historical review

The story of the discovery of heparin and warfarin

Douglas Wardrop and David Keeling
Oxford Haemophilia and Thrombosis Centre, Oxford Radcliffe Hospitals, Oxford, UK

Summary
Heparin and coumarins have been the mainstay of anticoagulant therapy throughout our working lives. As we stand on
the threshold of a new era of anticoagulants it is timely to look
back upon their discovery and development. Both have
fascinating stories to tell. Jay McLean claimed to have
discovered heparin whilst a medical student, although this is
disputed. The story of warfarin leads us from a mysterious
haemorrhagic disease of cattle to the development of a rat
poison which became one of the most commonly prescribed
drugs in history. Many people were involved in both stories
and we owe them all a debt of gratitude.
Keywords: heparin, warfarin, discovery.
Heparin and vitamin K antagonists have been the main
anticoagulant drugs for decades. We are now approaching an
era of many new anticoagulants as reviewed in this journal
recently (Bates & Weitz, 2006). It is thus timely to look back at
the discovery of heparin and warfarin in the first part of the
20th century.

The discovery of heparin

Heparin, one of the oldest drugs still in widespread clinical use,
is a naturally occurring glycosaminoglycan whose main
function is to inhibit the coagulation of blood. It was
discovered almost a century ago and took many years to
move from the laboratory to the bedside. There has been
significant controversy regarding the distribution of credit its
discovery. James Marcum has chronicled both the discovery
and development (Marcum, 1990, 1997), and the dispute
(Marcum, 2000).

Initial discoveries: from fat-soluble phosphatides to

water-soluble heparin
In 1916, at Johns Hopkins Medical School, Baltimore, USA, a
second year medical student, Jay McLean, was working under

Correspondence: Dr D. Keeling, Oxford Haemophilia and Thrombosis

Centre Churchill Hospital, Oxford OX3 7LJ, UK.
E-mail: david.keeling@ndm.ox.ac.uk

the physiologist William Henry Howell (Fig 1). Howells main

interests were the substances controlling blood clotting; he
thought there was a balance between a clotting inhibitor
(termed antithrombin) and a procoagulant (termed thromboplastin). He believed that the release of cephalin (so called
because it was first isolated from canine brain) from platelets
and leucocytes neutralised antithrombin, permitting activation
of prothrombin by calcium (Howell, 1912). McLean had come
up to Baltimore the previous year and was assigned by Howell
to examine the chemical purity of cephalin preparations, and
to demonstrate that it was cephalin and not a contaminant in
the preparation that accounted for the procoagulant activity.
After finishing this work early, McLean extracted phosphatides
(fat soluble compounds) from canine liver that appeared to
demonstrate anticoagulant, properties in vitro and subsequently led to excessive bleeding in experimental animals.
McLean then moved to the University of Pennsylvania to
research cephalins further under Richard Mills Pearce. In
October 1917, he returned to Baltimore but did no further
research on the phosphatides he had isolated the previous year.
Instead, he continued research on cephalin, feeling that work
on a procoagulant rather than an anticoagulant, was better for
the ongoing efforts in The Great War.
Back in Howells laboratories, work on anticoagulants
continued. Alongside another medical student L. Emmett
Holt Jr, Howell had isolated another fat soluble anticoagulant
apparently distinct from that isolated by McLean 2 years
previously (Howell & Holt, 1918). The term heparin was
coined by Howell from the Greek hepar, or liver, the tissue
from which it was first isolated. At an annual meeting of the
American Physiological Society in 1922, Howell introduced an
aqueous extraction protocol for isolating heparin and, at The
12th International Physiological Congress in 1926, he presented refinements to this protocol and identified the watersoluble carbohydrate as glucuronic acid. This he correctly
claimed was a compound distinct both to the entity isolated by
himself and Holt in 1918 and by McLean in 1916.
This water soluble heparin began to be produced commercially by a local pharmaceutical company in Baltimore,
Hynson, Westcott, and Dunning, but studies conducted at
Mayo Clinic, Minnesota, by Edward Mason demonstrated that
this preparation caused side effects including headaches, fevers
and nausea (Mason, 1924). Howell was concerned production
would cease as its toxic effects might preclude widespread use

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Historical Review

Fig 1. William Henry Howell (courtesy of USA National Library of

Medicine).

(Howell & MacDonald, 1930). However, heparin did continue

to be available commercially despite these fears, although the
pharmaceutical company did not advance its isolation beyond
Howells original protocol. In 1931, Howell retired from his
post at Johns Hopkins and did no further research on heparin.

Bringing heparin to the bedside

Investigators in other parts of the world were working on a way
to better purify heparin and thus avoid its side effects. In 1928,
the physician and physiologist Charles Best (Fig 2), most
famous for his work on insulin at the Connaught Laboratories,
Toronto, began to assemble a team of biochemists, physiologists and clinicians at the citys university. He had spent the
last few years in the National Institute of Medical Research
(established in London in 1913 as the first institute of the
Medical Research Council) and decided to develop heparin
into something useful for research and clinical purposes. In
1929 he became Professor and Head of Physiology at the
university and it was at this time that he and his graduate
student, Arthur Charles, began work in earnest. Their aims
were twofold; to further purify heparin to reduce or eliminate
its side effects and to demonstrate its effects in the prevention
of thrombus formation. In 1929, Erik Jorpes, a Swedish
physiologist visited Best to observe the production of insulin at
Toronto. Jorpes was shown around the Connaught Laborato758

Fig 2. Charles Best (courtesy of USA National Library of Medicine).

ries and introduced to the work on heparin. He subsequently

returned to Stockholm and began his own attempt to isolate
and characterise the substance.
It was not until 1933, four years after Bests team had begun
serious work on the project, that Charles, and his more
experienced colleague David Scott, who had served as an
assistant director at the Connaught Laboratories, published a
series of papers on their work thus far (Charles & Scott,
1933a,b,c). In the first paper (Charles & Scott, 1933a) they
outlined a protocol for isolating a crude heparin preparation
from bovine liver. To increase the amount of heparin yielded,
the tissue had to be autolysed but the smell of the decaying
tissue was so bad that the production had to be moved from
the laboratories in the city to the local Connaught Farm! Their
next paper outlined a survey of extra-hepatic tissues where
heparin could be identified, partly because of the high cost of
liver (Charles & Scott, 1933b). They concluded that liver,
muscle, and lung tissues were where heparin was most
abundant. The only tissue found to have little or none isolated

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Historical Review
was the tissue considered most integral to its mode of action;
blood. Almost a decade earlier Howell had claimed that
heparin was responsible for the fluidity of blood, he believed
that although the amount of heparin in the circulation was
probably small, its overall potency was greater there (Howell,
1925). The third and final paper in the series presented a
purification protocol for heparin (Charles & Scott, 1933c). As
Best later clarified, the preparations were not pure in the
chemical sense but rather free from toxic components. It was
hoped that the preparations would be of uniform potency but,
although Charles and Scott were finally able to produce a
crystalline form of heparin, there were problems getting
consistent results from batch to batch. This not only hampered
clinical progress but also sparked complaints from researchers
who had bought heparin from Connaught laboratories for
their own research purposes. One such investigator was Robert
Cornish who was experimenting with dogs. In 1934, he wrote a
letter to the Connaught laboratories complaining that the
heparin he had bought caused failure of two of [their]
experiments as well as damage to blood. He went on if you
intend to sell much more heparin you should avoid such
serious misbranding in the future!.
To address the clinical and physiological aspects the
Canadians worked in two teams; Murray led a team at the
Toronto General Hospital while Bests team continued to
work in the Department of Physiology and School of Hygiene.
Their initial publication was on the application of heparin for
thrombus prevention in dogs (Murray et al, 1937), where they
showed that heparin prevented thrombus formation in veins
traumatised by mechanical or chemical means. The first use
of this newer, purer, form of the anticoagulant in a human
was 16 April 1937 a solution of heparin in saline was passed
into the brachial artery resulting in a significantly increased
clotting time during the 2-h infusion. There were no toxic
side effects. Murray tentatively claimed during a Hunterian
lecture in the same year that although its development was
still in its early days, its use could potentially extend to
embolectomy, splenectomy, venous grafts and pulmonary
embolism.
In 1939 Jay McLean, the medical student who first isolated
the anti-coagulant fat-soluble phosphatides over 20 years
previously, had began to investigate the clinical efficacy of
heparin (along with sulfapyridine) in patients with endocarditis (McLean et al, 1941). Unfortunately, both patients
succumbed to the disease despite the treatment. More
promisingly, in 1943, heparin was used to preserve a gangrenous leg from full amputation (McLean & Johnson, 1946).
Following discussions with McLean, Kurt Lange from New
York Medical Center reported that gangrene resulting from
frostbite, and military trauma such as paratroopers landing
injury might be treated with heparin (Lange et al, 1945).
After the war, Connaught Laboratories continued to
produce heparin and attempted to increase its potency.
However, by 1949, Drs Peter Moloney and Edith Taylor had
patented a method that obtained a greater yield of heparin at

lower cost, making heparin cheaper to produced elsewhere. By

the early 1950s, Connaught had stopped producing the drug it
had pioneered altogether (Rutty, 2000).

The distribution of credit

Before the 1940s, most researchers in the biomedical community regarded Howell as the discoverer of heparin (Murray,
1940). According to James Marcums account of the origin of
the dispute over heparin, Jay McLean, unhappy that he had not
received appropriate recognition for heparin (something he
saw as his own discovery) began a campaign in the 1940s to
re-dress the balance of distribution of credit (Marcum, 2000).
McLean gave several national lectures and wrote a number of
letters to Best claiming that he, and not Howell, was the
discoverer of heparin. However, McLean kept his campaign
relatively discreet until Howells death in 1945, largely because
he wanted to avoid controversy because of his long-standing
relationship with Howell. It is important to note, as Marcum
points out (Marcum, 2000), that it was not the intention of
McLean to deceive but rather correct the perception of the
biomedical community that Howell was responsible for the
discovery of the anticoagulant. Louis Jaques was irritated by
McLeans claims to be the discoverer of heparin and claimed
that McLeans contribution was part of American medical
folk-lore (Jaques, 1978) and in a letter written in 1987 he
stated the key person for heparin was Charles Best as he had
the novel combined role of top academician and director of
production of biological products (Marcum, 2000). McLeans
efforts in persuading the biomedical community of his
discovery were largely fruitful. After his death in 1959, his
obituary credited him with the accolade discoverer of heparin
and did not mention Howell at all (Marcum, 2000). In 1963, a
plaque was unveiled in Johns Hopkins to commemorate the
major contribution [of McLean] to the discovery of heparin in
1916 in collaboration with Professor William Henry Howell
(Ulin & Gollub, 1964).

The discovery of warfarin

The sweet clover problem
Warfarin is the most widely used anticoagulant in the world. In
the UK it is estimated that at least 1% of the population and
8% of the over-80s are taking it regularly (Pirmohamed, 2006).
The fascinating story of its discovery begins on the prairies of
Canada and the Northern Plains of America in the 1920s.
Previously healthy cattle in these areas began dying of internal
bleeding with no obvious precipitating cause. Given that
livestock was one of the most important industries in these
areas and because most North Americans were already severely
economically wounded by The Great Depression, this was a
devastating blow for the farmers livelihoods. As there was an
apparent lack of a recognisable pathogenic organism or
nutritional deficiency responsible for the haemorrhage, the

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diet of the livestock was questioned. The cattle and sheep had
grazed on sweet clover hay (Melilotus alba and Melilotus
officinalis) and the incidence of bleeding occurred most
frequently when the climate, and therefore the hay, in these
areas were damp. Such damp hay became infected by moulds
such as Penicillium nigricans and Penicillium jensi which
appeared to be integral in the disease process occurring in the
cattle (Schofield, 1924; Roderick, 1929, 1931). As Duxbury and
Poller point out in their review article on warfarin, such hay
would normally have been discarded if it spoiled in storage but
in the financial hardship of the 1920s few farmers could afford
to buy supplementary fodder for their cattle and thus the
mouldy hay was used to feed them (Duxbury & Poller, 2001).
The resultant haemorrhagic disease, which became known as
sweet clover disease, became manifest within 15 d of ingestion and killed the animal within 3050 d (Duxbury & Poller,
2001). Schofield and Roderick, two local veterinary surgeons,
had demonstrated sweet clover disease to be potentially
reversible if the offending mouldy hay was removed, or if
fresh blood was transfused into the bleeding animals (Schofield, 1924; Roderick, 1929). The recommendations to local
farmers were that they should avoid feeding their cattle with
the mouldy sweet clover hay. Roderick showed that the
acquired coagulation disorder was caused by what he called a
plasma prothrombin defect (Roderick, 1929).
Fig 3. Karl Link in his laboratory (courtesy of University of Wisconsin).

Isolation of the oral anticoagulant

Ten years after the original outbreak of sweet clover disease, a
young Wisconsin farmer, Ed Carlson, was at his wits end from
losing so many of his prized cows and bulls from internal
bleeding. Like so many local farmers he had no faith in the
theory of sweet clover disease. After all, they had fed the cows
with the hay for generations and to no ill effect. One winters
day he travelled 200 miles in a blizzard, with a dead cow in the
back of his truck, to the local agricultural experimental station
where investigators Karl Link and his senior student Wilhelm
Schoeffel were working. As the story goes, Carlson entered
Links office (the only one he found open in the building)
carrying a milk can of unclotted blood. Although clearly
sympathetic, all that Link could recommend was the avoidance
of the mouldy hay and the possibility of a transfusion of blood,
as Schofield and Roderick had demonstrated some years
previously. Karl Link (Fig 3) had only become interested in the
sweet clover problem a month earlier. Nonetheless it would
appear that Carlson had indeed come to the right place.
Schofield experimented with the blood that evening and, as
Duxbury and Poller comment, The can of uncoagulated blood
lying on the floor of Links laboratory was to change the course
of history, and little did Link know what the long-term
implications would be (Duxbury & Poller, 2001). Although
the cause of the haemorrhagic malady had been found, in the
sweet clover, the actual active compound had yet to be
identified or even isolated. Link and colleagues got to work on
finding the active substance from the spoiled hay.
760

A new in vitro clotting assay using plasma from rabbits was

developed to guide chemical fractionation of compounds
found in the hay. After some 6 years of intensive work, Links
laboratory was finally able to crystallise the substance. It
proved to be 3,3-methylene-bis[4-hyfroxycoumarin] (Campbell et al, 1940, 1941; Campbell & Link, 1941; Stahmann et al,
1941). They found that that natural coumarin became oxidised
in mouldy hay, to form the substance that would become
better known as dicoumarol. Large scale isolation of dicoumarol was accomplished by graduate student Mark Stahmann
who went on to become a professor of the biochemistry
department at Wisconsin (Last, 2002). The work was funded
by the Wisconsin Alumni Research Foundation (WARF), and
patent rights for dicoumarol were given to WARF in 1941.

From test tube to rat poison

In 1945, whilst recovering in a sanatorium from wet pleurisy,
Link got the idea of using a coumarin derivative as a
rodenticide, the rodents dying of internal haemorrhage. He
reviewed all the bioassay data to select the best variations of
dicoumarol to create what he called better mousetraps. He
thought dicoumarol a poor rodenticide because it acted too
slowly (Last, 2002). Link and colleagues, still funded by WARF
began working on several variations of the naturally occurring
coumarin. Number 42 of a list of 150 appeared to be
particularly active; warfarin (named after the authority with

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responsive commercial thromboplastins were used larger doses
were given to meet the target PTR. This led to overdosage and
widespread reports of bleeding. In the UK more sensitive
thromboplastin was used than in the US and it became clear
that the UK had fewer bleeding complications. It was later
realised that if samples are taken from patients on vitamin K
antagonists and the PTs or PTRs obtained with two different
thromboplastins plotted against each other in a log-log plot the
points lay on a straight line. Based on this fact the World
Health Organisation (WHO) in 1982 adopted a model to
convert the PTR obtained with any reagent to an International
Normalised Ratio (INR), that is the PTR that would have been
obtained if an International Reference Preparation (IRP) had
been used (Kirkwood, 1983; WHO Expert Committee on
Biological Standardization, 1983). If the PTRs using the IRP
are plotted on the y-axis and the PTRs using the local
laboratory reagent on the x-axis the slope of the line is known
as the International Sensitivity Index (ISI). The INR is then the
PTR found in the local laboratory raised to the power of the
ISI. This system standardised anticoagulant control worldwide.

Moving into the modern era of clinical trials

Fig 4. Karl Link promoting warfarin as a rodenticide (courtesy of

University of Wisconsin).

the financial muscle that funded the research) was born. It was
promoted in 1948 as a rodenticide (Fig 4).

From rat poison to clinical application

After its success as a rodenticide, the transition of warfarin to
clinical application was made under the name Coumadin.
Other anticoagulants were available; but of these heparin
required parenteral administration and dicoumarol had a long
latent period before onset of therapeutic effect. The principal
advantages of warfarin were its high water solubility and high
oral bioavailability (Last, 2002). It was more potent than
dicoumarol but retained the ability to have its effect reversed
by vitamin K (Overman et al, 1942).
In 1955, Warfarin was given to President Dwight Eisenhower following a myocardial infarction As Duxbury and
Poller point out; What was good for a war hero and the
President of the United States must be good for all, despite
being a rat poison! (Duxbury & Poller, 2001).
A major problem in the widespread clinical application of
warfarin proved to be the laboratory method used for dosage
control; the prothrombin time (PT). In the 1950s, commercial
sources of thromboplastin became available but they varied
markedly in their responsiveness to the defect induced by
vitamin K antagonists. As a result the PT varied greatly
depending on the thromboplastin used. Expressing the results
as a prothrombin ratio (PTR) did not solve the problem. If less

The first randomised trial of these anticoagulants was

performed in 1960 (Barritt & Jordan, 1960). Patients with
pulmonary embolism were randomised to anticoagulation
with heparin and nicoumalone or to no anticoagulation. Of
the 16 patients randomised to anticoagulation none died from
pulmonary embolism and there were no non-fatal recurrences.
Of the 19 patients randomised to no treatment, five died from
pulmonary embolism and there were also five non-fatal
recurrences. The importance of the initial treatment with
heparin was confirmed much more recently when heparin plus
acencoumorol was compared with acencoumorol alone for the
initial treatment of proximal deep vein thrombosis (Brandjes
et al, 1992). In the 60 patients treated with heparin and
acencoumorol there were no extensions of the thrombus and
there were two pulmonary emboli and two recurrences. In the
60 patients treated with acencoumorol alone there were two
extensions of the thrombus, two pulmonary emboli and eight
recurrences. The importance of heparin was also illustrated by
studies that looked at the adequacy of the dose (Hull et al,
1986; Raschke et al, 1993). Hull et al (1986) compared
subcutaneous and intravenous heparin for the treatment of
proximal DVT. It was noticed that, irrespective of mode of
delivery, inadequate heparinisation in the first 24 h resulted in
a 25% recurrence rate whilst it was only 16% in those
adequately anticoagulated. Raschke et al (1993) compared two
intravenous heparin regimens. The fixed dose regimen resulted
in an inadequate anticoagulation in 68% at 6 h and 23% at
24 h, the figures for the weight based regimen were 14 and 3%
respectively. The risk of recurrent thromboembolism was
fivefold greater in the former group. From these studies it
seemed that an inadequate activated partial thromboplastin
time response to unfractionated heparin in the first 24 h

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increased the risk of recurrence. However, a meta-analysis has
suggested that this does not seem to be critical if the starting
rate is at least 1250 U/h (Anand et al, 1996).
The dosing of warfarin was also controversial (see above).
Was dosing in the UK too low, increasing the incidence of
thromboses, or was the dosing in the USA excessive, leading to
unacceptable bleeding risks? The matter was resolved in a
randomised trial in which patients with venous thromboembolism were assigned to a target PTR of 2030 using either
the British thromboplastin (supplied by Dr Leon Poller) or the
less sensitive thromboplastin used at McMaster Hospital. The
incidence of recurrent thrombosis was 2% in both groups but
bleeding rates were five times higher if the North American
thromboplastin was used (22% vs. 4%) (Hull et al, 1982). As
the British reagent had an ISI of 10 this lent to the widespread
adoption of an INR target of 2030.
Low molecular weight heparins have now largely replaced
unfractionated heparin. The key reason is that they produce a
much more predictable anticoagulant response. This, combined with the fact that they have very high bioavailability after
subcutaneous injection, means that the dose can be calculated
by body weight and be given subcutaneously without any
monitoring or dose adjustment. They are at least as effective
and at least as safe as unfractionated heparin even when given
once a day and this made out-patient treatment possible
(Koopman et al, 1996; Levine et al, 1996). We now await the
results of phase III clinical trial of direct oral thrombin
inhibitors and direct oral anti-factor Xa inhibitors. These drugs
will surely be available in the next few years. Will they be
suitable for all patients and for all indications (no trials are
taking place in patients with prosthetic heart valves)? We are
left to speculate whether heparin and warfarin will still be used
100 years after their discovery.

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