Blood Pa Tho Physiology

8/2/2019 Blood Pa Tho Physiology

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Composition of Blood:

(1) Plasma ~ 55% :a. Solutes 10%:

i. Electrolytes (Na+,Cl-,HCO3-,K+)ii. Nutrients, Hormones, Urea.iii. Plasma proteins

(Albumin, globulin, fibrinogen)

b. Water ~ 90% .(2) Formed elements ~ 45% :

a. Platelets“Thrombocytes” ~250*103 /µl(cmm).

b. WBCs “Leukocytes” (Neutrophils,Lymphocytes,Monocytes,Eosionphils,Basophils).

c. RBCs “Erythrocytes” ~5*106/µl*Lifespan = 120 days*anucleated.*Contain no mitochondria.

*The relative amount of RBCs to the total blood volume is

called hematocrit (Male = 40-45 % , Female = 37-47%)



Control of Erythropoiesis

The rate of RBC’s production bybone marrow is well balanced,under normal conditions, with

the rate of RBC’s destruction. Production of RBC’s by bonemarrow is regulated byglycoprotein called

Erythropoietin which is producedmainly by the kidneys.(~ 90% of erythropoietin isproduced by the kidneys).

Small amount is produced byliver.



Control of Erythropoiesis Erythropoietin MW is ~ 40000. The

main stimulus for erythropoietinsecretion is Hypoxia.Androgens (male sex hormones) alsostimulate secretion erythropoietin.Erythropoietin acts on red bone

marrow increasing the production of RBC’s.

It increases the production of proerythroblast from the committedstem cells of bone marrow and it alsospeeds up the division of theerythroblasts and therefore the endresult will be more RBC’s formation.



Hemoglobin

It is a protein with MW of ~ 64000.It consists of 4 subunits, eachone contains a heme moiety

conjugated to a polypeptide.Heme is a porphyrin with ironatom in a ferrous state (Fe2+).

There are two pairs of polypeptides in each Hbmolecule.



Hemoglobin

- HbA (adult Hb) 2 α + 2 β 141 a.a 146 a.a

- HbA2 (about 2.5% of Hb inadults is HbA2) 2 α + 2 δ Delta

- HbF (Hb during fetal life) 2 α + 2 Gamma



Hemoglobin

Substitution of one or more of amino

acids in the polypeptide changes thecharacteristic features of the Hbmolecule, for Ex. HbS (Sickle Hb)contains 2 α and 2 β polypeptide butglutamic acid in position 6 in B chain

is replaced by valine . Hb synthesis starts during

erythroblast stage of theeyrhtropoiesis process and it'ssynthesis continues up toreticulocytes stage.Mature RBC’s do not synthesize Hb.Hb synthesis needs iron, vitamins andproteins (amino acids).



Hemoglobin

The main function of Hb is to carryO2.It combines with O2 formingoxyhaemoglobin.O2 is attached to Fe2+ atom in Hbmolecule. Oxidation of Fe2+ into Fe3+ (Ferric) renders Hb to useless

molecule as far as O2 carriage isconcerned (Hb contains Fe in ferricstate is called MetHaemoglobin whichcan not carry O2).



Nutritional requirements for Hbsynthesis:

1.Amino acids.

2.Iron.

3.Intrinsic factor and vitaminB12 (for normal division of precursor cells in bone marrow).



Anaemia Anaemia is clinically defined as a

state in which the blood hemoglobin

level is below the normal range forpatient's age and sex.

Since the main function of Hb is tocarry O2 then anaemia results inreduction in O2 - carrying capacity of the blood. This reduction in O2carriage is due to:

1. Decrease in no. of RBC.2. Decrease in Hb amount in RBC.



Clinical features of anaemia

Are mostly due to the decrease inO2 carriage by blood.These include: lassitude, fatigue,breathlessness on exertion,

palpitation, dizziness, headache,dimness of vision, insomnia,parashtesia in fingers and toes,

pallor of the skin and mucousmembranes and conjunctivaetachycardia.



Effect of Anaemia on thecirculatory system:

Due to decrease in RBC’s number, theViscosity of blood is decreased.This decreases the resistance to bloodflow in the peripheral vessels and this

increases the venous return to theheart hypoxia caused by anaemiacauses vasodilatation and this leadsto an increase in venous return.So there will be an increase in cardiac

output (i.e. increased workload on theheart).The increase in COP offsets someeffects of anaemia on tissues(hypoxia). However when tissuedemands of O2 during exercise.



Causes of anaemia

i- Decrease in RBC formation orHb synthesis.

ii- Excessive destruction or loss

of RBC.



Causes of anaemia due to less

RBC formation or production

A. Nutritional causes 1.Anaemia due to iron deficiency.

2.Anaemia due to Vitamin B12 and folicacid deficiency.

B. Failure of bone marrow to produceRBC "Aplastic anaemia"

1.Hypoplasia of the bone marrow.

2.Invasion of bone marrow bymalignant cells.

3.Chronic infection.

C. Decrease or absence of

erythropoietin as in renal diseases.



Anaemia due to excessivedestruction of RBC or excessive

loss of blood1. Excessive destruction of RBC"Hemolytic anaemia"

a. Abnormal shape of RBC – spherocytosis.

b. Abnormal Hb - HbS, thalassemia.

c. Deficiency of RBC enzyme G6PD deficiencyd. Effect of certain drugs.

e. Invading of RBC by parasites anddestruction of RBC – Malaria.

f. Autoimmune hemolytic anaemia abnormalantibodies against RBC.

g. Blood groups incompatibility

"erythroblastosis fetalis“.



Anaemia due to excessivedestruction of RBC or excessive

loss of blood2. Excessive loss of blood - bloodloss anaemia:

a. Excessive bleeding fromwounds.

b. Excessive natural loss of bloodlike excessive menstruation.



Absorption & transport of iron: Iron is absorbed from small intestine into blood

where it combines with Beta-globulin calledApotransferrin forming Transferrin in blood.



Iron deficiency anaemia (IDA):

It is the most common type of anemia. It is due to deficiency of

iron which is essential forsynthesis of Hb.

IDA could be due to:

1.Loss of iron because of bleeding

2.Inadequate iron in the diet

3.Malabsorption




IDA in infants:It may occur if the infant is notweaned at proper time.

Feeding only milk to the infantafter one year of age leads todevelopment of IDA because milk

is poor source for iron.




IDA in adolescents:Occurs if the requirement of ironexceeds the iron absorption from

small intestine.This could happen during periodof rapid growth.




IDA in women at child bearing age(reproductive age):

This may be due to excessive

menstruation specially if it isprolonged.About 30 mg of iron is lost per monthdue to menstruation.

This loss must be compensated byincreasing iron absorption and intake.





During pregnancy, the iron demand isincreased to:

1. Supply enough iron for synthesis of RBC in the baby.

2.Synthesize more RBC in motherbecause blood volume of the motheris increased.





Additional amount of iron is lostduring labour.

The demand of pregnant women of iron is increased with the progress of

the pregnancy.For the above reasons IDA is morecommon in females than males duringthe reproductive years (~ 14 - 45

years).




* Gastro-intestinal bleeding is the mostcommon cause of IDA in menopausalwomen and adult men.

* Gastro-intestinal bleeding is due to:

1.Gastric erosions2.Peptic ulcers3.Neoplastic disease

* IDA in tropical and subtropicalregions could arise from infestationwith parasites like schistosoma(bilharziasis)

H l i l fi di i IDA



Hematological findings in IDA: MCV* is reduced & Hb content of RBC

is also reduced. These findings suggest hypochromic

microcytic type of anemia.

- Hb level in the blood is reduced.

- The no. of RBC is either normal orreduced.

- Plasma iron level is reduced.

- Normal value of MCV is around90 femtoliter.* MCV = Mean corpuscular (cell)

volume



Megaloblastic Anaemia: It is due to deficiency of vitamin B12

&/or folic acid.Both folic acid & vitamin B12 areneeded for proper proliferation of bone marrow cells.

DNA synthesis in dividing cells needspresence of both vitamin B12 & folicacid, therefore division of bonemarrow cells is delayed if either oneor both mentioned factors are absentor deficient.



Megaloblastic Anaemia Hematological picture of megaloblastic

anaemia:

- Hb content is reduced.- MCV value is increased ( May be more

than 120fl )The RBC size is large

(Macrocytic anaemia) & oval in shape.- Red blood cells count is reduced.- Reticulocyte count is low.- Serum iron is elevated.



Megaloblastic Anaemia

Causes of vitamin B12 deficiency:

1. Inadequate intake.2. Intrinsic factor deficiency Gastrectomy Gastric atrophy ( Pernicious anemia)3. Diseases of terminal ileum

(site of B12 absorption).4. Removal of vitamin B12 from intestine by

parasites (Fish tapeworm).

Causes of folic acid deficiency:1. A decrease in folic acid intake.2. Malabsorption.

(Folate is mainly absorbed in jejunum)3. An increase demand for folic acid.

( ex. Pregnancy & Hemolysis)



Megaloblastic Anaemia

Why the size of RBCs is increased in

megaloblastic anemia?

If vitamin B12 &/or folic acid supply is less,the ability of bone marrow cells to

synthesize DNA is decreased. This leads toslow division & less reproduction of cells.The RNA synthesize in the cytoplasm of dividing cells is not affected, so the RNA

amount is more than normal resulting inexcess production of cytoplasmic Hb & otherorganelles inside developing RBC leading tolarge size RBC.



Megaloblastic Anaemia Due to DNA abnormalities in these

large RBCs, the cell membrane & cytoskeleton of these cells are notnormal & this leads to:

a. abnormal cell shape.b. Flimsy cell membrane which is

liable for rupture (i.e. the RBCs aremore fragile & lifespan of RBCs is

shortened (1/3 or ½ of normallifespan)



Aplastic Anaemia: It is due to:

- Failure of bone marrow to produce RBCs

(Aplasia of bone marrow).- Reduction in the ability of the bonemarrow to produce RBCs (Hypoplasia).

Aplastic anemia is either idiopathic orsecondary to another factor.

Causes of secondary aplastic anaemia:1. Bone marrow inhibition by drugs

- Chloramphinicol- Indomethacine

- Cytotoxic drugs- Anticonvulsants2. Chemical like benzene toluene solvents.3. Radiation.4. Diseases like viral hepatitis.



Aplastic Anaemia: Hematological picture of aplastic anaemia:

- Blood film shows pancytopenia(A decrease in all types of blood cells i.e.RBCs, WBCs & platelets). Some casesshow that one type of cell is affected(most probably neutrophils).

- The anemia is normochromic, normocyticanemia.

- It is marked anemia.



Anaemia of chronic diseases: It is a common type of anemia.

It is associated with chronic diseases. The characteristic features of this anemia:

1. It occurs in the setting of chronicinflammation or neoplasm.

2. It is not related to bleeding orhemolysis.3. It is mild anemia Normocytic,Normochromic type.

Mechanism of anemia associated withchronic diseases is thought to be due to theinhibitory effects of various cytokines whichare released during the course of thechronic disease on iron metabolism orerythropoiesis process.

H l ti i



Haemolytic anaemia"Anaemia due to excessive destruction

of RBC’s"

The production of RBCS frombone marrow does notcompensate for those RBC’s

which are:Hemolysed –Leads Anaemia



Haemolytic anaemia

Lifespan of RBC’s is shortened RBC’s production is increased

–leads An increase in

reticulocytes no. In peripheralblood.

If the destruction is large andstimulation of bone marrow isintense this leads to appearanceof erythroblasts in peripheralblood.



Haemolytic anaemia Excessive destruction of RBC’s in

short time results in an increase inbilirubin levels in the blood(Unconjugated bilirubin).

Sites of destruction of RBC’s:

1. Extravascular (Phagocytes of spleen, liver, bone marrow).

2.Intravascular (Liberation of Hb intoPlasma)



Haemolytic anaemia Intravascular destruction of RBC’s :

Hb is liberated from RBC’s into plasma Hb is carried (combined) with specialplasma protein called Haptoglobulin.*Haptoglobulin:

Produced by liver, It can bind Hb 1:1.it’s level in plasma is ~ 100mg/100ml. Therefore haptoglobulin can bind Hb up to

100mg of Hb / 100ml of plasma.



Haemolytic anaemia Intravascular destruction of RBC’s :

If the hemolysis is excessive and Hb levelsin blood is more than 100mg/100ml thenthe free Hb will be carried to the kidneys Hb appears in the urine

“Hemoglobinuria” which is Dark urine(Black Urine).If the hemolysis is excessive and largeamount of Hb appears in urine, then thereis a possibility that Hb precipitates in renaltubules, blocking then and this may leadto renal failure. This situation may be seenafter excessive hemolysis of RBC’s due toblood mismatched transfusion.



Renal failure caused by massive

hemolysis:

1. Blockage of renal tubules

2. Vasoconstriction of renal bloodvessels by toxic substances liberatedfrom the hemolyzed RBC’s.

3. Decrease in renal tissue perfusioncaused by the circulatory shockresulted from hemolysis.

Haemolytic anaemia



Causes of hemolytic anaemia

I. Congenital

1. Red blood cell membrane abnormalities(ex. Spherocytosis).

2.Haemoglobinopathies(ex. Thalassemias, Sickle cell anaemia)

3. RBC’s enzyme defects. (ex. G6PD deficiency)

II. Acquired

1.Immune antibodies formed against RBC’s.

2.Non - immune :

a. Mechanical causes(Burns, Artificial Cardiac valve)

b. Infections

c. Drugs an chemicals

d. Malaria



Spherocytosis

Autosomal dominant disorder. Abnormal cell membrane of RBC

deficiency of protein called spectrin RBC cell membrane is abnormallypermeable RBC’s loss theirbiconcave shape RBC’s becomemore susceptible to osmotic lysis Spherocytes are destroyed by spleenleading to anemia.

(That is why removal of spleen ,"Splenectomy" results inimprovement of clinical picture of anemia due to spherocytosis) .

Hemolytic anemia due to




hemoglobinopathy "due to abnormal Hb"

Causes:

1.Due to alteration in amino acidstructure of the polypeptide chains

Best example HbS found in sickle cellanemia.

2.Due to impairment or absence of polypeptide production, example

Thealassemias (the sequences of amino acid is normal)




hemoglobinopathy "due to abnormal Hb"

Type of Hb Beta polypeptide chain of Hb

1.Alteration in amino acid structure of the polypeptide chain:

A.A A.A A.A A.A

1 3 6 146

HbA Valine Leucine Glutamicacid

Histidine

HbS Valine

HbC Lysine



Sickle cell anemia

Inheritance:

Autosomal recessive trait.25% (AA) Normal(RBC’s contain HbA). 50% (AS) Sickle cell trait(RBC’s contain HbA & HbS). 25% (SS) Sickle cell anemia(RBC’s contain HbS mostly).

*Patients with sickle cell anemia & traithave high resistance to lethal effects of falciparum malaria in early childhood.



Sickle cell anemia

The effect of HbS on RBC’s:

Deoxygenated HbS moleculestend to polymerize (Hb becomesinsoluble) The RBC’s are

converted into sickle shape* Presence of HbC with HbS

increases the polymerization of Hb.

* While presence of HbF inhibitsthe polymerization of Hb.



Sickle Cell Anemia

Deoxygenation of HbS Sickle cells this will lead to:

1.Incresed Fragility Hemolysis

a. Anemia.B. Jaundice.

2.Increased blood viscosity Slowcirculation Obstruction of bloodflow Thrombosis Ischemia.



Th l i



Thalassemias Hb Molecule:

2 Alpha chains + 2 Beta chains

1.Impairment of alpha chain synthesis leadsto alpha thalassemia "seen in south eastAsia“.

* The genes responsible for synthesis of alpha

chain are on chromosomes 16.* There are 4 alpha genes.

* One gene is deleted harmless.

* Two genes are deleted mild anemia.

* Three genes are deleted

HbHHbH contains only Beta chain “useless Hb”.

* Four genes are deleted stillborn "deadfetus“.

Th l i



Thalassemias2.Impairment of beta chain production

leads to beta thalassemia"Seen in Mediterranean area”.

It’s of two types:

A. Thalassemia Minor"heterozygous” Mild anemia.B. Thalassemia Major

“Homozygous”

Severe anemia.* The beta chains are produced by

genes present on chromosome 11.

Anemia due to G6PD deficiency



Anemia due to G6PD deficiency Glucose–6-Phosphate

Dehydrogenase Deficiency.

G6PD is an enzyme produced byhexose monophosphate shunt of Embden-meyerhof pathway for

glycolysis in RBC's.`*This pathway generates NADPH

(reduced form of nicotinamide

Adenin dinucleotide phosphate).



Anemia due to G6PD deficiency

A i d t G6PD d fi i



Anemia due to G6PD deficiency Exposure of RBC’s to offending drugs forms

low level of hydrogen peroxide and freeradicals.Detoxification of these products needsNADPH.

Since RBC’s deficient in G6PD can not form

NADPH at normal rate to detoxify theseradicals. So these radicals are accumulatedand cause damage of Hb and cell membrane.

* Ingestion of certain food like broad beancauses hemolysis of RBC’s in people with

G6PD deficiency.Also dapsone and sulphonamides can inducehemolysis in G6PD deficient individuals.

* G6PD deficiency is inherited as X-linked

disorder .

Acquired hemolytic anemia




1.Autoimmune hemolytic anemia

"Destruction of RBC’s due toformation of antibodies againstRBC’s antigens"

*The antibodies are classifiedinto (according to their thermalcharacteristics):

A. Warm Antibodies.B. Cold Antibodies.




1.Autoimmune hemolytic anemiaa. Warm antibodies * Mostly of IgG type* Their optimal activity is at 37oC* The hemolytic anemia caused by

warm Abs is mostly idiopathic butsome cases are associated with:

a. Chronic leukemia.

b. Lymphoma .c. Systemic lupus erythromatosis (SLE).d. Drug like methyldopa.




1.Autoimmune hemolytic anemiab. Cold antibodies

* They are of IgM and complements

* They have a thermal optimum of 4o

C* The hemolytic anemia due to cold Abs

is mostly seen in old people

* The RBC’s are agglutinated by cold Ab

in the microcirculation of feet andhands where blood is cooled.

* The anemia is worst in cold weather

1.Autoimmune hemolytic anemia




Acquired hemolytic anemia2. Non - immune acquired hemolytic anemia

I. Anemia due to mechanical trauma Destruction of

RBC’sex. - Incompetent heart valves- Fibrin deposited in blood vessels- Disseminated malignancy- Uremic syndrome- Toxemia of pregnancy- Severe burns- Vigorous contact activity (karate)- Prolonged marching

II. Infection: - malariaIII. Drugs and chemicals:

Drugs:Dapsone & salazopyrine seen in slow acetylators.Chemicals: - Arsenic gas

- Copper- Nitrates

- Chlorate- Nitrobenzene

Erythroblastosis fetalis



Erythroblastosis fetalis"Hemolytic disease of newborn"

* Occurs in Rh+ve fetuses & neonates whose mothers

areRh-ve some Rh+ve fetal RBC’s leak into mothercirculation at the time of delivery.

* Rh-ve mother develops anti Rh antibodies(i.e. antibodies attach Rh+ve RBC’s)

* During subsequent pregnancies , these antibodies

cross the placenta to the fetus.If the fetus is Rh+ve then these antibodies attackRh+ve fetal RBC’s causing hemolysis.

* Excessive hemolysis causes an increase in bilirubinlevels in the blood "jaundice" and excessivestimulation of RBC’s forming organs causes

production of early erythroblasts and these appear incirculation.* If the levels of unconjugated bilirubin are high, it will

cross the blood brain barrier of the fetus & depositedin motor areas of the brain destroying them causesKERNICTERUS.

Polycythemia



Polycythemia An increase in RBC’s no. & consequently an increase in Hb

concentration.Types:

1. Relative Polycythemia: - Dehydration.- Reduction in plasma volume.

2. True polycythemia :

- Primary “Polycythemia Vera”

- Secondary polycythemia:A. Inappropriate erythropoietin

production:-Renal: cysts, carcinoma,

hydronephrosis.-Tumor: Liver, Uterus.

B. Hypoxia:-High altitude-Lung diseases-Cyanotic heart diseases-Smoking-Abnormal hemoglobin with high affinityto O2.

ec o po ycy em a on :Blood pressure in 1/3 of polycythemia patients is



Blood pressure in 1/3 of polycythemia patients iselevated

Effect of polycythemia on CVS:

Hemostasis :



Hemostasis :* Is a mechanism by which the bleeding from

damaged blood vessels is arrested (stopped).

* To achieve hemostasis, three events occur in theinjured blood vessel. These are:1. Local vasoconstriction - contraction of injured B.V.2. Formation of platelets plug - temporary one.

3. Formation of a definitive blood clot.* Local vasoconstriction of injured B.V occurs

immediately after injury. It aims to reduceblood flow or to stop it completely.It is due to :

a. Neural reflex stimulation of pain receptorsb. Myogenic reaction action potential in

smooth muscle in wall of injured B.V.c. Liberation of vasoconstrictor substances

thromboxane A2

Hemostasis



Hemostasis*PLATELET HEMOSTATIC PLUG:

It starts by adhesion of platelets tothe exposed collagen fibers and roughsurface of injured B.V.Adhesion of the platelets leads toactivation of these platelets.

* The activated platelets:

1. Change their shape

2. Discharge their granules

3. Become sticky* Platelets plugs are important in

controlling bleeding from capillaries,venules and erosions of mucosal

surfaces.

PLATELETS:



PLATELETS:*Are small granulated discs. Produced

by megakaryocytes of bone marrow.*Their no. is ~ 200-300 x 103

/µL.

*Platelets lifespan is ~10 days.

*Large No. of platelets are stored inspleen. Splenectomy causes anincrease in platelet count(thrombocytosis).

*platelets production bymegakaryocytes is regulated by:

1. Colony stimulating factors

2. Thrombopoietin

PLATELETS



PLATELETS* Platelets are unnucleated discs.

The cytoplasm of platelets contains

1. Dense granules:a. Serotoninb. ADP, ATPc. Ca2+

2.α Granules:

a. Von willebrand factorb. Clotting factor like factor Vc. Platelet - derived growth factor (PDGF)

3. Actin and myosin proteins which areimportant in clot retraction

4. Lysosomes5. Thromboxane A2*Pletelets membrane contains phospholipids

which are essential for blood coagulation

(Intrinsic pathway).

CLOTTING OF BLOOD



(COAGULATION)* Clotting of blood can be initiated by

two mechanisms:a. Intrinsic pathwayb. Extrinsic pathway.

* Both pathways, through series and

complex activation of certain proteins(clotting factor), form prothrombinactivator which activatesprothrombin.into thrombin "converts“ Which in

turn acts on fibrinogen forming fibrinwhich makes the network of fibrinthreads (clot).

CLOTTING OF BLOOD



CLOTTING OF BLOOD(COAGULATION)

Blood coagulation



gIt can be started through twomechanisms:

a. Intrinsic pathway:Starts by activation of clotting factorXII and platelets when they areexposed to the collagen fibers ininjured blood vessel.b. Extrinsic pathway:Starts by activation of clotting factorVII by tissue thromboplastin which isliberated from the damaged tissues.

Both pathways lead to activation of factor X which with Ca2+,phospholipid and factor V will convertprothrombin to thrombin.



Blood coagulation

Clotting factors



Clotting factors 1. Are mostly proteolytic proteins(some are cofactors).2. Most of them are synthesized bythe liver.*In hepatocellular disease, theconcentrations of almost all clottingfactors fall.3. Activation of most clotting factorsneeds Ca2+.4. They are found in inactive forms inplasma.5. The synthesis of clotting factors II,VII , IX and X in the liver needsvitamin K.



Clotting factorsFactor I Fibrinogen

Factor II ProthrombinFactor III Tissue thromboplastinFactor IV Ca2+ (cofactor)Factor VFactor VIIFactor VIII Antihemophilic factor AFactor IX Antihemophilic factor B

"Christmas factorFactor X Stuart - power factor

Factor XIFactor XII Hageman factorFactor XIII Fibrin - stabilizing factor

Thrombin is active proteolytic enzyme which actson fibrinogen converting it into fibrin which



on fibrinogen converting it into fibrin whichinturn polymerized into threads which formnetwork that can seal

the break in the blood vessel wall.

*Cli i ll th t i i th i



* Clinically the extrinsic pathway isassessed by prothrombin time

test (normally = 12-14 seconds)while:

* Activated partial thromboplastintime (APTT) is used to assess the

intrinsic pathway

(normally = 30 - 40 seconds) .

Prevention of blood clotting in normal blood



Prevention of blood clotting in normal bloodvessels:

a. Smoothness of the endothelium

(of blood vessels)* Prevents initiation of clotting through

“intrinsic pathway“.

b. Presence of antithrombin III

* Protein produced by liver. It inhibitsthrombin and Xa.

The effect of antithrombin III is greatlyincreased by heparin.

-Heparin is produced by mast cells andbasophils.

c. Protein C - is produced by liver. It'ssynthesis needs vitamin K.

* It is activated by protein S.

* Activated protein C inhibits factor Va.

Bleeding disorders



Bleeding disorders1. Vessel wall abnormalities:

Due to delay or interference with the initial

platelets plug formation or abnormal vesselwall reaction to trauma.

* Result in Purpura (means confinedhemorrhagic areas in the skin due to leaks

from tiny breaks in small blood vessel wall).* This type of purpura is called non-thrombocytopenic purpura.

* Causes:1. Senile purpura.

2. Vasculitis.3. Embolic purpura.4. Henoch - schonlein purpura

"Small vessels vasculitis"

Bleeding disorders



Bleeding disorders

2.Platelets disorders:

a. Abnormal functioning platelets"Thromboasthenia“.

b. A decreased in platelets no.

"Thrombocytopenia“.

3.Coagulation factors: abnormalities:

a. Congenital causes.

b. Acquired causes.

Platelets functional disorders:



* Abnormalities in platelets functioncould arise from defects in:

a. Platelets membraneb. Platelets granules

* The function of platelets may be

inhibited by certain drugs like Aspirinand other non-steroidalanti-inflammatory drugs.

* These drugs inhibit platelet

cyclo-oxygenase enzyme & thusreduce formation of thromboxanewhich is important for formation of platelet plugs.

Platelets function disorders:



Platelets function disorders: Drugs that inhibit platelets function:i. NSAIDs:

-Aspirin.-Indomethacin.-Phenylbutazone

ii. Antibiotics:

-Penicillins.-Cephalosporins.

iii. Dextran.iv. Heparin.

v. B-Blockers* Note:

The no. of platelets is normal in theseabnormalities.

Thrombocytopenia:



o bocytope a Reduction in the No. of functioning

platelets. Causes spontaneous bleeding

from mucous membrane like:a. Epistaxis

b. Gastro intestinal bleeding

* Spontaneous bleeding usuallyoccurs when platelets count fallsbelow 30’000/cmm (ul, µl)

* Bleeding severity is increased when

platelets count is reducedgreatly and platelets transfusionmust be given if platelets count is

less than 10x109/liter.

Thrombocytopenia:



Thrombocytopenia:Causes of thrombocytopenia:

1. Less production of platelets by bone

marrow.2. Increased platelets consumption as indisseminated intravascular coagulation

3. Rapid or premature removal of plateletsfrom circulation as in:

Idiopathic thrombocytopenic purpura inwhich antibodies are formed against

platelets membrane resulting inpremature removal of platelets by

monocytes - macrophages system. ITP in children develops after viral infection.

in adults, sometimes it is associated withrheumatoid arthritis.

Bleeding disorders due to



abnormalities in clotting factorsI .Congenital causes:

Partial or complete absence of one ormore of clotting factors leads tobleeding tendency.Absence of clotting factor is due to

abnormalities in the gene that code aparticular clotting factor, Example ishemophilia.

II. Acquired causes:

Many conditions causes a decrease orabsence of clotting factors,Example: liver disease and warfarintherapy.

Hemophilia A:



Hemophilia A:Haemophilia A:

is due to congenital deficiency of clotting

factor VIII.

The characteristics of factor VIII:

a. Is mainly produced by liver. Small

amounts are produced by spleen, kidneysand placenta.

b. It's half - life is ~ 12 hours.

c. It is carried in the plasma attaching toanother factor called vonWillebrand

factor (vWF)d. It is sex-linked disorder. It's gene is on

X chromosome.

G i f h hili A



Genetics of hemophilia A:

* It is transmitted genetically by X(female). Chromosome as arecessive trait.

• Females are carriers while malesare affected by the disease(Hemophiliacs).

G i f h hili A



Genetics of hemophilia A:

Hemophiliac fathertransmits carrier state toall his daughters while hissons are healthy.

A carrier wife transmits the disease to 1/2 of her sons and carrier



A carrier wife transmits the disease to 1/2 of her sons and carrierstate to 1/2 of her daughters.

The possibility of hemophiliac sisters to becomecarrier is 50% .

The male hemophiliacs inherit the disease from theirmother and pass it to their daughters.

Clinical features of hemophilia



p

Hemophiliac babies do not show

signs of bleeding until they startto move and expose to trauma.

* Sever hemophilia (depends on

level of factor VIII deficiency)leads to recurrent hemorrhage inlarge joints like knees, hips,ankles and elbows.Sometimes the bleeding beginsspontaneously without apparenttrauma.




Clinical features of hemophilia Recurrent bleeds into joint lead to

destruction of the joint and osteoarthritis .

Bleeding into the joint makes the joint verypainful.

Hemophiliacs bleed into muscles like psoasmuscle may press on femoral nerve

causing parasthesia in the thigh. Bleedings into confined spaces like

intracranial area are very dangerous andmay be fatal if not treated quickly.

Moderate hemophiliacs bleed after minortrauma while these with mild hemophiliaexperienced bleeding following major trauma orsurgery.




C ca eatu es o e op aTreatment:

Infusion of factor VIIIconcentrate.

Complications of infusion of factor VIII:

- INFECTIONS .

- Development of anti-factorVIII antibodies .

H hili B (Ch i t di )



Hemophilia B (Christmas disease)

Bleeding disorder due to reduction inclotting factor IX in the plasma.The gene responsible for productionof factor IX is present on Xchromosome.

Deficiency of factor IX leads tobleeding tendency which is related to

the extent of deficiency.

Von Willebrand's disease :



It is an autosomal genetic bleeding disorder.

It is due to low level of Von willebrand

factor (VWF).VWF is a protein produced by endothelialcells and megakaryocytes. VWF acts as acarrier for clotting factor VIII & allows theplatelets to adhere to damaged blood

vessels & therefore helps in sealing off (closure) the breaks that occur in bloodvessels.

Deficiency of VWF leads to bleeding aftertrauma (bleeding time is prolonged) and a

decrease in plasma VIII level. Clinically deficiency of VWF causes

epistaxis, bruising, menorrhagia and gastrointestinal bleeding.

Acquired bleeding disorders:



q ga. Disseminated intravascular coagulation

(DIC) * It means widespread intravascular

clotting.* It is due to activation of clotting process

inside circulation .The activation of clotting process insidebody may be due to:

1. Damaged tissue - liberation of thromboplastin

2. Activation of endothelial cells bybacterial infection to produce tissuefactor.

When excessive clotting occurs, theplatelets and clotting factors areconsumed rapidly and theirconcentrations in blood are decreasedleading to bleeding tendency.




q gb. Liver disease:

* Liver is the site where most of clotting factors are synthesized,therefore in sever

parenchymal liver disease bleeding

occur specially from abnormal siteslike peptic ulcer

* Synthesis of clotting factors II, VII,IX and X by the liver needs vitamin K,

so when vitamin K is deficient theconcentration of these clotting factordecreases leading to bleeding.




q gb. Liver disease:

Vitamin K is fat -soluble vitamin, so in caseof less bile salts reaching small intestine theabsorption of vitamin K from intestine isdecreased.

Coumarin drugs such as warfarin competewith vitamin K for the reactive sites in theenzymatic processes for formation of factorsII, VII, IX and X .Warfarin is used as anticoagulant drug. It'saction is not immediate (time is needed forconsumption of already formed clottingfactors).

* Excess warfarin causes bleeding tendency,because it reduces the level of clotting

factors, that need vitamin K, in the blood .




q gC. Renal failure:

Bleeding tendency in renalfailure is due to:

1. Decreased no. of platelets

2. Inhibition of plateletsfunction by accumulatedwaste products.

* Common bleeding site in renal

failure is gastrointestinalbleeding.

Blood Pa Tho Physiology

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