6 - Aplastic Anemia, Myeloid Growth Factors, and EPO

What is aplastic anemia and why do they lead to

1. Bone marrow __cellularity

2. Peripheral ___

3. Absence of abnormal __

4. No increase in __

Aplastic anemia is a condition where hematopoietic stem cells in the bone marrow are severely depleted, leading to failure of all blood cell lines

1. Bone marrow hypocellularity: The HSCs are killed, and instead adipocytes take the empty space

2. Peripheral pancytopenia: Less HSCs lead to less blood cells of all types being made(RBCs, WBCs, platelets)

3. Absence of abnormal cellular infiltrate: Not like leukemia where there are malignant blasts

4. No increase in marrow reticulin: Something that happens in chronic marrow injury with reactive fibrosis, not aplastic anemia

What are the main symptoms of aplastic anemia?

• Anemia: Due to less RBCs to deliver oxygen

• Infections/fever: Less neutrophils to kill bacteria

• Bleeding: Decreased platelet number

Give examples of 4 risk factors of AA and their brief mechanisms

1. Fanconi Anemia: A genetic mutation that leads to damage of a repair mechanism of crosslinking of dividing cells, leading to HSCs sustaining damage and being unable to divide more

2. Drugs like Thiazide: Via idiosyncratic rxn, it’s metabolites can trigger T-lymphocytes

3. Viruses: Can trigger T-cells as well

4. การทำอาชีพเกษตรกรรม: Benzene damages the DNA in HSCs

Main cause of aplastic anemia

• Idiosyncratic T-cell attacks

Camitta Criteria

• Does what

• What is it?

• Diagnoses and determines the severity of aplastic anemia

• Requirements: 2/3 cytopenias at least, and a hypocellularity of <25%

• Severity: Less than ANC of 500 cells/microL, platelets of <20k/microL, and < 1% CRC

  • Very severe would have ANC of less than 200 cells/microL

If a patient has aplastic anemia that is inherited/genetic, what does that mean we can’t do?

We can’t use immunosuppresive therapy, because T-cells aren’t the ones attacking the HSC

Aplastic anemia blood smear(3 observations)

1. Normochromic normocytic: When RBCs DO get made, they’re okay

2. Relative lymphocytosis: Longer lifespan than other WBCs

3. Decreased platelets

Pathophysiology of AA

1. A virus, drug metabolite, toxin, or something else will cause HSCs to present altered antigen on MHC class 1

2. APCs show CD4+ T helper cells which boost IL-2 to boost polyclonal expansion and activates CTLs

3. CTLs and CD4+ release IFN gamma and TNF alpha to upregulate Fas on HSC allowing CTLs to bind and kill them

Why can too many transfusions be bad, and how can we reduce that risk?

• A transfusion exposes patients to foreign HLA antigens, which can cause alloimmunization(making antibodies against these foreign antigens) and make future transplants more likely to be rejected

• Leukocyte depletion, aka removing the white cells from blood about to be transfused

Explain these 2 types of IST and how are they used?

1. ATG

2. CSA

1. Anti-thymocyte globulin: Infusing horse/rabbit made antibodies made against human lymphocytes and injecting them into us

2. Cyclosporine A: Inhibits T-cell activation

• Normally used together for ATG to kill existing ones while CSA prevents new activation and joined with eltrombopag

Eltrombopag

• A thrombopoietin receptor agonist, aka it mimics thrombopoietin which stimulates HSC and megakaryocytes

• Used with ATG and CSA

Why do anabolic steroids work in NSAA?

• They work because they stimulate telomerase to protect surviving HSCs

What is the best, possible treatment of AA, but it’s not recommended in ___

Bone marrow transplant from an HLA matched sibling because it can add a pool of healthy donor cells permanently, but not recommended in patients above 40-50

HLA stands for and is ___

Human leukocyte antigen, expressed on cells

Allogenic SCT means

• Allogenic: From outside

• SCT: Stem Cell Transplant

What is conditioning before an allogenic SCT and why do we need it?

It is a process where we destroy the old reactive T-lymphocytes and make space in the bone marrow for the new cells. This is to prevent the host attacking the donor cells

What type of drugs are anabolic steroids, and what does that mean for their side effects?

• Synthetic androgens

• Will stimulate things like acne, deepened voice, hirsutism(unwanted male effects)

If a patient survives 6M of IST, they should do well with…

Anabolic steroids

EPO stands for

• Erythropoietin

EPO

• Hormone type

• Location and produced when?

• Mechanism(Brief)

• Glycoprotein hormone

• Peritublar cells in kidney in response to decreased oxygen levels in blood

• Binds CFU-E cells on future RBCs

rHuEPO stands for, and what is it?

• Recombinant Human Erythropoietin, so a human EPO gene made in an outside host cell and used as a drug

What are the two types of rHuEPO, and how are they given?

• Alfa and beta, and they are given subcutaneously/intravenously

Why can giving EPO result in functional iron deficiency, what can happen, and how do we deal with it?

• When we have too much EPO, we demand more iron to be mobilized, and if we can’t do it in time, it’ll lead to hypochromic microcytic RBCs like in IDA, so we have to take these drugs with iron supplementation

ADR of EPOs

• Boosts endothelin and decreases nitric oxide → Hypertension

  • So avoid in patients with hypertension since it can cause headaches, encephalopathy, seizures

What is Darbepoetin alfa?

• A type of EPO that uses Novel Erythryopoeisis Stimulating Protein(NESP) that has more carbohydrate chains which allows it to have a longer half-life

What are myeloid growth factors, and what are the main ones?

• Signaling proteins that stimulate the bone marrow to release myeloid cells(Future neutrophils, monocytes, eosino, baso, etc.)

• GM-CSF and G-CSF, G-CSF focuses only on granulocytes, so mainly neutrophils

Main G-CSF drug

• Function

• Route

• Mechanism

• ADR

• Filgrastim

  • To boost levels of neutrophils

  • SC/iV

  • Binds G-CSF receptors of myeloid progenitor cells like how EPO boosts erythroid progenitors

  • Bone pain

When could we use Filgrastim?

• After cancer chemotherapy

Pegfilgrastim difference from Filgrastim

• Has pegylation: Aka a polymer chain added to the drug, helping it last longer

Lenograstim difference from Filgrastim

• Produced in Chinese hamster ovarian cells, and are glycosylated which helps it from being degraded too fast