Topic #4

Blood
Part 1
Joanna Komorowski, Ph.D.

Learning objectives Marieb and Hoehn 8th ed.

4.1.1 Describe the composition of blood (pp. 634-637)
4.1.2 Erythrocytes: describe their structure, function & life cycle (pp. 637-643)

The major components of whole blood

Blood is a specialized type of connective tissue It contains: - living blood cells called formed elements - nonliving blood plasma

Blood is slightly alkaline (pH = 7.35-7.45 Its temperature = ~ 38C (somewhat higher than body temp.) 8% body weight (5-6 L ; 4-5 L )

Functions of blood
Transport (distribution): - O2, nutrients - CO2, metabolites, nitrogenous waste products - hormones Regulation: - body temperature - pH - fluid volume Protection: - prevention of blood loss - prevention of infections (antibodies, complement proteins)

Blood
Blood plasma 90% water Contains solutes: nutrients, respiratory gases, hormones, electrolytes, proteins (albumin, globulins), and wastes (e.g., byproducts of protein breakdown)

Formed elements Erythrocytes, leukocytes, and platelets Erythrocytes and platelets do not divide!!

Erythrocytes
Structure & basic characteristics Small biconcave cells that lack nucleus and organelles Contain protein spectrin that helps RBC to be flexible, change shape, and squeeze through narrow capillaries
Huge

surface area for gas exchange High hemoglobin content Anaerobic metabolism sparing O2 consumption

Figure 17.3

Hemoglobin (Hb)

Hemoglobin is made up of four protein globin subunits, each bound to the iron binding red heme pigment Each iron atom can combine reversibly with one molecule of oxygen (4 per Hb molecule; each RBC contains 250 million Hb molecules!!) Each globin molecule is made of 2 and 2 polypeptide subunits Hemoglobin carrying O2 = oxyhemoglobin Hemoglobin carrying CO2 = carbaminohemoglobin O2 combines with heme group, but CO2 combines with globin part

RBC standard values

Mattson Porth Essentials of Pathophysiology 2007

Red Blood Cell production = hematopoiesis = hemopoiesis

Red blood cells are continuously renewed by division of cells in red bone marrow (reticular connective tissue bordering on large capillaries called blood sinusoids) The production of RBCs requires:
Functional hematopoietic stem cells (pleuripotent, at this stage can develop to any blood cell type) Erythropoietin Iron Folate Vitamin B12

Red Cell Production

Stem cells

Erythropoietin Erythroblasts

Reticulocytes

Red blood cells

Life span of RBC is 100-120 days

Erythropoesis
Fig. 17.5

15 days
The appearance of the membrane surface receptors for specific growth factors and hormones that push the cell towards specialization

RBC development

Mattson Porth Essentials of Pathophysiology 2007

Erythropoetin (EPO) mechanism for regulating erythrocytes

When cell O2 falls, oxygen sensor in kidney and liver (a heme protein) stimulates transcription of EPO

Kidney produces 85%90% of EPO

Other stimulators of EPO - Catecholamines - Androgens - Alkalosis

 EPO production can result from: blood content, e.g., hemorrhage Insufficient Hb per RBC O2 availability

Athletes & EPO abuse: can increase hematocrit from 45% to 65%; BUT increased viscosity plus dehydration during race can clotting, stroke, heart failure

Life cycle of RBC

Most hemoglobin degradation in the macrophages of the spleen Iron is reused Heme is reduced to bilirubin and eventually converted to urobilinogen metabolised by bacteria to stercobillin an excreted in feces

Iron uptake, incorporation into hemoglobin and storage

Iron is transported by transferrin and stored inside cells as protein-iron complex ferritin and hemosiderin

Iron uptake, incorporation into hemoglobin and storage

The most common areas of iron storage in our bodies: liver, bone marrow, intestinal mucosa and spleen

If the body does not need iron, it is stored in the mucosal cells and lost when these cells die and are slough

Cofactors for RBC Production

Dietary iron:
Heme iron is better absorbed than non-heme iron

Vitamin B12 and folate

Vitamin B12 and folate are necessary for synthesis of nucleic acids and nuclear maturation of the RBC Vitamin B12 requires intrinsic factor for effective absorption

Iron
Found in every living cell Occurs in foods in various forms Heme iron (in hemoglobin and myoglobin) is found in: - organ meats (liver, heart, kidney) - red meet (beef, pork, veal, lamb) - fish (clams, oysters, sardines) - poultry

Iron, cont.
Non-heme iron (all iron found in vegetables, grains and supplements): - legumes, dry fruits, enriched cereals and pasta - dark green leafy vegetables, eggs There is more iron in meat than in plant foods!! Heme iron is absorbed more readily!!!

Iron in foods

Sizer & Whitney, Nutrition Concepts & Controversies, West/Wadsworth, 1997

Practical Dietary Strategies to Meet Iron Needs

Eat hem rich foods (red meats, shellfish,
liver)

Enhance the absorption of non-hem iron by including

vitamin C at the same meal

Be aware that some foods interfere with non-hem iron absorption (excess bran,
strongly brewed tea, oregano)

Only take iron supplements at the advice of a dietitian or physician Cook foods in black cast iron pots and pans

Folate deficiency anemia

Folate, from Latin folium meaning leaf Involved in metabolism of DNA, amino acids and their derivatives Often works together with vitamins B12 and B6 and produces deficiency syndromes often identical to vitamin B12 deficiency

Folate is necessary for the formation of all new cells including RBC!!!

Folate, cont.
Found mainly in dark green, leafy vegetables, liver, legumes, fortified cereals Folate from eggs, dried beans and oranges not as well absorbed Milk increases folate absorption!!
Cooking and storage destroy as much as 50%-90% of folate in foods Of all vitamins, most likely to interfere with medications (e.g.,antiacids, aspirine and its relatives, anticonvulsants, oral contraceptives diminish use by the body) Recommended dose for adults 400 microgram/day

Folate deficiency
Folate deficiency can result from: - insufficient intake and/or absorption (e.g., alcoholism, Crohns disease, anorexia, bulimia)
- increased requirements (pregnancy, lactation) - insufficient utilization due to other factors such as vitamin B-12 deficiency

Megaloblastic anemia caused by folate or vitamin B12 deficiency

Vitamin B12
Vitamin B-12 is required for the production of red blood cells (it helps in recycling of folate coenzymes), for the maintenance of the sheets surrounding and protecting nerve fibers
Found mainly in animal products such as meat (especially organ meats), poultry, seafood and eggs but also in fortified cereals and milk About 50% of Vitamin B-12 is absorbed by healthy adults Pernicious anemia (pernicious means leading to death) an autoimmune disorder related to production of the intrinsic factor, needed for transport and absorption of Vitamin B12

Decreased absorption of vitamin B12

Absorption can be interrupted by: - absence of: R protein, pancreatic proteases, or intrinsic factor produced in the stomach as well as defective binding of the intrinsic factor - absence of much or all of the stomach and ileum - bacterial overgrowth - tapeworm infestation - some ulcer medications (e.g., Omeprazole) - chronic malabsorption (Crohns disease, AIDS)

RBC disorders
Anemia
Deficit of RBC Low Hb levels Possible low ferritin levels Abnormal Hb (Sickle cell anemia, Thallasemia)

Polycythemia
High RBC count Can be caused by: EPO doping, low atmospheric oxygen, dehydration, etc.

Anemia = the most common disorder of the blood impairment in oxygen availability hypoxia

Anemia

Mattson Porth Essentials of Pathophysiology 2007

General Signs and Symptoms of Anemia

Increased respiration Increased heart rate Fatigue Decreased activity tolerance Pallor Murmur

Causes of anemia
1. An insufficient number of RBC Hemorrhagic anemias Aplastic anemias (destruction or inhibition of red bone marrow) 2. Low Hb content Microcytic anemia - iron deficiency anemia (also vitamin B6 deficit) Megaloblastic anemia - folate deficiency - vitamin B12 deficiency (pernicious anemia) 3. Abnormal hemoglobin Thallasemias Sickle cell anemias

RBCs in different types of anemia

Vitamin B12 and folate deficiency

Mattson Porth Essentials of Pathophysiology 2007

Stages of iron deficiency

Two stages of iron deficiency:

1. Depletion of iron stores and iron deficiency without anemia

2. Iron deficiency anemia

Iron deficiency anemia can: - reduce ability to undertake physical activity - cause disturbance in brain metabolism - cause disturbance in muscle metabolism - impair immunity and temperature control

Sports anemia
Occurs in athletes early in training program, especially after a rest period or injury or after an endurance phase of training Is not related to genuine iron deficiency but is mainly due to expanded plasma volume The phenomenon is usually transitory Does not require iron supplements

Assessment of Iron deficiency

Iron deficiency anemia can be found by performing a hematocrit (% of blood volume occupied by RBC) - values below 34%-37% suggest iron deficiency anemia Marginal deficiency anemia is not detected by hematocrit so blood ferritin measurements or transferrin receptors measurements are required - marginal anemia may cause weakness and decreased exercise performance!!!

Hematocrit

Mattson Porth Essentials of Pathophysiology 2007

Thallasemia
Thalassemias (Greek ="sea") underproduction of one of the globin chains leading to abnormal hemoglobin formation and decreased RBCs survival rates; one of the most frequent inherited disorders worldwide; transmitted in an autosomal recessive fashion

Two types of thallasemia depending on whether there is a deficient synthesis of the alpha or beta globin chains of hemoglobin: alpha-thalassemia and beta-thalassemia

Thalassemia major

Thalassemia minor

Two factors contribute to thalassemia-related anemias: - Reduction in the synthesis of hemoglobin - Imbalance in the production of the hemoglobin chains

Thallasemia
A person can be heterozygous and have a minor form, or homozygous with the associated major form of the disease -talssemia is particularly prelevant in Asian population Usually patients with - thalassemia have silent or mild to moderate signs and symptoms (infants with Barts pale, edematous, hepatomegaly, splenomegaly, ascites) Diagnosis is confirmed by electrophoresis of hemoglobin

- Thallasemia
- thalssemia is found mainly in people of Mediterranean descent (Greek islands, Italy) but is also found in Middle East and parts of India and Pakistan Signs and symptoms of - thalssemia: skull bone deformities Mongoloid faces bowing and rarefaction ( bone density) of long bones extension of bone marrow into paraspinal and intraabdominal tumours jaundice hepatomegaly, splenomegaly, cardiac failure, hypogonadism, etc.

Thallasemia treatment and complications

Treatment: Blood transfusions Splenectomy if needed Iron supplements should be avoided!!!! Bone marrow transplants

Iron toxicity in thallasemia major: hemochromatosis = iron overload due to repeated blood transfusions, saturation of iron-binding proteins and of hemosiderin in the liver tissue (can be treated by periodic blood removal or drugs enhancing excretion)

Sickle cell anemia

Sickle-cell anaemia - anemia characterized by RBC with an abnormal, rigid, sickle shape that decreases the cells' flexibility and results in their restricted movement through blood vessels and restricted delivery of oxygen More than 400 variants; large number of those are clinically silent, others give rise to major disorders

The most common, and most severe form, is the sickle cell anemia, very frequent among Blacks from the sub-Sahara Africa (9-10% are gene carriers)

Mechanism of sickling
Abnormal hemoglobins are characterised by the replacement of an amino acid in one of the chains, secondary to a mutation of a base on the DNA

Sickle-cell anemia
Complications: vascular occlusion, venous thrombosis, arterial emboli, cardiac failure, renal failure, frequent, often serious, even lethal infections (following splenic atrophy), retinopathies (due to microthrombosis), pregnancy accidents Acute episode of hemolytic or vascular crisis

Signs and symptoms

Sickle-cell anemia treatment

The disease has no widely available cure at the moment There are treatments for the symptoms and complications of the disease

New treatment strategies include bone marrow stem cell transplantations that may offer a cure in some cases; inhalation of nitirous oxide (dilate blood vessels); switching back on fetal hemoglobin production (it does not sickle)
IMPORTANT: Avoid dehydration, infections, fever, acidosis, hypoxemia and cold exposure

Thalassemia/sickle cells anemia inheritance

Polycythemia
Polycythemia
Red cell mass

Increased Normal relative polycythemia, e.g. due to dehydration Primary (Polycytemia vera)

secondary

Polycythemia abnormally high content of RBC per unit of blood