Myeloproliferative Disorders Flashcards
What are MPN?
clonal haemopoietic stem cell disorders with an INCR. prodn of ONE or MORE types of haemopoietic cells
How is MPN diff. from acute leukaemia?
- maturation is relatively preserved in MPN
What is BCR-ABL 1?
- a when ABL gene from Chr. 9 fuses with the BCR gene on chromosome 22
- it form a fusion gene on chromosome 22; known as the Philadelphia Chromosome
Who carries the Philadelphia chromsome?
- those who have CHRONIC MYELOID LEUKAEMIA
- —also seen in Acute Lymphoblastic Leukaemia and Acute myeloid leukaemia
- “BCR-ABL1 + “
Are MPN BCR-ABL 1 +?
NO
- they are philadelphia chr. -
Name BCR- ABL 1 -ve disorders.
- primary myelofibrosis
- Polycythemia vera
- essential thrombocytopenia
- primary myelofibrosis
When do you suspect MPN?
- high granulocyte count
- High RED CELL count/ Hb
- High PLATELET counts
- Eosinophilia and Basophilia
- SPLENOMEGALY
- Thrombosis in an unusual place
What is CML?
- chronic myeloid leukaemia
- —proliferation of MYELOID cells ! (granulocytes and their precursors) & other lineages (platelets)
How does CML progress over the years?
- initial CHRONIC phase with INTACT maturation for 3-5 years (slow progression)
- half of CML cases enter accelerated phase
- final transformation into condition similar to ACUTE leukaemia
- –followed by blasts crisis (maturation defect)
CML is fatal without _________
stem cell/ bone marrow transplant !
What are the clinical fts of CML?
- asymptomatic ; nonspecific ( FATIGUE/ weak/ WGT LOSS)
- 1st sx: DRAGGING sensation (splenomegaly)
- hypermetabolic symptoms
- miscel.: problems related to hyperleucocytosis, priapism
What occurs in the accelerated phase of CML?
- marked ANAEMIA
- new thrombocytopenia
What are some blood count changes seen with CML?
- NORMAL/ decr. Hb
- leucocytosis with Neutrophilia and myeloid precursors, eosinophila, basophilia
- thrombocytosis
So how does the Philadelphia chromosome bring about the hematological changes in CML?
- the gene product that results from the genetic changes is TYROSINE KINASE
—-> causes abnormal phosphorylation (signalling) leading to CML
What can be given to treat CML?
IMATINIB
—–d.t response with this tyrosine kinase INHIBITOR
What are fts common to MPN?
- incr. cellular turnover (wgt loss/ gout/ fatigue/sweats )
- signs/sx d.t splenomegaly
- marrow failure (FIBROSIS/ leukaemic transformation: lower with PRV and ET)
- thrombosis (arterial/ venous- TIA/ MI/ abdominal thrombosis/ claudication/ erthromyelgia)
What is Polycythaemia vera?
- high Hb/ Hematocrit accompanied by erythrocytosis (true incr. in red cell mass)
- excessive proliferation of erythroid, granulocytic and megakaryocytic elements
Polycythaemia Vera should be distinguished from?
- IIary Polycythaemia (chronic hypoxia/ smoking/ erythropoietin-secreting TUMOR)
- Pseudopolycythaemia (dehydration/ obesity/ diuretic therapy)
How to tell pseudopolycythaemia from True polycythaemia?
- TRUE: actually has an INCR. RED CELL MASS
Clinical Fts of PV?
- headache/ fatigue (BLOOD viscocity raised- not plasma)
2. ITCH
What ivx could be done for polycythaemia?
- hx ( r.o IIary and pseudo-)
- examination
- FBC/ FILM
- JAK2 mutation status!
What particular genetic mutation is seen in 95% of PV?
- JAK2 mutation
—a kinase; the mutation results in LOSS of AUTO-INHIBITION
> activation of erythropoiesis in the ABSENCE of A ligand
What should be done during the INITIAL screening of PCV?
- mutational ANALYSIS!
- –it has replaced a no, of other tests in routine practise!
What are the ivx for PCV?
- ivx to R.O secondary/pseudo cause: CXR, O2 sat., arterial blood gases, drug hx)
- JAK2 analysis
- infreq. tests: erythrpoietin levels, bone marrow biopsy
Name some erythropoietin secreting tumors.
- Renal cell carcinoma
- Hepatocellular CA
- Adrenal Adenoma
- Uterine tumors
How to treat PV?
- venesection until haematocrit <0.45
- aspirin
- cytotoxic oral chemo (hydroxycarbamide)
What is essential Thrombocytopenia?
- uncontrolled prodn of ABNORMAL platelets!
- platelet fxn that is abnormal (==> thrombosis/ at HIGH levels may cause BLEEDING due to acquired vWF disease)
What are the clinical fts of ET?
- common to MPN (esp. vasoocclusive complications)
- bleeding (unpredictable risk esp. at surgery )
How to come to the dx of ET?
- EXCLUDE reactive thrombocytosis (blood loss/ inflammation/ malignancy/ iron def.)
- exclude CML
- characteristic marrow fts
- genetics test
What genetic changes are seen in ET?
- JAK2 in 50-60%
- MPL (5%)
- -CALR (in approx. 25%)
- 10-20% of pts will be TRIPLE NEGATIVE
How to treat ET ?
- anti-platelet agents: ASPIRIN
- cytoreductive therapy to control proliferation (hydroxycarbamide/ anagrelide/ interferon alpha)
When may myelofibrosis occur?
after Essential Thrombocythaemia
What are the clinical fts of myelofibrosis?
- marrow failure (anaemia/ bleeding/ infection)
- splenomegaly
- LUQ pain
- portal hypertension - hypercatabolism
What occurs pathologically in the course of idopathic myelofibrosis?
- MARROW FAILURE (variable degrees)
> bone marrow fibrosis
> haematopoiesis shifts to the LIVER, spleen and lymph nodes
How does idiopathic myelofibrosis, appear on film?
- LEUKOERYTHROBLASTIC film appearances
- TEARDROP-shaped RBCs in peripheral blood
- fibrosis on trephine biopsy
What mutations are seen in MF?
- JAK2 > CALR> MPL
- —10% is triple negative
When may leukoerythroblastic film appear?
- reactive (sepsis)
- marrow infiltration
- myelofibrosis
What is meant by leukoerythroblastic film?
- the presence of IMMATURE cells (normoblasts/ myelocytes) seen in the peripheral blood film
- norochromic, normocytic anaemia =- numerous poikilocytes
- low gr. reticulocytosis
- immature WHITE cells (myelocytes and promyelocytes)
- thrombocytopenia > thrombocythaemia
Thrombocythaemia vs thrombocytosis?
- thrombocythaemia = when the elevated platelet count is d.t an UNKNOWN cause !
How to treat myelofibrosis?
- supportive care = blood transfusion/ platelets/ antibiotics
- allogenic stem cell transplantation
- splenectomy
- JAK2 inhibitors (improves spleen size/ constitutiona symptoms)
Name reactive causes of granulocytosis.
What is this form of reactiton called and what should this be distinguished from?
- infections: pyogenic bacteria (neutrophilia!)
- physiological (post-surgery; surgery; steroids )
- leukamoid reaction; diff. from CML
What are reactive causes of platelets?
- infection
- iron def.
- malignancy
- blood loss
Reactive causes of high RED cell ounts?
- dehydration (diuretics)–> PSEUFOPOLYCYTHAEMIA
- secondary polycythaemia (hypoxia induced)
How to distinguish leukamoid rxn from CML?
-testing for presence BCR-ABL fusion gene —done by PCR assay/ karyotyping
How to confirm is it’s a leukamoid reaction?
- ELEVATED LAP score
leukocyte alkaline phosphatase
