Lecture 4: Anemia II Flashcards
What is aplastic anemia?
Failure of hematopoietic bone marrow due to suppression of or injury to stem cells.
What is the MC of aplastic anemia?
Idiopathic autoimmune suppression of hematopoiesis.
What kind of diseases result in aplastic anemia?
PNH
SLE
Transfusion GVHD
What toxins can cause aplastic anemia?
BENZENE
toluene
insecticides
mercury
What medications can cause aplastic anemia?
CHEMO
anticonvulsants
chloramphenicol
cimetidine
sulfa
What infections can cause aplastic anemia?
HEPATITIS
EBV
Parvovirus B19
CMV
What other things can cause aplastic anemia?
Radiation exposure
Pregnancy
Congenital
Describe the pathology of aplastic anemia.
Hypoplasia of hematopoietic bone marrow leads to decrease in ALL hematopoietic cell lines.
Note:
This means platelets and WBC production are affected as well.
What does hypoplastic bone marrow look like?
Very white due to increased fat deposits and reduced hematopoeisis.
How does aplastic anemia present clinically?
Decreased WBCs leads to increased infections.
Decreased RBCs leads to pallor, fatigue, dyspnea, and palps.
Decreased platelets leads to bruising, bleeding from mucosa and skin.
Exam findings:
Pallor, purpura, petechiae.
Lack of hepatomegaly or splenomegaly.
How do I differentiate rashes from petechiae/purpura?
Rashes will blanch when pressure is applied.
How does aplastic anemia present on lab findings?
WBC: decreased
Platelets: decreased
Retic: Little to none
MCV: normal or increased
MCH: normal
Bone marrow biopsy would show hypocellular aspirate with little to no hematopoietic precursors.
What kind of anemia is aplastic anemia usually? (Morphologically)
Normocytic normochromic anemia.
What kind of supportive treatment can be given with aplastic anemia?
RBC transfusion
Platelet Transfusion
Antimicrobials
Note:
Do not transfuse WBCs, since risk of fever or autoimmune reaction is high.
What kind of growth factors can be given for aplastic anemia? Why?
Multilineage: Eltrombopag/Promacta. Helps boost RBC and WBC production.
Erythropoietic: Epoetin, Darbepoetin
Myeloid: Filgrastim, Sargramostim
What are the two major treatments for aplastic anemia?
Bone marrow transplants for pts under 40 yo with full HLA-matched sibling donors.
Immunosuppression for ineligible transplant candidates.
Equine ATG + cyclosporine + steroids +/- eltrombopag + bone marrow stimulating drug
Why are corticosteroids given with horse/equine ATG?
Preventing anaphylaxis.
What are epoetin and darbepoetin?
Human EPO made via recombinant DNA.
Darbepoetin alfa has 3x the halflife of epoetin alfa
They are also cytokines and growth factors.
What is the purpose of human EPO?
It stimulates division and differentiation of the erythroid precursors.
What are the other indications of human EPO?
Anemia due to CKD, chemotherapy, and myelodysplasia
What are the CIs for human EPO?
Allergy
Uncontrolled HTN
Pure red cell aplasia post tx
What is pure red cell aplasia?
RBC production suddenly stops, meaning the bone marrow is too dependent on EPO.
What are the main SE associated with human EPO?
HTN and thrombosis.
Most increased risks of death are due to an infarct or thrombosis.
What should be monitored in someone being given human EPO?
CBC
Iron
BP
Hb (weekly)
What is sideroblastic anemia?
A mixed group of disorders sharing abnormalities in heme synthesis and mitochondrial function.
All of them result in ring sideroblasts when a bone marrow aspiration is performed.
What is the etiology of sideroblastic anemia?
Decreased Hb synthesis 2deg
Reduced ability to synthesize heme bc of impaired ability to incorporate iron into protoporphyrin IX. (precursor to heme)
What does a ring sideroblast look like?
Ring of blue
What are the causes of inherited/congenital sideroblastic anemia?
X-linked (MC inherited)
Autosomal recessive
Mitochondrial inheritance
AKA males are more likely.
What are the causes of acquired sideroblastic anemia?
Acquired is the most common type of sideroblastic anemia.
Often part of a general myelodysplastic syndrome.
Chronic alcoholism
Lead poisoning
Copper deficiency
Chronic infection/inflammation
Medications: mainly antimicrobials such as isoniazid, linezolid, and chloramphenicol.
Why does lead poisoning cause sideroblastic anemia?
Lead gets stored in the bones in excess.
How does sideroblastic anemia present clinically?
General anemia symptoms.
S/S of myelodysplastic syndrome are possible too.
What PE finding on the hand is suggestive of anemia?
Palmar creases.
What lab findings would I expect in sideroblastic anemia?
Hb/Hct: variable decreases, mainly in Hct.
MCV: can be decreased, but sometimes elevated in acquired.
RDW: increased
Retic: normal or decreased
TIBC: normal or minor decrease
Transferrin sat: increase since more iron is being carried.
Iron: increased
Ferritin: increased
Why does iron increase in sideroblastic anemia?
Iron increases because there is more available since the protoporphyrin IX can’t incorporate the iron into the heme.
How does sideroblastic anemia present on peripheral smear?
Basophilic stippling
Poikilocytosis
Anisocytosis
Polychromasia
What test must be done to confirm sideroblastic anemia?
Bone marrow aspiration with a prussian blue stain.
What exactly is a ring sideroblast?
Erythroid cells with iron deposits in mitochondria encircling the nucleus.
What does erythroid hyperplasia on a bone marrow aspirate indicate?
Ineffective erythropoiesis.
How do I treat congenital sideroblastic anemia?
Some forms will respond to B6 (pyridoxine) or B1 (thiamine).
How do I treat drug-induced sideroblastic anemia?
Stopping the med.
If it was due to isoniazid, B6/pyridoxine may help.
What is the MC of anemia worldwide?
Iron deficiency.
What is the MC of anemia in the US?
Folate deficiency.
What are the two types of iron, and which one is best absorbed?
Heme, 40% of meat, which is 10-20% absorbed.
Non-heme, 60% of meat, 100% of veggies, which is 1-5% absorbed.
10% overall absorption in an ACIDIC environment.
What is ferroportin?
Major iron transporter and the only exporter of iron from cells.
What is hepcidin?
Promotes the breakdown of ferroportin and thus inhibits iron release.
Note:
This is why chronic inflammation alters iron concentrations. Hepcidin is induced via IL-6.
Why do vegan diets and chronic antacid use impair iron absorption?
Veggies have non-heme iron, which is poorly absorbed.
Chronic antacids neutralize stomach acidity, but iron is best absorbed in an acidic environment.
When is increased iron needed?
Pregnancy
Lactation
Growth spurts
What are the causes of iron deficiency?
Deficient diets
Increased usage of iron
Chronic blood loss
Decreased absorption
Iron Sequestration
What can cause decreased iron absorption?
Gastritis
Chronic diseases like celiac sprue or Crohn’s
Gastric surgery
Zinc deficiencies
Hereditary iron-deficiency anemia
How does iron deficiency anemia present?
General anemia symptoms
Key:
Plummer-vinson syndrome on EGD.
Koilonychia
Smooth tongue
Brittle nails
Cheilosis
Pica
Restless leg syndrome, neurodevelopmental delay
What is pica?
Craving for substances not rich in iron, like ice, clay, and dirt.
How does iron deficiency progress?
Low iron with no anemia => Normocytic anemia => Microcytic anemia
What lab findings would I expect in iron deficiency anemia?
Hb/Hct: variable decreases
MCV: normal early, decreased later.
MCH: decreased
Retic: normal or decreased
TIBC: increased (want iron but have none)
Transferrin sat: decreased (don’t actually have iron)
Iron: decreased
Ferritin: decreased
How does iron deficiency anemia present on peripheral smear?
Hypochromic, microcytic cells
Target cells
Poikilocytosis
Anisocytosis
Increased platelets (different from thalassemia)
What is the main treatment for iron deficiency anemia?
Oral Iron supplementation.
Ferrous sulfate 325mg PO TID on an empty stomach.
What should improve CBC lab-wise with iron supplement?
Hct should go to halfway normal in 3 weeks.
Baseline in 2 months.
Retic should rise in a week and peak in 1.5 weeks.
What are the main SE of iron supplementation?
Nausea, vomiting, and constipation in 15-20% of pts.
What can you do to improve iron supplementation?
Gradually escalating dosage.
Taking with food if SE are too strong.
Ascorbic acid
QOD frequency
Make sure you take it for 6 months even after anemia resolves.
How does pH affect iron absorption?
Acidic = better absorption.
What is a common second-line iron supplement?
Ferrous gluconate, if people have severe GI upsets.
What kind of anemia should never be given iron supplements?
Extravascular hemolytic anemias.
What are the CI of iron supplementation?
Allergies
Hemochromatosis
Hemolytic anemias
What lab finding responds very quickly to iron supplementation?
Retic count
What is the alternative to oral iron supplementation?
Parenteral iron replacement therapy.
IV infusion for a few minutes.
What is normally added to parenteral iron supplementation?
EPO, which will increase bone marrow response to iron.
Why was parenteral iron supplementation not preferred before?
Iron dextran was the older form that took hours and had anaphylaxis risk.
IM forms had iron staining (cutaneous siderosis)
How is anemia caused by inflammation/infection?
Proinflammatory cytokines => increased hepcidin => decreased iron absorption and availability.
How does anemia of chronic inflammation present clinically?
Similar to iron deficiency anemia.
Mainly normocytic (75%) but sometimes microcytic (25%)
Decreased iron levels.
Increased/normal ferritin w/ hx of inflammation or infection separates it from iron deficiency anemia.
How is anemia caused by CKD?
Failure to secrete adequate EPO by the kidneys.
CKD severity correlates with anemia severity.
How does anemia of CKD present clinically?
Normocytic, normochromic anemia.
Normal iron studies.
Pts on dialysis can develop secondary iron/folate defiencies.
What are the anemias of hypometabolic states?
Anemia of endocrine disorders
Anemia of chronic liver disease
Anemia of starvation
What is anemia of endocrine disorders?
Decreased EPO secretion, which results in normocytic, normochromic anemia.
Mainly seen in decreased hormone secretion, such as decreased thyroid, testosterone, and/or cortisol.
What is anemia of chronic liver disease?
Cholesterol deposits in the RBC membranes shorten their survival + the body is secreting insuffficient EPO.
Typically, it is in alcoholics, who also have other nutritional deficiencies.
Macrocytic anemia! (cholesterol deposits increase RBC size)
What is anemia of starvation?
Decreased protein intake leads to decreased metabolism which leads to decreased EPO.
Commonly seen in people starving themselves, eating disorders, and elderly pts.
What is anemia of the elderly?
Occurs in 20% of pts >85 yo.
Caused by resistance to EPO, decreased EPO secretion, and a chronic low-level inflammation.
Presents with anemic s/s but has a negative work-up for anemia etiology.
Treated sometimes with EPO, but it may require a lot if resistant.
What kind of anemia is a B12 deficiency?
Megaloblastic anemia.
What is the role of B12?
Conversion of MMA to Succinyl-CoA
Conversion of homocysteine to methionine.
These are both part of DNA synthesis in erythroid precursors.
Where does B12 come from?
Animal-based foods, fortified foods.
What kind of vitamin is B12?
Water-soluble, so it is mainly stored in the liver.
What is required to absorb B12?
Intrinsic factor from the stomach, which binds to B12 so it can be absorbed in the ileum.
What causes a B12 deficiency?
Dietary deficiencies (vegan, alcohol, elderly)
Decreased intrinsic factor (pernicious anemia or gastric surgery)
Pancreatic insufficiency
Transcobalamin II deficiency (inherited disorder. Transcobalamin is similar to transferritin)
Medications: Metformin, PPIs, colchicine.
Competition of B12 (blind loop syndrome or a fish tapeworm)
Decreased B12 absorption (Surgical small bowel resection or Crohn’s)
How does B12 deficiency present clinically?
Insidious onset of general S/S of anemia, along with decreased WBC and platelets.
Unique:
Gradual onset neuropathy, starting with peripheral paresthesia.
What kind of anemia is a B12 deficiency?
Macrocytic hyperchromic anemia.
What lab findings do I expect in a B12 deficiency?
Hb/Hct: variably decreased
MCV: increased
MCH: increased
MCHC: normal
Serum B12: decreased
Homocysteine & MMA: increased
Retic: normal or decreased
WBC & platelets: normal or decreased
LDH and bilirubin: increased (intramedullary destruction of abnormal RBCs)
How does B12 deficiency anemia present on peripheral smear?
Hypersegmented neutrophils
Macro-ovalocytes
Bizarre RBC shapes (poikilocytosis due to DNA synthesis errors)
Basophilic stippling
What are the main tests to check for pernicious anemia?
Anti-intrinsic factor antibodies: elevated in 50% of pts. specific but non-sensitive.
Anti-parietal cell antibodies: elevated in 85% of pts, non-specific
Gastrin levels: elevated in 80-90% of pts, non-specific
Gastric biopsy on EGD
Schilling Test (OLD TEST) w/ B12 IM.
How is B12 deficiency treated?
B12 injection therapy. 1mg IM.
Oral B12 therapy once correction is fixed at 1mg/day.
Folic acid 1mg/day also.
Transfusions PRN
Dietary counseling
Why can pernicious anemia not be treated by oral B12?
Impaired absorption since it is related to intrinsic factor.
How quickly is the response to Oral B12 tx?
Reticulocytosis in 1 week.
Normal CBC in 2 months.
What is cyanocobalamin?
Synthetic B12 to replace cobalamin in the body.
Only CI is allergy.
SE include HA, paresthesia, GI upset, and glossitis.
What is the role of folate in the body?
Conversion of homocysteine to methionine.
Where does folate come from?
Fruits and veggies, specifically citrus and leafy greens.
How much folate do we use daily and eat/absorb?
We use up 50-100 mcg/day.
We eat 250 mcg/day and absorb about 125 mcg/day.
How much folate do we store and where?
5-10mg stored in the liver.
Where is folate absorbed?
Upper SI.
Jejunum
What is the main cause of a folate deficiency?
Not eating enough folate.
Alcoholism, lack of fruits/veggies, overcooking, or anorexia.
What other conditions can cause folate deficiencies?
Pregnancy
Chronic hemolytic anemia
Exfoliative skin disease
Methotrexate
Hemodialysis
Tropical sprue w/ concurrent B12 deficiency
Phenytoin, sulfasalazine, and trimethoprim-sulfamethoxazole.
What is the metabolite absorption mnemonic?
DI
JF
IB
Dude Is Just Feeling Ill Bro
Duodenum-Iron
Jejunum-Folate
Ileum-B12
How does folate deficiency present clinically?
S/S of anemia, insidious onset.
Similar to B12 EXCEPT no neuropathy!!!!!!
What lab findings would I expect in folate deficiency?
Hb/Hct: variable decrease
MCV: increased
MCH: increased
MCHC: nrormal
B12: normal
Homocysteine: Increased
MMA: normal
Retic: Normal/decreased
WBC/platelets: normal/decreased
RBC folate/folic acid: decreased
Serum folic acid is preferred over RBC folate bc it checks more recent folic acid intake and is cheaper.
How does folate deficiency present on peripheral smear?
Hypersegmented neutrophils
Macro-ovalocytes
How is folate deficiency treated?
Folic acid PO 1-5 mg/daily for 4+ months.
RULE OUT B12 DEFICIENCY
L-methyfolate is the active form.
Transfusions are rare.
Note:
Malabsorption doesn’t affect the entire jejunum so malabsorption is rarely an issue.
How quickly is the response to folate deficiency treatment?
Reticulocytosis in 1 week.
CBC normalization in 2 months.
Why is folic acid used in pregnancy?
To prevent neural tube defects.
What is a myeloproliferative disorder?
Any disorder that is categorized by excessive growth of 1+ hematopoietic stem cell lines.
What are the myeloproliferative disorders?
Polycythemia vera: excessive production of all hematopoietic cells, esp. RBCs.
Essential thrombocytosis: Excessive platelet production
Myelofibrosis: excessive production of collagen or fibrous tissue in the marrow.
Chronic myelogenous leukemia (CML): excessive production of granulocytes
How do myeloproliferative disorders generally present?
General: fatigue, anorexia, weight loss, night sweats
GI: Hepatosplenomegaly, abdominal discomfort, early satiety.
Skin: pallor, easy bruising, petechiae, bleeding, superficial vein thrombosis.
Which myeloproliferative disorder causes flushing and plethora instead of pallor?
Polycythemia vera.
How do myeloproliferative disorders cause anemia?
Abnormal cell growth competes with erythroid precursors for space.
How are myeloproliferative disorders worked up lab-wise?
CBC and bone marrow biopsy.
How is polycythemia vera treated?
Regular phlebotomies and myelosuppression.
How is essential thrombocytosis treated?
Myelosuppression if symptomatic, otherwise observe.
How is myelofibrosis treated?
Myelosuppression if symptomatic or bone marrow transplant. Observe if asymptomatic.
How is CML treated?
Chemotherapy, myelosuppression, bone marrow transplant.
Why does bone marrow suppression work on myeloproliferative disorders?
Bone marrow suppression targets the most metabolically active cells first.
