Erythropoiesis
Erythropoietic stimulating agents used for:
-Chronic kidney disease -Preparation for surgery with high risk of blood loss -Anemia from zidovudine (HIV med) or chemotherapy -Prematurity related anemia
Megaloblastic anemia?
B12 deficiency, reduced ability to make DNA, most common form of macrocytic anemia.
Describe the sequence of erythropoiesis.
Blast forming unit-erythroid (BFU-E) --> colony forming unit-erythroid (CFU-E) --> proerythroblast --> basophilic erythroblast --> polychromatic erythroblast --> orthochromatic erythroblast --> reticulocyte (first anucleate stage) --> erythrocyte
What makes RBCs after age 20?
Bone marrow no longer does. Vertebrae are the most important sources of RBCs at this point and flat bones play a small role as well.
Myelophythisic anemia?
Bone marrow wasting. Increased hematopoietic destruction, usually from invasive carcinoma, hypocellular bone marrow.
What makes RBCs near birth?
Bone marrow.
One problem with phlebotomy.
Can cause an iron deficiency.
Physiologic anemia.
Due to normal responses to high altitudes, smoking, etc. Or compensation for lung or CV disease.
What are the two limiting factors of erythropoiesis?
EPO and iron.
When is EPO excreted and from where?
EPO is excreted when O2 delivery to the kidney is low. Excreted from kidney.
What does EPO stimulate/inhibit?
EPO stimulates erythropoiesis (direct effect) and inhibits hepcidin secretion (indirect effect).
Why does hepcidin need FPN?
For absorption in epithelial cells. Epithelial cells have 2 membranes so hepcidin needs FPN to get across 2nd membrane.
What cell do all blood cells come from?
Hemocytoblast.
What happens when iron levels are low?
Hepcidin activity decreases.
What does hepcidin inhibit and what does that cause?
Hepcidin inhibits ferroportin (FPN), a membrane ion transporter, to reduce: -GI iron absorption -Macrophage RBC breakdown -Hepatic iron release
Why is hepcidin secreted? What does it do?
Hepcidin is secreted by the liver when plasma iron levels are high. Inhibits RBC breakdown (because breaking down RBCs frees up iron) and the absorption of circulating iron. Hepcidin protects against excessive circulating iron.
What is polycythemia?
High RBC count (hematocrit >55%).
What is secondary polycythemia?
High erythropoietin.
Other regulatory factors for erythropoiesis?
Hormones (thyroid hormone, cortisol, estrogen/testosterone) and cytokines (IL3, CSF).
Treatment of aplastic anemia?
If autoimmune derived, immunosuppression. If cogenital, bone marrow transplant (good if under age 40, not used over age 65). Blood transfusion (last resort).
Myelodysplastic syndrome (MDS)?
Ineffective/abnormal hematological cells, hypercellular bone marrow, diversion of stem cells to dysplastic line, usually cancerous.
What is aplastic anemia? What is it induced by?
It is bone marrow failure, so reduced cell numbers in a biopsy. It is viral/myobacteria induced.
Is aplastic anemia normo, macro, or microcytic. Is it normo, macro, or microchromic?
It is normocytic and normochromic (occasionally microcytic).
Describe the response to EPO.
It starts in days but is complete in weeks.
What does EPO do in regard to BFUs and CFUs?
It stimulates BFUs and BFUs make CFUs, which form colonies in bone marrow.
What will RBC count look like if kidney damaged?
Kidney can't make EPO so will see a decreased RBC count.
Hematopoietic cancers?
Leukemia, lymphoma, multiple myeloma. Diversion of precursor cells to the cancerous lines.
Fungal infections present greatest risk to which kind of patients?
Leukopenic patients (low WBCs).
Cause and symptoms of anemia.
Low RBCs. Pale, headache, palpitations, fatigue, pale gums.
Causes and symptoms of leukopenia.
Low WBCs. Recurrent infections in mouth/pharynx, oral ulcers, systemic infections.
Causes and symptoms of thrombocytopenia.
Low platelets. Mucosal and gingival bleeding, purple/red spots on skin caused by internal bleeding of underlying small vessels.
Describe the myeloid line and give examples.
Myeloid line found in bone marrow. Includes RBCs, platelets, mast cells, monocytes, macrophages, basophils, neutrophils, eosinophils, and dendritic cells.
What is primary polycythemia?
Myeloproliferative condition (too many RBCs being made), often cancerous stem cell line.
Low EPO (renal) anemia is:
Normocytic and normochromic (occassionally microcytic).
How long does it take for a deficiency in iron to get corrected?
Only a few days (up to 3 days).
Describe the lymphoid line and give examples.
Only a few of these circulate, most are in lymph tissue throughout the body. Examples are natural killer cells, B (plasma) cells, and T and dendritic cells.
Treatment of polycythemia.
Phlebotomy (drawing blood/testing in lab), myelon suppressants.
What are reticulocytes?
RBC precursors.
What is one cause of anemia?
Reduced renal function (40-50%).
Treatment for renal anemia.
Replacement of EPO.
What happens when hepcidin levels are high?
Serum iron falls due to iron trapping within macrophages and liver cells and there is a decrease in gut iron absorption.
Which stages depend on iron?
The final maturation stages (erythroblast --> reticulocyte).
What are the 2 main branches of hematopoiesis?
The lymphoid line and the myeloid line.
What stimulates erythropoiesis?
The renal hormone erythropoietin (EPO).
Is the response faster to iron or EPO?
The response to EPO is a little slower than the response to iron.
What are cytokines? Give examples.
Things that cause differentiation. Includes interleukins and colony stimulating factors (CSF).
If bone marrow affected, what other cells are affected and what does this cause?
WBCs and platelets are both affected. Makes it easier to get infections, causes clotting problems, and fungal infections.
What is hematopoiesis?
Where pluripotent stem cells give rise to all blood cells.
What does it mean if there are high levels of reticulocytes in the bloodstream?
You are making more blood (erythropoiesis stimulated).
Properties of RBCs and side effects of these properties.
-No nuclei: can't synthesize RNA/proteins, cytoskeleton weakens as cells age, recognition proteins lost as cells age -No mitochondria: almost all energy from glycolysis, absolutely NEED glucose, can't use fatty acids, amino acids, or keto acids -Lifespan 100-120 days: 90% destroyed by macrophages in spleen/liver (10% hemolyzed in kidney)
Why are RBCs normally constant?
-Regulation by renal EPO secretion in response to blood oxygen -Regulation by hepcidin secretion in response to blood iron
Symptoms of polycythemia.
-Thicker blood viscosity (hypertension, headache, vertigo, angina pectoris, visual problems, ringing in ears (tinnitus), cramping) -Thrombosis: blood clots, stroke, heart attack -Enlargement of liver (hepatomegaly) or spleen (splenomegaly) -High histamine (if basophils are increased) -Erythema (ruddy complexion)
Aplastic anemia is how much genetic and how much acquired?
20% genetic and 80% acquired.
What is the half-life of EPO and hepcidin?
6-8 hours
How much EPO does kidney make? Where does rest come from?
90%. Liver.
How much of the hematopoietic line is usually affected from aplastic anemias?
All of it.
Causes of aplastic anemia?
Congenital (20%) and acquired (80%). Big ones are infections, autoimmune, and radiation therapy.
If reticulocytes not elevated:
cannot really tell whether acute or chronic anemia
If reticulocytes are elevated, sign of:
chronic anemia