Clinical Aspects of Anemia Flashcards
Work Up of Anemia
Rule out hemorrhage vs sequestration (rare)
Etiology can be found with the H&P, Reticulocyte count, CBC and the Peripheral Smear
Then classify as either:
Hypoproliferative (not making them)
Hemolytic (survival defect)
Production Defects
Reticulocyte count- Decreased
Morphology- Normal
Etiology-
Decreased Erythropoeitin
Bone Marrow Failure
Examples- Chronic Renal Disease Anemia from Bone Marrow Damage Anemia of Chronic Disease (ACD) Anemia of Hypometabolic states: hypothyroidism, Addison Disease, hypogonadism, and panhypopituitarism
Anemia of Chronic Disease
Is the most common cause of anemia in the hospitialized medical patient
Inflammation leads to production of IL-6 which then produces hepcidin. This then decreases the release of iron from macrophages.
Causes- most common:
Chronic rheumatic
Infectious
neoplastic
Iron Studies for Fe Deficiency and ACD
Fe Deficiency: low Fe, low ferritin, high TIBC, low transferrin saturation (bound), and high soluble transferrin receptor (unbound)
Anemia of Chronic Disease: low Fe, low high ferritin (acute phase reactant), low TIBC, low/normal transferrin saturation, and normal soluble transferrin receptor
Maturation Defect: Cytoplasmic
Reticulocyte count- Decreased
Morphology- Hypochromic, Microcytic
Etiology
Impaired Hgb synthesis
Protoporphyrin deficiency
Globin synthesis deficiency
Examples
Fe Deficiency
Sideroblastic anemia
Thalassemias
Iron Deficiency PE
Fatigued, tachycardic, dyspnea, cheilosis, esophageal webs (Plummer-Vinson), pica
History: pregnancy, diet, family history
Normal Volume
Low MCV
Fe Deficiency: Labs
Fe is essential for Hb production and a deficiency will lead to impaired erythropoeisis.
Red cells are microcytic and hypochromic
Reticulocyte count is low
Serum Fe and ferritin are low
Transferrin levels are high with elevated TIBC
You must pursue the etiology
Siderblastic Anemia
Moderate to severe anemia- Hb 4-10 mg/dl
Indices Serum Iron is elevated Serum Ferritin is elevated TIBC is normal Reticulocyte count is low MCV is low
Smear will show anisocytosis and poiklocytosis
Bone Marrow will show erythyroid hyperplasia with a maturation arrest.
**Prussian Blue stain of the marrow will show the mitochondrial iron deposition which will result in the ringed sideroblasts.
Types of Sideroblastic Anemia: Hereditary
Hereditary
Congenital X-linked- ALAS-2 mutations
ALAS is a rate limiting enzyme in heme biosynthesis
Mitochondrial cytopathy
Autosomal recessive sideroblastic anemia involves mutations in the SLC25A38 gene
Types of Sideroblastic Anemia: Acquired
Acquired
Myelodysplasia
Copper deficiency- copper is needed for iron metabolism
Pyridoxine deficiency- can be caused by isoniazid
Drugs/Toxins
Toxins- Lead, Zinc, auto-antibodies
Drugs- Ethanol, Isoniazid, Cycloserine, Chloramphenicol, Busulfran
Copper chelators- Penicillamine, Trientene- These meds are used for the treatment of Wilson’s disease.
Sideroblastic Anemia: Tx
Rule out reversible causes
Eliminate any drugs that may be causing it
Transfusion
Need to watch out for iron overload
Pyridoxine therapy
Little downside to using it, may help the anemia
Alpha Thalassemia
Due to gene deletion with reduced alpha chain synthesis
Severity is determined by absence of 1-4 alpha chains
Deletion of all 4 chains (β4) results in hydrops fetalis - fatal
Seen in people of China and SE Asia
Microcytosis worse than degree of anemia
Hb H of requires frequent transfusions throughout life
Alpha Thalassemia: 4 Deletion Types
1) α- Thalassemia trait- 1 loci affected, asymptomatic, no hematologic abnormalities.
2) α- Thalassemia Minor- 2 loci affected, asymptomatic, MCV low, little to no anemia.
3) HbH- 3 loci affected, unpaired β chains form β4 tetramers called HbH, these form inclusions in peripheral cells. Intermediate anemia with avoidance of transfusions until adulthood.
4) Hb Barts- 4 loci affected, no effective hemoglobin, causes death in utero.
Beta Thalassemia
Due to a point mutations
Alpha chain hemoglobins are unstable in the absence of beta chains and precipitate which damages RBC membranes
Peripheral RBC destruction
Hyperplastic bone marrow due to anemia
Greek and Mediterranean predominance
Low MCV common
Hb electrophoresis
Homozygous is Major, asymptomatic until 6 months then major issues leading to early death by 20-30 years old
Heterozygous is Minor, microcytic anemia but normal life expectancy, odd peripheral smear.
Beta Thalassemia: Three Categories
β- thalassemia- three categories
1) β- thalassemia minor- mild or no anemia with a disproportionate degree of microcytosis.
* *2) β- thalassemia major- Cooley anemia- Have no β chain production. This forms insoluble α chains which precipitate into inclusion bodies. These cause death within the marrow and splenic removal which causes a severe anemia. This will cause high erythropoeitin levels which then cause erythroid hyperplasia. If this is severe, it can cause extramedullary hematopoiesis. These patients are usually transfusion dependent and develop iron overload.
3) β- thalassemia intermedia- homozygous. Can range from asymptomatic to transfusion dependent. Minor defects of β globin production with α-thalassemia trait lead to decreased inclusion bodies.
Maturation Defect: Nuclear
Reticulocyte count- decreased
Morphology- Megaloblastic
Etiology- DNA synthesis defects
Examples
B12 deficiency
Folate deficiency
B12/Folate Deficiency
Megaloblastic anemias result from impaired DNA synthesis.
Glossitis, gastrointestinal issues, anorexia, diarrhea, neurological defects ranging from paresthesias to frank psychosis.
High MCV >100+fL
Anisocytosis, poikilocytosis
Differentiate with B12 and folate levels
LDH may be high
May coexist with Thalassemia or iron deficiency and MCV may be normal
B12/Folate Deficiency: Peripheral Smear
The main feature is oval macrocytes with considerable anisocytosis and poikilocytosis.
The MCV is > 100fL (unless a cause of microcytosis is present)
Neutrophils are hypersegmented ( > 5 lobes )
A degree of neutropenia
Thrombocytopenia
The severity of these changes will parallel the severity of the anemia
B12/Folate Deficiency: Bone Marrow
In the severely anemic patient, the marrow is hypercellular with an accumulation of of primitive cells d/t selective death by apoptosis of more mature forms.
The cells are larger than normoblasts and can have eccentric lobulated nuclei.
Giant and abnormally shaped metamyelocytes and enlarged hyperpolyploid megakaryocytes are characteristic.
Ineffective Hemopoiesis: B12/Folate Deficiency
There is and acumulation of unconjugated bilirubin in plasma due to the death of nucleated red cells in the marrow.
Other findings are elevated urine urobilinogen, reduced haptoglobins, positive urine hemosiderin, and a raised serum lactate dehydrogenase.
Folate vs. B12 Deficiency Causation
Folate Deficiency is caused by
Poor diet
Increased demand (pregnancy)
B12 Deficiency results from
Strict vegan diet- Inadequate dietary intake is the number one cause of B12 deficiency.
Inability to release B12 from food sources
Decreased Intrinsic Factor (pernicious anemia)
Defects in ileal function
Diagnosis with Shilling Test ( radiolabeled B12): methylmalonic acid (MMA) and homocysteine; both can be used to diagnose an early deficiency, but many other conditions can cause elevations of the levels which lowers the accuracy of the tests.
Diagnosis of Folate Deficiency
Serum Folate
This is measured by an ELISA assay. The normal range is from 2.0ug/L - 15ug/L. The serum folate levels will rise in cobalamin deficiency because of the block in the conversion of MTHF to THF inside the cells.
Red Cell Folate
The red cell folate assay is a valuable test of body folate stores. It is less affected by recent diet and traces of hemolysis. Normal range is 880-3520umol/L.
Dx of Cobalamin (B12) Deficiency
Serum Cobalamin
Normal serum ranges are 160-1000ng/L
In a megaloblastic anemia, the level is usually
Tx of Cobalamin Deficiency
It is usually necessary to treat patients who are deficient with regular and lifelong injections of cyanocobalamin. Some patients can have the cause corrected and not have to receive lifelong therapy.
Cobalamin should be given routinely to all gastrectomy and ileal resection patients.
Cyanocobalamin is usually given at 1000ug IM a month.
Because of passive absorption thru mucus membranes, large dose oral replacement can be used.
Tx of Folate Deficiency
Oral doses of 5-15mg/d are usually sufficient. The length of therapy is usually 4 months. This allows folate deficient red cells to be elminated from the bone marrow.
Cobalamin deficiency must be excluded before folate replacement is started. If there is a deficiency, then the cobalamin must be corrected first.
Patients with chronic dialysis and hemolytic anemias must continue with folate replacement for life
Oral Folic Acid
Prophylactic Folic Acid- In many countries, food (grain and flour) is fortified with folic acid to prevent neural tube defects.
Pregnancy- 400 ug daily should be given as a supplement before and throughout pregnancy.
Infancy and Childhood- The incidence of folate deficiency is so high in premature babies during the first 6 weeks of life that folic acid should be given routinely (1mg/d) to babies weighing
Survival Defects
Supplemental Hemolysis Lab Tests
Haptoglobin- If Low = Hemolysis. The released Hb will bind to haptoglobin and then be consumed by macrophages. Nonspecific for the type of hemolysis.
Urine Hemosiderin- If high = intravascular hemolysis.
LDH levels are elevated in both types of hemolysis.
Coombs Test- tests for extrinsic causes
Direct vs. Indirect Coombs Test
Direct: autoAb against IgG or C3 prepared in animal mixed with patients blood, RBCs agglutinate meaning IgG or C3 on surface of RBC = positive test
Indirect: done to see if patient’s serum contains Ab that cause agglutination of other RBCs; RH and ABO compatible RBCs are mixed with patients serum and positive test is caused by agglutination
Survival Defects: Intrinsic
Reticulocyte count- Increased
Morphology- Spherocytes, sickle cells, bite cells
Etiology
1) Membrane cytoskeleton protein
2) Metabolic enzymes
3) Hemoglobinopathy
Examples
1) Spherocytosis
2) G6PD deficiency
3) SS Disease, HbC, HbD, HbE
Hereditary Spherocytosis
Variable anemia
Due to a defect in spectrin and actin which acts to deform RBC and disrupt their deformability properties
Spleenic trapping
May see an elevated MCHC >36g/dL
Severe anemia may be seen in aplastic crisis with folate deficiency or infections
Splenectomy
G6PD Deficiency
Glucose 6-phosphate dehydrogenase
This deficiency is mainly distributed in tropical and sub tropical parts of the world. It can provide resistance to malaria.
Most patients will remain clinically asymptomatic
Hemolysis can be mild to massive.
X-linked recessive disorder resulting in a reduced state of Glutathione. Glutathione protects against oxidative stressors
Peripheral smear will reveal Bite cells and Heinz bodies.
Check G6PD levels for diagnosis.
Acute hemolytic anemia will usually be triggered by:
Fava beans
Infections
Drugs- Primaquine, Dapsone, Nitrofurantoin, Pyridium, Sulfa drugs, Cipro, etc.
G6PD Symptoms and Tx
A hemolytic attack will start with malaise, weakness, abdominal/lumbar pain. After 2-3 days, the patient will develop dark urine d/t the hemoglobinuria.
Major complication is the development of ARF.
For most cases, removal of the inciting drug/bean/infection is the only treatment.
Transfusions may be required.
Survival Defect: Extrinsic
Reticulocyte count- Increased
Morphology- Spherocytes, schistocytes
Etiology
1) Antibody or compliment mediated
2) Microangiopathy
Examples
1) Auto immune hemolysis
2) Malaria
3) DIC
4) Vascular hemolysis
Malaria
High fever, diaphoresis, chills, headache, vomiting, severe influenza-like symptoms
P. falciparum can exceed 10% of RBCs versus 1-2% for other forms.
Fatal events within 24 hours of symptoms
ATN, hepatitis, convulsions, water balance disturbances, dysrhythmias, gastrointestinal hemorrhage
Therapies include oral and parenteral: Quinine, Primaquine, Chloroquine, Pyrimethamine, Mefloquine
Transfusion Reaction
Profound and immediately life threatening anemias
Fever, chills, backache, headache, dyspnea, hypotension, apprehension, vascular collapse
DIC, oliguria, acute renal failure (consider signs with surgical patients who are under anesthesia)
Usually caused by ABO incompatibility
Clerical errors are a major issue
Dose dependent reactions
May be delayed for several days
Stop transfusion, check for free hemoglobin, consider hydration and dialysis
Sequestration
Reticulocyte count- Increased
Morphology- Normal
Etiology- Hypersplenism
Examples
Portal hypertension
Splenic sequestration crisis
Blood Loss
Reticulocyte count- Increased if Fe stores are normal
Morphology- Normal or hypochromic
Etiology- GI hemorrhage Retroperitoneal bleed Intrapulmonary Trauma
One of the biggest causes of anemia
Normal MCV, when does it change to low MCV? Blood loss anemia causes iron stores to be depleted located in the liver, and the amount iron stored is checked by FERRITIN (KNOW), so liver will transfer iron to bone marrow to back RBCs and once depleted and get iron deficiency anemia and early on you will be normal because no idea they are bleeding and then later become fatigued and what not and have hypochromic anemia
