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OS1 - Heme > Elevated Blood Counts- Weir > Flashcards

Elevated Blood Counts- Weir Flashcards

1
Q

Describe the mechanism of action of the Jak2 V617F mutation.

A

this mutated Jak2 is associated with the EPO receptor in erythroid cells and is constitutively active. When it signals (via Stat2, ras/raf/mek/erk, or PI3K/AKT/mTOR pathways) it induces cell proliferation. This is the driving mutation at the heart of myeloproliferative disorders.

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2
Q

What are the diagnostic criteria for polycythemia vera?

A

•Elevated red cell mass >25% above normal, or Hgb >18.5d/dl (men), >16.5g/dl (women)
•JAK2 V617F mutation, or functionally similar mutation
•Minor:
BM biopsy showing panmyelosis; prominent erythroid and megakaryocyte proliferation
Low serum EPO (or normal)
Endogenous erythroid colony formation in vitro

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3
Q

What are the diagnostic criteria for essential thrombocythemia?

A
  • Sustained platelet count > 450 K/uL
  • BM biopsy: Meg proliferation without significant left shift nor increased erythropoiesis
  • Ruling out PCV, PMF, CML, MDS, and other myeloid neoplasms
  • JAK2 V617F mutation, or no evidence for reactive thrombosis
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4
Q

What are the diagnostic criteria for primary myelofibrosis?

A

•Atypical megs proliferating, with reticulin or collagen fibrosis
•Rule out PCV, CML, MDS, or other myeloid neoplasms
•JAK2 V617F mutation or rule out other cause of bone marrow fibrosis
•Minor:
Leukoerythroblastosis
Increased serum LDH
Anemia
Palpable splenomegaly

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5
Q

What are the diagnostic criteria for chronic myeloid leukemia (CML)?

A

t(9;22) seen on FISH or PCR

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6
Q

Name the major causes of erythrocytosis.

A
  • Reduced plasma volume – acute conditions causing fluid loss
  • Appropriately increased EPO – COPD, cyanotic heart disease, smokers, sleep apnea, drugs
  • Inappropriately increased EPO – RCC, non-neoplastic renal lesions, HCC, uterine fibroma, meningioma, cerebellar hemangioblastoma, other tumors
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7
Q

What are complications of P. vera?

A

THROMBOSIS/thromboembolism, progression to AML or other malignancy, hemorrhage, myelofibrosis/myeloid metaplasia, and others

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8
Q

What are the treatment options for P. vera?

A
  • Phlebotomy: median survival 14yrs
  • Aspirin: lowers risk of thrombosis/CV-related death
  • Hydroxyurea – reduces thrombosis, lowers Hct
  • Interferon – controls platelets and Hct in most patients; may work after hydrea fails
  • JAK2 inhibitors
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9
Q

Name the major causes of neutrophilia.

A
  • Most common: Infection
  • Inflammation
  • If not sick most common: smoking or obesity
  • Drugs – corticosteroids (back injections for pain), lithium
  • Myeloproliferative neoplasms – CML, PCV, myelofibrosis
  • malignancy
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10
Q

Name the major causes of eosinophilia.

A

•Idiopathic
•Reactive
•Hypereosinophilic syndrome = >1500, >6mo, organ damage
- Idiopathic
- Chronic – eosinophilic leukemia (CEL)
- Hematopoietic neoplasms accompanied by eosinophilia
**Also: increased eosinophils seen in MYH11-CBFB mutation in AML.

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11
Q

Describe the mutation and MOA of the Philadelphia chromosome.

A

This is the t(9;22) that results in BCR-ABL fusion protein with TK activity; turns on proliferative TFs, Bcl-2 anti-apoptosis family, and activates motility/decreases adhesion

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12
Q

What is the the current best therapy for CML, and what is its MOA?

A

imatinib - inhibits the BCR-ABL fusion tyrosine kinase protein by binding. In many cases this causes depletion of the clonal population and may be curative.

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13
Q

Describe the peripheral blood smear of a patient with CML.

A
  • Elevated neutrophil count
  • Left shift with myelocytosis (more than promyelocytes)
  • No increase in blasts (then may be AML)
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14
Q

What are dacrocytes and what are they associated with?

A

they are teardrop red blood cells almost always seen in myelofibrosis because it is having to squeeze out through abnormal bone marrow architecture
See a teardrop cell, think bone marrow issue

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15
Q

True or false: myelodysplastic disorders are associated with increased cell mass, clonal origin, committed stem cell mutations, and full maturation.

A

False - myeloproliferative disorders are associated with these four things

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16
Q

In working up a patient with suspected essential thrombocythemia who is negative for a Jak2 mutation, what mutation would you screen for next?

A

calreticulin - this is the driving mutation in 25% of ETs (2nd place to Jak2 mutation)

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17
Q

What 3 MPNs can be caused by a Jak2 V617F mutation?

A

Polycythemia vera
Essential thrombocythemia
Primary myelofibrosis

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18
Q

What is the clinical presentation of primary myelofibrosis?

A

splenomegaly, hepatomegaly, fatigue (“these patients just feel bad”), anemia, elevated platelet count and/or leukoerythroblastic picture, thrombosis

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19
Q

On bone marrow biopsy what is a telltale difference between ET and primary myelofibrosis?

A

bone marrow biopsy shows more reticulin fibers in primary myelofibrosis

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20
Q

What are viable treatment options for primary myelofibrosis?

A
  • Jak2 inhibitor - it won’t remove the clone but it will relieve the symptoms
  • Allogeneic bone marrow transplant
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21
Q

What is the treatment for CEL/hypereosinophilia syndrome?

A
  1. imatinib

2. to treat organ damage: glucocorticoids, hydroxyurea, interferon

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22
Q

True or false: one of the goals of phlebotomy as treatment for P. vera is to make the patient platelet deficient.

A

False - phlebotomy helps P. vera patients when it makes them iron deficient, because that will keep their RBC counts under control

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23
Q

What is the role of basophilia in P. vera?

A

there is a slight basophilia seen in P. vera but not as much as in CML

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24
Q

What is the most common cause of death in patients with P. vera?

A

thrombosis

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25
Q

If you suspect P. vera in a patient and the screen for Jak2 V617F is negative, what do you test to determine diagnosis?

A

Next test EPO levels.

  1. if low then do a bone marrow biopsy to look for Jak2 Exon 12 mutation; if positive then the diagnosis is P vera
  2. If EPO is not low then the symptoms are probably due to appropriate erythrocytosis
26
Q

If a patient has increased platelets, what is the top of your differential?

A

iron deficiency

27
Q

Why do essential thrombocythemia patients have a risk of bleeding? That’s counter-intuitive, isn’t is?

A

Patients with >1.5 million platelets may acquire von Willebrand disease (vWF deficiency). This will be reversed with platelet reduction. In the meantime the patient is at risk of bleeding.

28
Q

Name the treatment options for ET.

A

First of all, treatment may not be required. High platelets won’t hurt you unless they are symptomatic or the patient is high-risk for thrombosis.

  • platelet reduction
  • hydroxyurea
  • anagrelide (back-up drug)
  • interferon (safe in pregnancy)
29
Q

Myelofibrosis may be secondary to other conditions. What are some of the major conditions in which myelofibrosis may occur?

A

neoplastic - MPN, PV, CML, AML, MDS, ALL, HCL, myeloma, carcinoma, systemic mastocytosis, others
non-neoplastic - granulomatous disease, paget disease, hypo/hyperparathyroidism, osteoporosis, vitamin D deficiency, SLE, systemic sclerosis, others

30
Q

Describe peripheral blood smear findings in chronic idiopathic myelofibrosis.

A 
frequent dacrocytes
thrombocytosis - giant/bizarre platelets
mild reticulocytosis
nRBCs
left-shift leukocytosis
baso/eosinophilia (10-30%)
31
Q

Describe the clinical presentation of CML.

A
  • elevated neutrophil count
  • often palpable spleen
  • myelocytes on peripheral smear
  • *the peripheral smear looks like a bone marrow aspirate**
32
Q

What are complications of eosinophilia?

A

myocarditis, lung infiltration, enteritis, encephalopathy, neuropathy, thromboses, eczema, angioedema

33
Q

What are other conditions to consider when a patient presents with eosinophilia?

A

drugs, parasites, strongyloidiasis, dermatitis, respiratory illness, vasculitides, solid tumors, tissue damage (check pulmonary function, echo, troponins)

34
Q

What mutation is associated with eosinophilia (CEL) and what drug might this respond to?

A

FIP1L1-PDGFRA

responds to imatinib

35
Q

What mutation is central to the Dx of polycythemia vera?

A

Jak2 mutation

36
Q

What medicine is most important in treating chronic myelogenous leukemia?

A

Tyrosine kinase inhibitor (imatinib)

37
Q 
What is a common cause of elevated platelets from the list below?
Splenectomy
b12 deficiency
Cirrhosis
Folic acid deficiency
Beta thalassemia
A

Splenectomy.

All the rest, except for beta thal, will lower platelets.

38
Q

Why would smoking cause elevated RBC #s?

A

Smoking = hypoxemia = increased EPO release –> more RBCs produced

39
Q

What is the most common cause of neutrophilia?

40
Q

If no infection is present, what are the two other major causes of neutrophilia?

A

cigarette smoking, obesity

41
Q

You’ve got cells that are fully matured but there are just too many of them. This is called:

A

Myeloproliferative disease.

42
Q

Name the myeloproliferative disorders we need to know.

A

CML
polycythemia vera
essential thrombocythemia
primary myelofibrosis

43
Q

Is myeloproliferative disease clonal?

44
Q

What is a plethoric face?

45
Q

What is the main thing we try to prevent in myeloproliferative disease?

A

thrombosis

46
Q

B12 levels will be up or down in P. vera pts?

47
Q

EPO levels will be reduced or elevated in a pt with P. vera?

A

Reduced.
P. vera due to Jak2 mutation, resulting in constitutive activation of EPO receptor. Body will sense elevated RBC levels and reduce EPO release.

48
Q

You have a pt with elevated Hb and/or Hct. What do you want to know?

A

Red cell mass and plasma volume measurements.

49
Q

You have a pt with elevated Hb and/or Hct and elevated red cell mass. What do you want to know now?

A

O2 saturation

50
Q

You have a pt with elevated Hb and/or Hct and elevated red cell mass and O2 sat <93%. What is your Dx?

A

hypoxic erythrocytosis

51
Q

You have a pt with elevated Hb and/or Hct and elevated red cell mass and O2 sat >93%. What do you want to do now?

A

Test for Jak2 V617F mutation.

52
Q

You have a pt with elevated Hb and/or Hct and elevated red cell mass and O2 sat >93%. They are Jak2 V617F negative. What do you want to know next?

A

Serum EPO level

53
Q

You have a pt with elevated Hb and/or Hct and elevated red cell mass and O2 sat >93%. They are Jak2 V617F negative and EPO is low. What is in your differential Dx?

A

P. vera
Jak2 exon12 mutation
others we don’t know yet

54
Q

You have a pt with elevated Hb and/or Hct and elevated red cell mass and O2 sat >93%. They are Jak2 V617F negative and EPO is elevated. What is in your differential?

A

Renal disease
Tumors
VHL mutation
High affinity Hb for O2, tricks body into thinking O2 levels are low and more RBC, thus EPO needed.

55
Q

In P. vera, what are we going to treat, primarily?

A

Thrombosis. Want to keep Hct <45%

56
Q

Your pt comes in with a cough but all else is normal. Except that their platelets are 900 K/uL. What test should you perform next to help ID the cause?

A

Serum ferritin

57
Q

Your pt comes in with a cough but all else is normal. Except that their platelets are 900 K/uL. What is in your differential?

A

Inflammation
Trauma
Malignancy
Fe deficiency- causes elevation of platelets
Splenectomy- spleen holds most of the platelets in your body
Myeloproliferative neoplasm- essential thrombocythemia

58
Q

What is erythromelalgia?

A

A condition where the digits are red and painful. Seen in some pts with essential thrombocythemia. Due to platelet plugging of peripheral vessels.

59
Q

When you see tear drop cells in a peripheral smear, you should think there is a problem with the:

A

Bone marrow
Almost always seen in myelofibrosis.
Infiltrative bone diseases

60
Q

If you start seeing myelocytes in peripheral blood in a pt, what should you start thinking about?

A

Myeloproliferative disease, especially CML

OS1 - Heme (31 decks)

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