John Freedman John W Semple Alan H Lazarus Valery Leytin Heyu Ni

1. John Freedman John W Semple Alan H Lazarus Valery Leytin Heyu Ni Margaret L Rand Victor S Blanchette Toronto Platelet Immunobiology Group (T-PIG) SMH HSC CBS

2. ITP Idiopathic thrombocytopenic purpura Immune thrombocytopenic purpura From Hippocrates to Bussel (and a few side-trips in between) purpura immune thrombocytopenia

3. Greco-Roman:Hippocrates, Galen – life based on four elements: Fire, air, earth, water Blood was one of the four ‘humors’ (air):made in liver, sloshed around through heart where mixed with air Brew of willow tree leaves (salicylates) as analgesic and antipyretic Spleen: source of black bile; “organ full of mystery” Hippocrates 460-377 BCE Red “eminences”/spots associated with pestilential fevers (plague). Galen CE 129-circa 210 [Juliana Anicia Ms, CE 487]

4. Purpura Porphyra πορφυρα Gastropod mollusc janthina janthina

5. C10th:Avicenna (Canon) ---chronic purpura

6. Amatus Lusitanus (Jono Rodrigues de Castelo Branco) [1511-1568] Physician, researcher in anatomy, internal medicine, dermatology, mental illness. Peripatetic Converso who fled from Salamanca to Portugal, Ferrara, Ancona, Dubrovnik, Salonika, but was nonetheless physician to several monasteries and to Pope Julius III. Between 1541 and 1561 wrote seven centuriae: each 100 case histories, their treatment, results and pathology, accompanied by learned explanations.

9. 1658

12. Anton van Leeuwenhoek X 300 1632-1723

13. 1735 poet composer linguist physician

14. 1775

16. 1808

20. The Englishman, William Hewson (1739-1774) was probably the first to observe some platelets.

21. 1828 Joseph Lister, Lord 1827-1912 Founder of aseptic surgery Joseph Jackson Lister 1786-1869 Wine merchant

22. 1842 Alfred Donne (1801-1878) Child care; breastfeeding + Foucault = daguerrotype

23. 1840s to 1860s: Gulliver, Addison: independently made what are probably the first drawings of platelets Zimmerman: ‘elementary bodies’ which came from lymphatics and were precursors of red blood cells; (Hematoblasts) Jones, Beale, Simon, Schultze: platelets were fibrin clots (? derived from leukocytes) Schmidt in Estonia: ? A cell between erythrocyte and leukocyte Addison 1842

25. Professor of Anatomy, Bonn Brewer DB: Br J Haematol 133:251-258, 2006

26. 1874 Osler “It must still be confessed that we know nothing about the origin or destiny of these corpuscles” Aequanimitas

27. 1882 “The existence of a constant blood particle, differing from red and white blood cells, has been suspected by several authors for some time”

30. Despite the work’s title (“…et sur son importance dans la trombose et dans la coagulation”), Bizzozero did not focus on the hemostatic or hemorrhagic role of platelets, and appears not to have recognized platelets as a factor in purpura. Georges Hayem (1841-1935): A founder of haematology. Small elements in blood; tendency to clump and to change shape;in 1883, coined term platelet. rbc platelets Hôpital Tenon; St Antoine: several anemias, digestion, stomach, rbc counting, cholera

31. In 1884, Krauss related purpura hemorrhagica to a decrease in circulating platelets 1887

32. 1895

33. 1890

34. Relation of megakaryocytes to platelets

35. Take off full screen

36. 1915: Frank (Breslau) recognized that megakaryocytopoiesis was normal in ITP

37. 1915

38. 1916 Minot Failure of transfusion in ITP 1916 Minot Platelet destruction due to “some reaction” 1916 Kaznelson Spleen site of platelet destruction? (Prague) Splenectomy in ITP Other treatments at this time included irradiation by mercury vapor lamps, snake venom, splenic irradiation.

39. 1938 Troland & Lee ‘Thrombocytopen’ from ITP splenic extracts Platelet count

40. Damashek & Miller, however, continued to argue that ITP was due to a fundamental abnormality of the spleen which ‘exerts an unusual effect on the production of platelets from the megakaryocytes in the marrow’ 1940 Wiseman Clinical diagnostic criteria for ITP 1946 Curtis Failure of splenectomy due to accessory spleen

41. 1951 Passive transfer of ITP with ITP plasma plasma Carl V Moore Harrington et al, J Lab Clin Med 38:1, 1951

42. 1951 Evans Plasma factor = anti-platelet antibody 1951 Damashek Distinction of acute versus chronic ITP 1951 Wintrobe Use of corticosteroids in ITP William Damashek Maxwell Wintrobe

43. 1984: First randomized trial of steroids in ITP 1972 --- Sartorius, Am J Ped Hematol Oncol 6:165, 1984

44. 1970s Lien

45. 1975 Dixon Measurement of PA-IgG 1981 Imbach IVIG in ITP 1983 Salama Anti-D in ITP 1970s – 1990s Humoral immunity in ITP; antibody specificity New drugs for refractory patients 1990s - Dysregulation of cellular immunity in ITP

48. Literature on history of platelets • Jones HW, Tocantins LM: The history of pupura hemorrhagica. Ann Med Hist 5:349-359, 1933. • Robb-Smith AHT: How the platelets were discovered. Br J Haematol 13:618-639, 1967. • Blanchette M, Freedman J: The history of idiopathic thrombocytopenic purpura (ITP). Transfus Sci 19:231-236, 1998. • Freedman J, Blanchette M: Idiopathic thrombocytopenic purpura (ITP): a historical odyssey. Acta Paediatr Suppl 424:3-6, 1998. • Mustard JF, Kinlough-Rathbone RL, Packham MA: History of platelets. In: Platelets in thrombotic and nonthrombotic disorders: pathophysiology, pharmacology and therapeutics. Gresele P, Page C, Fuster V, Vermylen J, eds. Cambridge University Press, Cambridge, 2002. • Imbach P, Kuhne T, Signer E: Historical aspects and present knowledge of idiopathic thrombocytopenic purpura. Br J Haematol 119:894-900, 2002. • Izaguirre-Avila R: El descubrimiento de las plaquetas. Revista Biomedica Vol 8, 1997.