Hypoproliferative Anemia Flashcards by Victor Redmon

What are the characteristic lab findings of hypoproliferative anemias?

Anemia and low reticulocyte count in lab

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What are the types of hypocellular bone marrow/hypercellular bone marrow?

Hypocellular bone marrows

Stem cell disorders
Drugs/Treatments

Hypercellular bone marrows

infiltration
Ineffective erythropoiesis

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What should the differential for pancytopenia be?

Stem cell disorders – Aplastic anemia, PNH
Ineffective hematopoiesis – MDS, Megaloblastic anemia
Marrow infiltration – Leukemia/lymphoma, metastatic carcinoma, myelofibrosis
Splenic sequestration – Massive splenomegaly
Drugs/Treatments – Immunosuppressants, Chemotherapy/radiation, other medications

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What is associated with hypersplenism?

Variable cytopenias – Estimated that 1/3 of platelets are stored in spleen

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What are the major steps involved in the folate pathway?

Purine synthesis

Conversion of dUMP to dTMP

One carbon for S-adenosylmethionine

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How is folate activated? What is it inhibited by?

Takes folate which is activated to THF via DHF reductase

Two step
Inhibited by MTX

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What does thymidylate synthetase do?
What inhibits it?
What does it require?

Conversion of dUMP to dTMP

Inhibited by 5-FU derivative FdUMP

Requires THF

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What are potential etiologies of megaloblastic anemia?

DHF reductase deficiency via MTX
Thymidylate synthetase deficiency – 5FU
Folate deficiency
Vitamin B12 deficiency

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What is the prurpose of the folate one-carbon?
What is it required for?

Purine synthesis
Required for thymidylate synthetase for conversion of dUMP to dTMP for DNA synthesis
Synthesis of methionine for SAM

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What is 5-Adenosylmethionine used for?

Methyl donation via methyl transferases

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What does methionine synthetase require?

Requires methyl THF and Vitamin B12

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What is Vitamin B12 bound to and how is it taken and transferred?

Bound to food
Released in stomach by HCl and pepsin
Binds mainly to R-protein but some to IF
In duodenum, R-protein degraded releasing Vitamin B12
Vitamin B12 binds intrinsic factor
Complex binds IF receptor
Vitamin B12 transferred to transcobalamin

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What are the causes of vitamin B12 deficiency?

Impaired absorption
IF deficiency
Ileal resection
Pancreatic insufficiency

Increased requirement (Pregnancy)
Decreased intake (strict vegans)
Tapeworm – Diphyllobothrium latum

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What are the clinical manifestations of Vitamin B12?

Megaloblastic anemia, pernicious anemia

Subacute combined degeneration
Dorsal and lateral tract demyelination
Parasthesias
Spastic paraparesis
Sensory ataxia

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What is pernicious anemia? What is its etiology?

Secondary B12 def to IF abnormalities
Most frequent cause of B12 deficiency
Autoantibodies against IF – Required for diagnosis

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What are the lab values of vitamin B12?

Low vitamin B12 levels
Low reticulocyte count
Auto-antibodies to IF or parietal cells (if pernicious anemia)
Elevated methylmalonic acid

What are the causes of folate deficiency?

Decreased intake – Alcoholism, poverty
Increased requirements – Growth, pregnancy, high cell turnover: hemolytic anemias, leukemias
Defective absorption – Jejunal resection or malabsorption
Folic acid antagonists

What are the clinical manifestations of folate deficiency?

Megaloblastic anemia

Neural tube defects
300,000 children/year
Spina bifida occulta – Anencephaly
Importance of supplementation

What is the therapy for megaloblastic anemia?

Vitamin B12 or folate supplementation
Oral vs IM injection

Do not treat vitamin B12 deficiency with folate
Anemia will reverse
Neurological manifestations will not

What are the diagnostics for megaloblastic anemia in PB and BM?

PB
Hypersegmented neutrophils – 5 or more lobes
Macrocytic anemia with oval macrocytes
Anisopoikilocytosis

BM – Not needed for diagnosis
Hypercellularity
Giant bands
Nuclear to cytoplasmic dyssynchrony (megaloblastic change) in erythroids, granulocytes

What is the functional role of iron?
Where is iron stored?

Component of heme (80%)
Component of myoglobin, cytochromes, catalases (20%)

Liver, spleen, marrow
Hemosiderin: Breakdown of ferritin
Ferritin

What is the epidemiology for iron deficency?

Most common worldwide nutritional disorder
4-5 billion people worldwide
2 billion with IDA
Infants, children, and women are most susceptible

What are the clinical outcomes for iron deficient?

Iron Deficient Anemia (IDA)
Impaired cognition, work capacity
Immune deficiency

What are the causes for iron deficiency?

Dietary lack, i.e. milk-fed infants

Impaired absorption (duodenum)

Increased requirement

Chronic blood loss
GI source (>50 y/o)
Menstrual bleeding

What transporter moves heme iron? What transporter moves non-heme iron? What is mucosal ferritin ?

Heme iron transporter Reduced by duodenal cytochrome B – Vitamin C to ferrous iron (Fe2+) Dication metal transporter – DMT-1 Huge complex 4500 molecules of iron per ferritin

What is the ferroportin transporter regulated by? What kind of iron does it require?

Regulated by Hepcidin – Liver feedback of iron and inhibits Ferroportin 1 Must be ferrous

What oxidizes the iron? What moves iron to the cells? How can iron be lost?

Hephaestin oxidizes to 3+ Binds transferrin to moves it to cells Iron can be lost via shedding of the GI epithelial cells

What is the serum ferritin study? What is the difficulty with using ferritin?

Most sensitive assay for iron deficiency anemia Ferritin has a high sensitivity and specificity for IDA when a cut-off equal to 30 microg/L is used \<12 is diagnostic of IDA Ferritin is an acute phase reactant (increases during inflammation) making its usage during a chronic inflammatory process more cloudy

What is the use of serum iron study?

Not sensitive or specific Many metabolic variations affect level

What is the total iron binding capacity study?

Essentially equivalent to a transferrin concentration Normally 30% of transferrin is saturated with iron Qualitatively opposite of serum ferritin levels

What is the defintion of percent iron saturation?

Serum iron/TIBC

What are the two bone marrow studies?

Storage iron: Macrophages within particles Sideroblastic iron: Within eryhtroid precursors

What is anemia of a chronic disease??

Most common anemia in hospitalized patients Mild to moderate

What are the clinical associations of anemia of chronic disease?

Chronic infections Immune dysfunction disorders Neoplastic disorders

What is the mechanism of anemia of chronic disease? What is the diagnostic criteria? What is the treatment for it?

Mechanism: Block in transport of irons from macrophages into erythroid precursors mediated by hepcidin (inverse relationship) Diagnosis Mild normocytic (80%) or microcytic (20%) anemia Without significant anisopoikilocytosis Iron studies Treatment Treat underlying disorder EPO or iron therapy

What is the anemia of renal failure? What medical treatment is associated with it? What cellular finding is associated with it? What is the treatment?

Decreased EPO production due to kidney damage Hemodialysis blood loss also contributes Hypoplastic erythroids Tx: EPO

What is pure red cell aplasia? What is the cause?

Selective absence of marrow erythroid precursors (differs from aplastic anemia which involves all 3 myeloid lineages) Difficult to identify etiology in many cases Seen in association with Thymic hyperplasia or thymomas (excision may be curative) Autoimmune disorders Drugs Large granular lymphocytic leukemia

What is myelophistic anemia? What kind of plastic state is it? What cellular finding is associated with it?

Anemia secondary to marrow infiltration by metastatic carcinoma Leukoeryhtroblastic reaction Tear drop cells