Introduction to Hematology

THE HEMATOLOGIC SYSTEM

Overview of Anatomy and Physiology The structures of the hematologic or hematopoietic system include the blood, blood vessels, and bloodforming organs (bone marrow, spleen, liver, lymph nodes, and thymus gland). The hematologic system also pays an important role in hormone transport, the inflammatory and immune responses, temperature regulation, fluid-electrolyte balance, and acid-base balance.

Hematology

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Bone Marrow A. Contained inside all bones, occupies interior of spongy bones and center of long bones; collectively one of the largest organs of the body (4%-5% of total body weight) B. Primary function is hematopoiesis (the formation of blood cells)

C. Two kinds of bone marrow, red and yellow 1. Red (functioning) marrow a. Carries out hematopoiesis; production site of erythroid, myeloid, and thrombocytic components of blood; one source of lymphocytes and macrophages b. Found in ribs, vertebral column, other flat bones

2. Yellow marrow: red marrow that has changed to fat; found in long bones; does not contribute to hematopoiesis. All blood cells start as stem cells in the bone marrow; these mature into the different, specific types of cells, collectively referred to as formed elements of blood or blood components: erythrocytes, leukocytes and thrombocytes.

Spleen
A. Largest lymphatic organ: functions as blood filtration system and reservoir. B. Vascular, bean shaped; lies beneath the diaphragm, behind and to the left of the stomach; composed of fibrous tissue capsule surrounding a network of fiber. C. Contains two types of pulp 1. Red pulp: located between the fibrous strands, composed of RBCs, WBCs, and macrophages. 2. White pulp: scattered throughout the red pulp, produces lymphocytes and sequesters lymphocytes, macrophages, and antigens

D. 1%-2% of red cell mass or 200 ml blood/minute stored in spleen; blood comes via the splenic artery to the pulp for cleansing, then passes into splenic venules that are lined with phagocytic cells, and finally to the splenic vein to the liver. E. Important hematopoietic site in fetus; postnatally produces lymphocytes and monocytes. F. Important in phagocytosis; removes misshapen erythrocytes, unwanted parts of erythrocytes.

G. Important in phagocytosis; removes misshapen erythrocytes, unwanted parts of erythrocytes. H. Also involved in antibody production by plasma cells and iron metabolism (iron released from Hgb portion of destroyed erythrocytes returned to bone marrow I. In the adult, functions of the spleen can be taken over by the reticuloendothelial system

Liver

A. Involved in bile production (via erythrocyte destruction and bilirubin production) and erythropoiesis (during fetal life and when bone marrow production is insufficient B. Kupffer cells of the liver have reticuloendothelial function as histiocytes; phagocytic activity and iron storage. C. Liver also involved in synthesis of clotting factors, synthesis of antithrombins

Blood & Its Components

Blood

Life-sustaining fluid, circulates through the heart and blood vessels

Is connective tissue Transports vital substances Maintains stability of interstitial fluid Distributes heat Oxygen & nutrients to tissues Waste products to lungs, liver & kidneys

Carry

The amount of blood varies with body size, changes in fluid concentration, changes in electrolyte concentration, and amount of adipose tissue Blood is about 8% of body weight Adult blood volume is about 5 liters

Composed of plasma (55%) and cellular components (45%)

Blood in coagulating agent Separated under influence of gravity

Centrifuged Blood Sample

Liquid (plasma) Buffy coat (white blood cells and platelets) Red blood cells

Peripheral Blood Smear White blood cells

Red blood cells

Platele ts

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Capillary tube

Plasma = 55% Buffy coat Red cells = 45% (hematocrit) Plu g

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Cellular Components Cellular components or formed elements of blood are erythrocytes (red blood cells [RBCs]), which are responsible for oxygen transport; leukocytes (white blood cells [WBCs]), which play a major role in defense against microorganisms; and thrombocytes (platelets), which function in hemostasis. A. Erythrocytes 1. Bioconcave disc shape, no nucleus, chiefly sacs of hemoglobin 2. Cell membrane is highly diffusible to O2 and CO2 3. RBCs are responsible for oxygen transport via hemoglobin (Hgb)
- Normal blood contains 12-18g Hgb/100 ml blood; higher (14-18 g) in men than in women (12-14 g)

B. Hematocrit -Reflects portion of blood composed of red blood cells -Centrifugation of blood results in separation into top layer of plasma, middle layer of leukocytes and platelets and bottom layer of erythrocytes. -Majority of formed elements is erythrocytes; volume of leukocytes and platelets is negligible C. Distribution -1300 ml in pulmonary circulation a. 400 ml arterial b. 60 ml capillary c. 840 ml venous -3000 ml in systematic circulation a. 550 ml arterial b. 300 ml capillary c. 2150 ml venous

Plasma - Liquid part of blood; yellow in color because of pigments - Consists of serum (liquid portion of plasma) and fibrinogen -Contains plasma proteins such as albumin, serum globulins, fibrinogen, prothrombin. -Albumin: largest of plasma proteins, involved in regulation of intravascular plasma volume and maintenance of osmotic pressure -Serum globulins: -. Fibrinogen,prothrombin,plasminogen

Plasma

Transport mechanism

90-92% water. 6-7% proteins 2-3%

Fats Carbohydrates (glucose) Electrolytes Gases (O2, CO2) Chemical messengers

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14.3: Blood Plasma

Blood plasma is: Straw colored The liquid portion of blood 55% of blood volume 92% water Includes transporting nutrients, gases, and vitamins Helps regulate fluid and electrolyte balance and maintain pH

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Plasma Proteins
These are the most abundant dissolved substances (solutes) in plasma

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Gases and Nutrients

The most important blood gases: Oxygen Carbon dioxide Plasma nutrients include: Amino acids Simple sugars Nucleotides Lipids Fats (triglycerides) Phospholipids Cholesterol

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Nonprotein Nitrogenous Substances

These are molecules containing nitrogen but are not proteins In plasma they include: Urea product of protein catabolism; about 50% of nonprotein nitrogenous substances Uric acid product of nucleic acid catabolism Amino acids product of protein catabolism Creatine stores phosphates Creatinine product of creatine metabolism BUN blood urea nitrogen; indicates health of kidney

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Plasma Electrolytes

Plasma contains a variety of these ions called electrolytes

They are absorbed from the intestine or released as by-products of cellular metabolism

They include: Sodium (most abundant with chloride) Potassium Calcium Magnesium Chloride (most abundant with sodium) Bicarbonate Phosphate Sulfate

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4 5 % Formed elements

Blo od

Plas ma

5 5 %

Platel ets (4. 8% )

Red blood cells (95. 1%)

White blood cells

(0. 1% )

Electrolyte s

Wat er (9 2 %)

Protei ns ( 7 % )

Waste s

Nutrie nts Vitamin s Hormon es

Ga ses

Neutrophi ls (54 62%)

Eosinophi ls (1 3%)

Basoph ils (< 1 %)

Monocyt es (3 9%)

Lymphocyt es (25 33%)

Albumi ns

Globuli ns

Fibrinog en

N 2

O 2

C O 2

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Hematopoiesis

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Blood cells originate in red marrow from hemocytoblasts or hematopoietic stem cells Stem cells can then:

Give rise to more stem cells Specialize or differentiate

Hematopoiesis The formation of blood or all types of blood cells in the living body.

The Origin of Blood Cells

Hematopoietic stem cell
Myeloid stem cell Lymphoid stem cell

Proerythrobl ast In red bone marrow Megakaryob last

Myelo blast

Mono blast

Lymphobla st T cell precursor

Lymphobla st B cell precursor

Progranulo cyte

Erythrob last

Neutrophil ic myelocyte

Basophil ic myelocy te

Eosinophil ic myelocyte

Promono cyte

Prolympho cyte

Prolympho cyte

Normo blast Megakaryo cyte Reticulo cyte Activated in tissues In circulating (some cells)blood
Neutrophil ic band cell Basophil ic band cell Eosinophil ic band cell

Erythro cyte

Thrombocyte s Neutr (platelets) ophil

Bas ophil Granuloc ytes

Eosino phil

Mono cyte

T lymphocy te Agranuloc ytes

B lymphocyt e

( a )

Macrop hage

Plasma cell

Red Blood Cells & Hemoglobin

Characteristics of Red Blood Cells

Red blood cells are: Erythrocytes Biconcave discs One-third hemoglobin or: Oxyhemoglobin Deoxyhemoglobin Able to readily squeeze through capillaries Lack nuclei and mitochondria
Top view

7.5 micrometers

2.0 micrometers Sectional view

( a )

( b b: Bill Longcore/Photo Researchers, Inc.

Hemoglobin

Function carry oxygen from lungs to tissues Transport CO2 from tissues to lungs Destroy nitric oxide molecule Structure Contain 2 pairs of unlike polypeptide chains or -like

Non- (, or )

Hemoglobin A: 22, majority normal adult Hb Hemoglobin F: 22, fetal Hb Hemoglobin A2: 22, minor component of normal adult Hb

Hemoglobin

Synthesis

Heme synthesized in mitochondria & cytosol of immature RBCs Globin in ribosome

Continues from proerythroblast to reticulocyte stages

Hemoglobin

Highly efficient in performing its transport functions

Oxygen affinity allows complete saturation with oxygen in lungs + efficient oxygen unloading in tissues Its affinity increases with oxygenation; sigmoid oxygen dissociation curve deoxyHb binds proton, oxyHb releases proton

DeoxyHb OxyHb + H+

Note the 4 protein chains that make up 1 molecule of Hb.

Note that, in muscle, myoglobin (Mb) binds oxygen. Mb consists of only 1 protein chain.

Hemoglobin

OxyHb deoxyHb CarbaminoHb CarboxyHb NitroxyHb

Erythropoiesis - The formation or production of red blood cells only.

Red blood cell or erythrocyte

erythrocyte

Note the loss of the nucleus Your baseline production of red blood cells represents about 20% of your total capacity and is the amount of production that normally occurs just to keep you healthy.

So, how many red blood cells die and must be replaced each second in your body?

Facts: 1. 25 trillion r.b.c. per person 2. r.b.c. live ~120 days

Question:

What are we trying to find?

Answer:

r.b.c./sec (r.b.c. per second)

How can this be done?

Thats right ladies and gentlemen. You guessed it!!

Its a Math Problem!!! Yeah!!!!

Additionally needed facts: (things you already know) 3. 1 day = 24 hours 4. 1 hour = 60 minutes 5. 1 minute = 60 seconds Lets begin!!

25 trillion = 25,000,000,000,000 =

2.5 x 1013

1 2 3 4 5 6 7 8 9 10 11 12 13 How can this number be converted to scientific notation?

Now remember your basic algebra! (We called it conversion factor math in Chemistry!)
2.5 x 1013 r.b.c. 1 day x 120 days x hrs 24 1 hr x 60 min 1 min =0 sec 6 2.4 x 106 r.b.c. or 2,400,000 r.b.c. or 2.4 million r.b.c.

After birth, erythropoiesis takes place in the red bone marrow in the ends of some long bones such as the femur and humerus, and in the red marrow of the ribs, vertebrae, sternum, pelvic girdle, and portions of the skull.

The need for new red blood cell production is monitored by receptor sites for blood oxygen concentration located in the kidneys (and some in the liver).

Any drop in the oxygen content of the blood will cause the kidney to secrete an enzyme that acts on a non-nutrient plasma protein to for a key hormone called erythropoietin.

Erythropoietin targets the red bone marrow and stimulates the production of red blood cells. The more hormone, the more red blood cells made. The production of red blood cells will continue until the production of erythropoietin stops.

Red Blood Cell Production and Its Control

Low blood oxygen causes the kidneys and the liver to release erythropoietin (EPO) which stimulates RBC production This is a negative feedback mechanism Within a few days many new blood cells appear in the circulating blood

Low blood oxygen Li ve r Kidn ey

Release into bloodstrea m Stimulati on Inhibiti on

Erythropoiet in Increase d oxygencarrying capacity Increase d number of red blood cells

Bloodstrea m

Red bone

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Dietary Factors Affecting Red Blood Cell Production

Vitamin B12 and folic acid are necessary They are required for DNA synthesis making them necessary for the growth and division of all cells Iron is also necessary It is required for hemoglobin synthesis

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Bo ne 3

Red bone marrow Red blood cells produced 4 Red blood cells circulate in bloodstream for about 120 days

Blood transports absorbed nutrients 1 Absorptio n

Nutrients from food Vitamin B12 Folic acid Iron

5 Macropha ge

Old red blood cells

Blo od 7 Li ve r

Hemoglob in Globin + Heme Iron + Biliverdin Bilirub in 8 B il e

Small intestin e

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Production a. Start in bone marrow as stem cells, release as reticulocytes (immature cells), mature into erythrocytes b. Erythropoietin stimulates differentiation; produced by kidneys and stimulated by hypoxia c. Iron, vitamin B12, folic acid, pyridoxine (vitamin B6), and other factors required for erythropoiesis

Hemolysis (destruction) a. Average life span 120 days b. Immature RBCs destroyed in either bone marrow or other reticuloendothelial organs (blood, connective tissue, spleen, liver, lungs and lymph nodes c. Mature cells removed chiefly by liver and spleen

d. Bilirubin: byproduct of Hgb released when RBCs destroyed, excreted in bile e. Normal age RBCs may be destroyed by gross damage as in trauma or extravascular hemolysis (in spleen, liver, bone marrow)

Leukocytes

Leukocytes: granulocytes and mononuclear cells: involved in protection from bacteria and other foreign substances 1. Granulocytes: eosinophils, basophils and neutrophils a. Eosinophils: involved in phagocytosis and allergic reactions b. Basophils: involved in prevention of clotting in microcirculation and allergic reactions c. Eosinophils and basophils are reservoirs of histamine, serotonin and heparin d. Neutrophils: involved in short-term phagocytosis 1. mature neutrophils: polymorphonuclear leukocytes 2. immature neutrophils: band cells (bacterial infection usually produces increased numbers of band cells)

2. Mononuclear cells: monocytes and lymphocytes: large nucleated cells a. Monocytes: involved in long-term phagocytosis; play a role in immune response -largest leukocyte -produced by bone marrow: give rise to histiocytes (Kupffer cells of liver), macrophages and other components of reticuloendothelial system b. Lymphocytes: immune cells; produce substances against foreign cells; produced primarily in lymph tissue (B cells) and thymus (T cells)

Neutrophils
Light purple granules in acid-base stain Lobed nucleus Other names Segs Polymorphonuclear leukocyte Bands (young neutrophils) First to arrive at infections Phagocytic 54% - 62% of leukocytes Elevated in bacterial infections

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Ed Reschke

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Eosinophils
Deep red granules in acid stain Bi-lobed nucleus Moderate allergic reactions Defend against parasitic worm infestations 1% - 3% of leukocytes Elevated in parasitic worm infestations and allergic reactions

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Ed Reschke

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Basophils
Deep blue granules in basic stain Release histamine Release heparin Less than 1% of leukocytes Similar to eosinophils in size and shape of nuclei

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Ed Reschke

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Monocytes
Largest of all blood cells Spherical, kidneyshaped, oval or lobed nuclei Leave bloodstream to become macrophages 3% - 9% of leukocytes Phagocytize bacteria, dead cells, and other debris

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R. Kessel/Visuals Unlimited

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Lymphocytes
Slightly larger than RBC Large spherical nucleus surrounded by thin rim of cytoplasm T cells and B cells Both important in immunity B cells produce antibodies 25% - 33% of leukocytes

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Ed Reschke

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Functions of White Blood Cells

WBCs protect against infection These leukocytes can squeeze between the cells of a capillary wall and enter the tissue space outside the blood vessel (called diapedesis)

Connectiv e tissue

Blood capillary Leukocy te

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Splinter punctur es epider mis

Bacteria are introduced into the dermis

Bacteri a multipl y

Injured cells release histamine, causing blood vessels to dilate

Epider mis

Der mis

Blood vessels

Neutrophils move through blood vessel walls and migrate toward bacteria

Neutrophils destroy bacteria by phagocytosis

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White Blood Cell Counts

A procedure used to count number of WBCs per cubic millimeter of blood Typically 5,000 10,000 per cubic millimeter of blood Leukopenia: Low WBC count (below 5,000) Typhoid fever, flu, measles, mumps, chicken pox, AIDS Leukocytosis: High WBC count (above 10,000) Acute infections, vigorous exercise, great loss of body fluids Differential WBC count Lists percentages of types of leukocytes May change in particular diseases

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Platelets

Blood Platelets
Platelets are also known as thrombocytes They are cell fragments of megakaryocytes They lack a nucleus and are roughly half the size of a RBC There are approximately 130,000 360,000 per cubic millimeter of blood They help repair damaged blood vessels by sticking to broken surfaces

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Thrombocytes (platelets) 1. Fragments of megakaryocytes formed in bone marrow 2. Production regulated by thrombopoietin 3. Essential factor in coagulation via adhesion, aggregation and plug formation 4. Release substances involved in coagulation

14.4: Hemostasis
Hemostasis refers to the stoppage of bleeding Actions that limit or prevent blood loss include: Blood vessel spasm Platelet plug formation Blood coagulation

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Blood Vessel Spasm

Blood vessel spasm Triggered by pain receptors, platelet release, or serotonin Smooth muscle in blood vessel contracts

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Platelet Plug Formation

Platelet plug formation Triggered by exposure of platelets to collagen Platelets adhere to rough surface to form a plug
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Endothelial lining

Collagen fiber

Break in vessel wall

Plate let

Red blood cell

Blood escaping through break

Platelets adhere to each other , to end of broken vessel, and to exposed collagen

Platelet plug helps control blood loss

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Blood Coagulation

Blood coagulation Triggered by cellular damage and blood contact with foreign surfaces A blood clot forms This is a: Hemostatic mechanism Causes the formation of a blot clot via a series of reactions which activates the next in a cascade Occurs extrinsically or intrinsically
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Extrinsic Clotting Mechanism

Extrinsic clotting mechanism Chemical outside of blood vessel triggers blood coagulation Triggered by tissue thromboplastin (factor III) (not found in blood) A number of events occur that includes factor VII, factor X, factor V, factor IV, and factor II (prothrombin) Triggered when blood contacts damaged blood vessel walls or tissues This is an example of a positive feedback mechanism

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SPL/Photo Researchers, Inc.

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Intrinsic Clotting Mechanism

Intrinsic clotting mechanism Chemical inside blood triggers blood coagulation Triggered by Hageman factor XII (found inside blood) Factor XII activates factor XI which activates IX which joins with factor VIII to activate factor X Triggered when blood contacts a foreign surface
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Extrinsic Clotting Mechanism Tissue damage Relea ses Tissue thromboplastin (Factor lll) Activat es (C a+ 2) Factor Vll Activat (C es a+ 2) Facto rX Facto rV Activat es (C a+ 2)

Intrinsic Clotting Mechanism Blood contacts foreign surface Activat es Hageman Factor Xll Activat es Factor Xl Activat es Factor lX Activat es (C a+ Facto2) rX Activat es (C a+ 2)

Factor Vlll platelet phospholipids

Facto rV

Prothrombin (Factor ll)

Prothrombin activator Conve rts

Thrombin (Factor lla) Conve rts Fib rin Stabiliz es Factor Xlll

Fibrinoge n (Factor l)

Fibri n

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Fate of Blood Clots

After a blood clot forms it retracts and pulls the edges of a broken blood vessel together while squeezing the fluid serum from the clot Platelet-derived growth factor stimulates smooth muscle cells and fibroblasts to repair damaged blood vessel walls Plasmin digests the blood clots A thrombus is an abnormal blood clot An embolus is a blood clot moving through the blood vessels

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( a )

Lum en

Artery wall

The McGraw-Hill Companies, Inc./Al Telser, photographer b

( )

Lum en

Plaq ue

Artery wall

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Blood Groups A. Erythrocytes carry antigens, which determine the different blood groups. B. Blood-typing systems are based on the many possible antigens, but the most important are antigens of the ABO and Rh blood groups because they are most likely to be involved I transfusion reactions.

1. ABO typing a. Antigens of system are labelled A and B b. Absence of both antigens results in type O blood c. Presence of both antigens is type AB d. Presence of either A or B results in type A and type B respectively e. Nearly half the population is type O, the universal donor f. Antibodies are automatically formed against the ABO antigens not on persons own RBCS; transfusion with mismatched or incompatible blood results in a transfusion reaction

2. Rh typing a. Identifies presence or absence of Rh antigen (Rh positive or Rh negative). b. Anti-Rh antibodies not automatically formed in Rhnegative person, but if Rh-positive blood is given, antibody formation starts and a second exposure to Rh antigen will trigger a transfusion reaction. c. Important for Rh-negative woman carrying Rh-positive baby; first pregnancy not affected, but in a subsequent pregnancy with an Rh-positive positive baby, mothers antibodies attack babys RBCs.

Blood Coagulation- conversion of fluid blood into a solid clot to reduce blood loss when blood vessels are ruptured.

14.5: Blood Groups and Transfusions

In 1910, identification of the ABO blood antigen gene explained the observed blood type incompatibilities Today there are 31 different genes known to contribute to the surface features of RBCs determining compatibility between blood types

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Antigens and Antibodies

Terms to become familiar with: Agglutination clumping of red blood cells in response to a reaction between an antibody and an antigen Antigens a chemical that stimulates cells to produce antibodies Antibodies a protein that reacts against a specific antigen

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Red blood cell Antigen A

Anti-B antibody Antigen B

Red blood cell

Anti-A antibody

Type A blood Red blood cell Anti-A antibody

Type B blood Anti-B antibody

Antigen A Antigen B

Red blood cell Type AB blood Type O blood

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Antigen A

Red blood cell

Agglutinated red blood cells

Anti-B antibody ( a )

Anti-A antibody ( b )

( c )

( d c: G.W. Willis/Visuals Unlimited; figure d: George W. Wilder/Visuals Unlimited )

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14.1 From Science to Technology

Blood Typing and Matching: From Serology to DNA Chips

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ABO Blood Group

Based on the presence or absence of two major antigens on red blood cell membranes Antigen A Antigen B

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Rh Blood Group
The Rh blood group was named for the rhesus monkey The group includes several Rh antigens or factors Rh positive presence of antigen D or other Rh antigens on the red blood cell membranes Rh negative lack of these antigens The seriousness of the Rh blood group is evident in a fetus that develops the condition erythroblastosis fetalis or hemolytic disease of the newborn

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+ + + + + + + + + Rhnegative woman with Rhpositive fetus

++ + ++ + + + + + + + + + + + + + + Cells from Rh-positive fetus enter womans bloodstrea m

+ Woman becomes sensitized antibodies ( + ) form to fight Rh-positive blood cells

In the next Rh-positive pregnancy, maternal antibodies attack fetal red blood cells

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Important Points Outcomes to be Assessed

14.1: Introduction Describe the general characteristics of blood and discuss its major functions.

Distinguish among the formed elements of blood and the liquid portion of blood.

14.2: Blood Cells

Describe the origin of blood cells.

Explain the significance of red blood cells counts and how they are used to diagnose disease.

Discuss the life cycle of a red blood cell. Summarize the control of red blood cell production.
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Important Points Outcomes to be Assessed

Distinguish among the five types of white blood cells and give the function(s) of each type.

Describe a blood platelet and explain its functions. Describe the functions of each of the major components of plasma. Define hemostasis and explain the mechanisms that help to achieve it. Review the major steps in coagulation. Explain how to prevent coagulation.

14.3: Blood Plasma

14.4: Hemostasis

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Important Points Outcomes to be Assessed

14.5: Blood Groups and Transfusions Explain blood typing and how it is used to avoid adverse reactions following blood transfusions.

Describe how blood reactions may occur between fetal and maternal tissues.

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