HEMATOPOIESISHEMATOPOIESIS

Dr. Talib Hussein KamoonaDr. Talib Hussein Kamoona

Assistant ProfessorAssistant Professor

HEMATOPOIESISHEMATOPOIESIS

• Hemato: Referring to blood cells• Poiesis: “The development or

production of”• The word Hematopoiesis refers to the

production & development of all the blood cells: – Erythrocytes: Erythropoiesis – Leucocytes: Leukopoiesis– Thrombocytes: Thrombopoiesis.

CLONAL HYPOTHESISPLURIPOTENT STEM CELL

STEM CELL

MULTIPLICATION COMMITTMENT

COMMITTEDSTEM CELL

COMMITTEDSTEM CELL

MULTIPLICATION

PROGENITOR CELL

CFU: COLONYFORMING UNIT

Myeloid (blood producing) tissue is Myeloid (blood producing) tissue is found in the found in the red bone marrow red bone marrow located in the spongy bonelocated in the spongy bone . .

As a person ages much of this As a person ages much of this marrow becomes fatty and ceases marrow becomes fatty and ceases production. But it retains stem cells production. But it retains stem cells and can be called on to regenerate and can be called on to regenerate and produce blood cells later in an and produce blood cells later in an emergency. RBCs enter the blood at emergency. RBCs enter the blood at a rate of about a rate of about 2 million cells per 2 million cells per secondsecond . .

Production of Red Blood Cells BodyProduction of Red Blood Cells Body

Areas of the Body That Produce Red Areas of the Body That Produce Red Blood CellsBlood Cells . .

In the early weeks of embryonic life- In the early weeks of embryonic life- yolk yolk sacsac..

During the middle trimester of gestation: During the middle trimester of gestation: liverliver (main), (main), spleenspleen and and lymph nodes lymph nodes (additional sites)(additional sites)..

Then, during the last month of gestation Then, during the last month of gestation and after birth: exclusively in and after birth: exclusively in bone bone marrowmarrow-.-.

Till 5 yrs age: The bone marrow of Till 5 yrs age: The bone marrow of essentially all bonesessentially all bones

55 –– 2020 years age- The marrow of the long years age- The marrow of the long bones, becomes fatty and produces no bones, becomes fatty and produces no more red blood cells after about age more red blood cells after about age 20 years20 years . .

Beyond 20 years, most red cells are Beyond 20 years, most red cells are produced in the marrow of the produced in the marrow of the membranous bones, such as the membranous bones, such as the vertebrae, sternum, ribs, and iliavertebrae, sternum, ribs, and ilia . .

Genesis of Blood CellsGenesis of Blood Cells

Pluripotential Hematopoietic Stem Pluripotential Hematopoietic Stem Cells, Growth Inducers, and Cells, Growth Inducers, and Differentiation InducersDifferentiation Inducers . .

The blood cells begin their lives in the The blood cells begin their lives in the bone marrow from bone marrow from pluripotential pluripotential hematopoietic stem cell (PHSC)hematopoietic stem cell (PHSC)..

There are successive divisions of the There are successive divisions of the pluripotential cells to form the pluripotential cells to form the different circulating blood cellsdifferent circulating blood cells . .

The intermediate-stage cells are very The intermediate-stage cells are very much like the pluripotential stem much like the pluripotential stem cells, but are committed to a cells, but are committed to a particular line of cells and are called particular line of cells and are called committed stem cellscommitted stem cells..

AnemiasAnemias Anemia means deficiency of hemoglobin in the Anemia means deficiency of hemoglobin in the blood, which can be caused byblood, which can be caused by : :

.1.1Blood Loss AnemiaBlood Loss Anemia . ..a.aAfter rapid hemorrhage, the body replaces the After rapid hemorrhage, the body replaces the

fluid portion of the plasma in 1 to 3 days, but this fluid portion of the plasma in 1 to 3 days, but this leaves a low concentration of red blood cells. The leaves a low concentration of red blood cells. The Hb returns to normal by 3 to 6 weeksHb returns to normal by 3 to 6 weeks..

.b.bIn chronic blood loss, a person frequently cannot In chronic blood loss, a person frequently cannot absorb enough iron from the intestines to form absorb enough iron from the intestines to form hemoglobin as rapidly as it is lost. Red cells are hemoglobin as rapidly as it is lost. Red cells are then produced that are much smaller than normal then produced that are much smaller than normal and have too little hemoglobin inside them, giving and have too little hemoglobin inside them, giving rise to rise to microcytic, hypochromic anemia,microcytic, hypochromic anemia, which is which is shown in Figure in next slideshown in Figure in next slide..

22 . .Aplastic Anemia. Aplastic Anemia. Bone marrow aplasiaBone marrow aplasia means means lack oflack of

functioning bone marrow. For instance, a person functioning bone marrow. For instance, a person exposed to gamma ray radiation from a nuclear exposed to gamma ray radiation from a nuclear bomb blast can sustain complete destruction of bomb blast can sustain complete destruction of bone marrowbone marrow

33 . .Megaloblastic AnemiaMegaloblastic Anemia . .

Deficiency of Vitamin BDeficiency of Vitamin B1212, folic acid, and , folic acid, and absence of intrinsic factor from the absence of intrinsic factor from the stomach mucosa lead to slow stomach mucosa lead to slow reproduction of erythroblasts in the bone reproduction of erythroblasts in the bone marrowmarrow . .

As a result, the red cells grow too large, As a result, the red cells grow too large, with odd shapes, and are called with odd shapes, and are called megaloblastsmegaloblasts..

Thus, atrophy of the stomach mucosa, as Thus, atrophy of the stomach mucosa, as occurs in occurs in pernicious anemia,pernicious anemia, or loss of or loss of the entire stomach after surgical total the entire stomach after surgical total gastrectomy can lead to megaloblastic gastrectomy can lead to megaloblastic anemiaanemia..

Also, patients who have intestinal sprue, Also, patients who have intestinal sprue, in which folic acid, vitamin Bin which folic acid, vitamin B1212, and other , and other vitamin B compounds are poorly vitamin B compounds are poorly absorbed, develop megaloblastic anemiaabsorbed, develop megaloblastic anemia . .

44 . .Hemolytic Anemia. Due to Breakdown Hemolytic Anemia. Due to Breakdown of RBCsof RBCs . .

Inherited defects of Red cell membrane Inherited defects of Red cell membrane make the cells fragile, so that they make the cells fragile, so that they rupture easily as they go through the rupture easily as they go through the capillaries, especially through the spleencapillaries, especially through the spleen . .The number of red blood cells formed The number of red blood cells formed may be normal in hemolytic diseases but may be normal in hemolytic diseases but the life span of the fragile red cell is so the life span of the fragile red cell is so short that the cells are destroyed faster short that the cells are destroyed faster than they can be formedthan they can be formed . .EgEg a. a. hereditary spherocytosis-hereditary spherocytosis- the red cells the red cells are very small and are very small and sphericalspherical rather than rather than being biconcave discs. These cells cannot being biconcave discs. These cells cannot withstand compression forces because withstand compression forces because they do not have the normal loose, they do not have the normal loose, baglike cell membrane structure of the baglike cell membrane structure of the biconcave discs. On passing through the biconcave discs. On passing through the splenic pulp and some other tight splenic pulp and some other tight vascular beds, they are easily ruptured by vascular beds, they are easily ruptured by even slight compressioneven slight compression . .

b. b. Sickle cell anemiaSickle cell anemia-- The RBCs have an abnormal type of hemoglobin The RBCs have an abnormal type of hemoglobin called called hemoglobin S,hemoglobin S, containing faulty beta containing faulty beta chains in the hemoglobin moleculechains in the hemoglobin molecule,,When this hemoglobin is exposed to low When this hemoglobin is exposed to low concentrations of oxygen, it precipitates into long concentrations of oxygen, it precipitates into long crystals inside the red blood cellcrystals inside the red blood cell . .

These crystals elongate the cell and give it the These crystals elongate the cell and give it the appearance of a sickle rather than a biconcave appearance of a sickle rather than a biconcave disc. The precipitated hemoglobin also damages disc. The precipitated hemoglobin also damages the cell membrane, so that the cells become the cell membrane, so that the cells become highly fragile, leading to serious anemiahighly fragile, leading to serious anemia . .

Such patients frequently experience a circle of Such patients frequently experience a circle of events called a sickle cell disease events called a sickle cell disease ““sicke cell sicke cell crisis," in which low oxygen tension in the tissues crisis," in which low oxygen tension in the tissues causes sickling, which leads to ruptured red cells, causes sickling, which leads to ruptured red cells, which causes a further decrease in oxygen which causes a further decrease in oxygen tension and still more sickling and red cell tension and still more sickling and red cell destructiondestruction . .

c. Erythroblastosis fetalis,c. Erythroblastosis fetalis, Rh-positive red blood Rh-positive red blood cells in the fetus are attacked by antibodies from cells in the fetus are attacked by antibodies from an Rh-negative mother. These antibodies make an Rh-negative mother. These antibodies make the Rh-positive cells fragile, leading to rapid the Rh-positive cells fragile, leading to rapid rupture and causing the child to be born with rupture and causing the child to be born with serious anemiaserious anemia . .

Effects of Anemia on Function of the Effects of Anemia on Function of the Circulatory SystemCirculatory System . .The blood viscosity fallsThe blood viscosity falls . .

This decreases the resistance to blood This decreases the resistance to blood flow in the peripheral blood vessels, so flow in the peripheral blood vessels, so that far greater than normal quantities that far greater than normal quantities of blood flow through the tissues and of blood flow through the tissues and return to the heart, thereby greatly return to the heart, thereby greatly increasing cardiac outputincreasing cardiac output . .

Moreover, hypoxia resulting from Moreover, hypoxia resulting from diminished transport of oxygen by the diminished transport of oxygen by the blood causes the peripheral tissue blood causes the peripheral tissue blood vessels to dilate, allowing a blood vessels to dilate, allowing a further increase in the return of blood further increase in the return of blood to the heart and increasing the cardiac to the heart and increasing the cardiac output to a still higher level-output to a still higher level-sometimes three to four times normalsometimes three to four times normal..Thus, one of the major effects of anemia Thus, one of the major effects of anemia is greatly is greatly increased cardiac output,increased cardiac output, as as well as well as increased pumping workload increased pumping workload on the hearton the heart . .

55 . .When a person with anemia begins When a person with anemia begins to exercise, the heart is not capable of to exercise, the heart is not capable of pumping much greater quantities of pumping much greater quantities of blood than it is already pumping. blood than it is already pumping. Consequently, during exercise, which Consequently, during exercise, which greatly increases tissue demand for greatly increases tissue demand for oxygen, extreme tissue hypoxia oxygen, extreme tissue hypoxia results, and results, and acute cardiac failureacute cardiac failure ensuesensues

CCLASSIFICATIONLASSIFICATION OFOF LLEUCOCYTESEUCOCYTES

LEUCOCYTES100

GRANULOCYTES AGRANULOCYTES

EOSINOPHILS2.3

BASOPHILS0.4

NEUTROPHILS62

MONOCYTES 5.3

LYMPHOCYTES30

EOSINOPHILS33 –– 8%8% of the of the

LeucocytesLeucocytes..Have a typical Have a typical

‘‘Spectacle Spectacle shapedshaped’’, bilobed , bilobed

nucleusnucleus..Have coarseHave coarse

bright pinkbright pink staining staining granulesgranules in the cytoplasmin the cytoplasm..

LYMPHOCYTES:LYMPHOCYTES: IMMUNOCYTESIMMUNOCYTES

MorphologicallyMorphologically,,LARGE LARGE

LymphocytesLymphocytes : :Sized about 12 – Sized about 12 –

15 15 µµThin cytoplasmic Thin cytoplasmic

rimrimLarge spherical Large spherical

nucleusnucleusNo cytoplasmic No cytoplasmic

granulesgranules..

LYMPHOCYTES: LYMPHOCYTES: IMMUNOCYTESIMMUNOCYTES

SmallSmall LymphocytesLymphocytes::

Sized about 8 Sized about 8 µµ.. ( (Smallest Smallest

LeucocytesLeucocytes))Thin cytoplasmic Thin cytoplasmic

rim & Large rim & Large spherical spherical

nucleusnucleus..No granules No granules

visiblevisible..

Aplastic AnemiaAplastic Anemia

Bone Marrow Failure & ↓ cells Bone Marrow Failure & ↓ cells productionproduction

Better called Hypoplastic Anemia ( Better called Hypoplastic Anemia ( rarity of total bone marrow rarity of total bone marrow aplasia)aplasia)

This leads to failure of production This leads to failure of production of various cell lineages (Anemia, of various cell lineages (Anemia, Leukopenia & Leukopenia & Thrombocytopenia)Thrombocytopenia)

EtiologyEtiology

I. Hereditary II. AcquiredI. Hereditary II. AcquiredHereditary Hereditary –– e.g. Fanconi Aplastic Anemia e.g. Fanconi Aplastic Anemia

Acquired Acquired –– Idiopathic Idiopathic

-- -- Radiation ExposureRadiation Exposure

-- -- Chemicals e.g. BenzeneChemicals e.g. Benzene

-- -- Drugs e.g. Chloramphenicol, Cytotoxic drugs, Drugs e.g. Chloramphenicol, Cytotoxic drugs, gold saltsgold salts

-- -- Viruses e.g. Parvovirus B19, EBV, HBV, HIVViruses e.g. Parvovirus B19, EBV, HBV, HIV

-- -- Bone marrow destruction & infiltration e.g. Bone marrow destruction & infiltration e.g. OsteopetrosisOsteopetrosis

-- -- Paroxysmal Nocturnal Hburia (PNH)Paroxysmal Nocturnal Hburia (PNH)

-- -- Conn ts dis e.g. SLEConn ts dis e.g. SLE

-- -- PregnancyPregnancy

Fanconi AnemiaFanconi Anemia

* *AR inheritanceAR inheritance

* *11stst described by Fanconi 1927 (3 described by Fanconi 1927 (3 brothers)brothers)

* *Defect in genes modulating DNA Defect in genes modulating DNA stabilitystability

* *After 5 y age After 5 y age –– anemia, bleeding, caf anemia, bleeding, caféé au lait skin pigmentation, short au lait skin pigmentation, short stature, microcephaly, hypoplastic stature, microcephaly, hypoplastic thumb, dysplastic radii, mental thumb, dysplastic radii, mental retardation, hypogonadismretardation, hypogonadism

Clinical Features Clinical Features Aplastic AnAplastic An

* *Gradual onsetGradual onset

* *Pallor, easy fatigue, SOB, Skin Pallor, easy fatigue, SOB, Skin bruises, epistaxis, vaginal bruises, epistaxis, vaginal bleeding, CNS hgbleeding, CNS hg

* *Fever, chills, pharyngitisFever, chills, pharyngitis

* *No splenomegaly or LNNo splenomegaly or LN

DXDX

CBC CBC –– Pancytopenia (Anemia, Pancytopenia (Anemia, Leukopenia, Thrombocytopenia)Leukopenia, Thrombocytopenia)

-- -- Low reticulocyte countLow reticulocyte count

-- -- relative lymphocytosisrelative lymphocytosis

BMA&BiopsyBMA&Biopsy ––

devoid of active hematopoietic tissuedevoid of active hematopoietic tissue

-- -- replaced by fatty tissuereplaced by fatty tissue

-- -- lymphocytes seenlymphocytes seen

DDDD

11 - -MDS MDS –– hyperplastic BM hyperplastic BM

22 - -Acute Leukemia- hyperplastic Acute Leukemia- hyperplastic BM, BlastsBM, Blasts

33 - -PNH PNH –– CD59 CD59 ––veve

44 - -Hairy cell Leukemia Hairy cell Leukemia –– splenomegalysplenomegaly

55 - -SLESLE

TreatmentTreatment

11 - -BMT & stem cell T BMT & stem cell T –– best ttt child, best ttt child, healthy adults & for severe cases & healthy adults & for severe cases & refractory ptrefractory pt

* * Matched healthy relative donorMatched healthy relative donor

22 - -Conservative therapyConservative therapy::

a) a) Anti-thymocyte globulin (ATG) Anti-thymocyte globulin (ATG) 15-40 15-40 mg/kg/d for 4 days + Methyl PDN pulsemg/kg/d for 4 days + Methyl PDN pulse

S/E serum sickness, allergyS/E serum sickness, allergy

3535 % % relapse within 5 yearsrelapse within 5 years

b) b) CyclosporineCyclosporine

–– cyclic polypeptide inhibiting IL-2 cyclic polypeptide inhibiting IL-2 production by T cellsproduction by T cells

- - orally 10-12 mg/kg/d for 4-6 orally 10-12 mg/kg/d for 4-6 monthsmonths..

- - S/E hypertension, hyperglycemia, S/E hypertension, hyperglycemia, hypertelorismhypertelorism

- - equally effective as ATGequally effective as ATG

c) c) CyclophosphamideCyclophosphamide

–– alkylating agent, alkylating agent, immunosuppressantimmunosuppressant

- - high dose neededhigh dose needed

- - 65%65% CRCR

d) d) AndrgensAndrgens

–– not effective in trialsnot effective in trials

e) e) CytokinesCytokines

–– G-CSF, GM-CSFG-CSF, GM-CSF

- - not much beneficialnot much beneficial

33 - -Others - Others - IVIGIVIG

PrognosisPrognosis

**Before BMT & Immunoth Before BMT & Immunoth –– 25% 25% die in 4 months & 50% in 1 ydie in 4 months & 50% in 1 y

* *BMT cure 80% < 20 y ageBMT cure 80% < 20 y age

70%70% 20-40y20-40y

50%50% > > 4040 yy

BF-- NBF-- N

BM--- AABM--- AA

Normal BMNormal BM