William Osler’s Impact on the Principles and Practice of Medicine

William Osler’s Impact on the Principles and Practice of Medicine Barry Cooper, MD Baylor Sammons Cancer Center Dallas, Texas

“Blood Plates” in 1892 • Physiology of platelets uncertain • Difficulty of enumerating platelets without standard anticoagulants • Site of platelet production unknown

Early Descriptions of Blood Platelets in 1842 • 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.

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 • 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) • Reports of French physician beginning in 1877 helped establish that platelets were distinct cellular entities • Accurately enumerated platelets • Noted role of platelets in coagulation • Maintained that platelets as “haematoblasts” were an early stage of erythrocyte development

Giulio Bizzozero (1846-1901) • Published a monograph in 1882 introducing the term blood plates or “Plättchen” • Studies done on mesenteric vessels of live animals whereas Osler’s work was on excised tissue • Popularized the concept that blood plates represented an independent cell line with the specialized function of hemostasis or arresting the flow of blood • Noted hemostasis and blood coagulation were not synonymous

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 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 • 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

Paul G. Werlhof (1699-1767) Blood, Pure and Eloquent, p.548

Osler’s 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.

Reports of Hereditary Epistaxis in 19th Century • Sutton article in 1864. • Babbington in 1865 noted epistaxis in five generations of one family but telangiectasias not described. • Vascular abnormalities with familial epistaxis by Legg in 1816, but also described nevi. • Chiari reported typical findings in two families in 1887 but incorrectly diagnosed hemophilia. • 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 • 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) • Blue extremities bulging veins with cyanosis and intense redness of face. • Hepatosplenomegaly confirmed at autopsy. • Red cells quantitated at 8,900,000/mm³. • 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 (BLOOD89: 3354-60, 1997) • Drug induces cytodifferentiation and apoptosis of malignant promyelocytes and requires the presence of the PML-RAR protein specific for that disease

William Osler’s Impact on the Principles and Practice of Medicine