Aplastic anemia

Question 1

definition

Answer 1

🧩Aplastic anemia is a physiologic and anatomic failure of the bone marrow characterized by a marked decrease or absence of blood-forming elements in the marrow and peripheral pancytopenia.

🧩Splenomegaly, hepatomegaly, and lymphadenopathy are not characteristic of this condition.

🧩It may be congenital or acquired.

Question 2

Fanconi anemia

Answer 2

⭕️Congenital aplastic anemias

⭕️Fanconi anemia (FA) is a rare autosomal recessive inherited bone marrow failure syndrome generally associated with multiple congenital anomalies.

⭕️The median age at hematologic presentation of patients is approximately 7 years. Bone marrow failure is virtually occurring in 90% by 40 years of age.

⭕️Hematologic dysfunction usually presents with macrocytosis, followed by thrombocytopenia, often leading to progressive pancytopenia and severe aplastic anemia (SAA).

⭕️FA frequently terminates in myelodysplastic syndrome (MDS) and/or AML.

Question 3

Diagnosis (fanconi anemia)

Answer 3

🔴chromosome breakage test: FA cells are hypersensitive to chromosomal breaks induced by DNA cross linking agents (clastogens); diepoxybutane (DEB) and mitomycin C (MMC) are the agents most frequently used in vitro to induce chromosome breaks, and other structural abnormalities.

🔴Bone marrow examination reveals: ➰hypocellularity
➰and fatty replacement consistent with the degree of peripheral pancytopenia.
▪️Residual hematopoiesis may reveal ➰dysplastic erythroid (megaloblastoid changes, multinuclearity)
➰and myeloid (abnormal granulation) precursors
➰and abnormal megakaryocytes.

🔴additional studies
🔹Endocrine studies
🔹Radiological Imaging and ultrasonography
🔹echocardiography
🔹Family survey for Fanconi anemia
🔹HLA matching of the patient and family member

Question 4

Associated congenital anomalies (fanconi anemia)

Answer 4

➰ increased pigmentation of the skin along with café au lait and hypopigmented areas
➰short stature (impaired growth hormone secretion),
➰skeletal anomalies (especially involving the thumb, radius, and long bones),
➰male hypogenitalism,
➰microcephaly
➰abnormalities of the eyes (e.g., microphthalmia, ptosis) and ears including deafness.
➰developmental delay
➰renal and cardiac anomalies.

Question 5

Management (fanconi anemia)

Answer 5

● Androgen (oxymetholone) and cytokine therapy (granulocyte colony-stimulating factor [G-CSF] or granulocyte-macrophage colony-stimulating factor [GM-CSF]) should be administered when moderate to severe cytopenia is present.

● Supportive transfusions: Blood products should be irradiated, leukocyte depleted, and of single donor origin.
Blood relatives should not be used as blood donors until a matched allogeneic related donor transplant is ruled out.

●***Allogeneic hematopoietic stem cell transplantation: HLA typing should be done at diagnosis. The donor should be evaluated to exclude a diagnosis of Fanconi anemia.

Question 6

Causes of acquired aplastic anemia

Answer 6

1️⃣ Idiopathic (70% or more of cases)

2️⃣ Secondary
🔹Drugs:
〰️Predictable, dose dependent, rapidly reversible (chemotherapy, chloramphenicol).
〰️Unpredictable: Antibiotics (chloramphenicol, sulfonamides), anticonvulsants (mephenytoin), antirheumatics (gold), antidiabetics (chlorpropamide), antimalarial (quinacrine).
🔹Chemicals: insecticides (e.g., DDT, Parathion, Chlordane).
🔹Toxins (e.g., benzene, carbon tetrachloride, glue, toluene).
🔹Irradiation
🔹Infections: viral hepatitis, HIV infection, EBV, rubella, influenza, parainfluenza…etc.
🔹Aplastic anemia preceding acute leukemia (hypoplastic preleukemia)
🔹Myelodysplastic syndromes, thymoma, paroxysmal nocturnal hemoglobinuria
🔹Malnutrition, kwashiorkor, marasmus, anorexia nervosa
🔹Pregnancy

Question 7

Severity of fanconi anemia

Answer 7

⭕️Mild aplastic anemia
bone marrow cellularity of more than 50%
➕ granulocyte count, > 1,000/mm3, or platelet count, >50,000/mm.

⭕️Moderate aplastic anemia
bone marrow cellularity of more than 20-50%
➕ granulocyte count, > 500-1,000/mm3, or platelet count, 20,000-50,000/mm3.

⭕️Severe aplastic anemia
bone marrow cellularity of less than 25%
➕ granulocyte count, <500/mm3 (<200/mm3 in very severe aplastic anemia), or platelet count, <20,000/mm.

Question 8

Treatment of fanconi anemia

Answer 8

🔮 mild to moderate aplastic anemia ➡️should be observed for spontaneous improvement or complete resolution.

🔮 severe ➡️ The treatment of choice for SAA
➰hematopoietic stem cell transplantation
➰In the absence of an HLA-matched sibling marrow donor treat the patient with ATG, cyclosporine A (CSA), methylprednisolone, and growth factors such as G-CSF or GM-CSF.

Question 9

cardinal features (Hemolytic Anemias)

Answer 9

pallor
jaundice
with or without splenomegaly

Question 10

Lab features(hemolytic anemia)

Answer 10

anemia
reticulocytosis
indirect hyperbilirubinemia

Question 11

Suggestive Features (hemolytic anemia)

Answer 11

⭕️Ethnic factors: High incidence of sickle cell disease in the south of Iraq, thalassemia trait in Mediterranean people

⭕️History of anemia, jaundice, or gallstones in family

⭕️Intermittent bouts or persistent indirect hyperbilirubinemia/jaundice

⭕️Dark color urine and hemoglobinuria

⭕️Presence of multiple gallstones

⭕️Development of anemia or hemoglobinuria after exposure to certain drugs

Question 12

Extravascular vs Intravascular hemolysis

Answer 12

🟢 Markers of Extravascular Hemolysis
1. Increased unconjugated bilirubin.
2. Increased lactic acid dehydrogenase in serum.
3. Decreased plasma haptoglobin.
4. Increased fecal and urinary urobilinogen.

🟢Markers of Intravascular Hemolysis
1. Increased unconjugated bilirubin.
2. Increased lactic acid dehydrogenase in serum.
3. Hemoglobinuria.
4. Low or absent plasma haptoglobin.

Question 13

Classification of Hemolytic Anemia

Answer 13

🔹I. Inherited disorders
1. RBC membrane defect: Hereditary spherocytosis
2. Enzyme defect: G6PD deficiency
3. Hemoglobin defects: Thalassemia

🔹II. Acquired disorders
1. Immune mediated; i. Autoimmune (autoimmune hemolytic anemia), ii. Alloimmune (hemolytic transfusion reaction)
2. Non-immune: valve prosthesis, microangiopathy.

Question 14

Normal Hemoglobins

Answer 14

🔴Hemoglobin A: It is the designation for the normal hemoglobin that exists after birth. Hemoglobin A is a tetramer with two alpha chains and two beta chains (2

🔴Hemoglobin A2: It is a minor component of thehemoglobin after birth; it consists of two alpha chains and two delta chains (22). Hemoglobin A2 generally comprises 2-3.4% of the total red cell hemoglobin

🔴 Hemoglobin F: It is the predominant hemoglobin during fetal development. The molecule is a tetramer of two alpha chains and two gamma chains (22).

Question 15

Hb according to age

Answer 15

🔺After the 8th gestational wk  Hb F is the predominant Hb

🔺 At 24 wk gestation  Hb F constitutes 90% of the total Hb 5-10% of Hb A is present

🔺During the 3rd trimester  there is a gradual decline of Hb F

🔺At birth  Hb F averages 70% of the total; Hb A averages 30%.

🔺By 6-12 mo of age  less than 2% of Hb F can be detected; Hb A predominates

Question 16

B-Thalassemias(types)

Answer 16

I. B-thalassemia trait/thalassemia minor: Deficiency of one beta genes leads to essentially no significant hemolysis and no unusual signs or symptoms.

II. Thalassemia major: Deficiency of both genes leads tosignificant hemolytic anemia.

III. Thalassemia intermedia: is a condition in which the degree of hemolysis is milder even though the patient may have a deficiency of both beta genes. There is minimal or no need for transfusions.

Question 17

B-thalassemia major Pathophysiology

Answer 17

0 . absence bta gene

1. There is an excess of α-globin chains
2. The α-globin tetramers (α4) are formed, and these inclusions interact with the red cell membrane and shorten red cell survival
3. The γ-globin chains are produced in normal amounts, leading to an elevated Hb F (α2γ2)
4. The δ-globin chains are also produced in normal amounts, leading to an elevated Hb A2 (α2δ2)

Question 18

Clinical Features( B thalassemia)

Answer 18

🔹Anemia first becomes apparent between 3-6 months when production of Hb F declines, the infant clinically normal at birth (as fetal Hb does not contain ß chains), then during first year of life Progressive anemia will occur. The severity of this anemia results from a combination of ineffective erythropoiesis and shortened survival of the red blood cell in circulation

🔹Failure to thrive

🔹Hepatosplenomegaly & jaundice

Question 19

Complications (B thalassemia)

Answer 19

🔴1-Complications of hemolytic anemia: include expansion of bones leads to thinning of cortex & tendency to fractures,
bossing of skull, and specific facies with hair-on-end appearance on x-ray, gallstones, and chronic leg ulcers.

🔴2-Complications of Iron overload: caused by repeatedtransfusion, increased iron absorption due to ineffectiveerythropoiesis; the complications of iron overload affect all
organs of the body, including the heart (arrhythmias, heart
failure), liver (cirrhosis), thyroid (hypothyroidism), pancreas (diabetes), and hypothalamic-pituitary axis
(delayed growth and sexual maturity) unless chelation therapy is given.
🔴3-Infections: secondary to splenectomy & blood transfusion

Question 20

Laboratory diagnosis ء(B thalassemia)

Answer 20

⭕️I. Complete blood picture:
 In the severe forms of thalassemia, the Hb level ranges from 2-8 g/dL.
 Microcytic hypochromic anemia.
 Blood film shows nucleated red cells, target cells,polychromasia, basophilic stippling and anisopoikilocytosis
 MCV and MCH are significantly low; normal RDW

⭕️II. Hemoglobin electrophoresis: elevated Hb F (>50%) with variable A2.

⭕️III. Evidence of hemolysis: Unconjugated hyperbilirubinemia

⭕️IV. High serum iron level and high serum ferritin level

⭕️V. DNA analysis: This test is used to investigate deletions and mutations in the beta globin producing genes.

⭕️VI. Both parents have β -thalassemia trait

Question 21

Management (B thalassemia)

Answer 21

🟢I. Blood transfusion: children are entirely transfusion dependent,
to maintain the Hb > 10g /dl, by transfusion every 4-6 weeks
with fresh, filtered blood

🟢 II. Iron chelation: start after 10-15 units of blood,
➰ 1. Desferoxamine by subcutaneous infusion over 8-12 hours,
5-7 days weekly,
➰ 2. Deferasirox (Exjade): a new oral chelator, with few side
effects

🟢III. Splenectomy: indicated if the spleen is enlarged substantially
or there is evidence of hypersplenism, to reduce the transfusion frequency.

🟢IV. Stem cell transplantation (SCT): survival exceeds 90%.

Question 22

α-thalassemia

Answer 22

•In α-thalassemia there are relatively fewer α-globin chains and an excess of β- and γ-globin chains.

• These excess chains form Bart’s hemoglobin (γ4) in fetal life and Hb H (β4) after birth. These abnormal tetramers are not as lethal but lead to extravascular hemolysis

Question 23

Laboratory Diagnosis (sickle cell anemia)

Answer 23

The diagnosis is made by identifying the precise amount and type of hemoglobin present using hemoglobin electrophoresis

🔴In Sickle cell anemia
➰Hb S 85-95%
➰Hb A 0%
➰Hb F 5-15%
➰Hb A2 2-3%

🔴In Sickle cell trait
➰Hb S 40-45%
➰Hb A 55-60%,
➰Hb A2 2-3%

Question 24

treatment of sickle cell anemia

Answer 24

I. Treatment of vaso-occlusive crisis (hydration, pain control, empirical antibiotics, blood transfusion whether simple or exchange transfusion)
II. Chronic transfusion therapy (stroke, acute chest syndrome)
III. Medical intervention: increased hemoglobin F production (hydroxyurea)
IV. Stem cell transplant
VI. Prophylactic oral penicillin
VI. Routine childhood immunizations
VII. Annual administration of influenza vaccine is highly recommended.

Question 25

Complications of sickle cell anemia

Answer 25

1. ⭕️Splenic sequestration crisis: life-threatening, hyperacute decline in the hemoglobin level (blood volume) secondary to splenic pooling of the patient’s RBCs and sickling within the spleen.
   The spleen is moderately to markedly enlarged, with reticulocytosis.
2. ⭕️Aplastic crisis: parvovirus B19 infects RBC precursors in the bone marrow and induces transient RBC aplasia with reticulocytopenia and a rapid worsening of anemia.
3. ⭕️Hyperhemolytic crisis: Acute decrease in hemoglobin, associated with medications or infection. The level of bilirubin increases, and reticulocytosis and accentuated jaundice may occur. Patients usually have associated G6PD deficiency.
4. ⭕️Acute chest syndrome: vaso-occlusive crisis within the lungs, often associated with infection and infarction.
   •The patient may first complain of pain; within a few hours he develops cough, increasing respiratory and heart rates, hypoxia, and progressive respiratory distress.
   •Treatment involves early recognition and prevention of hypoxemia Oxygen, fluids, judicious use of analgesics, antibiotics, bronchodilators, and RBC transfusion; rarely exchange transfusion
5. ⭕️Vaso-occlusive crises: Occur in any organ of the body and are manifested by pain or significant dysfunction.
   -clinical or “silent” stroke, manifested by sudden onset of an altered state of consciousness, seizures, or focal paralysis.
   - Priapism occurs most typically in boys between 6 and 20 years old
   - hand-foot syndrome is the most common type of vaso-occlusive event. The pain usually localizes to the long bones of the arms or legs, but may occur in smaller bones of the hands or feet in infancy; it usually lasts 2 to 7 days.
   •Therapeutic steps of veno-occlusive crises include 
6. Administration of oxygen
7. Fluids
8. Transfusion to achieve a hemoglobin S less than 30% (often by

Question 26

Sickle Cell Disease pathogenesis

Answer 26

In sickle cell disease, there is a single amino acid substitution (valine for glutamic acid at the β6 position)

•Sickle hemoglobin crystallizes and forms a gel in the deoxygenated state

•As the oxygen is low and saturation declines, sickling may occur, occluding the microvasculature. The surrounding tissue undergoes infarction, inducing pain and dysfunction.

•This sickling phenomenon is exacerbated by hypoxia, acidosis, fever, hypothermia, and dehydration.

Question 27

Clinical Manifestations sickle cell anemia

Answer 27

A child with sickle cell anemia is vulnerable to life-threatening infection by 4 months of age

•By that time, splenic dysfunction is caused by sickling of the RBCs within the spleen, resulting in an inability to filter microorganisms from the blood stream

•Splenic dysfunction is followed eventually by splenic infarction, usually by 2 to 4 years of age.

In the absence of normal splenic function, the patient is susceptible to overwhelming infection by encapsulated organisms, especially S. pneumoniae and other pathogens
• The hallmark of infection is fever.

•Current precautions to prevent infections include prophylactic daily oral penicillin begun at diagnosis and vaccinations against pneumococcus, H. influenzae type b, hepatitis B virus, and influenza virus.

•The anemia of SS disease is usually a chronic, moderately severe, compensated anemia that is not routinely transfusion dependent.