Bone marrow disorders

Question 1

What is polycythaemia?

Answer 1

An increase in Hb concentration above the upper limit for a person’s age and sex.

Question 2

How is polycythaemia classified?

Answer 2

Relative (normal red cell mass but LOW PLASMA VOLUME) and absolute (true) polycythaemia (raised red cell mass)

Question 3

What is the aetiology of absolute polycythaemia? (x2 (x3 and x5))

Answer 3

• PRIMARY: polycythaemia vera or polycythaemia rubra vera is when excess RBCs are produced by the bone marrow.
• SECONDARY: APPROPRIATE INCREASED ERYTHROPOIETIN caused by chronic hypoxia (for example, chronic lung disease, sleep apnoea or altitude) leasing to upregulation of erythropoiesis. INAPPROPRIATE INCREASED ERYTHROPOIETIN caused by renal carcinoma, renal cysts, hepatocellular carcinoma, fibroids, cerebellar hemangioblastoma.

Question 4

What is polycythaemia vera?

Answer 4

Neoplastic clonal haematopoietic disorder characterised clinically by erythrocytosis and often thrombocytosis, leukocytosis, and splenomegaly. Aka polycythaemia rubra vera.

Question 5

What is the pathophysiology of polycythaemia vera?

Answer 5

In 95% of cases, a JAK2 tyrosine kinase mutation gives haematopoietic stem cells in the bone marrow a proliferative advantage causing a trilineage expansion of morphologically normal RBCs, WBCs and platelets.

Question 6

What is the aetiology of relative polycythaemia? (x2)

Answer 6

Dehydration, Gaisbock’s syndrome (seen in young male smokers with raised vasomotor tone and hypertension resulting in reduced plasma volume and relative increase in RBC count).

Question 7

What is the epidemiology of polycythaemia: Incidence? Age?

Answer 7

Polycythaemia rubra vera has annual UK incidence of 1.5 in 100 000. Peak age is 45-60 years.

Question 8

What are the signs and symptoms of polycythaemia? How is this related to pathophysiology? (x10 +6) How ‘Bout DaT, TPPSSH (sassy ‘tutting’)

Answer 8

• Related to hyper viscosity: headaches, dyspnoea, tinnitus, blurred vision
• Thrombosis (from hyperviscosity and pro-inflammatory environment produced by raised WCC)
• Plethoric complexion (red)
• Pruritus after hot bath, night sweats
• Splenomegaly in 75% of patients
• Hypertension
• Pain from peptic ulcer disease, conjunctival suffusion (redness like in conjunctivitis without inflammatory exudate), retinal venous engorgement, angina, gout, choreiform movements (jerky)

Question 9

What does FBC show in polycythaemia? (x3)

Answer 9

Raised Hb, raised Hct, low MCV (because most also present with iron deficiency anaemia)

Question 10

What additional investigations are there in polycythaemia vera? (x4)

Answer 10

• FBC also shows raised WCC, platelets, decreased serum erythropoietin
• JAK2 mutation screen – present in almost all but not specific to polycythaemia vera
• Bone marrow trephine biopsy – shows erythroid hyperplasia and raised megakaryocytes
• USS showing splenomegaly

Question 11

What additional investigations are there for secondary polycythaemia? (x3)

Answer 11

• Raised erythropoietin
• Pulse oximetry, ABG and CXR to exclude chronic lung disease
• Abdominal CT or brain MRI to look for erythropoietin-secreting tumours

Question 12

How are isotope dilution techniques used to investigate polycythaemia?

Answer 12

Infusion of radiolabelled albumin and RBCs allow confirmation of plasma volume and red cell mass and distinguish between relative (low PV, normal RCM) and absolute (normal PV, raised RCM) polycythaemia.

Question 13

What is myelofibrosis?

Answer 13

Disorder of haematopoietic stem cells characterised by abnormal production of RBCs, WBCs and platelets, in association with progressive marrow fibrosis, extramedullary haematopoiesis (outside medulla of bone) and splenomegaly. It is REACTIVE and REVERSIBLE.

Question 14

What is the aetiology of myelofibrosis? (x1 and x4)

Answer 14

• Primary myelofibrosis – unknown aetiology characterised by leukoerythroblasts (myeloid cell precursor – gives rise to erythrocytes, multinucleated WCCs and platelets) and splenomegaly
• Secondary myelofibrosis – reactive to malignant bone marrow disorders such as leukaemia, benign bone marrow disorders such as polycythaemia vera, hypothyroidism or drugs.

Question 15

What is the pathophysiology of primary myelofibrosis? (x4 points)

Answer 15

• Thrombocytosis and megakaryocytic dysplasia and clustering leads to cytokine release, fibroblast proliferation and collagen deposition in bone marrow
• This also causes extramedullary haematopoiesis mostly in liver and spleen
• Circulating levels of TGF-beta are increased which impairs osteoclast formation and promotes osteosclerosis (abnormal bone hardening).
• There is also increased marrow angiogenesis

Question 16

What other pathology may cause extramedullary haematopoiesis?

Answer 16

Thalassaemia.

Question 17

What is the epidemiology of myelofibrosis: Age? Gender?

Answer 17

50-70 years is peak age of onset. Males predominantly affected, though girls more affected if diagnosed when young.

Question 18

What are the signs and symptoms of myelofibrosis? (x5)

Answer 18

• Constitutional symptoms from hypercatabolic state (high energy output): weight loss, fever, night sweats, pruritus
• Splenomegaly present in almost all patients, with 50% also with hepatomegaly. Splenomegaly may present with LUQ pain.
• Signs of extramedullary haematopoiesis: haemorrhage at site of haematopoiesis e.g., GI tract, haematuria, haemoptysis, spinal cord compression etc.
• Bone pain from osteosclerosis
• Bleeding from thrombocytopenia

Question 19

What are the investigations in myelofibrosis? (x5 +3)

Answer 19

• BLOOD: anaemia later in disease progression, with leukopenia and thrombocytopenia. LFTs may be abnormal in hepatomegaly
• BLOOD FILM: leucoerythroblastic changes (teardrop red blood cells (black arrows), myelocyte (red arrow), promyelocyte (blue arrow) and nucleated RBCs)
• BONE MARROW ASPIRATE: an unsuccessful aspiration (‘dry’ tap) is characteristic
• BONE MARROW BIOPSY: shows fibrotic hypercellular marrow, with dense reticulum (type III collagen) fibres on silver staining
• Coomb’s test positive
• Autoimmune phenomena such as ANA and RF are characteristic
• Elevated CD34+ cells characteristic

Question 20

What is myelodysplasia?

Answer 20

Haematological conditions characterised by ineffective/dysplastic haematopoiesis resulting in at least one chronic cytopenia (anaemia, neutropenia, thrombocytopenia) and abnormal cellular maturation. AKA MDS (myelodysplastic syndromes).

Question 21

What is the aetiology of myelodysplasia?

Answer 21

• Primary
• Chemotherapy or radiotherapy for previous malignancies
• Chromosomal abnormalities – deletions are most common (in Chr5,7,11,12,13 and 20), monosomy 7, trisomy 8 or complex karyotypes with multiple abnormalities

Question 22

What risk factors are there for myelodysplasia? (x7)

Answer 22

Smoking and benzene exposure. Congenital neutropenia, Down’s syndrome, Fanconi’s anaemia, xeroderma pigmentosum, aplastic anaemia.

Question 23

What is the pathophysiology of myelodysplasia?

Answer 23

There is creation of a neoplastic multipotent haematopoietic stem cell which produces defective cells prone to apoptosis. As such, most die before reaching maturity, bone marrow responds by increasing its activity leading to hyperplasia, but cytopenia still occurs because of the defect introduced by the neoplastic clone.

Question 24

What are the types of myelodysplasia? (x5)

Answer 24

• MDS with single lineage dysplasia (MDS-SLD): less than 5% blasts in bone marrow
• MDS with multilineage dysplasia (MDS-MLD): less than 5% blasts in bone marrow but 2 or 3 dysplastic lineages and at least 1 cytopenia
• MDS with ringed sideroblasts and single lineage dysplasia (MDS-RS-SLD): less than 5% blasts in bone marrow and at least 15% ringed sideroblasts in blood
• MDS with ringed sideroblasts and multilineage dysplasia (MDS-RS-MLD): less than 5% blasts in bone marrow and at least 15% ringed sideroblasts in blood. 2 or 3 dysplastic lineages and at least 1 cytopenia
• MDS with excess blasts: can be multi or single lineage, between 5 and 20% blasts in bone marrow.

Question 25

What does a patient have if over 20% blasts in bone marrow?

Answer 25

Patient considered to have AML.

Question 26

What are ringed sideroblasts?

Answer 26

Erythrocyte precursor with nucleus and granules of iron in mitochondria.

Question 27

What is the epidemiology of myelodysplastic syndromes: Age? Gender?

Answer 27

65-75 years old. More common in males.

Question 28

What are the signs and symptoms of myelodysplastic syndromes?

Answer 28

• Asymptomatic
• BONE MARROW FAILURE: anaemia, neutropenia (recurrent infections), thrombocytopenia (easy bruising, epistaxis)
• Hepatosplenomegaly and lymphadenopathy except in a type of MDS called chronic myelomonocytic leukaemia (CMML) which is characterised by up to 20% blasts in bone marrow and elevated peripheral blood monocyte count

Question 29

What are the investigations for MDS? (x4)

Answer 29

• FBC: pancytopenia.
• Erythropoietin high
• BLOOD FILM: normocytic/macrocytic red cells, ovalomacrocytosis, variable microcytic red cells in MDS-RS, reduced/absent granulation (WCCs with granules include eosinophils, neutrophiles), raised monocytes (in CMML), and myeloblasts
• BONE MARROW ASPIRATE/BIOPSY: hypercellularity, ringed sideroblasts, abnormal granulocyte precursors and megakaryocytes.