Patho Chapter 13

Components of Blood

• Red blood cells (erythrocytes)

• White blood cells (leukocytes)

  • Granular leukocytes: neutrophils, eosinophils, basophils

  • Agranular leukocytes: lymphocytes (T cells, B cells, and natural killer cells), monocytes

• Platelets (special cell fragments)

Bone Marrow

• Yolk Sac: very early embryo

• Liver, Spleen: newborn

• Childhood: Axial and appendicular skeleton have red (active) marrow

• Adult: Axial skeleton has red marrow, appendicular skeleton has yellow marrow

Pathology of Blood

• Conditions affecting blood cells:

  • Red blood cells (RBC): Anemia, Polycythemia

  • White blood cells (WBC): Infection, Inflammation, Malignancy, Immunodeficiency

  • Platelets and Coags: Hypercoagulable state, Hypocoagulable state, smokes hemophilia

Red Blood Cells (Erythrocytes)

• Circulate for 120 days

• Transport oxygen to tissues

• Remove carbon dioxide from the tissues

• Buffer blood pH

• Adult Reference Ranges:

  • Hemoglobin:

    • Men: 13.6 – 17.2 gm/dL

    • Women: 12.0 – 15.0 gm/dL

  • Hematocrit:

    • Men: 39 – 49 %

    • Women: 33 – 43 %

  • Red cell count:

    • Men: 4.3 – 5.9 * 10^6 /µL

    • Women: 3.5 – 5.0 * 10^6 /µL

  • Reticulocyte count: 0.5 – 1.5 %

Hemoglobin

• Oxygen-carrying protein in mature red blood cells

• Comprises 90% of a cell’s dry weight

• Consists of two pairs of polypeptide chains, the globins

• Each globin contains a heme molecule composed of iron and protoporphyrin

Red Blood Cell Production (Erythropoiesis)

• Regulated by the concentration of hemoglobin in blood

• In response to decreased hemoglobin, the kidney secretes erythropoietin

• External respiration (pulmonary gas exchange) occurs in pulmonary capillaries.

• Internal respiration (systemic gas exchange) occurs in systemic capillaries.

Red Blood Cell Destruction

• Occurs in macrophages of the liver or spleen

• Globin portion is broken down into amino acids and recycled

• Heme portion is split into iron (Fe^{3+}) and biliverdin (green pigment)

Oxygen Transport

• Each hemoglobin molecule can bind 4 atoms of oxygen

• Average person has about 15 g of hemoglobin per 100 ml of blood

• Partial pressure of oxygen reflects the pressure or tension that oxygen exerts when it is dissolved in blood

• Oxygen combines with the heme portion to form oxyhemoglobin

Carbon Dioxide Transport

• Hemoglobin binds with CO_2 to form carbaminohemoglobin

• Carbonic anhydrase in the RBC helps to form carbonic acid

• 90% of CO_2 in arterial blood and 60% in venous blood is transported as bicarbonate

Regulation of Acid-Base by the Lungs

• The processes involving CO2, bicarbonate (HCO3^-), carbonic acid (H2CO3), and carbonic anhydrase in both body tissues and the lungs for acid-base regulation are shown.

Carbon Dioxide Transport

• Transported in the blood by:

  • Dissolved gas

  • Bicarbonate ion

  • Bound to hemoglobin

• Partial pressure of carbon dioxide reflects the pressure or tension it exerts when dissolved in blood

Erythrocyte Disorders

• Anemia: A group of disorders characterized by a deficit of red blood cells.

  • Low oxygen-carrying capacity leads to hypoxia

  • Relative anemia: normal total red cell mass with disturbances in regulation of plasma volume

  • Absolute anemia: actual decrease in number of red cells

• Polycythemia: An excess of red cells

  • Increased blood viscosity and volume

Anemia

• Causes:

  • Blood loss (acute: trauma, chronic)

  • Increased destruction (hemolytic)

  • Decreased production

• The definition of anemia is a decrease in oxygen-carrying capacity rather than just a decrease in red blood cells as enough functioning blood cells are crucial.

Causes of Decreased RBC Production

• Kidney failure leads to decreased erythropoietin (EPO) production because the kidneys produce erythropoietin, which stimulates the manufacture and maturation of RBCs in the bone marrow.

• Bone marrow problems: if the factory is broken or not working to full capacity, not enough RBCs are made

• Deficiencies in Iron, B12, and Folate: Building materials required by the factory to make its product. Any deficiency will cause decreased RBC production

Bone Marrow Problems

• Aplastic anemia: loss of hematopoietic cells causing pancytopenia (a decrease in RBCs, WBCs, and platelets)

  • Causes:

    • Viral: hepatitis, Epstein-Barr virus, cytomegalovirus

    • Autoimmune: Lupus (immune system attacks the bone marrow)

    • Drug: chloramphenicol

Features of Anemias

• Pallor

• Tiredness

• Weakness

• Dyspnea

• Palpitations

• Heart Failure (high output)

General Effects of Anemia

• Reduction in oxygen-carrying capacity leading to tissue hypoxia

• Compensatory mechanism to restore tissue oxygenation

  • Increased heart rate, cardiac output, circulatory rate, and flow to vital organs

  • Increase in 2,3-DPG in erythrocytes and decreased oxygen affinity of hemoglobin in tissues

Manifestations of Anemia

• Mild Anemia:

  • Hemoglobin above 8g/dl

  • Minimal symptoms

  • Elderly with cardiovascular, pulmonary disease may have symptoms

• Moderate/Severe Anemia:

  • Hemoglobin below 8g/dl

  • Orthostatic hypotension/nonorthostatic

  • Pallor

  • Tachypnea (rapid respiration rate)

  • Lightheaded, fainting

  • Angina, heart failure

  • Nighttime leg cramps

  • Tinnitus or roaring in ears

  • Fatigue, weakness

RBC Shape/Function

• RBC shape is important for carrying oxygen

Blood Smear and Anemia Classification

• Anemias can be classified based on the appearances of RBCs on a blood smear

  • Microcytic: occurs in iron deficiency, Thalassemia (may also cause target-shaped RBCs)

  • Macrocytosis: RBCs are released from the bone marrow too early. Causes: B12 or Folate deficiency. WBC nuclei are also affected, resulting in hypersegmented PMNs

Types of Anemia Based on MCV (Mean Corpuscular Volume)

• Normal: 80-100 fL (Normocytic)

• <80 fL: Microcytic

• >100 fL: Macrocytic

Definitions

• Ferritin: intracellular protein that stores iron

• TIBC (Total Iron Binding Capacity): Available binding sites for iron on Transferrin

• Peripheral Smear: Microscopic visualization of blood

Types of Anemia (MCV Based)

• Microcytic:

  • Iron Deficiency

  • Anemia of Chronic Disease

  • Thalassemia

  • Lead Poisoning

• Macrocytic:

  • Folate Deficiency

  • Decreased B12

• Normocytic:

  • Aplastic Anemia

  • Anemia of Chronic Renal Failure

Investigation of Normocytic Anemia

• Reticulocyte Count: measures young red blood cell percentage.

• Normal Reticulocyte Count: 1 - 1.5%

• > 4% Loosing RBCs

• < 1% Not Making RBCs

Definition: Young Red Blood Cell

• Reticulocyte count measures the percentage of young red blood cells. Normal range is 1-1.5%.

Hematopoiesis

• Process of blood cell formation from hematopoietic stem cells, leading to the production of various blood cells including erythrocytes, thrombocytes, lymphocytes, monocytes, and granulocytes.

Causes of Normocytic Anemia (MCV 80-100)

• Reticulocytes >4% (increased production):

  • RBC Destruction

  • Bleeding

• Reticulocytes <1% (decreased production)

  • Decreased Production

Reticulocyte Count and Anemia

• Low Retic count: DECREASED PRODUCTION FROM BONE MARROW

• High Retic count: RBC DESTRUCTION VS BLEEDING

  • Destruction=LYSIS HEMOLYTIC STUDIES: LDH unconjugated BILIRUBIN INCREASED IN lysis PERIPHERAL SMEAR

Schistocytes

• Schistocytes indicate mechanical damage

• Destroyed RBCs

Aplastic Anemia: Etiology and Pathogenesis

• DECREASED red blood cell production.

• Stem cell disorder characterized BY REDUCTION OF HEMATOPOIETIC TISSUE in the bone marrow, fatty marrow replacement and pancytopenia

• Caused by toxic, radiant, or immunologic injury to the bone marrow stem cells

Aplastic Anemia: Symptoms

• Insidious onset of symptoms

• Late symptoms include weakness, fatigue, lethargy, pallor, dyspnea, palpitations, transient murmurs and tachycardia

• Pancytopenia and granulocytopenia

Aplastic Anemia: Treatment

• Identify and avoid further toxic exposure

• Type human leukocyte antigen (HLA) and ABO to identify serologically defined loci and potential donors

• Maintain minimally essential levels of hemoglobin and platelets

• Prevent and manage infection

• Determine efficacy of bone marrow transplantation

• Administer immunosuppressive therapy or stimulate hematopoiesis and bone marrow regeneration

Normocytic Anemia Types

• Aplastic Anemia

• Anemia of Chronic Renal Failure

  • Failure of the renal endocrine function IMPAIRS ERYTHROPOIETIN PRODUCTION

  • Decreased red blood cell (RBC) count

  • Low hematocrit (HCT) and hemoglobin (HGB) level

  • Treatment consists of dialysis and administration of erythropoietin

Investigations of Macrocytic Anemia

• MegaloBLASTIC: MCV >125

• Folate Deficiency Anemia

Vitamin B12 Absorption

• Vitamin B12 is consumed.

• Intrinsic Factor Excreted in Stomach by Parietal Cells

• B12 Binds to Intrinsic Factor

• Intrinsic Factor binds to receptor in Terminal Ileum

• B12 is absorbed

Anemia Related to Vitamin B12 (Cobalamin) or Folate Deficiency

• Disruption in DNA synthesis of BLAST CELLS in bone marrow produces MEGALOBLASTS

• Low RBC, WBC, and platelet counts with increased mean corpuscular volume (MCV); megaloblastic dysplasia

• Treatment: replacing nutritional deficiencies

MEGALOBLASTIC ANEMIA

• Folate /B12 Deficiency Due to inadequate INTAKE Seen in Alcoholism and strict vegetarian diets

• Or INCREASED DEMAND Seen in Pregnancy and malignancy

• Rx: Supplementation

• DECREASED intrinsic factor (IF) the B12 carrier molecule

• Or Defective UPTAKE In terminal ileum (final portion of small intestine)

• Dx: Schilling Test

Schilling Test – localize pathology of B12 Deficiency

• Administer B12 injection IM – saturate receptors

• Give radioactive B12 PO

• Collect urine – if radioactive B12 is present (normal)

• If abnormal – Repeat PO radioactive B12 plus intrinsic factor

• Collect urine – if the urine is now positive for radioactive B12 decreased intrinsic factor was the cause supporting the diagnosis of pernicious anemia

• If the urine is negative for radioactive B12, terminal ilium disease is the likely diagnosis – The Ilium is the site of absorption for B12/intrinsic factor complex

Causes of Decreased Intrinsic Factor

• PERNICIOUS ANEMIA AUTOIMMUNE disorder in which the body destroys parietal cells

• Damaged Parietal Cells (chronic gastritis etc.)

Investigation of Microcytic Anemia

• SERUM FERRITIN

• TOTAL IRON BINDING CAPACITY (TIBC)

• RBC COUNT

• PERIPHERAL SMEAR

IRON DEFICIENCY ANEMIA

• MCV<80

• Low Ferritin

• Increased TIBC

• Hypochromia

• MICROCYTIC HYPOCHROMIC ANEMIA

Iron Deficiency Anemia

• Most common nutritional deficiency in the world

• Insufficient iron for hemoglobin synthesis

• Hypochromic, microcytic RBCs; low MCV, MCH, and MCHC

• Treatment: oral administration of ferrous sulfate or intravenous ferric gluconate (MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration)

• THE ONLY WAY WE CAN LOSE IRON IS BY LOSING BLOOD, because FE is recycled!

Iron Deficiency Anemia populations

• Adult men: GI Blood Loss

• PRE menopausal women: menorrhagia

• POST menopausal women: GI Blood Loss

• Pale and small RBCs

Compare Lab Results

• Iron Deficiency Anemia

  • Low Serum Iron

  • LOW Ferritin

  • INCREASED TIBC

• Anemia of Chronic Disease

  • Low Serum Iron

  • HIGH Ferritin

  • DECREASED TIBC

Vitamin Deficiency

• Iron • Needed for hemoglobin production • Deficiency causes hypochromic (pale), microcytic (small) anemia • Will also see decreased ferritin and increased TIBC due to unsaturated transferrin • Pica – craving ice and non- food items

• B12 or folate • Causes RBC’s to be released prematurely when still large • Macrocytic anemia

• Hypersegmentation of PMN’s – 5-6 segment nucleus in neutrophils, eosinophil, and basophil • B12 deficiency also causes neuro symptoms – Numbness – Tingling – Affects dorsal column-medial lemniscus (fine touch, vibration, proprioception)

Compare Peripheral Smear

• Thalassemia: Target Cells

• Lead Poisoning: Basophilic stippling

Treatment of Anemia

• If autoimmune disease: treat primary disease.

• B12, Folate, & Iron supplements may be used for the specific deficient nutrient.

• Rare cases: blood transfusions.

POLYCYTHEMIA

• Relative (due to dehydration)

• Absolute

  • POLYCYTHEMIA VERA (Primary) (LOW EPO)

  • POLYCYTHEMIA (Secondary) (HIGH EPO)

    • HIGH ALTITUDE

    • EPO TUMORS

    • EPO “Doping”

POLYCYTHEMIA VERA

• A “myeloproliferative” disease

• ALL cell lines are increased, not just RBCs

• No cure – Reduce blood volume and viscosity, platelet count

• Symptoms – Related to increase red cell mass and blood viscosity