Far Eastern University – Nicanor Reyes Medical Foundation

Pediatrics 3B – Hematology A (Anemia)

Midred Tactacan-Rondilla, MD, FPPS
August 2019

System Observation Significance

Approach to Anemia
- Vit. B12 deficiency
Glossitis
- Iron deficiency
Anemia Angular stomatitis - Iron deficiency
− defined as a reduction of the hemoglobin concentration or Cleft lip/palate
- Diamond Blackfan
red blood cell (RBC) volume below the range of values syndrome
occurring in healthy persons. Mouth - Peutz-Jeghers
Pigmentation
syndrome
− “Normal” hemoglobin and hematocrit (packed red cell - Osler-Weber-Rendu
Telangiectasia
volume) vary substantially with age, sex and race. syndrome
− Physiologic adjustments to anemia include: Leukoplakia
- Dyskeratosis
o increased cardiac output, augmented oxygen congenita
extraction (increased arteriovenous oxygen Shield chest or - Diamond Blackfan
difference), and Chest widespread syndrome
o shunting of blood flow toward vital organs and tissues nipples
- Endocarditis
History and Physical Examination Murmur - Prosthetic valve
− Important historical facts should include age, sex, race and hemolysis
ethnicity, diet, medications, chronic diseases, infections, - Hemolysis
travel, and exposures. - Infiltrative tumor
Hepatomegaly - Chronic disease
− A family history of anemia and/or associated difficulties
- Hemangioma
such as splenomegaly, jaundice, or early age onset of - Cholecystitis
gallstones is also of consequence. - Hemolysis
− Few physical symptoms or signs that result solely from a - Sickle Cell Disease
low hemoglobin, particularly when the anemia develops - Thalassemia
slowly. Abdomen
- Malaria
− Clinical findings generally do not become apparent until the Splenomegaly - Lymphoma
hemoglobin level falls to <7-8 g/dL. - EBV
− Clinical features can include pallor, sleepiness, irritability, - Portal Hypertension
and decreased exercise tolerance. - Hemophagocytic
syndromes
− Pallor can involve the tongue, nail beds, palms, or palmar
Nephromegaly - Fanconi anemia
creases.
Absent kidney - Fanconi anemia
− S3 gallop and flow murmur is often present.
Hemorrhoids - Portal hypertension
− Ultimately, weakness, tachypnea, shortness of breath on Rectal Heme positive - Intestinal Hemorrhage
exertion, tachycardia, cardiac dilation, and high-output stool
heart failure will result from increasingly severe anemia, Absent thumbs - Fanconi anemia
regardless of its cause. Thenar eminence, - Diamond Balckfan
− There are unusual physical findings linked to particular hypoplasia syndrome
underlying disease etiologies (Table 1). Spoon nails - Iron deficiency
- Heavy metal
Table 1. Physical Findings in the Evaluation of Anemia
Beau lines (nails) intoxication
System Observation Significance - Severe illness
- Thalassemia major - Heavy metal
- Severe iron deficiency Extremities intoxication
Frontal Bossing anemia Mees lines (nails)
- Severe illness
- Chronic subdural - Sickle cell anemia
Head
hematoma
- Dyskeratosis
- Fanconi anemia Dystrophic nails
congenita
Microcephaly - Diamond Blackfan
- Milk-induced protein
syndrome
losing enteropathy
Microphthalmia - Fanconi anemia Edema
- Iron deficiency
Retinopathy - Fanconi anemia - Renal failure
Optic atrophy, - Osteopetrosis Irritable, Apathy - Iron deficiency
blindness Peripheral - Vit. B1/B12 deficiency
Eyes Blocked lacrimal - Dyskeratosis neuropathy - Lead poisoning
gland congenita Nerves Dementia - Vit. B1/B12 deficiency
Kayser-Fleischer - Wilson disease Ataxia, posterior - Vit. B1/B12 deficiency
ring column signs
Blue sclerae - Iron deficiency
Ears Deafness - Osteopetrosis

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 Hematology A – Anemias

System Observation Significance ▪ Abnormal looking red cells, white cells, and
- Sickle cell anemia platelets
Nerves Stroke - Paroxysmal Nocturnal o Aleukemic leukemia
Hemoglobinuria ▪ Pancytopenia, thrombocytopenia, anemia
- Fanconi anemia ▪ No peripheral lymphoid tissues, Bone marrow
Hyperpigmentation - Dyskeratosis tightly packed with leukemic cells which suppress
congenita normal cells
Café au lait spots - Fanconi anemia o Pancytopenia w/o organomegaly – aplastic anemia,
Vitiligo - Vit. B12 deficiency aleukemic leukemia, AML, ALL
Partial - Chediak-Higashi 5. Is it associated with reticulocytosis?
oculocutaneous Syndrome
o  Production
albinism
- Hemolysis o Hemolytic disease = look for triad Occult / overt
Jaundice bleeding
- Hepatitis
Skin - Bone marrow o Possible hookworm
infiltration o Recovering nutritional deficiency on
- Autoimmune iron/folate/B12 therapy
Petechiae,
hemolysis with o Myelostimulant = initial response is to  reticulocytes
purpura
autoimmune
thrombocytopenia Important Preliminary Tests for Anemia Work-Up
- HUS − Complete blood count including reticulocytes and platelet
- Parvovirus count
Erythematous rash
- EBV
− If Reticulocyte count is elevated
- Systemic lupus
Butterfly rash o Coombs test, occult blood
erythematosus
− If Cytopenic or Cytosis
o Bone marrow, WBC morphology
Questions to Ask Regarding a Pale/Anemic Child

- Deon Trans
1. Is the child pale or anemic? Laboratory Studies
o Hemoglobin/Hematocrit − Initial work-up includes
o Systemic disease (e.g. infection) o CBC
o Both o Red cell indices
o Reticulocyte count
2. Is it associated with jaundice? o Peripheral blood smear examination
o Hemolytic
▪ Reticulocyte count, Coombs Index Formula Normal Values
o Septic with DIC (microangiopathic anemia) MCV Hct x 10/RBC ct 81-100 fL
▪ Culture (blood/urine/stool), Urinalysis MCH Hgb x 10/RBC ct 26-34 pg
▪ X-ray MCHC Hgb x 10/Hct 31-36%
▪ Liver function, Bilirubin RDW 11.5-14.5%
▪ Alkaline Phosphatase, SGPT
− Additional studies depend on history, physical examination
TRIAD of Hemolytic Disease and results of the initial tests.
− Sudden onset of anemia (with reticulocytosis)
− Jaundice Differential Diagnosis
− Tea colored urine − Anemias may be classified based on their morphology
and/or physiology.
3. Is it associated with lymphadenopathy, hepatomegaly, − Anemia can be categorized morphologically of the basis of:
splenomegaly, or a mass lesion? o red cell size (MCV) and
o Organomegaly = LN, liver, spleen o microscopic appearance
o Proliferative disease, leukemia, myeloproliferative − It can be classified as: (Figure 1)
disease o Microcytic (low MCV)
o Solid tumors – Bone marrow, biopsy o Normocytic (normal MCV)
o Reactive (infections) – TB, viral, TORCH, parasitic o Macrocytic (high MCV)
− Examination of the peripheral blood smear will reveal
4. Is it associated with cytopenia? changes in RBC appearance (Figure 2).
o Absolute neutrophil count (WBC x % of segmenters)
▪ ANC: normal = 1500-2500
▪ Neutropenia <500
o Pancytopenia or neutropenia
o Aplastic anemia: hypocellular BM - ↓all 3 cell lines,
no hematopoetic cells
o Myelodysplastic (more in adult, a preleukemic
syndrome)

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 Hematology A – Anemias

Table 2. Peripheral Blood Morphologic Findings in Various

Anemias
MICROCYTES BASOPHILIC STIPPLING
Iron deficiency Thalassemia
Thalassemia Lead intoxication
Lead toxicity Myelodysplasia
Anemia of Chronic Disease
MACROCYTES BLASTS
Newborns Leukemia (ALL or AML)
Vit B12 or Folate deficiency Severe infection (rarely)
Diamond Blackfan syndrome Leukopenia,
Fanconi anemia thrombocytopenia
Aplastic anemia Fanconi anemia
Liver disease Aplastic anemia
Down Syndrome Leukemia
Hypothyroidism Hemophagocytic
histiocytosis
SPHEROCYTES HOWELL-JOLLY BODIES
Hereditary spherocytosis Asplenia, hyposplenia
Immune hemolytic anemia Severe iron deficiency
(newborn or acquired)
Hypersplenism
SICKLED CELLS TARGET CELLS
Sickle cell anemias Hemoglobinopathies (esp.
SS disease hemoglobin C, SC and
SC disease thalassemia)
S+ thalassemia Liver disease
S0 thalassemia Xerocytosis
ELLIPTOCYTES
Hereditary elliptocytosis
Iron deficiency
Megaloblastic anemia

Anemias may also be further divided on the basis of

underlying physiology.
The 2 major categories are:
1. Decreased RBC production
o consequence of ineffective erythropoiesis or complete
or relative failure of erythropoiesis
o with low or normal reticulocyte count generally
represent an inadequate response to anemia
associated with relative bone marrow failure or
infective erythropoiesis
2. Increased destruction or loss
o secondary to hemolysis, sequestration or bleeding
o increased numbers of reticulocytes represent a normal
bone marrow response to ongoing RBC destruction
(hemolysis), sequestration, or loss (bleeding)

− The peripheral blood reticulocyte percentage or absolute

Figure 1. Use of Mean Corpuscular Volume (MCV) and
Reticulocyte Count in the Diagnosis of Anemia
number will help to make a distinction between the 2
physiologic categories.
− The normal reticulocyte percentage of total RBCs
during most of childhood is approximately 1%,
o with an absolute reticulocyte count of 25,000-
75,000/mm3.
− In the presence of anemia, EPO production and the
absolute number of reticulocytes should rise.

Major Categories of Anemia Based on Underlying Physiology

Figure 2. Morphologic Abnormalities of RBC. A. Normal, B.
Macrocytes (Folic and Vit B12 deficiency), C. Hypochromic
microcytes (IDA), D. Target cells (HbCC disease), E.
Schistocytes (HUS)
Anemias of Inadequate Production
1. DECREASED RBC PRODUCTION because of
a. Bone marrow injury from toxic chemicals,
infections, drugs, radiation

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 Hematology A – Anemias

▪ Acquired Pure Red Cell Aplasia

▪ Aplastic Anemia
▪ Anemia of Chronic Disease and Renal Disease
b. Lack of nutrients (iron, folate, B12, B6, proteins)
for blood formation and other physiologic causes
▪ Iron Deficiency Anemia
▪ Megaloblastic Anemia
▪ Physiologic Anemia of Infancy
c. Genetically Defective Red Cell / Hemoglobin
Synthesis
▪ Diamond Blackfan Syndrome
▪ Pearson Syndrome
▪ Congenital Dyserythropoietic Anemias
▪ Other Microcytic Anemias

I. ANEMIAS OF INADEQUATE PRODUCTION

A. NUTRITIONAL ANEMIAS
Anemias Due to Increased Loss
1. Loss from hemorrhage Iron
2. Loss from Hemolysis or Destruction − Essential nutrient required by every human cell
a. INTRINSIC Hemolysis − Physiologic functions:
▪ Hemoglobinopathies – Thalassemias, Sickle Cell o As hemoglobin → carries oxygen
Disease o As myoglobin → facilitates oxygen use and storage
▪ RBC Membrane Defects – Hereditary in the muscles
Spherocytosis, Hereditary Elliptocytosis,
o As cytochromes → electron transport medium for
Hereditary Pyropoikilocytosis
electrons in cells
▪ Enzymopathies – G6PD Deficiency, Pyruvate
o Integral part of enzymes in various tissues
Kinase Deficiency
b. EXTRINSIC Hemolysis
Important Iron-Containing Compounds in The Body
▪ Immune Mediated – AHTR, Warm Reactive
Autoimmune Hemolytic Anemia, Alloimmune Compound Function
hemolytic Anemia, Drug Induced Alpha-Glycerophosphate
▪ Cold Agglutinins – Primary or Secondary Dehydrogenase
Work
▪ Others – Toxins, Venom, Sepsis
Mitochondrial DH Electron transport
c. Erythrocyte Fragmentation
▪ Thrombotic Microangiopathy ATP, CHON synthesis,
Cytochromes
▪ Systemic Disorders – DIC, HELLP, malignancy, electron transport
infection, APAS Monoamine oxidase Catecholamine metabolism
▪ Isolated Intravascular Sites of Hemolysis – Myoglobin Muscle work
Kasabach-Merritt Syndrome, Renal Artery
Stenosis Peroxidase Bacterial killing (infections)
Ribonucleotide reductase Lymphocyte DNA synthesis

Iron Metabolism
− Transferrin → bone marrow → hemoglobin synthesis →
after 120 days, stored again as ferritin
− Can only absorb a maximum of 5 mg/d in anemia
− Iron overload: can excrete a maximum of 4 g/d

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 Hematology A – Anemias

Cause of True Iron Deficiency Anemia

−  Iron loss,  Iron intake,  utilization

1. ↑ Iron loss
o Bleeding
o Menorrhagia
o Gastrointestinal
▪ Parasitism, meckel, PUD/ASA, mucosal
shedding
o Recurrent epistaxis
o Excessive phlebotomy
o Blood donations
2. ↓ Iron intake
o Inadequate iron supply
▪ Poor iron content in the diet
▪ Diets with insufficient bioavailable iron (presence
of inhibitors of iron absorption or low level of
IRON DEFICIENCY ANEMIA enhancers)
o Dietary sources of iron can be classified as food
− most widespread and common nutritional disorder in the sources and fortified foods
world o The amount of iron varies widely between foods
− estimated that 30% of the global population has iron- o Iron exists in food under two forms
deficiency anemia, and most of them live in developing ▪ Heme (30% absorbed)
countries ▪ Non-heme iron (3-5% absorbed)
− A full-term newborn infant contains about 0.5 g of iron,
compared to 5 g of iron in adults. Facilitator Inhibitor
o This change in quantity of iron from birth to adulthood Beef, pork, liver, ++++ Wheat bran, tea, +++
means that an average of 0.8 mg of iron must be fish (40% Heme, nuts, legumes,
absorbed each day during the first 15 year of life. 60% Non-Heme) leafy vegetables
− A small additional amount is necessary to balance normal Orange, pear, +++/++ Coffee, corn +++/++
losses of iron by shedding of cells. apple, pineapple (maize)
o It is therefore necessary to absorb approximately 1 juices
mg daily to maintain positive iron balance in Plum, banana, ++/+ Rice ++/+
childhood. mango
− Because <10% of dietary iron usually is absorbed, a dietary Carrot, potato, ++/+ Egg +
pumpkin, broccoli,
intake of 8-10 mg of iron daily is necessary to maintain iron
cauliflower,
levels.
tomato
− Breastfed infants have an advantage because they absorb Salad (lettuce, + Spinach +
iron 2-3 times more efficiently than infants fed cow’s milk. tomato, green
pepper,
Etiology cucumber)
− Inadequate dietary iron
− Undernutrition 3. ↑ Utilization of iron
− Blood loss o Pregnancy
o Rapid growth (Infants – 1-3g/kg/ RDA recommended)

WHO ARE MOST VULNERABLE?

− Pregnant mothers, particularly multiparous
− Growing children – increase demand from growth
− Adolescent – forcible dieting, menstrual loss
− Elderly – poor diet, malabsorption, bone marrow
hypoactivity, infections, co-morbidity
− Premature – low reserve, increase demand from growth
− From regions where hookworm is common

Physiologic Anemia in Normal Infants and Premature

− Normal infants: 2-3 months of age
− Premature: 1-2 months
− Blood volume increases 3-4 fold
− Hemoglobin iron diluted 3-4x
− Muscle mass increases 3-4x
o Poor iron intake
o Depletion of storage

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 Hematology A – Anemias

Other Signs of Nutritional Deficiencies DEVELOPMENT OF ANEMIA 2 TO IRON DEFICIENCY

− Pica
− Koilonychia
− Glossitis
− Malnutrition

Clinical Manifestation
− Most children with iron deficiency are asymptomatic.
− Pallor is the most important clinical sign of iron anemia but
is not usually visible until the hemoglobin falls to 7-8g/dL.
o most readily noted as pallor of the palms, palmar
creases, nail beds, or conjunctivae
− In mild to moderate iron deficiency (Hgb 6-10 g/dL), PHASE 1: IRON STORE DEPLETION (ISD)
compensatory mechanisms, including increased levels of 2,3- − Mildest form, first stage
diphosphoglycerate and a shift of the oxygen dissociation − Not associated with distinctive clinical findings
curve, may be so effective that few symptoms of anemia aside − Hemoglobin level is normal
from mild irritability are noted. − Serum iron is normal
o Cold intolerance, fatigue, exercise-induced dyspnea, − Only detected with decreased serum ferritin levels
decreased mental acuity − HIGH INDEX OF SUSPICION AMONG:
− Hgb <5 g/dL o Inadequate diet
o irritability, anorexia, and lethargy develop, and systolic o Rapid growth – infancy
flow murmurs are often heard o Adolescence
o As the hemoglobin continues to fall, tachycardia and o Normal menses
high output cardiac failure can occur. o Blood donation
− Non-hematologic systemic effects
o Impaired cognitive function in infancy, later possibly PHASE 2: IRON DEFICIENT ERYHTROPOIESIS (IDE)
irreversible, cognitive defects
− Limitation of bone marrow production (erythropoiesis)
o Increased risk of seizures, strokes, breath-holding
− Modest fall in the Hgb level bet 11-12 g
spells in children, exacerbation of restless leg
syndrome in adults − Decreased iron and serum ferritin levels
o Pica – desire to ingest nonnutritive substances; can − Little or no change in red cell morphology
result in ingestion of lead-containing substances and
result in concomitant plumbism PHASE 3: IRON DEFICIENCY ANEMIA (IDA)
o Pagophagia – desire to ingest ice − Full blown Hgb < 10g
o mild <12g
Non-Hematologic Complications of Iron Deficiency o moderate <10g
− As the body iron gets depleted, changes occur in many o severe <8g
tissues even before anemia supervenes. − Distinctive changes in the red cell morphology: size &
1. Impaired muscular function and exercise shape (anisopoikilocytosis)
tolerance − Symptomatic patients
▪ Musculoskeletal system: decreased physical o Fatigue
performance, tissue lactic acidosis on exercise, o Pallor
poor fracture healing o Sore mouth
▪ CV: fatigue, cardiac hypertrophy = increased CO o Koilonychia
2. Nervous system dysfunction o Learning and behavioral problems
3. Immune dysfunction and susceptibility to ▪ Very significant behavioral changes and poor
infection academic performance
4. Reduction in growth
5. Impaired thermoregulation Phase 1 Depletion of iron stores to compensate serum
6. Behavioral abnormalities Hgb
7. Metabolic abnormalities Depleted serum ferritin (seen in iron deficiency
▪ GI effects w/o anemia)
Tries to compensate for absence of iron in
8. Brain development; intelligence
tissues
▪ CNS manifestations: irritability, conduct disorders
low mental and motor developmental scores w/ Phase 2 Iron Deficient Erythropoiesis
significantly lower scholastic performance
Phase 3 Iron Deficiency Anemia
Iron Compartments *When you treat, it goes backward. So, if you give iron and the
− Plasma → Serum Iron patient is still anemic but iron tissues are high, then you are not
− Tissue → Serum Ferritin dealing with iron deficiency.
− RES →Iron tissue or Serum Ferritin

Table 4. Spectrum of Iron Deficiency and Laboratory Findings

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 Hematology A – Anemias

Spectrum of Iron Deficiency Microcytic Anemias

Laboratory Iron Anemia of Iron
Iron Store Iron Deficient Study  or 
Test Deficiency Chronic Deficiency
Depletion Erythropoiesis thalassemia
Anemia Disease Anemia
Hemoglobin Normal Decreased Decreased Hemoglobin Decreased Decreased Decreased
Mean Mean
Corpuscular Normal/ Corpuscular Normal -
Normal Decreased Decreased Decreased
Volume Decreased Volume Decreased
(MCV) (MCV)
Serum Decreased Red Cell Normal or
Decreased Decreased Normal -
Ferritin (SF) Distribution minimally Increased
Increased
Serum Iron Decreased Width (RDW) increased
Normal Decreased
(SI) Normal - Normal -
RBC Decreased
Serum Increased Decreased
Transferrin Serum
Normal Increased Increased Normal Increased Decreased
Receptor Ferritin (SF)
(sTR) Reticulocyte Normal -
Normal Decreased
Transferrin Count Decreased
Normal Decreased Decreased
Saturation Serum
Total Iron Transferrin
Normal Normal Increased
Binding Receptor
Normal Increased Increased
Capacity (sTR)
(TIBC) Transferrin
Normal Decreased Decreased
Erythrocyte Saturation
Zinc Normal Normal Increased Total Iron
Protoporphyrin Binding
(ZPP) Normal Decreased Increased
Capacity
Reticulocyte (TIBC)
Normal Decreased Decreased
Count Erythrocyte
Zinc
Normal Increased Increased
Peripheral Blood Smear in Iron Deficiency Anemia Protoporphyrin
− Small, pale (microcytic, hypochromic red cells with variable (ZPP)
size and shapes – anisopoikilocytosis) Note that  or  thalassemia here is a trait(?).

Differential Diagnosis Formula Thalassemia IDA

−  or  thalassemia RDW1
− Other hemoglobinopathies – Hgb C and E disorders MCV x RWD > 220 < 220
RBC
− Lead poisoning
Mentzer’s Index
− Anemia of inflammation MCV < 13 > 13
!MUST KNOW! RBC
Iron Deficiency Thalassemia
Anemia Prevention
Hemoglobin   − Breastfeeding with iron supplement at 4 months of age.
MCV   − Infants who are not breastfed should receive iron fortified
MCH   formula (12 mg iron per L) for the first year of life.
MCHC   − Routine screening with CBC at 9-12 months and earlier for
RDW   those who are high risk.
RBC  
Treatment
Serum Ferritin
  − Treatment goals:
(SF)
Reticulocyte o Iron replacement
  o Identification and treatment of the underlying cause
Count
Serum − Iron therapy – Elemental Iron
Transferrin  3mg/kg/day TID 6mg/kg/day TID
Receptor (sTR) - Hgb 12 g/dL - Hgb < 10 g/dL
Transferrin - 3 months to replete - 1 month OR
 
Saturation storage - until Hgb is 12
Total Iron
− Oral administration of simple ferrous salts provides
Binding  
Capacity (TIBC) inexpensive effective therapy.
Erythrocyte Zinc o Ferrous sulfate is 20% elemental iron by weight
Protoporphyrin   − Therapeutic dose: 3-6 mg/kg/day of elemental iron given
(ZPP) between meals with Vitamin C
IDA:  REST Thalassemia:  MST − Dietary iron should be increased especially from heme
Table 5. Laboratory Studies in Microcytic Anemias sources.

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 Hematology A – Anemias

− For mild anemia, repeat CBC after one month of initiation − Most cases of childhood megaloblastic anemia result from
of therapy. a deficiency of folic acid or vitamin B12 (cobalamin),
vitamins essential for DNA synthesis.

Table 7. Causes of Red Blood Cell Macrocytosis

Causative Conditions Hematologic Features
Megaloblastic Anemia
Cobalamin (vit B12) Megaloblastic changes
deficiency including hypersegmented
Folate deficiency neutrophils
Table 6. Responses to Iron Therapy in Iron Deficiency Anemia Antifolate drugs Macrocytosis can be severe
(Methotrexate) Mild reticulocytopenia
Time After Iron
Response Cytotoxic drugs Pancytopenia (when
Administration
(hydroxyurea, 5-FU) megaloblastic process is
12-24 hours Replacement of intracellular iron
Immunosuppressive drugs severe)
enzymes; subjective improvement;
(Azathioprine)
decreased irritability; increased appetite
Thiamine responsive
36-48 hours Initial bone marrow response; erythroid
anemias
hyperplasia
Hereditary orotic aciduria
48-72 hours Reticulocytosis, peaking at 5-7 days
Disorders of Erythroid Production
4-30 days Increase in hemoglobin level
Aplastic anemia, PRCA, Nonmegalobalstic
1-3 months Repletion of stores Diamond Blackfan Dyserythropoiesis and
Syndrome sometimes hyposegmented
Sideroblastic anemias, neutrophils
Dyserythropoiesis, Macrocytosis can be severe
Fanconi anemia, MDS, Reticulocytopenia
MPD
Reticulocytosis
Chronic hemolytic anemia Nonmegaloblastic;
no hypersegmented
neutrophils
Drugs and Toxins
Response: ↑ Hgb → ↑ Serum Iron → ↑ Serum Ferritin Alcohol abuse Mechanism of macrocytosis
Some antiviral drugs is often unknown
Response to Iron Supplementation Some anticonvulsant drugs No hypersegmented
− has also been used in order to assess iron deficiency neutrophils
anemia Non-Hematologic Diseases
− best strategy to assess iron deficiency Chronic liver disease Mechanism of macrocytosis
Hypothyroidism is often unknown
Failure to Increase Hgb in 1-2 Weeks of Iron Therapy Copper deficiency No hypersegmented
neutrophils
− Incorrect diagnosis
Macrocytes are rarely oval
− Continued bleeding
− Reticulocytosis w/o increase in Hgb
− Iron malabsorption FOLIC ACID DEFICIENCY
− Non-compliance
− Folic acid, or pteroylglutamic acid, consists of pteroic
acid conjugated to glutamic acid.
MEGALOBLASTIC ANEMIA o Biologically active as folates/tetrahydrofolates
o Essential for DNA replication and cellular proliferation
− group of disorders that are caused by impaired DNA − Dietary sources: green vegetables, fruits, and animal
synthesis organs
− RBCs are larger than normal at every developmental
stage, and there is maturational asynchrony between the Etiology
nucleus and cytoplasm of erythrocytes. − can occur as a consequence of
− Myeloid and platelet precursors are also affected. o inadequate folate intake,
o Giant metamyelocytes and neutrophil bands are often o decreased folate absorption, or
present in the bone marrow. o acquired and congenital disorders of folate
− There is often an associated thrombocytopenia and metabolism or transport
leukopenia.
− The peripheral blood smear is notable for large, often oval, Table 8. Causes of Folate Deficiency
RBCs with increased mean corpuscular volume. Inadequate Nutrition Disorders of Transport
o Neutrophils are characteristically hypersegmented, Poor diet Cerebral folate deficiency
with many having >5 lobes. Poor food preparation (genetic or acquired)
methods
Exclusive feeding with goat
meat

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 Hematology A – Anemias

Defects in Absorption Increased Requirements o The products and by-products of these enzymatic
Gastric achlorhydria or Losses reactions are critical to DNA, RNA, and protein
Diseases of the upper Pregnancy synthesis.
intestines Lactation − Cobalamin is synthesized exclusively by microorganisms
Tropical sprue Prematurity and humans must rely on dietary sources (animal
Celiac disease Chronic Hemolytic Anemia products including meat, eggs, fish, and milk) for their
Inflammatory bowel Dialysis
needs.
disease Hyperthyroidism
Oral pancreatic Lesch-Nyhan Syndrome
replacement therapy Etiology
Hereditary folate − result from:
malabsorption o inadequate dietary intake of Cbl,
Disorder of Cellular Multifactorial o lack of IF,
Metabolism Alcohol abuse o impaired intestinal absorption of IF-Cbl, or
Drugs inhibiting folate Anticonvulsants o absence of vitamin B12 transport protein
metabolism (antifolates, Oral contraceptives
pyrimethamine, Clinical Manifestation
sulfasalazine, valproic − Children with Cbl deficiency often present with nonspecific
acid) manifestations such as:
Inherited defects
o weakness, lethargy, feeding difficulties, failure to
thrive, and irritability
Clinical Manifestation
− Other common findings include:
− Irritability, chronic diarrhea, and/ or poor weight gain
o pallor, glossitis, vomiting, diarrhea, and icterus
− Hemorrhages from thrombocytopenia may occur in
− Neurologic symptoms can include:
advanced cases.
o paresthesia, sensory deficits, hypotonia, seizures,
developmental delay, developmental regression, and
Laboratory Findings
neuropsychiatric changes
− Macrocytic anemia (MCV >100 fL)
− Neurologic problems from vitamin B12 deficiency may
− Low reticulocyte count
occur in the absence of any hematologic abnormalities.
− PBS: nucleated RBC with megaloblastic morphology,
neutropenia and thrombocytopenia Laboratory Findings
o neutrophils are large, some hypersegmented
− Macrocytic anemia (MCV > 100 fL)
− BMA: hypercellular with megaloblastic changes
− Low reticulocyte count
− Low serum folate < 3 ng/mL (NV: 5-20 ng/mL)
− PCS: nucleated RBC with megaloblastic morphology;
− Low RBC folate (NV: 1500-600 ng/mL) - better indicator of prominent macro-ovalocytosis of RBCs
chronic deficiency o Neutrophils may be large and hypersegmented.
− Serum activity of lactate dehydrogenase is markedly o In advanced cases, neutropenia and
elevated thrombocytopenia can occur, simulating aplastic
o marker of ineffective erythropoiesis anemia or leukemia.
− Serum vitamin B12 levels are low (NV: 5-20 ng/mL)
Treatment
− Serum concentrations of methylmalonic acid and
− Folic acid may be administered oraly or parenterally at 0.5- homocysteine are usually elevated.
1.0 mg/day
− Serum Iron and Serum Folic Acid are normal orelevated.
− If the specific diagnosis is in doubt, smaller doses of folate
− Serum lactase dehydrogenase is markedly increased.
(0.1 mg/day) may be used for 1 wk as a diagnostic test,
− Serum bilirubin is mildly elevated (2-3 mg/dL)
because a hematologic response can be expected within
− Low level of total or TC bound vitamin B12 in blood
72 hr.
− Folic acid therapy (0.5-1.0 mg/day) should be continued for
Treatment
3-4 wk until a definite hematologic response has occurred.
− The cause of vitamin B12 deficiency should ultimately
− Maintenance therapy with a multivitamin (containing 0.2 mg
dictate treatment dosage as well as the duration of therapy.
of folate) is adequate.
− The physiologic requirement for vitamin B12 is about 1-3
μg/day.
VITAMIN B12 (COBALAMIN) DEFICIENCY − Cyanocobalamin may be given as nasal spray or
parenterally.
− Vitamin B12 is a generic term encompassing all
biologically active cobalamins.
o Methylcobalamin and adenosylcobalamin are the
metabolically active derivatives, serving as cofactors
in 2 essential metabolic reactions, namely:
▪ methylation of homocysteine to methionine (via
methionine synthase) and
▪ conversion of methyl-malonyl coenzyme A (CoA)
to succinyl CoA (via l-methyl-malonyl-CoA
mutase)

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 Hematology A – Anemias

The list includes the anomalies that are most characteristic of DBA
B. SELECTIVE RED CELL HYPOPLASIA
but is not exhaustive. Multiple anomalies, most commonly including
craniofacial, are present in up to 25% of affected individuals.
CONGENITAL HYPOPLASTIC ANEMIA
Laboratory Findings
(DIAMOND BLACKFAN SYNDROME)
− Macrocytic RBs
− Rare congenital bone marrow failure syndrome − Elevated fetal hemoglobin
symptomatic in early infancy − Increased expression of i antigen
− 90% of cases recognized in the first year of life − Increased erythrocyte adenosine deaminase (eADA)
− Normochromic, macrocytic anemia activity
o Reticulocytopenia − Low reticulocyte count
o absent/decreased red cell precursors in a cellular − Decreased bone marrow erythrocyte precursors
bone marrow
− 50% of cases have additional extrahematopoietic Table 10. Diagnostic Criteria for Blackfan Syndrome
anomalies Supporting Criteria
Diagnostic Criteria
Major Criteria Minor Criteria
Etiology - Age < 1 year - Pathogenic - Elevated red cell
− Mutation in RPS19 - Macrocytic mutations adenosine
o gene that encodes for 40S ribosomal subunit anemia - Positive deaminase
- Reticulocytopenia family - Congenital
o mutations in the RP genes (Ribosomopathy)
- Decreased BM history anomalies of
o autosomal dominant inheritance erythroid Diamond Blackfan
− GATA1 mutation precursors Anemia
o non-RP gene - Elevated fetal
o X-linked recessive hemoglobin
- No evidence of
Clinical Manifestations other inherited
− 25% anemic at birth bone marrow
− Profound anemia noted at 2-6 months of age failure syndromes
− 92% are diagnosed within the first year of life
Differential Diagnoses
− 40-50% have congenital anomalies
− Transient Erythroblastopenia of Childhood
Table 9. Congenital Anomalies in Diamond Blackfan Syndrome − Inherited Macrocytic Bone Marrow Failure Syndromes
Craniofacial Hypertelorism − Fanconi Anemia
Broad, flat nasal bridge − Shwachman-Diamond Syndrome
Cleft palate
High arched palate Treatment
Microcephaly − Corticosteroids – mainstay therapy
Micrognathia − Red Cell Transfusion
Microtia − Hematopoietic Stem Cell Transplant – curative
Low-set ears
Low hair line
Prognosis
Epicanthus
Ptosis − Cancer predisposition syndrome (preleukemic)
Ophthalmologic Congenital glaucoma o Higher risk of myelodysplastic syndrome, AML, colon
Strabismus cancer, osteogenic sarcoma, female genital cancers
Congenital cataract − Prone to iron overloading and related endocrine
Neck Short neck abnormalities
Webbed neck − Survival rate: 75%
Sprengel deformity
Klippel-Feil deformity
Thumbs Triphalangeal ACQUIRED PURE RED BLOOD CELL ANEMIA
Duplex or bifid
Hypoplastic
Flat thenar eminence TRANSIENT ERYTHROBLASTOPENIA OF
Absent radial artery
CHILDHOOD
Urogenital Absent kidney
Horseshoe kidney − Most common acquired red cell aplasia in children
Hypospadias
− Syndrome of severe, transient hypoplastic anemia
Cardiac Ventricular septal defect
Atrial septal defect − Occurs in previously healthy children between 6 months
Coarctation of the aorta and 3 years of age
Complex cardiac anomalies − Suppression of erythropoiesis has been linked to IgG, IgM,
Other Growth retardation and cell mediated mechanisms
musculoskeletal Syndactyly − Follows viral illness
Neuromotor Learning difficulties − Pure red cell aplasia, immune-mediated, self-limiting

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 Hematology A – Anemias

Laboratory Findings HEPCIDIN

− Moderate to severe normocytic anemia → Produced by hepatocytes (liver)
− Reticulocytopenia → Master physiological regulator of iron metabolism
− Normal MCV → Down regulates iron export to circulation transferrin by
− Normal fetal hemoglobin promoting the internalization and lysosomal degradation
− Normal RBC adenosine deaminase of ferroportin
▪ inhibition of iron absorption in gut
Prognosis ▪ inhibition of release of iron from macrophages →
− All children recover in 102 months iron cannot be incorporated in hemoglobin
− RBC transfusion may be necessary for severe anemia in → Decreased hepcidin production is seen with hypoxia
the absence of early recovery and in association with ineffective erythropoiesis, and
− Corticosteroids – not beneficial iron deficiency.

Ferroportin
Table 11. Comparison of Transient Erythroblastopenia of
→ Found in basolateral membranes of intestines, in
Childhood and Diamond Blackfan Syndrome
macrophages and hepatocytes
Feature TEC DBS
Male:Female 1:3 1:1
Age at Diagnosis
Male 26 10
Female 26 14
Laboratory
Hemoglobin 2.2-12.5 1.2-14.8
MCV N 
Hb F N 
Adenosine deaminase N 
i antigen N 

C. ANEMIA OF CHRONIC DISEASE AND RENAL

DISEASE

ANEMIA OF CHRONIC DISEASE (ACD)

− Also referred as Anemia of Inflammation

− Occurs in infection, malignancy, chronic renal disease,
autoimmunity, graft vs host
− Similar anemia is associated with chronic kidney disease
− Mild-moderate normocytic normochromic hypoproliferative
anemia associated with decreased serum iron and low
transferrin saturation
o Acute ACD: normocytic normochromic
o Chronic ACD: microcytic hypochromic

Etiology
− Decreased RBC lifespan Clinical Manifestations
o IL-1 → increase macrophage’s ability to ingest and − Important symptoms and signs are those of the underlying
destroy RBC disease, and the mild-moderate anemia
− Impaired Erythropoiesis
Laboratory Findings
o IL-1, IFN-γ, TNF
o Cell/cytokine driven inhibition of EPO production − Normocytic, normochromic
o Suppression of bone marrow o Decreased Hgb (6-9 g/dL)
− Increased uptake of Fe in the RES − N/ reticulocyte count
o Inflammation → excess HEPCIDIN → bind to − Low serum iron
ferrroportin → iron diversion from circulation to − Low to normal serum transferrin
reticuloendothelial system (RES) → functional Fe − Elevated serum ferritin
deficiency → impaired heme synthesis and iron − Normal soluble transferring receptor (sTfR)
restricted erythropoiesis → anemia
Diagnosis
− Soluble transferrin receptors (sTfR)
o Diagnostic test
o Distinguish ACD from IDA
▪ ACD – normal
▪ IDA – increased

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 Hematology A – Anemias

− Bone marrow
1. INHERITED PANCYTOPENIAS
o Normal cellularity
o RBS precursors – adequate/decreased
o Hemosiderin may be increased Pancytopenia with constitutional symptoms
o Granulocytic hyperplasia − Fanconi anemia
− Shwachman Diamond Syndrome
Treatment − Dyskeratosis Congenita
− Treatment of the underlying disorder
− Transfusion is rarely indicated. FANCONI ANEMIA (FA)

− Primarily inherited in an autosomal recessive manner

ANEMIA OF RENAL DISEASE o Uncommon form is X-linked recessive
− Common in children with chronic kidney disease − Bone marrow failure within first decade of life
− Hemoglobin decreases as GFR falls below 43 o Approximately 75% of patients are 3-14 years of age at
mL/min/1.73m2 the time of diagnosis.
− Etiology − With predisposition to malignancy (35-40%)
o Decreased erythropoietin production by the kidney, − High sensitivity to radiation and alkylating agents
o absolute or functional iron deficiency − Often with congenital anomalies
o Elevated Hepcidin levels o Skeletal anomalies
− Laboratory findings o Hyperpigmentation of the trunk, neck, intertriginous
o Normocytic, normochromic anemia areas
o Low EPO o Café au lait spots, vitiligo
o Normal or low reticulocyte count o Short stature, facial dysmorphisms
o Low serum ferritin if with concomitant iron deficiency o Urogenital, kidney, cardiovascular, CNS and GIT
− Treatment malformations
o Erythrocyte stimulating agents (ESAs)
▪ Mainstay of therapy Diagnosis
o Oral Iron therapy − FA should be considered in all children and young adults
with unexplained cytopenias.
− Abnormal hematologic findings and characteristic physical
D. PHYSIOLOGIC ANEMIA OF INFANCY anomalies suggest the diagnosis.
− At birth, the increase in blood oxygen content and delivery − Diepoxybutane (DEB)
results in down regulation of erythropoietin (EPO) o confirmed with a lymphocyte chromosomal
production, leading to suppression of erythropoiesis breakage study
o Aged RBC are not replaced
Treatment
− In healthy term infants: occurs at 8-12 weeks of age with
Hb concentration of 11 g/dL, rarely falls below 10 g/dL − HSCT – > 80% survival rate
− In premature infants, Hb falls to 7-9 g/dL at 3-6 weeks of
age SHWACHMAN-DIAMOND SYNDROME (SDS)
− Treatment
o Full term infants – no treatment − Autosomal recessive; ribosomopathy
o PRBC if necessary − mutant gene SBDS maps to chromosome 7q11
− Bone marrow failure
o characterized by dysfunctional hematopoietic stem cells,
E. PANCYTOPENIAS
accelerated apoptosis of marrow progenitors and a
− Reduction below normal values of all 3 peripheral blood defective marrow microenvironment that does not
lineages support and maintain normal hematopoiesis
o Leukocytes o usually include exocrine pancreatic insufficiency
o Megakaryocytes and skeletal abnormalities such as metaphyseal
o Erythrocytes dysplasia
− Pancytopenia with Hypocellular Bone Marrow − Fat malabsorption from birth, short stature
o Inherited BM failure syndromes − 25% develop MDS or leukemia
− Pancytopenia with Cellular Bone Marrow
o Primary BM disease − There is no increased chromosomal breakage after DEB
o Secondary to immune disorders testing of SDS lymphocytes.
− Pancytopenia with Bone Marrow Infiltration (metastatic
solid tumors) Treatment
o Myelofibrosis − HSCT – > 50-70% survival rate
o Hemophagocytic lymphohistiocytosis (HLH)
o Osteopetrosis

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 Hematology A – Anemias

Pathology and Pathogenesis

DYSKERATOSIS CONGENITA
− Hallmark of aplastic anemia
− Inherited multisystem telomere disorder o peripheral pancytopenia, coupled with
− X-linked recessive/autosomal recessive hypoplastic or aplastic bone marrow
o X-linked recessive form of DC maps to Xq28 − The severity of the clinical course is related to the degree
o Autosomal dominant form is due to mutations in TINF2, of myelosuppression.
or in TERC or TERT − immune-mediated process, with increased circulating
o Autosomal recessive DC is linked to mutations in activated T lymphocytes producing cytokines (interferon-γ)
NOP10, NHP2, RTEL1, TCAB1, and CTC1 that suppress hematopoiesis
− Varying degrees of bone marrow failure see in 90% of − Early apoptosis of hematopoietic progenitors
patients − Immunologic suppression of hematopoiesis,
− High risk of pulmonary and hepatic fibrosis, solid tumors, − Defective hematopoietic microenvironment
MDS, AML − Abnormalities of cytokines

Clinical Features Moderate Aplastic Anemia

− characterized by mucocutaneous abnormalities, bone
marrow failure, and a predisposition to cancer and MDS
− The diagnostic mucocutaneous (ectodermal) triad
o Lacy, reticulate skin pigmentation of the upper
body (chest)/neck (89%)
o Mucosal (oral) leukoplakia (78%)
o Nail dystrophy (dysplastic) (88%)
− Skin and nail findings become apparent in the first year of
life.
Diagnosis
− 2 out of 4: Skin, Nail, Oral, Bone marrow failure
Treatment
− HSCT – 50% survival rate
− absolute neutrophil count 500-1,500/mm3
− platelet count 20,000-100,000/mm3
− reticulocyte count <1%
− approximately 65% of patients may eventually progress to
meet criteria of severe disease
Severe Aplastic Anemia
− defined as a condition in which 2 or more cell components
have become seriously compromised in a patient whose
bone marrow biopsy material is moderately or severely
hypocellular
− absolute neutrophil count <500/ mm3
o normal: 1500-2500
− platelet count <20,000/mm3
− reticulocyte count <1% after correction for hematocrit

Clinical Features
2. ACQUIRED PANCYTOPENIAS
− Bleeding – due to thrombocytopenia
− Weakness, fatigue – due to anemia
APLASTIC ANEMIA − Infection – due to neutropenia
− Physical Examination
− Characterized by peripheral blood pancytopenia with o Pallor, purpura, ecchymoses, petechiae
associated bone marrow hypocellularity involving: o Noncutaneous hemorrhage
o Erythroid, Granulocytic, and Megakaryotic cell lines
Laboratory Findings
− Peripheral Pancytopenia
o Anemia
o Reticulocytopenia, Leukepenia/neutropenia
o Increases suppressor (CD8)
− Bone Marrow Biopsy/Aspirate
o Hypoplastic/aplastic marrow
o Increased fat cells, plasma cells, mast cells,
lymphocytes

CAMITTA’S CRITERIA for Severe Aplastic Anemia

− Blood (peripheral)
o absolute neutrophil count <500/ mm3
o platelet count <20,000/mm3
o reticulocyte count <1%
− Bone Marrow
o < 30% – moderate hypocellularity
o < 25% - severe hypocellularity

Treatment
− Blood product replacement
o PRBC
o Platelets, Granulocyte

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 Hematology A – Anemias

− Immunosuppression
o Horse ATGE
o Cyclosporine
▪ 70-80% response rate in 6 months
▪ 30% relapse rate
▪ 50% response rate to second course
− HSCT – 90% survival rate

Prognosis
− If left untreated, sever pancytopenia has an overall
mortality rate 50% within 6 months of diagnosis
o 75% of cases – infection and hemorrhage being the
major causes of morbidity and mortslity
− Clonal Bone Marrow Disease
o < 10% related to treatment

II. HEMOLYTIC ANEMIAS − In high hematocrit levels, the immature red cells stay longer
in the BM for maturation before being released in the blood.
− However, in cases of decreased hematocrit levels (as seen
− Hemolysis
in acute hemolytic crisis), the immature red cells are
o defined as the premature destruction of red blood cells
released early in the circulation and has longer maturation
(RBCs) (a shortened RBC life span)
time in the peripheral blood. This explains why the
− Anemia results when immature red cells (e.g. Normoblasts and reticulocytes) are
o rate of destruction exceeds the capacity of the marrow abundant in the circulation.
to produce RBCs
− Normal RBC survival time is 110-120 days (half-life: 55- Hemolytic Anemias May Be Classified as Either:
60 days) − Intrinsic/Intracorpuscular – resulting from cellular
o approximately 0.85% of the most senescent RBCs are abnormality (membrane, enzymes, or hemoglobin)
removed and replaced each day o Most cellular defects are inherited (paroxysmal
− During hemolysis, nocturnal hemoglobinuria is acquired).
o RBC survival is shortened → RBC count falls − Extracellular/Extracopuscular – resulting from
o Erythropoietin is increased antibodies, mechanical factors, or plasma factors
o Stimulation of marrow activity results in heightened o Most extracellular defects are acquired
RBC production (reflected in an increased percentage (abetalipoproteinemia with acanthocytosis is
of reticulocytes in the blood) inherited).
o Thus, hemolysis should be suspected as a cause of − Inherited vs Acquired
anemia if an elevated reticulocyte count is present.
− Immune vs Non-Immune
− The reticulocyte count may also be elevated as a response
− Acute vs Chronic
to acute blood loss or for a short period after replacement
− Intravascular (within blood vessels) vs Extravascular
therapy for iron, vitamin B12, or folate deficiency.
(reticuloendothelial system)
− Bone marrow compensation
o increase its output 2-3–fold acutely
Table 12. Classification of Non-Immune Hemolytic Anemias
o maximum of 6-8–fold in long-standing hemolysis
Laboratory
− The reticulocyte percentage can be corrected to measure Disorders/Causes
findings
Diagnostic Test
the magnitude of marrow production in response to CONGENITAL DISORDERS
hemolysis as follows: Membrane Disorders
Hereditary Spherocytes EMA binding,
spherocytosis osmotic fragility
Hereditary Elliptocytes Blood smear
elliptocytosis
where μ is a maturation factor of 1-3 related to the Hereditary Microcytes,
severity of the anemia pyropoikilocytosis fragments
Hemoglobin Disorders
− The normal reticulocyte index is 1.0
Sickle cell disease Sickle cells, Hemoglobin
− Index measures the fold increase in erythropoiesis target electrophoresis
(e.g., 2-fold, 3-fold). Unstable Bite cells Supravital stain,
− Normal Hct is usually 40. hemoglobins heat or alcohol
stability test
Enzyme Disorders
G6PD deficiency Bite cells, Supravital stain,
blister cells G6PD level
Others Variable Individual
enzyme levels

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 Hematology A – Anemias

ACQUIRED DISORDERS - History of Neonatal - Increased urinary

Microangiopathic Hemolytic Anemias Icterus urobilinogen
TTP, HUS, DIC, Schistocytes, Targeted to - Positive family history of - Decreased serum
Cancer, Heart valves RBC diagnosis anemia, splenectomy, haptoglobin
fragments cholecystectomy - Increased LDH level
Infections - Hemoglobinuria (+ dipstick
Malaria, Babesiosis, Parasites Giemsa stain result for blood, no RBC in
Clostridium (malaria, urine)
babesiosis)
Toxins and Physical Agents Table 15. Diagnostic Red Cell Morphology (Shape) in Hemolytic
Arsenic, Lead, Basophilic Element level Anemia
Copper stippling (lead) Sickle cells Sickle cell disease
Insect, Spider, Snake Schistocytes, Targeted to Target cells Hemoglobinopathies (HbC,
venoms fragments diagnosis HbS, thalassemia), liver dse
Systemic Diseases Schistocytes/burr cells/ Microangiopathic hemolytic
Liver diseases Acanthocytes, Liver function helmet cells/RBC anemia
target cells tests fragments DIC, HUS, TTP
Burns Spherocytes, Targeted to Spherocytes Hereditary spherocytosis, AIHA
blister cells diagnosis Cigar-shaped cells Hereditary elliptocytosis
Paroxysmal Nocturnal Variable Flow cytometry Bite cells G6PD deficiency
Hemoglobinuria Piokilocytosis, Hereditary poikilocytosis
microcytosis, fragmented
Table 13. Etiology of Hemolytic Anemias RBC, elliptocytes
INTRINSIC EXTRINSIC ERYTHROCYTE
HEMOLYSIS HEMOLYSIS FRAGMENTATION
A. Resulting from INTRINSIC FACTORS:
Hemoglobino- Immune Thrombotic
pathies Mediated Microangiopathy NON-IMMUNE Hemolytic Anemias
-thalassemia Primary Inherited
-thalassemia Warm reactive Acquired
AIHA HEREDITARY SPHEROCYTOSIS
Sickle cell
disease Alloimmune
− Common cause of hemolysis and hemolytic anemia, with a
RBC Membrane hemolytic Systemic prevalence of approximately 1 in 5,000 persons
Defects anemia Disorders
Acute − Most common inherited abnormality of the red blood cell
Hereditary DIC
spherocytosis hemolytic HELLP (RBC) membrane
Hereditary transfusion Malignancy − Affected patients may be asymptomatic, without anemia
elliptocytosis reaction Malignant and with minimal hemolysis, or they may have severe
Hereditary Delayed hypertension hemolytic anemia requiring regular blood transfusions and
stomatocytosis transfusion Infection a splenectomy
reaction
Drug-induced Etiology
Secondary
− usually is transmitted as an autosomal dominant (75%') or,
Enzymopathies Cold Agglutinin Mechanical Causes
less commonly, as an autosomal recessive disorder
G6PD deficiency Primary Heat
(HMP) Secondary Osmotic stress − Abnormalities of /-spectrin or ankyrin-1
Pyruvate kinase Others Mechanical o most common molecular defects
(EMP) Toxin, venoms trauma − β-spectrin and band 3
Hypersplenism o dominant defects
Drug-induced − α-spectrin and protein 4.2
o recessive defects
Initial Evaluation of Suspected Hemolytic Anemia includes: − A deficiency in spectrin, band 3, ankyrin, or protein 4.2
− Detailed history of the current illness with attention to o results in uncoupling in the “vertical” interactions
coexisting diagnoses (past medical history, family history, of the lipid bilayer skeleton and subsequent release of
detailed list of medications, or recent exposures) membrane microvesicles
− Complete blood count with erythrocyte indices − The loss of membrane surface area without a
− Peripheral blood smear examination proportional loss of cell volume causes sphering of the
− Reticulocyte count RBCs, and an associated increase in cation permeability,
− Direct antiglobulin test cation transport, adenosine triphosphate use, and
− Bilirubin, Lactate dehydrogenase glycolysis.
− The decreased deformability of the spherocytic RBCs
Table 14. Clinical and Laboratory Findings in Hemolytic Anemia impairs cell passage from the splenic cords to the splenic
- Pallor - Abnormal RBC morphology sinuses, and the spherocytic RBCs are destroyed
- Icterus - Increased reticulocyte count prematurely in the spleen.
- Splenomegaly - Increased RDW − Splenectomy markedly improves RBC life span and may be
- Gallstones - Indirect indirect bilirubin indicated in some patients with HS.

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 Hematology A – Anemias

Diagnosis
− Hemolytic anemia with reticulocytosis and indirect
hyperbilirubinemia
− Low normal of slightly decreased MCV
− Increased MCH (> 35g/dL)
− MCHC > 35.4 d/dL with RDW < 14%
o Used as screening test for HS
− Confirmatory test
o Flow Cytometry – EMA binding
▪ Binding of fluorescence labeled eosin-5-
maleimide (EMA) to band 3 and other membrane
proteins is decreased
▪ Good diagnostic sensitivity and specificity than
EOFT
▪ Not readily available (Still do EOFT)
o Erythrocyte Osmotic Fragility Test (EOFT)
▪ HS: hemolysis at 0.85-0.90 % saline solution
(increased EOFT)
▪ Normal: hemolysis at 45-55% saline solution

Differential Diagnosis
− Neonates: Hemolytic Disease of the Newborn
− Older children: AIHA, Hemolytic Transfusion Reaction

Treatment
Clinical Manifestations − Folic acid supplement
− In the neonatal period, o recommended in moderate and severe HS because of
o HS is a significant cause of hemolytic disease and can an enhanced requirement with increased
be manifest as anemia and hyperbilirubinemia erythropoiesis
sufficiently severe to require phototherapy or − Red cell transfusion
exchange transfusions.
− Splenectomy in severe HS, moderate HS, frequent
− Disease severity varies and can be used to clinically hypoplastic crisis, poor growth or cardiomegaly; after 6 year
classify HS. preferably

Classification % Presentation
Mild Asymptomatic, well HEMOGLOBINOPATHIES
20-30%
Spherocytosis compensated mild anemia
Partially compensated anemia − Hemoglobin is a tetramer consisting of 2 pairs of globin
Moderate chains
6-70% (Hb 8-12 g/dL) with
Spherocytosis − Hemoglobinopathies
reticulocytosis
Moderately Partially compensated anemia o Abnormalities in these proteins
Severe 10% (Hb 6-8 g/dL) with − Two hemoglobin gene clusters are involved in the
Spherocytosis reticulocytosis production of hemoglobin and are located at the end of the
Life threatening anemia short arms of chromosomes 16 and 11.
Severe
5% (Hb < 6 g/dL), transfusion o On chromosome 16:
Spherocytosis
dependent ▪ 3 genes within the alpha (α) gene cluster, namely
zeta (ζ), alpha 1 (α1), and alpha 2 (α2)
o On chromosome 11:
▪ 5 genes within the beta (β) gene cluster, namely
epsilon (ε), 2 gamma genes (γ), a delta gene (δ),
and a beta gene (β)
− The order of gene expression within each cluster roughly
follows the order of expression during the embryonic
period, fetal period, and eventually childhood.
o After 8 wk of fetal life, the embryonic hemoglobins are
formed.
▪ Gower-1 (ζ2ε2)
▪ Gower-2 (α2ε2)
▪ Portland (ζ2γ2)
o At 9 wk of fetal life
A, Hereditary spherocytosis. B, Hereditary elliptocytosis. C, ▪ major hemoglobin (Hb) is HbF (α2γ2)
Hereditary pyropoikilocytosis. D, Hereditary stomatocytosis. E, o HbA (α2β2) first appears at approximately 1 mo of
Acanthocytosis. F, Fragmentation hemolysis. fetal life, but does not become the dominant

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 Hematology A – Anemias

hemoglobin until after birth, when HbF levels start to Clinical Spectrum
decline. Minor Major
o HbA2 (α2δ2) is a minor hemoglobin that appears Mild anemia + Severe anemia, retarded
shortly before birth and remains at a low level after splenomegaly growth + chipmunk facie,
birth. cardiac failure,
− The final hemoglobin distribution pattern that occurs in hepatosplenomegaly
childhood is not achieved until at least 6 mo of age and
sometimes later.  - THALASSEMIA
− The normal hemoglobin pattern is ≥95% HbA, ≤3.5 HbA2,
and <2.5% HbF. − an absence or reduction in α-globin production
o Deletion mutations are common in α-thalassemia.
Alpha Gene Beta Gene − Normal individuals have 4 α-globin genes.
Hemoglobin
Chromosome 16 Chromosome 11 o 2 from each parent that control α-globin roduction
Gower 1 ζ ε − The more genes affected, the more severe the disease.
− α0-mutation
Gower 2  ε
o indicates no α-chains produced from that gene
Portland ζ γ − α+ mutation
Fetal  γ o produces a decreased amount of α-globin chain
− Syndrome varies from complete absence (hydrops fetalis)
Hb A2  δ to only slightly reduced (α-thalassemia silent carrier) α-
Hb A   globin production
− Excess - and -globin chains are produced forming the two
non-functional hemoglobins with very high oxygen affinity
THALASSEMIA SYNDROMES
o Bart hemoglobin (4) –1 up to 4 gene deletion
− refers to a group of genetic disorders of globin chain o HbH (4) – only in 3 gene deletion
production in which there is an imbalance between the α-
− Severe forms lead to fetal loss because of the absence of
globin and β-globin chain production HbF.
− Occur most commonly in Southeast Asia
Genetics
− Identified in newborn period by increased production of Bart
− A matter of chance – not AD or AR
hemoglobin (4)
− Thalassemia is an inherited disease, which means it is
− Four phenotypes (deletional mutations)
passed on from parents to their child thru their genes
− It is not infectious and cannot be “caught” like a cold. It will
Silent Trait/ - 1 -gene deletion
not develop later in life, nor can child outgrow it
Carrier - Not identifiable hematologically
− The inheritance of Thalassemia genes is purely a matter of - Newborn: < 3% Hb Bart
chance and cannot be altered. Trait - 2 -gene deletion
− Children born to parents who both carry the trait have a 1 (Minor) - manifest as a microcytic, hypochromic
in 4 chance with each pregnancy of inheriting the fatal form anemia
of the disorder. - Newborn: > 3% but < 8% Hb Bart
Hemoglobin H - 3 -gene deletion
- HbH Constant Spring (−α/α,αCS) is the
most common type of nondeletional
HbH disease.
- Newborn: > 25% Hb Bart
Barts - 4 -gene deletion
Hemoglobin/ - profound anemia during fetal life,
Hydrops resulting in hydrops fetalis
Fetalis - ζ-globin gene must be present for fetal
survival
- no normal hemoglobins present at birth
MAJOR = severe hemolysis, anemia, HUGE organomegaly, (primarily Hb Bart, with Hb Gower 1,
need PRBC very often Gower 2, and Portland)
- Newborn: Bart 80-90%, Gower 1 and 2,
− Major + none parent = all 4 have traits Portland
− Major + minor → 2 majors and 2 minor kids - Intrauterine transfusions may rescue
− Major + major → all 4 kids are major the fetus; develops congenital
anomalies and neurodevelopmental
Pathophysiology delay
- If the fetus survives, immediate
− In the absence of globin production by the defective globin
exchange transfusion is indicated.
gene, the free globing chains and inclusions are unstable,
- Severe α-thalassemia are transfusion
precipitate in RBC precursors, damage RBC membrane → dependent, and hematopoietic stem
shorten RBC survival → anemia and increased erythroid cell transplantation is the only cure.
production

Page 17 of 22

 - THALASSEMIA
− result from a decrease in β-globin chains, which results in
a relative excess of α-globin chains
− People of Mediterranean origin, and to a lesser extent,
Chinese, other Asians and blacks
− Caused by a mutation in the beta globin gene
− Affected children are normal at birth, but develop anemia
during the first year of life (6 months).
− β0-Thalassemia
o refers to the absence of production of the β-globin
o more severe than β+-thalassemia
o When patients are homozygous for the β-thalassemia
gene, they cannot make any normal β chains (HbA).
− β+-Thalassemia
o indicates a mutation that makes decreased amounts
of normal β-globin, but it is still present (HbA)
β-Thalassemia Major
− severe type
− requires early transfusion therapy (transfusion dependent)
− often is homozygous for β0 mutations (both β globins)
− may have 1 β thalassemia mutation
β-Thalassemia Intermedia
− less-severe clinical phenotype
− usually does not require transfusion therapy in childhood
β-Thalassemia Carrier
− single β-globin mutation
− generally asymptomatic
o EXCEPT for microcytosis and mild anemia
HOMOZYGOUS β-THALASSEMIA
(THALASSEMIA MAJOR, COOLEY ANEMIA)
Clinical Manifestations
− If not treated, children with homozygous β0-thalassemia
usually become symptomatic from progressive hemolytic
anemia, with profound weakness and cardiac
decompensation during the 2nd 6 mo of life.
− The developing signs of ineffective erythropoiesis such
as growth failure, bone deformities secondary to marrow
expansion, hepatosplenomegaly are important variables in
determining transfusion initiation.
− The classic presentation of children with severe disease
includes:
o thalassemic facies (maxilla hyperplasia, flat nasal
bridge, frontal
o bossing)
o pathologic bone fractures
o marked hepatosplenomegaly
o cachexia
Laboratory Findings
− Microcytosis (MCV), hypochromia (MCH), and target
characterize the red cells
− Nucleated red cells, marked anisopoikilocytosis, and a
relative reticulocytopenia (< 8%) are typically seen
− Unconjugated serum bilirubin (B1) level is usually elevated
− Newborn screening techniques such as hemoglobin
electrophoresis is not definitive.
Hematology A – Anemias
− DNA diagnosis of the β-thalassemia mutation, along
with testing for common genetic modifiers of the clinical
phenotype, is recommended.
Management and Treatment
− Transfusion Therapy with Leukoreduced PRBC
o Transfusions should generally be given at intervals of
3-4 wk, with the goal being to maintain a
pretransfusion hemoglobin level of 9.5-10.5 g/dL.
o Hypertransfusion (target Hgb 10-12)
▪ Compute RBC requirement (a small amount to
correct cardiovascular complication)
o Supertransfusion (target Hgb 12-14)
▪ Suppress erythropoiesis in face, liver and spleen
aesthetic
− Iron Overload Monitoring
o Excessive iron stores from transfusion cause many of
the complications of β-thalassemia major.
o Serial serum ferritin levels are a useful screening
technique in assessing iron balance trends
− Chelation Therapy
o should start as soon as the patient becomes
significantly iron overloaded (Serum ferritin > 1000
ng/mL)
o In general, this occurs after 1 yr of transfusion therapy
and correlates with the serum ferritin >1,000 ng/mL
and/or a liver iron concentration of >2,500 μg/g dry
weight.
o Deferoxamine (Desferal)
▪ most studied iron chelator
▪ excellent safety and efficacy profile.
▪ IV/SC 20-60 mg/kg/d, 5-6 days/week
o Deferasirox (Exjade)
▪ oral 20-30 mg/kg/d
o Deferiprone (Ferriprox)
▪ oral 25 mg/kg TID
− Hydroxyurea
o DNA antimetabolite, increases stress erythropoiesis,
which results in increased HbF production
o 10 mg/kg/day
− Hematopoietic Stem Cell Therapy (HSCT)
o at least 90% survival and an 80% event-free survival
− Splenectomy
o may be required in thalassemia patients who develop
hypersplenism
o Transfusion index 200 cc/kg/year
o Hypersplenism
− Psychosocial support
β-Thalassemia Intermedia / Thalassemia Trait
− nontransfusion-dependent thalassemia
− characterized by decreased production of β-globin chains
of HbA
− have significant ineffective erythropoiesis that leads to
microcytic anemia with hemoglobin of approximately 7 g/dL
(range: 6-10 g/dL)
− Thalassemia trait
o often misdiagnosed as iron deficiency in children
because of similar hematologic abnormalities on CBC,
and iron deficiency is much more prevalent.
o have a persistently normal red cell distribution width
and low mean corpuscular volume (MCV)
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α-Thalassemia
o compensatory Hb is Barts Hb and HbH
o severe forms may manifest even in utero (hydrops)
β- Thalassemia
o compensatory Hb if HbF
o becomes symptomatic at 6mos of age
HEMOGLOBINOPATHY C
− Mutation in the β-globin gene by lysine for glutamine
− African Americans
− HbAC: Asymptomatic
− HbCC: mild anemia, splenomegaly, cholelithiasis
− HbC crystallizes, disrupting the RBC membrane
− Expanded Newborn Screening: diagnosis
− Confirm by Hgb Electrophoresis
HEMOGLOBINOPATHY E
− Qualitative mutation in the β-globin gene
− 2nd most common globin mutation worldwide
− Southeast Asian Descent
− HbAE: Asymptomatic
− HbEE: mild anemia, splenomegaly, cholelithiasis
− HbE/β Thalassemia(interacting): moderate to severe
anemia depending
− On the thalassemia mutation;
o Hgb α2: >20%
− Newborn screening-diagnosis
ENZYMATIC DEFECTS
− Pyruvate Kinase Deficiency
o Low levels of ATP, pyruvate, oxidized from NAD
− Glucose-6-Phosphate Dehydrogenase Deficiency
GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD)
DEFICIENCY
− most frequent disease involving enzymes of the hexose
monophosphate (HMP) pathway
− responsible for 2 clinical syndromes
o episodic hemolytic anemia
o chronic nonspherocytic hemolytic anemia
− The most common manifestations of this disorder are
neonatal jaundice and episodic acute hemolytic
anemia
o which is induced by infections, certain drugs, and,
rarely, fava beans
− X-linked deficiency; 4.9 global prevalence
− Mutations are single base changes leading to amino acid
substitution and destabilization of G6PD enzyme.
o Milder disease – mutations near the amino terminus
of the G6PD molecule
o Chronic nonspherocytic hemolytic anemia –
mutations clustered near the carboxyl terminus.
− Normal variants: G6PD B+, G6PD A+
Hematology A – Anemias
EPISODIC or INDUCED ACUTE HEMOLYTIC ANEMIA
− G6PD catalyzes the conversion of glucose 6-phosphate to
6- phosphogluconic acid.
− This reaction produces NADPH, which maintains GSH in
the reduced, functional state.
− Reduced GSH provides protection against oxidant threats
from certain drugs and infections that would otherwise
cause precipitation of hemoglobin (Heinz bodies) or
damage the RBC membrane.
− Lyon-Beutler hypothesis
o the majority of RBCs is G6PD deficient in
heterozygous females because the inactivation of
the normal X chromosome is random and
sometimes exaggerated
− G6PD A−
o results in a deficiency of RBC G6PD activity (5-15% of
normal)
− G6PD B− (G6PD Mediterranean)
− G6PD Canton
o enzyme with markedly reduced activity occurs in
approximately 5% of the Chinese population
Clinical Manifestations
− Most individuals with G6PD deficiency are asymptomatic,
with no clinical manifestations of illness unless triggered by
infection, drugs, or ingestion of fava beans.
− Typically, hemolysis ensues in about 24-48 hr after a
patient has ingested a substance with oxidant properties.
− In severe cases, hemoglobinuria and jaundice result, and
the hemoglobin concentration may fall precipitously.
− The degree of hemolysis varies with the inciting agent,
amount ingested, and severity of the enzyme deficiency.
WHO Classification of G6PD Deficiency
Severe enzyme deficiency < 5% of normal,
with chronic hemolytic anemia
Chronic Congenital Non-Spherocytic
Class I
Hemolytic Anemia (CCNSHA)
Variant
Most severe form
Severe hemolysis at birth; not dependent
on oxidizing agent
Severe enzyme deficiency < 10% of
Class II normal, but only intermittent/episodic
Variant hemolysis (needs exposure or oxidizing
agents before hemolysis)
Severe enzyme deficiency < 10% of
Class III
normal, but only intermittent hemolysis
Variant
usually associated with infection or drugs
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 Hematology A – Anemias

B. Resulting from EXTRACELLULAR FACTORS:

IMMUNE Hemolytic Anemias

IMMUNE HEMOLYTIC ANEMIAS

− A number of extrinsic agents and disorders may lead to

premature destruction of red blood cells (RBCs).
− The hallmark is the positive result of the direct
antiglobulin (Coombs) test, which detects a coating of
immunoglobulin or components of complement on the RBC
surface.
− Hemolytic Disease of The Newborn (Erythroblastosis
Fetalis)
o The most important immune hemolytic disorder in
pediatric practice, caused by transplacental transfer of
maternal antibody active against the RBCs of the
fetus, that is, isoimmune hemolytic anemia.
− Other immune hemolytic anemias are autoimmune and
may be idiopathic or related to various infections,
immunologic disease, immunodeficiency diseases,
neoplasms and drugs.

Laboratory Findings
− Onset of acute hemolysis
o results in a precipitous fall in hemoglobin and
hematocrit
− If the episode is severe
o hemoglobin binding proteins, such as haptoglobin, are
saturated, and free hemoglobin may appear in the
plasma and subsequently in the urine
− Unstained or Supravital staining
o RBCs reveal precipitated hemoglobin, known as Heinz
bodies
− Blood film may contain bite cells and polychromasia (bluish,
larger RBCs) representing reticulocytosis

Diagnosis
− G6PD Assay
− Satisfactory screening tests: decoloration of methylene
blue, reduction of methemoglobin, fluorescence of NADPH

Prevention and Treatment

− Avoidance of oxidizing agents
− If severe hemolysis has occurred, supportive therapy may
require blood transfusion.

Red Cell Survival is dependent on the following pathways:

o Hexose Monophosphate Shunt
o Rapopost-Luebering Pathway
o Methemoglobin Reductase Pathway
The pathways above are the source of energy of red cells
to maintain its biconcave shape and hemoglobin in reduced
form.
*Only Class I variant is associated with severe hemolysis
without exposure to oxidizing agents.
**Other class variants develop hemolysis only when
exposed to oxidizing agents.
AUTOIMMUNE Hemolytic Anemias Associated
with WARM ANTIBODIES
− autoantibodies are directed against RBC membrane
antigens
− Molecular mimicry
o The autoantibody may be produced as an
inappropriate immune response to an RBC antigen or
to another antigenic epitope similar to an RBC antigen.
− An infectious agent may alter the RBC membrane so that it
becomes “foreign” or antigenic to the host.

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 Hematology A – Anemias

− The antibodies usually react to epitopes (antigens) that are Laboratory Findings
“public” or common to all human RBCs, such as Rh − Profound anemia, spherocytosis, polychromasia,
proteins. nucleated RBC, reticulocytosis, leukocytosis
− In most instances of warm antibody hemolysis, no o Evans syndrome – AIHA with thrombocytopenia
underlying cause can be found; this is the primary or − Positive Direct Antiglobulin Test (Coombs test) and free
idiopathic type (Table 464-1). antibody can sometimes be detected in the serum (Indirect
− If the autoimmune hemolysis is associated with an Coombs test)
underlying disease, such as a lymphoproliferative disorder, o antibodies are active at 35-40°C (95-104°F) (“warm”
SLE, Evans syndrome, or immunodeficiency, it is antibodies)
secondary. o most often belong to the IgG class
− In as many as 20% of cases of immune hemolysis, drugs
may be implicated (Table 19). Treatment
− Drugs (penicillin or sometimes cephalosporins) that cause − Mild disease / compensated hemolysis – no treatment;
hemolysis via the “hapten” mechanism (immune but not PRBC in severe anemia
autoimmune) bind tightly to the RBC membrane. − Severe hemolysis
o Glucocorticoids
Table 19. Selected Drugs That Cause Immune-Mediated ▪ Prednisone 2-6 mg/kg/day
Hemolysis o IV Ig if unresponsive to steroids
DRUG TERNARY AUTO- − Rituximab
MECHANISM ADSORPTION (IMMUNE) ANTIBODY o a monoclonal antibody that targets B lymphocytes, the
(HAPTEN) COMPLEX INDUCTION
Direct source of antibody production
Positive Positive Positive
antiglobulin
(anti-IgG) (anti-C3) (anti-IgG)
o useful in chronic cases refractory to conventional
test therapy
Site of
hemolysis
Extravascular Intravascular Extravascular − Splenectomy
Medications Penicillins Cephalosporin α-Methyldopa o may be beneficial but is complicated by a heightened
Cephalosporin Quinidine Cephalosporin risk of infection with encapsulated organisms,
6-mercapto- Amphotericin B Oxaliplatin
purine Hydrocortisone L-Dopa
particularly in patients <6 years old
Tetracycline Rifampin Procainamide − Prophylaxis with appropriate vaccines (pneumococcal,
Oxaliplatin (Rifadin) Ibuprofen meningococcal, and Haemophilus influenzae type b) before
Hydrocortisone Metformin Diclofenac
Quinine (Voltaren)
splenectomy and with oral penicillin after splenectomy are
Probenecid Interferon alfa indicated.
Chlorpromazin
e Course and Prognosis
Oxaliplatin
− Acute idiopathic autoimmune hemolytic disease in
Clinical Manifestations childhood varies in severity but is self-limited.
− Autoimmune hemolytic anemias may occur in either of 2 − Approximately 30% of patients have chronic hemolysis,
general clinical patterns. often associated with an underlying disease, such as SLE,
− Acute transient type lymphoma, or leukemia.
o lasting 3-6 months
o occurring predominantly in children ages 2-12 yr, AUTOIMMUNE Hemolytic Anemias Associated
accounts for 70-80% of patients with COLD ANTIBODIES
o frequently preceded by an infection, usually
respiratory − “Cold” antibodies agglutinate RBCs at temperatures <37°C
o Onset may be acute, with prostration, pallor, jaundice, (98.6°F).
fever, and hemoglobinuria, or more gradual, with o primarily of the IgM class and require complement for
primarily fatigue and pallor. hemolytic activity
o The spleen is usually enlarged and is the primary site
of destruction of immunoglobulin (Ig) G–coated RBCs. Cold Agglutinin Disease
o Underlying systemic disorders are unusual. − Cold antibodies usually have specificity for the
o A consistent response to glucocorticoid therapy, a low oligosaccharide antigens of the I/i system.
mortality rate, and full recovery are characteristic of
− They may occur in primary or idiopathic cold agglutinin
the acute form.
disease, secondary to infections such as those from
− Prolonged and Chronic course Mycoplasma pneumoniae and Epstein-Barr virus, or
o more frequent in infants and in children >12 years old secondary to lymphoproliferative disorders.
o Hemolysis may continue for many months or years.
o Abnormalities involving other blood elements are Paroxysmal Cold Hemoglobinuria
common, and the response to glucocorticoids is − mediated by the Donath-Landsteiner (D-L) hemolysin,
variable and inconsistent. which is an IgG cold-reactive autoantibody with anti-P
o The mortality rate is approximately 10%, and death is specificity
often attributable to an underlying systemic disease.

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 Hematology A – Anemias

C. Secondary to Other Extracellular Causes

FRAGMENTATION HEMOLYSIS

− Red blood cell (RBC) destruction may occur in hemolytic

anemias because of mechanical injury as the cells traverse
a damaged vascular bed.
− Damage may be microvascular when RBCs are sheared by
fibrin in the capillaries during intravascular coagulation or
when renovascular disease accompanies the Hemolytic-
Uremic Syndrome (HUS) or Thrombotic
Thrombocytopenic Purpura.
− Larger vessels may be involved in Kasabach-Merritt
syndrome (giant hemangioma and thrombocytopenia) or
when a replacement heart valve is poorly epithelialized.
− The blood film shows many “schistocytes,” or fragmented
cells, as well as polychromatophilia, reflecting the
reticulocytosis.

Reference:
− Lecture + Manual + Notes
− Nelson’s 20th/21st
− Deon Trans
− Use at your own risk.

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