B3.040 Blood Cell Disorders Flashcards
how do you get an absolute count of a specific WBC?
differential count (%) * total WBC count
what are myeloproliferative neoplasms?
neoplasms of hematopoietic stem cells with proliferation of one or more of the myeloid lineages with accumulation of maturing or mature cells
-proliferation with maturation
5 principle myeloproliferative disorders
chronic myeloid leukemia (CML) polycythemia vera (PV) primary myelofibrosis (PMF) essential thrombocytosis (ET) mastocytosis
what is the underlying cause of myeloproliferative neoplasms?
mutated, constitutively activated tyrosine kinase
what is a diagnostic hallmark of CML?
BCR/ABL-1 fusion
t(9;22) promoter drives production of TK from the ABL region, making it constitutively expressed
Philadelphia chromosome produces novel protein product & lots of it
what is the product of BCR/ABL-1 fusion in CML?
P210 fusion protein
what is the significance of the P210 fusion protein?
has tyrosine kinase activity
since the mutation is intracellular, it evades the immune system
how is P210 fusion protein inhibited?
small molecule inhibitors
enters cell, and competitively binds ATP binding site of the kinase
doesn’t kill cell, just blocks its function
what is the result of a JAK2 mutation?
point mutation in pseudokinase domain
pseudokinase domain is supposed to inhibit JAK2, but can’t when mutated
loss of autoinhibition
increased phosphorylation of downstream targets
what effect does increased phosphorylation of downstream targets like STAT5 have on the cell?
promotes cytokine independent growth
hypersensitivity to growth factors (EPO and IL3)
what myeloproliferative disorders are/are not associated with JAK2 mutations?
almost all PV cases
50% of PMF and ET cases
NOT PRESENT in CML or lymphoproliferative disorders
what other genetic abnormalities are associated with specific myeloproliferative disorders?
calreticulin - 25-35% of PMF and ET
MPL (TPO receptor) - in 1-10% of PMF and ET
KIT - in mastocytosis
general features of CML
neoplasm of pluripotential hematopoietic stem cell (can be myeloid or lymphoid)
marked granulocytosis including all stages of maturation
BCR-ABL rearrangement
general features of PV
neoplasm of multipotential hematopoietic stem cell, predominant effects on erythroid lineage
markedly increased total body erythrocyte mass
general features of PMF
neoplasm of multipotential hematopoietic stem cell with reactive fibrosis
probiotic growth factors (PDGF, TBF-B) from megakaryocytes
general features of ET
neoplasm of multipotential hematopoietic stem cell with uncontrolled proliferation of megakaryocytes without fibrosis growth factors
markedly increased platelets and abnormal platelet function
general features of mastocytosis
neoplasm of mast cells
increased and morphologically abnormal mast cells in various tissues
clinical features of all myeloproliferative disorders
slow growing/ slowly progressing
diagnosed after several months to years
incidental discovery common
clinical features of CML
initially asymptomatic
non spec symptoms- fatigue, malaise, fever, weight loss
splenomegaly - often massive leading to early satiety, LUQ discomfort
thrombosis or bleeding (due to widespread consequences on cell lines)
clinical features of PV
increased RBC mass - plethora, headache, dizziness, visual disturbances, angina, intermittent claudication
splenomegaly
thrombosis or bleeding
sludging and resulting local hypoxia/ischemic events
clinical features of PMF
non spec- fatigue, malaise, weight loss
splenomegaly - often massive leading to early satiety, LUQ discomfort
infections
hemorrhage
clinical features of ET
often asymptomatic
thrombosis of large vessels- lower extremities, heart, intestines, kidney
bleeding due to platelet functional abnormalities
erythromelalgia (intense burning and redness of extremities)
clinical features of mastocytosis
urticaria pigmentosa - localized cutaneous disease (50%), usually in kids
systemic mastocytosis - multi organ involvement (10%), in adults
blood diagnostic findings of CML
leukocytosis >20,000, often >100,000
all stages of maturation: myelocytes and neutrophils predominant
basophilia, eosinophilia, mild anemia, thrombocytosis
blood diagnostic findings of PV
elevated RBS, hemoglobin, hematocrit
normochromic, normocytic RBCs (can be hypo/micro when iron def manifests bc iron is used up from production of unnecessary RBCs)
mild to moderate leukocytosis, thrombocytosis, eosinophilia and basophilia
low or normal serum EPO (suppressed)
blood diagnostic findings of PMF
leukoerythroblastosis
prominent anisopoikilocytosis w tear drop shaped RBCs
blood diagnostic findings for ET
marked thrombocytosis (>450,000) with abnormal morphology; circulating megakaryocytic fragments
mild anemia
mild to moderate leukocytosis
bone marrow diagnostic findings for CML
markedly hypercellular with granulocyte predominance
blasts <10%
mild fibrosis
bone marrow diagnostic findings for PV
markedly hypercellular with erythrocyte predominance
increased and clustered megakaryocytes
decreased or absent iron
mild to moderate fibrosis
bone marrow diagnostic findings for PMF
hypercellular - mostly granulocytic and megakaryocytic
increased, clustered, atypical megakaryocytes
reticulin and collagenous fibrosis and osteosclerosis
bone marrow diagnostic findings for ET
variably hypercellular with megakaryocytic predominance
sheets and clusters of atypical megakaryocytes
mild or no fibrosis
bone marrow diagnostic findings for mastocytosis
aggregates of mast cells - positive for metachromatic stains (toluidine blue), CD 117, tryptase
histo features of CML
different stages of neutrophils
heavily weighted towards granulocytes in blood and marrow
lots of cellularity in marrow
histo features of PV
round nuclei aka nucleated RBCs in marrow
histo features of PMF
tear drop cells
precursors of erythroid and myeloid cells in blood (marrow letting it out early due to fibrosis distortions)
in marrow you can stain for collagen to see fibrosis
histo features of ET
lots of platelets in blood
lots of megakaryocytes in marrow
histo features of mastocytosis
lots of cells in the dermis
ovoid nuclei and granular cytoplasm
stains for CD117
what are some diagnostic findings from the spleen?
significant splenomegaly -expanded red pulp with extramedullary hematopoiesis -fibrosis -infarcts (due to thrombi formation)
course and prognosis of chronic phase CML
chronic phase - 2-8 years; prolonged with TKI therapy
course and prognosis of accelerated phase CML
accelerated phase - blasts 10-19%, increased basophils, persistent thrombocytopenia or thrombocytosis, increased splenomegaly and WBC, karyotypic evolution
course and prognosis of blast crisis CML
blast crisis- survival <1 y
-blasts >20% (acute leukemia)
course and prognosis of PV
proliferative phase- erythroid proliferation
-median survival 10 y, manage w phlebotomy
spent phase - stable or decreased erythroid mass
post-polycythemic myelofibrosis- 15-20%
AML - 2%
course and prognosis of PMF
median survival - 3-5 years
AML - 5-20%
course and prognosis of ET
median survival - 10 years
AML - rare
what is the primary difference between myeloproliferative neoplasms and non-neoplastic proliferations of cells?
non-neoplastic lack genetic abnormalities (non-clonal)
far more common
can differentiate with BCR/ABL or JAK2 testing
what are some non-neoplastic causes of neutrophilia
infections (primarily) bacterial, immunological inflammatory disorders, neoplasia (paraneoplastic syndrome), drugs
what are some associated features of neutrophilia?
toxic granulation
Dohle bodies
what are some non-neoplastic causes of erythrocytosis?
relative due to hemoconcentration
increased EPO due to hypoxia (altitude, COPD, heart disease)
increased EPO from tumors (paraneoplastic syndrome with other tumors)
what are some non-neoplastic causes of thrombocytosis?
acute phase reaction
iron def
drugs
what is a Dohle body
blue areas of basophilia inside neutrophils
