic analgesics for abdominal pain
    • Phenothiazines for nausea and vomiting
    • IV glucose (300g/day) can be helpful with continuous parenteral infusion if the pt cannot maintain oral intake.
    • IV heme is probably the most effective therapy if given early.
  • Some women have cyclical attacks, which can be prevented with a LH-release hormone analog.

Question 107

Porphyria Cutanea Tarda (PCT)
- Most common of the porphyria

• Path: Congenital or acquired deficiency of the hepatic synthetic enzyme _______, which allows buildup of phototoxic porphyrins in the skin
• Pt:
  
  • ______ are the predominant clinical feature.
    
    • Cutaneous photosensitivity and develop fluid-filled vesicles and bullae
  • Hypertrichosis and hyperpigmentation are also typical.
  • Usually have liver damage and are predisposed to develop ___. There is also an association with _____.
• Labs:
  
  • Affected pts have increased urinary coproporphyrins and uroporphyrins.
  • The urine of affected pts fluoresces pink with Wood’s lamp examination
• Dx: Increased ____ levels in liver, plasma, urine, and stool.
  
  • Types II and III can be diagnosed by finding decreased UROD activity in RBCs
• Tx:
  
  • Prevent exposure to offending agent
  • Usually, ____ to reduce hepatic iron can achieve complete response.
  • Can also treat with chloroquine or hydroxychloroquine; these combine with excess porphyrins and enhance excretion.

Answer 107

Porphyria Cutanea Tarda (PCT)
- Most common of the porphyria

• Path: Congenital or acquired deficiency of the hepatic synthetic enzyme uroporphyrinogen decarboxylase (UROD), which allows buildup of phototoxic porphyrins in the skin
• Pt:
  
  • Blistering skin lesions are the predominant clinical feature.
    
    • Cutaneous photosensitivity and develop fluid-filled vesicles and bullae
  • Hypertrichosis and hyperpigmentation are also typical.
  • Usually have liver damage and are predisposed to develop hepatocellular carcinoma. There is also an association with hepatitis C.
• Labs:
  
  • Affected pts have increased urinary coproporphyrins and uroporphyrins.
  • The urine of affected pts fluoresces pink with Wood’s lamp examination
• Dx: Increased porphyrin levels in liver, plasma, urine, and stool.
  
  • Types II and III can be diagnosed by finding decreased UROD activity in RBCs
• Tx:
  
  • Prevent exposure to offending agent
  • Usually, phlebotomy to reduce hepatic iron can achieve complete response.
  • Can also treat with chloroquine or hydroxychloroquine; these combine with excess porphyrins and enhance excretion.

Question 108

X-Linked Sideroblastic Anemia (Also see “Anemia, Microcytic”)

• Path: Due to deficient activity of the erythroid form of ______ and results in ineffective erythropoiesis
• Bone marrow studies: Show hypercellular marrow with megaloblastic erythropoiesis.
• Dx: Find mutations in the erythroid ALA synthase gene
• Tx: Anemia typically responds to ______

Answer 108

X-Linked Sideroblastic Anemia (Also see “Anemia, Microcytic”)

• Path: Due to deficient activity of the erythroid form of aminolevulinic acid (ALA) synthase and results in ineffective erythropoiesis
• Bone marrow studies: Show hypercellular marrow with megaloblastic erythropoiesis.
• Dx: Find mutations in the erythroid ALA synthase gene
• Tx: Anemia typically responds to pyridoxine (vitamin B6)

Question 109

Erythropoietic Protoporphyria (EPP)
- Most common porphyria in children 

• ____inheritance? disease. Inheritance pattern appears to be AD with incomplete penetrance
• Path: Due to partial deficiency of ___. ____ accumulates abnormally in erythroid cells and plasma and is excreted in bile and feces.
• Pt:
  
  • Skin photosensitivity is the major clinical feature and begins in childhood.
  • Different from other porphyrias in that _____ are not common - and pigment changes, severe scarring, and hypertrichosis are unusual.
• Dx: Elevated levels of ____ in bone marrow, RBCs, plasma, bile, and feces.
  
  • Urinary levels of porphyrin and its precursors are normal
• Tx: _____ improves tolerance to sunlight.

Answer 109

Erythropoietic Protoporphyria (EPP)
- Most common porphyria in children 

• AR disease. Inheritance pattern appears to be AD with incomplete penetrance
• Path: Due to partial deficiency of ferrochelatase. Protoporphyrin accumulates abnormally in erythroid cells and plasma and is excreted in bile and feces.
• Pt:
  
  • Skin photosensitivity is the major clinical feature and begins in childhood.
  • Different from other porphyrias in that vesicles are not common - and pigment changes, severe scarring, and hypertrichosis are unusual.
• Dx: Elevated levels of protoporphyrin in bone marrow, RBCs, plasma, bile, and feces.
  
  • Urinary levels of porphyrin and its precursors are normal
• Tx: Oral beta-carotene improves tolerance to sunlight.