Hematology Physiology 1Erythropoiesis

Brenda Beckett, PA-C

Terms to Understand

HematopoiesisErythropoiesisPluripotent hematopoietic

stem cell (PHSC)Committed stem cell

(progenitor cell)DifferentiationMaturationSelf-renewalProliferation

Reticulocyte

Polychromasia

Normocyte

Erythropoietin

Adult hemoglobin

Fetal hemoglobin

Apotransferrin

Transferrin

Apoferritin

Terms, continued

Ferritin

Hemosiderin

Serum iron

Total iron binding capacity

-thalassemia

-thalassemia

Hemoglobinopathy

Anemia

Porphyria

A,B,O,Rh blood types

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

Red Blood Cell

Mature RBC has no nucleus 5,200,000 (males), 4,700,000 (females)

per cubic milliliter Lifespan of 100-120 days Derived from pleuripotent hematopoietic

stem cells (PHSC)

PHSC

Retained in bone marrow Reproduction controlled by growth

inducers Differentiation controlled by

differentiation inducers– Will become committed stem cell

(progenitor cell)

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

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

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

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.

Hemoglobin

Binds loosely and reversibly with O2 Oxygen atom binds loosely with iron

atom in hemoglobin Bound as O2, released as dissolved O2

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

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

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

Globin chains

4 globin chains combine with heme to make hemoglobin molecule

95-97% of adult hgb has 2 -chains and 2 -chains (22) aka Hgb A

Fetal hgb (Hgb F) has 22. High O2 affinity, mostly changes to HgbA by birth

Hgb A2 (22), 3-5% of adult

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

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

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

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

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)

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

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

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)

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

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

G6PD Deficiency

Hereditary Low levels of G6PD (enzyme) Certain triggers lead to hemolysis,

anemia, jaundice Foods, medications, infection Protective against malaria

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

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

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

Effects of anemia

Lack of oxygen in tissues Symptoms can be vague

– Weakness, fatigue, malaise– Dyspnea– Pallor

Increased cardiac output: plapitations, heart failure

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

Rh Typing

Other antigens can be present on RBCs Antibodies develop if exposed to

antigen D (Rh), d, C, c, E, e Erythroblastosis fetalis

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.

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.

HGB/HCT

The overall concentration of hemoglobin in the blood, ex pressed 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 (%).

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 10-15 liters. The terms used to describe an erythrocyte with a normal, decreased, or increased cell volume are normocyte, microcyte, and macrocyte, respectively.

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.

MCH

mean cell hemoglobin, the average quantity of hemoglobin in individual erythrocytes, expressed as picograms (pg) per cell. One picogram is the equivalent of 10-12 grams.

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.

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.

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.