Bone Marrow Failure And Other Haematological Disorders

Front 1

How much bone marrow is there in the body and where is most of it found?

Back 1

-~3kg in adult male
-Predominantly in pelvis, ribs and long bones

Front 2

What are the two types of bone marrow and in which does haemopoeisis occur?

Back 2

-Red and yellow marrow
-Haemopoiesis occurs in active red marrow

Front 3

What is the ratio of red bone marrow to yellow bone marrow? Does this change throughout life?

Back 3

-Red marrow 100% at birth
-Red marrow replaced by inactive yellow marrow (to 50%) increasing with age

Front 4

What is the structure of bone marrow?

Back 4

-Composed of network of epithelial cell-lined sinusoids interpersed with islands of haemopoietic cells supported by connective tissue elements in the bone marrow stroma (fibroblasts, reticulin, adiposed tissue and endothelial cells)
(diagram)

Front 5

Define bone marrow failure

Back 5

-Impaired progenitor production of mature cells
-Normal cell morphology and stromal cell function
-Stop progress along lineage

Front 6

What are the 2 types of bone marrow failure? Is the stage in the lineage important?

Back 6

-Pluripotent stem cell failure affects all 3 cell lineages and results in aplastic anaemia
-Committed stem cell failure affects 1 cell lineage and causes single cell deficiency

Front 7

What is aplastic anaemia?

Back 7

-Pluripotent stem cell failure resulting in pancytopoienia (multicell failure) anaemia (Hb<100g/L), leukopoienia (WCC<4x10^9) and thrombocytopoienia (Plts<100x10^9/L)
-Mechanism is replacement of red marrow with yellow marrow
-Diagnosis is based on absence of cells
(diagram)

Front 8

What happens to bone marrow in aplastic anaemia?

Back 8

Red marrow is replaced with yellow marrow (fat)

Front 9

What are the types of single cell deficiencies?

Back 9

-Pure red cell aplasia
-Neutropoienia
-Amegakaryocytic thrombocytopoienia
(diagram)

Front 10

What is the clinical presentation of bone marrow failure?

Back 10

-Non specific; malaise, fatigue
-Anaemia; dyspnoea, pallor, oedema, palpitations
-Neutropenia; infection, fever, mouth ulceration
-Thrombocytopenia; bleeding, petechiae, bruising
-FBE; dysmorphic features
*think of what cell production is inhibited

Front 11

How often does bone marrow failure occur?

Back 11

Rare, ~1-2 cases/10^6 population per year

Front 12

What are the main causes of bone marrow failure?

Back 12

-~60-70% idiopathic causes; ?Genetic predisposition, ?primary haemopoietic stem cell defect, ?secondary to environmental insult on a normal haemopoietic stem cell
-Drugs; anticonvulsants, antithyroid, antibiotics, cytokines
-Viruses; hepatitis, EBV, parvovirus
-Inherited; Fancomi's anaemia (autosomal recessive) leads to pancytopoienia and Kostmann's syndrome (autosomal recessive) leads to neutropoienia
-

Front 13

What is Myelodysplastic syndrome (MDS)?

Back 13

-Group of disorders arising from an abnormal pluripotent stem cell
-Results in morphological abnormalities in blood and bone marrow
-This problem does not stop lineage but just produced mutated cells

Front 14

What is the clinical presentation of myelodysplastic syndromes (MDS)?

Back 14

-Usually incidental finding (50%)
-Majority present with Macrocytic anaemia, and less commonly with additional cytopoienias or pancytopoienias
-Abnormal blood film
-Symptoms of bone marrow failure
-Rash
-Serous effusions
-Splenomegaly

Front 15

How is are myelodysplastic syndromes (MDS) classified?

Back 15

-Morphology
-Depends on; lineage invloved, blast count, presence or absence of ringed siderblasts, precense or absence of a monocytosis & cytogenetics
(diagram)

Front 16

What is the aetiology of myelodysplastic syndrome (MDS)?

Back 16

-Unknown in majority of cases (genetic predisposition may be in younger patients)
-Therapy related (chemotherapy/radiotherapy)

Front 17

How can myelodysplastic syndrome (MDS) progress to acute myeloid leukaemia?

Back 17

-Increased frequency of cytogenetic abnormalities and molecular lesions targeting tumour supressor genes (oncogenes)
-Clonal evolution can lead to excess proliferation and no differentiation
(diagram)

Front 18

What is the treatment of bone marrow failure and myelodysplastic syndrome (MDS)?

Back 18

-Treatment and prevention of infections
-Treatment and prevention of bleeding complications
-Blood product support (RBC, platelets)
-Select use of cytokines (EPO;red cells) to increase number of normal cells
-Antibiotics
-Management of iron overload (iron chelators)

Front 19

How is haemopoiesis restored after bone marrow failure or myelodysplastic syndrome?

Back 19

-Mild cases may need no specific therapy
-Immunosuppressive therapy targeting t-cell suppression of haemopoeisis (t-cells found to cause suppression of haemopoiesis in infective bone marrow failure); antilymphocyte globulin, cyclosporin, anabolic steroids
-Bone marrow transplantation
-Selected use of cytokines
-Bone marrow transplant

Front 20

How is the abnormal clone in bone marrow failure or myelodysplastic syndrom eradicated?

Back 20

Chemotherapy (has limitations to effectiveness, risk of prolonged aplasia and difficulties in young and old patients)
-Bone marrow transplantation has potential for cure

Front 21

How are haematological malignacies classified?

Back 21

-Morphology
-Site (blood/bone marrow=leukaemia v. lymphoid organs=lymphoma)
-Course of disease (acute v. chronic)
-Cell type (myeloid v. lymphoid v. hairy cell v. myeloma)
-Differentiation status (M0-M7(diagram), L1-L3)

Front 22

What are acute leukemias?

Back 22

-Disorder of stem cell/early progenitor cell
-Increased proliferation and loss of differentiation
-Results in accumulation of nonfunctional precursur 'blasts' with organ infiltration
-Hypercellular bone marrow with peripheral blood cytopoienias

Front 23

How do acute leukaemias cause mortality?

Back 23

Due to marrow failure

Front 24

How do acute myeloid leukaemias affect other lineages?

Back 24

They crowd out other cell types causing dysfunction
(diagram)

Front 25

What are the causes of acute leukaemia?

Back 25

-Aetiology unknown however role of cytotoxics and radiation
-?research into genetic causes

Front 26

What is the treatment principles of acute leukaemia?

Back 26

-Eridicate clone with cytotoxic chemicals and support patient with blood products and antibiotics
-Facilitate differentiation
-Low dose chemotherapy

Front 27

How common are lymphomas as a malignancy in the community?

Back 27

6th most common malignancies in the community (5% and rising)

Front 28

In what age are lymphomas most common?

Back 28

Middle life

Front 29

What cells are most affected by lymphomas?

Back 29

B cells

Front 30

What is hodgkins lymphoma?

Back 30

-Painless lymphadenopathy with variably associated constitutional disturbance (fever, weight loss)
-B cell affected
-Diagnosed by lymph node biopsy

Front 31

What is the cause of hodgkins lymphoma?

Back 31

Unknown, peaks in 20's and 50's (bi-modal)

Front 32

What is the treatment for hodgkins lymphoma?

Back 32

Early; radiation
Most; combined chemotherapy and deep xray therapy
-Focus on preventing long term morbidity

Front 33

What is non-hodgkins lymphoma?

Back 33

-Any lymphoma that is not hodgkins lymphoma
-Caused by disorder of precurser B cells, mature B cells, precursor T cells and mature T (and NK cells)

Front 34

How are non-hodgkins lymphomas classified?

Back 34

-Indolent
-Aggressive
-Very aggressive

Front 35

What is the aetiology of non-hodgkins lymphoma?

Back 35

-Genetic translocations
-Viral (EBV, HIV)
-Bacterial (h.pylori)

Front 36

What are the clinical signs and treatment of indolent non-hodgkins lymphoma?

Back 36

-Signs; lymphadenopathy, cytopoienias and immune dysfunction
-Treatment; monoclonal antibodies, chemotherapy, antibodies

Front 37

What are the clinical signs and treatment of aggressive/very aggressive non-hodgkins lymphoma?

Back 37

Signs; lymphadenopathy and constitutional disturbance
-Treatment; combination chemotherapy

Front 38

What are chronic myeloproliferative disorders?

Back 38

-Stem cell disorder
-Increased proliferation and maintenance of differentiation
-Results in excess of myeloid cells especially RBC's, platelets and neutrophils
-Leads to thrombotic state
-Increased cell cycling creates propensity for blastic transformation (more turn over more chance of mistake)

Front 39

List examples of chronic myeloproliferative disorders

Back 39

-Polycythaemia vera (PV)
-Chronic idiopathic myelofibrosis (with extramedullary haemopoiesis) (IMF)
-Essential thrombocythaemia (ET)
-Chronic myeloproliferative disease, unclassifiable
-Chronic myelogenous leukaemia (CML)
-Chronic neutrophilic leukaemia (CNL)
-Chronic eosinophilic leukaemia (& hypereosinophilic syndrome) (CEL)

Front 40

How does polycythaemia vera affect the lineage and production of cells?

Back 40

(diagram)

Front 41

How does chronic myeloid leukaemia affect the lineage and production of cells?

Back 41

(diagram)

Front 42

What are the causes of myeloproliferative disorders?

Back 42

-PV, IMF, ET; Jak2 kinase mutation(downstream of EpoR+TpoR), TpoR mutation
-Erythrocytosis; EpoR truncation
-CML; BCR-ABL translocation t(9,22)(q34,q11)

Front 43

What are the treatments of myeloproliferative disorders?

Back 43

-Phlebotomy
-Anti-thombolytic agents
-If specific cause known; CML-BCR-ABL inhibitor (Gleevac), PV-Jak 2 inhibitor

Front 44

What is Jak 2?

Back 44

Switch responsible for turning on and off receptors in particular lineages in the presence of soluble factors