Exam 2 (1)Erythrocytes

Describe the composition of whole blood:

• Plasma:

  • Proteins (7%) = albumins: help make more soluble (57%); globulins (38%); fibrinogen: important in clotting/hemostasis (4%); prothrombin (1%)

  • Water (91%)

  • Other solutes (2%): ions, nutrients, waste products, gases, regulatory substances

• Formed Elements:

  • Platelets: hemostasis (140,000-340,000)

  • Leukocytes: (5,000-9,000) = neutrophils (60-70%); lymphocytes (20-25%); monocytes (3-8%); eosinophils (3-4%); basophils (0.5-1%)

  • Erythrocytes (4.2-6.2 million)

Describe the chemical composition of hemoglobin:

• Hemoglobin structure, function:

  • Adult hemoglobin (HbA) is composed of two α globin chains and two B globin chains (α2B2)

    • Each globin chain is bound to a heme group

  • Iron in the heme group binds O2 reversibly in a concentration-dependent manner (high O2=bind; low O2=release)

    • oxyhemoglobin is bright red, while deoxyhemoglobin is dark red

  • Fetal hemoglobin (HbF) has two y globin chains instead of B globin chains (α2y2)

    • HbF has higher affinity for O2 than HbA allowing the fetus to acquire O2 from the mother

    • It is replaced within 6 months of birth by HbA

Describe the structure and function of erythrocytes:

• Erythrocyte structure/functions:

  • specialized to transport O2

  • 97% hemoglobin (dry-weight)

  • Anaerobic and lack of nuclei and organelles (don’t consume the oxygen they are carrying)

  • Biconcave shape provides higher surface volume ratio which aids gas exchange

    • Shape is maintained by spectrin bound indirectly to transmembrane proteins

  • Flexible: larger than smallest capillaries (bend and flex to go through)

Explain process and regulation of erythropoiesis

• Erythrocyte productions:

  • Erythropoiesis is red blood cell formation and occurs in the red bone marrow

  • All blood cells arise from hematopoietic stem cells (hemocytoblasts) located in the red bone marrow (most bones - long bones - have yellow bone marrow - fat cells - in adults, red bone marrow is found in irregular shaped bones)

  • Must balance number of erythrocytes to:

    • Maintain adequate O2 delivery

    • Prevent excessive blood viscosity

  • # = rate of production - rate of destruction

  • Average production is 2 × 10^6 / second

Erythropoiesis:

• Reticulocytes enter the bloodstream and mature into erythrocytes within two days

  • Reticulocytes account for ~2% of the total RBC population

Erythropoietin: The rate of erythropoiesis is regulated by the level of erythropoietin (EPO) and the availability of iron

• The level of EPO increases in response to hypoxia (decreased O2 delivery to tissue)

• EPO is produced by fibroblasts in the kidney cortex > testosterone enhances EPO production by kidneys

Response to Ischemia/Hypoxia:

• Hypoxia leads to an increase in the level of transcription factors called hypoxia inducible factors (HIF)

  • HIF increases transcription of many genes in different cell types to promote metabolism, angiogenesis, and cell survival during hypoxia = hypoxia transcriptional program

  • Fibroblasts in the kidney cortex respond to hypoxia by increasing the level of HIF which then increases transcription of erythropoietin

• HIF is rapidly degraded during normoxia

  • The enzyme prolyl hydroxylase adds hydroxyl groups to two proline residues

    • This reaction requires sufficient levels of oxygen

  • Hydroxylated prolines are recognition sites for ubiquitin ligase leading to rapid proteasonal degradation of HIF

• During Hypoxia, prolyl hydroxylase activity is decreased, and HIF is not rapidly degraded

Hypoxia Response Element

• HIF binds to the promoter of the EPO gene and increases (erythrocyte production) its transcription

  • Contains a hypoxia response element

Causes of Hypoxia

• Decreased O2 availability   

  • high altitude

  • lung disease

• Increased O2 demand by body

  • heavy exercise

• Decreased O2 carrying capacity

  • anemia (diminished ability to carry O2 in blood)

Describe the turnover of erythrocytes, the metabolism and excretion of heme, and the scavenging of iron.

Turnover of Erythrocytes:

• the normal elimination of erythrocytes occurs via the RES (reticuloendothelial system) composed of sinusoidal capillaries (big gaps and openings) located primarily in the spleen

  • like all cells, erythrocytes become damaged over time and lose flexibility

    • Because they have no nuclei or organelles, they cannot repair the damage

  • Erythrocytes that have lost flexibility become trapped in the sinusoidal capillaries

    • average lifespan is 120 days

• Trapped cells are phagocytosed by tissue-resident macrophages located outside the capillaries

• smaller amounts of erythrocytes turnover may also take place in the liver, bone marrow, and lymph nodes

Extravascular Hemolysis: (in stroma of spleen)

• tissue-resident macrophages phagocytose the trapped erythrocytes

• Globin chains are degraded by proteases

• iron is removed from heme and transferred to carrier protein transferrin in the blood

• heme groups salvaged and oxidized to bilirubin by cellular enzymes

Excretion of Bilirubin:

• it is transported through the blood to the liver bound to a carrier protein called heptoglobin

  • bilirubin has very poor solubility in the plasma

• In the liver the bilirubin is conjugated (linked) to a molecule of glucuronide to make it more soluble and less toxic

• the conjugated bilirubin is added to the bile (made in liver) which is secreted into the intestines and excreted with feces

Scavenging and Recycling of Iron

• iron can be released into the circulation and returned to the bone marrow for incorporation into new RBC or to the liver

  • iron binds to the carrier protein transferrin which ferries to other tissues

• in the red bone marrow, iron can be removed from transferrin and used to synthesize new hemoglobin in erythropoiesis

• in other cells, especially the liver, transferrin is endocytosed, the iron is removed, and it then binds to the cytosolic protein ferritin

  > really important part of erythrocyte turnover