William Osler’s Impact on the
Principles and Practice of
Medicine
Barry Cooper, MD
Baylor Sammons Cancer Center
Dallas, Texas
“Blood Plates” in 1892
1. Physiology of platelets uncertain
2. Difficulty of enumerating platelets without
standard anticoagulants
3. Site of platelet production unknown
Early Descriptions of Blood Platelets in
1842
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French physician Albert Donne noted “globular masses”
in blood
British physician George Gulliver published first
drawing of platelet but did not associate these particles
with fibrin formation
British physician William Addison noted “a great
number of extremely minute particles or granules
varying in size, the largest being at least eight or ten
times less than the colorless corpuscles.”
Robb-Smith AHT. Why the Platelets Were Discovered, Brit J Haemat., 1967, 13, 618-637.
Robb-Smith AHT. Why the Platelets Were Discovered, Brit J Haemat., 1967, 13, 618-637.
Osler during his postgraduate stay in London
Osler’s Original Description of Platelets
Careful investigation of the blood proves that, in addition to
the usual elements, there exist pale granular masses, which
on closer inspection present a corpuscular appearance. In
size they vary greatly from half or quarter that of a white
blood-corpuscle, to enormous masses….They have a
compact solid look…. While in specimens examined
without any reagents the filaments of fibrin adhere to them.
An Account of Certain Organisms Occurring in the Liquor Sanguinis
Proc Roy Soc Lond 1874;22:391-8
“An Account of Certain Organisms Occurring
in the Liquor Sanguinis”
Osler W. Proc Roy Soc 22:391, 1874
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Published in 1874 and credited Schultze’s observation of
“granular masses”
Examined blood in mesenteric and subcutaneous vessels
of rats
Blood vessels contained individual pale round disks
showing no tendency to adhere to one another but readily
coalesced when blood was shed
Untenable these particles due to leukocyte degeneration
Nothing can be said of their nature or relation to bacteria
Osler W, The Third Corpuscle of the Blood, 1883
Georges Hayem (1841-1935)
1. Reports of French physician beginning in 1877
helped establish that platelets were distinct
cellular entities
2. Accurately enumerated platelets
3. Noted role of platelets in coagulation
4. Maintained that platelets as “haematoblasts”
were an early stage of erythrocyte development
Giulio Bizzozero (1846-1901)
1. Published a monograph in 1882 introducing the
term blood plates or “Plättchen”
2. Studies done on mesenteric vessels of live animals
whereas Osler’s work was on excised tissue
3. Popularized the concept that blood plates
represented an independent cell line with the
specialized function of hemostasis or arresting the
flow of blood
4. Noted hemostasis and blood coagulation were not
synonymous
Cartwright Lectures - 1886
I.
The Blood Plaque or Third Corpuscle
1. Reviewed platelet morphology, number, and
formation of the granular masses of Schultze
2. Speculated concerning the origin of platelets
3. Discussed role of “plaques” in disease:
increased in all chronic wasting diseases and
some cases of leukemia and Hodgkin’s
Disease; may be scanty with profound
anemia
Cartwright Lectures - 1886
II.
Degeneration and Regeneration of the Corpuscles
“This it is which makes the blood such a puzzle, for
the corpuscles, so far as observation goes, neither
die nor are born in the circulating fluid, but appear
to enter it as perfect elements and are removed from
it before they are so changed as to be no longer
recognizable.”
Cartwright Lectures - 1886
III. The Relation of the Corpuscle to
Coagulation and Thrombosis
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Blood plaques, not leukocytes, are the initial
cellular element of thrombosis
Plaques are the elements which first settle on
the edges of a wounded vessel and form the
basis of thrombosis
White thrombi are composed almost entirely
of blood plaques
Cartwright Lectures, 1886
Cartwright Lectures, 1886
Paul G. Werlhof (1699-1767)
Blood, Pure and Eloquent, p.548
Osler’s Initial Report on
Telangiectasias
1. Published in 1901 in the JHH Bulletin.
2. Two brothers with recurrent nosebleeds
and dilated blood vessels on eats, nose,
cheek, tongue, and lips.
3. Normal coagulation times.
4. A third patient with telangiectasias.
Reports of Hereditary Epistaxis in
19th Century
1. Sutton article in 1864.
2. Babbington in 1865 noted epistaxis in five generations
of one family but telangiectasias not described.
3. Vascular abnormalities with familial epistaxis by Legg
in 1816, but also described nevi.
4. Chiari reported typical findings in two families in 1887
but incorrectly diagnosed hemophilia.
5. Rendu in 1896 described typical case in 52 year old
man.
Characteristic facial lesions as originally published by Kelly, Osler and Hanes
Drawing of a microscopic slide of a skin biopsy from a cheek telangiectasia, originally published by Hanes
Clinical Features of Hereditary
Hemorrhagic Telangiectasia
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Prevalence of 1:50,000 with complete penetrance by age 40
Autosomal dominant with a 20% spontaneous mutation rate
Epistaxis presenting symptom in 90% of patients
Visceral lesions common in stomach, respiratory tract,
bladder and liver
• Pulmonary arteriovenous malformations in 5 to 30%
• Recurrent cerebral embolism and abscess secondary to
paradoxical emboli
Vaquez Description of Polycythemia
(1892)
1. Blue extremities bulging veins with
cyanosis and intense redness of face.
2. Hepatosplenomegaly confirmed at autopsy.
3. Red cells quantitated at 8,900,000/mm³.
4. Postulated disease caused by functional
hyperactivity of hematopoietic organs.
“If a law were passed, compelling physicians
to confine themselves to two remedies only in
their entire practice, arsenic would be my
choice for one, opium for the other. With
these two I believe one could do more than
any two of the pharmacopoeia.”
(I. L. Crawcour, Journal, Louisiana State
Medical Society, 1883)
Properties of Arsenic
• Common substance rarely found in pure elemental
state
• Three inorganic forms of arsenic: red, yellow, white
• Red (realgar) and yellow (orpiment) arsenic are toxic,
chemically unstable complex sulfides
• White arsenic (arsenic trioxide) is produced by
roasting ores (realgar) and purifying smoke
• Organic arsenicals linked covalently to carbon are
more stable and less toxic than inorganic forms
Medicinal Uses of Arsenic Prior to
the 18th Century
• Hippocrates used realgar and orpiment as remedies for
ulcers
• Dioscorides used orpiment as a depilatory in the 1st
century
• Schabir in the 8th century roasted realgar to obtain
white arsenic
• Jean de Gorris in 1500’s recommended arsenic as
sudorific
• In 1600’s arsenic was used by Angelus Salva against
plague and by Lentilius to treat malaria
Fowler’s Solution
• Introduced in 1786 by Thomas Fowler, physician to
the General Infirmary of the County of Stafford,
England to treat intermittent fever
• Boiling arsenious acid with alkali to make more
soluble, solution was 1% (w/v) arsenic trioxide in
potassium bicarbonate
• Empirically used for asthma, chorea, eczema,
pemphigus, psoriasis and blood disorders (anemia,
Hodgkin’s disease, leukemia)
• Intoxication caused nausea, vomiting, colic, diarrhea,
dehydration, dementia, heart failure
Initial Observations of Arsenic on
Leukocytosis and Normal Blood
• Cutler and Bradford published article in 1878 in Am J
Med Sci entitled “Action of Iron, Cod Liver Oil, and
Arsenic on Globular Richness of Blood”
• Arsenic reduced red cells and leukocytes in two
healthy subjects
• Transient improvement in anemia of two patients
• Twenty-seven year old man with white blood cell
count of 1,754,000 reduced to 8,700 after ten weeks of
3-6mg/day arsenic (Fowler’s solution)
On the Use of Arsenic in Certain
Forms of Anemia
• Arsenic may improve some secondary anemias:
valvular heart disease, malaria, certain anemias of
gastric origin
• No personal cases of responses to leukemia
• Potential improvement in Hodgkin’s disease
• Reports of benefit in pernicious anemia
Osler, W Therapeutic Gazette, 3rd series 2:741, 1886
Arsenic in Acute Promyelocytic Leukemia
(APL)
• 1970’s – “Ailing-1” a solution of crude arsenic trioxide and
herbal extracts used to treat APL in China. Traditional Chinese
medicine had used arsenic for centuries
• Initial studies at Harbin Medical and Shanghai Second Medical
University documented remarkable efficacy with daily IV dose
of 10mg arsenic trioxide
• 90% of relapsed patients had a complete remission without bone
marrow suppression and limited toxicity (BLOOD 89: 3354-60,
1997)
• Drug induces cytodifferentiation and apoptosis of malignant
promyelocytes and requires the presence of the PML-RAR
protein specific for that disease