Introduction to Introduction to HematologyHematology

What is What is hematologyhematology??

Hematology is the study of blood.Hematology is the study of blood. Blood: is the fluid where the cells Blood: is the fluid where the cells

are free and suspended.are free and suspended.It can cross the tissues.It can cross the tissues.has red color.has red color.Has volume of 5-6 liters, this is 7-Has volume of 5-6 liters, this is 7-

8% of the total body weight.8% of the total body weight.

Has PH of 7.3-7.4 (alkaline).Has PH of 7.3-7.4 (alkaline).Specific gravity is 1.055-1.056Specific gravity is 1.055-1.056 It is composed of plasma (~53-58% It is composed of plasma (~53-58%

of the blood volume), before of the blood volume), before clotting occurs, and serum after clotting occurs, and serum after clotting occurs.clotting occurs.

Plasma consists of 91-92% water, Plasma consists of 91-92% water, and 8-9%solids.and 8-9%solids.

Solids are:Solids are: Albumin. Albumin. Glucose.Glucose. Fibrinogen.Fibrinogen. Sodium.Sodium. Calcium.Calcium. Potassium. Potassium. Cholesterol.Cholesterol. Magnesium.Magnesium. Carbon dioxide.Carbon dioxide. Phosphorus.Phosphorus.

Neutral fats. Neutral fats. NPN group.NPN group. Oxygen.Oxygen. Many other Many other

products.products.

Also there are such substances, like Also there are such substances, like antibodies, hormones, complement and antibodies, hormones, complement and enzymes.enzymes.

Cellular parts of the blood (45-47%):Cellular parts of the blood (45-47%): Consists of:Consists of:

– The erythrocytes (RBCs) (~45%)The erythrocytes (RBCs) (~45%)Contain hemoglobin Contain hemoglobin Function in the transport of OFunction in the transport of O22 and and

COCO22

•The LeukocytesThe Leukocytes

(WBCs) and platelets (WBCs) and platelets (thrombocytes) (~1%)(thrombocytes) (~1%)Leukocytes are involved in the Leukocytes are involved in the body’s defense against the invasion body’s defense against the invasion of foreign antigens.of foreign antigens.

PlateletsPlatelets

are involved in hemostasis which are involved in hemostasis which forms a barrier to limit blood loss forms a barrier to limit blood loss at an injured site.at an injured site.

The cells are forming about 45-47% The cells are forming about 45-47% of the total blood volume in male and of the total blood volume in male and 42% in female. This percentage is 42% in female. This percentage is determined by centrifugation and is determined by centrifugation and is known as heamatocrit (PCV), which known as heamatocrit (PCV), which is the percentage of the packed red is the percentage of the packed red blood cells.blood cells.

Functions of the bloodFunctions of the blood::

1.1. Nutritive: The blood transports Nutritive: The blood transports nutrients from the gut to all parts of nutrients from the gut to all parts of the body for use or storage.the body for use or storage.

2.2. Respiratory: the blood carries the Respiratory: the blood carries the oxygen to the tissue and remove oxygen to the tissue and remove carbon dioxide and other waste carbon dioxide and other waste products from the tissues to be products from the tissues to be excreted by the lung, kidney, liver, excreted by the lung, kidney, liver, and skinand skin

3- 3- The blood regulates the temperature of the The blood regulates the temperature of the body, because it is constantly in motion.body, because it is constantly in motion.

4- Transportive: The blood transports the 4- Transportive: The blood transports the hormones from the endocrine glands to the hormones from the endocrine glands to the tissues.tissues.

5- Excretory: To excrete the waste products 5- Excretory: To excrete the waste products of metabolism, for example urea, and uric of metabolism, for example urea, and uric acid.acid.

6- Protection: versus invading microorganisms

Blood Cell Production (Hematopoiesis or

hemopoiesis) Hematopoiesis is a term describing the

formation and development of blood cells. In humans, occurs in bone marrow

exclusively All cellular elements derived from

pluripotent stem cell (PPSC) PPSC retains ability to both replicate itself and

differentiate Types of differentiation determined by the

influence of various cytokines Only mature cells are released into the

peripheral blood.

Why do we need the Hematopoiesis?

– Cells of the blood are constantly being

lost or destroyed. Thus, to maintain

homeostasis, the system must have the

capacity for self renewal.

Sites of productionSites of production::

– Fetus: Fetus: 0-2 months (yolk sac).0-2 months (yolk sac).

2-7 months ( liver and 2-7 months ( liver and spleen).spleen).

5-9 months (bone marrow).5-9 months (bone marrow).– infants: bone marrowinfants: bone marrow– Adults: bone marrow, ribs, sternum, Adults: bone marrow, ribs, sternum,

skull, sacrum and pelvis.skull, sacrum and pelvis.

– Hematopoiesis in the bone marrow is Hematopoiesis in the bone marrow is called called medullary hematopoiesismedullary hematopoiesis

– Hematopoiesis in areas other then Hematopoiesis in areas other then the bone marrow is called the bone marrow is called extramedullary hematopoiesisextramedullary hematopoiesis

– Extramedullary hematopoiesis may occur in fetal hematopoietic tissue (liver and spleen), and in adult when the bone marrow cannot meet the physiologic needs of the tissues. This can lead to hepatomegaly and/or splenomegaly (increase in size of the liver or spleen because of increased functions in the organs).

Hematopoietic tissues ARE:Hematopoietic tissues ARE:

Includes tissues involved in the Includes tissues involved in the proliferation, maturation, and proliferation, maturation, and destruction of blood cellsdestruction of blood cells

Derivation of blood cells

- The committed lymphoid stem cells will be involved in lymphopoiesis to produce lymphocytes- The committed myeloid stem cell can differentiate into any of the other hematopoietic cells including erythrocytes, neutrophils, eosinophils, basophils, monocytes, macrophages, and platelets.

 

1. Erythrocyte:

• Normal erythrocyte is a round highly flexible biconcave

discs like cell; it is non-nucleated, containing haemoglobin.

• It measures about 7.2-7.8 microns, 80-100 femtoliters in

volume

• Flexibility essential for passage through capillaries

• Life span: the average is 80-120 days.

• Function: RBC carry oxygen from the lung to the body

cells and carry carbon dioxide from the body cells to the

lung.

Terminology: Erythrocytosis: increased in the blood cells count,

which may lead to Reticulocyte: is a very young erythrocyte which

contains remainant of RNA. The precipitated RNA is seen when stained with a supravital stain such as new methylene blue or brilliant crystal blue dyes.

Reticulocytosis: increased blood reticulocyte count. Thrombocytopenia : decrease platelets number in the

blood Thrombocytosis: increase platelets number in the

blood

1. Splenectomy (removal of the spleen), Hypersplenism

(splenomegaly) – in a number of conditions the spleen may

become enlarged.

2. Leukopenia decreased WBCs count.

3. Leukocytosis: increased WBCs count.

4. Pancytopenia: when all three cell types are decreased, which

may lead to anaemia.

5. Polycythemia which is an increasing in the Hg concentration

above 17.5 g/dl in adult males and 15.5 g/dl in adult females,

with elevated haematocrit and RBCs count.

Blood Cell Production Blood Cell Production (Hemopoiesis)(Hemopoiesis)

Red bone marrow produces RBCs, WBCs and platelets

Stem cells called hemocytoblasts multiply continually and are pluripotent (capable of differentiating into multiple cell lines) committed cells are destined to continue down one specific cell line

Stimulated by different Cytokines: erythropoietin, thrombopoietin and colony stimulating factors (CSFs).

B. Erythropoietin and Its B. Erythropoietin and Its ReceptorReceptor : :

Cytokine – 90% is produced in the kidney and the rest is produced in a variety of extrarenal sites.

Necessary for erythroid proliferation and differentiation

Absence results in apoptosis (programmed cell death) of erythroid committed cells

Anemia of renal failure leads to lack of EPO

The signal that causes erythropoietin-secreting cells to synthesize and release the cytokine is hypoxia.

Whenever the oxygen level within the cytoplasm of erythropoietin-producing cells falls below a critical level, erythropoietin is synthesized in the kidney and secreted into the bloodstream.

Once synthesized and released from the cell, erythropoietin travels in the bloodstream to the bone marrow, where it binds to receptors on erythroid cells, thereby initiating their proliferation and differentiation.

Erythrocyte Homeostasis:

Classic negative feedback controlHypoxemia in kidneys leads to increased EPO production Stimulation of bone marrowRBC count ↑ in 3-4 days

Stimuli for erythropoiesis

Low levels of O2 Increase in exerciseHemorrhaging

RBC Precursors

 

1.Pronormoblast or Proerythroblast.

2.Basophilic (early) normoblast

3.Polychromatophilic (intermediate) Normoblast

4.Orthrochromatophilic ( late) Normoblast

5.Reticulocyte

6.Mature Red Blood Cell

Erythrocyte Production

Erythropoiesis produces 2.5 million RBCs/second from stem cells (hemocytoblasts) in bone marrow

Pronormoblast has receptors for erythropoietin (EPO) from kidneys; EPO stimulates development of erythroblast

Erythroblasts multiply & synthesize hemoglobin (late normoblast and reticulocyte).

Late Normoblasts discarddiscard their nucleus to form a reticulocyte (named for fine network of endoplasmic reticulum)

Reticulocyte Enters bloodstream as 0.5 to 1.5% of circulating RBCs

Development takes 3-5 days This mechanism will involve reduction in cell

size, increase in cell number, synthesis of hemoglobin & loss of nucleus

Blood loss speeds up the process increasing reticulocyte count

RETICULOCYTE: Young red blood cell; still have small amounts of

RNA present in their cytoplasm Tend to stain somewhat bluer than mature RBC’s

on Wright stain (polychromatophilic) Slightly larger than mature RBC Undergo removal of RNA on passing through

spleen, in 1st day of life Can be detected using supravital stain

Nutritional Needs for Erythropoiesis

Iron :is key nutritional requirement for erythropoiesisLost daily through urine, feces, and bleedingDietary iron in 2 forms: ferric (Fe+3) and ferrous (Fe+2)Stomach acid converts Fe+3 to absorbable Fe+2Gastroferritin from stomach binds Fe+2 & transports it to intestine

Absorbed into blood & binds to Absorbed into blood & binds to transferrintransferrin to travel bone marrow to travel bone marrow uses to make uses to make hemoglobinhemoglobin, , musclemuscle used used to make myoglobin and all cells use to to make myoglobin and all cells use to make make cytochromescytochromes in mitochondria in mitochondria

Liver binds surplus to apoferritin to Liver binds surplus to apoferritin to create ferritin for storagecreate ferritin for storage

2-B12 & folic acid2-B12 & folic acid (for rapid cell division).(for rapid cell division).3-Vitamin C & copper 3-Vitamin C & copper (for cofactors for (for cofactors for

enzymes synthesizing RBCs)enzymes synthesizing RBCs)

22 - -Leukocyte Production Leukocyte Production (Leukopoiesis)(Leukopoiesis)

Committed cell types -- B and T progenitor Committed cell types -- B and T progenitor lymphocytes and granulocyte-macrophage lymphocytes and granulocyte-macrophage colony-forming unitscolony-forming units

Possess receptors for colony-stimulating Possess receptors for colony-stimulating factors released by factors released by mature WBCs in in response to infectionsresponse to infections

Red bone marrowRed bone marrow stores and releases stores and releases granulocytes and monocytesgranulocytes and monocytes

Some lymphocytes leave bone marrow Some lymphocytes leave bone marrow unfinished go to unfinished go to thymusthymus to complete their to complete their development (T cells)development (T cells)

Circulating WBCs do not stay in Circulating WBCs do not stay in bloodstreambloodstream

Granulocytes leave in 8 hours & live Granulocytes leave in 8 hours & live 5 days longer5 days longer

Monocytes leave in 20 hours, Monocytes leave in 20 hours, transform into macrophages and live transform into macrophages and live for several yearsfor several years

WBCs providing long-term immunityWBCs providing long-term immunity (lymphocytes) last decades(lymphocytes) last decades

Leukocyte Descriptions (WBCs)Leukocyte Descriptions (WBCs) GranulocytesGranulocytes

– eosinophils - 2-4%eosinophils - 2-4%– basophils - <1%basophils - <1%– neutrophils - 60-70%neutrophils - 60-70%

AgranulocytesAgranulocytes– Lymphocytes (B and T cells) - 25-Lymphocytes (B and T cells) - 25-

33%33%– Monocytes - 3-8%Monocytes - 3-8%

Granulocyte FunctionsGranulocyte Functions

Neutrophils Neutrophils (↑ in bacterial infections)(↑ in bacterial infections) Phagocytosis of bacteriaPhagocytosis of bacteria Releases antimicrobial chemicalsReleases antimicrobial chemicals

Eosinophils Eosinophils ↑ ↑ in parasitic infections or allergiesin parasitic infections or allergies Phagocytosis of antigen-antibody complexes, allergens Phagocytosis of antigen-antibody complexes, allergens

& inflammatory chemicals& inflammatory chemicals

Release enzymes destroy parasites such as wormsRelease enzymes destroy parasites such as wormsBasophils Basophils (↑ in chicken pox, sinusitis, diabetes)(↑ in chicken pox, sinusitis, diabetes) Secrete histamine (vasodilator)Secrete histamine (vasodilator) Secrete heparin (anticoagulantSecrete heparin (anticoagulant

Agranulocyte FunctionsAgranulocyte Functions

Lymphocytes (↑ in diverse infections & immune Lymphocytes (↑ in diverse infections & immune responses)responses)

Destroy cancer & foreign cells & virally infected Destroy cancer & foreign cells & virally infected cellscells

““Present” antigens to activate other immune cellsPresent” antigens to activate other immune cells Coordinate actions of other immune cellsCoordinate actions of other immune cells Secrete antibodies & provide immune memorySecrete antibodies & provide immune memory

Monocytes (↑ in viral infections & inflammation)Monocytes (↑ in viral infections & inflammation) Differentiate into macrophagesDifferentiate into macrophages Phagocytize pathogens and debrisPhagocytize pathogens and debris ““Present” antigens to activate other immune cells Present” antigens to activate other immune cells

(APC)(APC)

Platelet Production (Thrombopoiesis)Platelet Production (Thrombopoiesis)

Hemocytoblasts that develop receptors for Hemocytoblasts that develop receptors for thrombopoietinthrombopoietin from from liver or kidney liver or kidney become megakaryoblastsbecome megakaryoblasts

Megakaryoblasts repeatedly replicates its Megakaryoblasts repeatedly replicates its DNA without dividing forms gigantic cell DNA without dividing forms gigantic cell that remains in bone marrow called that remains in bone marrow called megakaryocyte (100 μm in diameter)megakaryocyte (100 μm in diameter)

Infoldings of megakaryocyte cytoplasm Infoldings of megakaryocyte cytoplasm splits off cell fragments that enter the splits off cell fragments that enter the bloodstream as platelets (live for 10 days)bloodstream as platelets (live for 10 days)

Some stored in spleen and released as Some stored in spleen and released as neededneeded

PlateletsPlatelets

Small fragments of megakaryocyte Small fragments of megakaryocyte cytoplasmcytoplasm

2-4 μm diameter & containing 2-4 μm diameter & containing “granules”“granules”

Pseudopods provide amoeboid Pseudopods provide amoeboid movement & phagocytosismovement & phagocytosis

FunctionsFunctions::

Secrete clotting factors, growth Secrete clotting factors, growth factors for endothelial repair, and factors for endothelial repair, and vasoconstrictors in broken vesselsvasoconstrictors in broken vessels

Form temporary platelet plugsForm temporary platelet plugs Dissolve old blood clotsDissolve old blood clots Phagocytize bacteriaPhagocytize bacteria Attract WBCs to sites of inflammationAttract WBCs to sites of inflammation