Anemia VR

HY:Anemia

Gonzalez MD

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Students Resources (Exam focus)

Pathophysiology - Histopathology

Clinical setting

Lippincott Illustrated Reviews: Physiology (Lippincott Illustrated Reviews Series) Adrenal Glands

Myeloid Neoplasms

Myeloid Neoplasms

Morphological characteristics of Red Blood Cells

Normal shape: A biconcave disc, a disc shaped cell that is compressed at the centre in both directions. This allows an increased surface area for diffusion of oxygen. Typical diameter of 7.2um (normal: 6.2um and 8.2um) They contain no nucleus, to maximize volume of Hb (carriage of oxygen).

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Morphological characteristics of Red Blood Cells: color and pallor

Central pallor: In healthy conditions it occupies 1/3rd of total cell diameter.

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Anemia: Concept

A person is considered anemic if their blood HGB level is below what is considered normal for a healthy person. WHO defines anemia as HGB levels below 12 g/dL in women and below 13 g/dL in men. *** Note: the normal reference range can vary with factors such as age, ethnicity, and physiological status (e.g., pregnancy)

A complete blood count is the main test for identification of anemiasThe RBC components of the CBC are: • Red blood cell count (RBC) • Hemoglobin (HGB) • Hematocrit (HCT) • Mean cell volume (MCV) • Mean cell hemoglobin (MCH)

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Interpretation of the RBC parameters of the CBC:

The following steps can be used for interpretation of the RBC parameters of the CBC: 1. Assess the Hgb levels to confirm and determine the severity of the anemia 2. Assess MCV to determine class of anemia (macrocytic, normocytic, or microcytic). 3. Assess the MCHC (hypochromic or normochromic) 4. Examine the RBC morphology under the microscope and correlate findings 6. Use related test results when available to verify CBC findings and for additional diagnostic information.

**Note: Among factors that can affect the results from the automated cell count:

1. Lipemia
2. Elevated WBC count (falsely elevated HGB value)
3. Blood clotting (falsely low HCT)
4. Hemolysis (falsely elevated MCHC).

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Red cell indices

The MCV is the first branch point in the differential diagnosis of anemia

Variations in Size: MCV

The most important red cell index for discussing the variations in size of blood cells is the Mean Corpuscular Volume. Its reference value: 80fL – 95fL (100fL) Any variation in size of the RBCs is known as anisocytosis, and the degree of anisocytosis in a sample of blood is known as the red cell distribution width.

A varying MCVs: microcytic, macrocytic, and normocytic anemias

Utility in helping determine the etiology of anemia

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Variations in Size: MCV

RBC calculations & indices

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Reticulocyte COUNT and index

The number of reticulocytes is an accurate reflection of the amount of RBC produced in bone marrow and entering the peripheral blood. It is therefore an index of effective erythropoiesis. Normal fraction is low (0.5% to 2.5% in adults and 2% to 6% in infants) because there is a homeostasis between destruction of aged abnormal RBC and a low level of marrow activity required to maintain normal hemoglobin levels

If the patient has moderate or severe anemia, the bone marrow will release reticulocytes prematurely into the blood “shift reticulocytes”, and they will circulate in the peripheral blood for longer than normally released reticulocytes.

RBC calculations & indices

1. Anemia Y/N 2. Volume 3. BM FUNCTION

1. CBC:Hb (Hct) 2. SMEAR:MCV 3. BM: Ferritin & Iron Retic V.12 deficiency/ Neutroph. morphology

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

RBC calculations & indices

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Most common types of anemia by classification

Microcyte (not microcytosis - not microcytic)

A microcyte, is a red blood cell by definition, a small (micro-) mature cell (-cyte). In terms of MCV, a microcyte has an MCV below 80fL. Microcytes indicate some problem with the manufacturing system of red blood cells (deficiency). The diseases include:

• Iron Deficiency Anemia
• Sideroblastic Anemia
• Beta thalassemias
• Lead Poisoning

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

Microcyte (not microcytosis - not microcytic)

Deficiency of iron leads to a scenario where the red blood cell cannot be filled with Hb and thus is an overall smaller cell, since there is less Hb. Sideroblastic Anemia (defective heme synthesis, bone marrow releases immature red blood cells, sideroblasts). These sideroblasts have rings of iron around their nucleus, microcytes with iron rings . Beta thalassemias (the beta chain of Hb is usually missing or deformed---leads to the underproduction of HBA in turn leads to microcytic anemia). Lead Poisoning: lead interferes with the activity of ferrochelatase, both involved in the formation of heme. Microcytosis occurs due to lack of heme, which leads to a lack of Hb and thus a deficiency, causing smaller RBCs.

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B thalassemia

Beta thalassemias The beta chain of Hb is missing or deformed (leads to microcytic anemia) Blockage to the HBB gene --- (Chromosome 11)

Inherited as an autosomal recessive disorder (missense/non-sense mutation)

Thalassemia major: severe, transfusion-dependent anemia. Thalassemia minor: mild to moderate microcytic anemia. Treatment: transfusion therapy, iron chelation, splenectomy, hematopoietic stem cell transplantation, gene therapy

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B thalassemia: Clinical setting

The excess unpaired alpha-globin chains aggregate to form precipitates that damage red cell membranes, resulting in intravascular hemolysis. Premature destruction of erythroid precursors results in intramedullary death and ineffective erythropoiesis: extramedullary hematopoiesis.

The iron overload resulting from transfusion and increased iron absorption. The skin may show pallor from anemia and jaundice from hyperbilirubinemia, and the skull and other bones may be deformed secondary to intramedullary expansion and cortical bone thinning.

B thalassemia

Lab features MCV, MCHC, MCH and TIBC decreased. Pathological findings: Target cells (Characteristic finding). These are RBC’s with lump of hemoglobinized cytoplasm within area of normal central pallor resulting in “Bull’s eye” target.

DiagnosticIron studies (iron, transferrin, ferritin) Definitive diagnosis requires measuring either the alpha-beta chain synthesis ratio Treatment: iron chelation-supportive

Iron deficiency anemia

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IRON DEFICIENCY ANEMIA (Hypochromic) Iron deficiency anemia is a laboratory diagnosis Commonest nutritional deficiency disorder throughout the world No ferric iron being utilized for maturation of erythroid precursors

Develops gradually (nutritional/blood loss)

CBC findings: Low: MCV, MCHC Smear: RBCs are microcytic and hypochromic Iron tests: Low serum iron and ferritin levels with an elevated TIBC are diagnostic

Symptoms: Leg crampsTachycardia Heart failure Fatigue Pallor Pagophagia (PICA)

Koilonychia Atrophic glossitis Angular stomatitis

Etiology: Malabsorption of iron Achlorhydria (Acidic conditions are required to release ferric iron from food) then it is chelated Surgical removal of the proximal small bowel Bariatric surgery Gastric bypass surgery Bypass of the duodenum Malabsorption Gastrointestinal bleeding

Treatment: Treat main cause

Iron therapy (0-3 months)

Response to iron therapy can be documented by an increase in reticulocytes 5-10 days after the initiation of iron therapy. The hemoglobin concentration increases by about 1 g/dL weekly until normal values are restored.

Lead poisoning

Lead Poisoning: lead interferes with the activity of delta-aminolevulinic acid dehydratase (ALAD) and ferrochelatase, both involved in the formation of heme. Microcytosis occurs due to lack of heme, which leads to a lack of Hb and thus a deficiency, causing smaller RBCs.

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq

RBC calculations & indices: Iron - Hb defects (filling defects: MCV + RDW

Macrocyte: Immature cells --- DNA synthesis impairment

A large (macro-) mature cell (-cyte).In terms of MCV, a macrocyte has an MCV above 95 It is thus an enlargement of red blood cells with a near constant concentration of hemoglobin. Megaloblastic Anemia/////The most common cause of macrocytic anemia, which is the result of impaired DNA synthesis. Although DNA synthesis is impaired, RNA synthesis is not, and RNA continues to be produced, increasing the nuclear matter within RBCs that is not being converted to DNA. Thus, the cell gradually enlarges due to increased nuclear matter, causing macrocytosis. Vitamin B12 deficiency and Folate deficiency (synthesis of Thymidine and Purines), and thus DNA synthesis is impaired in these deficiencies

Megaloblastic anemia

Abnormal erythropoiesis (reduced HB levels): 1. Impaired DNA synthesis (normal RNA)→ delayed nuclear maturation → nuclear:cytoplasmic dyssynchrony: megaloblasts (macroovalocytes) Etiology: vitamin B12 or folate deficiency, pernicious anemia Smear: Megaloblastic neutrophils: Nuclear hypersegmentation of neutrophils Megaloblast: abnormal erythroid precursors showing nucleo:cytoplasmic dyssynchrony (more immature nucleus for the degree of maturity of the cytoplasm) Macrocyte: mature red blood cell with increased MCV (100 - 110 fL) Macroovalocyte: mature red blood cell with macrocytosis and oval shape with reduced or absent central pallor

Etiology

Vitamin B12 deficiency (daily intake of 2.4 mcg)

1. Long term vegans (baseline stores of B12 exceed daily requirement by 1,000 times; thus, it takes years to develop deficiency)
2. Breastfed infants of vegan mothers

Lack of intrinsic factor:

1. Chronic gastritis, Gastric surgery, Congenital absence of IF, Pernicious anemia (autoimmune), Small bowel bacterial overgrowth, Malabsorption of B12, Familial selective vitamin B12 malabsorption (Imerslund-Gräsbeck syndrome)

Drug induced: Proton pump inhibitors, H2 receptor antagonists, metformin, anticovulsivants, trimethropim Others: regional enteritis, ileal resection, alcoholism, jejunal resection Increased requirements: Pregnancy

Clinical features

How does a vitamin B12 deficiency affect the nervous system (disequilibrium, peripheral nerve damage, dementia)?

Clinical features

Weakness Dyspnea HF Pallor Hyperbilirrubinemia (ineffective erythropoiesis) Neurological manifestations: paraesthesias, disequilibrium disorders, peripheral neuropathy; visual disturbances due to optic atrophy, dementia, Beefy red tongue due to atrophy of papillae, aphthous stomatitis Clinical signs: Romberg test, Babinski reflex, hyporeflexia, clonus Increased incidence of arterial and venous thrombosis due to raised plasma homocysteine levels, dementia Clinical features of pernicious anemia: Classic triad at presentation: weakness, sore throat, paraesthesia

Aplastic anemia Bone marrow disorder characterized by pancytopenia Bone marrow trilineage hypoplasia in the absence of any underlying neoplasia Bone marrow is hypocellular, with spaces replaced by fatty cells Residual nucleated cells No increase in blasts Differential dx: Hypoplastic myelodysplastic syndrome / acute myeloid leukemia Bimodal age distribution: first peak at 10 - 25 years; second peak at > 60 years Treatment: supportive therapy

Diagnosis: Persistent (> 6 months) pancytopenia Absolute neutrophilic count < 1.5 x 109/L Platelet count < 50 x 109/L Hemoglobin < 10 g/dL

RBC calculations & indices

ERSpublications A review of ventilation–perfusion relationships and gas exchange, basic concepts and their relation to clinical cases http://ow.ly/wMUwq