Intro to Hemolytic Anemias - Harrington Flashcards
Jaundice is detectable in fair-skinned individuals at approximately what concentration in the blood?
What is scleral icterus? At what concentration can it be detected?
>2.5 mg/dL
Yellow discoloration of the sclera of the eyes. Detectable at >1.7 mg/dL
Which is more common: extravascular or intravascular pathologic hemolysis?
Extravascular
Name some sites of extravascular patholgic hemolysis and the describe the relative frequency of each.
Spleen >>>>> liver, bone marrow
Name some causes of acquired (extrinsic) hemolytic anemia
Autoimmune
Mechanical trauma
infection
chemical
splenic sequestration
Name some causes of inherited (intrinsic) hemolytic anemia
RBC membrane disorders
RBC enzyme deficiencies
Hemoglobinopathies
Define hemolytic anemia
RBC destruction resulting in loss of RBC mass and release of cellular contents
Extravascular or intravascular hemolysis?
- RBC membrane disorders
- RBC enzyme disorders
- Sickle cell anemia
- Thalassemia
- Autoimmune hemolysis
- PNH
- Mechanical
- Malaria
- extravascular
- both
- both
- extravascular
- both (extravascular = antibody, intravascular = complement)
- intravascular
- intravascular
- intravascular
What aspect of hemolysis is indicated by increased LDH, ASATS, or potassium?
Release of cellular contents
Haptoglobin is responsible for what?
Scavenge free Hb in the plasma
Is hemoglobinemia generally more pronounced in intravascular hemolysis or extravacular hemolysis?
intravascular
What is hemoglobinuria? What is the source of hemoglobinuria? Is it more common with intravascular or extravascular hemolysis?
What is hemosiderinuria? What is the source? Is it more common with intravscular or extravascular hemolysis?
Hemoglobin in the urine (hemoglobin not scavenged by haptoglobin. Mostly observed with intravascular hemolyis.
Hemosiderin in the urine, due to iron deposited in the renal epithelium and later shed in the urine. Mostly obserced with intravascular hemolysis.
Why is phlebotomy-induced hemolysis a problem for laboratory diagnostics?
Hemoglobin released by phlebotomy-induced hemolysis may interfere with spectrophotometry, leading to false results.
What (2) symptoms are associated with hemolysis, regardless of underlying etiology?
anemia
hyperbilirubinemia
Why is it important to have baseline hemoglobin values for patients being evaluated for anemia?
Severity of symptoms are closely related to actuity of hemolysis (i.e. the change in hemoglobin compared to baseline levels). Patients (especially children) with chronically-low baseline values can often tolerate levels otherwise considered ‘extreme’ for normal patients.
What signs/symptoms are expected for the following % hemolysis values?
- <20% (~>11g/dL)
- 20-30% (10-11g/dL)
- 30-40% (8-9g/dL)
- >40% (<8g/dL)
- Restlessness, few symptoms otherwise
- Anxiety, dyspnea with exertion, orthostatic hypotension, tachycardia with exertion
- Syncope, orthostatic hypotension, tachycardia at rest
- Confusion, shock
Is >5mg/dL indirect bilirubin usually observed in hemolytic anemia? Why?
No.
The liver usually compensates - indirect bilirubinemia generally only rises to >5mg/dL in the setting of liver dysfunction.
Name and describe (3) relatively rare complications of hemolytic anemia
- Pigment-induced kidney injury - heme pigments cause tubular obstruction, direct tubular necrosis, and vasoconstriction
- Folate deficiency - increase utilization of folate
- Thrombosis
Describe this:
What disease is this associated with?
“Chipmunk facies”
Skeletal changes due to expansion of the marrow
Associated with Thalassemia major
Describe microangiopathic hemolytic anemia
With what conditions is it generally associated?
Microvascular infarction causing: AKI, liver disease, abdominal pain, fever, mental status changes, thrombocytopenia, rash, hemorrhagic diarrhea. RBCs are destroyed as the pass through small vessels of the circulation.
TTP, HUS, DIC, malignant hypertension, CREST syndrome, vasculitis, HELLP syndrome
What cells are seen below? What would be different on lab tests?
Increased mean cell hemoglobin concentration
How do spherocytes compare to normal red blood cells?
Increased hemoglobin concentration
less flexible
shortened life span
What are the two conditions that can cause spherocytic hemolytic anemia?
Hereditary spherocytosis
Autoimmune hemolytic anemai
What is the pathology behind autoimmune hemolytic anemia?
What is the difference between warm AIHA and cold AIHA?
Antibodies bind to the surface of the red blood cell and portions of the cell are eaten by macrophages
Antibody affinity for binding; cold AIHA also typically includes agglutination
What is the pathology behind hereditary spherocytosis or hereditary elliptocytosis?
Defects in structural proteins
Which proteins are mutated in hereditary spherocytosis?
Ankyrin (most common)
alpha/beta spectrin
band 3
band 4.2
How can hereditary spherocytosis present clinically?
asymptomatic to severe hemolysis
splenomegaly
aplastic crisis (following parvo infection)
Gallstones
Jaundice
What is a possible surgical option for hereditary spherocytosis?
Partial splenectomy
Without the spleen, RBCs are subjected to decreased stress and will not lyse as frequently.
What is a DAT?
What does it test? How does it work?
Direct Antiglobin Test
tests whether hemolysis is immune-meidated. If red blood cells fall out of solution when anti-IgG antibodies are added, it indicated antibodies are binding to the cells.
Which antibodies are seen in warm AIHA? Which are seen in cold AIHA?
IgG- warm
IgM- cold
What symptoms might you see in warm AIHA vs. cold AIHA?
Warm
- organomegaly
Cold
- acrocyanosis
- raynaud phenomenon
Is warm or cold AIHA more common?
Warm - 80%. Cold - 20%.
What are major causes of warm AIHA?
- 60% are idiopathic (primary)
- Secondary causes:
- Lymphoproliferative disorders
- Autoimmune disorders
- Non-hematopoietic neoplasms (e.g. ovarian cancer)
- Drugs (e.g. alpha-methyldopa, cephalosporins)
What are major causes of cold AIHA?
Which cause the acute form vs. the chronic form?
- Idiopathic (Primary)
- Secondary causes:
- Postinfectious (Acute form)
- Mononucleosis
- Mycoplasma
- Lymphoproliferative disorders (Chronic form)
- Postinfectious (Acute form)
Does warm AIHA present with mostly extravascular or intravascular hemolysis?
What about cold AIHA?
Warm: Extravascular
- **IgG **or complement mediated
Cold: Both
- **IgM **or complement mediated
What are the effects of the agglutinins seen in cold AIHA?
- Usually do not cause anemia
- Can cause obstructive symptoms
- About how much glucose-6-phosphate (G6P) proceeds through the pentose phosphate pathway vs. glycolysis?
- What important cofactor affects this ratio?
- 90% to glycolysis, 10% to PPP
- NADPH. NADPH is a product of the PPP and serves as negative feedback for the PPP when levels are sufficient enough.
Name two congenital red cell enzyme disorders and the metabolic pathways those enzymes are required for.
- G6P-dehydrogenase (G6PDH) deficiency (PPP)
- Pyruvate kinase deficiency (glycolysis)
Explain the pathogenesis of G6PDH. How does a lack of this enzyme cause RBC damage?
- G6PDH is required for the PPP.
- A product of this pathway is NADPH.
- NADPH is used to replenish antioxidant stores, i.e. reduced glutathione
- Without glutathione, RBCs are prone to oxidant stress that can cause hemolysis
Does G6PDH deficiency cause intra- or extravascular hemolysis? What pathological RBC component, formed via excessive oxidant stress, causes this hemolysis?
**Both. **The damage is due to denatured Hb, aka Heinz bodies.
- Intravascular:
- Heinz bodies directly damage the RBC
- Extravascular:
- The spleen removes RBCs with Heinz bodies
Name three oxidant stressors that could exacerbate anemia in a person with G6PDH deficiency.
- Infection
- Fava beans
- Drugs:
- Dapsone
- Sulfonamindes
- Primaquine
- Nitrofurantoin
- Quinolones
- What geographic areas is G6PDH deficiency common in?
- What inheritance pattern does G6PDH deficiency have?
- Malarial endemic areas (the allele serves as malarial resistance, similar to Sickle trait?)
- X-linked
- How many variants are there?
- Name two normal G6PDH variants and the populations they are found in.
- Name three hemolytic G6PDH variant and the populations they are found in.
- Over 400, with varying severity depending on the activity of the mutated enzyme.
- Normal:
- G6PDH A (20% of African Americans)
- G6PDH B (All ethnicities)
- Abnormal:
- G6PDH A- (AAs)
- G6PDHMED (Whites)
- G6PDHCANTON (Asians)
G6PDH A-, found in 11% of AA males, leads to an “unstable enzyme”. How does this specific mutation affect RBCs?
- 100% activity in new RBCs & Reticulocytes
- 5-15% activity in “old” RBCs
- Leads to self-limited hemolysis upon oxidant exposure
- (only old RBCs hemolyze)
G6PDH Deficiency
- What are the PB smear findings?
G6PDH Deficiency
- Bite cells (degmacytes)
- Result from the removal of Heinz bodies (denatured Hb) by splenic macrophages
G6PDH Deficiency
- How can it be screened for?
- What is the confirmatory test?
G6PDH Deficiency
- Screen with NADPH fluorescence
- Affected males will have:
- low fluorescence, or
- normal if during a hemolytic reaction
- Not sure why - beware the false negative!
- Affected males will have:
- Confirmatory: Quantitative Assay
What is another term for schistocytes? What causes their morphology?
Helmet cells. They result when RBCs are torn by shear forces as they travel through obstructed vessels, or by excessive heat/burning.
N.B. The cells are fragmented in two. Helmet cells reflect the larger remnant. Smaller, fragmented-looking cells can form from the smaller remnant as well.
Name some causes of shear stress in the vasculature that could cause the formation of fragmented cells.
- Defective cardiac valves
- Microangiopathic hemolytic anemias
- TTP (emergency)
- Malignant hypertension
- Antiphospholipid Ab Syndrome
- DIC
- Disseminated cancer
What change in blood vessel morphology is noted with a hypertensive emergency / malignant hypertension?
Thickening of the walls due to hyalinization
Paroxysmal Nocturnal Hemoglobinuria (PNH)
- What mutation leads to PNH? How is it inherited?
- Explain the pathogenesis.
- What cells are affected?
Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Mutation in PIGA gene. X-linked.
- PIGA mutation leads to a decrease in GPI-linked proteins on the cell surface. Anti-complement proteins are GPI-linked; thus, the mutation makes cells susceptible to complement-mediated lysis.
- All myeloid lineages, but RBCs especially.
Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Name 4 ways in which PNH can clinically present.
- What finding gives PNH its name?
Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Chronic, low-level hemolysis
- The classic PNH finding in noticeable hematuria in the morning (after the urine has built up / concentrated during sleep) that becomes less noticeable throughout the day, but this is only seen in ~1/4 of cases.
- Acute, episodic hemolysis events
- Hemoglobinuria
- Venous thromboses
Paroxysmal Nocturnal Hemoglobinuria (PNH)
How is PNH diagnosed? Be specific.
Paroxysmal Nocturnal Hemoglobinuria (PNH)
- Flow cytometry for GPI-linked proteins
- CD55 (DAF)
- CD59
- Examined on both WBCs and RBCs
