Haemopoiesis, blood
malignancies, coagulation and
platelet function defects

Dr H.M.D.Moratuwagama
Department of Pathology...
Haemopoiesis
Sites of Haemopoiesis
• Yolk sac
• Liver and spleen
• Bone marrow
– Gradual replacement
of active (red) marrow
by inactive...
Sites of Haemopoiesis
• Fetus- 2 months –Yolk sac
2-7 months-Liver/Spleen
5-9 months-BM
• Infants-BM
• Adult-Axial skeleto...
Components of Haemopoiesis
• Cells
• Bone marrow stroma
• Growth factors
Cells
• Stem cells
• Self renewal
• Plasticity

• Progenitor cells
• Developmentally-restricted cells

• Mature cells
• Ma...
Haemopoiesis

Common myeloid progenitor cell

Common lymphoid 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
G...
Haemopoietic growth factors cont.

• Cytokines
•
•
•
•
•
•
•

IL 1 (Interleukin 1)
IL 3
IL 5
IL 6
TNF
SCF (Stem cell facto...
Role of growth factors in normal
haemopoiesis
Erythropoiesis and erythrocytes
• Lifespan – 120 days
• Non nucleated
• Biconcave disc
• Production regulated by Epo
• Nee...
Granulopoiesis
• Granulocytes

E

– Neutrophils
– Eosinophils

– Basophils

• Only mature cells are
present in peripheral
...
Granulopoiesis
• Neutrophil
– 2-5 lobe nucleus
– Primary or secondary
granules
• Pink (azurophilic granules)
• Grey-blue g...
Monocytes
• Larger than lymphocyte
• Oval or indented nucleus
• Monocytes >>>>to
macrophage
• Specific function depends
on...
Lymphopoiesis
Thrombopoiesis
• Platelet play a major
role in primary
hemostasis
• Life span 7-10 days
• Production, fragmentati
on of cy...
Summary
• Normal haemopoiesis is necessary for the
survival
• It is under the control of multiple factors
• Normal bone ma...
Blood malignancies
Blood malignancies
LEUKAEMIA

LYMPHOMA
Blood malignancies
Leukaemia

Acute
Chronic
Myeloid Lymphoid Myeloid
Lymphoid
AML
ALL
CML
CLL
Aetiology of haemopoietic
malignancies
• Idiopathic
• Inherited factors-Down’s syn.,Blooms
syn.,Fanconi’s anaemia
• Chemic...
Leukemia
• Acute leukemias: rapid onset, rapid death if
treatment is not successful
• Chronic leukemias: natural history m...
Two-hit model of leukemogenesis
Loss of function of
transcription factors needed
for differentiation

eg. FLT3, c-KIT muta...
ALL
naïve
B-lymphocytes

Lymphoid
progenitor

Plasma
cells
T-lymphocytes

AML
Hematopoietic
stem cell

Myeloid
progenitor
...
Myeloid maturation
myeloblast

promyelocyte

myelocyte

metamyelocyte

band

neutrophil

MATURATION
Adapted and modified f...
Acute Leukemia
• accumulation of blasts in the PB/BM
AML
Auer rods in AML
ALL
Classification of acute leukemias
ALL

AML

• mainly children
• curable in 85% of
children
• curable in minority of
adults...
Clincal manifestations
• symptoms due to:
– marrow failure
– tissue infiltration
– leukostasis
– constitutional 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: ...
Constitutional symptoms
•
•
•
•

Fever
sweats
weight loss
LOA
Investigations
•
•
•
•
•

FBC+BP
Bone marrow aspiration & trephine biopsy
Special stains-Sudan black/PAS
Flow cytometry
Cy...
Principles of treatment
• combination chemotherapy
– first goal is complete remission
– further Rx to prevent relapse

• s...
CML
•
•
•
•

Clonal disorder of pluripotent stem cell
Philadelphia chromasome t(9,22)
Enhanced thyrosine kinase activity(T...
CLL
• Common in elderly/west
Lymphoma
Clonal proliferation of lymphoid cells
Non Hodgkin
B cell
T cell
Follicular
Mantle
DLBCL

Hodgkin
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
Radiother...
Haemostasis
HEMOSTASIS
Definition

• Hemostasis: drives from the Greek
meaning “The stoppage of blood flow”.
• Components involved in ...
Vessel wall, Blood flow & Coagulation Substances

drmsaiem
In Case if there is an Endothelial Injury
(Bleeding must be prevented at site of injury)

drmsaiem
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 tests
1.FBC+BP
2.BT
3.PT
4.APTT
5.TT
6.Fibrinogen
Others: Factor assays/VWF ...
Abnormal bleeding
• Vascular disorders
• Platelet disorders-Thrombocytopenia
Platelet function defects
• Defective coagula...
Platelet function disorders
Congenital
• Glanzmann’s disease
/Thrombasthenia
• Bernard- Soulier syndrome
• Storage pool di...
Glanzmann’s disease /Thrombasthenia
• Def. Gp 11b/111a
• Platelet aggregation –only with ristocetin
Bernard-Soulier syndro...
Bernard-Soulier vs Glanzmann’s
Coagulation disorders
Congenital
• Haemophilia A(F VIII)
• Haemophilia B(F IX)
• VWD
• Fibrinogen,XI,X,V,II def

Acquired
...
THANK YOU
Haemopoiesis, blood malignancies, coagulation and platelet
Haemopoiesis, blood malignancies, coagulation and platelet
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Haemopoiesis, blood malignancies, coagulation and platelet

  1. 1. Haemopoiesis, blood malignancies, coagulation and platelet function defects Dr H.M.D.Moratuwagama Department of Pathology Faculty of Medicine-Ragama
  2. 2. Haemopoiesis
  3. 3. 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
  4. 4. Sites of Haemopoiesis • Fetus- 2 months –Yolk sac 2-7 months-Liver/Spleen 5-9 months-BM • Infants-BM • Adult-Axial skeleton
  5. 5. Components of Haemopoiesis • Cells • Bone marrow stroma • Growth factors
  6. 6. Cells • Stem cells • Self renewal • Plasticity • Progenitor cells • Developmentally-restricted cells • Mature cells • Mature cell production takes place from the more developmentally-restricted progenitors
  7. 7. Haemopoiesis Common myeloid progenitor cell Common lymphoid progenitor cell
  8. 8. BM • Stromal cells -adipocytes,fibroblasts,osteoblasts,endothelial cells ,macrophages • Microvascular network
  9. 9. Regulation of haemopoiesis • Transcription factors -CEBP-Myeloid -GATA 1-Erythroid • Growth factors
  10. 10. 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
  11. 11. 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
  12. 12. Role of growth factors in normal haemopoiesis
  13. 13. Erythropoiesis and erythrocytes • Lifespan – 120 days • Non nucleated • Biconcave disc • Production regulated by Epo • Needs Fe, B12, folate & other elements for development
  14. 14. Granulopoiesis • Granulocytes E – Neutrophils – Eosinophils – Basophils • Only mature cells are present in peripheral blood N B
  15. 15. 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)
  16. 16. Monocytes • Larger than lymphocyte • Oval or indented nucleus • Monocytes >>>>to macrophage • Specific function depends on the tissue type
  17. 17. Lymphopoiesis
  18. 18. Thrombopoiesis • Platelet play a major role in primary hemostasis • Life span 7-10 days • Production, fragmentati on of cytoplasm • Megakaryocytes undergoes endomitotic division
  19. 19. 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
  20. 20. Blood malignancies
  21. 21. Blood malignancies LEUKAEMIA LYMPHOMA
  22. 22. Blood malignancies Leukaemia Acute Chronic Myeloid Lymphoid Myeloid Lymphoid AML ALL CML CLL
  23. 23. 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
  24. 24. Leukemia • Acute leukemias: rapid onset, rapid death if treatment is not successful • Chronic leukemias: natural history measured in years, even without initial treatment
  25. 25. Two-hit model of leukemogenesis Loss of function of transcription factors needed for differentiation eg. FLT3, c-KIT mutations N- and K-RAS mutations BCR-ABL TEL-PDGF R eg. AML1-ETO CBF -SMMHC PML-RAR differentiation block Gain of function mutations of tyrosine kinases + enhanced proliferation Acute Leukemia
  26. 26. ALL naïve B-lymphocytes Lymphoid progenitor Plasma cells T-lymphocytes AML Hematopoietic stem cell Myeloid progenitor Neutrophils Eosinophils Basophils Monocytes Platelets Red cells
  27. 27. Myeloid maturation myeloblast promyelocyte myelocyte metamyelocyte band neutrophil MATURATION Adapted and modified from U Va website
  28. 28. Acute Leukemia • accumulation of blasts in the PB/BM
  29. 29. AML
  30. 30. Auer rods in AML
  31. 31. ALL
  32. 32. Classification of acute leukemias ALL AML • mainly children • curable in 85% of children • curable in minority of adults • mainly adults • curable in minority of adults
  33. 33. Clincal manifestations • symptoms due to: – marrow failure – tissue infiltration – leukostasis – constitutional symptoms – Others- DIC (acute promyelocytic leukaemia) • usually short duration of symptoms
  34. 34. Marrow failure • Neutropenia: :infections, sepsis • Anaemia : fatigue, pallor • Thrombocytopenia: bleeding
  35. 35. Infiltration of tissues/organs • enlargement of liver, spleen, lymph nodes • gum hypertrophy • bone pain • other organs: CNS, skin, testis, any organ
  36. 36. Constitutional symptoms • • • • Fever sweats weight loss LOA
  37. 37. Investigations • • • • • FBC+BP Bone marrow aspiration & trephine biopsy Special stains-Sudan black/PAS Flow cytometry Cytogenetics-t(15,17)-Acute promyelocytic leukaemia
  38. 38. 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
  39. 39. CML • • • • Clonal disorder of pluripotent stem cell Philadelphia chromasome t(9,22) Enhanced thyrosine kinase activity(TK) Clnical features: due to hypermetabolism, splenomegaly,BMF,leukosta sis Treatment-TKI
  40. 40. CLL • Common in elderly/west
  41. 41. Lymphoma Clonal proliferation of lymphoid cells Non Hodgkin B cell T cell Follicular Mantle DLBCL Hodgkin
  42. 42. Clinical presentation • • • • Lymphadenopathy Bone marrow failure Organ involvement Constitutional symptoms(B symptoms)
  43. 43. Investigations • • • • • • • FBC+BP ESR LDH Radiology Biopsy Flow cytometry Immunohistochemistry
  44. 44. Management • • • • Aggressive/indolent Stage-early/advanced Patient factors Options-watch and wait Chemotherapy Radiotherapy Immunotherapy BMT
  45. 45. Haemostasis
  46. 46. HEMOSTASIS Definition • Hemostasis: drives from the Greek meaning “The stoppage of blood flow”. • Components involved in haemostasis *Blood vessel *Platelets *Coagulation factors *Coagulation inhibitors *Fibrinolysis
  47. 47. Vessel wall, Blood flow & Coagulation Substances drmsaiem
  48. 48. In Case if there is an Endothelial Injury (Bleeding must be prevented at site of injury) drmsaiem
  49. 49. HEMOSTASIS Under normal conditions, the formation and dissolution of thrombi is maintained in a delicate balance.
  50. 50. Clotting cascade
  51. 51. Fibrinolysis
  52. 52. Tests used in coagulation disorders Screening tests 1.FBC+BP 2.BT 3.PT 4.APTT 5.TT 6.Fibrinogen Others: Factor assays/VWF assays/platelet function tests/D-dimer/PFA 100/TEG ect.
  53. 53. Abnormal bleeding • Vascular disorders • Platelet disorders-Thrombocytopenia Platelet function defects • Defective coagulation
  54. 54. Platelet function disorders Congenital • Glanzmann’s disease /Thrombasthenia • Bernard- Soulier syndrome • Storage pool diseases Acquired • Anti platelet drugs • Hyperglobulinaemia • MPD/MDS • Uraemia
  55. 55. Glanzmann’s disease /Thrombasthenia • Def. Gp 11b/111a • Platelet aggregation –only with ristocetin Bernard-Soulier syndrome • Gp 1b def. • Large platelet • Thrombocytopenia • Platelet aggregation-not with ristocetin
  56. 56. Bernard-Soulier vs Glanzmann’s
  57. 57. 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
  58. 58. THANK YOU

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