CLINICAL HAEMATOLOGY AN OVERVIEW. October 2016

Transcription

1 CLINICAL HAEMATOLOGY AN OVERVIEW October 2016

2 WHAT IS HAEMATOLOGY?

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4 ANCIENT ROME: Gladiators drank the blood of fallen combatants

5 VENESECTION: Depicted on an ancient scroll

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7 RUINS: Ancient Roman Water Supply Architects recognised the toxicity of lead

8 HAEMOPHILIA: Carrier state identified by ancient rabbis

9 LEVITICUS 17:11 the life of the flesh is in the blood

10 LEECHES: Applied for relief of a variety of maladies.

11 TIMELINE OF MAJOR HAEMATOLOGY LANDMARKS 1 Ancient Blood letting instruments are used. Egypt 460 Hippocrates teaches the humoral theory, a hypothetical system to 377 BC explain illness in which balance equals health. Excess or deficiency equals illness William Harvey introduces the controversial concept of circulation Anthony van Leeuwenhoek constructs a microscope and distinguishes blood cells Christopher Wren gives the first intravenous (IV) injection in animals J. C. Major gives the first IV injection in humans Richard Lower performs the first documented blood transfusion using dogs and notes a color difference between veins and arteries Jean Baptist Denis in France and Richard Lower in England separately report giving the first human blood transfusion with blood from lambs. Within 10 years, transfusing the blood of animals to humans becomes prohibited by law, delaying transfusion advances for about 150 years.

12 TIMELINE James Blundell performs the first successful transfusion of human blood to a patient. Between 1825 and 1830, he performs ten transfusions, five of which prove beneficial to his patients, and publishes these results. He also devises various instruments for performing transfusions and proposed rational indications At St. George s School in London, Samuel Armstrong Lane performs the first successful whole blood transfusion to treat hemophilia Alexandre Donne identifies platelets English surgeon Joseph Lister uses antiseptics to control infection during transfusions Paul Ehrlich develops techniques to stain blood cells to improve microscopic visualization The Diseases of Infancy and Childhood contains a 20-page chapter on diseases of the blood and is the first American pediatric medical textbook to provide significant hematologic information.

13 TIMELINE Rudolph Virchow, during a long and illustrious career, demon strates the importance of fibrin in the blood coagulation process, coins the terms embolism and thrombosis, identifies the disease leukemia, and theorizes that leukocytes are made in response to inflammation Karl Landsteiner and colleagues identify blood groups of A, B, AB, and O Ludvig Hektoen suggests that the safety of transfusion might be improved by crossmatching blood between donors and patients to exclude incompatible mixtures. Reuben Ottenberg performs the first blood transfusion using blood typing and crossmatching in New York. Ottenberg also observes the Mendelian inheritance of blood groups and recognizes the universal utility of group O donors.

14 TIMELINE The first clinical description of sickle cell published in medical literature Sodium citrate is found to prevent blood from clotting, allowing blood to be stored between collection and transfusion Pediatrics is the first comprehensive American publication on pediatric hematology Alfred P. Hart performs the first exchange transfusion Thomas Cooley describes a Mediterranean hematologic syndrome of anemia, erythroblastosis, skeletal disorders, and splenomegaly that is later called Cooley s anemia and now thalassemia Chicago s Cook County Hospital establishes the first true blood bank in the United States Dr. Louis Diamond (known as the father of American pediatric hematology ) along with Dr. Kenneth Blackfan describes the anemia still known as Diamond-Blackfan anemia The Atlas of the Blood of Children is published by Blackfan, Diamond, and Leister.

15 TIMELINE Coombs, Mourant, and Race describe the use of antihuman globulin (later known as the Coombs Test ) to identify incomplete antibodies The blood product cryoprecipitate is developed to treat bleeds in people with hemophilia. 1950s The butterfly needle and intercath are developed, making IV access easier and safer The role of platelet concentrates in reducing mortality from hemorrhage in cancer patients is recognized The first antihemophilic factor concentrate to treat coagulation disorders in hemophilia patients is developed through fractionation S. Murphy and F. Gardner demonstrate the feasibility of storing platelets at room temperature, revolutionizing platelet transfusion therapy.

16 TIMELINE Hepatitis B surface antigen testing of blood begins in the United States Apheresis is used to extract one cellular component, returning the rest of the blood to the donor Hematology of Infancy and Childhood is published by Nathan and Oski. 1980s HIV is identified, but the virus has already decimated the hemophiliac population Blood can be tested for HIV, and heat-treated factor becomes avail able, making it safe to treat hemophiliac patients again without fear of patients contracting AIDS. 1990s G-CSF, GM-CSF, Epogen, and Neumega (IL3) become clinically available. 1990s Recombinant factor replacement products become clinically available. 2000s The possibilities are endless

17 HAEMATOLOGY THE SCIENCE OF HAEMOPOIETIC ORGANS IN HEALTH AND DISEASE CLINICAL HAEMATOLOGY - DIAGNOSTICS - THERAPEUTICS

18 INTRODUCTION Recent global trend Cellular & molecular pathophysiology Disease categories Laboratory diagnostics Target therapy

19 ASH MEMBERSHIP Ernst R. Jaffé, and Kenneth Kaushansky Blood 2008;111: by American Society of Hematology

20 INTRODUCTION Disorganised therapeutic intervention > undefined doctor group Sophisticated paradigms of therapy > defined subspeciality HPCSA PROMULGATION 2001

21 ORGANISATIONS CMSA: 3 routes of specialisation SACHAS SASCeTS SASH SASTH

22 FOOTPRINT Small fraternity with recent growth Work closely with haematopathologists and histopathologists Significant burden of in-hospital referrals

23 HAEMATOLOGY vs ONCOLOGY

24 HAEMATOLOGISTS vs ONCOLOGISTS

25 SPECTRUM OF HAEMATOLOGY Chemokines, Cytokines, and Interleukins Gene Therapy Haematopoiesis Immunobiology Lymphoid Neoplasia Myeloid Neoplasia Neoplasia Other Macrophages Granulocytes, and Myelopoiesis Platelets and Thrombopoiesis Red Cells and Erythropoiesis Stem Cells in Haematology Thrombosis and Hemostasis Transfusion Medicine Transplantation Vascular Biology

26 THERAPEUTIC SPECTRUM BENIGN MALIGNANT TRANSPLANT APHERESIS

27 Immune - ITP, TTP Bleeding disorders DIC Anaemias Thrombotic disorders Haemoglobinopathies Storage disorders BENIGN

28 MALIGNANT Acute leukaemia Aplastic Anaemia Chronic Myeloproliferative Syndromes incl. CML Myelodysplastic Syndromes Multiple Myeloma Lymphoma HODGKIN DISEASE NON HODGKIN LYMPHOMA incl. CLL

29 TRANSPLANT Allogeneic MRD/MUD - ACUTE LEUKAEMIA Autologous MYELOMA RELAPSED/ REFRACTORY HD

30 APHERESIS Stem Cell Collection Leucopheresis Plasmapheresis

31 HAEMATOPOIESIS Process -! immature cells develop into mature blood cells Current theory -! single type = MULTIPOTENT STEM CELL (adult/somatic) (Not pluripotent..embryonic/cord blood)

32 SITES OF HAEMATOPOIESIS Age of animal Embryo 3 rd to 7 th month 4 th and 5 th months Site of hematopoiesis yolk sac then liver spleen marrow cavity - esp. granulocytes and platelets 7 th month marrow cavity - erythrocytes Birth mostly bone marrow; spleen and liver when needed Birth to maturity Adult number of active sites in bone marrow decreases but retain ability for hematopoiesis bone marrow of skull, ribs, sternum, vertebral column, pelvis, proximal ends of femurs

33 BONE MARROW VASCULAR : Nutrient artery -! branches -! sinuses -! converge to form veins EXTRAVASCULAR: Site of haematopoiesis Stromal network + cells DAILY PRODUCTION: 2.5 billion RBC 2.5 billion platelets 100 million granulocytes

34 HAEMATOPOIESIS

35 PROLIFERATION One becomes many Courtesy of Dr Vernon Louw

36 DIFFERENTIATION Cells change into different cells with different functions Courtesy of Dr Vernon Louw

37 PATHOPHYSIOLOGY NORMALLY DNA Blood / Circulation Bone Marrow Stem cells Red blood cells Mature Oxygen transport White blood cells Platelets Mature Mature Infection management Coagulation

38 BONE MARROW FAILURE SYNDROME DNA abnormal Blood / Circulation Bone Marrow Stem cells Red blood cells Anaemia White blood cells Infection Platelets Bruising / bleeding

39 THERAPEUTIC TRANSLATION LYMPHOMA Inhibition of surface antigen CHRONIC MYELOID LEUKAEMIA Inhibition of gene product MYELOMA Inhibition of cellular pathways

40 MONOCLONAL ANTIBODIES Cluster of Differentiation CD Immunophenotyping Patterns of expression Quantifiable MONOCLONAL ANTIBODIES

41 RITUXIMAB Surface molecules on cancer cell defined Antibodies developed! targetted therapy Prototype = anti-cd20 molecule CD20 on most B cells & > 90% of B cell lymphomas Binds to CD20 on lymphoma cells and destroys cells by a variety of mechanisms. Has become standard of care by addition to chemotherapy for DLBCL

42 CD20-ANTI-CD20 BINDING

43 ACTION OF RITUXIMAB

44 GENE PRODUCT Various methodologies: Standard karyotyping/fish/molecular techniques/gene editing Translated into therapeutics Prototype is Chronic Myeloid Leukaemia + in vivo manipulation of product of abnormal GENE PRODUCT

45 PHILADELPHIA CHROMOSOME Brian J. Druker Blood 2008;112: by American Society of Hematology

46 MECHANISM OF ACTION OF IMATINIB. Brian J. Druker Blood 2008;112: by American Society of Hematology

47 CELLULAR PATHWAY 2004 Nobel Prize in Chemistry Proteasome Ubiquitin-tagged proteins Transcription factors Anti-apoptotic factors, cell adhesion molecules and cytokines Inhibition > APOPTOSIS

48 UBIQUITIN PROTEASOME PATHWAY

49 ACTION OF BORTEZOMIB

50 ACTION OF BORTEZOMIB

51 CRISPR-CAS9 New gene editing technique modify DNA 20 peer- reviewed papers/week 2 competing patent claims NIH human embryo editing not funded Nominated: Nobel Prize in Medicine 2016 Clustered Repetitive Interspaced Short Palindromic Repeats

52 CRISPR-CAS9

53 CONCLUSION Introduction Historical Vignettes Context of Clinical Haematology Spectrum of Physiology and Disease Haematopoiesis and the Stem Cell Translational Therapies Gene editing