Aplastic Anemia - Margolis Flashcards
Broadly, what is aplastic anemia? What are the two major types?
A disease caused by too few hematopoietic progenitor cells, which can lead to cytopenias of all hematopoietic lineages. (Note: **SAA **= Severe Aplastic Anemia)
Two major types: Inherited and Acquired.
What leads to Acquired SAA? What are some specific triggers?
- An inciting event leads to autoimmune destruction of blood progenitor cells
- Triggers:
- Viral Infection: CMV, EBV, HHV-6, Parvovirus, Hepatitis viruses
- Possibly some medications? (Not sure if this would be autoimmune)
- Possibly radiation exposure? (Not sure if this would be autoimmune)
What is a common clinical symptom of aplastic anemia?
A history of jaundice
In detail, what are the Camitta Criteria for Severity of Aplastic Anemia?
- Marked Pancytopenia
- At least 2 of 3 of the following findings in peripheral blood:
- PMN < 500/ul
- Platelets < 20x103/ul
- Reticulocytes < 20x103/ul (corrected retic < 1%)
- Marrow findings:
- Marked hypocellularity
- Less than 65% of residual marrow cells being non-hematopoietic (I assume this is to rule out an invasive proliferation of other cells as the cause?)
- Marked hypocellularity
- At least 2 of 3 of the following findings in peripheral blood:
There are several well-recognized inherited marrow failure syndromes.
Can you name 8 specific diseases?
[Other than a few questions later in this deck - it is likely more important to just recognize these names instead of knowing them in detail.]
- Amegakaryocytic Thrombocytopenia
- Diamond-Blackfan Anemia
- Dyskeratosis Congenita
- Fanconi Anemia
- Pearson Syndrome
- Severe Congenital Neutropenia
- Schwachman-Diamond Syndrome
- Thrombocytopenia Absent Radii
- aka TAR, literally present with a lack of radius bone in forearm
Name three types of treatment for SAA.
- Bone Marrow Transplant
- Intensive Immunosuppression
- Thrombopoietin receptor agonists
- Eltrombopag
Name three types of bone marrow transplant options for SAA.
- Bone Marrow Transplant
- Matched Sibling
- Unrelated Donor, HLA-matched
- Double Cord BMT
- Two umbilical cords worth of HSCs is generally enough to sucessfully repopulate the bone marrow target
Name five immunosuppressive drugs useful in treating SAA.
Intensive Immunosuppression:
- Anti-thymocyte globulin (ATG)
- Cyclosporine A (CsA)
- Prednisone
- Alemtuzumab
- Cyclophosphamide
- Improper maintenence and protection of telomeres can result in marrow failure, as well as what other diseases?
- What is the classic bone marrow disease due to telomere dysfunction?
- Liver & Lung fibrosis (& cirrhosis) , due to aberrant tissue repair & regeneration
- Dyskeratosis Congenita
The average telomere length in normal blood leukocytes decreases with what physiological process?
Aging!
- Name two specific genes that lead to telomerase-related aplastic anemia when mutated.
- What is seen in the telomeres of pts with mutations in this gene?
- TERT - Telomerase Reverse Transcriptase
- TERC - Telomerase RNA Component (telomerase is a ribonucleoprotein!)
- Significantly shorter telomeres than a normal person
How does short vs. normal telomere length correspond with:
- Primary therapeutic response to ATG
- Risk of relapse
- Risk of clonal evolution (dysplasia-promoting mutations)
- Unrelated to ATG response
- Short telomeres = 2x risk of relapse
- Short telomeres = 5-6x risk of clonal evolution (e.g. MDS, AML)
- How are telomerase deficiencies screened for?
- How can telomerase deficiencies be treated?
- Telomere length of leukocytes
- Treatments:
- Avoidance of regenerative stress (smoke, EtOH, etc.)
- Chemotherapy (?)
- Sex hormones (they can modulate TERT)
Your patient presents with pancytopenia. Other than an inherited or acquired aplastic anemia, what else is on your differential?
- MDS
- Leukemia
- Autoimmune disease (that is not attacking the HSCs)
- Nutritional Deficiency
- HLH
Because it was discussed here again…
What is HLH and how is it caused?
HLH is due to uncontrolled T-cell and histiocyte activation. The condition is considered an emergency as **rapidly fatal cytokine storms **are possible. It can be inherited or acquired secondary to EBV, autoimmune disease, etc.
How is HLH diagnosed?
5+ of the following:
- Splenomegaly
- Fever
- Cytopenias in 2+ cell lines
- Hypertriglyceridemia / Hypofibrinogenemia
- Hepatitis (Hyperbilirubinemia)
- Low NK cell activity
- HIGH FERRITIN
- SOLUBLE CD25
What is dyskeratosis congenita? What are some specific clinical findings outside of the bone marrow?
- Poor telomere maintenence leads to progressive, severe effects on the skin (appears similar to advanced aging / progeria) and bone marrow failure
- Findings:
- Leukoplakia (white patches on tongue / in mouth)
- Lacy pigmentation
- Abnormal finger & toe nails
- Lung & Liver disease
What is the DEB test and what condition is it used to screen for?
If the DEB test is abnormal, what is done next?
The DEB (diepoxybutane) test looks for chromosomal breakage. Used to screen for Fanconi Anemia. 40% of FA pts will not have physical stigmata, so it is important to use the DEB test.
If the DEB is abnormal, follow it up with genetic testing to classify the defect.
Schwachman-Diamond Syndrome
- What mutation causes it?
- What are the major two clinical findings to look for?
- Name two effective screening tests.
- Can it be genetically tested for?
Schwachman-Diamond Syndrome
- SBDS gene defect
- Sxs:
- Exocrine pancreatic deficiency
- Neutropenia
- Screening:
- Isoamylase
- Trypsinogen
- Yes!
Congenital Amegakaryocytic Thrombocytopenia
- What mutation causes it?
- What clinical presentation is noted, even immediately at birth?
- Is genetic testing available?
Congenital Amegakaryocytic Thrombocytopenia
- MPL gene defect
- Profound thrombocytopenia
- Yes!
