RBCs Disorders 3

Dr. Nabila Hamdi

MD, PhD

ILOs • Discuss the classification of anemia into hypochromic-microcytic, normochromic-

normocytic and macrocytic.

• Categorize laboratory test procedures used in the diagnosis of anemia, outlining the basic workup of a patient who presents with anemia.

• Understand the utilization of peripheral blood and bone marrow smears to assess the deviations from normal marrow response which occur in different types of anemia.

• Compare and contrast anemia secondary to acute vs. chronic blood loss.

• Discuss the different types of hemolytic anemia in terms of: genetics - molecular changes, etiology, pathogenesis, morphology, laboratory diagnosis and clinical features and course.

• Compare and contrast warm vs. cold antibody immunohemolytic anemias.

• Compare and contrast intravascular vs. extravascular hemolysis.

• Discuss and contrast the different types of anemia of diminished erythropoesis in terms of etiology and pathogenesis, marrow and peripheral blood morphology, laboratory diagnostic criteria and clinical features and course.

Outline

I. OVERVIEW

II. ANEMIA OF BLOOD LOSS: HEMORRHAGE

III. HEMOLYTIC ANEMIAS 1. Hereditary Spherocytosis

2. Sickle Cell Anemia

3. Thalassemia

4. Glucose-6-Phosphate Dehydrogenase Deficiency

5. Immunohemolytic Anemia

6. Mechanical Trauma to Red Cells

IV. ANEMIAS OF DIMINISHED ERYTHROPOIESIS 1. Iron Deficiency Anemia

2. Megaloblastic Anemias

3. Aplastic Anemia

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Overview

DIMINISHED ERYTHROPOIESIS

Inadequate dietary supply

• Iron • Folic acid • Vitamin B12

Bone marrow failure

Systemic inflammation Bone marrow infiltration

(Aplastic anemia)

(Anemia of chronic disease) Tumor/inflammatory cells (Myelophthisic anemia)

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Iron Deficiency Anemia

Pathogenesis: The most frequent cause of anemia

In the Western world, chronic blood loss is the most important cause

• GIT tract (peptic ulcers, colonic cancer, hemorrhoids)

• The female genital tract (abnormal menstruation, cancers).

In the developing world, low intake and poor bioavailability due to predominantly vegetarian diets are the most common causes of iron deficiency.

Increased demands not met by normal dietary intake occur worldwide during pregnancy and infancy.

Malabsorption: chronic diseases of GIT or after gastrectomy.

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Iron Deficiency Anemia

Pathogenesis: Regardless of the cause, iron deficiency develops insidiously.

Iron stores are depleted first, marked by a decline in serum ferritin and the absence of stainable iron in the bone marrow.

These changes are followed by a decrease in serum iron and a rise in the serum transferrin.

Ultimately, the capacity to synthesize hemoglobin, myoglobin, and other iron-containing proteins is diminished, leading to microcytic anemia, impaired work and cognitive performance.

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Iron Deficiency Anemia

Clinical Features: In most instances, iron deficiency anemia is usually mild and asymptomatic.

Nonspecific manifestations, such as weakness and pallor, may be present in

severe cases.

With long-standing anemia, abnormalities of the fingernails, including thinning, flattening, and “spooning,” may appear.

Atrophic glossitis : swollen or sore tongue, beefy-red tongue.

A curious but characteristic neurobehavioral complication is pica, the compunction to consume non-foodstuffs such as dirt or clay.

In peripheral smears red cells are microcytic and hypochromic.

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Iron Deficiency Anemia

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http://www.nhs.uk/conditions/nail-abnormalities/Pages/Introduction.aspx

Indented spoon-shaped nails

http://pedemmorsels.com/pica/

Pica

Iron deficiency anemia—peripheral blood smear Note the increased central pallor of most of the red cells. Scattered, fully hemoglobinized cells, from a recent blood transfusion, stand out in contrast.

Atrophic glossitis

https://www.memorangapp.com/flashcards/77085/Anemia+(using+Pathoma)/

Iron Deficiency Anemia

Diagnosis: Hypochromic and microcytic anemia

Low serum ferritin and iron levels

Low transferrin saturation

Increased total iron-binding capacity

Ultimately, response to iron therapy

For unclear reasons, the platelet count often is elevated.

Erythropoietin levels are increased, but the marrow response is blunted by the iron deficiency; thus, marrow cellularity usually is only slightly increased.

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Megaloblastic Anemias

• The two principal causes of megaloblastic anemia are folate deficiency and vitamin B12 deficiency.

• Both vitamins are required for DNA synthesis and the effects of their deficiency on hematopoiesis are essentially identical.

• However, the causes and consequences of folate and vitamin B12 deficiency differ in important ways.

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Megaloblastic Anemias

Normoblasts Megaloblasts

Megaloblasts are larger, have relatively immature nuclei with finely reticulated chromatin, and abundant basophilic cytoplasm.

(Courtesy of Dr. José Hernandez, Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.)

Nuclear-cytoplasmic asynchrony

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Megaloblastic Anemias

Peripheral blood in megaloblastic anemia showing a hypersegmented neutrophil (solid arrow) with nine lobes. The enlarged, egg-shaped red blood cells (macro-ovalocytes; interrupted arrow) are characteristic of macrocytic anemias.

http://studydroid.com/printerFriendlyViewPack.php?packId=474391 12

Megaloblastic Anemias

Folate (Folic Acid) Deficiency Anemia: • Folate is present in nearly all foods but is destroyed by 10

to 15 minutes of cooking.

• The principal site of intestinal absorption is the upper third of the small intestine; thus, malabsorptive disorders that affect this level of the gut, such as celiac disease, can impair folate uptake.

• It is converted from dihydrofolate to tetrahydrofolate by dihydrofolate reductase. Tetrahydrofolate acts as an acceptor and donor of one-carbon units in several reactions that are required for the synthesis of purines and pyrimidine, the building blocks of DNA.

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Megaloblastic Anemias

Diagnosis of Folate Deficiency Anemia: • Unlike in vitamin B12 deficiency, neurologic abnormalities do

not occur.

• The diagnosis of a megaloblastic anemia is readily made from examination of smears of peripheral blood and bone marrow.

• The anemia of folate deficiency is best distinguished from that of vitamin B12 deficiency by measuring serum and red cell folate and vitamin B12 levels.

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Megaloblastic Anemias

Vitamin B12 (Cobalamin) Deficiency Anemia • Vitamin B12 deficiency can cause a demyelinating disorder of

the peripheral nerves and the spinal cord. In time, axonal degeneration may supervene.

• Long-standing malabsorption underlies the vast majority of cases of vitamin B12 deficiency.

• Once vitamin B12 is absorbed, the body handles it very efficiently. It is stored in the liver, which normally contains reserves sufficient to support bodily needs for 5 to 20 years.

• Deficiencies due to diet are rare, being confined to strict vegans.

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1. Peptic digestion releases dietary vitamin B12, allowing it to bind a salivary protein called haptocorrin.

2. On entering the duodenum, haptocorrin–B12 complexes are processed by proteases; this releases B12, which attaches to intrinsic factor secreted from the parietal cells of the gastric fundic mucosa.

3. The intrinsic factor–B12 complexes pass to the distal ileum and attach to cubulin, a receptor for intrinsic factor, and are taken up into enterocytes.

4. The absorbed vitamin B12 is transferred across the basolateral membranes of enterocytes to plasma transcobalamin, which delivers vitamin B12 to the liver and other cells of the body.

Vitamin B12 absorption

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Megaloblastic Anemias

Vitamin B12 Deficiency Anemia: Pernicious anemia is the most frequent cause of vitamin B12 deficiency.

• This disease seems to stem from an autoimmune reaction against parietal cells and intrinsic factor itself, which produces gastric mucosal atrophy.

• Autoantibodies are present in the serum and gastric juice of most patients.

• Three types of antibodies have been found:

Parietal antibodies (parietal cells)

Blocking antibodies (binding of vitamin B12 to IF)

IF–B12 complex antibodies (prevent the complex from binding to cubulin)

• Pernicious anemia frequently occurs concomitantly with other autoimmune diseases.

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Megaloblastic Anemias

Vitamin B12 Deficiency Anemia: Chronic vitamin B12 malabsorption is also seen after:

• Gastrectomy (loss of IF–producing cells)

• Ileal resection (loss of IF–B12 complex–absorbing cells),

• Disorders that disrupt the function of the distal ileum (such as chronic inflammatory diseases of GIT)).

• Particularly in older persons, gastric atrophy and achlorhydria may interfere with the production of acid and pepsin, which are needed to release the vitamin B12 from its bound form in food.

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Megaloblastic Anemias

Vitamin B12 Deficiency Anemia: As with all anemias, findings include pallor, easy fatigability,

and, in severe cases, dyspnea and even congestive heart failure.

The spinal cord disease begins with symmetric numbness, tingling, and burning in feet or hands, followed by unsteadiness of gait and loss of position sense, particularly in the toes.

Although the anemia responds dramatically to parenteral vitamin B12, the neurologic manifestations often fail to resolve.

Patients with pernicious anemia have an increased risk for the development of gastric carcinoma.

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Megaloblastic Anemias

Vitamin B12 Deficiency Anemia: The diagnostic features of pernicious anemia include

(1) low serum vitamin B12 levels

(2) normal or elevated serum folate levels

(3) serum antibodies to intrinsic factor

(4) moderate to severe megaloblastic anemia,

(5) leukopenia with hypersegmented granulocytes,

(6) a dramatic reticulocytic response (within 2 to 3 days) to parenteral administration of vitamin B12.

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Aplastic Anemia

Aplastic anemia is a disorder in which multipotent myeloid stem cells are suppressed, leading to bone marrow failure and pancytopenia.

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Aplastic Anemia

http://encyclopedia.lubopitko-bg.com/Blood_Cells.html

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Aplastic Anemia

Pathogenesis: In more than half of the cases, aplastic anemia is idiopathic.

The remaining cases are due to an exposure to a known myelotoxic agent:

• Antineoplastic drugs (alkylating agents, antimetabolites)

• Benzene

• Chloramphenicol

In other instances, marrow toxicity occurs a hypersensitivity reaction to small doses of known myelotoxic drugs which are not myelotoxic in other persons (chloramphenicol) or to drugs such as sulfonamides.

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Aplastic Anemia

Pathogenesis: The pathogenic events leading to marrow failure remain vague, but

it seems that autoreactive T cells play an important role.

• This is supported by a variety of experimental data and clinical experience showing that aplastic anemia responds to immunosuppressive therapy aimed at T cells in 70% to 80% of cases.

• Much less clear are the events that trigger the T cell attack on marrow stem cells.

From 5% to 10% of patients with aplastic anemia have inherited defects in telomerase and thus premature senescence of hematopoietic stem cells (short telomeres).

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Aplastic Anemia

Clinical course: Aplastic anemia affects persons of all ages and both sexes.

The slowly progressive anemia causes the insidious development of weakness, pallor, and dyspnea.

Thrombocytopenia often manifests with petechiae and ecchymoses.

Granulocytopenia may be manifested by frequent and persistent minor infections or by the sudden onset of chills and fever.

No splenomegaly; if it is present, another diagnosis should be considered.

Typically, the red cells are normochromic and normocytic.

Reticulocytes are reduced in number (reticulocytopenia).

Bone marrow is hypocellular.

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Differential Diagnosis

Serum iron, serum iron-binding capacity, transferrin saturation and serum ferritin concentrations help distinguishing iron deficiency anemia from other types.

Plasma unconjugated bilirubin, haptoglobin, and lactate dehydrogenase levels are abnormal in hemolytic anemias.

Serum and red cell folate and vitamin B12 concentrations are low in megaloblastic anemia.

Hemoglobin electrophoresis is used to detect hemoglobin disorders (sickle cell, thalassemia)

Coombs test is used to detect antibodies or complement on red cells in immunohemolytic anemia.

In some instances (pancytopenia), a marrow examination usually is useful. 26

Summary

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Summary

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References

ROBBINS Basic Pathology 9th Edition Source of the cover: http://kidney2.blogspot.com/2012_07_01_archive.html

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Thank you…

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