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1946 1: 3-9

BLOOD : A BRIEF SURVEY OF ITS CHEMICAL COMPONENTS AND OF THEIR NATURAL FUNCTIONS AND CLINICAL USES
EDWIN J. COHN

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BLOOD A
BRIEF SURVEY NATURAL OF ITs CHEMICAL AND COMPONENTS CLINICAL AND OF THEIR

FUNCTIONS

Usv.s*

By

EDWIN

J.
more

COHN,

PH.D. in recent years than has any

B
tion large

LOOD

has

probably

been

studied

intensively

other tissue. in the scheme amounts

This is partly of life, and

because of the ancient partly because of the from or injected have into given

tradition of its central posisafety with which relatively man, in health or disease, for how-

can be withdrawn and

study or for therapy. The availability of blood

its fluidity

a deceptive

impression,

ever, that it can be characterized as a whole. The brilliant steiner at the turn of the century resulted in the recognition blood, and their number has increased as more and more carried tinins out, which have react antibodies, which and do,

investigations of a series observations,

of Landof types of carefully

revealed greater and greater complexity. Besides the isoaggluwith the A1, A2, or B agglutinogens, there are the various types anti-Rh0, have been characterize anti-Rh, recognized the whole the certain anti-Rh, by the blood and the late or blocking phenomenon of cell agglutination. in terms of these categories. To the of cell agglutination variables, and The the isoagglutinins coagulating, and normally within the depends a very small are not the or the pressor represent less its envelope the other of a of

of anti-Rh antibodies We must, best upon group carriers properties

of our knowledge, the surface of the of plasma proteins, of the immune, of the blocd. of the
i

however, red cell, the

phenomenon environmental

isoagglutinins.

the osmotic, the respiratory, They are a genetic inheritance

than a tenth Although series

#{231}er cent importance chemical upon carbonic

of the plasma proteins. of the red cell in concentrating reagents which blood anhydrase, within the red cannot be overemphasized, grouping depends, the hypertensinase, cells remain

of specialized

specificity

cell agglutination, hemoglobin, the enzymes whose

does not involve or the host of

functions

to be apprehended.

Safety

red cell transfusion demands agglutination phenomenon

From *Our the Department of Physical of blood has knowledge

an ever increasing and of its control,

Chemistry, accumulating Harvard been

and more detailed knowledge of the and the steady growth of hematology
Medical School, centuries space blood
1945,

Boston. that this blood adequate brief references essay. to the

for so many occupy more

literature regarding and physiology, to this plasma tributed in Science rated

Investigation,

each point referred to would and histology, A partial University which

2.3,

than and
319-13.

Immunology all consepais published upon 8io,

of Clinical
1945;

pharmacology knowledge. Yale

physics, chemistry, regarding Series, uses

i,

medicine,

and surgery have derivatives Recent in the

704,

bibliography Press, Fourth to clinical volume led

1944;

in Progress,

pages been

studies
Journal

components volume

have 4i7-6c6,
02.6,
1945;

have

reported
671,

pages

pages 66i,

698,

793,
Medical
12.7,

and page
of the

and articles to be published volume volume

Academy
02.4,

shortly in the same ,o88,

of the

journal; in the Journal page

1945; 2.10,

of the
1944

American

Association,

page 976, 944; volume pages io6i

Journal

pages 469, 674, 68o, and 944, and volume

2.!, 12.9, 2.02., 2.70,

volume volume

44, 945;
New York
1945;

ii8,

and

1945;

in the Bulletin i8,

of Medicine,

Second

Series, volume
Medical

page

in Surgery, page 66i,

1945.

page

347,

and in the American

Sciences,

volume

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4 is yielding such knowledge, as well

BLOOD

as knowledge

of the diverse

products blood

and which

proccon-

esses upon which the multiple functions of the blood depend. Bacteriology has long recognized groups of substances in the tribute to resistance to infection. Early workers distinguished and specific Complement of which near their antibodies on the basis is, however, a complex have been isoelectric recognized and points. No one of the greater thermolability of at least four different

between

complement

of complement. components, certain

concentrated as euglobulins by precipitation of the components of complement that have the per

been thus separated represents as much as i per cent of the plasma proteins. The group of globulins which have thus far been most clearly identified with antibody functions of the blood, the v-globulins, represent approximately
ii

cent of the plasma proteins. In this bundle of globulins are concentrated the antibodies to many of the common infectious agents to which man has been exposed. The v-globulins will, therefore, differ not only in amount, but also in kind, from man to man, and from time to time in the same man, depending on the one hand upon his response to new antigens and on the other upon the complex system which controls the equilibrium between these and other from which they come and in which they are stored. from a population offers a means of characterizing plasma proteins and the tissues The pooling of the v-globulins the state of immunity of that

population. Even when injection of such antibodies is proven to have prophylactic value, however, as in the case of measles and infectious hepatitis, the immunization is short-lived, rather than lasting. Lasting tissue mechanism of antibody production like all plasma proteins pattern immune have which bodies but a short the the repeating posed. Just as the against conceived reflects immunity presumably rather than upon the life in the antigens blood to which stream the depends antibodies, and body has upon the which in exbeen

are released

of the blood involved mechanism

are considered preventing the

as a protective loss of the

mechanism may be fluid

infection,

so the substances

in the coagulation

of the blood circulating

of as a protective

of the body externally, ism are component the solid blood clot

or into tissue spaces. Most parts of the plasma and are must always be present, and many

of the molecules proteins. Since of them exist theory,

in this mechanthe elements of in had which structural represents the flowing

blood in a precursor state. Physiology, on the basis the existence recent years of the per cent increase fibrin the

of experiments

a developing

postulated have in element but so greatly as to imthrombin 3

of many substances involved been concentrated and purified. clot, viscosity the long of the rod-shaped Were blood, heart. to fibrin
it

in blood coagulation, Among them is the molecule, in larger of its asymmetric protein, which amount

fibrinogen present by virtue

of the plasma

proteins.

it

would

structure, but

pose a great Fibrinogen

burden on the is transformed

by another

thrombin,

too exists in the blood in a precursor state as prothrombin. The production of prothrombin by the tissues is related to vitamin K, and this substance can be used to influence, within limits, the concentration of prothrombin in the blood stream. The transformation of prothrombin to the active state, thrombin, requires the

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EDWIN

J.

COHN

5 thromboplastin thrombin, and by virtue of at least certain so that we involved knowledge the the clot, clot.

presence of calcium and this property Fibrinogen,

.

of tissue vitamin

lipoprotein, called K, prothrombin,

tissue thromboplastins may look forward in the may the coagulation also blood lead fibrinogen stream

have now to very careful process and control.

been prepared in sufficiently pure states studies of the chemical transformations to the possibility the components enzyme capable that this increasing to form

to increasing and carries

Besides Moreover, precursor formed.

prothrombin, a fibrinolytic evidence activation enzyme

necessary

of dissolving

there is some state requiring This proteolytic

that this enzyme also exists in the before its full proteolytic function has thus far Its related been possible to the less completely value clotting thrombin. plasma in therapy of the

plasma in a can be perstudied than remains blood has antiI in

fibrinogen and prothrombin and to be determined. Another component of normal

been recognized because of its absence in a group of individuals. The hemophilic globulin has been concentrated in a fraction of plasma the system represented suggests in systems that from in figure this which
i)

so-called (Fraction the may not

which

also has

contains been

fibrinogen, Its presence individual has

but

evidence be demonor by heat

available strated coagulation.

globulin fibrinogen

is not

fibrinogen.

removed

by thrombin

Although

its separation capacity blood of the to normal, and

as a chemical antihemophilic both in vivo therapy of this

as yet

been

accomplished, the time of hemophilic tial value in the

globulin to bring the clotting and in vitro, indicates its potenserious disease.

prophylaxis

In the coagulation process, most of them proteins, thus appears to interact to produce case of the stances has proteins heretofore involved been

as in the action of complement, many substances, play interrelated roles. Another group of substances widespread constriction of blood vessels. As in the in blood developed coagulation, our knowledge of these sublargely in physiology. Something of their however, would and their separation appear to be possible. and concentraIn this system

chemical nature begins to be known, tion to any necessary degree of purity also the component hypertensinogen. in vitro (under appears circulating Hypertensinogen

in plasma is a precursor substance, protein in nature, is one of the a-globulins. It is somewhat labile with a substance, yield a peptide which leads renin-liberated from called hypertensin.* to constriction rapidly plasma, kind of the kidney tissue Hypertensin blood vessels. enzyme, amount and the in the same

and in vivo interacts certain conditions)-to to be the active in blood Hypertensinase

substance

Its concentration hypertensinase.

plasma is, however, is present in the between the same enzymes

reduced by an but in far larger in the plasma Are they

in the red blood cell. What are the interrelations red cell? Do they perform chemically, tions? There have functions
Various workers

of this

or supplementary

functions?

or will they is phosphatase related enzymes

have

reveal chemical differences related to their specific funcin the red cells. Phosphatase and cholinesterase clearly to the phosphatides lipoproteins,
names to all of these

and

cerebrosides, and proteins,

e.g., substances,

and of the

the

lipases
has also

and
been

proteolytic
*

to the
given

lipids,
various

blood

stream.

hypertensin

called

angiotonin.

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BLOOD

The have

complex in some
PLASMA

interrelations as well degree

THEIR

of the revealed
FuNcTIoNs

many and

substances released to, years.

CLINICAL

constantly or absorbed Their

USES AND

being from,

built the

up and tissues and

destroyed,

as transported been

in recent
AND

detailed
SEPARATION

exploration
INTO FRACTIONS

PROTEINS:

NATURAL

4Poprofejnemia.

GE%

Fio. This figure is taken

to represent

from

that in Science in the (Annals Isoagglutinin

(Vol.
fractionation

roi, Reagents

No.

i6zi, pp. 5i-6, See also by York

1945),

somewhat

modified

the most recent advances Anti-B, and and L. Anti-Rh K. Diamond

process.

Methods M. Melin, of Sciences,

for the Preparation

of Anti-A, D. A. Richert,

J.

L. Onclev, Academy

J.

sV.

Cameron,

of the

New

In Press).

exploitation be accomplished. Lipoproteins

in the

interests

of chemical, kinds have been

and

perhaps

of clinical, from the

control plasma, and

remains their

to in-

of many

separated

vestigation as chemical substances tions. Lipids have been found $-globulins. The lipid components

may well in more or of these

throw light on their less labile combination complexes are

nature and funcwith a- and carote-

phosphatides,

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EDWIN

J.

COHN

7 other
it

noids, mode that lieved under

fatty many

acids of the

and fatty

cholesterol, is by no means components

and

presumably but plasma

fatlike had

substances. significance been

The be-

of combination to be free controlled

proven, of the

is of unquestioned which previously

appear to be combined chemical conditions The best estimate

with protein. has routinely at the

Moreover, their concentration yielded a series of characteristic time is that about a quarter

lipoprotein

fractions.

present

of the plasma proteins are lipoproteins. Three groups of the plasma proteins that have been prepared state are substantially free of lipids: fibrinogen, the v-globulins, Certain a- and $-globulins, IV-3 4) and studied both tween these investigated. Albumins purified and is composed which most these substances globulins, are by far crystallized. poor in lipid, in the laboratory lipid-free the and have also and in the been clinic. with

in relatively pure and the albumins.

prepared (in Fraction The interrelation belipid, remains to be

in combination

most abundant of the plasma proteins. They are readily Free of carbohydrates, crystallized human serum albumin to the amino acids of specific properties that problems. solutions with have whole one is

of a small percentage of fatty acids in addition proteins are constituted. The nature of the contribute to the albumins also raises most symmetrical of the plasma viscosity, a 2.5 per cent solution is half hundred

interesting

Albumins are the therefore the lowest blood. sixth

proteins. Their being iso-viscous

The molecular weight of the albumins that of fibrinogen. Only one in every whereas two out for most of the for the maintenance volume in shock nephrosis specialized in very
i

that of most globulins and plasma protein molecules

fibrinogen, responsible responsible tion rhosis The functions of blood

of every osmotic and

three are albumin efficiency of the volume. conditions The other

molecules. The albumins are plasma and are thus largely use of albumin and as a diuretic in the restoraagent in cir-

of blood

of the liver and different highly and are present

is discussed proteins different

i

in a series of recent clinical papers. of the plasma perform very different amounts. component per cent, Thus the isoagglutinins repreof complement less than i per fibrinogen 3 per cent, the v-glo-

sent less than one tenth of cent, prothrombin less than

per cent, each one tenth of

bulins 11 per cent, the a- and i3-globulins, of which 2.4 per cent are lipoproteins, represent 31 per cent, and the albumins about per cent of the plasma proteins. All the plasma proteins together, however, represent but 7 per cent of the normal plasma, or roughly 4 per cent of the blood. in the or The red
12.

amount cell.
tO 14

of protein

in the

plasma

thus is small the contents globin, three plasma. Hemoglobin, for the

in comparison with that of the red cell is hemoglobin, to four like

it

Since roughly 30 per cent of per cent of the blood is hemowithin stream, respiratory the red cell as in the

times the

as much other proteins The

protein

is present blood of the

of the

is highly function

specialized and the and clinical studies of

functions

performs.

importance

copiousness investigations,

of this blood-red supplemented

protein has led to a century of physiologic in more recent years by organic chemical and moiety, heme, by physicochemical which

the structure of the iron-containing attached to the protein globin,

is the prosthetic group studies upon hemoglobin

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8 and atomic oxygen group its interactions weight especially of oxygen with is i6 and

BLOOD

electrolytes, of iron
.

carbon Each iron

dioxide, atom

and

oxygen. with

The an

combines

molecule, that with a combining

is, two oxygen atoms. The iron, however, is part of the heme weight close to 700. The heme is attached to the globin, equivalent weight. known as myoglobin, a molecular weight Iron-containing proteins are of this size, but the of at least 33,400 and gen-

each iron concerned hemoglobin

atom to a unit of 16,700 with respiration in muscle, of the blood stream has

erally of 66,8co. In the former state it combines four, oxygen molecules. The molecules devised of oxygen to the tissues thus have a mass roughly transported. Why is the hemoglobin of the blood stream proteins are free which perform in the fluid part comparable of the blood. respiratory The proteins

and transports two, in the latter by nature for the efficient transport oo times that of the oxygen to be contained functions dissolved within cell walls? The

in many forms of life in the fluid part of the the

30 per cent of hemoglobin

blood of animals rarely hemoglobin contained were free in the blood

exceed io per cent, as contrasted with in the red blood cell. If this concentration stream,
it

of

would

bring

about

a redistribution

of many

com-

ponents other than oxygen. It is the way of concerned with the study of its mechanism, to the efficiency with which certain functions are The function of transporting oxygen by the volves the hemoglobin a complex lungs and unloads mechanism release of oxygen the oxygen permitting in the which tissues.
it

the body, or appears to be to those evolve processes which in enhancing performed do not inhibit others. hemoglobin within the red cell incombination As carbon dioxide Carbonic transported. with oxygen anhydrase in the increases,

maximum has

accelerates and renders more efficient this process. In addition, the red cells contain other enzymes, including a catalase and a phosphatase. The presence of these enzymes suggests the nature of certain of the chemical reactions which are involved in the internal economy of these cells. These vital processes also appear to limit the life of the red blood even the best methods cell, both in the of preservation blood stream and at present known. in the blood bank, under

No other part of human to the tissues, in permitting respiration. When, therefore, operation is to be performed, lescence from wounds must adequate to restore the

blood has so significant a function in transporting oxygen the very great activity and high order of mammalian there is great blood loss from a wound, when a major or when the anemia which frequently occurs in convabe combated, red blood cells must be supplied in amounts capacity of the blood. certain, but will prove of the by the conditions, in greater certain their components cells and In how many condinot necessarily all, of as valuable in therapy playing plasma may a role not in be

oxygen-carrying

tions red cells resuspended in media containing the plasma proteins and free of the iso-agglutinins as whole the control blood remains of the to be determined. functions performed in all available or in therapy value if made All of all

needed in prophylaxis may have far greater concentration It has proven prepare products

and those that are needed amount than their normal of the plasma uses. Other proteins, products to

in the blood or plasma. possible to purify and from them, and

concentrate

to determine

clinical

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EDWIN

J. fluid

COHN

derived able.

from Whether

the

cellular the

as well natural

as the products

part

of blood in specific

can within

also the

be made red cell as those from

availcan experithe for the agents that be that

or not employed free in the of these

concentrated of value

as effectively are usually ments. All

as concentrates, plasma, can only may products

conditions, and concentrated

be determined purified,

by careful,

long-range

be separated,

same blood. The chemist is fulfilling his function in developing methods preparation of derivatives which are more concentrated, stable, and specific than the blood from which they are derived. Starting with the assumption every make part of available human in the blood postwar protein, agents, and performs world, and fatty of value economical an important natural as we have in the war, components, in different use separated conditions, of the function, as many and in

we must as possible concentrated the interests which

it

of its diverse cellular, as specific therapeutic of the most effective contributes.

by a society

blood