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_MS2 HemeOnc > 8/3- Stem Cell Hematopoiesis, Erythropoiesis & Marrow Failure > Flashcards

8/3- Stem Cell Hematopoiesis, Erythropoiesis & Marrow Failure Flashcards

1
Q

What is this?

A

Bone marrow

(depleted- hypocellularity = bone marrow failure)

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2
Q

What is pancytopenia?

A

Decreased blood counts in all three lines

(RBCs, WBCs, platelets)

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3
Q

What is (BMF) bone marrow failure (def)?

A

A state of abnormal hematopoiesis due to bone marrow hypocellularity which results in abnormal production of 1 or all of blood cells

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4
Q

Broad categories that may cause pancytopenia (5)? Examples?

A
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5
Q

Pathology of bone marrow failure; which is normal/abnormal?

A

Top: abnormal; bone marrow failure

  • Hypocellular; cells replaced by fat tissue

Bottom: normal

  • Clearly more cells
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6
Q

What is severe aplastic anemia (SAA)?

A

Definition combines severe bone marrow hypocellularity (under 25%) and at least 2 blood cytopenias:

  • Absolute neutrophil count < 500/uL
  • Anemia w/ absolute retic count < 40,000/uL
  • Platelets < 20,000 uL
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7
Q

What may cause bone marrow failure (broad categories)?

A
  • Congenital disorders
  • Acquired disorders
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8
Q

What are some congenital disorders that may cause bone marrow failure?

A
  • Fanconi anemia
  • Dyskeratosis congenita
  • Shwachman-Diamond syndrome
  • Diamond-Blackfan anemia
  • Congenital amegakaryocytic thrombocytopenia
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9
Q

What are some acquired disorders that may cause bone marrow failure?

A
  • Toxic exposure, (eg, to benzene, radiation)
  • Drugs
  • Viral infections
  • Idiopathic- thought to be immune- mediated
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10
Q

Evaluation of BMF patients: what are some symptoms that may result from cytopenias?

A
  • Pallor/fatigue due to anemia
  • Bleeding/bruising due to thrombocytopenia
  • Fever/infection due to neutropenia

Sx are proportional to the degree of severity

Evaluation of presenting pts should be systemic and comprehensive

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11
Q

What are inherited bone marrow failure syndromes (broadly)?

A

A group of rare genetic disorders that share in common predisposition to bone marrow failure as well as certain cancers

  • May affect all blood cell lineages or one line primarily
  • Most are multi-system diseases, either as congenital abnormalities or as later manifestations of the disorder (e.g. lung fibrosis in adults with dyskeratosis congenita)
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12
Q

What is an example of an inherited BMF disorders that affect all blood cell lineages? Only one line primarily?

A

All: Fanconi anemia

One primarily: Diamond-Blackfan anemia

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13
Q

In what population is it especially important to distinguish inherited vs. acquired marrow failure?

A

Pediatrics

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14
Q

Different characteristics for Acquired AA vs. IBMFS (inherited bone marrow failure syndrome)?

A
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15
Q

What is Fanconi anemia (genetic characteristics)?

  • Inheritance pattern
  • Phenotype
  • Biochemical issue
  • Associations
A
  • AR inheritance (primarily)
  • Variable clinical: cafe au lait, microopthalmia, abnormal thumbs/radio-abnormalities
  • DNA-repair disorder
  • Hallmark is increased chromosomal breakage in response to DNA crosslinking agents (seen in chromosome breakage assay)
  • 15 genes indicated to date
  • Predisposed to AML/MDS as well as other cancers
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16
Q

What is this?

A

Hallmark of Fanconi anemia seen in chromosome breakage assay: increased chromosomal breakage in response to DNA crosslinking agents

17
Q

What is Dyskeratosis congenita?

  • Symptoms
  • Prevalence/epidemiology
  • Biochemical problem
  • Inheritance pattern
A

Classical mucocutaneous triad:

  • Abnormal (reticulate) skin pigmentation
  • Oral leukoplakia
  • Nail dystrophy

BMF develops in 90% of pts by age 30

Disorder of abnormal telomere biology

Variable inheritance

18
Q

What is Diamond-Blackfan anemia?

  • Basic characteristic
  • Epidemiology
  • Presenting symptoms
  • Bone marrow characteristics
  • Treatment
A
  • Congenital red cell aplasia
  • Pts mostly present within 1st year of life with macrocytic, hypoproductive anemia +/- congenital abnormalities (heart, kidney, limbs, craniofacial)
  • Bone marrow shows paucity of erythroid precursors in an otherwise normocellular marrow (also observed is an increase in number of eosinophils)
  • 85% of pts will respond to treatment with steroids (unclear why)
19
Q

What is acquired pure red cell aplasia?

  • Rare/common?
  • Occurs in what settings
A

Rare disorder that can occur in the following settings:

  • Thymoma, lymphoma, other autoimmune disorders (?immune-mediated)
  • Post-treatment with recombinant erythropoietin with formation of antibodies against endogenous as well as exogenous Epo
  • Parvovirus B19 infection, especially in patients with chronic hemolytic anemia
20
Q

What is idiopathic severe aplastic anemia?

  • Basic def
  • Requires what for diagnosis
  • Due to what
  • Spontaneous recovery expected?
  • Complications
A
  • Acquired severe marrow failure state
  • Extensive workup failed to identify an etiology/ cause of marrow failure
  • Considered to be due to immune dysregulation
  • Spontaneous recovery of marrow function is not expected; prompt treatment needed
  • Life-threatening disorder: Infections, iron overload, severe bleeding
21
Q

Treatment of idiopathic SAA?

A

Supportive care:

  • Transfusion
  • Judicious use of antibiotics and GCSF

Definition therapy (2 primary arms)

  • Hematopoietic stem cell transplant
  • Immunosuppressive therapy with ATG and cyclosporine
22
Q

General concepts of HSC transplant?

  • When used?
A

Utilizes the homing and reconstituting ability of HSC

Process whereby:

  • Collection of HSCs

(umbilical cord, autologous, allogeneic)

  • Recipient undergoes conditioning (varies depending in disease being treated)
  • Infusion of HSC and awaiting their engraftment

Wide utility in a variety of heme/onc diseases as well as immunological and certain metabolic diseases

23
Q

What is the probability of survival after allogeneic transplants for SAA?

A

By donor type and age

(best for young and with sibling donor)

24
Q

Another flowchart with HSC lineages/differentiation

A
25
Q

Erythropoiesis timeline/cell types

A
26
Q

What are these?

A

Red cell precursors

27
Q

Regulation of Erythropoiesis

A

Triggered by:

  • Red cell destruction (or acute blood loss) decreases red cell mass and blood volume; decreased vascularity then triggers the kidney to make erythropoetin
  • Decreased CO/pulmonary fct/atmospheric O2
28
Q

What is erythropoeitin (EPO)?

What organ(s) produce(s) it?

Normal levels?

When is it produced?

A
  • Drives erythropoeisis (increased RBC production)
  • Produced by interstitial renal tubular cells (about 10% produced by the liver)
  • Normal levels are about 10-20 U/mL
  • Renal insuffiiciency causes normochromic normyctic anemia
  • Prevents apoptosis of erythroid progenitors
29
Q

Other GFs for erythroid cells: Stimulators? Inhibitors?

A

Stimulators:

  • GM-CSF
  • IL-3
  • Insulin like growth factor (ILGF)
  • Androgens

Inhibitors:

  • Gamma interferon
  • IL-1
  • TNF
30
Q

More about EPO:

  • Gene on what chromosome
  • Native MW
  • Biochem characteristics
  • rHEPO is more/less glycosylated?
  • A novel rHEPO, ___, has ____, which results in _____
A
  • Gene on: chromosome 7
  • Native MW: 34 KD
  • Biochem characteristics: heavily glycosylated
  • rHEPO is somewhat less glycosylated
  • A novel rHEPO, Darbepoietin, has additional glycosylation site that results in a longer half life
31
Q

EPO is (directly/inversely) proportional to __

A

EPO is inversely proportional to Hct

32
Q

What is one of the main inducible factors of EPO?

A

Hypoxia

33
Q

What is HIF-alpha?

A

Hypoxia Inducible Factor-alpha (HIF-a)

34
Q

How does the EPO receptor function?

A
  • EPO binds receptor
  • EPO receptor binds JAK2 in the cytoplasmic domain
  • Phosphatase of JAK2 then activated???

Mutation -> polycythemia vera??

35
Q

Specifics/characteristics of EPO receptors?

  • Member of what broad chemical family
  • Gene on what chromosome
  • Interaction with receptor
  • Mutations associated with what diseases
A
  • Member of the cytokine receptor family
  • Gene is on chromosome 19
  • Interaction with EPO -> dimerization of cytoplasmic domain
  • Downstream signaling
  • Abnormal EPOr and signaling mutations are associated with polycythemia
  • EPOrs are also found on a wide variety of non-erythropoietic cells

_MS2 HemeOnc (33 decks)

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