PBL REPORT MODULE 3

Immunology and Hematology

Tutor : dr. Nurul Fadilah Ali Polanunu

Group 9B

11020200167 Andi Fahira Chaidir

11020200174 Lulu Luqyana Amirah Salsabila

11020200187 Nurul Ainun Annisa

11020200190 Andi Fitri Nurul Khazanah T.D

11020200198 Ratna Febirianti

11020200203 Andi Mappaita El Firman

11020200211 Salma Umarella

11020200219 Regina Lestari

11020200224 Mega Alfima

11020200238 Nirwana

11020200247 Rahmatillah

BLOK IMUNOLOGI DAN HEMATOLOGI

FAKULTAS KEDOKTERAN UNIVERSITAS MUSLIM INDONESIA

 PREFACE

Assalamu’alaikumwarahmatullahiwabarakatuh
Praise be to Allah SWT for giving us convenience so that we can complete this report in a timely
manner. Without His help, of course, we would not be able to complete this report properly.
Prayers and greetings may be abundantly bestowed upon our beloved king, the Prophet
Muhammad, whom we will later turn to his shari'a in the hereafter.

We give thanks to Allah SWT for the abundance of His healthy favors, both in the form of
physical health and reason, so that we are able to complete the report as a tutorial for
immunology & hematology blocks.

We certainly realize that this report is far from perfect and there are still many errors and
shortcomings in it. For this reason, we expect criticism and suggestions from our tutors for this
report, so that this report can later become a better report. Then if there are many errors in this
report we apologize profusely.

We also thank all parties especially to our group 9 tutors who have guided in writing this report.

Thus, hopefully this report can be useful. Thank you.

Waalaikumussalamwarrohmatullahiwabarokatu

Makassar, July 16th, 2021

SCENARIO 3

A 53-year-old man came to the general practitioner with complaints of weakness for the past
1 month. Complaints accompanied by feeling easily tired, nausea, vomiting, decreased
appetite, a little tightness, and swollen legs. The patient has been diagnosed with kidney
failure since 3 months ago and has been receiving regular treatment. Physical examination
revealed anemic conjunctiva, spoon nails, and edema in both legs. In the laboratory results
obtained MCV 75, MCHC 28.

DIFICULT WORD

1. MCV (Mean Corpuscular Volume) is a measurement of the volume or average size

of red blood cells.
2. MCHC (Mean Corpuscular Haemoglobin Concentration) is calculation of the
average concentration of hemoglobin in one red blood cell

Reference:

Laloan,R.J. et al. 2018.RELATIONSHIP OF SMOKING WITH ERRYTHROCYTE INDEX VALUE (MCV, MCH,
MCHC) IN STUDENT smokers. Journal of Medicine and Rehabilitation.Vol1 No 2.

KEY SENTENCES

1. 53 years old man

2. Complaints off weakiness since last 1 month
3. Easly tired , nausea , vomiting, decreased appetite, a litle tightness , and swallen feet
4. Diagnosed with kedney failure 3 month ago and has been receivengreguler treatment
5. Physical examination of anemic conjungctiva , spoon nails , and edema in both leg .
6. Laboratory results obtained MCV 75 , MCHC 28

QUESTION

1. Explain the basic hematologi in general?

2. What is the definition and etiology of anemia ?
3. Explain the classification of anemia !
4. Explain the differential diagnosis related to the scenario?
5. What the interpretion of MCV and MCHC ?
 6. Explain the diseases associated with the scenario !
7. Explain the diagnostic step from scenario !
8. Explain the islamic perspective according to the scenario !

DISCUSSION
1. Explain the basic hematologi in general ?

Hematopoietic stem cells are rare cells with the ability to self-renew and give rise to
multilineage and unilineage progenitor cells. Multilineage progenitor cells , such as colony
forming unit–granulocytic-erythroid-monocytic-megakaryocytic cells (CFU-GEMM), can give
rise to more than one type of lineage-committed precursor cell, whereas unilineage progenitor
cells , such as colony forming unit–erythroid (CFU-E) cells, give rise to only one type of
precursor cell. Stem cells and progenitor cells are primitive undifferentiated cells that display no
identifiable morphologic features. Stem cells express specific cell surface proteins, including
CD34, which mediates adhesion to marrow stroma; CD117 (c-kit), the SCF receptor that induces
stem cell proliferation when bound by SCF (kit ligand, produced by endothelial cells); CD133,
which induces development of cell membrane protrusions; and c-mpl, the TPO receptor that
promotes stem cell growth.
In contrast, precursor cells display lineage-specific morphologic and phenotypic features. For
example, erythroid precursor cells contain hemoglobin-rich cytoplasm, myeloid precursor cells
contain myeloperoxidase (MPO)-positive cytoplasmic granules, and megakaryocyte precursors
display enlarged hyperlobated nuclei and cytoplasmic buds. Precursor cells also express lineage-
specific molecules that can be exploited as phenotype markers when detected with monoclonal
antibodies by flow cytometry, immunohistochemistry, or cytochemistry. Examples include
glycophorin A, CD71 (transferrin receptor), and hemoglobin for erythroid precursors; CD13,
CD33, MPO, and alpha naphthyl acetate esterase (ANAE) for myeloid precursors; CD41, CD61,
and von Willebrand factor (VWF, factor VIII-related antigen) for megakaryocyte precursors;
cytoplasmic CD3 (cCD3), CD7, and terminal deoxynucleotidyltransferase (TdT) for T cell
precursors; CD19, paired box (PAX) protein 5 (PAX-5), cCD22, and TdT for B cell precursors;
CD14, CD68, CD163, and alpha naphthyl butyrate esterase (ANBE) for monocyte precursors;
and CD117 and mast cell tryptase for mast cell precursors.

The normal bone marrow contains both stromal and hematopoietic elements . Bone marrow
cellularity can be determined by examination of a bone marrow biopsy and aspirate. Bone
marrow cellularity is calculated as the ratio of hematocellular marrow volume to fatty marrow
volume. Normal iliac crest marrow cellularity in a newborn is 90%, with a steady reduction to
30%-40% in the elderly. The normal marrow is populated by myeloid and erythroid cells in
approximately a 3 : 1 ratio . Most myeloid cells are neutrophilic, with scattered eosinophils,
basophils, and mast cells . In the normal marrow most neutrophilic cells are mature (band
neutrophils and segmented neutrophils) with lesser numbers of myelocytes and promyelocytes.
Myeloblasts (and stem cells) are rare cells in the normal marrow, accounting for no more than
1%-3% of the marrow cell count. Lymphocytes account for about 10%-15% of the marrow
cellularity in adults, while in young children they may account for up to 50%. Monocytes and
promonocytes account for 2%-3% of the marrow cellularity. Relatively few megakaryocytes
(approximately 0.1%) are scattered throughout the normal marrow, often in proximity to vascular
structures.

Under normal circumstances only fully mature (enucleated) erythroid cells and myeloid cells are
released into the bloodstream from the bone marrow. Under stress conditions (infection,
inflammation, blood loss, trauma, etc.) less mature cells are released into the blood. For example,
acute bacterial infection leads to release of immature myeloid cells (band neutrophils,
metamyelocytes, and myelocytes) and blood loss leads to release of reticulocytes and nucleated
red cells. While mature erythrocytes remain in the bloodstream, myeloid cells (neutrophils,
eosinophils, and basophils) and monocytes are recruited to inflamed tissues under the influence
of a closely related group of chemoattractant cytokines known as chemokines .Chemokines are
produced by a range of cell types, including endothelial cells, macrophages, T cells, fibroblasts,
keratinocytes, and stromal cells.

Under normal conditions, neutrophils migrate from the blood to bronchial and intestinal
submucosa, where they serve as first responders to infection. Blood neutrophils also rapidly
migrate to localized sites of acute infection or injury. Intravascular neutrophils reside in two
freely exchangeable pools: the circulating pool and the marginal pool . At any time, most
intravascular neutrophils are not circulating and are instead marginating along capillary and
venular walls (the marginal pool). In response to infection or inflammation, cells within the
marginal pool rapidly enter the circulating pool. The total intravascular granulocyte pool
(circulating and marginal) is supported by the marrow granulocyte reserve. This reserve,
primarily composed of mature myeloid cells, is approximately 20 times larger than the blood
granulocyte pool and capable of rapidly repleting the blood granulocyte pool in the face of
infection or inflammation. The rapid migration of blood neutrophils into sites of inflammation is
mediated by the chemokine IL-8 (CXCL-8) produced by activated macrophages.

Eosinophils and basophils in blood migrate to and reside within the submucosa of the
aerodigestive tract and, like neutrophils, enter other tissues in response to chemokines released,
in turn, in response to infection or inflammation. Eosinophils are recruited to inflamed tissues by
IL-5, eotaxin, and chemokine ligand 5 (CCL-5), while basophils are recruited by CCL-2 and
CCL-5. Mast cells, unlike basophils, are not typically found in peripheral blood, instead homing
to perivascular sites within a variety of connective tissues, including marrow stroma. But mast
cells, like basophils, participate in allergic responses with release of the vasoactive factor
histamine.

Many blood monocytes, like neutrophils, reside in the marginal pool and rapidly enter tissues to
undergo further differentiation into several specialized cell types of the mononuclear phagocyte
system, including histiocytes (macrophages), dendritic cells, osteoclasts, and microglial cells.
Blood monocyte-derived macrophages are particularly numerous in organs such as liver, spleen,
lymph node, and lung that capture and process antigen .To replenish macrophages in inflamed
tissues, blood monocytes are recruited to areas of inflammation by the chemokine CCL-2 (also
known as macrophage chemoattractant protein-1).

Megakaryocytes remain in the marrow in the vicinity of vascular sinuses, producing platelets by
cytoplasmic budding and releasing them directly into the bloodstream.

In response to the chemokine IL-13 (CXCL-13), naïve immunoglobulin M (IgM) and/or IgD
positive B cells enter peripheral lymphoid tissues via high endothelial venules and home in on
lymphoid follicles in lymph nodes and spleen to await antigen-driven germinal center maturation
. Naïve CD7+, CD3− T cells home to the thymic cortex to begin the complex process of T cell
maturation . NK cells are released into the bloodstream as fully mature and functional cells,
homing primarily to lymphoid tissues and submucosal sites. Circulating NK cells also enter sites
of inflammation in response to the cytokine IL-12 produced by activated macrophages.
 Reference :Hudnall,S,D.2012. Hematology.Elsevier Inc.

2. What is the definition and etiology of anemia ?

Anemia is defined as a reduction in hemoglobin (Hb) two standard deviations below the mean,
based on age-specific norms. 1

Anemia is defined as a reduction of the hemoglobin concentration or red blood cell (RBC)
volume below the range of values occurring in healthy persons. “Normal” hemoglobin and
hematocrit (packed red cell volume) vary substantially with age and sex .There are also racial
differences, with significantly lower hemoglobin levels in African American children than in
white non-Hispanic children of comparable age. Anemia is a significant global health problem
affecting children and reproductive-age women.2

Anemia may result from a variety of intrinsic red cell defect, as well as extrinsic causes. Based
upon physiologic mechanism, the anemias can be broadly classified into those due to blood
loss,decreased red cell production , or increased red cell destruction. More simply, anemia can
also be classified into two broad groups based upon the presence or absence of compensatory
reticulocyte response. Type of anemia marked by deficient erythropoiesis (and thus a low
reticulocyte count) includethpse due to nutrient deficiens and hem biosynthesis defects. Type of
anemia marked by increased reticulocytes ( reticulocytosis) include those due to blood loss and
hemolysis. Under normal conditions, given the 120 day lifespan of red cells, about 1%-2% of red
celss must be replaced each day. The replacements are reticulocytes, relatively, large red cells
newly released from the marrow that retain a loose reticulated network of rough endoplasmic
reticulum that staind light blue (polychromatophilic) with the wright stain. Staining reticulocytes
with RNA binding dyes such as new methylene blue or fluorochromethiazole orange provides
for improved accuracy in enumerating reticulocytes.2

DECREASED PRODUCTION INCREASED DESTRUCTION OR LOSS (HIGH

(LOW RETICULOCYTE RETICULOCYTE COUNT)
COUNT)
Nutritional Deficiency Blood Loss
• Iron •
deficiency—hemoglobin Menorrhagia
production defect
• Gastrointestinal bleeding
• Folic acid deficiency—DNA
production defect • Trauma

• Cobalamin deficiency—DNA
production defect

Bone Marrow Failure Hemolytic Anemia (Intrinsic)

• Fanconi anemia—autosomal• Hemoglobinopathy
recessive DNA repair defect
• Aplastic anemia—autoimmune o Thalassemia (reduced alpha or beta globin synthesis)
or toxin mediated
o Production of mutant globin protein (hemoglobins S, C, D, E,
Red Cell Aplasia etc.)
• Diamond-Blackfan anemia—
autosomal dominant • Cell membrane defects (spectrin, ankyrin)—membrane
instability
• Anemia of renal disease—EPO
deficiency o Hereditary spherocytosis

• Parvovirus B19 infection o Hereditary elliptocytosis

• Enzyme deficiency—oxidative damage to cellular proteins

Sideroblastic Anemia (Defective
Heme Synthesis)
o Glucose-6-phosphate dehydrogenase deficiency
• Lead poisoning
o Pyruvate kinase deficiency
• Ethanol toxicity
• Paroxysmal nocturnal hemoglobinuria—
• Myelodysplasia
glycosylphosphatidylinositol anchoring defect (PIG-A
mutation) leading to loss of CD55 and CD57 and
hypersensitivity to complement-mediated lysis

Myelophthisis (Marrow Hemolytic Anemia (Extrinsic)

Infiltration with Loss of
Normal Hematopoietic Tissue)
• Granulomatous disease • Autoimmune hemolytic anemia—immune-mediated
hemolysis
• Metastatic cancer
• Microangiopathic hemolytic anemia—mechanical damage to
• Leukemia red cells by microvascular thrombi, cardiac valve defects,
thermal injury
Chronic Inflammation
• Anemia of chronic disease— • Hypersplenism—congestive and infiltrative diseases of the
hepcidin-mediated iron spleen
utilization defect
• Drug induced

• Non-immune (dapsone, sulfasalazine)

• Immune mediated (penicillin, cephalosporin, methyldopa,

levodopa, quinidine)
3

Reference:
 1. Calihan,J. 2021.Harriet Lane HandbookTwenty Second Edition.Elsevier, Inc.

2. Thornburg,C,D. 2020.Nelson Textbook of Pediatrics.Elsevier Inc.

3. Hudnall,S,D.2012. Hematology.Elsevier Inc.

3. Explain the classification of anemia !

Anemia Classified by Pathophysiologic Mechanism. 1

I. Dilutional (expansion of the plasma volume)

• Pregnancy
• Hyperglobulinemia
• Massive splenomegaly

II. Decreased RBC production

A. Bone marrow failure

• Decreased building blocks or stimulation
a. Iron, protein
b. Chronic infection, chronic renal disease
• Decreased erythron
a. Hypoplasia (hereditary, drugs, radiation, toxins)
b. Marrow replacement (tumor, fibrosis, infection)
B. Ineffective production
• Megaloblastic (vitamin B 12 and folate deficiency, myelodysplasia,
erythroleukemia)
• Normoblastic (refractory anemia, thalassemia)

III. Increased RBC loss. 1

A. Acute hemorrhage
B. Hemolysis
• Intrinsic RBC disorders
a. Hereditary
✓ Hemoglobinopathies
✓ RBC enzyme deficiency
✓ Membrane defects
✓ Porphyrias
b. Acquired
✓ Paroxysmal nocturnal hemoglobinuria
 ✓ Lead poisoning

• Extrinsic RBC disorders. 1

a. Immune
b. Mechanical
c. Infection
d. Chemical agents
e. Burns
f. Hypersplenism
g. Liver disease

Morphologic Classification of Anemia

1. Microcytic Anemia
The microcytic anemias are characterized by abnormal Hb synthesis with normal RBC
production. A logical progression of diagnostic steps requires, first, that iron deficiency anemia
be ruled out . If iron deficiency anemia is diagnosed rather than ruled out, it is important to
consider gastrointestinal bleeding as the cause, although it is rare in pregnant women. This can
be accomplished by testing the stool for the presence of occult blood with guaiac to assess for
upper gastrointestinal bleed or an immunoassay against hemoglobin for lower gastrointestinal
bleed. If a microcytic anemia is not the result of iron deficiency, another cause should be sought,
such as hemoglobinopathy including thalassemia, chronic infection or inflammatory disorder, or
one of the sideroblasticanemias. For this purpose, the following tests should be considered: 1

• Peripheral blood smear examination

• Serum iron studies (iron, TIBC, percent saturation) and ferritin
• HPLC
• Whole-blood lead level
• Molecular testing for α- and β-thalassemias
• Bone marrow examination

As noted, iron deficiency anemia is associated with decreased serum iron, increased TIBC
(>400 µg/dL), decreased percent saturation, and decreased ferritin concentration (<20 µg/L).
Because iron deficiency is the most common anemia in pregnancy, it is reasonable and cost-
effective to screen all women with microcytic anemia with ferritin initially. A ferritin level of
less than 20 µg/L is generally diagnostic of iron deficiency anemia. However, iron deficiency
anemia may still be present when the serum ferritin level is greater than 20 µg/L, particularly in
the setting of other conditions including chronic disease. Additional tests to confirm iron
deficiency may be warranted in such settings. Anemia of chronic disorders is associated with
decreased serum iron level but paradoxically normal or increased ferritin and decreased TIBC. If
the iron studies and ferritin are normal, the patient should be evaluated for thalassemia or a
sideroblastic anemia. Hb evaluation by HPLC can help diagnose thalassemias and
hemoglobinopathies; however, concurrent iron deficiency may mask HPLC abnormalities seen
in thalassemia and therefore iron deficiency should be evaluated first and treated before
performing HPLC. Molecular testing for thalassemia confirmation may also be considered. Ring
sideroblasts are present in the bone marrow of individuals with hereditary or acquired
sideroblastic anemia (e.g. lead poisoning, alcohol abuse, arsenic, excess dietary zinc). 1

2. Normocytic Anemia
Because of the diverse nature of normocytic anemia, it is the most difficult type to evaluate. The
reticulocyte count varies according to whether RBC production is increased, normal, or
decreased. If erythropoiesis is increased, one must differentiate between hemorrhage and an
increased rate of destruction. The blood smear may reveal a type of RBC shape that can be
virtually diagnostic. Schistocytes are seen in microangiopathic hemolysis—as in the HELLP
syndrome ( h emolysis, e levated l iver enzymes, l ow p latelets) and thrombotic
thrombocytopenic purpura—and in association with prosthetic heart valves. Other types of
poikilocytes that may be encountered on peripheral blood smear examination and that may
suggest an etiology include sickle cells, target cells, stomatocytes, ovalocytes, spherocytes,
elliptocytes, and acanthocytes. 1

The Coombs test differentiates immune from nonimmune causes of hemolysis. Immune
hemolysis is related to alloantibodies, drug-induced antibodies, and autoantibodies. Nonimmune
causes of hemolysis include various hereditary disorders such as hemoglobinopathies, disorders
of the RBC membrane (hereditary spherocytosis and hereditary elliptocytosis), deficiency of an
RBC enzyme, or the porphyrias, and acquired, nonimmune hemolytic anemias may be caused by
PNH or lead poisoning. 1

Bone marrow examination can be helpful for evaluation of patients who have
hypoproliferativeanemias with normal iron studies, and folate and vitamin B 12 levels. If
increased ring sideroblasts are identified, both acquired and hereditary forms of sideroblastic
anemia must be considered. If erythropoiesis is normoblastic, etiologic mechanisms fall into two
major categories. The first category has myeloid-to-erythroid production ratios greater than 4 : 1
and includes red cell aplasia, primary marrow-based disorder (e.g., chronic myeloid leukemia),
effects of chronic diseases, infection (e.g. parvovirus), and endocrine disorders such as
hypothyroidism and hypopituitarism. In contrast, the myeloid-to-erythroid ratio is decreased
(e.g., 2 : 1 or less) when erythroid hyperplasia is present, as with relatively acute hemolysis or
myelodysplastic syndrome (MDS) if in conjunction with significant dysplasia. If there is
megaloblastic erythropoiesis and erythroid hyperplasia, considerations include nutritional
deficiencies such as folate and vitamin B 12 deficiencies, MDS, drugs, particularly those that
interfere with nucleotide synthesis, and toxins (benzene, arsenic). 1

3. Macrocytic Anemia
Macrocytic anemia is associated with either: (1) an increased rate of RBC production and release
of less than fully mature RBCs, or (2) disorders of impaired DNA synthesis. Abnormal serum
vitamin B 12 or serum and RBC folate levels allow a diagnosis of vitamin B 12 or
folatedeficiency. If a diagnosis of folate deficiency is confirmed, the various causes of decreased
deconjugation of the polyglutamate and malabsorption must be considered. Folic acid, the
polyglutamate present in food, must be deconjugated by intestinal enzymes such as
dihydrofolatereductase for absorption. Causes of decreased deconjugation and hence poor
absorption of folate include alcoholism, and folate antagonists (methotrexate, pyrimethamine,
trimethoprim), which inhibit dihydrofolatereductase. Additional causes of malabsorption causing
folate deficiency are celiac sprue, inflammatory bowel disease, and gastric bypass surgery. If
vitamin B 12 deficiency is diagnosed then, causes of malabsorption such as pernicious anemia or
small bowel malabsorption should be considered. Pernicious anemia, the most common cause of
B 12 deficiency, is diagnosed when anti–intrinsic factor antibodies are present. These antibodies
bind intrinsic factor produced in the stomach and thus inhibit B 12 absorption. If anti–intrinsic
factor antibodies are negative, then referral to gastroenterology for appropriate evaluation for
small bowel malabsorption is appropriate. 1

Use of the mean corpuscular volume (MCV) and reticulocyte count in the diagnosis of anemia.

CATEGORY CLASSIFICATION DISEASE PROCESS

Decreased RBC Microcytic Iron deficiency
production Thalassemia
(hypoproliferative) Sideroblastic
Chronic disease (neoplasm, infection,
diabetes, uremia, thyroid disease, cirrhosis)
Normocytic Primary bone marrow problem (aplastic,
myeloid metaplasia, myelofibrosis,
myelophthisic anemia, Diamond-Blackfan
anemia)
Secondary bone marrow problem (uremia,
liver disease, endocrinopathy, chronic
inflammation)
Macrocytic Folic acid deficiency
Liver disease
Vitamin B 12 deficiency
Scurvy
Hypothyroidism
Chemotherapy, immunosuppressive therapy
Increased RBC Intrinsic Membrane disorder (spherocytosis, sickle cell,
destruction (hemolytic) stem cell disorder, elliptocytosis, spur cell)
Extrinsic Hemoglobin disorder (thalassemia,
autoimmune, hemoglobinopathies)
Infections (hepatitis and cytomegalovirus,
Epstein-Barr virus, typhoid fever, Escherichia
coli )
Medications (penicillin, antimalarials, sulfa
drugs, or acetaminophen)
Leukemia or lymphoma
Autoimmune disorders (systemic lupus
erythematosus, rheumatoid arthritis, Wiskott-
Aldrich syndrome, ulcerative colitis)
Enzyme defect (G6PD)
RBC loss (hemorrhagic) Acute or chronic Gastrointestinal tract
Traumatic
Intraperitoneal
Extraperitoneal
Gynecologic
Urinary
Pelvic
Drug related
Epistaxis, hemoptysis
3

Reference :

1. Kilpatrick, S,J.,Kitahara, S. 2019.Creasy and Resnik's Maternal-Fetal Medicine:

Principles and PracticeEighth Edition.Elsevier, Inc.

2. Thornburg,C,D. 2020. Nelson Textbook of Pediatrics.Elsevier Inc.

3. Ezenkwele,U,A. 2013. Emergency MedicineSecond Edition.Elsevier Inc

4. Explain the differential diagnosis related to the scenario?

The differential diagnosis of anemia is facilitated by classification of the anemia into one of three
groups: decreased RBC production, increased RBC destruction, and blood loss. A
 complementary approach uses RBC morphology and indices

Reference : Janz,T,G.,Dupre,A,A. 2018. Rosen’s Emergency Medicine: Concepts and Clinical

Practice Ninth Edition. Elsevier,Inc.

a) Iron deficiency anemia

Iron deficiency anemia classically presents with decreased hemoglobin; microcytic, hypochromic
RBCs; and decreased iron stores. Symptoms may reflect hypoxic functioning (as with any anemia)
or may be more specific to iron deficiency (eg, pagophagia).Groups at physiologic high risk for
iron deficiency include predominantly breastfed infants without iron supplementation; toddlers and
young children with a high intake of cow's milk; female adolescents in their growth spurt; and
pregnant women. Dietary insufficiency, malabsorption, and acute or chronic blood loss (which may
be occult) are other common causes.Iron deficiency without anemia may cause subtle, often
neurocognitive symptoms; these symptoms can be confirmed retrospectively as being due to iron
deficiency if they abate after iron therapy. Presentation of iron deficiency anemia (defined as a
hemoglobin level lower than 2 standard deviations below the mean) varies; it may be asymptomatic
if chronic. When present, symptoms reflect hypoxic functioning common to any anemia (eg,
fatigue, dyspnea, headache) or may be more specific to iron deficiency (pagophagia). Infants and
toddlers may present with irritability, lethargy, or feeding difficulties. In young children (and
sometimes in pregnant women) a decreased hemoglobin is presumed to be due to iron deficiency,
and an empiric trial of iron supplementation—if it successfully increases hemoglobin level by 1
mg/dL—is both diagnostic and therapeutic. .Laboratory values consistent with iron deficiency or
iron deficiency anemia include mean corpuscular volume less than 80 fL, elevated RBC
distribution width, decreased reticulocyte count, decreased ferritin level, decreased serum iron
level, increased total iron-binding capacity, and decreased transferrin saturation level. Ferritin level
lower than 15 ng/mL is the single test result most highly suggestive of iron deficiency in adults
(lower than 12 ng/mL in children). In the setting of comorbidities that cause increased ferritin level
as an acute phase reactant, the likelihood ratio remains positive at a ferritin level as high as 70
ng/mL.

An oral iron supplement, typically ferrous sulfate, is the treatment of choice for most patients
unless they have issues with intolerance or malabsorption (eg, celiac disease, Helicobacter
pylori colonization, inflammatory bowel disease). For adults, 60 to 120 mg/day of elemental iron is
recommended for iron repletion. For children, 3 to 6 mg/kg/day is recommended.Although
historically oral iron supplements were administered 2 to 3 times per day, newer evidence suggests
that 1-time daily dosing may improve absorption and decrease gastrointestinal adverse effects.
Taking the supplement with a meal that includes vitamin C (and no coffee or tea, which hinders
absorption) is a reasonable strategy .IV iron therapy can be considered for some patients including
those with inflammatory bowel disease, chronic kidney disease, or chronic heart failure; those in
the second or third trimester of pregnancy; or any patient who is intolerant of or nonadherent with
oral iron. Full repletion doses can usually be given in a single infusion, depending on the
formulation .Screening recommendations for high-risk groups vary. American Academy of
Pediatrics recommends universal hemoglobin screening at 12 months and screening for iron
deficiency anemia risk factors at all well-child visits, with targeted laboratory screening if risk
factors are present. American College of Obstetricians and Gynecologists recommends universal
screening of pregnant women .Prognosis if favorable when adherence to therapy for iron repletion
is followed and cause is treated.

Reference : Clinical Overview,2021.Iron Deficiency Anemia. Elsevier,BV.

b) Anemia of Chronic Disease

The anemia of chronic disease, or anemia of inflammation, is a multifactorial anemia that occurs
in a wide spectrum of disorders, including chronic infections, rheumatologic diseases, chronic
kidney disease (CKD), inflammatory bowel diseases, hematologic and solid cancer, chronic heart
failure, and chronic obstructive pulmonary disease. It also accounts for a component of the
anemia of the elderly. The anemia of inflammation is the second most frequent anemia
worldwide and the first among hospitalized patients. Acute forms of anemia of inflammation
occur in intensive care units, secondary to sepsis, extensive burns, or polytrauma.

• Pathobiology
The anemia of inflammation is associated with increased production of proinflammatory
cytokines, upregulation of hepcidin, and deregulation of iron homeostasis. Pathogenic
mechanisms are multiple, including relative erythropoietin deficiency, blunted erythropoietic
response, macrophage iron sequestration, iron-restricted erythropoiesis, and shortened
erythrocyte survival. The different mechanisms play a variable role depending on the condition;
for example, erythropoietin deficiency dominates in CKD, and reduced erythrocyte lifespan is
seen in acute forms because of excessive, uncontrolled erythrophagocytosis. Anemia in both
hematologic malignancies (lymphoma and myeloma) and solid tumors (ovarian and colon
cancer) is even more complex; inflammation in cancer is often present together with blood loss
or chemotherapy-induced bone marrow toxicity, malnutrition, or concomitant infections. The
anemia of inflammation may coexist with absolute iron deficiency due to blood loss, as may
frequently occur in inflammatory bowel diseases and colon cancer.

IL-6 and lipopolysaccharide increase hepcidin expression through IL-6 receptor and JAK/STAT3
signaling, causing hypoferremia and macrophage iron retention. Also, IL-1 may increase
hepcidin both directly and indirectly through IL-6 stimulation. There is a crosstalk between the
IL-6 inflammatory pathway and the BMP/SMAD pathway to increase hepcidin expression. 17

TNF-α and IL-1β produced by peripheral blood monocytes reduce the erythropoiesis response,
whereas interferon-γ (IFN-γ), secreted by activated T and natural killer (NK) cells, switches
erythropoiesis to leukopoiesis by suppressing the essential erythroid transcription factor GATA1
and upregulating the myeloid-lymphoid transcription factor PU.1 in common progenitor cells. In
addition, IFN-γ increases endothelial and macrophage activation and consequently the
erythrophagocytosis process ( Fig. 150-3 ). Most mechanisms are adaptive: leukocytosis is a
defense against pathogens, and hepcidin-induced hypoferremia impairs extracellular
microorganism growth. 18 In the absence of hepcidin, hypoferremia is not observed, but mild
anemia is still present, indicating that the anemia of inflammation is only partially hepcidin and
iron dependent.
 • Clinical Manifestations and Diagnosis
Clinical manifestations are those of the underlying disorder. Anemia is usually of moderate
degree (8 to 10 g/dL) and asymptomatic. However, it may be aggravated by concomitant iron
deficiency, especially in CKD and inflammatory bowel diseases. Anemia may worsen the
outcome of the underlying disorder.

Anemia is usually normochromic and normocytic. High serum ferritin as a result of

inflammation and macrophage iron retention, associated with low-normal iron and total iron
binding capacity (or transferrin levels), and decreased percent transferrin saturation suggest
inflammation. Elevated C-reactive protein associated with high ferritin levels suggests
inflammation. Soluble transferrin receptor (sTfr), increased in iron deficiency or when
erythropoiesis is expanded, may help to differentiate the anemia of inflammation and iron
deficiency. In general, an increased sTfr is found in iron deficiency, with or without coexisting
inflammation. The sTfr/log ferritin index is considered the best indicator for discriminating
anemia of inflammation (ratio of about 1) from iron deficiency in anemia of inflammation (ratio
of more than 2) ( Table 150-4 ). In practice, the diagnosis of iron deficiency in inflammatory
conditions relies on an arbitrary cutoff of ferritin (<100 μg/L) or percent saturation of transferrin
(<20%) in case the ferritin is higher than 100 μg/L (usually between 100 and 300). This is
supported by experts and society guidelines and practically confirmed by response to therapeutic
administration of iron, especially in CKD and heart failure.

• Treatment

Treating the underlying disease, when possible, should correct or improve the anemia. In the
other cases, symptomatic anemia should be treated. Iron and erythropoiesis-stimulating agents
(ESAs) may be used in selected cases. The widest experience in their use is derived from
treatment of CKD patients.

Clinical trials in this condition showed that intravenous iron, administered both with and without
ESAs, is superior to oral iron in correcting the anemia. In addition, data suggest that the use of
intravenous iron may reduce the dose of ESA required or delay its need. In inflammatory bowel
disease, intravenous iron should be preferred in case of disease flares because oral iron is less
tolerated and may even cause further mucosal damage. 19

Indications for ESA outside CKD are limited. They are used in selected patients with
myelodysplastic syndromes and in cancer patients undergoing chemotherapy. Recommendations
are to use the lowest dose of ESA that allows the avoidance of blood transfusions. Addition of
iron should be considered when ESA alone is ineffective to maintain transferrin saturation 20%
or higher and serum ferritin 100 μg/L or higher. In this functional iron deficiency, intravenous
iron is more effective than oral iron. ESA is not recommended in cancer patients outside
chemotherapy because of increased thrombotic complications and mostly theoretical concerns
about adverse effects on disease progression and outcome.

There are no specific guidelines indicating when intravenous iron supplementation should be
initiated and when it should be discontinued. Ferritin, at variance with iron deficiency, cannot be
used as a biomarker to guide therapy.

Concomitant folate or vitamin B 12 deficiency should be corrected. Blood transfusions are

indicated only to alleviate anemia-related symptoms but should be avoided as chronic treatment
because of transfusion-associated risks.

Experimental therapies that antagonize hepcidin (e.g., by binders, antibodies) or its effect on
ferroportin are under development. However, it is unlikely that this treatment alone will fully
correct the multifactorial anemia of inflammation.

Reference :Lee,G. &Andrew,S. 2020. Goldman-Cecil Medicine, Twenty Sixth Edition.

Elsevier,Inc.

c) Thalassemia

The thalassemias, or more comprehensively the thalassemia syndromes, are a heterogeneous

group of inherited hemolytic anemias characterized by deficient or absent production of one of
the globin chains of hemoglobin. This leads to imbalanced globin chain synthesis that is the
hallmark of all the thalassemia syndromes.

• Pathobiology
Normal adult red cells contain 97% adult hemoglobin (HbA: α 2 β 2 ), with approximately 2.5%
of the minor component HbA 2 (α 2 δ 2 ) and a small amount of fetal hemoglobin (HbF: α 2 γ 2 ).
Because the stable tetramer α 2 β 2 is the major component of hemoglobin after birth, there are
two main forms of thalassemia: α-thalassemias and β-thalassemias. Because β-chain synthesis is
fully activated only after birth, it follows that the β-thalassemias are not expressed as a disease in
intrauterine life; they are manifested as γ-chain synthesis declines during the first year of life. In
contrast, because α chains are shared by both fetal and adult hemoglobin, α-thalassemias are
manifested in both fetal and adult life.

GENETIC CLINICAL
α-Thalassemias α 0 α-Minor
α+ HbH disease
Deletion (−α) Hydropsfetalis
Nondeletion (α Τ )
β-Thalassemias β 0 β-Minor
β+ Thalassemia intermedia
Variant with high HbA 2 Thalassemia major
Normal HbA 2
Silent
Dominant
Unlinked to β-gene cluster
δβ-Thalassemia (δβ) 0 δβ-Minor
(δβ) + Thalassemia intermedia
( A γδβ) 0
HPFH Deletion Silent increase in HbF
Nondeletion
Unlinked to β-gene cluster

The diagnosis of thalassemia may be required in a patient with an appropriate, suggestive clinical
picture or for the identification of a heterozygote subject as part of a family study or population
screening program. The general approach is common to any form of thalassemia, regardless of
presentation. The primary evaluation is based on hematologic changes; the red cell indices by
electronic cell counter and the red cell morphology examined on a well-stained blood film are
sufficient to direct further investigations. Individuals with mean corpuscular volume below 80 fL
and mean corpuscular hemoglobin below 27 pg with normal iron parameters need to be further
investigated. The red blood cell number is usually higher than normal. In the presence of anemia
with thalassemic red cell changes, the next step is the evaluation of hemoglobin fractions (HbA,
HbA 2 ,HbF, or hemoglobin variants) by electrophoresis on cellulose acetate at alkaline pH or,
even better, by high-performance liquid chromatography that enables the precise measurement of
HbA 2 , HbF, and HbA and the provisional identification of a large number of hemoglobin
variants, including HbE. An HbA 2 level above 3.5% associated with hypochromic microcytic
red cells is diagnostic of β-thalassemia minor. HbA 2 values between 3.2 and 3.5% (borderline)
should be interpreted with care because they could be due to interaction of more than one
thalassemic defect (α and β), a silent β mutation, or concomitant iron deficiency. If iron
deficiency is present, it should be corrected and the HbA 2 estimation repeated. The majority of
individuals with thalassemic red cell indices with normal or low HbA 2 and normal HbF will be
α 0 -thalassemia carriers or α + -thalassemia homozygotes. Carriers of α 0 -thalassemia may have
a few red cells with HbH inclusions. Microcytosis with low or normal HbA 2 levels with elevated
HbF (2 to 20%) indicates heterozygosity for δβ-thalassemia. Patients with HPFH usually have
normal red blood cell indices but increased levels of HbF with different intercellular distribution
(homogeneous or pancellular with the exception of heterocellular HPFH) compared with δβ-
thalassemia (uneven or heterocellular).
A radioactive method for measuring the α/β-globin synthesis ratio was introduced in the mid to
late 1960s, and it was largely directed at prenatal diagnosis in the pre-DNA era. Although it
gives a quantitative assessment of globin production, today its use is limited to difficult cases
because of interaction of different globin chain defects. The definitive diagnosis of the
thalassemia syndromes involves the identification of the underlying mutations through DNA
analysis. There are several methods available for the diagnosis of any particular mutation, such
as polymerase chain reaction (PCR) restriction enzyme analysis, PCR allele-specific
oligonucleotides, gap PCR, and direct sequencing that at present is probably the easiest and most
reliable method. For deletion forms of α-thalassemia, the multiplex ligation-dependent probe
amplification is a recently introduced, useful method.

During their clinical course, patients affected by different forms of thalassemia develop several
complications mainly due to iron overload, which requires monitoring to direct iron chelation
therapy. The principal methods of determining body iron levels ( Chapter 201 ) are
measurements of the serum ferritin level and assessment of liver iron concentration from biopsy
tissue or, as an alternative noninvasive method, by R2 MRI. The reciprocals of T2 and T2∗,
known as R2 and R2∗, are directly proportional to iron content and demonstrate the most
promising results. High serum ferritin levels (>2500 µg/L) and high liver iron concentration (>15
g/dry weight) indicate high risk for significant morbidity and mortality. A cutoff of 800 µg/L
ferritin and more than 7g/dry weight liver iron concentration have been associated with high risk
for morbidity in thalassemia intermedia and other forms of non–transfusion-dependent
thalassemias. Cardiac iron can be measured by a T2∗ MRI procedure that allows estimation of
the cardiac iron load. MRI T2∗ values below 10 milliseconds are always associated with severe
iron load and high risk for heart failure within 1 year. MRI T2∗ values above 20 milliseconds are
considered normal, meaning no iron in the heart. Echocardiography may also be useful to
evaluate functional changes. For other complications, including endocrinopathies, liver disease,
lung disease, thrombophilia, and bone disease, the diagnostic approaches are similar to those
used in clinical practice; these are performed with consideration of test cost, performance
characteristics, and preferences of the patients, as described in the corresponding chapters.

• Treament

Conventional Treatment
No specific treatment is required for α- or β-thalassemia heterozygotes (carriers, thalassemia
minor), but they should receive appropriate genetic counseling. During pregnancy, thalassemia-
carrying women may become more anemic, so they should be observed carefully, mainly during
the second and third trimesters, and supported with folic acid. When real iron deficiency is
associated with thalassemia traits, iron supplementation should be provided, monitoring
transferrin saturation and ferritin. A few cases of in utero blood transfusions have been reported
with hemoglobin Bart hydropsfetalis syndrome; most of the infants have been delivered
prematurely by cesarean section, subsequent development has been abnormal, and survivors
required regular blood transfusions after birth. HbH patients in general have higher hemoglobin
levels (8 to 9 g/dL) and do not need regular blood transfusion. Supplementation with folic acid (2
to 5 mg/day) is generally recommended, especially in pediatric patients. The major
complications in HbH disease are hemolytic crises that may occur during or after acute
infections; in such cases, immediate intervention, including blood transfusions and treatment for
infections, should be promptly administered.

The clinical management of thalassemia major and thalassemia intermedia remains the major
issue. The quality and duration of life of thalassemia major and thalassemia intermedia patients
have been transformed in this century, with life expectancy increasing well into the third and
fourth decades. Nevertheless, prolongation of life is accompanied by several complications,
partly due to the underlying disorder and partly as a consequence of the treatment with blood
transfusions and iron overload. Moreover, we are starting to deal with aging-related
complications in the context of a multiorgan disease that requires management by a team of
clinicians who have specific knowledge of thalassemias in adults, working together with
different specialists and well-trained nurses. The conventional treatment of thalassemia major
patients includes regular transfusion therapy and iron chelation. The definition of the optimal
transfusion and iron chelation regimen has been the most important advance in the management
of thalassemia major patients, with the primary objective being to control the ineffective
erythropoiesis, its consequences, and the body iron burden. The optimal transfusion regimen
involves regular blood transfusions, usually administered every 2 to 5 weeks, to maintain the
pretransfusion hemoglobin levels above 9 to 10.5 g/dL. The decision to initiate lifelong
transfusion therapy should be based on a definitive diagnosis of severe thalassemia, taking into
account the molecular defects, the severity of anemia on repeated measurement, the level of
ineffective erythropoiesis, and the clinical criteria (such as failure to thrive or bone changes). It is
advisable that thalassemia major patients receive leukoreduced packed red cells to minimize
transfusion reactions and pathogen transmission. Adverse reactions to red blood cell transfusions
may occur during or after transfusion and can be hemolytic and nonhemolytic. Transfusion-
related acute lung injury is rare but severe and must be immediately managed ( Chapter 167 ).

Many patients with thalassemia major require splenectomy because of hypersplenism. However,
optimal clinical management may delay or even obviate the need for splenectomy that was
common in the past. Splenectomy should be considered only for patients whose annual blood
consumption increases progressively and is responsible for significant increases in iron stores
despite good chelation therapy or in the presence of symptoms due to spleen enlargement.
Clinical problems related to leukopenia or thrombocytopenia due to hypersplenism could also be
the reasons for considering splenectomy. 15 The major complication of splenectomy is severe and
sometimes overwhelming infection. Because removal of the spleen may reduce the primary
immune response to encapsulated organisms, it is advisable to delay splenectomy until patients
are at least 5 years old. The mortality rate for postsplenectomy overwhelming infection in
thalassemia patients is approximately 50% despite intensive supportive care. Therefore, it is
mandatory to adopt preventive measures including immunoprophylaxis (vaccination
against Streptococcus pneumoniae , pneumococcus, and meningococcus) ( Chapter 159 ),
chemoprophylaxis, and education of the parent and patient to recognize and to report febrile
illnesses. Increase of thrombotic risk has been well documented in thalassemia patients after
splenectomy; thus this procedure must be avoided as much as possible.

Iron overload is an inevitable and serious complication of long-term blood transfusion therapy
and hyperabsorption of dietary iron that requires adequate treatment to prevent early death,
mainly from iron-induced cardiac disease. Optimal chelation therapy extends complication-free
survival (see Fig. 153-3 ). The standard chelation therapy for more than 40 years was
deferoxamine, given for 10 to 24 hours daily as a continuous subcutaneous infusion 5 to 7 days
per week. A1 The long-term efficacy of deferoxamine has been extensively documented in large
cohorts of patients in Italy and elsewhere. Unfortunately, compliance with the rigorous regimen
of daily subcutaneous infusions is a serious limiting factor, and life expectancy in noncompliant
patients is not different from that in the pre-deferoxamine era. This has been the rationale behind
the intensive effort to identify alternative, orally effective iron chelators. At present, two oral
iron chelators are on the market: deferiprone and deferasirox. Deferiprone is registered in Europe
and more recently in the United States. By the guidelines of the EMEA countries (Europe,
Middle East, and Africa), treatment with deferiprone at doses of 75 to 100 mg/kg/day is
restricted to patients unable to use deferoxamine or patients with an unsatisfactory response to
deferoxamine as judged by serum ferritin levels and by liver iron concentrations. Studies indicate
that deferiprone may be more effective than deferoxamine in protecting the heart from the
accumulation of iron. A2 A potential benefit of combined deferoxamine and deferiprone therapy
has been observed, and according to Thalassemia International Federation guidelines, a
combination treatment (deferoxamine and deferiprone) should be considered for patients with
high levels of heart iron or cardiac dysfunction. The new orally effective iron chelatordeferasirox
has been shown to be effective and safe in removing excess iron from different organs, including
the heart. A3 , A4 Deferasirox is now available in most countries throughout the world as first-line
treatment. Its use has clearly demonstrated that iron chelation is not a standard treatment, but it
should be individualized according to age, history of compliance with previous chelation, and
other factors. Monitoring and adjustment of iron chelation by repeated measurements of ferritin,
calculation of iron intake by transfusions, and, whenever possible, measurement of cardiac and
liver iron at least once by MRI are mandatory. A prospective phase 2 study evaluating
combination of deferasirox with deferoxamine in patients with severe transfusional myocardial
siderosis showed clinically meaningful improvements in cardiac MRI results. In patients with
thalassemia major and cardiac siderosis, amlodipine added to chelation therapy reduced cardiac
iron more effectively than chelation therapy alone, but larger studies will be required to inform
the evaluations. A5 The use of proton pump inhibitors may further reduce serum ferritin levels. A6

The management of thalassemia intermedia patients is more complicated because of the wide
heterogeneity of thalassemia intermedia phenotypes. A number of options are currently adopted
for treatment of thalassemia intermedia patients, including transfusion therapy, splenectomy,
modulation of HbF production, and hematopoietic stem cell transplantation (HSCT). However,
increasing evidence is documenting the benefit of transfusion therapy in decreasing the incidence
of complications. Thus, although the common practice has been to initiate transfusion when
complications ensue, it may be worthwhile to start transfusion therapy earlier as a preventive
approach, which will also help alleviate the increased risk for alloimmunization with delayed
initiation of transfusion. The initiation of iron chelation therapy in patients with thalassemia
intermedia depends not only on the amount of excess iron but also on the rate of iron
accumulation, the duration of exposure to excess iron, and various other factors in individual
patients.

Bone Marrow Transplantation and Experimental Therapies

Allogeneic HSCT in thalassemia syndromes has been increasingly successful during the past two
decades, mainly in β-thalassemia major. 17 Predictors of poor transplant outcome are
hepatomegaly, history of irregular chelation, and hepatic fibrosis. Patients are categorized into
three risk classes. Class 1 patients have none of these adverse risk factors, class 2 patients have
one or two adverse risk factors, and class 3 patients have all three. In the most recent update of
the Pesaro group’s experience, the probabilities of thalassemia-free survival for patients younger
than 17 years at the time of HSCT receiving the allograft from an HLA-identical relative were
87% and 85%, respectively, in patients belonging to class 1 and class 2 and much lower in young
patients in class 3. The progressive adjustment of conditioning regimens in class 3 patients and in
adults (>17 years old) has significantly reduced the incidence of transplant-related mortality in
patients in class 3. Only 25 to 30% of patients with diseases potentially curable by HSCT have a
suitable HLA-compatible sibling. Bone marrow transplantation from unrelated donors increases
significantly the incidence of acute and chronic graft-versus-host disease, particularly in
thalassemia. A study from the Eurocord cooperative group reported the outcome of 33 patients
with thalassemia belonging to class 1 and class 2 (Pesaro classification) who received cord blood
hematopoietic stem cells from an HLA-identical sibling; no patient died of transplant-related
complications, suggesting that related cord blood HSCT is a safe procedure for thalassemia
patients.

Two new molecules, sotatercept 18 and luspatercept, 19 which are activin-type IIA and IIB
receptor fusion proteins, can increase the release of mature erythrocytes into the circulation by
acting mainly on late-stage erythropoiesis. In patients with transfusion-dependent β-thalassemia,
luspataercept (a recombinant fusion protein that binds to select transforming growth factor β
superfamily ligands at 1 to 1.25 mg/kg) can reduce transfusion requirements significantly. A6b

An alternative treatment of β-thalassemia consists of the pharmacologic stimulation of HbF

synthesis. In humans, hemoglobin switch from HbF to HbA occurs in the period around birth as
a result of γ- to β-globin gene switching. A number of pharmacologic agents able to reactivate
HbF synthesis have been identified, including hypomethylating agents, histone deacetylase
inhibitors, and hydroxyurea. Whereas the effect of these pharmacologic treatments (particularly
hydroxyurea) in sickle cell disease is clear ( Chapter 154 ), their benefit on the clinical course of
β-thalassemia is presently limited. The discrepancy between these two conditions in the response
to HbF inducers may be mainly related to the higher level of HbF required in β-thalassemia to
achieve clinical results compared with those observed in sickle cell disease. The limited clinical
response to γ-globin inducers observed in the majority of β-thalassemic patients may be also a
reflection of the unfavorable effects of these agents on the other globin genes (i.e., increased α-
globin synthesis). Although much attention has been paid to pathways that increase γ-globin
expression, and hence the production of fetal hemoglobin, the reduction of α-globin expression
may provide an equally plausible approach to ameliorating clinically severe forms of β-
thalassemia, especially in patients with hemoglobin E β-thalassemia, who comprise about 50% of
all patients born each year with severe β-thalassemia.

Gene therapy is an attractive approach for thalassemia syndromes; however, this strategy poses
major challenges in terms of controlling transgene expression, which should be erythroid specific
and sustained over time. Treatment of β-thalassemia, sickle cell disease, and other disorders
through lentivirus-mediated gene transfer has been reported in murine and primate models. At
present, several phase 1/2 clinical studies are ongoing with encouraging results. Genome editing
through CRISPR/Cas9 technology increases fetal hemoglobin production. It is in preclinical
phase and will possibly enter the clinical phase in 2019. Moreover, new molecules with a
potential ability to correct ineffective erythropoiesis or to generate iron-restricted erythropoiesis
are in phase 1 clinical trials.

Reference :Lee,G. &Andrew,S. 2020. Goldman-Cecil Medicine, Twenty Sixth Edition.

Elsevier,Inc.

5. What the interpretion of MCV and MCHC ?

Age Hb HCT MCV MCHC Reticulocytes WBCs Platelets

(g/dL) a (%) a (fL) a (g/dL (×10 3 /mL) b (10 3 /mL) b
RBC) a
26–30 weeks 13.4 41.5 118.2 37.9 — 4.4 (2.7) 254 (180–
gestation c (11) (34.9) (106.7) (30.6) 327)
28 weeks 14.5 45 120 31.0 (5–10) — 275
32 weeks 15.0 47 118 32.0 (3–10) — 290
Term d (cord)
16.5 51 108 33.0 (3–7) 18.1 (9–30) e 290
(13.5) (42) (98) (30.0)
1–3 days 18.5 56 108 33.0 (1.8–4.6) 18.9 (9.4– 192
(14.5) (45) (95) (29.0) 34)
2 weeks 16.6 53 105 31.4 — 11.4 (5–20) 252
(13.4) (41) (88) (28.1)
1 month 13.9 44 101 31.8 (0.1–1.7) 10.8 (4– —
(10.7) (33) (91) (28.1) 19.5)
2 months 11.2 35 95 (84) 31.8 — — —
(9.4) (28) (28.3)
6 months 12.6 36 76 (68) 35.0 (0.7–2.3) 11.9 (6– —
(11.1) (31) (32.7) 17.5)
6 months–2 12.0 36 78 (70) 33.0 — 10.6 (6–17) (150–350)
years (10.5) (33) (30.0)
2–6 years 12.5 37 81 (75) 34.0 (0.5–1.0) 8.5 (5–15.5) (150–350)
(11.5) (34) (31.0)
6–12 years 13.5 40 86 (77) 34.0 (0.5–1.0) 8.1 (4.5– (150–350)
(11.5) (35) (31.0) 13.5)
12–18 Years
Male 14.5 43 88 (78) 34.0 (0.5–1.0) 7.8 (4.5– (150–350)
(13) (36) (31.0) 13.5)
Female 14.0 41 90 (78) 34.0 (0.5–1.0) 7.8 (4.5– (150–350)
(12) (37) (31.0) 13.5)
Adult
Reference :Calihan,J. 2021.Harriet Lane HandbookTwenty Second Edition. Elsevier, Inc.
6. Explain the diseases associated with the scenario !

• Koilonychia (spoon nails),The nail plate is thinned and flattened with upward eversion of
its lateral and distal edges, leading to a concave spoon-like shape Koilonychia, especially
of the 2nd–4th toes in young children (1–4 years of age), is physiologic and eventually
resolves spontaneously. In adults, koilonychia is rare and occurs in association with
severe iron deficiency and systemic amyloidosis. It can also be seen in manual laborers
who have contact with irritants and detergents that damage the nail plate.

Reference: Tosti,A.Piraccini B,M. 2018. Dermatology Fourth Edition. Elsevier Limited

• Anemis conjunctiva. The conjunctiva is a thin layer in the eye that serves to protect the
sclera (white area of the eye). Conjunctiva is an indentation in the eye, normally the
conjunctiva is reddish in color, in certain circumstances (eg in anemia) the conjunctiva
will be pale in color which is called anemic conjunctiva. Because in anemia there is a
shortage of erythrocytes (red blood cells) so that the blood that should be flowed
throughout the body sufficiently becomes uneven, meanwhile the conjunctiva is a
sensitive area which if it is not drained of blood perfectly it will look pale as is the case
with the sclera, lips and lips. nail area, so that in addition to the conjunctiva, lips and nails
also look pale. So the conjunctiva picture can be said as one of the predictors of anemia
status.

Reduced hemoglobin will cause a decrease in oxygen levels in the blood because the
function of hemoglobin is to bind oxygen in the blood. This will lead to decreased tissue
oxygenation. To adjust to this condition the body willvasoconstrict blood vessels to
maximize oxygen delivery to vital organs. To be pale in this state would cause paleness.
Skin color is not a reliable index of pallor because it is influenced by skin pigmentation,
temperature, and the depth and distribution of capillary beds. Nail pads, palms, and
mucous membranes of the mouth and conjunctiva are better indicators of pallor.

Reference :Qalbi, Muhammad Nur. 2019.

JurnalIndikatorAntropometridanGambaranKonjungtivaSebagaiPrediktor Status Anemia
PadaWanita.UniversitasHasanuddin.

• Chronic Kidney Failure is a disease due to a gradual decline in kidney function that
causes an imbalance of fluids, electrolytes, and waste disposal in the body. Generally this
disease is caused by high blood pressure, diabetes, smoking, obesity, and heart disease.
Symptoms that occur in this disease are breath or urine that smells like urine, pale skin or
 lack of blood, feeling weak when doing work, easily tired when working lightly,
dizziness when standing or walking, frequent urination, no appetite accompanied by
eating disorders, and swollen feet.

Reference :Yurian Prabowo.2017.Implementasi SistemPakarUntuk

DiagnosisPenyakitdenganGejalaAwal Kaki
Bengkak.JurnalTeknikInformatikadanSistemInformasi. Vol 3, No 3.

7. Explain the diagnostic step from scenario !

The diagnosis of anemia and the assessment of its severity are best made by measuring the Hb
concentration rather than the hematocrit (Hct). Hb is a stable analyte that is measured directly in
a standardized fashion, whereas the Hct is relatively unstable, indirectly derived by automatic
analyzers, and lacking standardization. Within-run and between-run coefficients of variation in
automated analyzer measurements of Hb are half and one third those for Hct, respectively.

There is considerable variability in the Hb threshold used to define anemia. According to the
most recent definition in the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines,
anemia should be diagnosed at Hb concentrations of less than 13.0 g/dl in men and less than
12.0 g/dl in women. These values represent the World Health Organization definition of anemia.
In children, age-dependent differences in the normal values have to be taken into account.
Normal Hb values are increased in high-altitude residents. It is important to note that thresholds
for the diagnosis of anemia and evaluation of the causes should not be interpreted as being
thresholds for treatment of anemia.

In addition to the Hb value, the evaluation of anemia in CKD patients should include a complete
blood count with RBC indices (mean corpuscular Hb concentration [MCHC], mean corpuscular
volume [MCV]), white blood cell count (including differential), and platelet count. Although
renal anemia is typically normochromic and normocytic, deficiency of vitamin B 12 or folate may
lead to macrocytosis, whereas iron deficiency or inherited disorders of Hb formation (such as
thalassemia) may produce microcytosis. Macrocytosis with leukopenia or thrombocytopenia
suggests a generalized disorder of hematopoiesis caused by toxins, nutritional deficit, or
myelodysplasia. Hypochromia probably reflects iron-deficient erythropoiesis. An absolute
reticulocyte count, which normally ranges between 40,000 and 50,000 cells/µl of blood, is a
useful marker of erythropoietic activity.

Iron status tests should be performed to assess the level of iron in tissue stores or the adequacy of
iron supply for erythropoiesis. Although serum ferritin is the only available marker of storage
iron, several tests reflect the adequacy of iron for erythropoiesis, including transferrin saturation
(TSAT), the percentage of hypochromic red blood cells (PHRC), the reticulocyte hemoglobin
content (CHr), the MCV, and the MCHC. Storage time of the blood sample may elevate PHRC,
and MCV and MCHC are below the normal range only after long-standing iron deficiency; in
clinical practice, TSAT remains the most frequently used parameter.
It is important to identify anemia in CKD patients because it may signify nutritional deficits,
systemic illness, or other conditions that warrant attention. Moreover, even at modest degrees,
anemia reflects an independent risk factor for hospitalizations, cardiovascular disease (CVD),
and mortality. 12 The diagnosis of renal anemia, that is, anemia caused by CKD, requires careful
judgment of the degree of anemia in relation to the degree of renal impairment and exclusion of
other or additional causes. Because there is significant variability in the degree of anemia in
relation to the impairment in renal function, no simple diagnostic criteria can be applied. Causes
of anemia other than EPO deficiency should be considered when (1) the severity of anemia is
disproportionate to the impairment of renal function, (2) there is evidence of iron deficiency, or
(3) there is evidence of leukopenia or thrombocytopenia. Concomitant conditions such as sickle
cell disease may exacerbate the anemia, as can drug therapy. For example, inhibitors of the
renin-angiotensin system may reduce Hb levels by (1) direct effects of angiotensin II (Ang II) on
erythroid progenitor cells, (2) accumulation of N -acetyl-seryl-lysyl-proline (Ac-SDKP), an
endogenous inhibitor of erythropoiesis in patients treated with angiotensin-converting enzyme
(ACE) inhibitors, and (3) reduction of endogenous EPO production, possibly because of the
hemodynamic effects of Ang II inhibition. Myelosuppressive effects of immunosuppressants
may further contribute to anemia. The measurement of serum EPO concentrations is usually not
helpful in the diagnosis of renal anemia because there is relative rather than absolute deficiency,
with a wide range of EPO concentrations for a given Hb concentration that extends far beyond
the normal range of EPO levels in healthy, nonanemic individuals. Abnormalities of other
laboratory parameters should be looked for, such as a very low MCV or MCHC, a high MCV, or
an abnormal leukocyte or platelet count, and further tests should be performed as indicated to
explore these potential contributory causes . However, when there are no such pointers to other
confounding causes of anemia, and iron deficiency has been excluded, a trial with rHuEPO or its
derivatives is warranted, even when the eGFR is only moderately reduced.

Reference :Macdougall.L.C&Eckardt.K.U. 2019. Comprehensive Clinical Nephrology Sixth

Edition. Elsevier,Inc,

8. Explain the islamic perspective according to the scenario !

QS. Al-Hadid Verse 25

Meaning:
And We created iron which has strength, great power and many benefits for mankind, and that
Allah may know who helps (religion) Him and His messengers even though (Allah) does not see.

Surah Al-Baqarah (2) verse 173:

Meaning:

Verily, Allah has only forbidden to you carrion, blood, pork, and animals slaughtered in the
name of other than Allah. However, whoever is in a state of necessity, does not intend to be
disobedient, and nor transgress, then there is no sin for him. Truly Allah is Most Forgiving and
Most Merciful.