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Plasma proteins.

This document provides information on plasma and plasma proteins. It discusses that plasma constitutes 55% of blood volume and is composed mainly of water (91%) and proteins (8%). The major plasma proteins are albumin, globulins, and fibrinogen. Albumin makes up 60% of total plasma proteins. Various plasma proteins and their functions are described in detail. Abnormalities in plasma proteins can provide clinical information on diseases.

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M.Prasad Naidu MSc Medical Biochemistry, Ph.D,.
 Total blood volume is 4.5-5 litres.  If blood containing anticoagulants (e.g.heparin , potassium oxalate) is centrifuged , the plasma separates out as a supernatant while the cells remain at the bottom.  About 55-60% of blood is plasma  The packed cell volume or hematocrit is about 40-45%
 Plasma is the clear straw coloured fluid portion of the blood minus its cellular elements.  It constitutes about 55% of the blood volume.  Serum is plasma minus clotting factors (fibrinogen & prothrombin ).  The defribrinated plasma is called serum
 PLASMA contains the following composition: WATER: Is the main constituent of Plasma – 91% SOLIDS: 9% of the plasma (1% inorganic molecules & 8% organic molecules)
OTHER ORGANIC MOLECULES Carbohydrates : Glucose ( 100-120 mg%) Fats : neutral fats, phospholipids (150- 300mg%) Cholesterol (150-240 mg%)
 Non protein nitrogenous substances : ammonia, amino acids, creatine, creatinine (0.6- 1.2 mg%) xanthine, hypoxanthine, urea (20-40 mg%) & uric acid (2-4 mg%).  Hormones enzymes & antibodies.
 Inorganic molecules are sodium, potassium, calcium, magnesium, chloride, iodide, iron, phosphates & copper.  Gases presents in the plasma are O2 ,Co2,& N2 .
plasma proteins… - forms 7% of the solids in plasma - their normal valves – 7.4 gm% ranges from (6.4 – 8.3 gm%)  INCLUDES: ALBUMIN GLOBULINS FIBRINOGEN
 Total protein content of normal plasma is 6 - 8 g/100ml  The plasma proteins consist of : 1)albumin (3.5-5 g/dl) 2)globulins (2.5-3.5 g/dl) 3)fibrinogen (200-400 mg/dl)
 The albumin : globulin ratio is usually between 1.2 :; 1 to 1.5 :1  Almost all plasma proteins , except immunoglobulins are synthesized in liver
 In clinical laboratory, separation is usually done by salts.  Thus , fibrinogen is precipitated by 10% and globulins by 22% concentration of sodium sulphate  Ammonium sulphate will precipitate : albumin by full-saturation globulin by half-saturation
 In clinical laboratory , total proteins of patients are estimated by Biuret method.  Albumin is quantitated by Bromo cresol green (BCG) method , in which the dye is preferentially bound with albumin , and the colour intensity is measured colourimetrically.
 OTHER METHODS:  Lowry’s method  Kjeldahl’s method  Dye-binding method  UV-absorption method
 The most common method of analyzing plasma proteins is by electrophoresis.  The term electrophoresis refers to the movement of chargeD particles through an electrolyte when subjected to an electric field
 In clinical laboratory , cellulose acetate is widely used as a supporting medium.  Its use permits resolution , after staining , of plasma proteins into five bands , designated albumin , α1 , α2 , β and γ fractions, respectively
 The stained strip of cellulose acetate is called electrophoretogram.  The amounts of these five bands can be conveniently quantified by use of Densitometric scanning machines.  Characteristic changes in the amounts of one or more of these five bands are found in many diseases.
 Various abnormalities can be identified in the electrophoretic pattern  1) CHRONIC INFECTIONS:  The gammaglobulins are increased
 2)MULTIPLE MYELOMA :  In para-proteinemias , a sharp spike is noted and is termed as M-band.  This is due to monoclonal origin of immunoglobulins
 PRIMARY IMMUNE DEFICIENCY :  The gamma globulin fraction is reduced  NEPHROTIC SYNDROME :  All proteins except very big molecules are lost through urine , and α-2-fraction will be very prominent
 CIRRHOSIS OF LIVER :  Albumin synthesis by liver is decreased , with a complementary excess synthesis by globulins by reticuloendothelial system
 CHRONIC LYMPHATIC LEUKEMIA:  Gamma globulin fraction is reduced  ALPHA-1-ANTITRYPSIN DEFICIENCY:  The alpha-1 band is thin or even missing
 Albumin (69 kDa) is the major protein in human plasma(3.4-4.7 g/dl)  It makes up approximately 60% of the total plasma protein.  About 40% of albumin is present in the plasma, and the other 60% is present in the extracellular space.
 The liver produces about 12g of albumin per day , representing about 25% of total hepatic protein synthesis  Albumin can come out of vascular compartment. So albumin is present in CSF and interstitial fluid.
 1)COLLOID OSMOTIC PRESSURE OF PLASMA:  The total osmolality of serum is 278-305 mosmol/kg.  This is exerted mainly by salts, which can pass easily from intravascular to extravascular space.  Therefore, the osmotic pressure exerted by electrolytes inside and outside the vascular compartments will cancel each other.
 But proteins cannot easily escape out of blood vessels, and therefore , proteins exert the „effective osmotic pressure‟.  It is about 25mm Hg, and 80% of it is contributed by albumin.  The maintenance of blood volume is dependent on this effective osmotic pressure
Gaw: Clinical Biochemistry; Churchill Livingstone (1999), p. 44.
 TRANSPORT FUNCTION:  Albumin is the carrier of various hydrophobic substances in the blood such as:  i)bilirubin & non-esterified fatty acids  ii)drugs (sulpha,aspirin,salicylate,)  iii)hormones(steroid hormones,thyroxine)  iv)metals (calcium,copper,heavy metals)
3)BUFFERING ACTION :  Albumin has maximum buffering capacity amongst all proteins  It has a total of 16 histidine residues which contribute to this buffering action.
4)NUTRITIONAL FUNCTION:  All tissue cells can take up albumin by pinocytosis.  It is then broken down to amino acid level.  So albumin may be considered as the transport form of essential amino acids from liver to extrahepatic cells.
1)BLOOD-BRAIN BARRIER:  Albumin-fatty acid complex cannot cross blood- brain barrier and hence fatty acids cannot be taken up by brain.
2)PROTEIN-BOUND CALCIUM:  Calcium level in blood is lowered in hypo- albuminemia  Thus , even though total calcium level in blood is lowered, ionised calcium level may be normal, so tetany may not occur.
 3) THERAPEUTIC USE:  Human albumin is therapeutically useful to treat burns,hemorrhage and shock.  4)EDEMA:  Hypo-albuminemia will result in tissue edema  Eg: a)malnutrition b)nephrotic syndrome c)cirrhosis of liver d)chronic congestive cardiac failure.
 CIRRHOSIS OF LIVER:  Synthesis is decreased.  MALNUTRITION:  Availability of amino acids is reduce and so albumin synthesis is affected.  NEPHROTIC SYNDROME:  Permeability of kidney glomerular membrane is defective , so that albumin is excreted in large quantities.
 PROTEIN LOSING ENTEROPATHY:  Large quantities of albumin is lost from intestinal tract.
 ALBUMINURIA:  Presence of albumin in urine is called albuminuria.  It is always pathological.  Seen in: a)Nephrotic syndrome(large quantities) b)Acute nephritis c)Inflammatory conditions of urinary tract.  Detection of albumin in urine is done by heat and acetic acid test.
 MICRO-ALBUMINURIA:  In micro-albuminuria or minimal albuminuria or plauci-albuminuria , small quantity of albumin (30-300 mg/dl) is seen in urine  It is estimated by RIA  Increased levels of microalbuminuria is an indication of early involvement of renal tissue in diabetic patients
 Albumin-globulin ratio :  In hypo-albuminemia, there will be a compensatory increase in globulins which are synthesized by the reticulo-endothelial system(plasma cells).  Albumin-globulin ratio (A/G ratio) is thus altered or even reversed.
 Hypoproteinemia :  Since albumin is the major protein present in the blood, any condition causing lowering of albumin will lead to reduce total proteins in blood
 HYPERALBUMINEMIA :  Increased levels of plasma albumin are present only in acute dehydration and have no clinical significance  ANALBUMINAEMIA :  Analbuminemia is a rare hereditary abnormality in which plasma albumin concentration is usually less than 1.0gm/L
 Globulins are bigger in size than albumin . Globulins constitute several fractions. These are:  α1- globulin  α2- globulin  β- globulin  γ- globulin
 Retinol binding protein(RBP)  α1 – fetoprotein(AFP)  α1 – protease inhibitor (API)  α1 - acid glycoprotein (AAG)  High density lipopprotein (HDL)  Prothrombin
 RETINOL BINDING PROTEIN (RBP)  Retinol (vitamin A) is transported in plasma bound to RBP.  Most retinol RBP in the plasma is reversibely complexed with transthyretin (thyroxine binding protein)  α1- FETOPROTEIN (AFP)  This is present in the tissues and plasma of the fetus  It may play an immunoregulatory role during pregnancy.
 α1- PROTEASE INHIBITOR (API) / α1- ANTITRYPSIN (AAT) :  API is one of the plasma proteins, that inhibits activity of proteases particularly elastase, which degrades elastin, a protein that gives elasticity to the lungs  α1-ACID GLYCOPROTEIN (AAG)  AAG also known as orosomucoid, contains a high percentage of carbohydrate with a large number of sialic acid residues  It is synthesized by liver parenchymal cells.
 PROTHROMBIN  It is synthesized by liver with the help of vitamin K and involved in blood clotting
 Ceruloplasmin(ferro-oxidase)  Transcortin / corticosteroid binding globulin  Haptoglobin  Thyroxine binding globulin(TBG)  α2 - macroglobulin (AMG)
 CERULOPLASMIN (FERRO-OXIDASE)  This is a copper containing protein.  It has oxidase activity  Ceruloplasmin is the major transport protein for copper, an essential trace element.  It is also essential for the regulation of oxiation- reduction , transport and utilization of iron  Plasma ceruloplasmin level is reduced in Wilson‟s disease in patients with malnutrition and in the nephrotic syndrome.
 TRANSCORTIN /CORTICOSTEROID BINDING GLOBULIN:  This binds cortisol  It is synthesized in liver and synthesis is increased by oestrogen  HAPTOGLOBIN:  It plays an important role in the conservation of iron by preventing its loss in the urine  Haptoglobin binds free Hb to form a complex which is too large to be filtered by the kidney and thus prevents the loss of iron in the urine.
 THYROXINE-BINDING GLOBULIN (TBG)  TBG is synthesized in liver  TBG has a electrophoretic mobility between α1 & α2 globulins  It transports thyroxine hormone(T3 & T4)  α2 - MACROGLOBULIN(AMG)  This is major α2 - globulin , which is a natural inhibitor of endopeptidases such as trypsin, chymotrypsin, plasmin, thrombin .etc.
 Haemopexin  Transferrin  β2 -microglobulin(BMG)  C-reactive protein(CRP)  Low density lipoprotein
 HAEMOPEXIN  Like haptoglobulin, haemopexin also plays an important role in the conservation of iron by preventing its loss in urine  TRANSFERRIN  Is synthesized in liver  It transports iron(2 molecules of Fe3+ per molecule of transferrin) through blood to the sites where iron is required
 C-REACTIVE PROTEIN(CRP)  CRP is involved in the body’s response to inflammations .mainly bacterial..  It is useful in differentiating bacterial from viral infections because the level of CRP is increased in bacterial infections only. 
MICROGLOBULIN  This protein forms part of the human leucocyte antigen(HLA) system  Plasma levels are increased whenever, there is malignant lymphoid or myeloid proliferation and renal failure
 The acute phase response is a non-specific response to the stimulus of tissue following trauma, infection ,inflammation, burn, etc  Following trauma etc , the body responds by initiating a series of mechanisms that lead to rapid decrease in the concentration of many proteins,eg  Albumin  Prealbumin  Transferrin  These are termed “negative acute phase reactants”
 An increase in the concentration of several specific proteins occur some hours after the injury. These proteins are called the positive acute phase proteins
Definition:  The Igs constitute a heterogenous family of serum proteins, which either function as antibodies or are chemically related to antibodies  The immunoglobulins are γ- globulins , called antibodies. All antibodies are immunoglobulin but all immunoglobulins may not be antibodies
 They constitute about 20% of all the plasma proteins  Igs are produced by plasma cells & to some extent by lymphocytes
 Immunoglobulins are glycoproteins made up of light(L) and heavy(H) polypeptide chains.  All Igs have the same basic structure. The basic Ig is a “Y” shaped molecule and consist of 4 polypeptide chains:  2 H chains  2 L chains  The 4 chains are linked by disulfide bonds
 An individual antibody molecule always consists of identical H chains & identical L chains  L chain may be either of 2 types, kappa(κ) or lambda(λ) but not both  The heavy chains may be of 5 types and are designated by greek letter:  Alpha(α)  Gamma(γ)  Delta(δ)  Mu(μ)  Epsilon(ε)
Five Classes of Immunoglobulin
 Igs are named as per their heavy chain type as IgA , IgG , IgD , IgM & IgE  The L and H chains are subdivided into variable and constant regions  L chain consists of one variable(VL) and one constant (CL) domain or region  Most H-chains consist of one variable(VH) and 3 constant(CH-1,CH-2 & CH-3) domains  IgG & IgA have 3 CH domains whereas IgM & IgE have 4
 Each Ig molecule has hinge region between CH- 1 & CH-2, which allows better fit with the antigen surface.  The variable regions of both L & H chains have 3 extremely variable amino acid sequences at the amino terminal end called hypervariable region  Enzyme(papain) digestion splits the Ig molecule into 2 fragments named as Fab (Fragment for antigen binding) and Fc (crystallizable fragment)
 The primary function of antibodies is to protect against infectious agents or their products.  Igs provide resistance because they can :  Neutralize toxins & viruses  Opsonize microbes so they are more easily phagocytosed  Activate complement & prevent the attachment of microbes to mucosal surfaces
 In addition to these functions, antibodies can act as an enzyme to catalyze the synthesis of ozone (O3) that has microbicidal activity.
 IgG (HEAVY CHAIN γ ) :  Is a monomeric molecule with 2 antigen binding sites  There are 4 subclasses, IgG1 to IGg4 based on antigenic differences in the H-chains and on the number and location of disulfide bonds  It is produced mainly in the secondary response and constitutes an important defence against bacteria & viruses
 IgG is the major class of immunoglobulin found in the serum which accounts for 70% of the total  IgG is the only antibody that crosses the placenta & therefore is the class of maternal antibody that protects the fetus  Functions:  Neutralizes bacterial toxins and viruses  Opsonises bacteria, making them easier to phagocytize  Activates complements which enhances bacterial killing
 IgA is the 2nd most abundant class constituting about 20% of serum immunoglobulins  IgA occurs in 2 forms:  Secretory IgA  Serum IgA  Secretory IgA is a dimeric molecule formed by 2 monomer units, joined together at their carboxy terminals by a protein termed J-chains
 Additionally secretory IgA has a secretory component attached to dimer  Secretory IgA is found in external secretions such as colostrum,saliva,tears and respiratory , intestinal & genital tract secretions  Serum IgA exists as monomeric form( found in internal secretions such as synovial,amniotic,pleural & CSF )
 Functions:  Secretory IgA prevents attachment of bacteria and viruses to mucous membranes and helps protect mucous surface from antigenic attack  Prevents access of foreign substances to circulation
 It is a pentamer consisting of 5 identical Ig molecules, joined together by disulfide bridges.  IgM accounts for some 10% of normal Ig  IgM is the main Ig produced early in the primary response  As it is pentamer, it has 10 antigen binding sites & is the most efficient Ig in agglutination, complement activation & other antibody reactions & is important in defence against bacteria & viruses
 The natural blood group antibodies, anti-A & anti-B are IgM  IgM present on the surface of B lymphocytes is monomer, where it functions as an antigen binding receptor for antigen recognition  IgM can be produced by fetus in certain infections.  Functions:  Activate complement, promotes phagocytosis & causes lysis of antigenic cells(bacteria)
 Waldenstorm’s macroglobulinaemia :  It is a malignant disease of lymphoid elements, characterized by high serum concentrarion of IgM
 It is a monomer and resembles IgG structurally  IgD has no known antibody function but may function as an antigen receptor  Like, IgM, it is present on the surface of many B lymphocytes  The circulating concentration of IgD in blood is very low  IgD is labile
 IgE is a monomeric molecule similar to IgG. It is sometimes called reagin  Although IgE is present in trace amounts, in normal persons with allergic activity have greatly increased amounts  Functions:  Antiallergic & antiparasitic
 IgE is responsible for anaphylactic(immediate) type of hypersensitivity & allergy. Its main activity is mediated by mast cells or basophils  Defends against worm infections by causing release of enzymes from eosinophils  Main host defence against parasites like helminthus, provides protection in the disease schistomiasis
 A malignant proliferation of plasma cells  Results in an abnormally high concentration of serum immunoglobulins, usually IgG or IgA
 In multiple myeloma, more light chains are produced than heavy chains and enter the bloodstream  Because they are of relatively low m.wt, they pass through glomerular membrane and appear in the urine, these protein chains of low m.wt are known as Bence Jones Proteins
 Bence Jones proteins have the remarkable characteristic of precipitating on heating urine from 450 – 600 C and redissolve when the heating is continued above 800 C  Multiple myeloma with Bence Jones proteins in the urine is called “light chain disease”
Plasma proteins.
Plasma proteins.
Plasma proteins.