body fluid
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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
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