Notes
Anemia
Sections
Anemias
Overview
Anemia is defined as the reduction in the number of circulating red blood cells, which is measured by hemoglobin (Hb) or hematocrit (Hct)
- Women: Hb < 11 g/dL
- Men: Hb < 13 g/dL
- Transfuse: Hb < 7 g/dL (non-cardiac patients), Hb < 8 g/dL (cardiac patients)
4 Broad Categories
Microcytic
Mnemonic: FAST
- F: Fe (Iron) Deficiency Anemia
- A: Anemia of Chronic Illness
- S: Sideroblastic Anemia
- T: Thalasemias
Macrocytic
B12 and Folate Deficiencies
Normocytic
Intravascular Hemolysis
- Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Glucose-6-Phosphage Dehydrogenase (G6PD) Deficiency
- Immune Hemolytic Anemia (IHA)
- Microangiopathic Hemolytic Anemia
Extravascular Hemolysis
- Hereditary Spherocytosis
- Sickle Cell Anemia
Underproduction
- Parvovirus B19
- Aplastic Anemia
- Myelophthisic Process
Clinical Presentation/Management
Symptoms
- Fatigue
- Dyspnea
- Headache
- Palpitations/Tachycardia
- Pallor (best noted in the conjunctiva or under the tongue)
- Orthostatic lightheadedness/syncope
- Blood in stool
- Jaundice
Management
- Immediate Stabilization: transfuse
- Workup: CBC, MCV, reticulocyte count, peripheral smear
- CBC: tells you if you have low hemoglobin
- MCV: differentiates if microcytic, normocytic, or macrocytic
- Reticulocyte: identifies if there is an underproduction problem from the bone marrow**
- Peripheral smear: can help identify what type of anemia, but specifically differentiates between hemolytic versus non-hemolytic anemias
- Iron Studies, Ferritin, B12, folate – are there deficiencies that can be supplemented?
- DAT/Coombs test: is this an autoimmune process?
- Treatment
Microcytic Anemias
Differential Diagnosis:
- Chronic blood loss
- Menstrual blood loss (Population: women)
- Dietary deficiency (Population: vegans/vegetarians)
- Cancer (Population: elderly)
Peripheral Smear Findings:
- Hypochromic: RBCs are paler than normal
- Microcytic: smaller size to RBCs
Workup/Lab Tests:
- Iron Studies: Serum Iron Levels, Total Iron Binding Capacity (TIBC), Ferritin, and Red Blood Cell Distribution Width (RDW)
- Iron Deficiency Anemia will demonstrate:
- LOW serum iron levels: this makes sense because you do not have enough iron in your system
- HIGH total iron binding capacity: this makes sense because your cells WANT to bind iron so they have lots of capacity to bind iron when you do not have any in your system
- LOW ferritin: this makes sense because iron is stored in the liver as ferritin and when you have low iron, your body will start to use up the iron that is stored, meaning it will use up the ferritin in your body
- HIGH red blood cell distribution width: this makes sense because your RBCs are trying to minimize the amount of iron they are taking up and so a variety of different sizes of RBC will be made with varying amounts of iron that are taken up by your RBCs
Treatment
IV or PO Iron Replacement
Clinical Vignettes:
Anemia of Chronic Illness
Differential Diagnosis:
- Chronic infection
- Chronic kidney disease
- Malignancy
- Inflammation
- Trauma
All of these release inflammatory cytokines that decrease RBC production or sequester iron
Peripheral Smear Findings:
- Hypochromic: RBCs are paler than normal
- Microcytic: smaller size to RBCs
Workup/Lab Tests:
- Iron Studies: Serum Iron Levels, Total Iron Binding Capacity (TIBC), Ferritin, and Red Blood Cell Distribution Width (RDW)
- Anemia of Chronic Illness will demonstrate:
- LOW serum iron levels: in inflamed states, your cytokines sequester iron and decrease serum iron levels
- NORMAL or LOW total iron binding capacity: this makes sense because your cells WANT to bind iron which has been sequestered by the cytokines, so depending on how much iron has been taken up by cytokines will determine if your total iron stores are able to pick up enough iron.
- HIGH ferritin: this makes sense because ferritin is an acute phase reaction and will be increased in an inflamed state.
- NORMAL or HIGH red blood cell distribution width: this makes sense because your cytokines are holding onto iron so depending on how much is being held by cytokines, you may or may not have varying sizes in the RBCs
Treatment
Treat underlying cause
Clinical Vignette:
Sideroblastic Anemia
Differential Diagnosis
- Congenital
- Acquired: alcohol abuse, lead poisoning, or B6 deficiency from isoniazid use
Peripheral Smear Findings:
- Ringed sideroblasts that stain blue with Prussian blue stain
- Iron accumulates in the mitochondria surrounding the nucleus because it cannot be appropriately transported out of mitochondria to make hemoglobin. This makes a ring.
Workup/Lab Tests:
- Iron Studies: Serum Iron Levels, Total Iron Binding Capacity (TIBC), Ferritin, and Red Blood Cell Distribution Width (RDW)
- Sideroblastic Anemia will demonstrate:
- HIGH serum iron levels: this makes sense because you have enough iron, you are just not able to use the iron appropriately to make the heme product for hemoglobin
- LOW or NORMAL total iron binding capacity: this makes sense because you have bound up lots of iron
- HIGH ferritin: this makes sense because iron is stored in the liver as ferritin and you have lots of iron being stored as ferritin in the liver
Treatment:
- Treat underlying condition, may require transfusions if severe
- Alcoholism: Stop drinking alcohol
- B6 Deficiency: Provide vitamin B6 supplementation (pyridoxine) with isoniazid treatment
Thalassemias
Differential Diagnosis
Reduced production of either the alpha or beta globin chains in hemoglobin:
- Beta-Thalassemia
- Alpha-Thalassemia
Peripheral Smear Findings
- Target cells form because of an uneven distribution of heme and globin (abnormal globin chain) making an abnormal RBC.
Workup/Lab Tests:
- Iron Studies: Serum Iron Levels, Total Iron Binding Capacity (TIBC), Ferritin, and Red Blood Cell Distribution Width (RDW)
- Thalassemias will demonstrate:
- NORMAL or HIGH serum iron levels: this makes sense because you have enough iron, you just don't have appropriate globin chains
- NORMAL total iron binding capacity: this makes sense because you are able to bind up iron appropriately
- NORMAL or HIGH ferritin: this makes sense because this is not an inflammatory state and iron that can't be used will be stored in the liver as ferritin
- NORMAL or HIGH red blood cell distribution width: this makes sense because you have normal globin helping make the structure of the RBC and therefore you may have varying sizes in the RBCs
- Hemoglobin Electrophoresis: differentiates between the different types of thalassemias
Beta-Thalassemia
Major: Homozygous Beta chain. Transfusions required to sustain life. Fatal.
Minor: Heterozygous Beta chain. Asymptomatic or mild anemia.
Intermediate: Become transfusion dependent as you age.
Alpha-Thalassemia
Silent Carrier: Asymptomatic.
Trait/Minor: 2 Alpha chain mutations/deletions. Mild anemia.
Hb H Disease: 3 Alpha chain mutations/deletions. Periodic transfusions required.
Treatment
Depending on type, may require transfusions
Clinical Vignette:
Macrocytic Anemias
B12 Deficiency
Clinical Presentation
Sore tongue, dementia, neuropathy, degeneration of the spinal cord (loss of positional and vibratory sensation)
Differential Diagnosis:
- Impaired absorption – Pernicious Anemia (autoimmune), gastrectomy, inadequate oral intake, alcoholic, Crohn's disease, resection of terminal ileum
Peripheral Smear Findings:
- Enlarged RBCs with Hypersegmented Neutrophils
Workup/Lab Tests:
- B12 levels
- If B12 levels are within normal limits, consider methylmalonic acid and homocysteine levels which will both be elevated
Treatment
IM Cyanocobalamin (B12) preferred
Clinical Vignette:
Folate Deficiency
Clinical Presentation
Anemia
Differential Diagnosis
- Inadequate oral intake: tea/toast diet or alcoholism
- Long term drug therpy: antibiotics, methotrexate, phenytoin
- Malabsorptive states: celiac disease
Peripheral Smear Findings
- Enlarged RBCs with Hypersegmented Neutrophils
Workup/Lab Tests
- Low folate levels
- High homocysteine levels
- Normal methylmalonic acid levels.
Treatment
Daily oral folic acid supplementation
Normocytic Anemias: Intravascular Hemolysis
Paroxysmal Nocturnal Hemoglobinuria
Presentation
- Acquired disorder affecting hematopoietic stem cells and cells of all blood lineages causing a deficiency in an anchoring protein that helps with the development of blood cell membranes.
- Easily lysed by a complement mediated process.
- Anemia/pancytopenia (destruction of all blood lineages), dark urine, jaundice, thrombosis
Differential Diagnosis
Any hemolytic anemia, iron deficiency anemia, or folate deficiency
Peripheral Smear Findings:
- Normochromic normocytic RBCs
Workup/Lab Tests
Normocytic anemia with elevated reticulocyte count because bone marrow is trying to replace the active complement medicated destruction.
- Elevated LDH: enzyme found in all living cells that is released from the inside of blood cells when they are lysed)
- Reduced haptoglobin: when RBCs are destroyed, they release hemoglobin into the circulate and this binds to haptoglobin. High amounts of free hemoglobin will bind haptoglobin, decreasing the amount of free haptoglobin in circulation
- Elevated indirect bilirubin: so much destruction is happening and bilirubin is being released from cells but the liver is unable to conjugate this to direct bilirubin
Treatment
- Eculizumab (monoclonal antibody that inhibits complement) when patients are transfusion dependent/have severe disease
- Folic acid supplementation
- Blood transfusions as necessary
- With goal of cure: bone marrow transplant
Clinical Vignette:
G-6-PD Deficiency
Clinical Presentation
- X linked disorder that primarily affects males that results in episodic hemolytic anemia 2/2 drugs, foods, or illnesses.
- Patients report dark urine and jaundice.
Differential Diagnosis
Any hemolytic anemia
Peripheral Smear Findings
- Characteristic for Bite Cells (RBCs that appear to have a bite taken out of them) - this is 2/2 splenic macrophages biting out/cleaning out the "Heinz Bodies" (abnormal hemoglobin precipitate within the RBCs that are recognized by the spleen as needing to be removed)
Workup/Lab Tests
- Elevated LDH: enzyme found in all living cells that is released from the inside of blood cells when they are lysed)
- Reduced haptoglobin: when RBCs are destroyed, they release hemoglobin into the circulate and this binds to haptoglobin. High amounts of free hemoglobin will bind haptoglobin, decreasing the amount of free haptoglobin in circulation
- Elevated indirect bilirubin: During episodes of hemolysis. So much destruction is happening and bilirubin is being released from cells but the liver is unable to conjugate this to direct bilirubin
- Decreased G6PD Level: Diagnostic
Treatment
Avoid drugs or foods that precipitate hemolysis (sulfa drugs, nitrofurantoin, fava beans), stay hydrated, and blood transfusions as necessary
Cold Immune Hemolytic Anemia
Clinical Presentation
Anemia and Jaundice (when hemolysis is occurring)
- Autoantibody IgM binds to RBCs at 0-5 degrees C (cold temperatures) resulting in complement activation and subsequent hemolysis.
Peripheral Smear Findings
- RBC aggregates for at cold temperatures when the antibodies bind the surfaces of RBCs together and start destruction/hemolysis
Workup/Lab Tests
- Elevated LDH: enzyme found in all living cells that is released from the inside of blood cells when they are lysed)
- Reduced haptoglobin: when RBCs are destroyed, they release hemoglobin into the circulate and this binds to haptoglobin. High amounts of free hemoglobin will bind haptoglobin, decreasing the amount of free haptoglobin in circulation
- Elevated indirect bilirubin: During episodes of hemolysis. So much destruction is happening and bilirubin is being released from cells but the liver is unable to conjugate this to direct bilirubin
- Direct Combs Test: + for complement on RBCs
- Positive Cold Agglutinin titer
Treatment
Avoid cold exposures, rituximab, and RBC transfusions as needed. Steroids are NOT helpful.
Warm Immune Hemolytic Anemia
Clinical Presentation
Anemia and Jaundice (when hemolysis is occurring)
- Autoantibody IgG binds to RBCs at 37 degrees C (warm temperatures) resulting in extravascular hemolysis in the spleen.
Differential Diagnosis
Any hemolytic anemia
Peripheral Smear Findings
- Spherocyte formation due to IgG negatively impacting the RBC membrane. This makes the RBC inflexible, round, and identified as cells that need to be destroyed by the spleen.
Workup/Lab Tests
- Elevated LDH: enzyme found in all living cells that is released from the inside of blood cells when they are lysed)
- Reduced haptoglobin: when RBCs are destroyed, they release hemoglobin into the circulate and this binds to haptoglobin. High amounts of free hemoglobin will bind haptoglobin, decreasing the amount of free haptoglobin in circulation
- Elevated indirect bilirubin: ***During episodes of hemolysis. So much destruction is happening and bilirubin is being released from cells but the liver is unable to conjugate this to direct bilirubin
- Direct Combs Test: + for IgG on rBCs
- Negative Cold Agglutinin titer
Treatment
Steroids are the mainstay of therapy, splenectomy for those who do not respond to steroids, rituximab, immunosuppression, folic acid supplementation, and RBC transfusions as needed
Microangiopathic Hemolytic Anemia
Clinical Presentation
RBCs are destroyed as they pass through the vasculature/circulation
Differential Diagnosis
TTP, HUS, DIC, HELLP, prosthetic heart valves, aortic stenosis
Peripheral Smear Findings
Schistocytes: RBCs that have been torn apart as they pass through the circulation
Workup/Lab Tests
- Elevated LDH: enzyme found in all living cells that is released from the inside of blood cells when they are lysed)
- Reduced haptoglobin: when RBCs are destroyed, they release hemoglobin into the circulate and this binds to haptoglobin. High amounts of free hemoglobin will bind haptoglobin, decreasing the amount of free haptoglobin in circulation
- Elevated indirect bilirubin: During episodes of hemolysis. So much destruction is happening and bilirubin is being released from cells but the liver is unable to conjugate this to direct bilirubin
Treatment
Treat the underlying condition, may need iron replacement, may need transfusions
Clinical Vignette:
Extravascular Hemolysis
Hereditary Spherocytosis
Clinical Presentation
- Autosomal Dominant trait that affects the genes encoding spectrin which affects the RBC membrane.
- This decreases the RBC volume resulting in a microcytic anemia with elevated RDW and is identified by macrophages in the spleen as a foreign entity and therefore is destroyed.
- Hemolytic anemia, jaundice, splenomegaly, gallstones, occasional hemolytic crisis
Differential Diagnosis
Any hemolytic anemia.
Appears similar to warm AIHA on peripheral smear.
Peripheral Smear Findings
Spherocytes due to abnormal RBC membrane in the setting of abnormal spectrin gene mutation
Workup/Lab Tests:
- Microcytic anemia
- Elevated Reticulocyte Count: the bone marrow is trying to compensate for the splenic sequestration and destruction of RBCs
- Direct Combs test: NEGATIVE. Helps distinguish this disease from warm AIHA.
- Osmotic Fragility Testing: place the RBCs in hypotonic solutions. Normal RBCs will swell and maintain their structure, however in hereditary spherocytosis, the RBC membrane is weak and therefore will rupture with the concentrated solution
Treatment
Transfusions, splenectomy
Sickle Cell Disease
Clinical Presentation
Autosomal Recessive disorder results in abnormal hemoglobin chain production.
- Types:
- Sickle Cell Disease – more severe
- Sickle Cell Trait – asymptomatic
- Pallor/Jaundice
- Pigmented gallstones
- Delayed growth and maturation
- High-output heart failure
Differential Diagnosis
Sickle Cell Disease versus Trait
- Sickle Cell Disease: homozygous for Hb S genes causing Hb A chain to be replaced by Hb S. This forms abnormal hemoglobin that is unable to carry oxygen to tissues. Easily sickled.
- Sickle Cell Trait: heterozygous for Hb S gene. No symptoms. Normal life expectancy.
Peripheral Smear Findings
Sickled RBCs
Workup/Lab Tests
- CBC demonstrating anemia
- Peripheral smear revealing sickled RBCs
- Hemoglobin Electrophoresis: Required for diagnosis. Done on newborn screenings.
Treatment
Prevent crisis by avoiding high altitudes, maintaining fluid intake, treating infections promptly.
- Hydroxyurea: enhances Hb F levels to reduce sickling
- Folic Acid supplementation
- Transfusions as needed
Clinical Vignette:
Underproduction
Aplastic Anemia
Clinical Presentation
Pancytopenia due to damage to hematopoietic stem cells.
Differential Diagnosis
2/2 drugs, chemicals, viruses, autoimmune disorders, and malignancies
Bone Marrow Findings
Empty, fat marrow. Hypocellular.
Workup/Lab Tests
- CBC demonstrating pancytopenia
- Low reticulocyte count because your bone marrow can't make any cell lines.
- Workup for other anemias negative
- Bone marrow biopsy
Treatment
- Treat underlying condition.
- Stop offending drug
- Immunosuppression if autoimmune related
- Bone marrow transplant
Myelophthisic Anemia
Clinical Presentation
Pancytopenia where a pathologic process (malignancy) replaces/infiltrates the bone marrow
Differential Diagnosis
Lymphomas and leukemias
Bone Marrow Findings
Hypercellular with one kind of predominating cell type
Workup/Lab Tests
- CBC demonstrating pancytopenia
- Workup for other anemias negative
- Bone marrow biopsy
Treatment
Treat underlying cancer. Bone marrow transplant.
Board Review
Anemia
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