Elekanglkrvetvorba Physiology of the bone marrow



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Elekanglkrvetvorba

Physiology of the bone marrow

1. Hemopoiesis as a self-renewal system. Stem cell of hemopoiesis

2. Unipotent (determined) progenitors, proliferation-differentiation and maturation compartments. Methods of their study

3. Regulation of the hemopoietic system

4. Systems analysis of the hemopoietic function in physiological and pathophysiological conditions

5. Structure and physiology of RBC




  1. Hemopoiesis as a self-renewal system. Stem cell of hemopoiesis

A self-renewal system loses mature (functional) cells steadily and replaces them continually. Normally it is composed of three cellular compartements:



  • pluripotent stem cells which are capable of

  • non declining (steady) autoreproduction

  • differentiating into various developmental lines (pluripotentiality)

  • unipotent cells capable of dividing (proliferation)

  • differentiated functional (postmitotic) cells unable of division

Blood forming organs represent a typical example of a self-renewal system (Fig. 1n = Haen 3.8). All non-stem populations are transitory. The transit times in the individual compartements – tab. 1 = Haen tab. 3.1.

Two types of damage:


  • loss of mature cells (e.g., bleeding, inflammation)

  • damage to the stem cell and precursor compartement (e.g., radiation, cytotoxic drugs)

Lymphatic organs are totally dependent on the marrow


Fig 2 = Haen 4.1: Erythropoiesis, the development and maturation of the red blood cells



  1. Unipotent (determined) progenitors, proliferation-differentiation and maturation compartments. Methods of their study

The historically first method of the stem cell detection: colony forming units spleen (CFU-S)

Fig 3 = stará blána fig. 2 A,B,C, Fig. 4 = fig. 3 stará blána: The stages which cannot be differentiated morphologically are detected by means of short-term colonies in vitro

Besides, the stem and precursor cells could be identified by means of flow cytometry ( numbers of different cells) and light-activated cell sorting ( preparing of homogenous cell populations) (Fig. 5 = fig. 4 stará blána)




  1. Regulation of the hemopoietic system

Fig. 6= fig, 6 stará blána: Hemopoietic inductive microenvironment (HIM)



  • fibroblast-type „reticulum“ cell – granulopoietic islands

  • macrophage-type „reticulum“ cell – erythroblastic islands

Cytokines = peptides taking part in the signalling among the immune and hematopoietic system cells. No hormones (endocrine). Types:

- Interleukins (Il-1, 2,...etc.)

MF, T cells, stromal cells (HIM) growth and differentiation of

- lymphocytes


  • hematopoetic stem cells (some of them are known as „colony stimulating factors“, CSF)

Interleukins taking part in steady-state hemopoiesis:

  • multi-CSF (= Il-3) from helper T-cells

  • GM-CSF

  • Il-6

  • Il-7 (development of B- and T-lymphocytes)

In non-steady-state-conditions: production of a number of growth factors more specific in their actions which are usually produced by activated blood cells or fibroblasts: Il-4 and Il-9 (production of basophils and mast cells), Il-5 (eosinophils), G-CSF, M-CSF, EPO



  • Interferons: induced in response to a variety of agents including viruses, microorganisms and endotoxins. Upon induction, they circulate to neighboring cells which they stimulate to make antiviral proteins

  • Lymphokines: Proteins secreted by some helper T cells after they are primed by contact with an antigen. Are not antibodies but are mediators of cellular immunity. They activate various white blood cells, incl. other lymphocytes. Examples: interleukin 2, some interferons, migration inhibition factor (MIF)

  • Tumor necrosis factors: have cytotoxic effects on tumor cells but not on normal cells. TNF is secreted by macrophages in response to bacterial infection and other challenges, TNF by helper T lymphocytes and cytotoxic lymphocytes. Synergistic with interferons




  1. Systems analysis of the hemopoietic function in physiological and pathophysiological conditions

The homeostasing of the blood cell production is regulated by several feedbacks. Their interplay may be rather complex and can be understood by means of mathematical modelling only (Fig. 7, 8, 9 = fig. 1, 7 a 8 z Wichmanna)




  1. Structure and physiology of RBC



The RBS have lost


- mitochondria, citric acid cycle and oxydative phosphorylation forming ATP  anaerobic glycolysis must be the main source of ATP in them;

- ribosomes  no protein synthesis, detrition of enzymes etc.

RBC membrane:

Fig. 10 = blána fig. 10: glycophorins can attach lectins = phytohemagglutinins, viruses and malaria parasites

Fig. 11 = blána fig. 11: Spectrin and aktin  filamentous network responsible for the biconcave shape of RBC; ankyrin links spectrin molecules to anion-transport proteins („band 3“)

Hemoglobin protection against oxidation (Fig. 12)

RBC shape and its life span (Fig. 13 = blána 12B)

Elekanglanemie

Anemias

1. In general


2. Decreased erythrocyte production

3. Increased erythrocyte loss





  1. In general



Definition


- traditional RBC or Hb or HTC

- alternative  Erythron (M)


M = I * T,
where I = amount of new RBC produced per unit of time

T = red blood cell life span

Example (extreme compensation): M = 8 * 1/8 = 100%
Symptoms: under 80g Hb/L

Hemolysis  jaundice, splenomegaly, cholelithiasis

 O2 diffusion  vasoconstriction of skin and kidneys

Pulmonary and cardiac function 

Medullary erythropoiesis 

2,3 diphosphoglycerate   shift of the Hb curve to the right   O2 delivery to the tissues

Acute blood loss:

30% of volume (1500 mL)  circulatory colaps, shock

 50% loss  death

 Hb after 2-3 days

No „emergency“ pool of RBC, premature release of reticulocytes only

The marrow RBC production can rise up to 8times, if there is Fe enough




Classification of anemias (Fig. 14 = Haen tab. 8.2)



2 Decreased erythrocyte production
21 Decreased proliferation of new erythrocytes = aplastic anemia s.l. = hypoproliferative anemia (Fig. 15 = Haen 9.1)

Reticulocyte index . Hypoplasia of the red cell line in the marrow  inability to react to anemia

Name: in fact, the anemia is hypoplastic only (never complete aplasia)

Symptomatology: pancytopenia always present (white cells, platelets), infections, bleeding, reticulocytes, plasma Fe, total binding capacity

Prognosis not very good. Ther.: bone marrow transplantations and immunosuppression (cyclosporine and antilymphocyte serum)


Etiology

  • „idiopathic“ – most often, probably caused by so far unknown pollutants

  • known causes

  • primary (= inborn) – Fanconi´ s anemia

  • secondary (= acquiered):


211 Decreased erythropoietin

Impaired production by the kidneys - anemia of renal failure

Low oxygen requirements - anemia of endocrine disease (hypothyreoidism)

Impaired stem cell response to erythropoietin - anemia of chronic diseases (see later)



212 Bone marrow damage or defect

Replacement of marrow by tumor (crowding out) - myelophthisic anemia

Replacement of normal marrow by cancerous cell line - anemia associated with myeloproliferative disease

Local competition for nutrients, secretion of inhibitory substances

Damage to bone marrow by physical or chemical agents, or infections – aplastic anemia s.s.

Benzene, chloramphenicol, analgesics, anticonvulsants, antianxiety drugs

Inherited bone marrow defect - Fanconi's anemia

Multiple congenital abnormalities, recessive gene


22 Impairment in the maturation of new erythrocytes  ineffective erythropoiesis

Subcellular pathology defective erythroblasts intramedullary hemolysis (50%). The marrow is hypercellular, in spite of this, the reticulocytes are scanty ineffective erythropoiesis



221 Macrocytic-normochromic erythrocytes


macrocytic

alcohol

liver dis.

myxedema

gravidity megaloblastic

myeloma







enzymatic disturb.

anomalous vitamins
folic acid and B12

Derangement of DNA synthesis

Slowering of cellular proliferation



Nucleo-cytoplasmic asynchrony („dissociation“)

Normal Hb production

Fe


PITR (plasma iron

transit rate)


RBC volume (MCV), ovalocytosis

normal Hb concentration inside (MCHC)

T

RBC, HTC, anisocytosis and poikilocytosis always present, leucocytes and platelets, hypersegmented neutrophils



Atrophic glossitis, purpura
Folic acid deficiency (Megaloblastic anemia, Fig. 16 = Haen 10.1)

Folate compounds widely distributed in nature, rich in the diet, but small body stores. Fig. 17 = tab. Haen 10.1. Decreased intake: alcoholism, hepatic diseases, tropical sprue (coliform bacteria), malabsorption, resections. Increased requirements: gravidity, growth, hematopoiesis. Folic acid antagonists: cytostatics, chemotherapeutics, antiparasitic and anticonvulsive drugs

Function of tetrahydrofolate: coenzyme for single-carbon transfers  necessary for thymidylate synthase  rate limiting for DNA synthesis
Vitamin Bl2 deficiency (Megaloblastic anemia)

Synthetized by microbes only  in foods of animal origin. Requirements small, stores large. Absorption of B12 Fig. 18 = Haen 10.8

Function of B12: myelin (funicular myelosis) and folate synthesis

Deficiency:

- total vegetarianism

- malabsorption syndromes (jejunal bacterial overgrowth, enteritis, intestinal parasites)

- lack of intrinsic factor  pernicious anemia

adults: genetic, autoantibodies against parietal cells or IF

 chronic atrophic gastritis

children: rare, inherited, abnormalities of IF


222 Microcytic-hypochromic erythrocytes

Iron deficiency (Iron deficiency anemia)



Fe absorption

in animal food – in hem



Fe2+ easily absorbable

in plant food – inorganic

Fe3+ presupposes low pH in the stomach for solubilization

Absorption is regulated by the needs (i.e., by hematopoiesis) – by the Fe content in the mucosal gut cells

Etiology of Fe deficiency: blood losses, need, malabsorption

Iron metabolism (Fig. 19 – Kaufm.)

Incorporation of Fe into the erythroblasts only from transferrin

Ferritin: a protein envelope surrounds a microcrystalic core of inorg. Fe

Fe overload: disturbance of the gut mucosal cells. Hemosiderosis = RES cell containing hemosiderin, hemochromatosis = various organs contain hemosiderin

Clinics: angular stomatitis, glossitis, koilonychia, dysphagia, pica, no sideroblasts, typical serum composition (Fig. 20 – Kaufm.)

Development of microcytic anemia (Fig. 21 – Kaufm.)
Other microcytic-hypochromic anemias

Abnormalities of the heme or globin synthesis  Hb production  more than 4 divisions  microcytosis and hypochromia

Unavailability of iron to blast cells - Anemia of chronic disease (ACD)

Block of Fe metabolism: macrophages degrading Hb of the decayed RBC are activated, proliferate and retain Fe for themselves

 hepatic syntheses  transferrin together with plasma Fe (Fig. 22 = fig. 14 na blánách)

Fe storage normal or 

Besides

-  EPO production or its binding to the stem cells (loss of EPO receptors, disturbed coupling)



-  RBC life span

Etiopathogenesis: foreign antigenes pertaining to the inflammatory process  activation of macrophages 

Il-1 and TNF production:  Fe metabolism in MF disturbed; direct inhibition of EPO production

Conditions: chronic inflammations (e.g. hepatitis), some malignancies, collagen-vascular diseases

Impairment of heme synthesis (Sideroblastic = sideroachrestic anemia)

Fe into mitochondrias  ring erythroblasts

Etiology:


  • inherited – aminolevulate synthetase – rate limiting

  • acquiered – somatic mutation – cell clone

Impairment of globin synthesis (Thalassemia syndromes)

Fig . 23 (má blána)




3 Increased erythrocyte loss

31 Hemorrhage  hemorrhagic anemia

Acute: influx of interstitial fluid into the circulation (several days)  progressive fall of Hb, HTC, RBC

EPO and reticulocyte response (Fig. 25 and 26 = Haen 13.1 a 13.2)

Chronic: GI ulcers and malignancies, menstruation. Iron stores 


32 Intravascular hemolysis or premature phagocytosis  hemolytic anemia

321 Hereditary factors

Defects in the erythrocyte membrane

Hereditary spherocytosis

RBC flexibility is conditioned by the unique structure of the RBC membrane, and this is maintained by actin, spectrin, and ankyrin. Spectrin gene mutates most often

a) Mutated RBC  loss of flexibility  pitting in the splenic sinuses  RBC shrinking  getting spherical  loss of flexibility  destruction in the spleen

b) Mutated RBC  slowering of the Na/K-ATPase  Na into RBC  water into RBC  getting spherical etc.

c) Mutated RBC  enhanced need of glucose  lowered glucose concentration in the spleen  enhanced trapping of the microspherocytes
Symptomatology:

Mild anemia only

Bilirubin gale stones

Osmotic fragility test - series of salt solutions of increasing concentration

 sensitivity of RBC to a medium without glucose

Survival time by 51Cr (Fig. 27 – Haen 14.2)

Surface counting patterns of 51Cr-labeled RBC (Fig. 28 – Haen 14.3)

Splenectomy!


Hereditary elliptocytosis

Mild anemia, in combination with other anemizing factors only

Again a membrane defect of actin-spectrin-ankyrin skeleton

No therapy


Defects in erythrocyte metabolism

G6-PD deficiency anemia

95% of all glucose metabolism enzyme deficiencies

Triggering factors: oxidizing drugs, infections ( activation of leucocytes producing active oxygen radicals)

Favism is a unique phenomenon – fava beans (contain an oxidant L-dopa)

Measuring of the G6-PD activity in the RBC  changing of the eating habits

Pyruvate kinase deficiency anemia

Embden-Meyerhof pathway, decline of ATP production, symptoms may be severe, specific enzyme assays (no other specific features), drugs not implicated in pathogenesis


Abnormal hemoglobin production

Point mutations of Hb are mostly innocent, a small fraction is pathogenic:  solubility and precipitation,  affinity to oxygen, unstability of quaternal structure and Hb denaturation


Sickle-cell anemia, HbC disease, HbD disease, HbE disease

See lecture on genetics


322 Acquired accelerated hemolysis

Approximately:

hereditary hemolysis  factors intrinsic to the RBC

acquiered hemolysis  factors extrinsic to the RBC

Physiological aging of RBC  their defense mechanisms  intravascular hemolysis or phagocytosis in mononuclear phagocytes (MF, reticular and endothelial cells). The environmental stressing factors shorten the RBC life span further. They are present to a degree already under physiologic conditions in most people. These physiological/pathophysiological factors are of chemical, physical or immunological nature. The boundary between physiological and pathological is fuzzy here:

- AB0 incompatibility is present in 23% of all gestations (hemolysis is very uncommon here, however)

- Paroxysmal nocturnal hemoglobinuria is rather common (mild hemolysis)

- Metabolic stress is ubiquitous



3221 Activation of the immune system  immunohemolytic anemia
Classification of immunohemolytic anemia (IHA)
Alloantibodies  hemolytic disease of the newborn (HDN)

AB0


Rh

Autoantibodies

Warm-active antibodies

Cold-active antibodies


Alloantibodies
AB0 incompatibility
Mother 0 has antibodies against A and B already spontaneously (in contradisticition to Rh- mothers, in whom the antibodies not are formed before the first parturition), and these reach the foetus via placenta. Not easily, however – they are IgM, therefore large molecules, so the symptoms are mild

Antigen-antibody complexes  complement activation  premature lysis of RBC


Rh incompatibility – (Fig. 29 = obr. Haen 15.2)
15% of Rh- mothers

At the first parturition, the RBC penetrate from the foetus into the mother  production of anti-Rh+-antibodies. The RBC having penetrated during the parturition could be killed by timely administration of anti Rh+ antibody (RhoGAM).

In the next gravidity, small numbers of the fetal RBC may get into the maternal circulation  anamnestic response  higher antibody titers of IgG (readily pass the placenta)  HDN in the foetus

Symptoms:

Hemolysis  erythroblastosis

Inability to conjugate bilirubin  jaundice (possibly s.c. kernikterus, into the basal ganglia)

Residual concentration of the mother´s antibody after birth  slowering of growth; exchange transfusion
Autoantibodies  autoimmune hemolytic anemias (AIHA)
Warm type AIHA
IgG against RBC membrane antigens

Types:


Idiopathic – antibodies against the proper RBC are formed. Common autoimmunity mechanisms could be considered:

- Molecular mimicry with some microbe

- Lowered function of TS  production of antibodies

- Polyclonal B cell activation

- Enhanced presentation of antigens etc.
Drug induced (Fig. 30 = obr. Haen 15.5)

The drug is a hapten and in a complex with a carrier protein  production of antibodies. Three possibilities:

- a drug with a surface RBC antigen  neoantigen  production of antibodies and opsonization, e.g., penicillin

- a drug and serum protein (instead of RBC protein)  neoantigen 

 complexes are deposited on RBC membrane, e.g., antimalarics, sulfonamides, phenacetin

Alfa-methyldopa (antihypertensive drug) triggers the gene for the Rh factor



With other diseases: leukemias, SLE, inf. mononukleosis
Pathogenesis of warm type AIHA (Fig. 31 = obr. Haen 15.4):

RBC coating with an antibody = opsonization  binding of MF on RBC  pitting by means of nipping of  RBC sphericity  loss of flexibility  trapping

Opsonization rarely leads to intravascular hemolysis
Symptoms of warm-type AIHA:

Are mild, hemolysis is compensated

Pitting  spherocytes, microcytes

Direct Coombs test (Fig. 32 = obr. Haen 15.8): Antiserum against anti-RBC antibodies is formed in rabbits  RBC agglutination. IgG alone cannot bridge the repulsive force between RBC (= zeta potential), IgG + anti-IgG antibody can do it  agglutination

Therapy: corticosteroids, immunosuppresive drugs

Cold type AIHA


IgM against s.c. I antigen on the RBC surface, present also normally. IgM bridge

the zeta potential  they activate complement easily

Etiology:

Enhanced anti-I antibodies

- idiopathic

- in infectious diseases (cause unknown): mycoplasma, inf. mononucleosis, lymphoproliferative diseases

Patogenesis:

cooling  I antigens are better accessible to the antibodies

Complexes on RBC  complement activation

 C3b fragment  intravascular hemolysis and agglutination

Symptoms:

Anemia only mild, but the blocking of small extremity and acral vessels  painful blanching of the skin

The withdrawn blood agglutinates spontaneously in the room temperature


3222 Physical factors  red cell fragmentation syndromes

Etiology:

a) Long-distance running or marching (intravascular destruction of the RBC in the microcirculation of the feet due to the repeated crashes of the soles with hard surfaces – march hemoglobinuria)

b) Artificial heart valves - traumatic cardiac hemolytic anemia. Schistocytes often present (sickles)

c) Vasculitis or disseminated intravascular coagulation (DIC  production of multiple intravascular thrombi)  the blood is driven through the narrowed vessels  mechanical damage to RBC

3223 Chemical agents

Various forms of hemolytic anemia


Lead, copper salts, nitrobenzene, aniline, naphtalene

Aspirin, phenacetin, antimalarics, sulfonamides…

In high doses, they damage not only the G6-PD defective RBC, but also normal ones

Natural poisons (spiders, insects, snakes)
3224 Microorganisms

Various forms of anemia (e.g., anemia of malaria)

Multiply in the RBC – genus Plasmodium

Lyse the membrane – Clostridium welchii

Produce polysaccharides which are adsorbed to RBC  antibodies

3225 Secondary to other diseases

Various forms of anemia (e.g., anemia of hepatic failure) Many inflammatory and malignant diseases

Renal failure – echinocytes (burr cells)

Hepatic diseases


3225 Sensitivity to complement  paroxysmal nocturnal hemoglobinuria

Unknown factor (somatic mution?)  complement activation in the RBC membranes (by the alternative way)

Pancytopenia

Loss of Fe via urine

Venous blood clots

Testing: a small quantity of complement lyses RBC







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