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the hematopoietic and lymphoid systems. hematopathology. blood lymphoid organs central: bone marrow thymus peripheral: lymph nodes MALT (Waldeyer´s ring, intestine...) splenic white pulp. hematopathology. leukaemia = neoplastic cells in peripheral blood
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hematopathology • blood • lymphoid organs • central: • bone marrow • thymus • peripheral: • lymph nodes • MALT (Waldeyer´s ring, intestine...) • splenic white pulp
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
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
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
diminished hematopoiesis B) selective • one or more of hematopoietic lineages critical is peripheral blood – marrow could be hypercelular = „ineffective hematopoiesis“
diminished hematopoiesis...anemia 1) anemia • ↓ total circulating RBC volume, +/- ↓Hb and ↓O2 • hypoxia of tissues = clinical symptoms
anemia...loss of RBC a) hemorrhage: blood loss anemia • hypovolemia → normocytic normochromic anemia → ↑ erytropoiesis (bone marrow) → reticulocytosis, hypochromic anemia
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
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
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
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“
anemias..hemolytic..intrinsic • acquired • membrane defect: paroxysmal nocturnal hemoglobinuria) • ↓resistance against C3 • granulocytes and plateles affected too → hemolysis, +/- trombotic complications and ↑ susceptibility to infections
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
anemias..hemolytic..extrinsic • autoantibodies • idiopathic (primary), drug associated, SLE • Coombs tests
anemias..hemolytic..extrinsic 2) mechanical trauma to RBCs • mikroangiopathic hemolytic anemias • DIC, TTP • mechanic traumatization of erythrocytes • dialysis, valves prosthesis 3) infections (malaria)
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
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
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
anemia...impaired RBC production • pernicious anemia • vitamin B12 (cobalamin) deficiency • diet, ↓intrinsic faktor (parietal gastric cells), terminal ileum • gross: atrophic glossitis, gastritis, demyelinization
anemia...impaired RBC production 6) lack of erythropoietin • kidney failure, parvovirosis (B19)
diminished hematopoiesis... leukopenia 2) leukopenia a) lymfopenia • hereditary immunity disorders, infections(viral), chronical diseases, steroid therapy
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
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!
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
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
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
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
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
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
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
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“)
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.
acute lymphoblastic leukaemias... histological classification • precursor B- and T- cell lymphoblastic leukaemia/lymphoblastic lymphoma
proliferation of macrophages, histiocytosis A) reactive proliferation of macrophages • bone marrow, many causes (hemosiderosis, aiha, viral infections) • lysosomal storage diseases (m. Gaucher, Niemann-Pick...)
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
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
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
metastasis • osteolytic x osteoplastic • prostate, breast, stomach, lung cancer
bone marrow necrosis • ischemia: • vascular collaps in hypercellular marrow • metastatic obstruction • sickle cell disease, DIC... • symptoms: pain, fever, hematopoietic precursors in peripheral blood
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
transplantation • bone marrow suppression → graft • hypocellularity → proliferation • immunosuppression! • GvHD acute x chronic: • skin, intestine, liver
Bleeding disorders • cause: • defect in the vessel wall • platelet deficiency or dysfunction • coagulation factors disorder
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
bleeding disorders...vascular 2) acquired a) avitaminosis C, ↑ corticosteroids • cutaneous, intramuscular, mucosal bleeding b) purpura Henoch-Schönlein • circulating IC → skin, kidney
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)
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
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
bleeding disorders...plateles • idiopathic thrombocytopenic purpura (ITP) • autoimmune origin • destruction in the spleen → splenectomy • bm +/- increased megakaryopoiesis