+,
R F A Z*aal and H C Hemker (Eds \. Blood Coagulatton
, Q 1 9 S 6E l s e r i e r S c r e n c eP u h l i s h e r sB V ( B l o m e d i c a l D i v i s i o n l
307
CHAPTER iO
Interplaybetweenmedicineand
biochemistrY
H. COENRAAD HEMKER
(Jniversityof Limburg, BiomedicalCentre,Maastricht(The Netherlands)
and sciMedical science, not surprisingly, flowers at the interface of medicine
Alence. Its bloom thus resulti trom ine confrontation of two different cultures.
is
it
two,
though it is good custom to emphasize the warm relations between the
Indeed
of nJ use to dissimulatethe distancethat separatesdoctors and scientists'
'two cultures' not exclusively as a
the gap is large enough to use the expression
is sufaesciiption oithe situation between the sciencesand the humanities' There
medconfronting
ficient reason to maintain that it applies as well to the sciences
and
patients
his
of
icine. A good doctor is primarily interested in the well-being
him
find
to
rare
is
It
uses scientific insight oniy ut one of the tools of his trade.
hand a
develop an expert knowledge in a branch of natural science. on the other
of
results
his
tofnd
be
may
he
scientiit opts fbr insight, no-matter how delighted
atin
difference
fundamental
The
use in the diagnosis and treatment of the sick.
between scititude between the two makes that the exploration of the interface
rn one
or
congress
symposium
every
ence and medicine often is difficult. In fact
sciand
doctors
although
that
us
teaches
field or another of human pathobiology
difficulty'
with
amalgamate
entists meet frequently, their views only
beThere is good ."uron to stress this point if one is to discuss the interplay
anhardly
is
There
coagulation.
blood
of
field
the
tween mediiine and sciencein
most
the
remained
have
clinics
the
where
biology
other subject of study in human
or imimportani source of information for so long. Whereas e.g. endocrinology
of
half
first
the
during
already
developed
components
munology had their science
There
doctors.
the
of
playground
the
remained
,.reurih
this ceniury, haemostasi.
probably are multiple reasons for this, such as the rarenessof congenital bleeding
of the
Oirord.ir, that are the most natural first object of study or the complexity
any
problem that presents itself already after the first few experiments' to defy
per
se
is
simplifying hypothesis etc. I would not maintain that blood coagulation
huof
rhan immunology or endocrinology or any other subject
.noi. **ltliiteO
It only presents its complexity right at th-ebeginning of the
path;physiology.
man
attempt at
most^simpli expe.iments. This makes people tend to shy away from an
field, my
the
a formal icientific approach. Even in 1962, when I planned to enter
of fish
that
kettle
colleaguebiochemisti were shocked to see that I would consider
alobjections
these
worth; of my attention. My medical colleaguesdid not share
308
though they failed to see why I should stop medical practice. while plaving around
with tubes. At that time the lab carrying most weight in the field of blood coagulation was that in Oxford where R.G. Macfarlane, M.D. and clinical pathologist.
together with Rosemary Biggs, Ph.D. and originally a botanist. formed a nucleus
around which many medical doctors and several scientists gathered and formed a
group that was responsiblefor many fine contributions. Yet, even there. the application of modern biochemical techniques was less fruitful than the typical coagulation approach, that in essenceexists of measuring clotting times in endless
'After all' Rosemary Biggs used to
permutations and combinations of mixtures.
say'After all it is more like cooking than like anything else'. In Detroit, Walter
Seegers,M.D. and professor of physiology, devoted his life to attempts at punfying prothrombin and other clotting factors. Rereading the articles from this group
one is struck by the tremendot'i amount of work, by the many observationsdone
that can only be explained in the light of our newestknowledge (cf. Ch. 98). Also
by the fact that the results did not even allow the construction of a refutable set
of hypotheses.
It must be said that, with all their cooking and curing the doctors had done a
'factors' had been defined as functions
good job. By 1960 most of the coagulation
lacking in haemophilic disorders. The role of blood platelets had been discerned
and the pathology of thrombosis had been described in great detail. A good start
had been made with anticoagulant treatment and with the treatment of haemophilia by the use of plasma fractions.
Mentioning the pathology of thrombosis automatically evokes Virchow and the
scientists of the 19th and early 20th centuries. What about the interactions between medicine and science in those days? Buchanan (M.D.) was the first to report (1836) that catalytic amounts of clotted blood could coagulate a fibrinogen
iolution. His fibrinogen solution was prepared involuntarily in the scrotum of patients suffering from a hydrocele. These experiments can a posteriori hardly
be thought to be conclusive but they did introduce the concept of coagulation by
enzymatic conversion that we now know to be correct. In the second half of the
19th century this concept was heavily opposed a.o. by Alexander Schmidt who favoured the idea that fibrin arises from a stoichiometric interaction between blood
proteins. Others, like e.g. Hammersten sustained Buchanan's view, often with experimental evidence that up to this moment seemsconvincing. Nevertheless, even
with all the old literature on one's desk it is hard to find out what was really meant.
Some workers like Hammersten describe experiments with meticulous precision;
others, like Schrnidt prefer general considerations but in any case our observation
of their results is tinged with our present knowledge. The controversy that dominates the blood coagulation literature in the latter half of the last century is that
between those who se. fibrin as the product of the catalytic action of thrombin on
fibrinogen and those who think fibrin to arise from the stoichiometric action of fibrinogen and a second substance. The gist of this controversy seems to be that at
that time no distinction could be made between the functions of thrombin and that
of thromboplastin. In trying to repeat the old experiments it often up to this day
309
The same
cannot be made clear in what modern terms they should be explained.
of
functions
two
the
when
confusion repeats itself about half a century later
'bloodit
and
we
know
as
thromboplastin are recognised: tissue thromboplastin
of crude
thromboplastin' now knlwn to be prothrombinase. With combinations
etc') ob(cells,
serum
preparations
blood fractions and thromboplastin-iontaining
others
but
interactions
stoichiometric
servations can be made that indeed suggest
nomenthat
this
to
well.
Join
as
possible
suggestive of enzymatic interaction are
cla"t*urein those duy, *u, confused to thi degree of complete incomprehensibility
one will
and that communications often hardly crossed the national borders then
around
until
reached
not
was
opinio
a
communis
that
be hardly surprised by the fact
that
reluctantly
to
accept
began
Schmidt
1876
After
the turn of the century.
cirit
that
postulated
he
and
of
fibrin
generation
in
the
role
thrombin might play a
state'
precursor
an
inactive
in
culates in the blood
medThe type of argument used in th; 19th century discussionsswitched from
esease,
astonishing
an
with
back
and
experiments
to
chemical
ical observations
and
pecially where, as in the .ur" of Schmidt, the borderline between discussion
physiology'
specutation faded. Schmidt was a medical doctor and professor of
the
Aammersten was a chemist. It would in my opinion be unjustified to attribute
would
I
difference in style between these two scientist to a difference in discipline'
even
rather see it as a question of temper. Temper anyhow spices these discussions,
the
of
literature
the
to a degree that we nowadays would think unpalatable. From
in
difwork
not
did
19th ce*nturythe impression remains that doctors and chemists
Outferent worlds but rather cooperated and penetrated each others fields freely'
conor,
rabies
who
cured
Pasteur
one might t-hink of the chemist
side coagulation
-of
medical
exclusively
almost
were
who
the first geneiation of biochemists
versely,
that one
doctois. perhaps inlhose times the new ground to cover was so enormous
to stick
we
tend
hand,
other
the
on
did not bother about subdivisions.Perhaps,
too much to our disciplines these days.
that up
In the field of blood coagulation there is a very interesting personality
Pekelharing
A'
Cornelis
deserves:
he
attention
to this moment did hardly [et ttre
uni(Fig. 1), a medical doctor who becameprofessorof general pathology at the
experiments
described
he
1894
In
1881.
in
*,"r!ity'of Utrecht, The Netherlands,
the existenceof
that up to this day can be easily repeated and that demonstrate
he obtained two
MgSOa
and/or
NaCl
with
precipitations
prothrombin. By repeated
of CaCl2
addition
upon
clotted
which
of
plasma,-neither
fractions from normal
adthese
after
however'
preparations,
the
of
One
and/or tissue thrombopiastin.
the
drew
Pekelharing
clot.
one
other
the
make
to
the
capacity
ditions acquired
influence
the
correct conclusion: R pioeniyme, prothrombin, is converted, under
that
can make fithrombin
enzyme,
an
into
caclr,
and
thromboplastin
of tissue
brinogen clot.
but also
ToLy knowledge this does not only mark the discoveryof prothrombin
that
shows
thus
It
is the first demonstration of a proenzyme-enzymeconversion'
semof
are
that
yield
results
the work of an M.D. on a medical problem often can
It thus is a perinal importance to biological sciences,to biochemistryin this case'
3r0
:|rt(.
' , .rI
(1848-f922)'
Fig. 1. CornelisA' Pekelharing
fectexampleofoneofthemainfeaturesoftheinteractionofmedicineandchemi s t r y : m e d i c a l p r o b l e m s a r e a t r e a s u r e t r o v e f o r t h e b i o c h etrying
m i s t wto
h ounderstand
t a k e s t h e p ahis
in
i;iting *ittr a clinician and
to understand them;;U.
p r o b l e m s m a y b e m o r e d i f f i c u l t t h a n r u n n i n g a n u l t r a c e n t r i f u g e o rbiochemists
i n t e r p r e t i n gand
kias fruitful]The traffic between
netic data but it mayi"-"ill""
underand
try
by the failure of either one to
medical doctors is oftJri i"-p"r"o
standtheother,slanguage.Nowthiscanindeedbedifficu
l t . I h a v e h a doft hblood
epleasin the paediatric clinics of a pioneer
ure to work as u .rintui assistant
he
which
with
uun creveid. The astonishing ease
coagulation r"r"ur.n,-proi- s.
c o u l d s u g g e s t t h e m o s t . o m p t i c a t e o b i o c h e m i c a l r e s e a r c h odisease')
n t h e s p uwas
r o f a only
p a t l erint
attack *n witt"utand's
seen (,After tnis uu.uiion Je will
such
under
find
indeed
the scientists did
valled by the astonisii'rif urr.*"., that
guidance. I remind you of the discovery of platelet factor 3 (Paulssen)or the punlcation of factor VIII (van Mourik). On the other hand scientiststend to impose
their way of thinking on their medical colleagues,more often focussingon problems that are likely to be solved than on those that will help to gain insight in pathophysiologicalmechanisms.Yet, up to this day, the liaisonsand cross-fertilisations
between scientistsand practitionersremain many and varied. We see Prof. Magnusson, M.D., solve the primary structure of prothrombin and Prof. Duckert, Ph.
D., solve many problems directly related to patient care. We see the medical doctors continuously improve on the quality of their clinical trials under the continuous criticism of the statisticiansand we continue to find patients that help us pose
problems of fundamental interest and solve them. It is only relatively recently that
the Fletcher and Fleaujac deficienciesled to the discovery of the details of contact
activation, that a study of the membrane proteins in congenital thrombopathies gave
important clues to the receptor functions in platelets or that the problems of the
control of oral anticoagulation inspired the experiments that led to the discovery
of carboxyglutamicacid and the mechanismof action of vitamin K.
'more than life size' example plays just at this moment (October 1984)in our
A
laboratory while Mrs. Scott is visiting us. Mrs. Scott is an American lady who was
treated by Dr. Weiss in New York for a mild thrombopathy that he could define
to be a lack of platelet procoagulant activity. Later the group of Dr. Majerus in
St. Louis also did experimentswith her plateletsand they concludedthat a membrane protein receptor for the formation of prothrombinase was lacking. On the
basis of quite different experimentsour group arrived at the conclusionthat it is
rather the transbilayer lipid movement in platelets that causesplatelet procoagulant activity. It makes phosphatidyl serine available at the outside of the membrane, which is crucial to the procoagulant activity of any phospholipid preparation. Now indeed if the platelets of Mrs. Scott can be shown to lack a protein
'American' view must be deemed right. On the other hand, if Mrs.
receptor the
Scott's platelets do not show phospholipid flip-flop, our concept of PF 3 is the more
likely one. So at this moment we are determining whether only prothrombinaseforming capacity is lacking in her plateletsor whether the capacity to support the
formation of the factor X-converting enzyme is lacking as well. If this is the case,
either the receptor is aspecific or two receptors are lacking at the same time' We
will also see whether or not phosphatidylserine will show up at the outside of her
triggered platelets. In this way we hope to settle a difference in opinion in a way
that will convince our American colleagues(cf. Rosing et al. (1985) Blood 65,
1ss7-1s61).
This case is a perfect modern example of the continuous need, also in modern
'the experiment of nature' that is to be found in the clinics. Also
biochemistry, of
of the continuous need for biochemistsalert for rare casespresentedby clinicians
and of the need for continuous attention from the side of the doctors, in order to
find those casesthat may help solve scientificproblems. Alas it must be said that
only a small part of the doctors burdened by an everydaypractice have the talent
and/or interest to pay attention to this part of medical science.And also that those
3ll
and wilting to listen to thetr stor\
who do. will often not find a scientistcompetent
think
thit such contactsare rare makes one
and grasp its possible rn"uning' The fact
ttrat"mucn valuable material slips constantl'
that
This is readily illustrated by the fact
genital fibrinogen abnormality seemsto c
iation tabs are to be found' One wonders
ical doctors responsiblefor the research.l
opln
still is often seen nowadaysis, in my
usually
so formidable that one of them
reb joins in an existing dialogue between
'casehunters' may be of great use' I
ion as
day is of
linics and basic science up to this
paramountimportanceinhaemostastsandthrombosisresearch.Wemustconfess
thatthedifficultiestt,utu,i,"inestablishingthenecessarylinksareoftenofanorganisationalunOp.ytftof'ogitut"ututt'Recognisingthismaybeafirststeptoasot"ti:ir"*
of
it is hardly usefur to publish a list
of the special subject of this articre
research
in the history of blood^coagulation
references. To the ,""d;; interested
anextensivebibliographyoftheliteratureuptoaroundlg00isavailableuponrequest.