Hypoproliferative Anemias Flashcards
What is the first lab value that would explicitly denote a hypo-proliferative anemia?
Low retic count
B12 and folate deficiency are the most common causes of what kind of anemia?
Hypoproliferative macrocytic megaloblastic anemia
A retic index of less than 2% or absolute retic count less than 75,000 is indicative of a ____ proliferative anemia
Hypo
Cobalamine = Vitamin ___
B12
Megaloblastic anemias are defined as a group of disorders characterized by a defect in _______ that leads to an immature nucleus and mature cytoplasm
DNA synthesis
On a peripheral smear of someone with megaloblastic anemia, what will be the morphology of the neutrophils?
Hyper-segmented (so more than 5 lobes)
In megaloblastic anemias, the MCV is ____ and the RDW is ____
Elevated; elevated
What are some non-hematologic findings of someone with megaloblastic anemia?
Glossitis (beefy red smooth tongue) seen in both B12 and folate deficiency and neuro/psychiatric features only seen in B12 deficiency
Would you see neuro/psychiatric features in someone that is folate deficient?
No, just B12 deficiency
Homocysteine is needed to form ______ that is needed for DNA synthesis
Methionine
Folate is needed to form ______
Methionine
B12 is needed to form ______ and succinic acid
Methionine
B12 is needed to form methionine and _______ acid
Succinic
Methylmalonic acid forms ______ acid
Succinic
______ acid forms succinic acid
Methylmalonic acid
Methylmalonic acid forms ______ acid that then goes to aid in myelin synthesis
Succinic
B12 from the diet binds to what protein in the saliva?
Protein R
_____ cells in the stomach secrete intrinsic factor
Parietal
Parietal cells in the _____ secrete ____ ____
Stomach; intrinsic factor (IF)
Enzymes produced by the ____ free B12 from being bound to protein R
Pancreas
B12-IF complex is taken up in the distal _____
Ileum
B12 is bound to [protein R/ IF] in the distal illeum
IF
In the blood, B12 is carried by _______ to the tissues
Transcobalamin II
What type of diet would cause B12 deficiency?
Vegan diet (no animal products)
Inadequate absorption of B12 may be due to what causes?
- Lack of gastric acid (meds, atrophic gastritis) - Destruction/removal of parietal cells (pernicious anemia, gastrectomy) - Gastric bypass surgery
In pernicious anemia, what is causing the lack of absorption of B12?
Autoimmune loss of parietal cells that produce IF
Where in the body is most B12 stored?
Liver
What is necessary for B12 to be absorbed?
Intrinsic factor
What enzymes are needed to free up B12 to bind IF?
Pancreatic enzymes
What are some conditions that can reduce B12 absorption in the ileum?
- Crohn’s disease - Sprue (celiac or tropical) - Metformin (diabetes treatment)
If there is a problem with the pancreas, what step of B12 absorption will be affected?
The step where pancreatic enzymes cleave protein R from B12
What are some competitors of B12 absorption that can be in the body?
Fish tapeworm, bacterial overgrowth
What molecule may inactivate cobalamin?
Nitrous oxide
What neurological condition can be caused by B12 deficiency and reversible if caught early?
Dementia
In B12 deficiency there will be subacute combined degeneration of the _____ and lateral spinal columns
Dorsal
There is a loss of _____ and position sense in B12 deficiency that is presented with tripping and falling and having problem buttoning shirt
Vibration
Pernicious anemia runs in families and on a smear would present with
Pancytopenia
In someone who is B12 deficient, what would you expect their lab values would be?
- Increased MCV (macrocytic) - Hypersegmented PMNs (neutrophils) - There could be pancytopenia if severe - Increased LDH and bilirubin due to intramedullary hemolysis in severe cases (pernicious anemia)
How would you diagnose B12 deficiency?
- Low B12 level - Elevated homocysteine - Elevated methylmalonic acid
If have someone who underwent gastric bypass surgery two months ago and is not taking B12 supplements, would you expect them to be severely B12 deficient?
No, it takes years (10) to develop B12 deficiency
Should you just go ahead and give B12 to someone with a deficiency first?
No, you should try to treat the underlying cause first
B12 deficiency generally requires lifelong _______ shots of B12
Intramuscular (IM)
Where is folate absorbed?
Small intestine (mainly to duodenum and jejunum)
Where in the diet is folate found?
Uncooked green leafy veggies, bread and cereals
_______ hepatic circulation is important for folate absorption and if a bile drain is put in, all folate may be lost in 6 hours
Enterohepatic
Cooking destroys _____ in veggies
Folate
What is the daily folate requirement for adults?
100 mcg
What is the daily folate requirement for children?
50 mcg
What is the daily folate requirement for pregnant or lactating women?
400 mcg
Someone with psoriasis or hemolysis should take what kind of supplements?
Folate
Where in the body is folate stored and for how long?
Liver; 2-5 months
Which parts of the small intestine are iron and folate absorbed?
Duodenum and jejunum
What are some causes of folate deficiency?
- Malnutrition - Malabsorption - Increased requirement (pregnancy, chronic hemolysis, psoriasis, chronic febrile illnesses) - Drugs (methotrexate, sulfa antibiotics)
What is the most common cause of folate deficiency?
Malabsorption
Patients with what kind of anemias should be supplemented with folate?
Hemolytic
About how much folate should be ingested in a day?
1-5 mg
______ will be increased and _______ ____ will be normal in folate deficiency
Homocysteine; methylmalonic acid
Methylmalonic acid levels will be normal in _____ deficiency because only ___ is needed in the conversion to succinate
Folate; B12
Aplastic anemia is defined as:
Pancytopenia seen in the peripheral blood smear, with a bone marrow biopsy showing hypocellularity (<25%) that arises from deficiency of hematopoietic stem cells
What type of anemia is there pancytopenia and hypocellularity of the bone marrow?
Aplastic anemia
Most aplastic anemias are ______ conditions
Autoimmune
Aplastic anemia is what kind of condition?
Autoimmune
What condition is depicted
Aplastic anemia
This is seen in what condition?
Megaloblastic anemia likely caused by B12 deficiency
What is the primary cause of aplastic anemia?
Idiopathic; autoimmune
What are some main secondary causes of aplastic anemia?
- Ionizing radiation
- Cytotoxic chemotherapy
- Benzene exposure
- Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Viruses: EBV and hepatitis (non A, B, C, D, and E)
In someone with aplastic anemia, will there be splenomegaly?
No
The presentation of aplastic anemia is consistent with deficiencies in what cell lines?
Red, white, and platelets (pancytopenia)
In someone with AA, why would the patient be more susceptible to infection and fever?
- Low neutrophil count (neutropenia)
If a patient is presenting with symptoms of AA and have pancytopenia, then what conditions should you rule out first?
- B12/folate deficiency
- Splenomegaly
- Alcohol is a marrow toxin, so check for excess intake
- Lupus
In order to make a proper diagnosis of AA, you should rule out other causes of _______ and do a ___ ____ biopsy
Pancytopenia; bone marrow
To make a diagnosis of pure AA, what should be done?
- Rule out other causes of pancytopenia
- Think about possible exposures to drugs and test for viruses
- Test for PNH
- Do a bone marrow biopsy
When a bone marrow biopsy is done to diagnose AA, what should you be looking for?
- Degree of cellularity
- Rule out cancer, infiltrative disorders (sarcoidosis, fibrosis)
- Rule out dysplasia (MDS)
When diagnosing AA, what is the main test that should be done?
Bone marrow biopsy
What are some treatment options for AA?
Supportive care
- Transfusions
- Antiobiotics
- Growth Factors
Definitive Care
- Stem cell transplant
- T- cell directed immunosuppression with antithymocyte globulin (ATg) and cyclosporine (relapses may occur)
In treatment of AA, what treatment would be preferred in younger patients?
Stem cell transplant
What type of stem cell transplant would be given to someone with AA?
- Allogenic bc is a source of undamaged stem cells
To treat certain cancers (leukemias), what stem cell transplant could be used when you want to do a lot of chemotherapy?
Autologous (patient’s own marrow) or peripheral blood stem cells (PBSC); there is no GVHD because the graft is the host
What is hemoglobinuria?
Hemoglobin in the urine
What is the definition of Paroxysmal Nocturnal Hemoglobinuria (PNH)?
An acquired clonal hematologic disorder in which an abnormal stem cell clone develops that gives rise to red cells, white cells, and platelets that are all missing proteins attaced to the cell surface via the GPI anchor
The abnormal clone in PNH is missing the ____ gene that is responsible for making GPI
PIG-A
The PIG-A gene encodes ___ that anchors CD55 and CD59 to the surface of red cells
GPI
What are the 2 GPI anchored proteins that are missing in PNH that are important in inhibiting complement binding to red cells?
CD55 and CD59
CD55 and CD59 are important in inhibiting _____ on the surface of red cells
Complement
PNH red cells are extremely sensitive to what kind if red cell destruction?
Complement-mediated
At what time of the day does the pH in the blood fall, which leads to more complement-mediated lysis?
Night
In PNH, what happens at night?
Hemolysis occurs and in the morning patients urinate and they get rid of hemoglobin (hemoglobinuria) and that leads to iron deficiency
____ deficiency is seen in patients with PNH
Iron
Thrombosis in the arteries and ____ occurs in PNH
Veins
Budd Chiari syndrome
Associated with PNH and is thrombosis of the hepatic vein that leads to liver failure
Budd-Chiari Syndrome is associated with what condition?
PNH
In PNH, patients will have ___ ____ failure as well as will be at a predisposition for MDS and ___
Bone marrow; AML (leukemia)
The intravascular hemolyis in PNH leads to low ___ ___ levels that lead to a defect in smooth muscle relaxation/contraction
Nitric oxide; relaxation
Patients with PNH may present with constriction of smooth muscle that leads to esophageal spasms, ____ dysfunction, and pulmonary hypertension
- Erectile
Eculizumab may be given to patients with _________
PMH
What is the MOA of eculizumab?
- Targets C5 and blocks activation of the terminal complement (MAC complex)
Someone on eculizumab is more suscpetible to what type of infections?
Neisseria
What are the treatments for PNH?
- Iron pills
- Anticoagulation
- ATG and cyclosporine (immunosuppression)
- Eculizumab
Fanconi’s Anemia is the most common form of inherited ____
AA
What is the inheritance pattern of Fanconi’s anemia?
Autosomal recessive or X-linked
Someone with fanconi’s anemia may present with ________ and then the disease progresses to pancytopenia
Thrombocytopenia
PNH can develop into AA or ___
AML
Clinical manifestations of fanconi’s anemia
- Pancytopenia
- Macrocytic
- May start with thrombopenia and then progress
- Somatic abnormalities: (short stature, cafe-au-lait macules, weird thumbs, micro- or hydrocephaly, hypogonadism, developmental delay)
- Increased incidence of acute leukemia and tumors
- Usually presents in childhood
What are some characteristic congential mutations of fancon’s anemia?
- short stature
- cafe-au-lait macules
- weird thumbs
- micro- or hydrocephaly
- hypogonadism
- developmental delay
To diagnose for fanconi’s you should take the lymphocytes or fibroblasts and then add ___ and look for abnormal ______ breakage
Diepoxybutane (DEB); chromosomal
You should suspect ___ in any child or young adult with bone marrow failure
FA
Suspect ___ in patients who have cancer at a young age or who have familial cancer
FA
To treat fanconi’s anemia, you should perform an _______ transplant with reduced intensity pre-transplant conditioning
Allogenic
People with Fanconi’s anemia have increased toxicity from _____ and chemotherapy
Radiation
What causes fanconi’s anemia?
A mutation in one of the 16 genes responsible for DNA repair –> several of these genes are tumor suppressors
Dyskeratosis congenita is an inherited disorder of _____ shortening and is also an inherited form of __
-telomeres; AA
What are some clinical characterisics of dyskeratosis congenita?
- Bone marrow failure
- Predisposition to acute leukemia and other solid tumors (typically squamous cancers)
-
Classic triad
- Mottled hyperpigmentation of skin that involves the arms, shoulders, neck, and torso
- Abnormal nails of fingers and toes
- Mucosal leukoplakia
- Pulmonary fibrosis
- Prematurely gray hair
- Cirrhosis of liver
Classic triad of what disease
Dyskeratosis congenita (DKC)
Excessive sweating (hyperhydrosis) is seen in what condition?
DKC
if have a negative genetic test for FA causing mutation, should you rule out FA?
No
What is the only curative treatment for DKC?
Allogenic stem cell transplant with reduced intensity pre-transplant
Patients with DKC have increased sensitivity of radiation and chemo in the ____ while the toxicity is in the ____ ____ in fanconi’s anemia
lungs; bone marrow
The FLAER test is used in ___ to test GPI-anchored proteins
PNH
