Myeloproliferative Disorders Flashcards
What is myeloproliferative neoplasms
Clonal HSCs disorder with increased production of RBCs &/ granulocytes &/ platelets (doesn’t affect lymphocytes)
What are the sub-types of chronic myeloproliferative neoplasms
BCR-ABL1 positive
- Chronic myeloid leukaemia
BCR-AB1 negative
- Primary myelofibrosis (abnormal proliferation fibroblasts)
- Essential thrombocythaemia (over production platelets)
- Polycythaemia Vera (over production RBCs)
What are 4 reactive causes of elevated RBCs (secondary polycythaemia)
- Chronic hypoxia (COPD, heart disease, OSA, smoking etc)
- Kidney disease
- Erythropoietin secreting tumour
- Medications (anabolic steroids, diuretics)
NOTE: diuretics/ dehydration cause pseudopolycthaemia (not a true elevation in RBCs)
What are 3 reactive causes of elevated neutrophils
Bacterial infections
Acute inflammation & tissue damage
Corticosteroids
What are 2 reactive causes of elevated eosinophils
Allergy
Parasitic infection
What are 4 reactive causes of elevated platelets
Infection
Iron deficiency
Malignancy
Blood loss
What would make you consider a myeloproliferative neoplasm
- High neutrophil +/- RBC +/- platelet +/- eosinophil/basophil
- With NO reactive explanation
- Splenomegaly or thrombosis in unusual place increases suspicion
List features common to myeloproliferative neoplasm
- Asymtpomatic
- Increased cell turnover - gout, fatigue, weight loss, sweats
- Splenomegaly S&S - referred pain, early satiety
- Marrow failure (less likely in Polycythaemia Vera and ET)
- Thrombosis (TIA, MI, claudication etc)
What is chronic myeloid leukaemia
A clonal stem cell disorder that affects the primitive compartment (HSCs & myeloid progenitors) & causes granulocytosis/ neutrophilia (+/- thrombocytosis)
What translocation & chromosome is characteristic of CML (~90%)
Translocation of ABL gene on chromosome 9 to attach with the BCR gene on chromosome 22
This causes a BCR-ABL1 gene aka Philadelphia chromosome
CML Pathophysiology
- BCR-ABL1 gene/translocation (Philadelphia chromosome)
- Increased transformation from HSCs to myeloid progenitors
- Subsequent excessive myeloid progenitor proliferation
- Then myeloid progenitor maturation (‘chronic’)
- Resultant excessive production of granulocytes & precursors (& occasionally thrombocytosis)
What are the three phases of CML
- Chronic (3-5yrs) - granylocytosis & myelocytosis +/- thrombocytosis, no maturation defect
- Accelerated phase - genetics ‘hits’, increase in blasts, loss of maturation
- Blast crisis - reminiscent of acute leukaemia with maturation defect
CML clinical features
- Common features of myeloproliferative neoplasms
- Hyperleucocytosis S&S
- Marrow failure similar to AML/ALL in blast crisis
CML blood findings (chronic phase)
- Normal or low Hb
- Leukocytosis with neutrophilia
- Myeloid precursors (myelocytes)
- +/- Eosinophilia, basophilia, thrombocytosis
CML investigations
Blood count & film
Cytogenetics using FISH to detect t(9;22) (of blood/ marrow)
Bone marrow biopsy not always necessary
What is the gene product of the BCR-ABL1 gene
A tyrosine kinase - causes abnormal phosphorylation
CML treatment
Tyrosine kinase inhibitors e.g. Imatinib
What is characteristic of polycthaemia Vera
High Hb accompanied by a TRUE INCREASE IN RBC MASS
Note: can also have excessive production of other lineages
Polycthaemia Vera vs secondary polycthaemia vs pseudopolycythaemia
Polycythaemia Vera - genetic mutation or defect in the bone marrow that produces a true increase in RBC mass
Secondary Polycythaemia - underlying condition that causes increased RBC production & hence increased RBC mass
Pseudopolycthaemia - High Hb without a true increase in RBC mass
Is there an increased plasma viscosity in polycthaemia Vera
No - only a raised blood viscosity
Polycthaemia Vera clinical features
Clinical features common to MPN
Clinical features of raised blood viscosity - headache, fatigue
Itch (aquagenic puritis)
What gene is usually mutated in Polycythaemia Vera
JAK2 gene mutation (~95%)
What is the impact of JAK2 mutation
Mutation (substitution) results in abnormal signalling =>
Activation of erythropoiesis in the absence of ligand
Polycthaemia vera investigations
History to check for secondary/pseudo polycthaemia
Examination to check for e.g. splenomegaly
FBC & blood film
JAK2 mutation
Polycthaemia Vera treatment
Venesection (immediate symptom control)
Aspirin (thrombosis prevention)
Cytotoxic oral chemotherapy e.g. hydroxycarbamide (definitive)
What is essential thrombocythaemia
Uncontrolled production of abnormal platelets
Why can essential thrombocythaemia cause both a thrombosis as well as bleeding
Increased platelets => thrombosis
Increased use of vWF => acquired vWF disease => bleeding
Essential thrombocythaemia clinical features
Common features of MPN
Thrombosis & bleeding
Essential thrombocythaemia investigations
- Exclude relative thrombocytosis!!! (B I M I)
- Exclude CML by BCR-ABL1 testing
- Blood genetics e.g. JAK2 mutations (diagnostic!)
- Bone marrow biopsy
(elevated megakaryocytes is characteristic of ET)
Essential thrombocythaemia treatment
Usual treatment - anti-platelets
(If very high risk of thrombosis) - hydroxycarbamide
Other - anagrelide, interferon alpha
What is myelofibrosis
Abnormal proliferation of marrow fibroblasts causing bone marrow fibrosis and lack of production of normal cells
Can be primary - idiopathic
Can be secondary - post-polycythaemia/ET
Characteristic blood film of myelofibrosis
Leukoerythroblastic blood film
+/- teardrop shaped RBCs
Myelofirbosis clinical features
Marrow failure - anaemia, bleeding, infection
Bone marrow fibrosis with no cause
Extramedullary haematopoiesis (hepato/splenomegaly)
Hypercatabolism - Night sweats & weight loss
What are three causes of leucoerythroblastic haematopoiesis
Reactive e.g. sepsis
Marrow infiltration e.g. malignancy
Myelofibrosis
Myelofibrosis investigations
Blood count & film - leukoerythroblastic & tear shaped RBCs
Bone marrow - dry aspirate, firbosis on trephine biopsy
Genetic testing - JAK2, CALR, MLP
Myelofibrosis treatment supportive care
Blood transfusion, platelets, antibiotics
Myelofibrosis gold standard treatment
JAK2 inhibitors
(Or allergenic stem cell transplantation in select few)
Essential thrombocythaemia diagnostic test
Blood genetics e.g. JAK2 mutation
Essential thrombocythaemia characteristic bone marrow features
Increased megakaryocytes
Hyperleukocytosis S&S
Abnormal aggregation & clumping of WBCs in blood vessels
=> impaired blood flow & oxygen delivery to tissues
=> e.g. headaches, confusion, SOB etc
What are symptoms of splenomegaly
Early satiety
Pain in LUQ & referred pain
Pancytopenia
Compression of nearby structures e.g. portal hypertension
Why does myelofirbosis cause hypercatabolism
Increased production of inflammatory cytokines by abnormal marrow cells => chronic inflammation
What are the three mutations in PV, ET & myelofirbosis (MPN)
JAK2 (main), CALR, MLP
