Haemopoiesis Clinical application

Dr. Tariq M. Roshan

Department of Hematology

PPSP

Introduction

Life span

Granulocytes Erythrocytes Platelets Lymphocytes

Introduction

Stem cells Self renewal Plasticity

Progenitor cells Developmentally-restricted cells

Mature cells Mature cell production takes place from the more

developmentally-restricted progenitors

Cell hierarchy (Haemopoiesis schematic representation)

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

Stem cells

Self-renewal Normally in G0 phase of cell cycle The capacity for self-reproduction is vastly in

excess of that required to maintain cell production for normal lifetime

As cells increase in number they differentiate as well

Multipotentiality Capacity to generate cells of all the

lymphohaemopoietic lineages

Progenitor cells

Encompasses from immediate progeny of stem cells to cells committed to one differentiation lineage

Progenitor cells become progressively more restricted in their differentiation and proliferation capacity

Late progenitor cells eventually restricted to one lineage

Regulation of Haemopoiesis

There should be a balance between cell production and cell death except at the times of requirement

Controlled cell death

Controlled cell production

Regulation of Haemopoiesis

Local environmental controlStromal cell mediated Haemopoiesis

Haemopoietic growth factors (Humoral regulation)Apoptosis

Interaction of stromal cells, growth factors and haemopoietic cells

Local and Humoral regulation of Haemopoiesis

Haemopoietic growth factors

GM-CSF Granulocyte-Macrophage colony stimulating factor

M-CSF Macrophage colony stimulating factor

Erythropoietin 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 Stimulates megakaryopoiesis

Haemopoietic growth factors

Cytokines IL 1 (Interleukin 1) IL 3 IL 4 IL 5 IL 6 IL 9 IL 11 TGF-β SCF (Stem cell factor, also known as kit-ligand)

Cytokines have no (e.g IL-1) or little (SCF) capacity to stimulate cell proliferation on their own, but are able to synergise with other cytokines to recruit nine cells into proliferation

Erythropoiesis and erythrocytes

Lifespan – 120 days

Non nucleated

Biconcave disc

Production regulated by Epo

Needs Fe, B12, folate & other elements for development

Functions of erythrocytes

Transport of respiratory gases

Large surface area : volume ratio

Flexible biconcave disc

Haemoglobin for exchange of gases

Capable of glycolysis for the source of energy for cell survival

Erythrocyte disorders

Qualitative Haemoglobin defect

(Anemia, Thalassaemia, sickle cell anemia etc) Membrane & enzyme abnormalities

(G6PD, eliptocytosis, stomato-ovalocytosis)

Quantitative Increased (polycythemia) inherited / acquired Decrease (inherited / acquired hypoplasia) Bleeding

Anaemia

Reduction in circulation haemoglobin

Nutritional deficiency anaemias Iron deficiency B12 & folate deficiency

anaemia Protein deficiency

anaemia Scurvy & other

element deficiency

Iron deficiencyanaemia

B12 & folate deficiency

Nutritional deficiency anaemiaclinical application

Angular Cheilosis

Koilonychia

Glossitis

Marrow iron storesPlummer-Vinsonsyndrome

Anaemia; Globin chain defects

Thalassaemias

Reduced globin chain synthesis

Alpha and Beta chain synthesis defects

Haemoglobinopathies

Abnormal globin chain synthesis

Sickle cell disease

Thalassaemia

Anaemia; Globin chain defects

X-ray appearance ofThalassaemic patient

Hemoglobin electrophoresisfor the diagnosis of thalassaemia

Anaemia; Membrane and enzyme defects Membrane defects

Elliptocytosis Hemolysis

Stomato-ovalocytosis Without haemolysis

Red cell enzymopathies G6PD

Hemolysis after oxidant stress

Blood loss

Elliptocytosis

G6PD deficiency

Anaemia; Reduced bone marrow erythroid Marrow failure Marrow infiltration

Trephine biopsy (AplasticAnemia)

Marrow infiltration Normal trephine

Leucocytes

Lymphocytes

Monocytes / Macrophages

Granulocytes Neutrophils Eosinophils Basophils

N

E

B

LM

Band

P

Lymphocytes

Count varies with age

1.5 – 3.5 x109/l The subset cells are

B-cells Antibody mediated

immunity T-cells

Cell mediated immunity

NK cells

Disorders of lymphocytesBenign disorders Lymphocytosis

Viral infections Bacterial infections Protozoal infections

Lymphopenia Marrow failure (drugs, irradiation) Infections (viral infections)

Immune-deficiency syndromes Antibody deficiency Cell mediated immune defiency Combined cell and antibody immune deficiency

Disorders of lymphocytesBenign disorders Infectious

mononucleosis Epstein-Barr virus

infection

Autoimmune lymphoproliferative syndrome

Disorders of LymphocytesMalignant disorders Acute lymphoblastic

leukemia (ALL)

Chronic lymphocytic leukemia (CLL)

Lymphomas Non Hodgkin’s

lymphoma Hodgkin’s disease

ALL

CLL

Monocytes

Count is 0.2-0.8 x 109/l Functions

Antigen presentation Cytokine production Phagocytosis

Disorders of Monocytes

Monocytosis Benign

Chronic bacterial infection

Malignant Chronic Myelomonocytic Leukaemia CMML

Neutrophils

Count 2.5 - 7.5 x 109/l Granular cytoplasm Transient stay in blood Major phagocytic role Bacterial killing 3-5 lobes of nucleus

Disorders of Neutrophil

Neutrophilia Infection (Bacterial) Inflammatory conditions Neoplasia Metabolic conditions

Uraemia Haemorhage / haemolysis Corticosteroids Marrow infiltration

CML

MM M

N

Baso

Disorders of Neutrophil

Neutropenia Count < 1.5 x 109/l Drugs Chemotherapy Viral infection Inherited disorders

Morphological abnormalities Pelger-Huet anomaly May-Hegglin anomaly Chediak-Higashi syndrome

Myeloid malignancies

Acute Myeloid Leukaemia

Chronic Myeloid Leukaemia

Myeloproliferative disorder

Acute Myeloid Leukaemia(AML M-3)

Chronic Myeloid Leukaemia

Eosinophils

Count 0.2 – 0.8 x 109/l

Bilobed nucleus

Phagocytic activity is low

Modulation of hypersensitivity and allergic reactions

Disorders of Eosinophil

Eosinophilia>0.8 x 109/l Allergic reactions Parasitic infections Malignancy

HD, NHL Inflammatory conditions Myeloproliferative disorders Hypereosinophilic syndrome

Basophils

Count 0.1 – 0.2 x 109/l

Bilobed nucleus

Nucleus is hided behind the granules

Inflammatory response

Basophilia is seen in Myeloproliferative disorders (CML)

Platelets

Platelets are fragments of cytoplasm of bone marrow megakaryocytes

Count 150 – 400 x 109/l

Major role in coagulation

Summary

As other rapidly regenerating tissues, the haemopoietic system is organized in hierarchical manner

Better understanding of the factors controlling haemopoiesis is leading a way to better patient care and reconstitution of different lineages, which has been refractory to stimulation efforts previously

Understanding of stem cell physiology & pathology will be essential in the coming years for a hematopathologist

Thanks.