the hematopoietic and lymphoid systems

1. the hematopoietic and lymphoid systems

2. hematopathology • blood • lymphoid organs • central: • bone marrow • thymus • peripheral: • lymph nodes • MALT (Waldeyer´s ring, intestine...) • splenic white pulp

3. hematopathology • leukaemia = neoplastic cells in peripheral blood • lymphoma = tumour of the lymph node • hemoblastosis • primary bone marrow • leukaemia + tumoriform • lymphomas • primary lymph nodes • lymphoma + leukemic phase

4. bone marrow

5. bone marrow • weight cca 1,5kg • red (hematopoietic) x yellow (adipose) • structure: • hematopoietic cells: granulopoiesis peritrabecular, erytropoiesis a megakaryocytes intertrabecular and perisinusoidal • corroborative elements: makrophages, fibroblasts, mastocytes, plazmocytes, lymfocytes • blood sinuses • bone trabeculas

6. diminished hematopoiesis A) total diminution aplastic anemia (panmyelophtisis) • hereditary: • Fanconi anemia • AR • death because of infectious and bleeding complications • +/- turn into AML • acquired: • infectious, irradiation, use of some drugs

7. diminished hematopoiesis B) selective • one or more of hematopoietic lineages critical is peripheral blood – marrow could be hypercelular = „ineffective hematopoiesis“

8. diminished hematopoiesis...anemia 1) anemia • ↓ total circulating RBC volume, +/- ↓Hb and ↓O2 • hypoxia of tissues = clinical symptoms

9. anemia...loss of RBC a) hemorrhage: blood loss anemia • hypovolemia → normocytic normochromic anemia → ↑ erytropoiesis (bone marrow) → reticulocytosis, hypochromic anemia

10. anemia...hemolytic b) increased rate of RBC destruction: the hemolytic anemias • anemia + reactive hyperplastic erytropoiesis • bm: ↑erytropoiesis/myelopoiesis, gaucheroid cells • +/- extramedullary hematopoiesis • Hb -emia, -uria

11. anemias..hemolytic..intrinsic I) intrinsic (intracorpuscular) abnormalities of RBC • hereditary: • 1) disorders of RBC membrane cytoskeleton • spherocytosis • erythrocytes spheroidal, less deformable and vulnerable to splenic sequestration and destruction • AD • anemia, splenomegalia a hemolytic icterus

12. anemias..hemolytic..intrinsic 2) RBC enzyme deficiencies 3) disorders of Hb synthesis: hem+globin • deficient globin synthesis: thalassemia syndromes • lack of or decreased synthesis of globin chains: α chains = α thalassemia β chains = β thalassemia • ↓ synthesis of Hb → anemia (microcytic hypochromic) + excess of α chains in β thalassemia → insoluble aggregats → damage RBC membrane → reduction of plasticity → phagocytosis,inefective erytropoiesis • heterozygous = thalassemia minor homozygous = thalassemia major

13. anemias..hemolytic..intrinsic • structurally abnormal globin synthesis (hemoglobinopathies): sickle cell anemia • structurally abnormal Hb S – on deoxygenation polymerization = gelation or crystallization → microvascular obstruction → ischemic tissue damage + ↑ removing in the spleen = „autosplenectomy“

14. anemias..hemolytic..intrinsic • acquired • membrane defect: paroxysmal nocturnal hemoglobinuria) • ↓resistance against C3 • granulocytes and plateles affected too → hemolysis, +/- trombotic complications and ↑ susceptibility to infections

15. anemias..hemolytic..extrinsic II) extrinsic (extracorpuscular) abnormalities 1) antibody mediated • isohemagglutinins • erythroblastosis fetalis • Rh (mother Rh-, father and child Rh+) • antibodies against fetal RBC • hydrops fetus universalis, mental retardation, ↑extramedulary hematopoiesis

16. anemias..hemolytic..extrinsic • autoantibodies • idiopathic (primary), drug associated, SLE • Coombs tests

17. anemias..hemolytic..extrinsic 2) mechanical trauma to RBCs • mikroangiopathic hemolytic anemias • DIC, TTP • mechanic traumatization of erythrocytes • dialysis, valves prosthesis 3) infections (malaria)

18. anemia...impaired RBC production c) diminished erythropoiesis 1)combination with the others in aplastic anemia 2) pure „erytroblastophtisis“ • Blackfan-Diamond syndrom • children • + thymomas and T-CLL 3) myelophtisic anemia • extensive replacement of the marrow by tumours or other lesions → extramedullary hematopoiesis, leukoerythroblastosis

19. anemia...impaired RBC production 4) iron deficiency anemia • most common • mikrocytar hypochromic • ↓low intake (diets, malabsorptions) x ↑ demands (pregnancy, infancy, chronic blood loss) • gross: hypoxic myocardial steatosis • marrow normal or hyperplastic erythropoiesis, decline in serrum ferritin and depletion of stainable iron in the bone marrow

20. anemia...impaired RBC production 5) megaloblastic anemia • disturbance of proliferation and differentiation of erythroblasts → megaloblasts, megakaryocytes • nuclear-cytoplasmic asynchrony • giant metamyelocytes → hypersegmented neutrophils • ineffektive erythropoiesis • folate (folic acid) deficiency anemia • tetrahydrofolate • neurologic abnormalities do not occur

21. anemia...impaired RBC production • pernicious anemia • vitamin B12 (cobalamin) deficiency • diet, ↓intrinsic faktor (parietal gastric cells), terminal ileum • gross: atrophic glossitis, gastritis, demyelinization

22. anemia...impaired RBC production 6) lack of erythropoietin • kidney failure, parvovirosis (B19)

23. diminished hematopoiesis... leukopenia 2) leukopenia a) lymfopenia • hereditary immunity disorders, infections(viral), chronical diseases, steroid therapy

24. leukopenia b) neutropenia (granulocytopenia) • increased susceptibility to infections • marrow failure (aplastic anemia) → agranulocytosis • inadequate or ineffective granulopoiesis: certain drugs: benzen, purin and pyrimidin analogs, anthracyklin x idiosyncrastic reaction (chloramfenikol, chlorpromazin, fenylbutazon) • accelerated removal or destruction of neutrophils: hypersplenism, certain drugs • bm: depend on the underlying basis: ↑ or ↓ granulopoiesis and +/- reaction to infection

25. increased hematopoiesis • transitory increasing of hematopoiesis 1) ↑erythropoiesis = polycythemia • increased erythropoietin levels: • appropriate: lung disease, high-altitude living, cyanotic heart disease • inappropriate: erythropoietin-secreting tumours, „doping“ • bm hypercellular, inappropriate increasing of erythropoiesis • no extramedullary hematopoiesis!

26. increased hematopoiesis 2) leukocytosis a) lymfocytosis: chronical infections (IM) b) granulocytosis: acute bacterial infections (pyogenic organisms), sterile inflammation (tissue necrosis, burns) → leukemoid reaction (like in CML) c) eosinophilia: allergic disorders, parasitic infestation, drug reaction, certain mlg 3) thrombocytosis: infections, chronical bleeding, tumours, iron deficiency

27. myelodysplastic syndromes • heterogeneous group of disorders • some evidence of bone marrow failure and dysplasia in one or more myeloid cell lineages • may evolve to AML • chromosomal aberrations • primary x secondary (radiotherapy, alkylating agent therapy) • bm hypercellular, ↑ erythropoiesis, morphological changes, +/- fibrosis

28. myelodysplastic syndromes...histological classification • refractory anemia (RA) • refractory anemia with ring sideroblasts (RARS) • refractory cytopenia with multilineage dysplasia • refractory anemia with excess blasts (RAEB) • MDS, unclassifiable

29. chronic myeloproliferative diseases • CMPDs: clonal haematopoietic stem cell disorders characterised by proliferation in the bone marrow of one or more of the myeloid (i.e. granulocytic, erythroid and megakaryocytic) lineages

30. CMPD A) chronic myelogenous leukaemia • most common • adults, 30-60eyars • neutrophilic leukocytosis in peripheral blood • Ph+ = t(9;22) = Philadelphia chr. • bm: hypercellular (↑granulopoiesis, ↑megakaryocytes), +/- fibrosis • extramedullary leukaemic infiltration: spleen, liver • → accelerated phase → blast phase

31. CMPD B) polycythaemia vera (polycythaemia rubra vera, m. Vaquez-Osler) • ↑ erythropoiesis • hypertension, thrombosis, haemorrhage • bm: • initial phase: hypercellular, with increased erythropoiesis + extramedullar infiltration → hepatosplenomegaly • +/- blast phase or „spent“ phase

32. CMPD C) essential thrombocythaemia • proliferation primarly magakaryocytic lineage • sustained thrombocytosis in the blood • bm: large, mature megakaryocytes D) chronic idiopathic myelofibrosis • proliferation of mainly megakaryocytes, associated with reactive deposition of bone marrow connective tissue and extramedullary hematopoiesis

33. acute leukaemias • causes: • complication of certain chromosomal diseases (m. Down, Fanconi anemia, Klinefelter´s syndroma...) • radiation • chemicals (benzen, alkylating agents, drugs) • viruses (HTLV-1) • AML, ALL • symptoms: combination of aplastic anemia and agranulocytosis • bm: leukaemic infiltration, +/- extramedullar infiltration (liver, spleen, kidney, CNS) • myelosarcoma („chloroma“)

34. acute myeloid leukaemias... histological classification • M0...acute myeloblastic l. minimally differentiated • M1 ...acute myeloblastic l. without maturation • M2...acute myeloblastic l. with maturation • M3...acute promyelocytic l. • M4...acute myelomonocytic l. • M5...acute monocytic l. • M6...acute erythroid l. • M7...acute megakaryoblastic l.

35. acute lymphoblastic leukaemias... histological classification • precursor B- and T- cell lymphoblastic leukaemia/lymphoblastic lymphoma

36. proliferation of macrophages, histiocytosis A) reactive proliferation of macrophages • bone marrow, many causes (hemosiderosis, aiha, viral infections) • lysosomal storage diseases (m. Gaucher, Niemann-Pick...)

37. proliferation of macrophages, histiocytosis B) hemofagocytic syndroma • ↑ proliferation of macrophages or histiocytic precursores → haemofagocytosis → cytopenia • + hepatosplenomegaly, fever • proliferating macrophages: clonal (mlg histiocytosis) x reaction (infection, Kawasaki, T lymphomas) • fatal haemofagocytosis

38. proliferation of macrophages, histiocytosis C) histiocytosis X (Langerhans cells histiocytosis) 1) solitary eosinophilic granuloma • bng • bones (unifocal lytic lesion), skin, lymph nodes, lungs • Langerhans cells (Birbeck granules) + eosinophils, +/- plasma cells and lymphocytes 2) m. Hand-Schüler-Christian • trias: multifocal lytic lesions of bone + exophtalamus + diabetes insipidus

39. proliferation of macrophages, histiocytosis 3) m. Abt-Letterer-Siwe • mlg • children before 2 years of age • cutaneous lesions resembling seborrheic skin eruptions + hepatosplenomegaly, lymphadenopathy, pulmonary lesions, osteolytic bone lesions → anemia and thrombocytopenia, reccurent infections

40. metastasis • osteolytic x osteoplastic • prostate, breast, stomach, lung cancer

41. bone marrow necrosis • ischemia: • vascular collaps in hypercellular marrow • metastatic obstruction • sickle cell disease, DIC... • symptoms: pain, fever, hematopoietic precursors in peripheral blood

42. transplantation • transplantation: bone marrow, peripheral stem cells • autologous x allogenneous (relatives, non-relatives) • indications: • hematological: tumours, immunodeficiency, anemias, b.m. aplasia • non-hematological: tumour metastasis

43. transplantation • bone marrow suppression → graft • hypocellularity → proliferation • immunosuppression! • GvHD acute x chronic: • skin, intestine, liver

44. Bleeding disorders • cause: • defect in the vessel wall • platelet deficiency or dysfunction • coagulation factors disorder

45. bleeding disorders...vascular A) defects in the vessel wall 1) hereditary a) m. Osler-Rendu-Weber (hereditary hemorhagic teleangiektasias) • capillary aneurysms in the skin and mucous membranes b) connective tissue disorders • m. Ehlers-Danlos • Marfan´s syndrome

46. bleeding disorders...vascular 2) acquired a) avitaminosis C, ↑ corticosteroids • cutaneous, intramuscular, mucosal bleeding b) purpura Henoch-Schönlein • circulating IC → skin, kidney

47. bleeding disorders...plateles B) plateles deficiency or dysfunction 1) thrombocytopenia a) decresed production • aplastic anemia • hereditary disorders (sy Bernard-Soulier, grey-plateles sy, m. Wiskott-Aldrich)

48. bleeding disorders...plateles b) increased destruction • splenomegaly, arteficial valves,... • DIC (disseminated intravascular coagulation) • activation of the coagulation sequence, leading to formation of thrombi throughout the microcirculation → consumption of plateles and coagulation factors and secondarily activation of fibrinolysis

49. bleeding disorders...plateles • thrombotic thrombocytopenic purpura (TTP) • thrombocytopenia, fever, microvessel obstruction symptoms • → microangiopathic hemolytic anemia • hyaline thrombi in the microcirculation • hemolytic-uremic syndrome (HUS) • E.coli • kidney cortex necrosis, intestinal bleeding

50. bleeding disorders...plateles • idiopathic thrombocytopenic purpura (ITP) • autoimmune origin • destruction in the spleen → splenectomy • bm +/- increased megakaryopoiesis