What is this?
(depleted- hypocellularity = bone marrow failure)
What is pancytopenia?
Decreased blood counts in all three lines
(RBCs, WBCs, platelets)
What is (BMF) bone marrow failure (def)?
A state of abnormal hematopoiesis due to bone marrow hypocellularity which results in abnormal production of 1 or all of blood cells
Broad categories that may cause pancytopenia (5)? Examples?
Pathology of bone marrow failure; which is normal/abnormal?
Top: abnormal; bone marrow failure
- Hypocellular; cells replaced by fat tissue
- Clearly more cells
What is severe aplastic anemia (SAA)?
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
What may cause bone marrow failure (broad categories)?
- Congenital disorders
- Acquired disorders
What are some congenital disorders that may cause bone marrow failure?
- Fanconi anemia
- Dyskeratosis congenita
- Shwachman-Diamond syndrome
- Diamond-Blackfan anemia
- Congenital amegakaryocytic thrombocytopenia
What are some acquired disorders that may cause bone marrow failure?
- Toxic exposure, (eg, to benzene, radiation)
- Viral infections
- Idiopathic- thought to be immune- mediated
Evaluation of BMF patients: what are some symptoms that may result from cytopenias?
- 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
What are inherited bone marrow failure syndromes (broadly)?
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)
What is an example of an inherited BMF disorders that affect all blood cell lineages? Only one line primarily?
All: Fanconi anemia
One primarily: Diamond-Blackfan anemia
In what population is it especially important to distinguish inherited vs. acquired marrow failure?
Different characteristics for Acquired AA vs. IBMFS (inherited bone marrow failure syndrome)?
What is Fanconi anemia (genetic characteristics)?
- Inheritance pattern
- Biochemical issue
- 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
What is this?
Hallmark of Fanconi anemia seen in chromosome breakage assay: increased chromosomal breakage in response to DNA crosslinking agents
What is Dyskeratosis congenita?
- Biochemical problem
- Inheritance pattern
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
What is Diamond-Blackfan anemia?
- Basic characteristic
- Presenting symptoms
- Bone marrow characteristics
- 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)
What is acquired pure red cell aplasia?
- Occurs in what settings
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
What is idiopathic severe aplastic anemia?
- Basic def
- Requires what for diagnosis
- Due to what
- Spontaneous recovery expected?
- 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
Treatment of idiopathic SAA?
- Judicious use of antibiotics and GCSF
Definition therapy (2 primary arms)
- Hematopoietic stem cell transplant
- Immunosuppressive therapy with ATG and cyclosporine
General concepts of HSC transplant?
- When used?
Utilizes the homing and reconstituting ability of HSC
- 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
What is the probability of survival after allogeneic transplants for SAA?
By donor type and age
(best for young and with sibling donor)
Another flowchart with HSC lineages/differentiation
Erythropoiesis timeline/cell types
What are these?
Red cell precursors
Regulation of Erythropoiesis
- 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
What is erythropoeitin (EPO)?
What organ(s) produce(s) it?
When is it produced?
- 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
Other GFs for erythroid cells: Stimulators? Inhibitors?
- Insulin like growth factor (ILGF)
- Gamma interferon
More about EPO:
- Gene on what chromosome
- Native MW
- Biochem characteristics
- rHEPO is more/less glycosylated?
- A novel rHEPO, ___, has ____, which results in _____
- 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
EPO is (directly/inversely) proportional to __
EPO is inversely proportional to Hct
What is one of the main inducible factors of EPO?
What is HIF-alpha?
Hypoxia Inducible Factor-alpha (HIF-a)
How does the EPO receptor function?
- EPO binds receptor
- EPO receptor binds JAK2 in the cytoplasmic domain
- Phosphatase of JAK2 then activated???
Mutation -> polycythemia vera??
Specifics/characteristics of EPO receptors?
- Member of what broad chemical family
- Gene on what chromosome
- Interaction with receptor
- Mutations associated with what diseases
- 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