Haemopoiesis, blood malignancies, coagulation and platelet function defects
Dr H.M.D.MoratuwagamaDepartment of Pathology
Faculty of Medicine-Ragama
Haemopoiesis
Sites of Haemopoiesis
• Yolk sac
• Liver and spleen
• Bone marrow– Gradual replacement
of active (red) marrow by inactive (fatty) tissue
– Expansion can occur during increased need for cell production
Sites of Haemopoiesis
• Fetus- 2 months –Yolk sac 2-7 months-Liver/Spleen 5-9 months-BM• Infants-BM• Adult-Axial skeleton
Components of Haemopoiesis
• Cells • Bone marrow stroma• Growth factors
Cells
• Stem cells• Self renewal• Plasticity
• Progenitor cells• Developmentally-restricted cells
• Mature cells• Mature cell production takes place from the more
developmentally-restricted progenitors
Haemopoiesis
Common lymphoid progenitor cellCommon myeloid progenitor cell
BM
• Stromal cells-adipocytes,fibroblasts,osteoblasts,endothelial
cells ,macrophages• Microvascular network
Regulation of haemopoiesis
• Transcription factors-CEBP-Myeloid-GATA 1-Erythroid• Growth factors
Haemopoietic growth factors• Glycoprotein hormones• GM-CSF
• Granulocyte-Macrophage colony stimulating factor
• G-CSF Granulocyte colony stimulating factor
• M-CSF• Macrophage colony stimulating factor
• Erythropoietin(kidney)• Erythropoiesis stimulating hormone
(These factors have the capacity to stimulate the proliferation of their target progenitor cells when used as a sole source of stimulation)
• Thrombopoietin(liver)• Stimulates megakaryopoiesis
Haemopoietic growth factors cont.
• Cytokines• IL 1 (Interleukin 1)• IL 3• IL 5• IL 6• TNF• SCF (Stem cell factor, also known as kit-ligand)• TGF-β/IFN-γ-Negative effect
Role of growth factors in normal haemopoiesis
Erythropoiesis and erythrocytes
• Lifespan – 120 days
• Non nucleated
• Biconcave disc
• Production regulated by Epo
• Needs Fe, B12, folate & other elements for development
Granulopoiesis
• Granulocytes– Neutrophils
– Eosinophils
– Basophils
• Only mature cells are present in peripheral blood
E
N
B
Granulopoiesis• Neutrophil– 2-5 lobe nucleus– Primary or secondary
granules• Pink (azurophilic granules)• Grey-blue granules
– Life 10 hours
• Precursors– Myeloblast <4%– Pro myelocytes– Myelocytes– Metamyelocytes– Band form (stab form)
Monocytes
• Larger than lymphocyte
• Oval or indented nucleus
• Monocytes >>>>to macrophage
• Specific function depends on the tissue type
Lymphopoiesis
Thrombopoiesis
• Platelet play a major role in primary hemostasis
• Life span 7-10 days• Production,
fragmentation of cytoplasm
• Megakaryocytes undergoes endomitotic division
Summary
• Normal haemopoiesis is necessary for the survival
• It is under the control of multiple factors
• Normal bone marrow environment is necessary for normal haemopoiesis
• Decreased production results in cytopenias
Blood malignancies
Blood malignancies
LEUKAEMIA LYMPHOMA
Blood malignancies
Leukaemia Acute ChronicMyeloid Lymphoid Myeloid Lymphoid AML ALL CML CLL
Aetiology of haemopoietic malignancies
• Idiopathic• Inherited factors-Down’s syn.,Blooms
syn.,Fanconi’s anaemia• Chemicals-ex:Benzene• Drugs-Alkylating agents• Radiation• Infections-viruses-HTLV-1/EBV/HHV8 Bacteria-H pylori-MALT Lymphoma
Leukemia
• Acute leukemias: rapid onset, rapid death if treatment is not successful
• Chronic leukemias: natural history measured in years, even without initial treatment
differentiation block
enhancedproliferation
AcuteLeukemia+
Gain of function mutations of tyrosine kinases
eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGFbR
Loss of function of transcription factors needed for differentiation
eg. AML1-ETO CBFb-SMMHC PML-RARa
Two-hit model of leukemogenesis
Hematopoieticstem cell
Neutrophils
Eosinophils
Basophils
Monocytes
Platelets
Red cells
Myeloidprogenitor
Lymphoidprogenitor
B-lymphocytes
T-lymphocytes
Plasmacells
naïve
ALL
AML
Myeloid maturation
myeloblast promyelocyte myelocyte metamyelocyte band neutrophil
MATURATION
Adapted and modified from U Va website
Acute Leukemia
• accumulation of blasts in the PB/BM
AML
Auer rods in AML
ALL
Classification of acute leukemias
ALL• mainly children• curable in 85% of children• curable in minority of adults
AML• mainly adults
• curable in minority of adults
Clincal manifestations
• symptoms due to:– marrow failure– tissue infiltration– leukostasis– constitutional symptoms– Others- DIC (acute promyelocytic leukaemia)
• usually short duration of symptoms
Marrow failure
• Neutropenia: :infections, sepsis
• Anaemia : fatigue, pallor
• Thrombocytopenia: bleeding
Infiltration of tissues/organs
• enlargement of liver, spleen, lymph nodes
• gum hypertrophy
• bone pain
• other organs: CNS, skin, testis, any organ
Constitutional symptoms
• Fever • sweats • weight loss • LOA
Investigations
• FBC+BP• Bone marrow aspiration & trephine biopsy• Special stains-Sudan black/PAS• Flow cytometry• Cytogenetics-t(15,17)-Acute promyelocytic
leukaemia
Principles of treatment
• combination chemotherapy– first goal is complete remission– further Rx to prevent relapse
• supportive medical care– transfusions, antibiotics, nutrition
• psychosocial support– patient and family
CML
• Clonal disorder of pluripotent stem cell• Philadelphia chromasome t(9,22)• Enhanced thyrosine kinase activity(TK)• Clnical features: due to hypermetabolism,
splenomegaly,BMF,leukostasis Treatment-TKI
CLL
• Common in elderly/west
LymphomaClonal proliferation of lymphoid cells
Non Hodgkin HodgkinB cell T cell FollicularMantleDLBCL
Clinical presentation
• Lymphadenopathy• Bone marrow failure• Organ involvement• Constitutional symptoms(B symptoms)
Investigations
• FBC+BP• ESR• LDH• Radiology• Biopsy• Flow cytometry• Immunohistochemistry
Management
• Aggressive/indolent• Stage-early/advanced• Patient factors• Options-watch and wait Chemotherapy Radiotherapy Immunotherapy BMT
Haemostasis
HEMOSTASISDefinition
• Hemostasis: drives from the Greek meaning “The stoppage of blood flow”.
• Components involved in haemostasis *Blood vessel *Platelets *Coagulation factors *Coagulation inhibitors *Fibrinolysis
drmsaiem
Vessel wall, Blood flow & Coagulation Substances
drmsaiem
In Case if there is an Endothelial Injury(Bleeding must be prevented at site of injury)
HEMOSTASIS
Under normal conditions, the formation and dissolution of thrombi is maintained in a delicate balance.
Clotting cascade
Fibrinolysis
Tests used in coagulation disorders
Screening tests1.FBC+BP2.BT3.PT4.APTT5.TT6.FibrinogenOthers: Factor assays/VWF assays/platelet function
tests/D-dimer/PFA 100/TEG ect.
Abnormal bleeding
• Vascular disorders• Platelet disorders-Thrombocytopenia Platelet function defects• Defective coagulation
Platelet function disorders
Congenital• Glanzmann’s disease
/Thrombasthenia• Bernard- Soulier syndrome• Storage pool diseases
Acquired• Anti platelet drugs• Hyperglobulinaemia• MPD/MDS• Uraemia
Glanzmann’s disease /Thrombasthenia• Def. Gp 11b/111a• Platelet aggregation –only with ristocetinBernard-Soulier syndrome• Gp 1b def.• Large platelet• Thrombocytopenia• Platelet aggregation-not with ristocetin
Bernard-Soulier vs Glanzmann’s
Coagulation disorders
Congenital• Haemophilia A(F VIII)• Haemophilia B(F IX)• VWD• Fibrinogen,XI,X,V,II def
Acquired• Liver disease• DIC• Vit K def
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