the blood. definition definition blood is a connective tissue, not a body fluid, made of fluid...

The BloodThe Blood

The BloodThe Blood

DefinitionDefinition

Blood is a connective tissue, not a body fluid, made of fluid Blood is a connective tissue, not a body fluid, made of fluid (plasma) and cellular elements (RBC, WBC, and platelets)(plasma) and cellular elements (RBC, WBC, and platelets)

Its volume is 5-6 L in males and 4-5 L in femalesIts volume is 5-6 L in males and 4-5 L in females

It is slightly alkaline, with a pH of ~ 7.4It is slightly alkaline, with a pH of ~ 7.4

Its color varies from bright to dark redIts color varies from bright to dark red

It has a salty metallic tasteIt has a salty metallic taste

The BloodThe Blood

FunctionsFunctions

The bloodThe blood is vehicular organ that reaches all the other tissuesis vehicular organ that reaches all the other tissues

Transports oxygen and nutrientsTransports oxygen and nutrients

Removes CORemoves CO22 and other by-products of cell activity and other by-products of cell activity

Pivotal in maintaining homeostasis, growth and tissue Pivotal in maintaining homeostasis, growth and tissue repairrepair

Participates in the defense against infectionParticipates in the defense against infection

Participates in hemostasisParticipates in hemostasis

Participates in body heat distribution and regulationParticipates in body heat distribution and regulation

Marieb and Hoehn Human Anatomy & Physiology seventh edition Pearson Benjamin Cummings

The BloodThe Blood

PlasmaPlasma

Straw colored fluid made of water (~90%), other contents include: Straw colored fluid made of water (~90%), other contents include:

Proteins make the bulk of the solutes: Proteins make the bulk of the solutes:

Albumens (60%), manufactured in the liver are the most abundantAlbumens (60%), manufactured in the liver are the most abundant

Globulins (36%) are immune bodiesGlobulins (36%) are immune bodies

Fibrinogen (4%) for blood clottingFibrinogen (4%) for blood clotting

Nutrients: glucose, amino acids, lipids, cholesterolNutrients: glucose, amino acids, lipids, cholesterol

Electrolytes: NaElectrolytes: Na++, K, K++, Ca, Ca++++, Mg, Mg++++, H, H++, Cl, Cl--, HCO, HCO33--, PO, PO44

----, SO, SO44----

Waste: urea, creatinine, uric acid, bilirubinWaste: urea, creatinine, uric acid, bilirubin

Gases: OGases: O22 , CO , CO2 2 , N, N22

Protein bound hormonesProtein bound hormones

Plasma without clotting factors is called “serum”Plasma without clotting factors is called “serum”

Peripheral blood smear


Pathophysiology McCance & Huether fifth edition Elsevier Mosby

Electron micrograph of blood smear

The BloodThe Blood

RBCRBC

An RBC is a 7.5 micron disc shaped body with a central An RBC is a 7.5 micron disc shaped body with a central depressiondepression

The cell is without a nucleus or mitochondriaThe cell is without a nucleus or mitochondria

AN RBC contains hemoglobin and filamentous proteins attached AN RBC contains hemoglobin and filamentous proteins attached to the cell wall to impart flexibility on itto the cell wall to impart flexibility on it

Antigens are embedded in the cell membrane, they decide the Antigens are embedded in the cell membrane, they decide the blood groupblood group

The RBC cytoplasm provides energy to maintain intracellular The RBC cytoplasm provides energy to maintain intracellular homostasishomostasis

This energy is generated mostly through anaerobic glycolysisThis energy is generated mostly through anaerobic glycolysis

RBCs function is gas exchange: ORBCs function is gas exchange: O22 to the tissues and CO to the tissues and CO22 to the to the lungslungs

The BloodThe Blood

RBCRBC

Structure of HemoglobinStructure of Hemoglobin

Each hemoglobin molecule is made up of four globin chains and fourEach hemoglobin molecule is made up of four globin chains and four heme moleculesheme molecules Heme molecule is a porphyrin type pigment with a ferrous ion (FeHeme molecule is a porphyrin type pigment with a ferrous ion (Fe++

++)) Globin is a 287 amino acid protein made of two Globin is a 287 amino acid protein made of two αα, and two non , and two non αα

chainschains Adult hemoglobin A is (Adult hemoglobin A is (αααα//ββββ), fetal hemoglobin F is ( ), fetal hemoglobin F is ( αααα//γγγγ)) An enzyme, 2,3 diphosphoglycerate (2,3 DPG) binds to hemoglobin An enzyme, 2,3 diphosphoglycerate (2,3 DPG) binds to hemoglobin molecule, it lowers its affinity to Omolecule, it lowers its affinity to O22

Binding of OBinding of O22 to heme breaks some of the globin bonds exposing to heme breaks some of the globin bonds exposing moremore

heme molecules to bind with Oheme molecules to bind with O22

Structure of hemoglobin


Each heme molecule combines with one oxygen atom

Davidson’s Principles and Practice of Medicine eighth edition, Churchill Livingstone

Structure of hemoglobin and the oxygen dissociation curve

The BloodThe Blood

RBCRBC

Development of RBCsDevelopment of RBCs Hypoxia Hypoxia → erythropoietin (kidney)→→ erythropoietin (kidney)→ red marrow of long bones red marrow of long bones→→

erythroid stem cell→ erythroblasts cell division→ smaller cells loosing nucleus erythroid stem cell→ erythroblasts cell division→ smaller cells loosing nucleus and gaining hemoglobin → reticulocyte→ mature RBC and gaining hemoglobin → reticulocyte→ mature RBC

Reticulocytes contain remnants of cell organellesReticulocytes contain remnants of cell organelles Their presence in excess in the peripheral blood (>2%) indicatesTheir presence in excess in the peripheral blood (>2%) indicates excessive RBC destructionexcessive RBC destruction The normal number of RBCs is 4.3-5 million/mmThe normal number of RBCs is 4.3-5 million/mm3 3 in the female and 5.1-5.8 million/mm3 in the male The normal values for Hgb are 13-15 gm/dl for females and 14-16 gm/dl in males

Amino acids, lipids, carbohdrates, iron, vitamin B12 and folic acid are essntial for hemoglobin synthesis

The BloodThe Blood

RBCRBC

Hemoglobin has a remarkable ability to bind with oxygen Hemoglobin has a remarkable ability to bind with oxygen

forming oxyhemoglobinforming oxyhemoglobin

It can also release the oxygen to the tissues becoming It can also release the oxygen to the tissues becoming deoxyhemoglobindeoxyhemoglobin

Hemoglobin combines with COHemoglobin combines with CO22 forming carbaminohemoglobin forming carbaminohemoglobin

The BloodThe Blood

RBCRBCDestructionDestruction Life span ~ 120 daysLife span ~ 120 days

RBCs are phagocytosed by the reticulo-endothlial cells of the spleenRBCs are phagocytosed by the reticulo-endothlial cells of the spleen

Globulin is hydrolyzed to amino acids that are recycledGlobulin is hydrolyzed to amino acids that are recycled

Iron is removed from heme and reused to synthesize HgbIron is removed from heme and reused to synthesize Hgb

Heme remnant converted to bilirubin Heme remnant converted to bilirubin

Bilirubin is conjugated with glucoronic acid, and secreted in bileBilirubin is conjugated with glucoronic acid, and secreted in bile

In the intestine most is converted to stercobilin and excreted In the intestine most is converted to stercobilin and excreted

A small amount of stercobilin is absorbed by the kidney andA small amount of stercobilin is absorbed by the kidney and

secreted as urobilinogensecreted as urobilinogen

The BloodThe Blood

RBCRBCDisorders of RBCsDisorders of RBCs

Anemia is reduced RBC countAnemia is reduced RBC count

Anemias can be caused byAnemias can be caused by

RBC loss or reduced production RBC loss or reduced production

Hemorrhage, hemolysis, depressed bone marrowHemorrhage, hemolysis, depressed bone marrow

Reduced hemoglobin content of RBCsReduced hemoglobin content of RBCs

Iron, intrinsic factor, folic acid, or BIron, intrinsic factor, folic acid, or B12 12 deficiencydeficiency

Congenital hemoglobin defectsCongenital hemoglobin defects

Thalassemia, sickle cell anemia, spherocytosisThalassemia, sickle cell anemia, spherocytosis

The BloodThe Blood

RBC RBC

Disorders of RBCsDisorders of RBCs PlolycythemiaPlolycythemia Bone marrow disorder causing an increased number of Bone marrow disorder causing an increased number of circulating RBCs and increased blood viscositycirculating RBCs and increased blood viscosity Aplastic anemiaAplastic anemia Results from bone marrow suppression or destruction Results from bone marrow suppression or destruction

(radiation,(radiation, drugs, chemicals)drugs, chemicals) All the blood elements are deficientAll the blood elements are deficient

Normal and sickle cell RBC

In sickle cell disease hemoglobin S replaces the β chain

In thalassemias, the α or β chains can be absent or defective


The BloodThe Blood

White Blood Cells (WBC)White Blood Cells (WBC)FunctionFunction

Lymphocytes are the effectors of the immune functionLymphocytes are the effectors of the immune function

WBCs main function is to fight bacterial infectionsWBCs main function is to fight bacterial infections WBCs are the only nucleated blood formed elementsWBCs are the only nucleated blood formed elements They exercise their functions in the tissues not the blood streamThey exercise their functions in the tissues not the blood stream Selectines induce the WBC to adhere to capillary endotheliumSelectines induce the WBC to adhere to capillary endothelium WBC migrate to the tissue spaces by diapeditic movement WBC migrate to the tissue spaces by diapeditic movement

between between endothelial cell, diapedesis is initiated by chemical attraction toendothelial cell, diapedesis is initiated by chemical attraction to the infection site initiated by damaged cells “chemotaxis”the infection site initiated by damaged cells “chemotaxis” WBC destroy the bacterial cell wall by oxidation and digestion byWBC destroy the bacterial cell wall by oxidation and digestion by proteins “defensisns”proteins “defensisns”

The BloodThe Blood

White Blood Cells (WBC)White Blood Cells (WBC)

TypesTypes

The total number of WBCs is 4000 to 10,000/mmThe total number of WBCs is 4000 to 10,000/mm33

There two main types of WBCs: granulucytes and agranulocytes

Granulocytes, are of three typesGranulocytes, are of three types

Neutrophils (polymorphs) 50-70%, oxidize bacteria Neutrophils (polymorphs) 50-70%, oxidize bacteria

Eosinophils, 2-4% bilobed nuclei, attack parasites Eosinophils, 2-4% bilobed nuclei, attack parasites

Basophils, 1% in peripheral blood, reside in the tissuesBasophils, 1% in peripheral blood, reside in the tissues, , contain histamine, involved in hypersensitivity reactioncontain histamine, involved in hypersensitivity reaction

The BloodThe Blood

White Blood Cells (WBC)White Blood Cells (WBC)

TypesTypes

Agranulocytes are of two typesAgranulocytes are of two types

Lymphocytes, the smallest and second most abundantLymphocytes, the smallest and second most abundant T cells (80%) mediate cellular immunity, express T cells (80%) mediate cellular immunity, express

CD1,2,3,4,5,7 & 8CD1,2,3,4,5,7 & 8 B cells mediate humoral immunity, express immunoglobulin B cells mediate humoral immunity, express immunoglobulin

light light chains on the surfacechains on the surface Monocytes, the largest, migrate to the tissues and become Monocytes, the largest, migrate to the tissues and become

macrophages involved in cellular immunity, secrete ILmacrophages involved in cellular immunity, secrete IL11 , TNF, , TNF, andand

CSFCSF

Davidson’s The Priciples and Practice of Medicine, eigthteenth edition Churchill Livingstone

White blood cells, the granulcytes

Monocytes and lymphocytes

Davidson’s The Priciples and Practice of Medicine, eighteenth edition Churchill Livingstone

The BloodThe Blood

WBCWBCDevelopmentDevelopment WBC WBC productionproduction isis Stimulated by two types of messengersStimulated by two types of messengers

Inerleukins: IL-3 stimulates basophils (also RBCs and platelets) Inerleukins: IL-3 stimulates basophils (also RBCs and platelets)

IL-5 stimulates eosinophilsIL-5 stimulates eosinophils

IL-3, IL-4 and IL-7 stimulate B lymphocytesIL-3, IL-4 and IL-7 stimulate B lymphocytes

IL-2, IL-4 and IL-7 stimulate T lymphocytesIL-2, IL-4 and IL-7 stimulate T lymphocytes

Colony stimulating factors (CSF)Colony stimulating factors (CSF)

G-CSF stimulate neutrophils (granulocytes)G-CSF stimulate neutrophils (granulocytes)

GM-CSF stimulate eosinophils and monocytesGM-CSF stimulate eosinophils and monocytes

WBC life span is 1 to 9 days WBC life span is 1 to 9 days

Vander’s Physiology eighth edition, Mc Graw Hill

Development of blood cells

The BloodThe Blood

WBCWBCLeukemiasLeukemias A single unspecialised WBC precursor cell “clones” itself A single unspecialised WBC precursor cell “clones” itself

uncontrollablyuncontrollably

The resulting “leukemia” is therefore “monclonal”The resulting “leukemia” is therefore “monclonal”

The more undifferentiated cells produce acute (blastic) leukemiasThe more undifferentiated cells produce acute (blastic) leukemias

The more differentiated (cytic) cells produce chronic typesThe more differentiated (cytic) cells produce chronic types

A leukemia is called according to the producing cellA leukemia is called according to the producing cell

Leukemias impair the bone marrow, and other blood cells Leukemias impair the bone marrow, and other blood cells functions functions

Death is inevitable unless treated, it results from bleeding or Death is inevitable unless treated, it results from bleeding or sepsissepsis

The BloodThe Blood

Blood CoagulationBlood Coagulation

Coagulation is a natural mechanism that acts to diminish Coagulation is a natural mechanism that acts to diminish blood loss from hemorrhageblood loss from hemorrhage

Coagulation (thrombosis) especially in the microcirculation is Coagulation (thrombosis) especially in the microcirculation is also a manifestation of inflammation and sepsisalso a manifestation of inflammation and sepsis

Coagulation occurs in three StagesCoagulation occurs in three Stages Platelet plugPlatelet plug The cascade leading to fibrin (clot) formationThe cascade leading to fibrin (clot) formation Clot retraction and repair (PDGF)Clot retraction and repair (PDGF)

The BloodThe Blood

Blood CoagulationBlood Coagulation The PlateletsThe Platelets

Structure and FunctionStructure and Function

Platelets are discoid shaped bodies of 2-4 Platelets are discoid shaped bodies of 2-4 μμm m Derived from megacaryocytes arising from lineage committed stem Derived from megacaryocytes arising from lineage committed stem

cellscells They are fragments of cells, they have no nucleiThey are fragments of cells, they have no nuclei They contain three types of granules in the cytoplasmThey contain three types of granules in the cytoplasm Alpha granules contain fibrinogen and von Willebrand factor (vWF)Alpha granules contain fibrinogen and von Willebrand factor (vWF) Delta (dense) granules store adenosine diphosphate and serotoninDelta (dense) granules store adenosine diphosphate and serotonin Lysosomes, contain acid hydrolasesLysosomes, contain acid hydrolases

The BloodThe Blood

Blood CoagulationBlood Coagulation

The Platelets The Platelets

Platelets are activated by thrombin, collagen, or ADP, they Platelets are activated by thrombin, collagen, or ADP, they discharge discharge

their content which leads to the formation of thrombaxane A2their content which leads to the formation of thrombaxane A2

Platelets adhere to exposed collagen in the presence of Platelets adhere to exposed collagen in the presence of

von Willebrand factor (vWF)von Willebrand factor (vWF)

Their life span is 8-14 days, they are destroyed in the cells of the Their life span is 8-14 days, they are destroyed in the cells of the RERE

systemsystem

The structure of a platelet

Davidson’s The Priciples and Practice of Medicine, eighteenth edition Churchill Livingstone

Initial vasoconstriction and platelet plug

vVander’s Physiology eighth edition Mc Graw Hill

Intrinsic and extrinsic coagulation pathways

Vander’s Physiology eighth edition Mc Graw Hill

Calcium ions are essential for the coagulation cascade

The role of the liver in blood coagulation

Vander’s Physiology eighth edition Mc graw Hill

EM of a blood clot: RBC’s and fibrin

NIBSC?Science Photo Libraray – Taken from Vander Physiology eighth edition Mc Graw Hill

Prostacyclin (PGI2 ) and nitric oxide inhibit platelet aggregation

Vander’s Physiology eighth edition Mc graw Hill

The BloodThe Blood

AnticoagulationAnticoagulation

Natural AnticoagulantsNatural Anticoagulants Tissue factor pathway inhibitor (TFPI)Tissue factor pathway inhibitor (TFPI)

Plasminogen - plasminPlasminogen - plasmin

HeparinHeparin

Antithrombin IIIAntithrombin III

Protein CProtein C

Protein S Protein S

Vitamin E quinoneVitamin E quinone

NaturalNatural anticoagulants also have anti inflammatory activity anticoagulants also have anti inflammatory activity

The BloodThe Blood


Massive blood flowMassive blood flow

The (Intact) EndotheliumThe (Intact) Endothelium Prevents platelet contact with collagenPrevents platelet contact with collagen

Displays heparin on its surfaceDisplays heparin on its surface

Secretes prostacyclin (PGAISecretes prostacyclin (PGAI22) and nitric oxide) and nitric oxide

Activates protein C via attached thrombomodulin-thrombin Activates protein C via attached thrombomodulin-thrombin complexcomplex

Secretes tissue plasminogen activatorSecretes tissue plasminogen activator

The BloodThe Blood


HeparinHeparin Is a natural anticoagulant found in the bodyIs a natural anticoagulant found in the body

Can be given by IV or subcutaneous routes for anticoagulationCan be given by IV or subcutaneous routes for anticoagulation

Can be easily neutralized (its action reversed) by protamineCan be easily neutralized (its action reversed) by protamine

It has an antithrombin effectIt has an antithrombin effect

Inhibits platelet functionsInhibits platelet functions

Its effect is measured by estimating the partial prothrombin time Its effect is measured by estimating the partial prothrombin time (PTT)(PTT)

The BloodThe Blood

AntigoagulationAntigoagulation

Aspirin (ASA)Aspirin (ASA)

Inhibits cyclooygenase (COX) that catalyzes the formation of Inhibits cyclooygenase (COX) that catalyzes the formation of thrombaxanethrombaxane

Mature platelets can not make new thrombaxane because their COX isMature platelets can not make new thrombaxane because their COX is

blockedblocked

Endothelial cells can synthesize new COX, therefore they are not Endothelial cells can synthesize new COX, therefore they are not affectedaffected

by ASAby ASA

Thrombaxane is important for platelet aggregationThrombaxane is important for platelet aggregation

Platelet function is assessed by the bleeding timePlatelet function is assessed by the bleeding time

New drugs that interfere with fibrinogen/platelet binding are now New drugs that interfere with fibrinogen/platelet binding are now

available available

The BloodThe Blood


Vitamin K antagonistsVitamin K antagonists Warfarin, also known as coumadinWarfarin, also known as coumadin

Interfere with the liver synthesis of coagulation factorsInterfere with the liver synthesis of coagulation factors

Effect measure by checking the protime (PT) now reported asEffect measure by checking the protime (PT) now reported as

international normalized ratio (INR)international normalized ratio (INR)

Vitamin E quinone is a potent anticoagulantVitamin E quinone is a potent anticoagulant

Inactivation of Factors VIII & V by thrombin activated protein C


Fibrinolysis, a mechanism for clot resorption


The BloodThe Blood

ThrombolyticsThrombolytics

Plasminogen activates plasmin, a natural fibrinolytic agentPlasminogen activates plasmin, a natural fibrinolytic agent Tissue Plasminogen Activator (t-PTA) activates plasminogenTissue Plasminogen Activator (t-PTA) activates plasminogen Plasmin dissolves an already formed clot (thrombolytic therapy)Plasmin dissolves an already formed clot (thrombolytic therapy)

Streptokinase and Urokinase Streptokinase and Urokinase Thrombolytic actionThrombolytic action Streptokinase has side effects but less costlyStreptokinase has side effects but less costly Urokinase has less side effects but more expensiveUrokinase has less side effects but more expensive

New drugs that interfere with fibrinogen/platelet binding are now New drugs that interfere with fibrinogen/platelet binding are now availableavailable

The BloodThe Blood

TransfusionTransfusion

The following blood elements can be transfused to cover a The following blood elements can be transfused to cover a deficiencydeficiency

in quantity or quality of one or more of the blood componentsin quantity or quality of one or more of the blood components

Whole blood does not allow time for checking for the presence of Whole blood does not allow time for checking for the presence of

infectious agentsinfectious agents

Packed RBC’c for low HbPacked RBC’c for low Hb

Platelets for thrompcytopenia and bleedingPlatelets for thrompcytopenia and bleeding

Plasma (fresh frozen) to replace deficient intrinsic factorsPlasma (fresh frozen) to replace deficient intrinsic factors

Cryoprecipitate for hemophiliaCryoprecipitate for hemophilia

The BloodThe Blood


Stored blood is acidified with citrates to prevent coagulationStored blood is acidified with citrates to prevent coagulation

It looses its plateletsIt looses its platelets

Has more potassium, and accumulates ammoniaHas more potassium, and accumulates ammonia

More hemolysed RBC as the storage is prolongedMore hemolysed RBC as the storage is prolonged

Hemoglobin tends to hold more to OHemoglobin tends to hold more to O22 because of the reduction because of the reduction in in

2,3 diphophoglyceric acid (2.3 DPG)2,3 diphophoglyceric acid (2.3 DPG)

The life span of RBCs stored at 4The life span of RBCs stored at 4oo C is about 28 days C is about 28 days

The BloodThe Blood

Blood TypesBlood Types

RBC’s have surface antigensRBC’s have surface antigens

RBC’s can be grouped according to the presence or absence RBC’s can be grouped according to the presence or absence of certain antigensof certain antigens

There are many RBC antigens but only a A, B, AB and the Rh There are many RBC antigens but only a A, B, AB and the Rh are of are of

clinical significanceclinical significance

Each one of the four types can be Rh positive or negativeEach one of the four types can be Rh positive or negative

Donor blood is mixed with recipient serum to decide Donor blood is mixed with recipient serum to decide compatibility, donor cell clumping indicate incompatibilitycompatibility, donor cell clumping indicate incompatibility

Major blood groups


A certain group posseses its antigen on the RBC surface and antibodies against the others

The BloodThe Blood


Transfusion of incompatible RBCs results in their hemolysis in the Transfusion of incompatible RBCs results in their hemolysis in the donordonor

This leads to blockage of the renal tubules, hypotension, fever, This leads to blockage of the renal tubules, hypotension, fever, back pain, and may prove fatalback pain, and may prove fatal

This is treated by stopping the transfusion, hydration, and This is treated by stopping the transfusion, hydration, and alkalinization of the urinealkalinization of the urine

Not every reaction to transfusion is due to infused RBC hemolysis, Not every reaction to transfusion is due to infused RBC hemolysis,

other less severe reactions can occur other less severe reactions can occur

Identification of the RBC group


The BloodThe Blood

Rh FactorRh FactorThere are no preformed Rh antibodies in RhThere are no preformed Rh antibodies in Rh-- individuals individuals

They develop after exposure to RhThey develop after exposure to Rh++ factors (antigens) factors (antigens)

This explains the fact that an RhThis explains the fact that an Rh++ fetus of an Rh fetus of an Rh-- mother mother

does not usually sufferdoes not usually suffer

But the RhBut the Rh-- mother can be sensitized to the Rh mother can be sensitized to the Rh++ antigens during antigens during the first pregnancy, especially during deliverythe first pregnancy, especially during delivery

Subsequent fetuses can suffer from the mother’s Rh antibodies Subsequent fetuses can suffer from the mother’s Rh antibodies passedpassed

to it and its blood hemolyzesto it and its blood hemolyzes

This can be prevented by giving the mother serum that blocks This can be prevented by giving the mother serum that blocks the Rhthe Rh++

factors antigenicityfactors antigenicity

The BloodThe Blood

Rh FactorRh Factor

Eighty five percent of the population have Rh antigens (RhEighty five percent of the population have Rh antigens (Rh++))There are several Rh groups (factors, antigens)There are several Rh groups (factors, antigens)Three groups: Rh, C, D, and E, are of clinical importanceThree groups: Rh, C, D, and E, are of clinical importanceAn RhAn Rh-- mother may develop antibodies against her Rh mother may develop antibodies against her Rh++ fetus fetusThe RhThe Rh-- mother antibodies can pass to the Rh mother antibodies can pass to the Rh++ fetus resulting fetus resulting

in hemolysis of its RBCs, a condition know as in hemolysis of its RBCs, a condition know as erythroblastosis fetaliserythroblastosis fetalis

This sequence usually occurs after the first pregnancyThis sequence usually occurs after the first pregnancy

the blood. definition definition blood is a connective tissue, not a body fluid, made of fluid...

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