2020 HMM204 Wk04 L10 Disorders of leukocytes PDF

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DEAKIN MEDICAL SCHOOL

Leucocyte and multi-lineage disorders Prof. Alister C. Ward [email protected]

Deakin University CRICOS Provider Code: 00113B

Class overview • Leucocyte disorders • Deficiencies • Excesses • Multi-lineage disorders • Bone marrow failure • Myelodysplastic syndrome • HaaG – Chapter 18

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Class learning objectives • Describe neutrophil deficiency disorders including neutropenia and recognise the effects of deficient or defective neutrophils and how this is treated • Understand the causes of leucocyte excesses • Describe the process of chronic inflammation • Describe the multi-lineage disorders including bone marrow failure and myelodysplasia including their clinical symptoms, diagnosis and treatment

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Leucocyte disorders

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Leucocyte deficiencies

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Neutrophil deficiency • The most common leucocyte deficiencies involve neutrophils • The deficiency can relate to the number of cells and/or their function

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Neutrophil deficiency (cont) • Reduced/defective neutrophils means that the ability to fight bacteria and fungi is greatly reduced − recurrent, prolonged infections (esp. mouth, throat and skin) − commensals (‘normal flora’) becomes pathogenic − ulcers − life-threatening septicaemia

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Reduced neutrophils (neutropenia) • Where there are insufficient numbers (neutropoienia), this may be due to: • decreased production or • increased destruction

• Can be: • inherited or • acquired

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Reduced neutrophils (neutropenia) (cont) • Primary (inherited) • eg. Severe congenital neutropenia –

neutrophils 7.5 x 103/μl Common Can lead to fever Causes: • • • •

Bacterial infection Inflammation/tissue necrosis (eg. trauma, cardiac infarct) Therapeutic (esp. corticosteroids, G-CSF, GM-CSF) Myeloproliferative diseases/cancers

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Eosinophil excess (eosinophilia) • • • •

> 1.5 x 103/μl Relatively common Can contribute to hyperallergic responses Causes: • • • • •

Parasitic infection Allergic diseases (eg. hay fever, food/drug sensitivity) Immune disorders (eg. dermatitis, psoriasis) Therapeutic (eg. GM-CSF) Certain cancers

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Basophil excess (basophilia) • > 0.1 x 103/μl • Uncommon • Causes: • Certain viruses (eg. chickenpox) • Myeloproliferative diseases

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Monocyte excess (monocytosis) • Infrequent • Causes: • • • • •

Chronic bacterial infection (eg. tuberculosis) Protozoan infection Chronic neutropenia Therapeutic (eg. GM-CSF, M-CSF) Myelodysplasia

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Macrophage excess (histiocytosis) • Very rare • Affects tissue macrophages (histiocytes) • Causes: • ??

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Chronic inflammation • This represents inflammation that fails to resolve • Causes: • Persistent infection: • Specific pathogens (eg. mycoplasma) • Immunodeficiencies

• Dysfunctional immune response • Hyperactivated macrophages

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Chronic inflammation (cont) • Sequence of events: –

Infiltration of mononuclear cells – –

– – –

Tissue destruction Attempt at healing by connective tissue replacement, accompanied by fibrosis → loss of function Macrophage fusion to form multinucleate giant cells

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

macrophages, lymphocytes and plasma cells exacerbated by macrophage proliferation

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Chronic inflammation (cont) • Can lead to the formation of a granuloma • eg. leprosy, syphilis, cat-scratch disease

• Treatments: immunosuppressive agents HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Multi-lineage disorders

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Multi-lineage disorders • Multi-lineage disorders are typically due to defects in haematopoiesis • Can be grouped into: • Bone marrow failures • Myelodysplastic syndromes

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Bone marrow failures

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Bone marrow failure • Impaired production of mature cells in the bone marrow (normal cell morphology) • Exact disorder dependent on exactly which cells are affected: • Pluripotent progenitor cell  aplastic anaemia (3 cell lineages affected) • Committed progenitor cell  single cell deficiency (1 cell lineage affected)

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Aplastic anaemia • ‘Stem cell failure’ resulting in replacement of red marrow with yellow marrow (fat) • Patients present with pancytopoienia ie.: – Anaemia: Hb < 100 g/L (NR 120-170) – Leucopoienia: WBC < 4 x 109/L (NR 4-11) – Thrombocytopoienia: Plts < 100 x 109/L (NR 150-450) • Diagnosis based on absence of cells

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Aplastic anaemia (cont)

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

eg: Aplastic anaemia Haematopoietic stem cell Common (HSC) Myeloid Progenitor (CMP)

Megakaryocyte/ Erythrocyte Progenitor Platelets Erythrocyte

Common Lymphoid Progenitor (CLP)

T cell Progenitor

T cell

Granulocyte

B cell Progenitor

Granulocyte/ Macrophage Progenitor

Monocyte/ Macrophage

B cell Deakin University CRICOS Provider Code: 00113B

eg: Aplastic anaemia (cont) Haematopoietic stem cell (HSC)

Common Myeloid Progenitor (CMP)

Megakaryocyte/ Erythrocyte Progenitor Platelets Erythrocyte

Common Lymphoid Progenitor (CLP)

T cell Progenitor

T cell

Granulocyte

B cell Progenitor

Granulocyte/ Macrophage Progenitor

Monocyte/ Macrophage

B cell Deakin University CRICOS Provider Code: 00113B

Single cell deficiencies • Pure red cell aplasia – erythrocyte precursor – idiopathic, autoimmune disorders, lymphoproliferative disease, thymoma & parvovirus • Neutropoienia – neutrophil precursor – congenital, drugs, viruses • Amegakaryocytic thrombocytopoienia – megakaryocyte precursor

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

eg: Red cell aplasia Haematopoietic stem cell (HSC)

Common Myeloid Progenitor (CMP)

Megakaryocyte/ Erythrocyte Progenitor Platelets Erythrocyte

Common Lymphoid Progenitor (CLP)

T cell Progenitor

T cell

Granulocyte

B cell Progenitor

Granulocyte/ Macrophage Progenitor

Monocyte/ Macrophage

B cell Deakin University CRICOS Provider Code: 00113B

eg: Neutropoienia Haematopoietic stem cell (HSC)

Common Myeloid Progenitor (CMP)

Megakaryocyte/ Erythrocyte Progenitor Platelets Erythrocyte

Common Lymphoid Progenitor (CLP)

T cell Progenitor

T cell

Granulocyte

B cell Progenitor

Granulocyte/ Macrophage Progenitor

Monocyte/ Macrophage

B cell Deakin University CRICOS Provider Code: 00113B

Bone marrow failure: clinical presentation • • • •

Non-specific: fatigue Anaemia: pallour, dyspnoea Neutropenia: infections, mouth ulcers Thrombocytopenia: bleeding, petechiae, bruising

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Bone marrow failure: incidence & epidemiology • Rare: ~ 1-2 cases/106 population/year • Idiopathic causes (~ 60-70% cases): – ? Genetic predisposition – ? Primary hematopoietic stem cell defect

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Bone marrow failure: incidence & epidemiology (cont) • Remaining cases: – Drugs • Anticonvulsants, antibiotics, cytotoxics

– Viruses • Hepatitis, EBV, Parvovirus

– Inherited • Fancomi’s anaemia – pancytopoienia • Kostmann’s syndrome – neutropoienia

•  risk of other ‘clonal’ disorders – Myelodysplastic syndrome, leukaemia HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Myelodysplastic syndromes

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Myelodysplastic syndromes (MDS) • Group of disorders arising from an abnormal pluripotent stem cell • Results in morphological abnormalities in cells of blood and bone marrow

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

MDS: clinical presentation • Up to 50% as incidental finding on blood examination • Majority present with macrocytic anaemia, less commonly additional cytopoienias or pancytopoienias • Overlap with symptoms of bone marrow failure • Incidence increases with age

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Aetiology of MDS • Unknown in the majority of cases (“primary” MDS) – Genetic predisposition (younger patients) • Therapy-related MDS (prior chemotherapy or radiotherapy) – Latency dependent upon agent

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Clinical progression of MDS • Associated with  risk of progression to leukaemia

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

eg: Myelodysplastic syndrome Haematopoietic stem cell (HSC)

Mutation 1

Common Myeloid Progenitor (CMP)

Megakaryocyte/ Erythrocyte Progenitor Platelets Erythrocyte

Common Lymphoid Progenitor (CLP)

T cell Progenitor

T cell

Granulocyte

B cell Progenitor

Granulocyte/ Macrophage Progenitor

Monocyte/ Macrophage

B cell Deakin University CRICOS Provider Code: 00113B

eg: Myelodysplastic syndrome (cont) Haematopoietic stem cell (HSC)

Mutation 1

Common Myeloid Progenitor (CMP)

Megakaryocyte/ Erythrocyte Progenitor Platelets Erythrocyte

Common Lymphoid Progenitor (CLP)

Granulocyte Mutation 2

T cell Progenitor

T cell

B cell Progenitor

B cell

Granulocyte/ Macrophage Progenitor

Monocyte/ Macrophage

1+2 Deakin University CRICOS Provider Code: 00113B

Bone marrow failures/MDS: treatment • Neutrophil deficiency: • G-CSF: increase production • antibiotics: treat infections

• Platelet deficiency: • packed platelet transfusion: increase number • anti-fibrinolytic agents: augment clotting

• Erythrocyte deficiency: • EPO: increase production • packed RBC transfusion: increase number • iron chelators: manage iron overload

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Summary

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B

Common Myeloid Progenitor

Megakaryocyte/ Erythrocyte Progenitor

Megakaryocyte Platelets Erythrocyte Granulocytes: neutrophils eosinophils basophils

Granulocyte/ Macrophage Progenitor

Haemostasis Gas transport

Infection Inflammation

Monocyte Macrophage

↓ number (eg. bone marrow failure, neutropenia) ↓ function (eg. MDS, Phox mutant)

HMM204 Haematology & Immunology DEAKIN MEDICAL SCHOOL

Prof Alister C Ward Deakin University CRICOS Provider Code: 00113B...