1. Hematology Physiology 1 Erythropoiesis
Brenda Beckett, PA-C

2. Terms to Understand Hematopoiesis Erythropoiesis
Pluripotent hematopoietic stem cell (PHSC)
Committed stem cell (progenitor cell)
Differentiation
Maturation
Self-renewal
Proliferation
Reticulocyte
Polychromasia
Normocyte
Erythropoietin
Adult hemoglobin
Fetal hemoglobin
Apotransferrin
Transferrin
Apoferritin

3. Terms, continued Ferritin Hemosiderin Serum iron
Total iron binding capacity
-thalassemia
-thalassemia
Hemoglobinopathy
Anemia
Porphyria
A,B,O,Rh blood types

4. Red Blood Cell Transports hemoglobin
Carries oxygen from lungs to tissues
Carries CO2 back to lungs
Biconcave disc
Able to change shape
Has excess membrane

5. Red Blood Cell Mature RBC has no nucleus
5,200,000 (males), 4,700,000 (females) per cubic milliliter
Lifespan of days
Derived from pleuripotent hematopoietic stem cells (PHSC)

7. PHSC Retained in bone marrow
Reproduction controlled by growth inducers
Differentiation controlled by differentiation inducers
Will become committed stem cell (progenitor cell)

8. Stem cells – become committed stem (either lymph or myeloid)

11. Erythropoiesis
Decreased O2 in tissues causes increased production of erythropoietin
Hormone
Formed in kidney (80-90%) and liver
Occurs in fetal liver and spleen, then shifts to fetal bone marrow
Occurs in axial skeleton and proximal end of long bones in adults
2. Production is different from children to adults

12. Reticulocytes Final cell produced in marrow before release
Basophilic remnants of endoplasmic reticulum remain, becomes mature RBC (normocyte) within one day
Normally ~1% of total RBCs

13. Reticulocyte Count
Can differentiate between anemias due to decreased production and those of increased destruction
Will see polychromasia on Wright’s stain, need to order separate test for reticulocyte count
i.e. – iron def. would have low retic. After tx, it should go up – monitor tx.

14. Hemoglobin Formation
Begins at proerythroblast stage, continues until reticulocyte (before leaving bone marrow)
Heme molecule combines with globin (long peptide chain) to form hemoglobin chain.
4 chains bind together to form hemoglobin molecule.

15. Hemoglobin Binds loosely and reversibly with O2
Oxygen atom binds loosely with iron atom in hemoglobin
Bound as O2, released as dissolved O2

16. Iron Metabolism
Iron important part of hemoglobin, myoglobin and other structures
~65% of total iron in hemoglobin
4% myoglobin
1% various heme compounds
0.1% in plasma combined with transferrin
15-30% stored in liver as ferritin
1.5 – ferritin – storage form of iron.

17. Iron Transportation & Storage
Absorbed in small intestine
Binds with apotransferrin (globulin) to form transferrin – loosely bound
Excess deposited in liver and bone marrow
In liver, combines with apoferritin to form ferritin.
Also stored as insoluble hemosiderin – iron overload
3. If goes to bone marrow – made into hgb

18. Iron Usage
If plasma iron low, iron removed from ferritin, transported as transferrin in plasma
Transferrin binds strongly with cell membranes on erythroblasts in marrow
Ingested, delivered to mitochondria
Heme synthesized

19. Globin chains
4 globin chains combine with heme to make hemoglobin molecule
95-97% of adult hgb has 2 -chains and 2 -chains (22) aka Hgb A
Fetal hgb (Hgb F) has 22. High O2 affinity, mostly changes to HgbA by birth
Hgb A2 (22), 3-5% of adult
2. Where we get Hgb A1C – glucose binds to it.
3. Fetus needs higher O2 affinity b/c of low O2 supply in utero.

21. Abnormal Hemoglobins
Hemoglobinopathies: hemoglobin chains are abnormal
Thalassemias: hemoglobin chains normal in structure but decreased or absent. Named for which chain is affected.
Genes are on chromosomes 11 & 16

22. Anemia Qualitative or quantitative deficiency of hemoglobin
Significant blood loss
Plasma replaced in 1-3 days
RBCs replaced in 3-4 weeks
Hemolysis
Deficient RBC production

23. Vitamin B12/Folate Important for final maturation of RBCs
Essential to synthesize DNA
Decrease in either leads to failure of nuclear maturation and division
RBCs also become larger, irregular shape, flimsy membrane
Carry O2 normally, have short lifespan
4. Means they have shorter lifespan

24. Vitamin B12/Folate Deficiency
Macrocytic or megaloblastic anemia
Pernicious anemia: inability to absorb Vitamin B12 from GI tract
Gastric mucosa secretes Intrinsic Factor (IF), combines with B12, available for absorption
B12 stored in liver and bone marrow
2. Need IF

25. Iron deficiency
When iron stores are depleted, stored iron is mobilized
When iron stores drop, hemoglobin synthesis is affected – iron deficient erythropoiesis. (hypochromic)
More severe, leads to decreased erythropoiesis, smaller cells (microcytic)
2. Lighter color

26. Iron Deficiency Anemia
Low iron stores = low Ferritin
Low circulating iron (transferrin) = low Serum Iron
Leads to increased Total Iron Binding Capacity (TIBC)
Hypochromic, microcytic anemia
3. All spots able to bind are empty = iron def.

27. Anemia of Chronic Disease
Most likely due to inflammation
Iron stores aren’t released
Decreased erythropoiesis
Upregulation of WBC production causes decreased erythropoiesis
Normocytic or microcytic
1 causes 4.
2 leads to 3.
5. Iron levels could be nl. Don’t assume iron def.

28. Hemolytic anemias RBCs are fragile, shorter lifespan
Rupture as pass through capillaries and spleen
Hereditary or acquired (immune mediated)
Increased destruction leads to increased bilirubin (jaundice)

29. Hemolytic anemias Hereditary spherocytosis (and others)
Cells are spherical, can’t withstand compression – easily ruptured
Sickle cell anemia
Abnormal Hgb S (on  chain)
Exposed to low O2, forms crystals, elongates cell – “sickle”
Sickle trait – protective against malaria

31. Thalassemias Autosomal recessive, Mediterranean
Reduced synthesis of one globin chain, leads to microcytic anemia
 or  chain affected
Can coexist with hemoglobinopathies
Carrier state can be protective against malaria

32. G6PD Deficiency Hereditary Low levels of G6PD (enzyme)
Certain triggers lead to hemolysis, anemia, jaundice
Foods, medications, infection
Protective against malaria
Enzyme important for cell membranes. Def can trigger hemolysis.

33. Polycythemia Increased number of RBCs – primary or secondary
High altitude – physiologic polycythemia
Cardiac failure, smoking, tumors
Polycythemia vera: blast cells continue to produce RBCs even though there are too many in circulation. Viscous blood. Treatment: phlebotomy
4. don’t get negative feedback.

34. Porphyria Inherited or acquired Disorder of enzymes in heme pathway
7 different types
Different combos of elevated porphyrins (heme precursors) in tissues
Excreted in urine and stool
Sx: photosensitivity, abd pain, port wine urine, muscle weakness, behavior changes

35. RBC/Hemoglobin destruction
Changes to plasma membranes as cell ages
Recognized by phagocytes
Phagocytosis in spleen
Heme broken down into iron & biliverdin
Biliverdin converted to bilirubin
Iron bound to transferrin

36. Effects of anemia Lack of oxygen in tissues Symptoms can be vague
Weakness, fatigue, malaise
Dyspnea
Pallor
Increased cardiac output: plapitations, heart failure
2. May not even realize sx if it’s gradual. they get used to it.

37. Blood Groups ABO A&B antigens: “agglutinogens” on RBC
Anti-A &/or Anti-B develop in absence of antigens
Will agglutinate RBCs, lyse, leads to renal failure, death

38. O – universal donor
AB – universal receiver

39. Rh Typing Other antigens can be present on RBCs
Antibodies develop if exposed to antigen
D (Rh), d, C, c, E, e
Erythroblastosis fetalis
Most are minor and don’t cause problems unless pt receives many transfusions which exposes them to more antigens. Can get harder and harder to find the right blood that matches them.
4. Fetal death due to hemolysis b/c of incompatible blood types with mother. Usually from D antigen. Now a shot that prevents it.

40. WBC
The overall concentration of white blood cells of all types in the blood, expressed as thousands of cells per cubic millimeter (mm3) of blood. The terms used to describe a decreased and an increased WBC are leukopenia and leukocytosis, respectively.

41. RBC
The concentration of erythrocytes in the blood, most commonly expressed as millions of cells per cubic millimeter (mm3). The terms describing a decreased and an increased RBC are erythrocytopenia and erythrocytosis, respectively, or, more commonly, anemia and polycythemia.

42. HGB/HCT
The overall concentration of hemoglobin in the blood, ex­pressed as grams of hemoglobin per 100 milliliters of blood.
The hematocrit, the percentage of the blood volume consisting of red cells, expressed as a percent (%).

43. MCV
mean corpuscular volume, the average volume of individual erythrocytes in a blood sample, expressed as femtoliters (fl) per cell. One femtoliter is the equivalent of liters. The terms used to describe an erythrocyte with a normal, decreased, or increased cell volume are normocyte, microcyte, and macrocyte, respectively.

44. MCHC
mean cell hemoglobin concentration, the average concentration of hemoglobin within erythrocytes, expressed as grams of hemoglobin per dL of cells. Because the intracellular hemoglobin concentration determines the density of color (suffix -chromia) of erythrocytes on a stained blood smear, the morphological descriptions associated with a normal, increased or decreased MCHC are normochromia, hyperchromia and hypochromia, respectively.
Lower concentration – ligher/ higher concentration - darker

45. MCH
mean cell hemoglobin, the average quantity of hemoglobin in individual erythrocytes, expressed as picograms (pg) per cell. One picogram is the equivalent of grams.

46. RDW
red cell distribution width, expressed as the coefficient of variation around the mean cell volume (MCV). The larger the value for RDW, the greater the variability in size within the erythrocyte population. The morphological correlate of an increased RDW is variation in the diameters of individual erythrocytes seen on the peripheral smear, or anisocytosis.
Anisocytosis – difference in size.
Way to tell if therapy is working

47. PLT/MPV
the concentration of platelets in the peripheral blood, expressed as thousands of platelets per cubic millimeter (mm3) of blood.
mean platelet volume, the average volume of individual platelets, expressed as cubic microns per platelet or as femtoliters per platelet.

48. RETIC
the reticulocyte percentage, or the percentage of immature erythrocytes in a peripheral blood sample. These immature cells usually constitute from 0.5 to 1.5% of the circulating red blood cell population. An absolute reticulocyte count, expressed as millions of cells per cubic millimeter (mm3), can be obtained by multiplying the RBC by the reticulocyte percentage.
Separate test.