Myeloproliferative disorders Flashcards
MYELOPROLIFERATIVE DISORDERS
clonal proliferation of bone marrow stem cells which can manifest as increased number of cells
Myeloproliferative disorders arise from
Hematopoietic stem cell
Characteristics of myeloproliferative disorders
Clonal - group of cells derived from a common progenitor which in this case is abnormal
Characterized by proliferation of
megakaryocytes
erythroid
granulocyte which will have the same abnormality
Classification of myeloproliferative disorders
Lineage of predominant proliferation
level of marrow fibrosis
clinical and laboratory data
How does clonal evolution occur
- The acquired abnormality is with the stem cell
2. The abnormal myeloid lineage proliferates into abnormal megakaryocytes, granulocytes, erythroid/red cell precursors
If granulocyte precursors are dominant it forms
Chronic myeloid leukemia
If red cell precursors are dominant it forms
polycythemia vera
If megakaryocytes are dominant in proliferation it forms
Essential thrombocytoss
70% of chronic myeloid leukemia transforms into
acute myeloid leukemia
10% of polycythemia vera patients can transform into
acute myeloid leukemia
30% of PV cases transform into
myelofibrosis
10% of myelofibrosis transforms into
Acute myeloid leukemia
Myeloproliferative disorders are found in
Adults usually in their 70s
Pathogenesis of myeloproliferative disorders
A genetic abnormality that inhibits the body’s ability to switch of the excess production of cells- thus a dysregulated proliferation leading to high amounts of a particular cell line in the system.
Most MPD results in
Bone marrow fibrosis
Polycythemia vera
Clonal stem cell disorder characterized by increased red cell production. Characterized by a raised packed cell volume or a raised Hb level
Classification of Polycythemia vera
NB not not all PV results from MPD
- Absolute polycythemia ; increase in RBC mass due to
* Primary causes ; PV
* secondary causes ; hypoxia, increased EPO production
* Idiopathic - Apparent polycythemia; Plasma volume changes due to i.e dehydration makes red blood cell count increase
Mutation responsible for polycythemia vera disorder
JAK2V617F mutation
Exon 12
Disease phases of polycythemia vera
3 phases.
Proliferative phase
spent phase
rarely transformed into acute leukemia
In proliferative phase of PV
Red cell and Hb count very high
Spent phase of PV
Here bone marrow fibrosis occurs and less space is available for RBC production. There is a start in decline of numbers, though they are still high
Clinical features
Age - 55-60 yrs may occur in young adults and rarely children Thrombosis DVT Hypertension headache poor vision skin complications i.e pruritis haemorrhhage due to platelet defect
Presentation of PV
Hepatosplenomegaly
Erythromelalgia ( red skin, burning sensation)
Lab findings in PV
high Hb and RBC
Associated increase in platelets, neutrophils
Normal neuclotide alkaline phosphatase
high plasma urate- high cell turnover
hypercellular bone marrow
Low serum erythropoietin
Treatment of PV
Venesection
Chemotherapy with hydroxyurea/gamma interferon
Treatment of complications
Secondary polycythemia causes
Compensatory increase in EPO
- high altitude
- pulmonary diseases
- heart diseases
- Abnormal Hb
- Heavy cigarette smoker
Abnormal increases in EPO
* Renal disease
Tumors
Relative polycythemia causes
stress burns smoking dehydration alcohol
What is myelofibrosis
Occur due to progressive fibrosis of the marrow with increased connective tissue
What genetic malformations cause myelofibrosis
JAK 2 55%
CALR 25%
MPL 10%
JCM
Characteristics of myelofibrosis
myeloid metaplasia leading to extramedullary erythropoiesis in spleen /liver(outside bone marrow)
abnormal megakaryocytes when trephine biopsy is done
Chronic idiopathic myelofibrosis characteristics
insidious onset splenomegaly bleeding issues bone pain gout
Presentation of myelofibrosis
Anemia high WBC initially, leukopenia later tear drop red cells no bone marrow aspiration; dry tap due to fibrosis increased NAP
Causes of leucoerythroblastic blood film(combination of normoblasts and nucleated rbcs)
Severe sepsis sick neonate severe hemolysis idiopathic myelofibrosis bone marrow infiltration
Treatment of myelofibrosis
Treatment aimed at reducing effects of anemia and splenomegaly
Blood transfusion
Folic acid
Ruxolitinib a JAK2 inhibitor
Hydroxycarbamide
Essential thrombocythemia is
Clonal myeloproliferative disease of megakaryocytic lineage
Essential thrombocytosis is characterized by
Sustained thrombocytosis for more than 6 months
Increased megakaryocytes
Thrombotic and hemorrhagic episodes can induce high platelet count
Mutation in essential thrombocytosis
JAK2
CALR
MPL
Diagnosis criteria for essential thrombocytosis
- sustained platelet count above 450*10 raised to power 9
- Prescence of JAK2 or CALR
- No other myeloid malignancy
- No reactive cause of thrombocytosis
- Bone marrow trephine biopsy showing increased megakaryocytes
- Normal iron stores
Causes of reactive thrombocytosis
Bleeding trauma post operation chronic iron deficiency malignancy chronic infection connective tissue disorders post splenectomy
Clinical features of essential thrombocythemia
Haemorrhage
microvascular occlusion
splenic /hepatic vein thrombosis
hepatosplenomegaly
TReatment for essential thrombocythemia
Anticoagulant Chemotherapy Hydroxycarbamide JAK 2 inhibitor Aspirin
Transformations that can occur from essential thrombocythemia
Acute myeloid leukemia
25% develop myelofibrosis
Death due to cardiovascular complication
myeloid leukemia is
neoplasm of white blood cells and its precursor leading to clonal proliferation and accumulation of cells in the marrow.
Acute/chronic
What is chronic myeloid leukemia
Characterized by increased proliferation of granulocytic cell line without the loss of their capacity to differentiate
You’ll see granulocyte at all stages of development
There is increased myeloid, erythroid,platelet cells in peripheral blood
Median age of CML
53yrs
Age group affected
All age groups
Cause of CML.
Fusion of BCR gene on chromosome 22 fusing with ABL gene on chromosome 9
This forms a BCR-ABL protein that transforms hematopoietic cells so their growth is independent of cytokines–> No apoptosis
This gene is present in 90-95% of CML patients
Philadelphia gene., an acquired cytogenic anomaly
Clinical features of CML
- About 40% asymptomatic
- Splenomegaly
- hypermetabolism
- Anemia
- Abnormal platelet function
- hyperleukocytosis- priapism, visual and hearing -impairment, gout
Phases of CML
Chronic phase
Acelerated phage
Transformation to acute leukemia
Perpheral blood findings in CML
Raised WBC count primitive blast cells granulocytes at all stages of development raised platelet count low Hb concs high basophils and eosinophils
Lab features
hypercellular bone marrow Myeloid- erythroid ratio is 10;1 as compared to 30;1 Predominant cells are myelocytes Myeloblast are less than 10 percent increased dysplastic megakaryocytes Reticulin fibrosis
Investigations for CML
full blood count neutrophil alkaline phosphatase urea, electrolytes serum lactate dehydrogenase bone marrow aspirate/trephine biopsy Vitamin B12 and B12 binding capacity test
Chronic phase of CML
Blast cell percentage is less than 10%
Basophil percentage less than 20%
Accelerated phase of CML
Blast cells are between 10-19% in blood
Basophil count more than 20%
Disease becoming more aggressive
Blastic or acute myeloid leukemia phase
Blasts are more than 20%
2/3 transform to myeloid blastic phase and 1/3 to lymphoid blastic phase
Treatment of CML
- Relieve symptoms of hyperleukocytosis, splenomegaly, thrombocytosis
- Control and prolong chronic phase using alpha interferon, hydroxyurea, chemotherapy, imatinib mesylate
-Eradicate malignant clone - curative
via transplantation or imatinin/glivec ; a tyrosine kinase inhibitor
Imatinib/Glivec MOA
It acts to inhibit the enhanced tyrosine kinase activity of BCR-ABL oncoprotein thus reversing the pathology
Drugs for chemotherapy
- Busulphan
- Hydroxyurea- inhibits ribonucleotide reductase; disease progression isn’t altered because of persistence of Philadelphia chromosome
If philadelphia chromosome is seen to be present ideal drug to be used to prevent progression from chronic phase is
Imatinib. tyrosine kinase inhibitor
