REVIEW ARTICLE

Year : 2021  |  Volume : 15  |  Issue : 1  |  Page : 13-23

Approach to anemia with caveats in focus

Amitesh Aggarwal, Sanat Kumar Thakur
Department of Medicine, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Delhi, India

Correspondence Address:
Dr. Amitesh Aggarwal
Department of Medicine, University College of Medical Sciences (University of Delhi) and Guru Teg Bahadur Hospital, Delhi - 110 095
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/upjimi.upjimi_2_21

Anemia being a very commonly encountered clinical condition can be a presentation of a wide range of underlying illness. This article tries to succinctly provide an approach to and give an overview of anemia without delving into any one particular type. To categorize anemia would help narrow down the list of differentials and enable diagnosing a large and varied number of conditions.

Keywords: Anemia, approach, functional classification, red blood cells morphology, reticulocyte count

Introduction

• Reduction in one or more of the major RBC measurements (Hb, hematocrit [Hct] or packed cell volume and RBC count)
• Qualitative or quantitative diminution of RBC and/or Hb concentration in relation to the standard limit for age and sex.

Table 1: Hemoglobin levels to diagnose anemia at sea level (g/dL)[4] Click here to view

• Signs and symptoms associated with other disorders or chronic illness associated with anemia such as rheumatoid arthritis (RA), chronic kidney disease (CKD), and tuberculosis (TB) (bleeding, fatigue, malaise, fever, weight loss, night sweats, and other systemic symptoms)
• Pica is seen in IDA and some psychiatric illness
• Dysphagia in PlummerVinson syndrome
• Bleeding from any site and amount, for example. hematemesis/melena/epistaxis/menorrhagia/hemorrhoids
• Blood transfusion frequency and blood products
• Episodes of jaundice or anemia exacerbated during acute illnesses or after drug intake
• Gallstones indicate chronic hemolysis
• Diarrhea seen in tropical sprue.

• Alcohol consumption
• Drug and toxin exposure
• Barefoot walking or fieldwork is associated with infection with parasites.

• Amount and frequency of blood loss.

• Chemical solvent/lead/benzene/insecticide exposure
• Farmer or field work.

• Bone marrow suppressant drug
• Radiation exposure
• Nonsteroidal anti-inflammatory drugs
• Hemolysis episodes seen in G6PD-deficient persons after antimalarial drug intake
• Zinc supplements/denture adhesives cause copper deficiency
• Previous surgery, for example, bariatric surgery/gastrectomy/ileal surgery/Roux-en-Y procedure lead to malabsorption of vitamins and minerals.

• Pure vegetarian or vegan diet may lead to B12 def
• Anorexia or dysphagia and poverty may lead to inadequate intake of vitamins and minerals.

• Similar illness in family points toward disease with genetic inheritance and effects of shared socioeconomic status, for example, thalassemia, HbE disease, hemophilia, and nutritional deficiencies

• G6PD deficiency and hemoglobinopathies are common in people of Middle Eastern or African origin
• β-thalassemia is commonly seen in Punjabis and Sindhis in India.

• Brittle hair
• Pale skin and mucous membranes (sites to look for pallor are lower palpebral conjunctiva, tongue [tip and dorsum], soft palate [anemia is noticed here earliest], nail beds, palmar creases [if it is as pale as surrounding skin, it indicates severe anemia], soles, and general skin surface)
• Glossitis (Vitamin B deficiency, IDA, tropical sprue, pernicious anemia, syphilis, congenital abnormality [median rhomboid glossitis], cirrhosis, and alcoholism)
• Angular stomatitis/cheilosis in Vitamin B deficiency
• Nails – brittle; platynychia; koilonychia in IDA; splinter hemorrhages in subacute bacterial endocarditis
• Finger deformities in rheumatoid arthritis
• Lemon yellow pallor in advanced pernicious anemia
• Knuckle pad hyperpigmentation in megaloblastic anemia
• Edema or anasarca is seen in severe anemia, congestive cardiac failure, renal disorder, hepatic disorder, hypoalbuminemia, and myxoedema
• Signs suggestive of infection
• Blood in stool or other orifices
• Lymphadenopathy hints toward a lymphoproliferative disorder
• Splenomegaly may be present in lymphoproliferative disorder, tropical infection, and extravascular hemolysis
• Petechiae indicate a platelet dysfunction
• Ecchymosis or bruise may be present in hematologic malignancy or aplastic anemia
• Icterus/dark urine–hemolytic anemia
• Pale retina.

• Tachycardia; Strong peripheral pulses
• Capillary pulsation
• Cervical venous hum
• Forceful heartbeat/hyperdynamic apex beat
• Systolic flow murmur (e.g., hemic murmur in pulmonary area)
• MS murmur due to functional MI (ring dilatation)
• Cardiomegaly or heart failure in severe and prolonged anemia.

• Basal crepitations.

• Polyneuropathy.

• Shock/low cardiac output states
• Conditions leading to vasoconstriction
• Acute myocardial infarction
• Severe aortic stenosis/mitral stenosis
• Vasovagal attack/fear/cold exposure/intense emotion
• Sheehan's syndrome/panhypopituitarism
• Thick skin (e.g., scleroderma)
• Edematous conditions/anasarca
• Myxedema
• Chronic renal disease/nephrotic syndrome.

Laboratory Investigations

1. RBC count: Hb, Hct, and reticulocyte count
2. RBC indices: mean cell volume (MCV), mean cell Hb (MCH), mean cell Hb concentration (MCHC), and red cell distribution width (RDW)
3. WBC count: total count, differential count, and nuclear segmentation of neutrophils
4. Platelet count
5. Cell morphology, i.e., peripheral blood smear: cell number, cell size, Hb content, anisocytosis, poikilocytosis, and polychromasia

1. Aspirate: myeloid: erythroid ratio, cell morphology, and iron stain
2. Biopsy: cellularity and morphology.

1. Hb electrophoresis
2. Test for hemolysis: Lactate dehydrogenase (LDH), haptoglobin, direct or indirect antiglobulin test, and Hb in serum and urine
3. Liver function test (LFT)
4. Kidney function test (KFT)
5. Stool examination
6. Vitamin B₁₂/folic acid/copper levels.

• Hct/Hb ratio may vary according to volume (size) of cells (Normally Hct/Hb around 3)
• Extreme microcytosis (e.g., thalassemia): RBC count may be increased despite anemia (therefore, RBC count is less preferred to diagnose anemia).

• Causes of lower values include intense physical activity (dilutional anemia from increased plasma volume, IDA, and march hemolysis), pregnancy (greater increase in plasma volume compared to red cell mass; do not warrant evaluation as long as Hb is ≥11.0, 10.5, and 10.5 g/dL in 1^st, 2^nd and 3^rd trimester, respectively), older age (nutritional deficiencies; kidney disease; anemia of chronic disease/anemia of inflammation [ACD/AI] and unexplained (often myelodysplastic syndromes, it is a diagnosis of exclusion, cytokine mediated), and African-American population compared to Caucasian in Americans.^{[9],[10],[11]}
• Causes of higher values include smoking or smoke exposure (increased levels of CO→ reduces O₂ delivery), hemoconcentration (due to dehydration or hypovolemia. Anemia becomes apparent on volume replacement or with the movement of interstitial fluid into the vascular compartment), high altitude (relative hypoxia), and sexually mature males (effect of androgen).^{[12],[13],[14]}

• Measures percentage of reticulocytes (immature RBCs) in peripheral blood. Corrected RC percentage or absolute numbers provide a reliable measure of effective red cell production
• In established anemia, reticulocyte response <2–3 times normal suggests an inadequate marrow response, whereas count >2% means an appropriate bone marrow response
• Calculation of reticulocyte production index (RPI).

• This correction produces the corrected reticulocyte count
• It is not done if the reticulocyte count is reported in absolute numbers.

Table 2: Hematocrit percentage and corresponding maturation correction factor[15] Click here to view

• RPI <2 in established anemia means a defect in erythroid marrow proliferation or maturation is must
• Higher values occur in conditions of acute blood loss, hemolysis, EPO, iron/B12 repletion, etc., Lower values are seen in conditions such as bone marrow ablative disorders, lack of substrate (iron/B12), low EPO, and conditions that impair erythropoiesis.

• Anisocytosis correlates with increase in RDW or range of cell sizes
• Poikilocytosis suggests defect in maturation of red cell precursors in bone marrow or fragmentation of circulating red cells
• Polychromasia is seen when reticulocytes (prematurely released from BM)-appear in circulation in response to EPO stimulation or architectural damage of BM (fibrosis, malignant infiltration, etc.)
• Howell–Jolly bodies – Absence of functional spleen
• Bite cells/blister cell – G6PD deficiency/oxidant injury
• Dacryocyte (teardrop) cell – Myelofibrosis
• Target cells – Cholestasis, HbC disease, thalassemia (target, teardrop, hypochromic, microcytic, and bizarre-shaped cells), IDA, liver disease
• Spherocytes/elliptocytes/stomatocytes – hereditary spherocytosis/elliptocytosis/stomatocytosis
• Sickle cells – sickle cell disease
• Schistocytes/fragmented red cells – Microangipathic hemolytic conditions and mechanical hemolytic anemia (e.g. disseminated intravascular coagulation, thrombotic thrombocytopenic purpura – hemolytic uremic syndrome HELLP syndrome, valvular heart disease (e.g. AS), prosthetic heart valves, and thermal injury),
• Burr cells/echinocytes – uremia (renal failure), malnutrition
• Spur cells/acanthocytes – Spur cell anemia and abetalipoproteinemia
• Basophilic stippling – Lead poisoning and sideroblastic anemia.

• Hypoproliferative anemia with a normal iron status
• Severe pancytopenia; pancytopenia with hemolysis or thrombosis; pancytopenia or bicytopenia in older individuals with normal B12, folate, and Cu levels
• Abnormal cells such as blasts, immature myeloid, immature lymphoid forms, hairy cells, LGL, and prolymphocytes seen in peripheral blood
• Leukoerythroblastosis ± dacrocytes.

• Serum iron alone is not a reliable indicator of iron stores as it can be increased acutely by recent transfusion
• Serum iron and hence transferrin saturation show diurnal variation
• Serum ferritin is an acute-phase reactant, hence can be falsely high in inflammatory states. Despite this, values >200 μg/L mean at least some iron in tissue stores is present, whereas values of 10–15 μg/L indicate depletion.

• Microcytic anemia (if no IDA or ACD/AI)
• Unexplained hemolytic anemia
• Abnormal-shaped RBCs in peripheral blood smear
• Family history of hemoglobinopathy
• Positive neonatal screen results
• Positive sickle cell or solubility test.

• Prolonged lifespan of erythrocytes or

• Shortened lifespan of erythrocytes or

Clinical Pearls

• Always send blood films in patients with an unclear etiology of anemia
• Consider screening for sickle cell thalassemia in patients with unexplained anemia or with family history of these conditions
• Patients often have nonspecific symptoms with anemia and a careful history and physical examination are needed
• In the adult population, evaluating the gastrointestinal system as a potential cause of iron-deficient anemia can be a diagnostic challenge
• Anemia is more common with advanced age, but not normal and should be worked up!

Classification of Anemia

Figure 1: Algorithm for physiologically classifying Anemia[5] Click here to view

1. Marrow damage



1. Infiltration/fibrosis
2. Aplasia



2. Mild-moderate IDA (marrow proliferation is blunted)
3. Inadequate stimulation



• Inflammation (IL-1 suppresses EPO production)
• Metabolic defect (Hypothyroidism – decreased tissue O2 need)
• Renal disease

1. Nuclear maturation defects (macrocytosis)



• Folate deficiency
• Vit B12 deficiency
• Drug toxicity (methotrexate, alkylating agents, and alcohol)
• Myelodysplasia



2. Cytoplasmic maturation defects (microcytosis and hypochromia)



• IDA (severe and prolonged anemia-hyperplastic marrow)
• Thalassemia
• Sideroblastic anemia

1. Blood loss
2. Intravascular hemolysis
3. Metabolic defect



• Deficiency of enzymes: G6PD, pyruvate kinase, glucose-phosphate isomerase, 5' nucleotidase
• Heavy metal excess (Wilson's disease, Copper toxicity, Arsine toxicity)
• Hypophosphatemia



4. Membrane abnormality



• Composition abnormality: Hereditary spherocytosis/elliptocytosis
• Hydration abnormality: Hereditary stomatocytosis/xerocytosis
• Liver disease



5. Hemoglobinopathy



• Sickle cell disease
• Thalassemia
• HbC, HbE, and unstable Hb variants



6. Immune destruction



• Warm autoimmune hemolytic anemia
• Drug-induced immune hemolysis
• Transfusion reactions (e.g., ABO incompatibility, alloantibodies)
• Paroxysmal cold hemoglobinuria
• Paroxysmal nocturnal hemoglobinuria
• Cold agglutinin disease
• Intravenous infusion of IVIG or anti-RhD immune globulin



7. Fragmentation hemolysis



• Microangiopathic hemolytic anemia
• Mechanical (intravascular devices, artificial heart valve, giant hemangioma, and foot strike hemolysis).

• If both BM suppression and blood loss/hemolysis is there, reticulocyte count will be inappropriately low
• Acute blood loss/very recent bleeding will not be associated with an increased RPI due to inadequate time for EPO and marrow response^[5]
• Subacute blood loss leads to modest reticulocytosis, whereas chronic blood loss presents often like IDA^[5]
• Chronic hemolysis states have stable Hb, high reticulocyte count, normal LDH, and normal bilirubin levels^[17]
• Intramedullary hemolysis due to ineffective erythropoiesis leads to elevated bilirubin and LDH without reticulocytosis^[17]
• In recovering state, there is increase in Hb, decrease in RPI and underestimation of HbA1C.^[22]

Classification and Causes OF Anemia On The Basis Of Morphology Of Red Blood Cells

Figure 2: Classification of anemia on the basis of RBC morphology Click here to view

1. IDA
2. Decreased globin chains (thalassemia, HbC, and HbE)
3. Decreased heme (sideroblastic anemia and lead poisoning)
4. ACD/AI.

Table 3: Iron deficiency versus anemia of chronic disease/anemia of inflammation versus both the conditions together[26],[27] Click here to view

1. Early stages of iron, Vitamin B12, folate, and copper deficiency
2. Combined microcytic and macrocytic anemia (dimorphic anemia)
3. ACD/AI (Commonly associated conditions)
4. Malignancy (hematological and solid tumor) and myelodysplastic syndromes
5. CKD
6. Rheumatological conditions (RA, SLE, vasculitis, sarcoidosis, etc.)
7. Aplastic anemias and clonal cytopenias of uncertain significance
8. Infections
9. DM
10. Anemia of heart failure
11. Endocrine disorders – hypothyroidism, androgen deficiency, adrenal insufficiency (caveat: may be masked by volume contraction)
12. Early blood loss
13. Hemolysis without mark reticulocytosis
14. Partially treated anemia/following transfusion
15. Pure red cell aplasia
16. Drug-induced
17. Liver disease or alcohol use.

• Mild-moderate anemia
• Red cells are typically normocytic normochromic though moderate degree of microcytosis (due to iron-restricted microcytosis) can also be seen.
• Iron status: (mentioned earlier).

• Low erythropoietic activity consistent with insufficient erythropoietin stimulation characterizes it, but EPO measurements are not routinely indicated
• Abnormalities of WBC count (total and differential) and platelet counts are not routine
• RC may be high (if blood loss/hemolysis) or low (hypoproliferative picture)
• Serum ferritin <=30 ng/mL indicates severe IDA (highly predictive), but values above it do not necessarily mean adequate iron stores due to subclinical inflammation.
• Levels ≥300 ng/mL indicates normal bone marrow iron stores.
• Measurement of hepcidin levels are not useful
• High-sensitivity C-reactive protein-occult inflammation

1. Abnormalities of DNA metabolism



• Vitamin B₁₂ deficiency
• Folate deficiency (Decreased intake, impaired absorption, increased requirements and inborn errors)
• Drugs



• Antiretroviral therapies for HIV
• Azathioprine
• Capecitabine
• Cladribine
• Cytosine arabinoside
• Hydroxyurea
• Imatinib
• Methotrexate
• Metformin
• Proton Pump Inhibitors



2. Shift to immature or stressed red cells



• High reticulocyte count/reticulocytosis (hemolysis, recovery from bleeding, removal of a bone marrow insult, repletion of deficient nutrients)
• Action of erythropoietin – Skip macrocytes and stress erythrocytosis
• Aplastic anemia/Fanconi anemia
• Pure red cell aplasia



3. Primary Bone marrow disorders



• Myelodysplastic syndromes
• Congenital dyserythropoietic anemias
• Some sideroblastic anemias
• Large granular lymphocyte (LGL) leukemia



4. Lipid abnormalities



• Liver disease
• Hypothyroidism



5. Spurious



• Increased Ig or acute phase proteins cause rouleaux formation (mistakenly counted as a large cell)



6. Unknown mechanism



• Alcohol abuse
• Multiple myeloma/plasma cell disorders.

Conclusion

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