Myeloproliferative Disorders (MPD) Flashcards by Aliya Hussain

Define myeloproliferative?

Proliferation down the myeloid bone marrow lineage, i.e: granulocytes, red cells and platelets

How well did you know this?

Not at all

Perfectly

What are MPDs?

Clonal haemopoietic stem cell disorders, with an increased production of one or more types of haemopoietic cells

NOTE - in contrast to acute leukaemia, maturation is relatively preserved

How well did you know this?

Not at all

Perfectly

Compare microscopy of normal bone marrow, acute leukaemia and MPD?

Normal - mixture of mature and immature cells, with some marrow spaces

Acute leukaemia - monomorphic, hypercellular appearance, with many of the same type of cell (monoclonal); there are many immature cells (blasts)

MPD - many mature myeloid cells are present (hypercellular)

How well did you know this?

Not at all

Perfectly

Major classification system of MPDs?

BCR-ABL1 -ve

BCR-ABL1 +ve

How well did you know this?

Not at all

Perfectly

Types of BCR-ABL1 -ve sub-types of myeloproliferative disorders?

Idiopathic myelofibrosis

Polycythaemia Rubra Vera - over-production of rbcs

Essential thrombocytopaenia - over-production of platelets

How well did you know this?

Not at all

Perfectly

Types of BCR-ABL1 +ve sub-types of myeloproliferative disorders?

Chronic Myeloid Leukaemia (CML) - over-production of granulocytes; characterised by the Philadelphia chromosome

How well did you know this?

Not at all

Perfectly

Signs potentially indicating MPD?

High Granulocyte count
\+/-
High Red cell count / haemoglobin
\+/-
High Platelet count
\+/-
Eosinophilia/basophilia (usually has a non-reactive cause)

Splenomegaly

Thrombosis in an unusual place

NOTE - without a reactive explanation

How well did you know this?

Not at all

Perfectly

Which MPD usually causes splenomegaly?

Myelofibrosis

How well did you know this?

Not at all

Perfectly

Areas in which thrombosis can occur with MPD?

Typical areas, e.g: DVT, MI

Atypical areas, e.g: portal vein thrombosis

How well did you know this?

Not at all

Perfectly

What does CML involve?

Proliferation of myeloid cells, mainly granulocytes and their precursors, although it also affects other lineages, like PLTs

How well did you know this?

Not at all

Perfectly

Manifestation of CML historically?

Chronic phase, with intact maturation, for 3-5 years, followed by a ‘blast crisis’ (similar to acute leukaemia with a maturation defect)

It was fatal without a stem cell/bone marrow transplantation in the chronic phase

NOTE - the chronic phase had excess, mature neutrophils and their precursors; the blast crisis inv. over-production of primitive blood cells

How well did you know this?

Not at all

Perfectly

Clinical features of CML?

Asymptomatic (often an incidental finding)

Splenomegaly

Hypermetabolic symptoms

Gout (due to high cell turnover)

Miscellaneous:
• Issues due to hyperleucocytosis
• Priapism, visual disturbances and other microvascular problems

How well did you know this?

Not at all

Perfectly

Diagnosis of CML?

Blood count:
• Normal or reduced Hb
• Leucocytosis with neutrophilia and myeloid precursors (myelocytes), eosinophilia, basophilia
• Thrombocytosis

Bone marrow

How well did you know this?

Not at all

Perfectly

Features of MPD blood count compared to reactive changes?

BASOPHILIA AND EOSINOPHILIA are less common with reactive changes

How well did you know this?

Not at all

Perfectly

What is the hallmark of CML?

Philadelphia chromosome (translocation from chromosome 22 to 9); this fuses 2 genes, BCR and ABL, forming a new chimeric gene

How well did you know this?

Not at all

Perfectly

Gene product of the philadelphia chromosome in CML?

Tyrosine kinase, which causes abnormal phosphorylation (signalling)

This leads to the haematological changes present in CML

How well did you know this?

Not at all

Perfectly

Treatment of CML?

Tyrosine kinase inhibitors, e.g: Imatinib

Types of BCR-ABL1 -ve myeloproliferative disorders?

Polycythaemic rubra vera (PRV)

Essential thrombocythemia (ET)

Idiopathic myelofibrosis (IMF)

Others

Clinical features common to MPD?

Often asymptomatic

Increased cellular turnover:
• Gout
• Fatigue
• Weight loss
• Night sweats

Symptoms/signs due to splenomegaly:
• Early satiety
• Abdominal mass
• Pain

Marrow failure, due to fibrosis or leukaemic transformation (lower with PRV and ET)

Thrombosis (arterial or venous):
• TIA
• MI
• Abdominal vessel thrombosis
• Claudication
• Erythromelalgia (sensation of heat in hands and feat)

What is PRV?

High Hb/Hct accompanied by erythrocytosis (a true increase in red cell mass

Can have excessive production of other lineages

What must PRV be distinguished from?

Secondary polcythaemia, e.g:
• Chronic hypoxia (COPD, sleep apnoea)
• Smoking
• Epo-secreting tumour

Pseudopolycythaemia (reduced plasma volume):
• Dehydration
• Diuretic use
• Obesity

Clinical features of PRV?

All those common to MPD

Headache, fatigue, plethoric appearance (due to increased blood viscosity)

Itch:
• Aquagenic pruritus is itch on exposure to warm water (very characteristic)

Ix for polycythaemia)

Hx (rule out features suggestive of a secondary polycythaemia)

Examination (splenomegaly, etc)

Ix for secondary / pseudo causes, e.g: CXR, O2 sats, ABGs

FBC, blood film

JAK2 mutation status; if this is -ve, it is unlikely to be PRV (present in 95%)

Infrequent tests:
• Epo levels
• Bone marrow biopsy

Why does a JAK2 mutation cause PRV?

JAK2 is a kinase; mutation in the gene results in a loss of auto-inhibition

There is activation of erythropoiesis in the absence of the ligand

Treatment of PRV?

Venesect until Hct is <0.45 Aspirin Cytotoxic oral chemotherapy (hydroxycarbamide)

What is essential thrombocythemia (ET)?

Uncontrolled production of abnormal platelets As platelet function is abnormal: • Thrombosis • Acquired von Willebrand disease (can occur at high levels) causes bleedinglevels

Clinical features of essential thrombocythemia?

All clinical features common to MPD, part. vaso-occlusive complications, e.g: toes Bleeding; risk is unpredictable, esp. at surgery

What does a thrombocytosis with abnormally large platelets indicate?

That the thrombocytosis is not reactive

Diagnosis of ET?

Exclude reactive thrombocytosis, e.g: blood loss, inflammation, malignancy, iron deficiency Exclude CML Genetics: • JAK2 mutations (50%) • CALR (calreticulin) may be mutated in those without mutant JAK2 • MPL mutations If all are -ve, bone marrow biopsy (increased platelet precursors, with the megakaryocytes clustering together)

Treatment of ET?

Anti-platelet agents (do not reduce production): • Aspirin Cytoreductive therapy to control proliferation: • Hydroxycarbamide • Anagrelide • Interferon alpha

Sub-types of myelofibrosis (MF)?

Idiopathic (AKA agnogenic myeloid metaplasia) Post-polycythaemia or essential thrombocythemia

Features of idiopathic myelofibrosis?

Marrow failure (variable degrees) Bone marrow fibrosis, with no secondary fibrosis Extremedullary haematopoiesis of the liver and spleen (myelofibrosis is a classic cause of massive splenomegaly) Blood film: • LEUKOERYTHROBLASTIC • Teardrop-shaped rbcs in peripheral blood

PC of MF?

Marrow failure: • Anaemia • Bleeding • Infections Splenomegaly: • LUQ abdominal pain • Early satiety • Complications, inc. portal hypertension Hypercatabolism Also, the clinical features common to MPD

Lab diagnosis of MF?

Typical blood film: • LEUKOERYTHROBLASTIC •TEARDROP shaped rbcs (poikilocytes) Dry aspirate (as bone marrow contains fibrosis) Fibrosis on trephine biopsy In a proportion of patients, JAK2 or CALR are mutated

Causes of a leukoerythroblastic blood film?

Reactive, e.g: sepsis (bone marrow stress) Marrow infiltration Myelofibrosis

Treatment of MF?

Supportive care: • Blood transfusion • Platelet transfusion • Antibiotics Allogeneic stem cells transplantation in a select few (older patients often affected so rarely viable) Splenectomy (controversial) JAK2 INHIBITORS (used even if the patient is not JAK2 +ve)

Effects of JAK2 inhibitors in MF?

Improve spleen size, QoL and potentially survival

Most common cause of high blood counts?

Reactive causes are more common than MPD

Reactive causes of high counts?

Granulocytes: • Infection • Physiological, e.g: post-surgery, steroids ``` Platelets: • Infection • Iron deficiency • Malignancy • Blood loss ``` Red cells: • Dehydration, e.g: with diuretics, causes a pseudopolycythaemic • Secondary polycythaemia, e.g: hypoxia-induced (COPD, sleep apnoea)

Compare the complications of high counts due to MPD to high counts due to reactive causes?

Reactive causes of high counts are unlikely to be associated with the complications of MPD, like thrombosis