Anemias Flashcards
Silent carrier of alpha thalassemia
Three alpha genes, with RBCs of low normal size, but usually completely asymptomatic are called ____, 36% of African- Americans
Alpha thalassemia minor
Two alpha genes (one missing on opposite chromosomes or the same), with small RBCs, but otherwise normal
Alpha thalassemia major
1 in 1600 SE Asian children have no alpha genes, and usually die in utero of hydrops fetalis
Alpha thalassemia intermedia
Inherit only one alpha gene. Marked anemia and microcytosis. Make hemoglobin H
Hemoglobin H
Tetramer of beta globins. Unstable and slowly preciptates to form Heinz bodies
beta thalassemia minor
Loss of one full beta gene, either from partial loss of both or full loss of one, four alpha and
Beta thalassema major and intermedia
Present in infancy when HbF production stops and HbA production does not start- jaundice, growth retardation and skeletal deformations possible
Thalassemias
Normal globin chains produced in abnormal number. RBC have low Hb content and often are small when unpaired globin chains precipitate and are removed along with membrane
Hemoglobinopathies
Abnormal alleles of globin chains are produced (ex. sickle cell)
HbS
Sickle cell hemoglobin, evolved at least 5 times in Africa under the pressure of falciparal malaria
Glu to Val (GAG to GTG)
In sickle cell, 6 AA of beta globin gene is changed from ____
Deoxyhemoglobin-S
Strands assemble in groups to form fibers from two strands of molecules held together by beta6 valines - fibers form fascicles, which can grow and distort red cells as conc increases
Drive sickle cell formation
Intracellular dehydration (increased Hb conc), low pH (low O2 tension), decreased transit time through vascular beds (normally in spleen, bone marrow and inflammation)
Aplastic crisis
Marrow is not functioning, is wiped out
Parvovirus B-19
Causes aplastic crisis anytime there is a red cell mutation
Sickle cell problems
Intravascular hemolysis - chronic hemolytic anemia. RBCs only survive 10 days (free Hb injures endothelium and scavenges NO-> pulm hypertensions), high rates of marrow turnover leads to folate deficiency
Functional asplenia
Problem in sickle cell- deoxygenation of RBC in splenic sinusoids leads to sequestration and infarction. Loss makes patients more susceptible to bacterial infections (pneumococcal pneumonia and salmonella osteolyelitis)
Renal injury
Symptom of sickle cell- papillary infarction and sloughing can lead to obstruction and chronic blood less, loss leads to systemic hyperosmolarity and more frequent sickling episodes
Bone infarction
Symptom of sickle cell- rigid blood vessels in bone obstruct easily. Marrow infarcts cause painful episodes and loss of productive marrow. Femoral and humeral head and other large bone infarcts can lead to orthopedic disability
Pulmonary infarction
Most common cause of death in sickle cell patients. Pneumonia can lead to lung hypoxia and lung vessel infarction. Lung infarcts cause areas of necrotic lung which are more susceptible to infection -> vicous cycle of infection and infarction leading to shunting and global hypoxia
Brain infarction
Second most common cause of death and most important cause of disability in sickle cell. Blood vessel injury from sickle cells leads to blood vessel thickening and increased susceptibility to stroke
Hydroxyurea
only drug approved for sickle cell. Increases HbF levels (prevents polymers with S and produces stable tetramers with alpha), reduces frequency of painful episodes, and works in about 40% of HbSS patients
Transfusions
Helps to prevent stroke in sickle cell
HbAS (sickle cell trait)
Generally benign, causes hematuria, can cause splenic infarction, rare infarction in orthopedic surgery and rare deaths in military recruits
HbC
Glu to Lys in B6 globin. Milder disease
microcytic anemia
iron deficiency causes
Macrocytic and megaloblastic anemias
Folate and B12 deficiencies cause
Iron deficiency anemia
Affects hemoglobin synthesis
Vitamin B12 and folate deficiency
Affects DNA synthesis
Transferrin
iron absorbed from the gut is bound to plasma ____ and transported to the marrow where it is incorporated into hemoglobin in developing RBCs. Iron is extracted when RBCs are ingested by macrophages and recycled back to this.
Synthesized in the liver
Ferritin
Soluble iron protein complex for storing iron
Hepcidin
Protein made in liver that blocks intestinal absorption and transport. Keeps track of much transferrin is bringing in iron and liver release this if there is too much iron
Release leads to downregulation of ferroportin so iron gets lost when duodenal epithelial cells are shred into the gut
Reduces transfer of iron from storage pool to developing erythroid precursors in bone marrow
Ferroportin
Allows iron absorbed into gut to be transferred to plasma transferrin
duodenum and prox jejunum
Iron absorbed in what part of gut
Markers of iron deficiency
Decreased serum iron, increased serum transferrin (also TIBC), decreased transferrin saturation (%sat= Fe/TIBC), increased soluble transferrin receptor, decreased ferritin (reflects low storage iron)
Microcytic
Iron deficiency causes this as anemia worsens. Decreasing MCV (mean corpuscular volume) - avg volume of a red cell
Hypochromic
Decreasing MCHC (mean corpuscular hemoglobin concentration)- avg conc of Hb in red cell. Reduced Hb. Cells become this as iron def anemia worsens
Anemia of chronic disease
Impaired red cell production associated with reduction in proliferation of erythroid progenitors and impaired iron utilization. Can be caused by infections (osteomyelitis), chronic immune disorders (rheumatoid arthritis) or malignancies
Have normal to increased amounts of bone marrow iron, but not released normally to blood- developing RBC starved for iron even though storage is present
Anemia of chronic disease pathophys
Cytokine mediated induction of hepcidin (largely by interleukin-6) -> decreased iron absorption, decreased release of macrophage iron, not responsive to iron supplementation. Cytokine mediated inhibition of erythropoiesis
Decreased iron release
Inflammation/anemia of chronic disease causes anemia because of ____
Decreased globin synthesis
Thalassemia causes anemia because of _____
Increased, reduced to normal
Transferrin is _____ in iron deficiency anemia and ______ in anemia of chronic disease
Reduced, normal to increased
Ferritin is ______ in iron deficiency anemia and _____ in anemia of chronic disease
Macrocytic anemias
Big cells, not all are megaloblastic. Folate and B23 deficiencies, reticulocytosis, liver disease, and other conditions cause
Megaloblastic cells
Have a characteristic nuclear maturation defect. Normal cytoplasmic maturation
Folate and B12
These are necessary for production of thymine. Deficiency causes a nuclear but not a cytoplasmic maturation defect
Folate deficiency
Causes developmental neurologic injuries
B12 deficiency
Causes an acquired central and long tract neurologic injury
Folate
Accepts one carbon units from donor molecules and passes them on -> methionine, purines, pyrimidines
Folate and B12
Needed to convert homocysteine to methionine
B12 only
Needed to convert methyl malonyl CoA to succinyl CoA in nerve cells. Methyl malonate (MMA) is neurotoxin, converted to methyl malonyl CoA then succinyl coA. Failure of normal detox system leads to neuron death
Megaloblastic changes in bone marrow
Large polychromatophilic normoblasts with poorly condensed chromatin. Nuclear-cytoplasmic dissynchrony
some cells fail to mature and undergo apoptosis, hematopoiesis becomes inefficient
Neural tube defects, intestinal dysplasia, hypercoagulable state
Non-hematologic problems associated with low folic acid
Folate deficiency
Anemia, usually macrocytic, pancytopenia (all cell lines of marrow affected), malabsorption (weight loss, diarrhea, ab pain, glossitis)
Alcohol has directly toxic effect (malabsorption, reduce tissue release, interruption of hepatoenteric circulation, increased urinary excretion)
R-binders
Contained in saliva, biind to B12 when B12 is released from food by action of pepsin in stomach
Gastric fundic parietal cells
Intrinsic factor is secreted by these cells. B12 is released from R-binder by pancreatic proteases and bound to IF
Cubilin
IF-B12 complex absorbed in terminal ileum
Transcobalamins I-III
carries B12 in the blood stream, II is required for transfer to tissues
IF deficiency
key cause of B12 deficiency, congential deficieny, gastric resection or destruction by autoantibodies
pernicious anemia
Intrinsic factor deficiency caused by destruction by autoantibodies
Type A gastritis- parietal cells destory
Type I anti-IF antibodies block IF binding, Type II anti-IF antibodies block absorption
Causes of B12 deficiency
Dietary insufficiency (rare), IF deficiency, competitive utilization (bacterial overgrowth or fish tapeworm), ileal disease
B12 deficiency symptoms
Anemia (pallor, dyspnea, palpitations, lassitude), GI (wt loss, diarrhea, pain), reproductive (infertility), neurological (loss of sensation), psych (depressed, confused), autoimmune diseases, behavorial (restricted diet)
Vitiligo
skin blotches, Associated with pernicious anemia and other autoimmune diseases
Neuro presentation of B12 deficiency
Peripheral neuropathy (paresthesias, hyporeflexia), spinal cord degeneration, memory loss, disorientation, depression
Schilling test
Test B12 absorption. Oral radioactive B12 given after IV load, percentage of b12 estimated from 24 hour urine collection. If abnormal, repeat with IF supplement. If still abnormal, antibiotics to treat bacterial overgrowth. If still abnormal, pancreatic enzyme supplementation
Tuberculous ileitis
Leads to malabsoprtion, causing B12 deficiency and brain atrophy. another cause of megaloblastic anemia
Fish tapeworm (diphyllobothrium latum)
parasite absorbs 80% or more of host’s B12 intake and causes megaloblastic anemia
