Hematology

Question 1

What is the factor deficiency in hemophilia A? Hemophilia B?

Answer 1

Factor 8 deficiency; Factor 9 deficiency
Explanation
Factor 8 deficiency (hemophilia A) is X-linked recessive; i.e., the patient is virtually always male, and the family history might be positive for bleeding in males on the maternal side of the family. Factor 9 deficiency (hemophilia B) is also X-linked recessive. Presentation is similar and is dependent on severity. With Factor 8 deficiency, the risk of bleeding correlates with the plasma levels of Factor 8:
Severe hemophilia has plasma levels < 1% of normal.
Moderate hemophilia has plasma levels 1–5% of normal.
Mild hemophilia has plasma levels > 5% of normal.

Question 2

Where is the first site of red blood cell (RBC) formation in the fetus?

Answer 2

Answer
Yolk sac
Explanation
RBC formation in the yolk sac begins at 2–3 weeks of gestation. By the 5–6th week, RBC formation shifts to the liver, increases, peaks at 5 months, and decreases thereafter. The spleen then takes over as the major site of activity until around 7 months of gestation, at which time the bone marrow takes over and remains the predominant site for RBC production

Question 3

Is a red cell distribution width (RDW) likely to be increased or decreased in patients with iron deficiency anemia?

Answer 3

Increased
Explanation
It is important to distinguish iron deficiency anemia from β- and α-thalassemia trait because microcytosis is present in all of these conditions. The fact that RDW is increased in early iron-deficient patients and normal in patients with thalassemia trait is one way to differentiate them

Question 4

A 9-month-old presents with:

Pallor
Irritability
Growth restriction
Hepatosplenomegaly
Jaundice
Hemoglobin electrophoresis shows “F only.”

What is the most likely diagnosis?

Answer 4

β-Thalassemia major (Cooley anemia)
Explanation
In β-thalassemia major (Cooley anemia), there is essentially no β-globin production. Expansion of the bone marrow space in the facial bones leads to the characteristic “chipmunk facies.” Hemoglobin electrophoresis shows HbF only because there is no β-globin production. Patients with β-thalassemia major are transfusion dependent and often develop iron overload, requiring chelation therapy.

Question 5

Autosomal recessive (AR)
Macrothrombocytopenia with giant platelets
The platelets do not aggregate to ristocetin, but do aggregate in response to adenosine diphosphate, epinephrine, and collagen.
What syndrome presents with these findings?

Answer 5

Bernard-Soulier syndrome
Explanation
Bernard-Soulier syndrome is an AR disorder with mild thrombocytopenia and giant, abnormal platelets. Patients have a deficiency of platelet glycoprotein 1b in the platelet membrane that results in the platelets not being able to aggregate properly. There is severe mucocutaneous bleeding starting in infancy.

Question 6

A 7-month-old presents with:

Thumb anomalies
Short stature
Short, webbed neck
Congenital heart disease
Gross motor delays
Now, the child presents with macrocytic anemia and reticulocytopenia—pure red cell anemia.

What is the most likely diagnosis?

Answer 6

Answer
Diamond-Blackfan anemia (DBA), a.k.a. congenital hypoplastic anemia
Explanation
About 1/3 of children with DBA have some of the listed congenital anomalies. DBA has normal bone marrow cellular components except for the red cell precursors, which are absent or diminished. The anemia responds to corticosteroids in up to 80% of patients. Chronic red blood cell transfusions or stem cell transplant are indicated for those who are steroid refractory or steroid-dependent. Consider bone marrow transplant for patients requiring chronic red cell transfusion therapy

Question 7

A patient has pre-op testing prior to tonsillectomy. He recently had a viral illness. The aPTT is prolonged. The PT and platelet count are normal. You perform a mixing study, mixing the patient’s plasma 1:1 with normal plasma. The aPTT of the mixed plasma is normal.

Based on these laboratory results, is the patient at risk for bleeding?

Answer 7

Yes
Explanation
If you do a mixing study and the aPTT normalizes, you should suspect a clotting factor deficiency, which could put the patient at risk for bleeding.

If the aPTT does not normalize with the mixing study, the patient has developed an inhibitor to a clotting factor protein, usually a lupus anticoagulant or Factor 8 inhibitor. Lupus anticoagulant prolongs the aPTT but does not cause bleeding. Transient lupus anticoagulants are often identified in children after viral illness.

Question 8

What is the predominant hemoglobin at birth?

Answer 8

Answer
HbF
Explanation
HbF accounts for 90% of the circulating hemoglobin in a fetus at 24 weeks of gestation, after which time it begins to be replaced by adult hemoglobin. At birth, 50–80% of the total hemoglobin is HbF

Question 9

A 14-year-old girl presents with heavy menstrual flow with her first menses. You perform laboratory tests.

PT is normal.
aPTT is normal.
Factor 8 is 38% (normal range: 50–150%).
von Willebrand factor (vWF) antigen is 32% (normal range: 50–150%).
Ristocetin cofactor activity is 30% (normal range: 50–150%).
What is the most likely diagnosis?

Answer 9

Answer
von Willebrand disease (vWD) Type 1
Explanation
vWD Type 1 is the most common of the 3 forms of vWD (90%) and is due to a decrease in the amount of vWF (i.e., is a quantitative problem). vWF helps platelets stick to exposed subendothelium and to other platelets; it is also the carrier protein for Factor 8. Symptoms of vWD include easy bruising, epistaxis, menorrhagia, and bleeding after trauma or surgery. A frequent 1st manifestation of vWD in girls is heavy menstrual bleeding. Laboratory testing for vWD Type 1 includes vWF antigen, ristocetin cofactor activity (functional assay of vWF), and Factor 8. In Type 1 vWD, Factor 8 activity may be low-normal or moderately reduced because the half-life of Factor 8 is shorter if it does not have vWF to bind. The aPTT will be normal unless the Factor 8 is < 30–35% (depending on lab).

Question 10

What is one of the first symptoms in children with sickle cell disease (SCD)?

Answer 10

Sickle cell dactylitis
Explanation
The first pain crisis in about 1/3 of children with SCD is sickle cell dactylitis, a symmetric painful swelling of the hands and feet. Pain crisis is the most common complication of SCD and the most common reason for hospitalization

Question 11

Which type of hemoglobin occurs because of the substitution of a lysine for the glutamic acid residue in the 6th position of the β-globin chain?

Answer 11

Hemoglobin C (HbC)
Explanation
People who inherit HbC from one parent and HbS from another parent have hemoglobin SC disease (HbSC), a form of sickle cell disease. These patients typically have a microcytic anemia with target cells on peripheral blood smear.

Homozygotes for HbC (hemoglobin C disease [HbCC]) have a mild hemolytic anemia and splenomegaly but do not have vasoocclusive problems. Heterozygotes for HbC (HbAC) have no symptoms and only a large number of target cells as the hematologic manifestation

Question 12

Caused by the point mutation in the 6th codon of the β-globin gene, which is located on the short arm of chromosome 11
Adenine is replaced by thymidine, which results in valine being encoded instead of glutamic acid.
What disease has these characteristics?

Answer 12

Sickle cell disease (SCD)
Explanation
SCD is composed of a group of inherited red blood cell (RBC) disorders characterized by the presence of HbS, which is caused by the described point mutation. HbS forms polymers that damage the RBC and decrease its lifespan. For example, the average lifespan of an RBC in the HbSS form of the disease is only 15–50 days (normal = 120 days).

Question 13

Autosomal recessive (AR) inherited white cell disorder
Presents at a young age with severe bacterial infection
Absolute neutrophil count < 200/µL
What syndrome has these characteristics?

Answer 13

Kostmann syndrome (severe congenital neutropenia)
Explanation
Kostmann syndrome is a rare AR disorder. Children with Kostmann syndrome are predisposed to severe bacterial infections and early death. Management includes high doses of granulocyte-colony stimulating factor. Bone marrow transplant is curative

Question 14

Which organ produces erythropoietin (EPO) in the fetus?

Answer 14

Liver
Explanation
Soon after birth, the kidneys take over producing EPO.

Question 15

Autosomal recessive
Presents in the neonatal period with bleeding
Thrombocytopenia is severe, but the rest of the blood lines are normal.
There are decreased or absent megakaryocytes in the bone marrow.
The newborn has no radii but has normal thumbs.
What syndrome presents with these findings?

Answer 15

Thrombocytopenia-absent radius (TAR) syndrome
Explanation
TAR syndrome can be differentiated from Fanconi anemia and trisomy 18 by the presence of normal thumbs, which are absent in Fanconi’s and trisomy 18. Most survive, and the platelet counts improve spontaneously over time

Question 16

Severe thrombocytopenia
Small platelets
Eczema
Immunodeficiency
X-linked
What syndrome presents with these characteristics?

Answer 16

Wiskott-Aldrich syndrome
Explanation
Wiskott-Aldrich syndrome is an extremely rare X-linked disorder characterized by severe thrombocytopenia and microthrombocytes presenting in the neonatal period. Contrast this syndrome with immune thrombocytopenia, in which platelets are large. Affected boys develop eczema and immunodeficiency in later childhood. There is also an increased risk of lymphoma later in life

Question 17

What organ is producing most of the fetal red blood cells (RBCs) at 3 months of gestation?

Answer 17

Liver
Explanation
At 5–6 weeks of gestation, the liver takes over from the yolk sac as the site of RBC formation. Liver RBC production peaks at 5 months and decreases thereafter. The spleen then takes over as the major site of activity until around 7 months of gestation, when bone marrow erythropoiesis takes over.

Question 18

A 9-year-old presents with a history of:

Short stature
Absent thumbs
Abnormal radii
Microcephaly
Café au lait spots
Dark pigmentation
Renal anomalies
Today, the child presents with pallor, fatigue, bruising, and petechiae. Blood counts show pancytopenia.

What is the most likely diagnosis?

Answer 18

Fanconi anemia
Explanation
Fanconi anemia is an autosomal recessive disorder involving poor DNA repair mechanisms. It presents with pancytopenia and occurs at a mean age of 8–9 years. Children with Fanconi anemia often have multiple congenital anomalies like those listed here, but such anomalies are not required for the diagnosis. It can present in children as macrocytic anemia with or without other cytopenias, although usually patients develop symptomatic anemia after the development of other cytopenias.

Question 19

A 4-year-old girl presents with the following sequence of events:

Two weeks ago, she had a viral infection (cold).
Now, she has the acute onset of bloody nose and noticeable petechial rash.
Hemoglobin is normal.
Platelet count is 4,000/μL (normal is 150,000–400,00/μL).
Peripheral smear is normal except for the lack of platelets, and the ones that are seen are large (but not giant) platelets.
What is the most likely diagnosis?

Answer 19

Immune thrombocytopenia (ITP)
Explanation
Children with ITP present with petechiae, bruising, and/or mucosal bleeding. Parents often report a preceding viral illness. Thrombocytopenia is caused by an immune-mediated destruction of circulating platelets (not a platelet production problem

Question 20

A 4-year-old girl presents with the following:

Fever
Oral ulcers
Cervical lymphadenitis
Occasional rectal and/or vaginal ulcers
Neutropenia
These signs and symptoms occur about every 21 days.

What is the most likely diagnosis?

Answer 20

Cyclic neutropenia
Explanation
Cyclic neutropenia occurs at regular intervals of 21 ± 3 days. During the 3- to 7-day periods of neutropenia, these children typically have an absolute neutrophil count < 200/μL. Management includes granulocyte-colony stimulating factor (G-CSF) and antibiotics for infections

Question 21

By how much does a red blood cell (RBC) transfusion of 10 mL/kg raise hemoglobin?

Answer 21

Answer
2.5–3 g/dL
Explanation
In RBC transfusions, packed RBCs (PRBCs) are the primary product used. Whole blood is rarely used. PRBCs are the product of choice and are ordered according to blood type. A unit is typically a total volume of 250–350 mL of PRBCs reconstituted in plasma.

Question 22

A 4-year-old girl presents with the following lab findings:

Iron is low.
Total iron-binding capacity (TIBC) is high.
Transferrin saturation is low.
Ferritin is low.
What is the most likely diagnosis?

Answer 22

Iron deficiency anemia
Explanation
Iron deficiency anemia is the most common anemia in children. It is caused by poor iron intake, poor iron absorption, or excess blood loss, with inadequate iron intake being the most common cause.

Question 23

Autosomal recessive (AR)
Neutropenia
Exocrine pancreatic insufficiency
Diarrhea
Short stature
Metaphyseal dysostoses
Recurrent infections
FTT
Name the syndrome with these findings.

Answer 23

Answer
Shwachman-diamond syndrome
Explanation
Shwachman-Diamond syndrome is an AR disorder resulting from mutations in the SBDS gene. It presents with the listed features, several of which are similar to those of children with cystic fibrosis. Unique features of Shwachman-Diamond syndrome include neutropenia and metaphyseal dysostoses.

Question 24

What is the Japanese term for the collateral formation of vessels that is often seen in children with sickle cell disease (SCD) and stroke?

Answer 24

Moyamoya
Explanation
Moyamoya disease occurs in some patients with SCD and is the collateral formation of vessels due to vascular occlusion. Moyamoya means “puff of smoke,” which describes the appearance of the vessels on angiography.

Question 25

What is the lifespan of a mature red blood cell (RBC)?

Answer 25

120 days
Explanation
The spleen removes old or damaged RBCs, which are then ingested by macrophages.

Question 26

Structural or functional abnormality of cytoskeleton proteins: spectrin, ankyrin, and less commonly band 3, or protein 4.2
Complications can include cholelithiasis due to bilirubin stones and aplastic crisis from parvovirus infection.
A positive osmotic fragility test confirms the diagnosis.
What congenital hereditary anemia has these characteristics

Answer 26

Hereditary spherocytosis (HS)
Explanation
HS is an autosomal dominant anemia with the listed characteristics. It is the most common congenital hemolytic anemia in populations of northern European origin, but it also, less commonly, affects other populations

Question 27

A patient presents with hemorrhage after tonsillectomy. aPTT is prolonged. PT and platelet count are normal. You perform a mixing study, mixing the patient’s plasma 1:1 with normal plasma. The aPTT of the mixed sample is normal.

What laboratory testing should you perform next?

Answer 27

Factor assays for Factors 8, 9, and 11
Explanation
The results of these tests show that one of the clotting factors is deficient and could be Factors 8, 9, or 11. Factor 12 deficiency could account for the prolonged aPTT but would not present with bleeding

Question 28

What is the leading cause of death in children and adults with sickle cell disease?

Answer 28

Answer
Acute chest syndrome (ACS)
Explanation
ACS is characterized by the development of a new pulmonary infiltrate with fever, chest pain, tachypnea, and/or hypoxia. It can progress rapidly to respiratory failure.