William Osler

1
William Oslers Impact on the Principles and
Practice of Medicine

• Barry Cooper, MD
• Baylor Sammons Cancer Center
• Dallas, Texas

2
Blood Plates in 1892

1. Physiology of platelets uncertain
2. Difficulty of enumerating platelets without
   standard anticoagulants
3. Site of platelet production unknown

3
Early Descriptions of Blood Platelets in 1842

1. French physician Albert Donne noted globular
   masses in blood
2. British physician George Gulliver published first
   drawing of platelet but did not associate these
   particles with fibrin formation
3. 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.

4
Robb-Smith AHT. Why the Platelets Were
Discovered, Brit J Haemat., 1967, 13, 618-637.
5
Robb-Smith AHT. Why the Platelets Were
Discovered, Brit J Haemat., 1967, 13, 618-637.
6
Osler during his postgraduate stay in London
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Oslers 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 187422391-8

8
An Account of Certain Organisms Occurring in the
Liquor SanguinisOsler W. Proc Roy Soc 22391,
1874

1. Published in 1874 and credited Schultzes
   observation of granular masses
2. Examined blood in mesenteric and subcutaneous
   vessels of rats
3. Blood vessels contained individual pale round
   disks showing no tendency to adhere to one
   another but readily coalesced when blood was shed
4. Untenable these particles due to leukocyte
   degeneration
5. Nothing can be said of their nature or relation
   to bacteria

9
Osler W, The Third Corpuscle of the Blood, 1883
10
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

11
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 Oslers 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

12
Cartwright Lectures - 1886

• The Blood Plaque or Third Corpuscle
• Reviewed platelet morphology, number, and
  formation of the granular masses of Schultze
• Speculated concerning the origin of platelets
• Discussed role of plaques in disease increased
  in all chronic wasting diseases and some cases of
  leukemia and Hodgkins Disease may be scanty
  with profound anemia

13
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.

14
Cartwright Lectures - 1886

• III. The Relation of the Corpuscle to Coagulation
  and Thrombosis
• 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

15
Cartwright Lectures, 1886
16
Cartwright Lectures, 1886
17
Paul G. Werlhof (1699-1767)
Blood, Pure and Eloquent, p.548
18
Oslers Initial Report on Telangiectasias

• Published in 1901 in the JHH Bulletin.
• Two brothers with recurrent nosebleeds and
  dilated blood vessels on eats, nose, cheek,
  tongue, and lips.
• Normal coagulation times.
• A third patient with telangiectasias.

19
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.

20
Characteristic facial lesions as originally
published by Kelly, Osler and Hanes
21
Drawing of a microscopic slide of a skin biopsy
from a cheek telangiectasia, originally published
by Hanes
22
Clinical Features of Hereditary Hemorrhagic
Telangiectasia

• Prevalence of 150,000 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

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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.

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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)
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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

27
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 1500s recommended arsenic as
  sudorific
• In 1600s arsenic was used by Angelus Salva
  against plague and by Lentilius to treat malaria

28
Fowlers 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,
  Hodgkins disease, leukemia)
• Intoxication caused nausea, vomiting, colic,
  diarrhea, dehydration, dementia, heart failure

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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 (Fowlers solution)

31
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 Hodgkins disease
• Reports of benefit in pernicious anemia

Osler, W Therapeutic Gazette, 3rd series 2741,
1886
32
Arsenic in Acute Promyelocytic Leukemia (APL)

• 1970s 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