Homeostasis

“Milieu Interieur”

State of constancy Dynamic Relative

Water – 45-75%

Skin, muscle and other organs

~75%

Bone 25%

Fat 10%

Accounts for the variation of body water % from individual to individual

Larger PROPORTION of body fat result in lower PERCENTAGE of water

** The actual VOLUME of water is essentially the

same in all body masses***

Variation of water proportion depends on the ration of this fixed water volume to variable body volume

Variation of body water with age and gender

MALE FEMALE

BABY 75% 75%

ADULT 60% 50%

ELDER 50% 45%

Insensible perspiration Pure water Passive evaporation Entire skin surface Continuous

Sweating Electrolyte solution Active secretion Sweat gland Activated by work

Quiz!

Jimmy weights 70Kg, what is his daily turnover of water in liters?

2.1 – 2.8 liters

Daily water turnover 3-4% of body weight in adult 10% in babies

Negative water balance

Reduced intake Excessive loss from gut Excessive sweating Excessive loss in expired air Excessive loss in urine

IMPORTANT TO REMEMBER

Total H2O ICF ECF ISF Plasma

(% BW) 60% 40% 20% 15% 5%

Cell membrane

ICF

ECF

Capillary wall

ISF

Plasma

Total Body Water

(Antipyrine, D2O, T2O)

Total ECF (inulin, sucrose, mannitol, Na2SO4)Evans’ Blue

Indicator has to be

Non-toxic Diffuse readily, distribute evenly Induce no changes in distribution of

water between compartments Easy to measure

V = Q/c Q – quantity of the indicator c – concentration of indicator in

plasma

Intracellular High in K+Low in Na+ and Cl-

ExtracellularHigh in Na+ and Cl-Low in K+

Quantity

7% of body mass ~ 5 L pH: 7.3-7.45, slightly basic

Blood accounts for 7-8% of total body weight in an average 70kg adult

Total volume of blood is about 5-6L The plasma is the fluid portion of the

blood: 90% water and 10% proteins: Albumin, Globulins, and Fibrinogen

Plasma protein can be separated by Precipitation by salt Sedimentation by centrifugation

Based on size Electrophoretic mobility

Size and charge Immunological characteristics

Quiz!

Are proteins negatively charged or positively charged?

Quiz!

What are the role of plasma proteins?

Role of Plasma proteins

Determining distribution of fluid between plasma and ICF (colloidal pressure)

Viscosity of plasma – maintain blood pressure

Contribute to buffering power of plasma (it is negatively charged, neutralize H+)

Albumin

Most abundant protein in plasma (60% of total)

Normal values in plasma: 4.5 g/dl Produced by the liver Greatest contributor to the

osmotic pressure It also serve as a carrier for other

substances like: hormones, drugs, fatty acids, billirubin and other ions, acting as a blood buffer

Globulins

Some produced by Liver others by Plasma cells

Normal values in plasma: 2.5 g/dl There are three types of globulins:

Alpha globulins that transport bilirubin and steroids

Beta globulins that transport iron and copper

Gamma globulins that constitute the antibodies of the immune system

Fibrinogen

Synthesize in the Liver Converted to Fibrin in the clotting

process Normal values in plasma: 0.3 g/dl

Albumin Fibrinogen

α1, α2, β Globulins

γ Globulin

LYMPHOID TISSUE

ISF

PLASMA

0.9% NaCl

300 mOsm

o.p. = 6.7 atms

= 5100 mm Hg

0.9% NaCl

300 mOsm

o.p. = 6.7 atms

= 5100 mm Hg

capillary wall

Only NON-DIFFUSIBLE solutes contribute to the effective o.p. of a solution

Diffusible solutes do NOT contribute, since they become equally distributed on the 2 sides of the membrane

PLASMA PROTEINS are NON-DIFFUSIBLE

therefore, they can exert an osmotic effect

This effect is known as the COLLOIDAL OSMOTIC (ONCOTIC) PRESSURE (C.O.P.) OF PLASMA

= 25 mm Hg

ISF PLASMA0.9% NaCl

300 mOsm

o.p. = 6.7 atms

= 5100 mm Hg

0.9% NaCl

300 mOsm

o.p. = 6.7 atms

= 5100 mm Hg

Colloidal Osmotic Pressure (C.O.P.) or Oncotic Pressure due to plasma proteins

= 25 mm Hg

Transport across capillary wall

BULK FLOW – a pressure difference Capillary hydrostatic pressure

FILTRATION – bulk flow across a porous membrane Takes into consideration permeability of

capillary

STARLING FORCES determine the distribution of ECF volume between Plasma and ISF

Starling’s Transcapillary Dynamics

Factors That Can Increase Capillary Filtration

Increase Capillary Hydrostatic

Pressure Decrease capillary Colloid Osmotic

Pressure

Major Factors that cause Increased Capillary Filtration of Fluid and Protein into the Interstitium

Increased capillary Hydrostatic Pressure

Decreased Plasma Colloid Osmotic Pressure

Erythrocytes

Most numerous type of blood cells RBCs life span 120 days,broken down

in the spleen RBCs express receptors for EPO Emerge from bone marrow as

reticulocytes, it takes 24-48 hrs to become a mature RBC

1% of the total RBCs is generated daily from bone marrow

Reticulocyte count reflects erythropoietic activity of the bone marrow

Quiz!

With no Mitochondria, how does RBC procure energy?

By means of glycolytic enzymes

Quiz!

Hb occupies what percentage of RBC ?

The majority of RBC is what?

Hb: 33% of RBC Majority of RBC is water Rest is lipid, protein and ions

Hemoglobin

Hgb is composed of two pairs of polypeptide chains

Each of the four polypeptide consist: Globin (protein) –

alpha and beta chain Heme unit which

surrounds an atom of iron

Quiz

What is solubility of O2 in plasma without Hb?

That is O2 carrying capacity with Hb?

0.3ml O2/100mL With Hb it is 20 ml O2/mL

A few values for Hb

Male 16 g/ 100ml blood Female 14 g /100ml blood Each gram of Hb holds 1.34 ml O2

Quiz

How long does it take for stem cell to become a MATURE

RBC?

3-5 days for division and differenciation

Then 24 as reticulocytes in circulation

Total of 4-6 days

Hematopoiesis

Commences in embryonic yolk sac, early red blood cells

After 6 weeks of gestation, fetal liver begins producing primitive WBCs,RBCs,and Plts

Spleen becomes a secondary site of blood cells production

Definitive long term site in the bone marrow

Active marrow sites, red bone marrow, in adult: sternum, scapula, vertebrae, pelvis, ribs, and proximal femur and humerus

Erythropoiesis

Regulated by decreased oxygen content sensed by the kidneys

Kidneys Increase production EPO, that stimulates release of large number of reticulocytes into circulation

Human EPO produced by recombinant DNA technology used for management of anemias

Hormonal effect on erythropoietin

TESTOSTERONE

Increase release of Erythropoietin

Increase sensitivity of RBC precursors to Erythropoietin

Estrogen has opposite effect

Hemoglobin-Iron cycle

Rate Hgb synthesis depends on availability of iron

80% of body iron complexed to Heme in Hgb

20% stored in bone marrow, liver, spleen, and other organs

Dietary Iron absorbed in the small intestine, especially duodenum

Absorbed iron enters circulation and combines with a beta globulin(apotransferrin) to form transferrin

Quiz

What is the normal level of reticulocyte?

Less than 1%

Number of reticulocyte reflects theamount of effective erythropoiesis in bone marrow

Hemorrages, decrease O2 avalability, or increase O2 requirement can increase the amount of reticulocytes in the body

Iron cycle

From plasma iron is stored in liver, spleen and gut as ferritin, a protein-iron complex

Serum ferritin levels are measured in the laboratory to determine body iron stores

Iron is taken up by developing red cells to form Hgb

Iron from the Hgb of RBC removed by the spleen, is released to the circulation and returned to bone marrow or liver to reuse

Erythrocyte destruction

Phagocytic cells ingest and destroy defective RBCs by enzymatic reactions

Amino acids from globin are salvaged for reuse

Most of the heme is converted to bilirubin which is transported by plasma proteins to the liver

Liver converts bilirubin and makes it water soluble

Excretion

Quiz

What is the normal level of bilirubin in the body?

1mg/dL

Quiz

What are possible causes of Jaundice (3)?

Excessive hemolysis Hepatic Damage Bile duct obstruction

Total RBC count

5 x 106 cells/ul - men 4 x 106 cells/ul - women 15-16%Hb

Polycythemia > 6 x 106 cells/ul >18g%Hb

Anemia <4 x 106 cells/ul or <11g% - men <3 x 106 cells/ul or <9g% -

women

Quiz!

What can cause physiological polycythemia?

High altitude Increased physical activity Chronic lung disease Heavy smoking

Factors in RBC synthesis

Globin Fe+ Vitamin B-12 (found in food)

Intrinsic factor secreted in stomach is needed in order to absorb B-12 in the duodenum.

erythropoietin - hormone synthesized by kidney

Classification by Color

1. hypochromic (decreased color)• Iron deficiency

2. normochromic (normal color) Everything else!

3. hyperchromic (increased color)

ANEMIAmorphologic classification

microcytic

MCV <80

normocytic

MCV 80-100

macrocytic

MCV >100

ANEMIA classification by volumeI. microcytic anemia (MCV <80)II. normocytic anemia (MCV 80-100)III. macrocytic anemia (MCV >100)

ANEMIA classification by volume

I. microcytic anemia (MCV <80)1. iron deficiency anemia2. thalassemia syndromes

Deficient synthesis of globin AA chain 3. anemia of chronic disease

II. normocytic anemia (MCV 80-100)1. Anemia of blood loss2. Aplastic anemia (bone marrow)3. Anemia resulting from renal disease

**stimulation failure**III. macrocytic anemia (MCV >100)

INEFFECTIVE MATURATION 1. Pernicious anemia 2. Folic Acid deficiency

ANEMIA - ethiologyI. Diminished Production

Abnormal site Aplastic

Abnormal stimulus Renal disease

Inadequate raw materials Iron

II. Ineffective maturation Vitamin B12 and Folic Acid

III. Survival disorders Hemolytic Spherocytosis Sicle cell anemia Thalassemia

Vitamin B12 / Folate Deficiency Vitamin B12 (cobalamin) -- a vital

ingredient for DNA synthesis and Krebs cycle

Methylcobalamin a coenzyme for tetrahydrofolate (FH4)

Vitamin B12 Deficiency

i. dietary deficiency ---- rare• Strict vegetarians

ii. decreased absorption1) decreased intrinsic factor2) Absorbed in Ileum 3) pancreatic insufficiency

folate deficiency

i. dietary deficiency• Poor consumption of fruits and vegetables • chronic alcoholics

ii. decreased absorption• Folate is absorbed in upper intestine

iii. increased requirement• pregnancy (folate def in pregnancy → neural tube

defects)• infancy

iv. folate antagonists• chemotherapy (i.e. methotrexate)

Quiz!

What is the RBC classification for Iron deficiency?

Microcytic and Hypochromic

Iron Deficiency Anemia

INADEQUATE RAW MATERIAL Due to

Loss of Fe in hemorrages Dietary deficiency Failure to absorb Iron

Iron: absorbed in duodenum

Quiz!

How much iron do women need to absorb per day?

2mg/day

Few numbers on Iron

Normal erythropoiesis require 25mg Fe/d You loose 1mg Fe/d

1g Hb contains 3.5 mg Fe 15g Hb/100ml of blood 50mg Fe/100ml of blood There are total of 4g of iron in the

body 65% in Hb

Quiz!

A person’s platelet count is 50,000, is this normal?

No!Normal platelet count should be 75,000

Haemostasis

1. Vasoconstriction2. Platelets activated by thrombin

form a platelet plug3. Fibrin mesh forms via activation of

the coagulation system to strengthen the clot

4. Clot dissolution via plasmin5. Normal blood flow past the clot

Haemostasis

1. PRIMARY HEMOSTASIS 1. Vascular response

Nervous Mygogenic Aided by chemical vasoconstrictors

2. Platelet response

2. SECONDARY HEMOSTASIS 1. Clot formation

Platelets

NO nucleus Granules Life span 7-10 days Produced in bone marrow Maturation is aided by

Thrombopoietin (from liver)

Platelets functions

Vasoconstricting agent Serotonin and TXA2

For platelet plug Initiated by VW factor, aided by ADP, TXA2

Release clotting factors Extrinsic pathway

Participate in clot retraction Maintenance of endothelial cell

integrity

Platelet plug formation

Adhesion Onset: collagen exposure Von Villebrand factor

Aggregation ADP TXA2 Von Villebrand factor

Vasoconstriction TXA2 Serotonin

Consolidation PF3 – source of phospholipids for coagulation Coagulation pathway

Coagulation forms fibrin mesh Biological amplification system which

converts soluble fibrinogen to an insoluble fibrin meshwork which coverts the primary platelet plug to a firm, definitive stable clot.

Required local concentration of clotting factors at site of injury

Surface mediated reactions on exposed collagen, platelet phospholipid or tissue factor

General Concept

Complex formation requiring calcium, phospholipid surface, protein plasma factors

Thrombin converts fibrinogen to fibrin monomer

Fibrin monomer crosslinked to fibrin

Forms "glue" for platelet plug

Coagulation cascade

XII

XI

IX

XVIII

Prothrombin (II)

thrombin

fibrinogen fibrin

STABILISED FIBRIN

V, Ca, P/L

VII

Intrinsic pathway

Extrinsic pathway

XIII

APTT

PT

VIIa

TF X Xa

II (Prothrombin)

IIa (Thrombin)

Va

VIIIa

VaXIa

INITIATION

IXa

AMPLIFICATION

Xa-Va-II

Prothrombinase

Platelet

IXa- VIIa-X

“tenase”

TF IX

VIIa

THROMBIN (IIa) FIBRIN

Quiz!

At 1min post injury, which pathway is most elicited?

EXTRINSIC PATHWAY! 15-20 sec

Intrinsic pathway does not activate until 3-6 min post-injury

Quiz!

Why is the extrinsic pathway not so effective?

Clotting is kept in check by inhibitors and anticoagulats

Tissue factor pathway inhibitor (TFPI) Binds and inhibits factor VIIa

Prostacyclin and Nitric Oxide

Quiz!

Liver or kidney diseases affect which component of

clotting?

Platelet production is regulated by thrombopoietin, a hormone usually produced

by the liver and kidneys. Disease of liver and kidney will decrease platelet count.

Quiz!

How does vit K affect clotting?

Vit K is cofactor in synthesis of Prothrombin, VII, IX and X

How do platelets contribute to clot retraction?

Without platelets, there is no clot retraction. Retraction depends on the presence of thrombosthenin, a contractile protein released by platelets.

Extrinsic tissue factors

Intrinsic endothelia factors

Coumarin Mainly

targets the extrinsic pathway

Antagonize the effect of

Vit K

Protein C Inhibition of

Co-stimulators

Heparin and Antithrombin

e III- Inhibition of activation and

action of THROMBIN

Intrinsic pathway