B3.040 Blood Cell Disorders Flashcards by Lauren Sinik

how do you get an absolute count of a specific WBC?

differential count (%) * total WBC count

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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

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5 principle myeloproliferative disorders

chronic myeloid leukemia (CML)
polycythemia vera (PV)
primary myelofibrosis (PMF)
essential thrombocytosis (ET)
mastocytosis

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what is the underlying cause of myeloproliferative neoplasms?

mutated, constitutively activated tyrosine kinase

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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

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what is the product of BCR/ABL-1 fusion in CML?

P210 fusion protein

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what is the significance of the P210 fusion protein?

has tyrosine kinase activity

since the mutation is intracellular, it evades the immune system

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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

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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

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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)

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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

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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

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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

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general features of PV

neoplasm of multipotential hematopoietic stem cell, predominant effects on erythroid lineage
markedly increased total body erythrocyte mass

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general features of PMF

neoplasm of multipotential hematopoietic stem cell with reactive fibrosis
probiotic growth factors (PDGF, TBF-B) from megakaryocytes

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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

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general features of mastocytosis

neoplasm of mast cells

increased and morphologically abnormal mast cells in various tissues

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clinical features of all myeloproliferative disorders

slow growing/ slowly progressing
diagnosed after several months to years
incidental discovery common

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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)

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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

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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