blood physiology

  ( blood physiology )or “ haematology “

  the blood:-

-blood is specialized connective tissue consisting of cellular elements suspended in plasma .
-the cells make up approximately 45% of the total blood volume .
-the blood is one of the largest organs of the body, which a volume of about 5 liters & a weight of 5.5 kg an average 70 kg man .
-blood circulates throughout the body , supporting the function of all other body tissues .
-normal peripheral blood is composed of three types of cell , red blood cells , white blood cells & platelets , suspended in a pale yellow fluid called plasma .

  (1) the cellular elements:-

a- red blood cells ( erythrocytes )
b- white blood cells ( leucocytes )
c- platelets .

-the red cell membrane is freely permeable to water & anions ( chloride & bicarbonate) transverse the membrane in less than second, & is relatively impermeable to cations .
-the chemical composition of membrane is approximately 42% lipid , 50% proteins & 8% carbohydrates .
-the major function of red cells is to transport hemoglobin , which in turn carries oxygen from the lungs to the tissues & transport co2 from tissues back to the lungs . also , hemoglobin is an excellent acid – base buffer .
-red blood cells contain a large quantity of carbonic anhydrase , which catalyzes the reaction between co2 & water , increasing the rate of this reaction many thousand fold .
-the rapidity of this reaction make it possible for the water in blood to react with large quantities of co2 & thereby transport it from the tissues to the lungs in the form of the bicarbonate ion (hco3-) .
-the percentage of the total blood volume comprised of red blood cells is called the hematocrit , & this is normally about 40% in women & about 45% in men .

(b):-white blood cells ( leucocytes ) :-

-the leucocytes are the mobile units of the body’s protective system .
-they are formed partially in the bone marrow ( the granulocytes & monocytes , & a few lymphocytes ) & partially in the lymph tissue (lymphocytes & plasma cells ) , but after formation they are transported in the blood to the different parts of the body where they are to be used .
-the number of white blood cells in the blood is normally only 1/600 the number of red blood cells .

-leucocytes are of two main types :-

(1) granular leucocytes .
(2) a granular  leucocytes .

(1):- granular leucocytes :-

- are the most numerous . always contain specific granules , & they are characterized by the presence of many lobed  nucleus for this reasons they are referred to as polymorphonuclear leucocytes .

-there are three types of granular leucocytes :-

(a):-neutrophils  (b):-eosinophils 
                              (c):-basophils .

(a):-neutrophils :-

-they are the most numerous of the leukocytes in human blood which constitute 50-70% of the total white blood cells .

-the neutrophil nucleus is highly polymorphous
which usually consist of from 3 to 5 irregular ovoid lobes connected by a thin chromatin strand .
-neutrophil  cytoplasm contains numerous fine neutrophilic  granules , which are a special types of lysosomes that contains principally hydrolytic enzymes .
-neutrophils constitute the first line of defense against invading organism so the main function of neutrophils  is bacterial killing by phagocytosis .
-neutrophils are highly motile , highly phagocytic , & are attracted out of the blood into tissue areas where tissue destruction is occurring by a process called chemotaxis ,which means attraction by the destruction products from the damaged tissues .
-once in the tissue area , the neutrophils phagocytized bacteria & small amounts of dead tissue debris .
 
(b):-eosinophil :-

-they normally constitute about 1 to 4 percent of the total white blood cells .
-the nucleus is usually bilobed .
-this name is derived from the staining 
characteristic  of the large cytoplasmic granules of uniform sized which stain strongly with the acidic dye eosin .
-eosinophils are similar to the neutrophils except that they are less chemotactic & less phagocytic.
-they are phagocytose antibody – antigen complex .
-eosinophils are produced in large numbers in persons with parasitic infections .
-the parasites are usually too large to be phagocytized , but the eosinophils attach themselves to the surface & release lethal substances that can kill many of the parasites.
-large numbers of eosinophils  also appear in the blood in allergic conditions & may help detoxify toxins that are released by allergic reactions .

-(c) basophils :-

-these cells are difficult to find in human blood , since they constitute only about 0.5 to 1 percent of the total number of leucocytes .
-the nucleus often is irregular in outline & partially constricted into two lobes ( s shape like ).
-the cytoplasmic granules are round & variable in size , which stain with basic dyes .
-the basophils are very similar to though not identical with the large mast cells located immediately outside many of the capillaries in the body .
-basophils & mast cells are important for allergic reaction .
-since , the type of antibody , the ige type , that causes allergic reaction binds to mast cells & basophils causing them to release various inflammatory products that in turn cause many of the manifestations of allergic reactions .
-also , basophils & mast cells liberate heparin into the blood , a substance that can prevent blood coagulation . as well as histamine & small quantities of bradykinin
-eosinophils can reduce the inflammation by inactivating the heparin & histamine , which are among the collection of substances released by allergen – stimulated mast cells & basophils , thus preventing spread of local inflammatory process , so the number of eosinophils is greatly increased in allergic conditions & parasitic infections .
-basophils differ from neutrophils in that they are no phagocytic .

(2) – a granular leucocytes :-
            - this cells have cytoplasm that appears homogenous & nuclei that are spherical to reniform in shape .

there are two types of a granular leucocytes :-

  (a):- lymphocytes:-
-lymphocytes are the second most common white cell in the peripheral blood , with arrange of 20 to 40 percent of circulating white blood cells .
-typically , lymphocytes are much smaller than monocytes ( 10 – 12 microne in diameter) .
-the majority of the lymphocytes are small in size, spherical cells , with small amount of cytoplasm surrounding dense, round nucleus.
-most of lymphocytes are formed in lymph nodes , thymus & spleen .
-lymphocytes are divided into two major populations , which play distinct roles in specific immunity .
-one of the population is responsible for forming the activated lymphocytes that provide cell - mediated immunity , which called t lymphocyte .
-the other population is for forming the antibodies that provide humoral immunity , which is called b lymphocytes .
-in the blood 70 – 80% of small lymphocytes are t cells & 15 – 20% are b cells .

(b):- monocytes:-

-monocytes are phagocytic leucocytes that play a major role in defense against pathogenic organism & foreign cells .
-the monocytes is larger than a nutrophils , & have abundant cytoplasm in relation to the nucleus .
-the nuclei of monocytes frequently are kidney shaped .
-monocytes enter the circulation from the bone marrow but after about 24 hours they enter the tissues to become tissue macrophage .
-the tissue macrophage system has generally been called the reticuloendothelial system .
-the macrophages migrate in response to chemotaxis stimuli & engulf & kill bacteria by phagocytosis .

  (3) – platelets:-

-blood platelets are small protoplasmic disks ,
  which are non – nucleated , granulated bodies ,    constitute about 300,000 per cu mm of
circulating blood .
-their number is difficult to count because they
adhere to each other & to all surfaces .
-blood stains demonstrate two regions of                                                                                                                                                                                                  platelet ,a deeply basophile zone (the chromomere ) usually centrally located & pale homogenous peripheral zone ( the hyalomere ) .
-the primary role of the blood platelet is in the
  arrest of blood loss . adequate number of
  functionally normal platelets are essential for
  optimal hemostasis .                                                                                                                                                                                                                                                                                                                                                                                                                                                                               

in their cytoplasm are such active factors as :-
-(1)-actin and myosin molecules ,which are contractile proteins similar to those found in muscle cells , and still another contractile protein , thrombosthenin, that can cause the platelets to contract.

(2)-residual of both the endoplasmic reticulum and the golgi apparatus that synthesize various enzymes and especially store large quantities of calcium ions.                          (3)-mitochondria and enzyme systems that are capable of forming adenosine triphosphate (atp) and adenosine diphosphate ( adp).                                                                                                                          (4)-enzyme systems that synthesize prostaglandins, which are local hormones that cause many vascular and other local tissue reactions.                                                                                                -(5)-an important protein called  fibrin – stabilizing factor which is important in blood coagulation.                                                         
-(6)-a growth factor that causes vascular endothelial cells, vascular smooth muscle cells , and fibroblasts to multiply and grow , thus causing cellular growth that eventually helps repair damaged vascular walls.                                                                                                                                 

life span of the white blood cells :-

-the subsequent life of the granulocytes once released from the bone marrow is normally 4 to 8 hours circulating in the blood & another 4 to 5 days in the tissues .
-in time of serious tissue infection , this total life span is often shortened to only a few hours because the granulocytes then proceed rapidly to the infected area , ingest the invading organisms , & in the process are themselves destroyed ( ex- a neutrophil can usually phagocytize 5 to 20 bacteria before becomes in activated & dies ) .
-the monocytes also have a short transit time in the blood ( about 10 hours ) before wandering through the capillary membranes into the tissues .
-however , once in the tissues they swell to much larger size to become tissue macrophages & in this form can live for months or even years unless destroyed by performing pagocytic function ( ex- often capable of phagocytizing as many as 100 bacteria ) .
-lymphocytes enter the circulatory system continually along with drainage of lymph from the lymph nodes .
-the total number entering the blood from thoracic duct in each 24 hours is usually several times the total numbers of lymphocytes present in the blood stream at any given time .
-therefore , the span of time that the lymphocytes remain in the blood must be only a few hours .
-the platelets in the blood are totally replaced approximately once every 10 days , in other wards, about 30,000 platelets are formed each day for each cubic millimeter of blood .

  (2) the plasma:-

-plasma is homogenous , slightly alkaline fluid which contains , in addition to the waste substances produce from the tissues , dissolved gases , inorganic salts , protein , carbohydrate & lipids that are in transit to various parts of the body .
-serum has the same composition as plasma except that its fibrinogen & clotting factors have been removed .

-plasma proteins :-

-the plasma proteins consist of albumin , globulin & fibrinogen fractions .
-the globulin fraction is subdivided into numerous components which are :-
? 1 ? 2 b 1   b 2 &   gamma globulins.
-the albumin  ? & b globulins & fibrinogen are manufactured in the liver while gamma globulin are manufactured in plasma cells .
-normally , total plasma proteins in human adults range in concentration from 6 to 8.0  gm /d1 ( d1 = deciliter ).
-they are most separated & estimated by electrophoresis .
-the major fractions resolved by this means are albumin ( 54 to 58 percent ) ? 1- globulins ( 6 to 7%) ? 2- globulins (8 to 9% ) b1 – globulins (13 to 14 %) &   gamma globulins ( 11 to 12% ) .
-the capillary walls are relatively impermeable to the proteins in plasma , & the proteins therefore exert on osmotic force of about 25 mm hg across the capillary wall (oncotic pressure ) that tend to pull water into the blood .
-the plasma proteins are also responsible for 15% of the buffering capacity of the blood , because of the weak ionization of their substituent – cooh & - nh2 groups .

- albumin :-
-is the major protein of human plasma , has mw            – 69,000 daltons.
-albumin , synthesized by the parenchymal cells of the liver is normally present at an average concentration of about 4 gm /di/ (range 3.5 –5.0 gm/di/).
-when the concentration of albumin is severely reduced ( as in liver disease because of protein synthesis is depressed or in nephritis because large amounts of albumin are lost in the urine ) , this lead to decrease in the plasma oncotic pressure , so excess extracellular fluid may accumulate .
-in extracellular tissues ,the fluid accumulation is described as edema.
-whereas in closed body cavities it is described as either ascites (in the peritoneal cavities) or effusion(in the pleural or pericardial cavities ) .
-albumin is also the carrier for substances ,these substances include normal components of blood , such as bilirubin & fatty acids as well as exogenous agents such as drugs .

-a decreased concentration of serum albumin may be caused by the following :-

(1):- an inadequate source of amino acids .this is the case in malnutrition & muscle – wasting disease .
(2):- liver diseases resulting in the inability of hepatocytes to synthesize albumin .
(3):- renal diseases loss of albumin in the urine .

-haptoglobins :-

-are glycoprotein which migrate with
          ? 2- globulins .     
-is synthesized in the liver & to very small extent in the cells of the other reticulo - endothelial system .
-  haptoglobin is composed of two ? - chains & only one form of b- chain of polypeptides .
-the b- chain contains the site with which the molecule binds hemoglobin .
-the molecular weight is about 85,000 daltons .
-their biological function is in the metabolism of plasma hb by preventing its glomerular filtration & confining its uptake to the liver .

-haemopexin:-
-is a beta -1 glycoprotein consist of a single polypeptide chain with a mw of about 57,000 .
-it is synthesized mainly in the liver .
-it binds heme in equimolar ratio ( 1:1 ratio) .
-neither hemoglobin nor bilirubin binds to haemopexin .
-the hemopexin – heme complex is removed from the blood by the liver .
-pregnant mothers have increased plasma haemopexin levels . also increased in diabetes mellitus .

-ceruloplasmin :-

-ceruloplasmin is a copper – containing protein that has enzyme activities ( ex.. copper oxidase , histaminase & ferrous oxidase ) .
-is an ? 2- globulin of approximately 160,000 mw.
-so named because of its blue color .
-it is synthesized in the liver , where eight cu+2 (copper) atoms are attached to an apoceruloplasmin .
-it is important in maintenance of cu+2      homoeostasis & serve in cu+2 transport , & carries 90% of the copper present in plasma .
-albumin carries the other 10% of plasma copper .
-adult females have higher concentration than do males ,& pregnancy , inflammatory processes, oral estrogen cause increased serum concentration.
-inherited wilson’s disease , plasma ceruloplasmin is markedly reduced & cu+2 levels increase in brain & liver with resultant neurological changes & liver damage .

transferrin :-         

-it is b- globulin , glycoprotein synthesized in the liver , with mw 80,000 .
-two molecules of ferric iron bind to each molecule of transferrin .
-the major function of transferrin are the transport of iron in the circulation to sites where iron is required & prevention of loss of iron through the kidney .
-transferrin transport iron to its storage sites & to the bone marrow to release the iron to the target cell .

-ferritin :-

-ferritin contains approximately 23% iron & apoferritin has a mw of approximately 440,000 .
-ferritin is the storage form of iron in the tissues which is found principally in the reticulo-endothelial cells of the liver ,spleen & bone marrow .
-normally , there is a little ferritin in human plasma.
-however ,in patients with excess iron ,the amount of ferritin in plasma is markedly elevated.

-fibrinogen :-

-fibrinogen is one of the largest glycoprotein present in the blood plasma.
-it is synthesized in the liver , & with a high mw 340,000.
-it is six times more viscous than albumin & is mainly responsible for blood viscosity .
-it is also essential in blood clotting process , so in the presence of thrombin ( an enzyme produced by the activation of the clotting mechanism ) fibrinogen is cleaved into fibrin which is insoluble protein that is responsible for clot formation .
-serum has no fibrinogen so total plasma protein minus serum proteins give a measure of fibrinogen.

-immunoglobulins (igs):-
-the antibodies are gamma globulins called immunoglobulins & they have a mw between approximately 150,000 & 900,000 , usually they constitute about 20% of all plasma proteins .
-there are five major groups of immunoglobulins in the serum , which are :- iga igg igm igd & ige "(damge)" which are produce by the lymphocyte – plasma cell system .
-all the immunoglobulins are composed of combinations of light & heavy polypeptide chains , most of which are a combination of two light & two heavy chains , some of the immunoglobulins have combinations of as many as ten heavy & ten light chains , which gives rise to the much larger molecular weight immunoglobulins .
-yet , in all immunoglobulins , each heavy chain is paralleled by a light chain at one of its ends , thus forming a heavy – light pair & there are always at least two such pairs in each immunoglobulin molecule .
-antibodies are protein synthesized by plasma cells , due to immune responses , b- lymphocytes that have been stimulated by antigens to differentiate into plasma cells , which are secrete different classes of immunoglobulins .
-antibodies provide a major defense against infectious agents .

-the ionic constituents of plasma :-

-the ionic constituents of plasma maintain the ph of blood within physiological limits .
-the chief inorganic cation of  plasma is sodium -plasma also contains small amounts of potassium , calcium , magnesium & hydrogen ions .
-the principle anion of plasma is chloride , & ionic equilibrium is maintained by the presence of other anions , including bicarbonate , phosphate , sulfate , plasma protein & organic acids .

-enzymes of plasma :-

-most plasma enzymes do not have metabolic roles in plasma , except for the enzymes concerned in blood coagulation .
-serum enzyme levels are often useful in the diagnosis of particular diseases or abnormal physiological conditions , such as the level of plasma acid phosphatase becomes very high in cases of prostatic cancer , & high alkaline phosphataes is also found in cases of hepatic obstruction .

-function of plasma proteins :-
-(1)-they act as protein reserve to the body , & can be used to supply body protein in states of starvation .
-(2)-the plasma proteins increase the viscosity of the blood .
-(3)-plasma proteins exert on osmotic pressure of about 25 mm hg , ( oncotic pressure ) which plays an important role in the reabsorption of  tissue fluid .
-(4)-they are important in transporting certain hormones , drugs & other substances in the blood.
-(5)-they also have the ability on neutralize both acids & alkalis , that is they act as a buffer .
-(6)-globulins acts as defense mechanism through formation of antibodies .

some constituents of plasma in adults :-

proteins  concentration  non-protein  concentrations  ionic constituents
- total protein
- albumin
- total globulin
- transferrin
- haptoglobin
- hemopexin
- eruloplasmin
- ferritin  6.0 –8.0 gm / dl
3.4 –5.0 gm / dl
2.2 –4.0 gm / dl
250 mg / dl
30 –205 mg / dl
50 –100 mg / dl
25 – 45 mg / dl
15 – 300 mg / l
  -cholesterol
- glucose
- urea
- uric acid
- creatinine
- iron   140–250 mg/ dl
70 –110 mg / dl
6 – 23 mg / dl
4.1 –8.5 mg / dl
0.7 –1.4 mg / dl
50 – 150 µ g/ dl  cations
- na+135 – 145 meq / l
- k+3.5 – 5.0 meq / l
- ca+22.2 – 2.5 meq / l
- mg+21.5 – 2.0 meq / l
anion
- cl- 95 – 107 meq / l
- hco3- 22-26 meq / l
- lactate 1.0–1.8 meq/ l
- sulfate i.0 meq / l
- phosphate 2.0 meq / l

((( the haemoglobin )))

-haemoglobin is the iron – containing pigment of the red blood cells that functions to carry oxygen from the lungs to the tissues .
-hb , a conjugated protein with a mw of approximately 64 , 450 daltons , synthesized in bone marrow by nucleated precursors of the erythrocytes since approximately 65% of hb synthesis occurs during the nucleated stages of rbc maturation & 35% occurs during the reticulocytes stage .
-hb is the main constituent of rbcs , which comprises 95% of the rbc’s dry weight .
-normal blood has about 16 gm/di (deciliter) of hb in adult men & about 14 gm/di in adult women .
-haemoglobin structure :-
-hb is a globular molecule made up of 4 subunits each subunit contains a heme conjugated to a poly peptide .

-heme structure :-
-heme is an iron – containing porphyrin , & the porphyrin contains four pyrrole – like rings linked by four methene bridges (= ch – groups) in an alternating double – bond ring system .
-porphyrins can combine with fe to form the heme , the fe++(as ferrous) is bound equally to all four nitrogen atoms of the pyrrole rings .
-                                                                                     
( ferroproto porphyrin )
                                                                        heme
- the globin structure:-

-the globin is consist of two pairs of polypeptides , one pair containing one type of polypeptide & the second pair containg another type.
-since in normal  adult human hb (hba) , the 2 types of polypeptide      are called the ? chains , each of which contains 141  a.a. residues , & b chains each of which contains 146 a.a. residues. -thus hba is designated ? 2b2 .
-not all the hb in the blood of normal adults is hb a. about 2.5% of the hb is hba2 , in which b chains are replaced by delta chains (?2 ?2) .
-the delta chains also contain 146 a.a residues,    but 10 individual residues differ from those in the b chains .
*  while the blood of the fetus normally contains fetal hb ( hbf ) .
-its structure is similar to that of hba except that the b chains are replaced by gamma chains.
-so hbf is designated ( ?2 ?2 ) .
- fetal hb is normally replaced by adult hb soon after birth .
-the gamma chains also contain 146 a.a  . residues but have 37 that differ from those in the b chain .
-in the body , its (hbf) o2 content at a given po2 is greater than that of adult hb because it binds to less 2,3 – dpg ( 2,3 – diphosphoglycerate ) .
-this facilitates the movement of o2 from the maternal to the fetal circulation .
* in young embryos there are , in addition , hb gower 1 composed of two zeta & two epsilon chains , & hb gower 2 composed of two alpha & two epsilon chains .

synthesis of haemoglobin :-

-normal hemoglobin production is dependent on three processes :-

  1- adequate iron delivery & supply .
  2- adequate synthesis of protoporphyrins ( the            precursor of heme ). 
  3- adequate globin synthesis .

- iron delivery & supply:-

-iron is delivered to the membrane of the rbc precursor by the transferrin.
-the majority of the iron that crosses the membrane & enters the cytoplasm of the cell is committed to hemoglobin synthesis & thereby proceeds to the mitochondria for insertion into the protoporphyrin ring to form heme.
-two thirds of the total body iron supply is bound to heme in the haemoglobin molecule . since one milligram of iron is required for each milliliter (ml) of red cells produced .
-each day 20 to 25 mg of iron are needed for erythropoiesis .
-95% of this required iron is recycled iron salvaged from normal rbc turnover & hb catabolism only 1mg per day is newly absorbed to balance minimal iron losses by fecal & urinary excretion as well as through sweating & desquamated skin .
-the remaining one third of the total body iron supply is stored within the liver & spleen .

- synthesis of heme (ferroprotoporphyrin 1x):-
-protoporphyrin synthesis begins in the mitochondria , in which succinyl coa combines with glycine to form delta aminolevulinic acid (?ala) , which is the major rate – limiting step in heme biosynthesis .
-the mitochondrial enzyme ?ala synthetase , which mediates this reaction, is influenced by erythropoietin & requires the presence of the cofactor pyridoxal phosphate ( vit b6 ) .
-in the cytoplasm , condensation of two molecules of  ?ala , catalyzed by ?ala dehydrase , produces the mono pyrrole porphobilinogen ( pbg ) .
-four molecules of porhobilinogen condense to form the tetrapyrrole uroporphyrinogen ? ( upg ? ) , a reaction catalysed by pbg – deaminase & upg – isomerase .
-coproporphyrinogen ? is next formed through decarboxylation reactions from uroporphyrinogen ?.
-the final steps of heme synthesis are carried out in the mitochondria & involve the formation of protoporphyrinogen 1x from coproporphyrinogen ? ( cpg ? ) & subsequently to form protoporphyrin 1x is by a series of decarboxylations .
-the insertion of iron into protoporyphyrin 1x to form heme which is catalysed by the enzyme heme synthetase .

( biosynthesis of heme )

                              glycine   succinyl coa   
        ala – synthetase                                                                         ?
?- aminolaevulinic acid
    ( ? - ala )    erythropoietin

                                                                            ? ala dehydrase
                                                porphobilinogen
                                                          ( pbg )
                                                                          pbg deaminase
                                                                          upg isomerase                               
                                        uroporphyrinogen ?
                                                                       
                                                                          upg decarboxylase
                                      coproporphyrinogen ?
                                                               
                                                                          cpg decarboxylase
                                                                            cpg oxidase
                                    protoporphyrinogen 1x
                                                                   
                                          protoporphyrin 1x
                                                                                                   
                                                      fe+2                    heme synthetase

                       
                                                            heme

the globin synthesis :-

-globin chain synthesis occurs on rbc –specific cytoplasmic ribosomes, which are initiated from the inheritance of  various structural genes . each gene results in the formation of a specific polypeptide chain .
-the rbc contains four alpha (?) genes , two beta (?) genes , two delta (?) genes & four gamma (?)genes .
-the alpha genes are located on chromosome 16 & the beta , delta & gamma genes are located on chromosome 11.
-the resulting gene product formed have been called alpha , beta ,delta & gamma chains .
-all adult normal hb are formed as tetramers consisting of  two alpha chains plus two ( non- alpha ) globin chains .

-normal adult rbc contain the following types of hemoglobin :-
   
-92 - 95% of hb is  hba which consist of  ?2 b2 chains.
-2 -3% of the hb is hba2,  which consist of  ?2 ?2 chains .
-1-2% of the hb is hbf ( fetal hb ) which consist of ?2 ?2 chains .             
-each synthesized globin chain links with heme (ferroprotoporphyrin 1x ) to form hemoglobin , which consist of two alpha chains , two beta chains & four heme groups .
-an adequate amount of globin chain synthesis is also important since decreased production of one of the polypeptide chains leads to a group of disorders known as thalassemia .
-since beta thalassemia , the more common form , refers to a decrease in beta chain production &   alpha thalassemia refers to a decrease in alpha  chain production .
-the rate of globin synthesis is directly related to the rate of porphyrin synthesis , since the proto porphyrin synthesis is reduced when globin synthesis is impaired .
- in the body of a 70 kg man , there is about  900 gm of hb ,& 0.3 gm of hb destroyed & 0.3 gm synthesized every hour.

-catabolism of hemoglobin :-

-the a average life span of normal erythrocyte in the  circulation is 120 days .   
-when old red blood cells are destroyed in the reticulo – endothelial system , the hb is first split into globin & heme .
-the heme ring is opend to give a straight  chain of four pyrrole nuclei , that is substrate from which the bile pigment are formed .
-the first pigment formed is biliverdin , but this is rapidly reduced to bilirubin , which is gradually released into plasma , immediately combines with plasma albumin .
-then this combination is transport to liver ,& the bilirubin is released from albumin .
-the bilirubin then conjugated with other  substances, about 80% of it conjugates with glucuronic acid to form bilirubin glucuronide & then is excreted into bile.
- in large intestinal tract (colon ) the bilirubin is reduced by bacterial enzymes to form urobilinogen & stercobilin & urobilin .
- the 5% of urobilinogen is excreted by the kidney into the urine , after exposure to air in the urine the urobilinogen become oxidized to urobilin , or in the feces it oxidized to form stercobilin (which provide the brown color of the stool ) .
-the iron from the heme is reused for hb synthesis .

- reaction of hemoglobin :-

-hemoglobin binds o2 to form oxyhemoglobin , the o2 attaching to the ferrous iron (fe+2) in the heme .
-the affinity of hb for o2 is affected by ph ,          temperature and the concentration of the 2,3 diphosphoglycerate (2,3-dpg) , since 2,3 –dpg compete with o2 for binding to hb .
-when blood is exposed to various drugs and other oxidizing agents invitro or in vivo , the ferrous iron (fe+2) in molecule is converted to ferric atom (fe+3) forming methemoglobin or sulfhemoglobin  is formed in present of  asulfur -containing  drug . these abnormal hb are unable to transport oxygen .
-carbon mono oxide (co) reacts with hb to form carboxy hemoglobin . the affinity of hb for o2 is much lower than its affinity for (co) carbon  monoxide.

- iron and iron metabolism :-

-the tissues of a 70 kg adult male contain between 3 and 4gm of iron which  is distributed in various compartment .
-70 %  of the iron in the  body is in hb , 3% in myoglobin and the remainder in ferritin .
-normal plasma iron level is about 130 µg /di in men and 110 µg /di in women .

- iron metabolism :-

-iron metabolism involves absorption , transportation , utilization , storage & excretion .

- absorption :-

-iron is absorbed in all parts of the small intestine , but absorbed almost entirely in the upper part of the small intestine , mainly in the duodenum .
-iron is released from food complexes by digestive enzymes & is partially reduced to the ferrous form (fe+2) .
-the intestinal mucosa controls iron absorption from food sources by an energy – dependent process but high iron content in intestinal tract may result in absorption by passive diffusion .
-the ferritin content of the intestinal mucosal cell determines the amount of iron absorbed , since a low ferritin level due to a low plasma ferritin allows iron absorbed into the cell to pass into circulation .
-elemental iron is biologically active in the ferrous (fe+2) & ferric (fe+3) states . in general an acidic condition , or lower ph , favors the ferrous state & iron absorption , whereas neutral & alkaline phs favor the ferric state & decreased iron absorption .
-the best sources of dietary iron are liver red meat , egg yolk , dried fruits .

- transport :-

-iron absorbed from the intestinal tract or released by hemoglobin catabolism .
-iron is transported from the mucosal cells to the blood in the ferrous state , where it is converted to the ferric state by serum ferroxidases .
-it is then incorporated into specific iron – transport protein , transferrin .
-one molecule of transferrin can bind two molecules of ferric iron .
-transferrin releases iron to erythroblasts & reticulocytes by attachment to specific receptors on the cell membrane & reduction of the ferric iron (fe+3) to ferrous iron (fe+2) .                    -excess iron in blood is deposited in all cells of the body but especially in the liver cells .
- utilization :-

-iron within the cell is found in the mitochondria.
-the mitochondrial iron is incorporated rapidly into protoporphyrin to form heme .

- iron storage :-

-iron is stored in the tissues in two forms : as a soluble form , called ferritin & as insoluble iron or hemosiderin .
-ferritin is found in all tissues & in high concentration in liver , spleen & bone marrow .
-about 70% of the storage iron is present as ferritin & the remainder as hemosiderin .
-hemosiderin is insoluble protein complex with higher iron content than ferritin (37%by weight) .
 
- requirement :-

-the average daily loss of iron in urine , faeces & sweat is 1-2 mg & although the normal diet contains about 15 mg of iron only (1-2 mg) are absorbed .
-since the average quantity of iron derived from the diet each day must at least equal that lost from the body .
-in menstruating women , the average blood loss is 60 to 80 ml / month , representing approximately 30 to 40 mg of iron lost per month , an additional 1 to 1.5 mg of iron daily is therefore needed to maintain iron balance .
-pregnancy creates an iron requirement of about 700 mg (fetus , placenta , blood loss & lactation) , so during pregnancy , iron absorption increases up to 20 percent .

vitamins needed for formation of rbcs :-

-vitamin b12 (cobalamin) or (cyanocobalamin) :-

-vitamin b12 or cobalamin has a similar structure to heme in having four pyrrole rings, but these are linked to a cobalt atom.
-vitamin b12 is formed mainly by bacterial synthesis & the only source to man is dietary & mainly in foods of animal origin, such as meats, eggs , dairy products & liver.
-vit. b12 is an essential nutrient for cells of the body ,& growth of tissues in general is greatly depressed when this vitamin is lacking .
-this results from the fact that vit .b12 is required for synthesis of dna. since tissues that produce rbcs are among the most rapidly growing & proliferating of all the body’s tissues ,lack of this vitamin especially inhibits the rate of rbcs production .
-furthermore , the erythoblastic cells of the bone marrow ,in addition to failing to proliferate rapidly , become larger that normal , developing into megaloblasts ,& the adult erythrocyte called a macrocyte .
-there fore , it is said that vit . b12 deficiency causes maturation failure in the process of erythropoiesis.   
-total body vit . b12 is about 3000µg & is stored mainly in the liver .
-between i to 4µg are required daily to replace that lost by the body .
-a normal diet contains over one microgram daily.

-absorption :-
-dietary vit. b12 is released from its binding to proteins by gastric & intestinal enzymes .
-passive absorption does occur but very small ( 1% of oral dose) & is ineffective unless there is a very high vit. b12 intake .
-the alternative & physiologically effective mechanism is by binding to gastric intrinisic factor (if) .

-intrinsic factor (if):-

-is a glycoprotein with amw of 45,000,which is secreted by parietal cells of the stomach .
-cyanocobalamine becomes firmly bound to if in the intestine , which one molecule of if binds one molecule of vit. b12.
-the intrinsic factor – cyanocobalamin complex (if-b12 complex ) then becomes bound to specific receptors on the ileal mucosal cells & this allowing vit b12 for absorption .
-the role of intrinsic factor in the process is to stimulate endocytosis , so the cyanocobalamin is transferred across the intestinal epithelium.
-vit. b12 is that released from the ileal cell & bound to a transport protein in the blood stream transcobalamin ? .
-in this bound state the vit b12 is protected from digestion by the gastrointestinal enzymes .
-once vit. b12 has been absorbed from the g.i.t it is stored in large quantities in the liver & then released slowly as needed to the bone marrow & other tissues of the body .
-the total amount of vit. b12 required each day to maintain normal red cell maturation is only about 5 micrograms ,& the normal store in the liver & other body tissues is about 1000 times this amount.
-there fore ,as many as 4 to 5 years of defective b12 absorption are required to cause maturation failure anemia .
-so in adequate absorption of this vit. b12 causes megaloblastic anemia which is called pernicious anemia .
-final lack of if, there fore , causes loss of much of the b12 because of both enzyme action in the gut & failure of  its absorption .

-folic acid :-             

-folic acid is also concerned with the maturation of rbcs . since folic acid , like vit . b12 , is required for formation of dna .
-if there is a deficiency of folic acid the marrow fills with megaloblasts & the number of mature red cells in the peripheral blood is reduced & cause megaloblastic anemia .
-dietary deficiency results from a poor diet usually owing to alcoholism , poverty , old age or chronic overcooking of vegetables .
-in the alcoholic , foliate deficiency is the number one cause of anemia . since alcohol has a direct antagonistic effect on folic acid metabolism .
-folic acid is present in green vegetables (especially spinach ) , liver & kidney .
-total body content is 6-10 mg present in the liver.
-in normal pregnancy 300-500 µg are required daily .

blood functions

(1):-transport of nutrients from digestive tract                                                                                                                  to tissues .
(2):-transport of metabolites ( eg . lactic acid                        from muscle to liver ) .
(3):-transport of excretory products from                                    tissues to excretory organs (urea in liver to                kidney ) .
(4):-transport of gases (o2& co2 )between                                  respiratory organs & tissues .
(5):-transport of hormones & vitamins .
(6):-transport of heat from deeper organs to surface.
(7):-coagulation , serves to protect against blood loss.
(8):-forms antibodies which helps to resisting                                                            the various specific infections .

- anaemias:-

-anaemia a functional in ability of the blood to supply the tissue with adequate oxygen for proper metabolic function , caused by reduction ( below normal ) in number of rbcs , quantity of hb & volume of pcv per 100 ml of blood .
 
-there are two main classifications of anaemia:-

(1):-the pathogenetic & aetiological classification .
(2):-morphological classification .

(1):-pathogenetic & aetiological classification:-
-the main pathogenic & aetiological factors responsible for causing anaemia are :-

(a):- impaired rbc’s production due to deficiency of various factors promoting erythropoiesis :-
eg :- iron deficiency anaemia:-                                               
-iron deficiency is a state in which body iron stores are depleted . the causes of iron deficiency are related to poor dietary supplementation , diminished absorption increased requirements & excessive iron (blood) loss .
-the iron enzyme myeloperoxidase is essential to neutrophil phagocytosis & bacterial killing & both functions may be diminished with iron depletion, so cell – mediated immunity (a t- cell function) can be impaired , but antibody production (a b – cell function) is normal .

-distribution of body iron
form   amount of iron average adult
  male (gm)                  female (gm)            % of total
haemoglobin   2.4  1.7  65
ferritin & haemosiderin  1.0  0.3  30
myoglobin   0.15  0.12  3.5
haeme enzymes     
cytochromes  0.02  0.015  0.5
catalase     
peroxidase     
flavoprotein     
transferrin bound iron   0.004  0.003  0.1

-an anaemia due to adeficiency of iron (iron deficiency anaemia) is associated with a deficiency of hb in the red cells ( hypochromic anaemia ) & cells that are smaller than normal (microcytic anaemia ) .
-other example is megaloblastic macrocytic anaemia:- due to deficiency of vitamin b12 or folic acid & cobalt . as described above , impaired dna synthesis can be caused by vit . b12 & folic acid deficiency . this anaemia is associated with a deficiency of red cells, but the cells that are present will be larger than normal & will contain an adequate amount of hb . in order to differentiate between these two types of anaemia , a red cell count ,a haemoglobin estimation & a haematocrit determination are made .

(b):-excessive loss of blood whether acute or chronic:-

-in acute blood loss , after rapid hemorrhage the body replaces the plasma within one to three days , but this leaves a low concentration of rbc’s . if a second hemorrhage dose not occur , the rbc’s concentration returns to normal within three to four weeks .

-in chronic blood loss , the person frequently cannot absorb enough iron from the intestine to form hb as rapidly as it is lost .
-therefore , rbc’s are then produced with too little hb inside them , giving rise to microcytic hypochromic anaemia .

-for examples of this anaemia are :

-acute post – haemorrhagic anaemia .
-chronic post – haemorrhagic anaemia .

(c):-excessive destruction of rbc’s as in :-

-haemolytic anaemia :-
-a haemolytic state exists when the in vivo survival of the red cell is shortened .
-the presence of anaemia in an individual patient is , however , dependent on the degree of hemolysis & the compensatory response of the erythroid elements of the bone marrow .            -normal bone marrow is able to increase its output about six –to eight – fold , so that anaemia is not manifest until this capacity is exceeded , corresponding to a red cell lifespan of about 15 to 20 days or less.

-haemolytic anaemias may be classified as follows:-

(1):-intracorpuscular defects:-
   
-such as hereditary defects:-   
as the following :-
-defects in the red cell membrane.
-enzyme defects.
-hemoglobinopathies.
-thalassemia syndromes.

(2):-extracorpuscular defects:-
-such as:-
-immune haemolytic anaemia.
-chemicals & toxins.
-physical agents.
-splenic sequestration ( hypersplenism ).
-infections.

-the examples of the red cell membrane defects      are :-

-hereditary spherocytosis (hs)

-in which the rbc’s are very small in size & they
are spherical in shape rather than being
biconcave discs .                           
-in hs is a loss of surface area of the red cell resulting in a decreased surface – to –volume ratio , therefore  these cells less deformable than normal .
-therefore , on passing through the splenic pulp they are easily ruptured by even slight compression .

-hereditary elliptocytosis ( ovalocytosis) (he)

-he is a disorder characterized by the presence of large numbers of elliptical red cells in the peripheral blood .

-hereditary stomatocytosis
-stomatocytes have a linear slit like unstained area in the center & gives the appearance of a mouth – like orifice ( hence the name – stomatocyte ).
   
-the example  for hereditary enzyme deficiencies is:-
glucose -6- phosphate dehydrogenase ( g6pd) deficiency:-

-g6pd deficiency is transmitted by a mutant gene , located on the x – chromosome .
-g-6- pd catalyzes the first step in the pentose phosphate pathway (aerobic pathway ).
-oxidative catabolism of glucose is accompanied by reduction of nadp to nadph ,which is required to reduce glutathione (gsh) .
- reduced glutathione is important source of reducing potential , that protects hb from oxidative denaturation .
- g6pd activity is highest in young erythrocytes & decreases as aging of the cell occurs .
- gsh deficiency results in oxidative destruction of certain erythrocyte components , including sulfhydryl group of globin chains & the cell membrane.
- more than 50 chemical agents may induce hemolysis in g6pd deficient erythrocytes .
-the drug – induced hemolytic results when g6pd deficient erythrocytes fail to produce sufficient nadph & subsequently fail to maintain adequate levels of gsh .
-drugs which may lead to haemolytic anaemia in g6pd deficiency :-
(a):-antimalarias – primaquin , chloroquin pamaquin , pentaquin .
(b):-analgesic – acetylsalicylic acid , & paracetamol .
(c):-anti – bacterial – sulphonamides , nitrofurones , penicillin , streptomycin , chloramphenicol .
(d):-miscellaneous – vitamin k methylene blue , naphthalene .
-certain g-6-pd- deficient individuals also exhibit a sensitivity to the fava bean (favism) these individuals develope severe hemolysis after ingesting the fava bean or even after inhaling the plant’s pollen .

-hemoglobinopathy syndromes :-
-as in sickle cell anemia :-

-the amino acid sequences in the polypeptide chains of hb are determined by globin genes.
-so there are 2 major types of inherited disorders of hemoglobin in humans :
-the hemoglbinopathies ( siclcle cell anemia ). in which abnormal poly peptide chains are produced , & the thalassemias , in which the chains are normal in structure but  produced in decreased amounts because globin genes have been deletingd or rendered nonfunctional .
-mutant genes that cause the production of abnormal hb are widespread & many abnormal hb have been described in humans .
-they are usually identified by letter – such as hbc ,e , i , j , s , etc  .
-in most instances , the abnormal hb differ from normal hba in the structure of the polypeptide chains
-in sickle cell anemia :- the rbc’s contain an  abnormal type of hb called hbs , in which the ?  chains are normal but the b chains are abnormal , because among the 146  a . a . residues in each b polypeptide chain , one glutamic acid residue has been replaced by avaline residue .
-hbs is very insoluble at low o2tensions ,so  when this hb is exposed to low concentration of o2 , it precipitates into long crystals inside the red blood cell
-these crystals elongate the cell & give it the appearance of being a sickle rather than a biconcave disc . the precipitated hb also damages the cell membrane. so that the cells become highly fragile .

-thalassemia:-
-is another hereditary type of anaemia in which the rbcs are unable to synthesize adequate amounts of either the alpha or beta poly – peptide chains required to form the hb.

-there are two major types of thalassemia:-

-alpha thalassemia :- which is caused by a defect in the rate of synthesis of ? chains .
-in ? thalassaemia hb a, a2 & f are equally depressed & there is microcytic, hypochromic anaemia . in the absence of ? chains ,b or y chains are produced more & form hb ( ?4 ) or hb bart’s (y4).

-beta thalassemia :- caused by a defect in the rate of synthesis of beta chains .
-in ? thalassaemia is reduced b chain production there fore hba produced is less & the anaemia produced is microcytic  , hypochromic anaemia .
-total hb is maintained by increase in gamma & delta chains so, hba2 & hbf increase.

(2):-morphological classification:-

-based on morphology of rbcs , which depend on the rbc indices .
- the rbc indices are the mean cell volume (mcv)                                                                                                                                            mean cell hemoglobin (mch), & mean cell hemoglobin concentration (mchc) .
-the mcv :- is used as an estimation of the average size of the rbc, & may be either calculated by dividing the hematocrit by the number of rbcs , or directly measured using most automated cell counters .if the mcv is in the reference range then the rbcs referred to as being normocytic rbcs . when the  mcv is less than normal , the rbcs are referred to as being microcytic , when greater than normal , macrocytic.
-the average volume of a red cell (mcv) is found by dividing the volume of red cells in one liter of blood by the number of cells in one liter of blood:-
  -when i femtoliter equals 10-15 liters )
-normal range is 85-93fi
-both mch & the mchc are used to determine the content of hb in rbcs .
-the mchc is said to be more reliable than the mch , because it considers the entire blood volume rather than a single cell.
-the mch is not dependable when rbcs vary markedly in size .
-if there is a normal mchc, then the rbcs are referred to as normochromic . hypochromic rbcs have a less than normal mchc
-mch is determined by dividing the amount of hb of one liter of blood by the number of cells in  one liter of blood .
-  exam ., normally ,

-the normal range is 27-32 pg.
-mchc  is found by dividing the hb content per liter by the hematocrit ( this gives the quantity of hb in a given volume of red cells.

  -normally                                                  ,
 
-the normal rang is 31-35%
- depend on this rbcs indices (mcv, mch,                                                        mchc) the anemia be typed as:-

(1):- macrocytic anaemias :-
there is increase in the volume of rbcs (mcv) (having a raised mcv),with mchc remaining normal .this type of anaemia usually occur in association with folate or vitamin b12 deficiency.

(2):- normocytic normochromic anaemia :-
  the number of rbcs is reduced , while the mcv, mch, & mchc remain practically un changed.
 
(3):- microcytic hypochromic anaemia:-
this anaemia usually related to iron – deficiency anemia .thalassemia ,ahemoglobinopathy is also a common cause of microcytosis .
- in which the mcv is reduced ( less than 76fi) & mchc is reduced less than 30 gm%.   
       
(hemopoiesis) or hematopoiesis

-hemopoiesis refers to the formation & development of the various types of blood cells from the bone marrow hemopoietic stem cell, so the number of blood cells within the blood is kept as a constant number by the formation of new blood cells.
-during the first weeks of embryonic life , hematopoiesis begins in the yolk sac with mesenchymal stem cells forming so – called blood islands . these nucleated cells differentiate into primitive erythroid cells that contain embryonic hb but do not mature into circulating erythrocytes .
-yolk sac stem cells migrate first to the liver & then to the spleen during the third month of fetal life , thus making the liver & spleen early sites of blood cell formation .
-erythropoiesis begins in the marrow about the 12th week of embryogenesis & is soon followed by granulopoiesis & megakaryopoiesis . eventually the bone marrow becomes the major site of blood cell development in the fetus.
-at the time of birth, the liver & spleen have ceased cell development & the active sites hematopoiesis are in bone cavities, since bone seems to provide the proper environment for proliferation & differentiation.
-hematopoiesis gradually decreases in the shaft of the long bones & after age 4 , fat cells begin to appear in the long bones .
-around age 18, hematopoietic marrow is found in the sternum, ribs , pelvis , vertebrae , & skull .

-there are two types of hemopoietic tissues:-
-(1):-myeloid tissue.
-(2):-lymphatic tissues.

-(1):- myeloid tissue:-
-by which the red blood cells & granular leucocytes derived.
-myeloid tissue is found in the marrow cavities of bone which is termed the bone marrow.
-two types of bone marrow have been described according to their appearance on gross examination: -

-(a):- red bone marrow: -
-whose color is due to the presence of numerous erythrocytes & their precursors in several phases of maturation.

-(b):– yellow bone marrow: -
-rich in adipose cells which dose not produce blood cells, except upon conversion into red bone marrow that is induced by sever bleeding or hypoxia.
-in new borns, all bone marrow is red & is therefore active in the production of blood cells. -as the child grows, most of the bone marrow changes into the yellow .
-in adults, red bone marrow is found principally in the skull, sternum , ribs & proximal epiphysis of some long bones.
-the bone marrow is actually one of the largest organs in the body, approaching the size & weight of the liver. it is also one of the most active.
-normally, 75% of the cells in the marrow belong to the white blood cell – producing myeloid series, & only 25% are maturing red cells, even though there are over 500 times as many red cells in the circulation as there are white cells . this difference in the marrow probably reflects the fact that the average life span of white cells is short, whereas that of red cells is long.

-(2) lymphatic tissue: -

-by which the lymphocytes & plasma cells derived.
-the stroma of lymphoid tissue, like that of myeloid tissue, contains a framework of reticular fibers closely associated with primative reticular cells.

-there are several theories about hemopoiesis: -
-(1) the monophyletic theory: -
-holds that all blood cells, red & white blood cells arise from a common stem cell.
-(2) the polyphyletic theory: -
-in which there is a primitive stem cell for each type of blood cells.
-today the monophyletic theory appears to be accepted by the majority of hematologists.

-production of the rbcs :-
-in the early few weeks of embryonic life , primitive red blood cells are produced in the yolk sac .
-during the middle part of the gestation the liver is the main organ for production of rbcs, at the same time quantity of rbcs is also produced by the spleen & lymph nodes .
-then during the latter part of gestation & after birth , rbcs  are produced exclusively by the bone marrow.

-erythropoiesis:-
-the blood cells are derived from a cell known hemocytoblast ( pluripotent marrow stem cell ) .
-the hemocytoblasts are derived from primitive reticular cells which are located through the bone marrow.
-the hemocytoblasts give rise to rbcs, granular leucocytes & platelets.
-the erythropoiesis involved anumber of
stages :-
1-proerythroblast
2-basophilic erythroblast
3-poly chromatophilic erythroblasts
4-normoblast
5-reticulocytes
6-erythrocytes ( mature rbcs)
1-proerythroblast :- 
-this cell is large cell about(12 to15microne ) in diameter , which is differentiate from hemocytoblast .
-it is small amount of hb can be detected in their cytoplasm .

2- basophilic erythroblasts :-

-this cell is differentiate from proerythroblast .    -these cells are smaller than proerythroblast & their cytoplasm is more basophilic .in which begins the synthesis of hb .

3-polychromatophilic erythroblast :- 

-when the eosinophilia are visible the cell is considered to be apolychromatophilic erythroblast.
-these small areas of eosinophilia are formed due to local accumulations of hb .

4-normoblast :- 

-the normoblast is small than the polychromatophilc erythroblast & contain a smaller nucleus which stain densely basophil .
-finally , after the cytoplasm of the normoblast has become filled with hb to a concentration of approximately 34 percent, the nucleus become extremely small & is extruded .
-the cell at this stage of development is called reticulocyte .

5- reticulocytes:-

- appear a little larger than mature rbc & exhibit a slight bluish after romanwasky staining , because of the present of the network of remanant rna .
-the majority of reticulocytes lose their reticular structure before leaving the bone marrow . then called erythrocyte .

- regulation of rbcs production:-

- tissue oxygenation as the basic regulator of rbcs production , since any condition that causes the quantity of oxygen transported to the tissues to decrease ordinarily increases the rate of rbcs production .
-thus , when a person becomes extremely anemic as a result of hemorrhage or any other condition , the bone marrow immediately begins to produce large quantities of rbcs .
-also,  destruction of major portions of the bone marrow by any means , especially x–ray therapy , causes hyperplasia of the remaining bone marrow .
- at very high altitude , where the quantity of oxygen in the air is greatly decreased , insufficient oxygen is transported to the tissues , & rbcs are produced so rapidly that their number in the blood is considerably increased .
-so tissue hypoxia is the main stimulus for the production of circulating hormone , erythropoietin by the kidney .
-erythropoietin is a glycoprotein hormone with mw of about 40,000.
-in the absence of erythropoietin , hypoxia has either no effect or very little effect in stimulating red blood cell production .
-in the normal person , 90 to 95% of all erythropoietin is formed in the kidneys .some researches has suggested that epo might be formed by the juxtaglomerular cells , cells in the walls of the afferent arterioles adjacent to the glomerulli.
-the other 5 to 10% of epo formed in other tissues mainly liver & macrophages .
-it is believed that when these kidneys become hypoxic , that they release enzyme called renal erythropoietic factor into the blood where it acts with in a few minutes on one of plasma proteins, a globulin , to split away the glycoprotein epo.
-epo is to stimulate the production of proerythroblasts from hemopoietic stem cells in the bone marrow .in addition , once the erythroblasts are formed , the epo causes these cells also to pass more rapidly through the different erythroblastic stages than normally , also speeding up the production of new cells .

- genesis of the leucocytes:-

- granulopoiesis:-   

- granulopoiesis or myelopoiesis refers to the production of neutrophils , eosinophils & basophils.
-maturation of the granulocytic series of cells is characterized by the development of primary blue - staining granules that are later replaced by secondary granules that differ in their affinity for various dyes , cells with affinity for basic dyes are basophils , those cells that stain reddish - orange with the acid dye are eosinophils the cells that do not stain intensely with either acid or basic dyes are called neutrophils , & the nucleus undergoes changes from round to multilobular forms.
-the granulocytes are stored within the marrow until they are needed in the circulatory system .
-normally about three times as many granulocytes are stored in the marrow as circulate in the entire blood. this represents about a six days supply of granulocytes .
-in general , the wbcs need essentially the same vitamins & amino acids as most of the other cells of the body for their formation .
- especially does lack of folic acid , acompound of vitamin b complex , block the formation of wbcs as well as prevent maturation of rbcs.

- the stages of granular leucocytes development & differentiation from the hemocytoblast are  :-
  1- myeloblast .
  2- promyelocyte .
  3- myelocyte .
  4- metamyelocyte.

        1:-myeloblasts :-

-myeloblasts are arise from hemocytoblast , which contain large spherical nucleus. the cytoplasm some what more basophil than that hemocytoblast .

2:-promyelocyte :-

- their cytoplasm is more basophilic than that of the myeloblast & contain a zurophil granules. this granules produced only in this stage .

3:-myelocytes :- 

-this cells are arise from promyelocyte through the differentiation of this cell .
-in the process of differentiation , the essential change is appearance of specific granules which have the size , shape & staining characteristic that allow the granular leucocytes to distinguish into neutrophil , eosinophil & basophils .

4:- meta myelocytes :-

- this cells are produced at the final division of the myelocytes. the nucleus at the first horse – shoe shaped.
-the late metamyelocyte is known as a band cell , in which the nucleus become lobation .
-the number of lobes usually from three to five .
-the mature cells enter the sinusoid of bone marrow & thus reach the blood stream .

    - hemocytoblast              myeloblast              promyelocyte               

myelocyte            basophils                          metamyelocyte 
                                                neutrophils
                                                eosinophils         
    mature  granulocytes                              band cell                                                                             
                                                                                                                                                         

-the development of monocyte :- 

-the monocyte is developed from stem cells within the bone marrow which are called monoblasts.
-the monoblasts gives rise to the promonocyte & the promonocyte differentiate to the monocyte which is smaller than the promonocyte.
-the monocytes present in both bone marrow & blood .
-monocytes leave the blood to enter the tissues.
 
monoblast                    promonocyte                monocyte

-the development of lymphocyte:-

-lymphocytes & plasma cells are produced in the various lymphogenous organs, including the lymph glands , the spleen , the thymus ,the tonsils & various lymphoid rests in the bone marrow, gut, & elsewhere .
-the lymphocytes are arise from large spherical cells which are called lymphoblasts . these cells are resemble the hemocytoblast of bone marrow.
-as the lymphoblast differentiation the nuclear chromatin become more dense & compact .
-these cells are reduced in size & are termed prolymphocyte . these cells give rise directly to the lymphocytes .
-the development of small lymphocytes , principally occur in the lymphnodes & spleen

{lymphoblast            prolymphocyte        lymphocyte}

-megakaryocytes & platelet formation:-
-the megakaryocytes are giant cells ( 30 to 100 µ or more in diameter ) .
-which are a rise from the hemocytoblast in bone marrow . and they may be found also in the hemopoietic tissues ( liver , spleen ) during embryonic development .
-the nucleus is lobed & these lobes are connected by fine strands of chromatin materials .
-with maturation of the megakaryocyte , numerous invagination of the plasma membrane occur through out the cytoplasm as compartments & then platelets are formed .

-hemocytoblast          megakaryoblast

promegakaryocyte            megakaryocyte      platelets         

( blood types ))
-the membranes of human red cells contain a variety of antigens called agglutinogens .
-the most important & best known of these are the a & b agglutinogens , & individuals are divided into 4 major blood types , type a , b , ab & o on the basis of the agglutinogens present in their red cells.
-there are a & b antigens in many tissues other than blood .
-they have been found in salivary glands , saliva , pancreas , kidney , liver , lungs , testes , semen & amniotic fluid .
-antibodies against agglutinogens are called agglutinins .
-they may occur naturally (ie , be inherited),or they may be produced by exposure to the red cells of another individual .
-this exposure may occur via a transfusion or during pregnancy , when fetal red cells cross the placenta & enter the circulation of the mother .
-agglutinins against a & b agglutinogens are inherited , whereas antibodies against the rh group & other agglutinogens are produced by exposure to foreign red cells .
-individuals with type a blood ( those have agglutinogen a on their red cells ) always have an appreciable titer of an antibody against agglutinogen b called the anti –b agglutinin.
-persons with type ab blood are called universal recipients because they have no circulating agglutinins.
-that can be given blood of any type without developing a transfusion reaction due to abo incompatibility .
-type o individuals are universal donors because there are no regular anti – o agglutinins & type o blood can be given to anyone without producing a transfusion reaction due to abo incompatibility .
-since group o red blood cells have no agglutinogens & therefore do not react with either the anti – a or the anti – b serum .
-the a group is subdivided into types a1 & a2 . -therefore there are 6 abo groups instead of 4 : b , o, a1 , a2 , a1b & a2b .
-in addition to the 6 antigens of the abo system in human red cells , there are over 500 billion possible known blood group phenotypes .
-the number of blood groups in animals is as large as it is in humans .
-the agglutinins are gamma globulins , as are other antibodies , & are produced by the same cells that produce antibodies to any other antigens .
-most of them are igm & igg molecules .
-the genetic determination of the agglutinogens , genes on two adjacent chromosomes , one gene on each chromosome , determine the abo blood groups .
-these are alleiomorphic genes that can be any one of three different types , but only one type on each chromosome:- type o, type a or type b.
-there is no dominance among the three different allelomorphs .
-however , the type o gene is either function less or almost functionless , so that it causes either no type o agglutinogen in the cells or such a weak agglutinogen that is normally insignificant .
-so the six possible combinations of genes are oo , oa , ob , aa , bb & ab .
-these different combinations of genes are known as the genotypes , & each person is one of the six different genotypes .
-since that a person with genotype oo produce no agglutinogens at all & therefore , the blood group is o .
-a person with either genotype oa or aa produce type a agglutinogens & therefore , has blood group a .
-genotype ob & bb give group b blood , & genotype ab gives group ab blood .

-aside from the antigens of the abo system , those of the rh system are of the greatest clinical importance .
-the rh factor named for the rhesus monkey because it was first studied using the blood of this animal , is a system composed of many antigens (c,d,e,c,d & e ) .
-d is by far the most antigenic , & the term rh – positive as it is generally used means that the individual has agglutinogen d.
-the rh – negative individual has no d antigen & forms the anti – d agglutinin when injected with d – positive cells .

-when rbc’s containing rh factor , are injected into a person without the factor, that is , into the rh negative person anti rh agglutinins develop very slowly , the maximum concentration of agglutinins occurring approximately two to four months later .
-this immune response occurs to a much greater extend in some people than in others .
-on multiple exposure to the rh factor , the rh negative person eventually becomes strongly sensitized to the rh factor , that is he or she develops a very higher titer of anti – rh agglutinins .
-another complication due to rh incompatibility arises when an rh – negative mother carries an rh – positive fetus .
-small amounts of fetal blood leak into the maternal circulation at the time of delivery , & some mothers develop significant titers of anti – rh agglutinins cross the placenta to an rh positive fetus , they can cause hemolysis , erythroblastosis fetalis .
-if hemolysis in the fetus is sever , the infant may die in uterus or may develop anemia .
-the usual treatment for erythroblastosis fetalis is to replace the newborn infant’s blood with rh negative blood .
-approximately 400 ml of rh- blood is infused over a period of 1.5 or more hours while the baby’s own rh+ blood is being removed .

-this procedure may be repeated several times during the first few weeks of life , mainly to keep the bilirubin level low & thereby to prevent kernicterus .
-the anti – rh agglutinins that had come from the mother will have been destroyed .
-approximately 85% of all caucasoids are rh+ & 15% rh- .

-the blood groups showing their genotypes & phenotype & their agglutinogens & agglutinins .
   
genotypes   blood groups  agglutinogens*  agglutinin**
oo  o  -  anti-a& anti-b
oa or aa  a  a  anti- b
ob or b  b  b  anti-a
ab  ab  a & b  none
*cell antigen
**serum antibodies

                                               
                                                  o
                                                                                                                                   
                                                                          a                                b
                   
                                                                                            ab 
                                                                                     
                                                                                           

 
(( transfusion ))

-the most common reason for transfusion is decreased blood volume .
-if a patient becomes severely anemic it may be no longer possible to treat this by simply improving the diet & to add iron , b12 or folic acid supplement . it may be necessary to give a blood transfusion .
-the blood for a blood transfusion is taken under sterile conditions .
-acid citrate is added to prevent the blood from clotting , & glucose ( dextrose ) added to feed the red cells (acd= acid citrate dextrose blood , -cpd= citrate phosphate (to maintain the level of 2,3 – dpg) , dextrose blood) .
-the wbcs do not survive for more than a few hours when the blood is taken for a blood transfusion & a transfusion of stored blood can therefore not be used to increase the number of white cells in the circulation .
-it is very important that none of the blood transfusion apparatus should contain any soap or detergent because these substances dissolve the outer fatty membrane of the rbc’s , & will thus destroy the cells .
-the blood is stored at 4c0 & care must be taken to ensure that the temperature does not fall below freezing point because this would destroy the rbc’s , due to the formation of ice crystals .

-if blood of one blood group is transfused to a recipient of another blood group , a transfusion reaction is likely to occur in which the rbc’s of the donor blood are agglutinated .
-it is very rare that the transfused blood ever causes agglutination of the recipient’s cells for the following reason :-
-the plasma portion of the donor blood immediately becomes diluted by all the plasma of the recipient , thereby decreasing the titer of the infused agglutinins to a level too low to cause agglutination . on the other hand , the infused blood does not dilute the agglutinins in the recipient’s plasma to major extend .
-therefore , the recipient’s agglutinins can still agglutinate to donor cells .
-harmful effects or even death can result from a blood transfusion if the donor’s rbc’s become agglutinated by antibodies in the recipient’s plasma .
-if a donors rbc’s do not contain any a or b antigen , they of course can not be clumped by anti – a or anti – b antibodies for this reason the type of blood that contains neither a nor b antigens – namely type o blood - can be used as donor blood without the danger of anti – a or anti – b antibodies clumping its red blood cells . -type o blood is therefore called universal donor blood .
-while universal recipient blood is type ab , it contains neither anti – a nor anti – b antibodies in its plasma . therefore it cannot clump any donor’s rbc’s containing a or b antigens .
-so it is very important to maintain the life must know the groups of blood before making transfusion of blood between two person to prevent the clotting of blood & subsequently prevent the death .

-red cell fragility

-the osmotic fragility of freshly taken red cells reflects their ability to taken up water without lysis & is determined by their volume to surface area ratio .
-the ability of the normal rbc’s to withstand hypotonicity results from its biconcave shape which allows the cell to increase its volume by about 70% before the surface membrane is stretched .
-once this limit is reached , lysis occurs . the increase in osmotic fragility is a property of the spheroidal shape of the cell .
-spherocytes which have a decreased surface to volume ratio demonstrate an increased osmotic fragility .
-since rbc’s in solutions with a lower osmotic pressure , they swell , becoming spherical rather than disk shaped , & eventually lose their hemoglobin (hemolysis) which dissolves in the plasma , coloring it red .
-when osmotic fragility is normal , red cells begin to hemolyze when suspended in 0.45% (may be 48%) saline , & hemolysis is complete in 0.35% (may be 0.33%) saline .
-in hereditary spherocytosis , the cells are spherocytic in normal plasma & hemolyze more readily than normal cells in hypotonic sodium chloride solutions .

-(( hemostasis & blood coagulation ))

-the term hemostasis means prevention of blood loss .
-whenever a vessel is ruptured , hemostasis is achieved by several different mechanism including :-

-(1):- vascular spasm .
-(2):- formation of platelet plug .
-(3):- blood coagulation .
-(4):- growth of fibrous tissue into the blood clot                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    to close the hole in the vessel permanently .

-(1) vascular spasm:-
-immediately after a blood vessel is cut or ruptured , the wall of the vessel contracts , this lead to reduce the flow of blood from the vessel rupture .
-the contraction results from both nervous reflexes & local myogenic spasm .
-the nervous reflexes are initiated by pain impulses originating from the traumatized vessel or from nearby tissues .

-(2) formation of the platelet plug:-
-the second mechanism for hemostasis is formation of the platelet plug .
-platelets repair of vascular opening is based on several important functions of the platelet
  it self :-
-when platelets come in contact with a damaged vascular surface , such as the collagen fibers in the vascular wall or a damaged endothelial cells , they immediately change their characteristics .
-they begin to swell , they assume irregular forms with numerous irradiating processes protruding from their surfaces .
-they become sticky so that they stick to the collagen fibers , & they secrete large quantities of adp (adenosine diphosphate) & enzymes that cause formation of thromboxane a2 in the plasma which used to induce platelet aggregation .
-so these accumulation of platelet lead to form a platelet plug .
-this is loose plug but it is usually able in blocking the blood loss if the vascular opening is small . but if there is a large hole , a blood clot in addition to the platelet plug is required to stop the bleeding.

-(3) blood coagulation:-
-the third mechanism for hemostasis is formation of the blood clot . the clot begins to develop in (15 to 20) seconds if the trauma of vascular wall has been sever & in one to two minutes if the trauma has been minor .
-mechanism of blood coagulation:-

-basic theory:-
-over (30) different substances that effect blood coagulation have been found in the blood & tissues , some promoting coagulation which are called procoagulants , & others inhibiting coagulation which are called anti coagulants .
-whether or not the blood will coagulate depends on the degree of balance between these two groups of substances .
-normally the anticoagulants predominate & the blood dose not coagulate but when a vessel is ruptured the activity of the procoagulants in the area of the damage become much greater than that of anticoagulants & then a clot dose develop.

-general mechanism:-

-the clotting takes place in three essential steps:-

-first:- thromboplastin formation via the extrinsic system & the intrinsic system .

-second:- thrombin formation .

-third:- the thrombin acts as an enzyme to convert fibrinogen into fibrin (fibrin formation) .

-conversion of prothrombin to thrombin (thrombin formation) :-

-after prothrombin activator (thromboplastin) has been formed as a result of rupture of the blood vessel or as a result of damage .
-the prothrombin activator can then cause conversion of prothrombin to thrombin , which in turn causes polymerization of fibrinogen molecules into fibrin .
-prothrombin is a plasma protein , alpha 2 – globulin , having amw of 68,700 . it is present in normal plasma concentration of about 15 mg per 100 ml .
-it is unstable protein that can split easily into smaller compounds , one of which is thrombin .
-the thrombin has a mw of 33 , 700 almost exactly half that of prothrombin .
-vitamin k is required by the liver for normal formation of prothrombin (stimulates liver cells to increase their synthesis of prothrombin).

-effect of prothrombin activator (thromboplastin) to form thrombin from prothrombin :-

-as in below the conversion of prothrombin to thrombin occur under the influence of prothrombin activator & calcium ions.
-the rate of formation of thrombin from prothrombin is almost directly proportional to the quantity of prothrombin activator .
-the rapidity of clotting process is proportional to the quantity of thrombin formed .

prothrombin
  extrinsic or intrinsic       
prothrombin activator    ca+2
thromboplastin)            thrombin
                               
                fibrinogen                                            fibrin monomer           
ca+2                                       
                                                                                                    fibrin
stabilizing factor           
                                                      fibrin threads

[ conversion of prothrombin to thrombin & polymerization of fibrinogen to form fibrin threads ]

-conversion of fibrinogen to fibrin :-
-thrombin is a protein enzyme with proteolytic activity .
-it acts on fibrinogen to remove two low molecular weight peptides from each molecule of fibrinogen , forming a molecule of fibrin monomer which has the automatic capability of polymerizing with other fibrin monomer molecules .
-therefore, many fibrin monomer molecules polymerize within second into long fibrin threads that form the reticulum of the clot .
-in the early stages of this polymerization, the fibrin thread are not cross-linked with each other & the result clot is weak & can be broken easily .
-so another process occurs during the following few minutes that greatly strength the fibrin reticulum .
-this involves a substance called fibrin stabilizing factor that is normally present in small a mount in plasma .
-before fibrin stabilizing factor that can have effect on the fibrin threads it must it self be activated & then this process lead to form covalent cross - linked bonds between the adjacent fibrin threads .
-the fibrin threads adhere to damaged surfaces of blood vessels , therefore the blood clot which composed of a mesh work of fibrin threads running in all directions & entrapping blood cells & plasma becomes adherent to any vascular opening & there by prevents blood loss .

-clot retraction :-
-with in few minutes after a clot is formed , it begins to contract & usually expresses most of the fluid from the clot within (30 to 60) minutes , this fluid expressed is called the serum because of its fibrinogen & most of the other clotting factor have been removed .
-platelets are necessary for clot retraction to occur , there fore , failure of clot retraction if the number of platelets in the circulating blood is low .
-further more , platelets entrapped in the clot continue to release procoagulants substances one of which is fibrin stabilizing factor that causes more & more cross linking bonds between the adjacent fibrin threads .
-as the clot retracts , the edges of broken blood vessel are pulled together .

-formation of prothrombin activator (thromboplastin)
-there are two basic ways in which prothrombin activator can be formed :-

-(1) extrinsic pathway :-
-begins with truma to the vascular wall or to the tissue outside the blood vessels .
-(2) intrinsic pathway :-
-that begins in the blood it self .
-in both the extrinsic & intrinsic pathways a series of different plasma protein , especially beta – globulins play major roles . these are called clotting factors .

-the extrinsic mechanism for initiating clotting :-
-the extrinsic mechanism occurs according to the following three basic steps :-

-(1) release of tissue factor & tissue phospholipids :-

-the traumatized tissue releases two factors that set the clotting process into motion .
these are:-
-a) tissue factor:-
- which is proteolytic enzyme .
-b) tissue phospholipids :-
-which are mainly phospholipids of the tissue cells membranes .

-(2) activation of factor x to form activated factor x – role of factor v11 & tissue factor :-
-the tissue factor complexes with blood coagulation factor v11 & this complex , in the presence also of tissue phospholipids , act enzymatically on factor x to form activated factor x .
-(3) effect of activated factor x to form prothrombin activator – role of factor v :-

-the activated factor x complexes immediately with the tissue phospholipids released from the traumatized tissue & also with factor v to form complex called prothrombin activator (thromboplastin) .
-with in a few seconds this splits prothrombin to form thrombin , & the clotting process proceeds as has been explained.

(1) 

(2)  x                                                                                                                                                      activated x
             
                                                                                                              v 
  (3)                                                             
prothrombin activator   ca+2
  prothrombin                                                                            thrombin
    ca+2
 

((the extrinsic pathway for initiating blood clotting ))

-the intrinsic mechanism for initiating clotting :-
-the intrinsic mechanism occurs according to the following steps :-

-(1):-activation of factor ?? & release of platelet phospholipids by blood trauma :-
-blood trauma alters two important clotting factors in the blood factor ?? & the platelets .
-when factor ?? coming into contact with collagen , it takes out a new configuration that converts it into a proteolytic enzyme called activated factor ?? .
-the blood trauma also damages the platelets , & this lead to release platelet phospholipids which is called platelet factor ?.

-(2) activation of factor ?? :-

-the activated factor ?? acts enzymatically on factor ?? to activate this as well .
-(3) activation of factor ?? by activated factor ?? .
-the activated factor ?? then acts enzymatically on factor ?? to activate this factor also .

-(4):-activation of factor ?-role of factor      v? .

-the activated factor ?? , acting with factor v? & with the platelet phospholipids from traumatized platelet , activates factor ? .
-(5):-action of activated factor ? to form prothrombin activator        role of factor v .
-in this step the activated factor ? combines with factor v & platelet phospholipids to form the complex called prothrombin activator (thromboplastin) .
-the prothrombin activator with in seconds acts to cleavage of prothrombin to form thrombin .

(1)                  ??                      activated ?? 

(2)  ??                                      activated ??
                                                                                                    ca+2 
(3)                                        ??                                             activated ??
                                                      v?
                                                                  ca+2
  (4)                              ?   activated ?
  ca+2
   
(5)
                                                                                                 
                                                                                            v  
                                                               
prothrombin activator
                            prothrombin                                                thrombin
                                                                    ca+2           

(( the intrinsic pathway for initiating blood clotting ))

-fibrinolysis ( fibrin – lysing ) :-
-the fibrin - forming & fibrin – lysing systems are intimately related .
-fibrinolysis , is the physiologic process of removing un wanted fibrin deposits , in which the liquefaction of a fibrin clot is achieved by splitting a small number of peptide bonds, of fibrin to form soluble fragments .
-these fragments are then removed from the circulation by the macrophages of the reticuloendothelial system .
-this action of the fibrinolytic system re – establishes blood flow in vessels occluded by a thrombus .
-the fibrinolytic system is mediated mainly by the enzyme plasmin , which acts on fibrin to produce lysis of the clot .
-plasmin is generated from the circulating inactive zymogen called plasminogen .
-plasminogen is a single – chain protein with a mw of 92000 , which is synthesized in the liver & in the kidney .
-plasmin is an endopeptidase with properties similar to trypsin .
-the conversion of the precursor plasminogen to plasmin requires splitting an internal arginyl - valine bond & the result is an active enzyme comprising two chains – a heavy chain ( mw 47000 ) & light chain (mw 28000) combined by a single disulphide bond . the active site of plasmin is on the light chain .

-plasminogen is activated to plasmin by various substances:-

-(1):-tissue plasminogen activator ( tissue kinase released from injured tissue ) .
-tissue plasminogen activator (tpa) is produced by vascular endothelial cells & selectively binds to fibrin as it activates fibrin - bound plasminogen .

-(2):-thrombin:-
-it is also important to note that thrombin generates fibrin & plasmin formation .
-(3):-kallikrein ( is enzyme that can act on kininogens & converts them to kinins , the kinins may include kallidin & bradykinin . also kallikrein indirectly initiate clotting as well as plasmin formation .
-(4):-other substances :-
-urokinase , streptokinase , & staphylokinase .
-urokinase:- is believed to produced in the renal mucosa this enzyme is responsible for avoiding fibrin deposits in the kidney following injury .
-streptokinase:- is non physiological activator of plasminogen
-it is a protein of bacterial origin from haemolytic streptococci.

-inhibitors of plasmin:-
-antiplasmins are the most important physiological pathway in which plasmin , once formed , is neutralized .
-?2 – antiplasmin:-

-is a single – chain glycoprotein (mw 70,000) which reacts rapidly with plasmin forming a stable stoichiometric complex (mw 140,000) .
-the complex loses proteolytic activity when the antiplasmin is bound to the light chain of the plasmin molecule .

-antaclotting mechanisms:-

-the tendency of blood to clot is balanced in vivo by limiting reactions that tend to prevent clotting inside the blood vessels & to break down any clots that do form .
-these reactions include removal of some activated clotting factors from the circulation by the liver & reduction in the supply of clotting factors to the degree that they are used up during clotting .
-another is the interaction between the platelet - aggregating effect of thromboxane a2  & the antiaggregating effect of prostacyclin ,( which causes clots to form in the walls of the injured blood vessels) lead to keeps the vessel lumens free from clot .
-the endothelium of the blood vessels also plays an active role in preventing the extension of clots to normal blood vessels .
-all endothelial cells except those in the cerebral microcirculation produce thrombomodulin , a thrombin – binding protein that converts thrombin into protein c activator . -this protein activator a naturally occurring anticoagulant protein that in activates factor v & v? & in activates an inhibitor of plasminogen activator , increasing the formation of plasmin .
-plasmin is the active component of the fibrolytic system , by which fibrin & fibrinogen are lyses .

-abnormalities of hemostasis:-

-in some genetic conditions , normal clotting factors are replaced by abnormal factors .

-hemophilia a:-
-is of  interest because it is relatively common .  -a congenital defect due to abnormalities of the gene on x chromosome that codes for factor v? .
-so this disease is therefore as a sex – linked hereditary bleeding disorder characterized by greatly prolonged coagulation time owing to a deficiency of factor v? .

-the hemophilia b or christmas disease:-
-also congental , a hereditary bleeding disorder caused by a deficiency of factor ?? .
-hemophilia c:-
-a hereditary bleeding disorder caused by a
  deficiency of factor ?? .                             
-another cause of depressed formation of clotting factors by the liver is vitamin k deficiency.
-vit . k is necessary to promote the formation of four of the most important clotting factors , prothrombin , factor v?, factor ix,& factor x . in the absence of vit .k , insufficiency of these coagulation factors can also lead to a serious bleeding tendency.
-vitamin . k is continually synthesized in intestinal tract by bacteria so that vit . k deficiency rarely , except in newborn children before they establish their intestinal bacterial flora . however , vitamin k deficiency does often occur as a result of poor absorption of fats from the git, because vit. k is fat soluble.               

-vit.k    stimulates liver cells to      increase their synthesis of prothrombin        increased prothrombin concentration in blood  faster thrombin formation            faster clot formation .
         
( how vit.k acts to accelerate blood clotting )

-thrombocytopenia means the presence of a very low quantity of platelets in the circulatory system .
-persons with thrombocytopenia have a tendency to bleed as do hemophiliacs , except that the bleeding is usually from many small capillaries rather than from larger vessels , as in hemophilia.
-as a result , small punctate hemorrhages occur throughout all the body tissues.
-the skin of such a person displays many small, purplish blotches , giving the disease the name thrombocytopenic purpura.
-since the platelets are especially important for repair of minute break in capillaries & other small vessels. indeed , platelets can aggregate to fill such ruptures without actually causing clots.
-ordinarily, bleeding does not occur until the number of platelets in the blood falls below a value of approximately 50,000 per mm3 rather than the normal 150,000 to 350,000.
-levels as low as 10,000 per cubic mm are frequently lethal .
-an abnormal clot that develops in a blood vessel is called a thrombus.
-once a clot has developed ,continued flow of blood past the clot is likely to break it away from its attachment ,& such freely flowing clots from its attachment , & such freely flowing clots are known as emboli.
-emboli generally do not stop flowing until they come to a narrow point in the circulatory system.
-thrombi may occur any where in the circulation , in arteries , veins , capillaries , or chambers of the heart.
-the causes of thromboembolic conditions in the human being are usually two fold :-
-first , any roughened endothelial surface of a vessel – as may be caused by arteriosclerosis, infection or trauma, – is likely to initiate the clotting process .
-second , blood often clots when it flows very slowly through blood vessels .since if the blood is flowing too slowly , the concentration of the procoagulants in local areas often rise high enough to initiate clotting 

( immunity )

-immunity is the resistance of the body to invasion by bacteria , viruses , or other infectious agents or toxins.
-a person is born with innate immunity .
-each person is born with a certain amount of innate immunity that results from several special mechanisms:-

1-the reticuloendothelial system & white blood cells .
2-resistance of the intact skin to invasion by microorganisms .
3-destruction of bacterial organisms by the digestive enzymes in the stomach .
4-substances circulating in the blood .

-acquired immunity occurs following exposure to invading a gent or foreign substances .
-in addition to the natural immunity that normally exists in all persons , a person can develop not naturally immune .
-most destructive agents , such as bacteria , viruses ,or toxins , are mainly composed of protein molecules.
-antibodies can be formed also against nucleic acid & lipids if these are presented as nucleoproteins & lipoproteins. as well as can be formed against complex carbohydrate moieties.

-on entering the body , these proteins act as antigens & cause two types of immunity :-

1:-humoral immunity .
2:-cell –mediated immunity .

1:-humoral immunity :-     

-introduced by fodor in 1886, who observed a direct action of an immune serum on microbes during the course of his studies on anthrax bacilli.
-in humoral immunity ,the body developes circulating antibodies.
-the foreign antigens first enter the lymphoid tissue ,especially the lymph nodes.
-is mediated by b lymphocytes.
-there they cause plasma cells, which are derived from lymphocytes , to produce large quantities of antibodies that are specifically reactive for the type of protein ( or their chemical ) that initiated their production .
-once these antibodies have been formed & released into the body fluids ,which usually requires i week to several weeks , they then destroy the specific invader that had caused their formation & can also destroy any future invader of this same typed. 
-antibody destroy an invading agent or make it more susceptible to phagocytosis.
-antibodies are large protein molecules , usually ? globulins , that attach to the surfaces of bacteria or viruses , or they combine directly with toxins.
-so , they either destroy the invading agent or make it more susceptible to phagocytosis by the tissue macrophages or by white blood cells, or ,in the case of toxins , the antibodies can simply neutralize these agents by combining chemically with them .
-in early fetal development of the lymph nodes , no lymphocytes are present in the nodes. instead ,the early lymphocytes are formed & processed in the liver & the thymus gland.
-after processing , the lymphocytes are released into the circulating blood & eventually become entrapped in the lymph nodes.
-once in these nodes , those lymphocytes processed in the liver eventually are converted into plasma cells that become part of the humoral immune process to form antibodies.
 
(2):-cell - mediated immunity ( cellular immunity ) :-
 
-the concept was introduced by metchnikoff (1887).
-is mediated by t lymphocyte.
-cell – mediated immunity involves activation of lymphocytes processed in the thymus gland.
-the lymphocytes that are processed in the thymus gland also end up in the lymph nodes & other lymphoid tissues of the body.
-however, instead of forming antibodies when the lymph node is exposed to antigens, these cells form so – called sensitized lymphocytes, also called t cells because of their earlier processing in the thymus.
-large numbers of t cells are then released into the circulating blood & they spread throughout the body.
-there are three major types of sensitized t cells:-

(1):-cytotoxic t cells:-

-this type of t cells combine directly with antigens on the surfaces of invading organisms & can therefore destroy the organisms.
 
(2):-helper t cells :- 

-that function mainly in association with the plasma cells in the lymph nodes .
-they multiply many fold the capability of the plasma cells to produce humoral antibodies          in response to antigens .

(3):-suppressor t cells :-
-that suppress some of the immune reactions, in this way preventing the immune system from running wild & becoming destructive to normal tissues.
 

-immune tolerance :-

-normally the immune system does not attack the body’s own tissues .
-the immune process of the normal human body does not develop antibodies or sensitized lymphocytes that can destroy the body’s own tissues , although the body tissues are to a great extent like bacteria in their chemical composition.
-this phenomenon is called tolerance to the body’s own proteins & tissues .
-this results mainly from destruction during fetal life of those primordial lymphocytes in the thymus & liver that are capable of forming antibodies or sensitized lymphocytes against the body’s own proteins & tissues .
-it is likely that special suppressor t cells also develop to help cause tolerance .
-failure of immune tolerance leads to autoimmune disease .
-autoimmunity occurs particularly in older age or after some disease causes destruction of 
large amounts of body tissue with release of tissue antigens into the circulating body fluids .
-once the immune process has caused production of antibodies or sensitized lymphocytes that can attack the body’s own tissues these will then react against specific tissues & cause serious debility .
-examples of autoimmune disease include rheumatic heart disease , rheumatoid arthritis , thyroiditis, acute glomerulonephritis.