Disorders of Red Blood Cells PDF

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Disorders of Red Blood Cells

Anemia: main red blood cell disorder   

A condition in which there is insufficient delivery of oxygen to the tissues because of inadequate # of mature, healthy RBCs in the blood Insufficient oxygen delivery to the tissues produces signs and symptoms related to cellular hypoxia and lack of cell energy (can lead to tissue damage) Iron deficient anemia is the most prevalent condition

1. Erythropoiesis: specific series of steps in the bone marrow that leads to the synthesis of mature RBCs  All RBCs begin as pluripotent stem cells ( hemocytoblast) in the bone marrow that are stimulated to become erythroid precursor cells (proerythroblast). The precursor goes through a series of changes until it becomes a mature erthryocyte released by the bone marrow.  RBC have no genetic material in their mature state

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Hypoxia stimulates the kidney to release erythropoietin >> erythropoietin stimulates bone marrow to synthesize RBCs **Substances needed for adequate synthesis of healthy RBCs include protein (amino acids), iron (Hb has 4 Fe; i.e. main element), vitamin B12, and folic acid. a) Breakdown of Hemoglobin  Heme is composed of iron (Fe2+) and porphyrin (four pyrrole rings linked by CH bridges).  Porphyrin is metabolized into biliverdin (green; colourizes bile, feces, and ecchymoses)

 Biliverdin is broken down into bilirubin (yellow; constituent of bile) which is released in the blood, transported with albumin >> picked up liver and secreted in bile. Intestines metabolize it into urobilinogen >> stercobilin, (brown; feces pigment)  When there is a high amount of RBC breakdown, bilirubin accumulates in the bloodstream causing hyperbililirubinemia  skin and sclera of the eye stain yellow, resulting in a condition called jaundice (also called icterus). b) Life Cycle of RBC (100 days)  Cells enter the circulation as reticulocytes (reticulocyte count is a good indicator of bone marrow activity)  The spleen (“RBC graveyard) removes abnormally shaped, rigid, fragile and hemolyzed RBCs from circulation; RBCs are broken down into their component parts by macrophages  Splenomegaly occurs when there is a large amount of RBC breakdown occurring in the body.  Amino acids and iron are recycled to make new RBCs. *Hb F(fetal) has four alpha chains and a very high affinity for oxygen (facilitates transfer of O2 across the placenta); replaced with Hb A after 6 months c) Abnormal Hemoglobin  In hemoglobinopathies, there is an abnormal structure of Hb because of a genetic mutation.  E.g. in sickle cell anemia, there is a mutation in one of the genes that direct the synthesis of the Hb beta polypeptide chains (there is an abnormal substitution of the amino acid valine for glutamic acid). I.e. people with sickle cell anemia have a different Hb called HbS. d) Iron Metabolism  Iron is absorbed in the duodenum/upper jejunum; some is sequestered in the intestinal cells and released into the bloodstream (transported by protein transferrin to the bone marrow for erythropoiesis)  Since many epithelial cells are sloughed off, there is a net loss of iron

 10-20% of iron is stored as ferritin complexes commonly found in bone marrow, liver and spleen  Total iron binding capacity (TIBC) = iron bound to transferrin/other proteins e) Oxy-Hb Dissociation Curve  Represents the relationship between PO2 (partial pressure of O2/amount of O2 in blood) and Hb affinity for O2  An important tool for understanding how blood carries and releases O2  When PO2 is 100 mm Hg, Hg is fully saturated with O2 atoms (this is the ideal/highest level of O2-Hb affinity)  At approx. PO2 of 60 mm Hg, Hb affinity drops and O2 is given up to tissues

 Oxygen delivery to tissues is affected by both oxy-Hb saturation and the amount of hemoglobin in the blood. If the oxygen saturation is 100% and Hb level is normal, oxygen delivery to the tissues is ideal.  However, if oxygen saturation of blood is 100% and Hb is low (as in anemia), oxygen delivery will be inadequate and cellular hypoxia will result. **Hb has a greater affinity for carbon monoxide than for O2 i.e. if there are high levels of CO in the environment, oxygen will be displaced from oxygen binding sites and they will become saturated with CO (often fatal; blood is bright red)

2. Blood Types a) ABO Blood Types

 Specific antigens on RBC surfaces are called agglutinogens (types A/B)  Individuals spontaneously develop antibodies to ABO antigens that are not the same as their own (e.g. a type A person has antibodies against type B)  Universal donor: A person with type O blood has no antigens on their RBC surface therefore they can donate blood to any blood type; however, they have both anti-A and anti-B antibodies  Universal recipient: A person with type AB blood has no antibodies therefore can receive any blood type  If a person receives a different blood type than their own, antibodies attack the infused RBCs and cause a transfusion reaction that involves hemolysis. b) Rh Factor  Rh factor/D antigen is also on RBC surface; if you have the D antigen surface antigens you are positive (Rh+) and can receive Rh- blood (no AB)  Rh- cannot receive Rh+ blood (first transfusion= no reaction; second transfusion= now making AB to Rh+) **pregnant Rh- mom with Rh+ baby #2 can cause harm to baby because AB created can cross placental barrier and harm baby

3. Anemia  Decreased RBC mass that becomes clinically apparent when Hb and hematocrit (Hct; % RBC) levels are lower than normal  Hb lower than 130g/L (M) or 120g/L (F)  Hct lower than 45-52% (M) or 37-48% (F)  A complete blood count (CBC) measures all RBCs/RBC characteristics  Different types of anemia produce different CBC results **Males have a higher hematocrit because testosterone signals the kidneys to release EPO, which signals the bone marrow to make RBCs.

a) CBC  Includes: Hb, Hct, # of RBC and reticulocyte count (indicates bone marrow activity; C/L)  Mean corpuscular volume (MCV): indicates size of RBC  Mean corpuscular hemoglobin (MCH): indicates RBC color  MCH concentration (MCHC): Also indicates RBC color

**people living at high altitudes have higher Hb/Hct due to low O2 (constantly stims renal erythropoietin) I.   

Mean Corpuscular Volume (MCV) The volume of one RBC (size) The normal MCV is 800-1000 femtoliters Used to classify the anemia as microcytic (small), megaloblastic/macrocytic (big) or normocytic (normal)

II.

Mean Corpuscular Hemoglobin (MCH) and MCH Concentration (MCHC)  MCH is the average amount of Hb/RBC (normal = 27-32 picograms)  MCHC is the average concentration of Hg in a given RBC volume (normal is between 32-36%)  MCH and MCHC can be used to indicate the colour of the RBCs. A low value for either is indicated by pale or hypochromic cells.

b) Normocytic Normochromic (NCNC) Anemia  The size and color of RBCs are normal (MCV/MCHC are normal)  Most common cause is blood loss c) Microcytic Hypochromic Anemia  When MCV and MCHC are both decreased, size and color of RBC is abnormal  Low MCV indicates small RBC  Low MCHC indicates pale colored RBC  Most common cause is iron deficiency d) Megaloblastic (Macrocytic) Anemia  When MCV is high, RBC are abnormally large (megaloblastic or macrocytic)  Most common causes are vitamin B12 or folic acid deficiency **Reticulocyte count measures # of immature RBC in blood and determines whether bone marrow is producing new RBC at an appropriate rate  Increased reticulocyte numbers associated with anemia suggests accelerated destruction or loss of RBC (normal count is 1% of RBC) like during bleeding, chronic blood loss or hemolytic anemia (RBC destruction)  Decreased Retic. % may correlate with conditions such as: Iron deficiency anemia, folic acid deficiency, aplastic anemia, bone marrow failure, radiation therapy (i.e. impaired red cell production)

e) Common Symptoms of Anemia I. Pallor of skin, conjunctiva, nailbeds, and buccal mucosa II. Excessive fatigue III. Weakness IV. Shortness of breath (especially with activity + exercise intolerance) V. Tachycardia (palpitations) VI. Chest pain VII. Dizziness (or feeling faint) VIII. Headache **Nutritional anemia can cause glossitis (swollen/discolored tongue), cheilitis (chapped lips), koilonychia (flat/cavity nails) or pica (crave/eat non-food items like dirt, clay, starch, baking soda)

f) Anemia caused by Acute Blood Loss (Hemorrhagic Anemia)  Adults have a total blood volume of approximately 5 liters.  Adults can usually lose 500 mL of blood without serious or lasting effects.  If the loss reaches 1,000 mL or more, serious adverse effects such as hypovolemic shock and cerebral hypoperfusion can occur  Acute blood loss is a rapid loss of blood as in hemorrhage caused by trauma, childbirth, rupture of a major blood vessel, or organ.  Severe gastrointestinal bleeding can occur in disorders such as esophageal varices (varicose veins…) or penetrating peptic ulcer. I.

Pathophysiology of Acute Blood Loss (Compensatory Mechanisms)  Normocytic/normochromic (NCNC) but deficient in number  Baroreceptors sense decreased BP  stimulation of the sympathetic nervous system →systemic arterial vasoconstriction  Stimulation of the RAAS (leads to vasoconstriction and retaining of water/salt)  Fluid shifts from tissues into the capillaries  Antidiuretic hormone (ADH) release  The lack of sufficient number of RBCs to carry oxygen causes tissue hypoxia  kidney  erythropoietin  bone marrow starts to synthesize RBCs.

 Reticulocytosis occurs if bleeding is severe II.

Symptoms of Significant Blood Loss  Hypotension  Tachycardia  Tachypnea  Pallor  Oliguria (production of abnormally small amounts of urine)  Thirst  Cool clammy skin (not a lot of blood flow + sweating)  Loss of consciousness 

III.

Blood Loss from GI Tract  Patients bleeding because of esophageal varices often exhibit hematemesis (vomiting blood).  Blood mixed with stomach acid and mucus in vomitus is referred to as “coffee ground” emesis.  Blood mixed in stool, causing tar-like stool, is called melena.  Patients losing large amounts of blood via the rectum exhibit hematochezia, bright red blood in the stool.

g) Chronic Slow Blood Loss I.

Most Common Causes  Peptic ulcer  Inflammatory bowel disease  Colon cancer  Menorrhagia (excessive monthly menstrual loss) **most commonly leads to iron deficiency anemia (RBC lost are largest stores of iron in the body)

II.

Diagnosis  Microcytic hypochromic anemia (low MCV and low MCH)  Low Fe2+  Low serum ferritin  High TIBC (total iron binding capacity)  Fecal occult blood test (FOBT)

h) GI Blood Loss and Iron Deficiency  For men, loss of GI tract blood is the most common cause for iron deficiency anemia; problems = gastritis, ulcerations, es. Varices, carcinomas (cancer)  In men and postmenopausal women, colon cancer frequently presents w/ iron deficiency anemia because of undetected chronic GI blood loss  Treatment a. Ferrous sulfate (iron supplement) b. Stop bleeding through surgery c. Transfusion if Hb decreases to 7 mg/dL **Remember the normal Hb! (13 for males, 12 for females)

i) Hemolytic Anemia I.

Causes  Drug reactions  Transfusion reactions  ABO or Rh incompatibility (mother/fetus)  Autoimmune diseases  Hemoglobinopathies (abnormal structure of one of the globin chains; sickle cell anemia)

 Prosthetic heart valves (mechanical hemolysis) II.

Signs and Symptoms  Fatigue  Pallor  Shortness of breath  Tachycardia (compensatory response)  Chills  Jaundice (hyperbilirubinemia; ↑ Hb breakdown>> ↑ bilirubin)  Dark urine (hyperbilirubinemia; presence of Hb)  Enlarged spleen (splenomegaly; hyperactivity of spleen)

**If the antibody causing the destruction of the RBCs is of the IgG class, the hemolysis will occur at any temperature, which is called warm agglutinin syndrome.

If the antibody against the RBCs is of the IgM class, this is called cold agglutinin syndrome, in which hemolysis occurs at low temperatures. j) Sickle Cell Anemia (SCA)  The SCA gene mutation causes one of the Hb beta polypeptide chains to be abnormal (AA valine is substituted for glutamic acid)  Changes the normal HbA into HbS, the major type of Hb in sickle cell anemia.  This mutation causes structural fragility of the sickle cell anemia RBCs, where upon exposure to hypoxia or stress, the RBC contorts into a sickle shape. **deoxygenation of HbS leads to a double strand of aggregated Hb S mol. I.

Epidemiology  Sickled RBCs become trapped in capillaries > block blood flow > ischemia/tissue hypoxia > organ damage (possible infarction).  The episodes of ischemia are painful vaso-occlusive crises; the chest, abdomen, long bones, and joints are most commonly affected.  Splenic dysfunction (excess RBC death)  low immunity  RBC breakdown  hyperbilirubinemia jaundice

II.

Treatment  Opioids for pain  Hydroxyurea: stimulates bone marrow to increase fetal Hb (not effected by sickle cell chromosome)  Nitric oxide (vasodilator)  Prophylactic antibiotics (for compromised immune system)  Blood transfusions: replace damaged RBCs (can lead to excess iron)  Iron-chelating agents: remove excess Fe++ from Hb breakdown  Splenectomy  Bone marrow transplant (introduce non-sickling stem cells)

4. Thalassemia  One or more of the genes that code for Hb (alpha or beta) are missing or variant; consequently, some proteins needed for Hb synthesis are abnormal or absent  In alpha thalassemia, the alpha chain is affected and in beta thalassemia the beta chain is affected or absent **Alpha thalassemia affects primarily Asian populations; beta thalassemia affect primarily Mediterranean and middle-eastern populations

 Imbalance between alpha and beta globin subunits  excess subunits precipitate/clump  abnormal RBCs  hemolysis  excessive bone marrow activity  osteopenia (reduced bone mass of lesser severity than osteoporosis)  Excess hemolysis jaundice  Accumulated normal polypeptide chains = Heinz bodies (precipitated Hb)  There are two forms of beta thalassemia… III.

IV.

Thalassemia minor: only one copy of the beta thalassemia gene with one normal beta-chain gene. The person is said to be heterozygous for beta thalassemia. Persons with thalassemia minor may have mild anemia but have a normal blood iron level. Thalassemia major (Cooley's anemia): two genes for beta thalassemia and no normal beta-chain gene causing a striking deficiency in beta chain production and in the production of Hb A. The child is homozygous for beta thalassemia.

**At birth, the baby seems entirely normal because the predominant hemoglobin is still Hb F (has no beta chains so the baby is protected at birth from the effects of thalassemia major).

5. Hemolytic Disease of the Newborn (HDN)  Antigen-antibody reaction between a mother’s antibodies and her newborn infant’s RBCs at the time of birth.  Maternal synthesis of antibodies against the surface A, B, or Rh antigens (D antigens) on fetal RBCs.  Antibodies against ABO blood antigens are of the IgM class and are too large in size and cannot pass through the placenta during pregnancy (a mother with a different blood type than the fetus can carry the pregnancy without problems) **It is only during delivery when fetal/maternal blood may mix that AB might attack FRBC causing mild hemolysis > mild hyperbilirubinemia > mild jaundice I.

Erythroblastosis Fetalis  Severe hemolytic disease when mother has Rh- and fetus has Rh+ (mother creates Rh antibodies against fetal Rh+ blood during birth)  With second pregnancy, mother’s anti Rh antibodies cross the placenta and attack fetal Rh+ RBCs  massive hemolytic reaction fetal death  Treated with rhogam (covers Rh+ RBC so they are undetected)

6. RBC Maturation Defects  Necessary nutrients for RBC synthesise include iron, vitamin B12, and folic acid.  Iron is an essential element of Hb synthesis.  Vitamin B12 and folic acid are necessary components of DNA synthesis.  Any deficiency of these components leads to decreased erythropoiesis in the bone marrow which, in turn, leads to anemia. a) Iron Deficiency Anemia I.

People Susceptible  Vegans (lots of iron in meat)  Women with excessive menstrual bleeding  Pregnant women  Elderly with achlorhydria (Gastric atrophy)  Children weaned from breast milk to cow’s milk  Teens in growth spurt  Persons with chronic slow GI bleeding  Males (must first rule out GI bleed from colon cancer or peptic ulcers)

**Achlorhydria: absence of hydrochloric acid in gastric secretions; occurs most commonly in atrophy of the gastric mucosa, gastric carcinoma, and pernicious anemia.

II.

Specific Signs  Hair loss  Cheilitis (chapped lips)  Glossitis  Nail changes (koilonychias)  Cold/numb fingernails  Pica (craving for non-food substances)

b) Pernicious Anemia// Vitamin B12 (cyanocobalamin) Deficiency  Cofactor for RBC DNA synthesis (activation of folic acid for DNA synthesis; supplementing just folic acid can mask B12 deficiency) and normal neural myelin synthesis

I.

People Susceptible  Elderly  Vegans  Lack of stomach HCl  Intrinsic factor deficiency (autoimmune destruction of parietal cells)

II.

Signs of Vitamin B12 Deficiency  Fatigue  Exercise intolerance  Dyspnea  Weakness  Tachycardia  Glossitis (skin issue)  Numbness and tingling in the hands and feet (neuro)  Unsteady gait  Balance problems  Mental changes  Depression/dementia

III.

Neuro Effects

 Myelin defects/abnormal neuron conduction occur in dorsal horns/corticospinal tract (subacute combined degeneration; numbness, weakness, gait disturbance)  Serotonin, NE and dopamine synthesis are also affected (causes mental status changes like depression and memory loss) IV.

Diagnosis  CBC: high MCV  Vitamin B12 levels/folic acid  Low reticulocyte count (longer time to divide due to low DNA syn)  Hypersegmented/multi-lobed neutrophils  Elevated bilirubin (death of immature RBC)

c) Folic Acid Deficiency (Megaloblastic Anemia) I.

Susceptible People  Pregnant/lactating women  Alcohol abusers  Certain drugs; phenytoin, oral contraceptives, anticonvulsants  Those with celiac or inflammatory bowel disease  Chronic inflammatory disorders (arthritis, TB, psoriasis, systemic infections)

II.

Megaloblastic Anemia  If DNA duplication is delayed, cell will continue to get bigger until it can divide  Spinal cord defects: spina bifida (can be decreased by 70% with folic acid supplements), myelomeningocele, anencephaly in fetus

III.

Homocysteine  An amino acid that requires folic acid for its breakdown (w/o FA, levels accumulate and cause injury to the arterial endothelial linings)  Some studies have linked elevated levels to CV conditions

7. Aplastic Anemia

 Complete disruption of bone marrow function that inhibits RBC manufacturing; caused by cancer, sepsis or radiation exposure  Bone marrow transplantation from an HLA-matched sibling donor is the preferred treatment. The risk of rejection, also called graft versus host disease (GVHD), increases with the age of the patient.  Prophylactic antibiotics and platelet, RBC, and WBC transfusions are necessary.  Bone marrow stimulants such as filgrastim (NeupogenR) and epoetin-alfa (EpogenR) can be used to stimulate the marrow to make more cells and provide symptom relief. 8. Polycythemia  The opposite of anemia; there is an overabundance of RBCs  Primary polycythemia: hyperproliferation of all blood cells; blood becomes viscous and requires periodic phlebotomy (controlled bleed to reduce amount of RBC).  Secondary polycythemia is more common, and it is a hyperproliferation of the RBCs in re...