Hemolytic Anemia

Question 1

Hemolytic anemia is RBC destruction resulting in…(2)

Answer 1

Loss of RBC mass

Release of cellular contents

Question 2

What types of inherited disorders cause hemolytic anemia?

Answer 2

RBC membrane disorders

RBC enzyme deficiencies

Hemoglobinopathies

Question 3

What types of acquired disorders cause hemolytic anemia?

Answer 3

• Autoimmune (antibody mediated) hemolysis
• Mechanical trauma
• Infections
• Chemical disorders
• Splenic Sequestration

Question 4

Is hemolysis more common extravascularly or intravascularly?

Answer 4

Extravascularly (Spleen > liver, bone marrow)

Question 5

What is the difference between extravascular and intravascular autoimmune hemolysis?

Answer 5

Extravascular involves antibodies

Intravascular involves complement

Question 6

Which types of pathologic hemolysis can be both extravascular and intravascular?

Answer 6

RBC enzyme disorders

Sickle cell anemia

Question 7

Which types of pathologic hemolsis disorders are only extravascular? Which are only intravascular?

Answer 7

• Extravascular
  
  • RBC membrane disorder
  • Thalassemia
• Intravascular
  
  • Paroxysmal nocturnal hemoglobinuria
  • Mechanical trauma
  • Malaria

Question 8

What findings in a laboratory evaluation are associated with hemolysis?

Answer 8

• Reticulocytosis (increased reticulocytes)
• Increased LDH, AST, potassium (released cellular content)
• Bilirubinemia - Unconjugated (indirect) or conjugated (with liver disease)
• Hemoglobinemia (free hgb in plasa)
• Decreased haptoglobin (scavenges free hgb)

Question 9

What test is ordered to check for an autoimmune hemolytic disorder?

Answer 9

DAT (direct antiglobulin test)

Question 10

Describe hemoglobinuria and hemosiderinuria

Answer 10

• Hemoglobinuria - Intravascular process (mostly) where Hgb is not scavenged by haptoglobin
• Hemosiderinuria - Intravascular process (mostly) where iron deposits in renal epithelium, then shed in urine

Question 11

What is a false hyperkalemia?

Answer 11

Phlebotomy induced hemolysis

Question 12

Why is spectrophotometry sometimes faulty in analyzing hemoglobin levels?

Answer 12

Hemoglobin absorbs at measured wavelengths, therefore, many assay produce falsely increased results in the setting of hemolysis

Question 13

Common symptoms in hemolytic anemia (regardless of etiology)

Answer 13

Anemia (obvi)

Hyperbilirubinemia

Question 14

Symptoms of anemia are more related to _____ of hemolysis

Answer 14

acuity (compare to baseline levels)

Question 15

Assuming a starting point at normal hemoglobin levels, describe the symptoms and signs associated with the following changes?

• <20% hemolysis (>11g/dL hgb):
• 20-30% hemolysis (10-11g/dL hgb):
• 30-40% hemolysis (8-9 g/dL hgb):
• >40% hemolysis (<8 g/dL hgb):

Answer 15

• <20% hemolysis (>11g/dL hgb):
  
  • Restlessness
• 20-30% hemolysis (10-11g/dL hgb):
  
  • Anxiety, dyspnea with exertion
  • Orthostatic hypotension; tachacardia with exertion
• 30-40% hemolysis (8-9 g/dL hgb):
  
  • Syncope
  • Orthostatic hypotension, tachycardia at rest
• >40% hemolysis (<8 g/dL hgb):
  
  • Confusion, shock

Question 16

Indirect bilirubin > 5mg/dL is almost always concurrent with ______ ______

Answer 16

liver disease

Question 17

What risks are associated with hyperbilirubinemia and at what levels of bilirubin do they occur?

Answer 17

Jaundice (>2.5 mg/dL)

Scleral icterus (>1.7 mg/dL)

Increased risk of bilirubin gallstone (pigmented)

Question 18

What are some rare complications of hemolytic anemia?

Answer 18

• Pigment induced kidney injury (tubular obstruction, vasoconstriction)
• Folate deficiency due to increased utilization
• Increased risk of venous and arterial thrombosis of atypical sites

Question 19

What are some clinical features associated with…

• Extra-medullary hematopoiesis (Thalassemia, hereditary spherocytosis):
• Beta thalassemia major:
• Sickle cell anemia:

Answer 19

• Extra-medullary hematopoiesis (Thalassemia, hereditary spherocytosis):
  
  • Splenomegaly and hepatomegaly
• Beta thalassemia major:
  
  • Skeletal changes related to expansion of marrow - “chipmunk facies”
• Sickle cell anemia:
  
  • Asplenia

Question 20

What are some clinical features of Microangiopathic Hemolytic Anemia?

Answer 20

• Microvascular infaction causing acute kidney injury
• Liver disease
• Abdominal pain
• Fever
• Mental status changes
• Thrombocytopenia
• Rash
• Hemorrhagic diarrhea

Question 21

Hereditary spherocytosis

• Inheritance:
• Defect:
• Lab diagnosis:
• Unique clinical features:

Answer 21

• Inheritance: 75% autosomal dominant; 25% sporadic
• Defect: Defect in ankyrin, band 3, band 4.2 or α/ß-spectrin leads to weakened or absent spectrin causing weakened cytoskeleton
• Lab diagnosis: Blood smear review
• Unique clinical features: Splenomegaly - aplastic crises caused by parvovirus

Question 22

Sickle cell anemia

• Inheritance:
• Defect:
• Lab diagnosis:
• Unique clinical features:

Answer 22

• Inheritance: Autosomal
• Defect: Point mutation in ß-hgb chain (chrms 11)
• Lab diagnosis: Hgb HPLC to identify HbS
• Unique clinical features: Pain crises; acute chest syndrome; stroke; asplenia

Question 23

Thalassemia

• Inheritance:
• Defect:
• Lab diagnosis:
• Unique clinical features:

Answer 23

• Inheritance: Autosomal
• Defect: Decreased production of ß or α hgb chains
• Lab diagnosis: Elevated hgb A₂ for beta-thal trait; gene sequencing; smear review
• Unique clinical features: Secondary hemochromatosis; skeletal deformities (due to marrow expansion)

Question 24

G6PDH deficiency

• Inheritance:
• Defect:
• Lab diagnosis:
• Unique clinical features:

Answer 24

• Inheritance: X-linked
• Defect: Deficiency in G6PDH enzyme - Deficient RBCs cannot reduce oxidant stresses and accumulate, denature, form precipitated hgb (Heinz bodies) - cause lysis or removed in spleen
• Lab diagnosis: Blood smear review for bite cells
• Unique clinical features: Males preferentially affected; hemolysis dependent on inciting oxidant stresses

Question 25

Paroxysmal Nocturnal Hemoglobinuria * Pathophysiology: * Lab diagnosis: * Unique clinical features:

Answer 25

* Pathophysiology: **Stem cell with deficiency in GPI-linked proteins** including the anti-complement proteins CD55 and CD59 on RBCs and WBCs * Lab diagnosis: **Flow cytometry** for **CD55** and **CD59** * Unique clinical features: **Hypercoagulability** (thrombi at unusual sites); may have **accentuation of lysis at night**

Question 26

Warm autoimmune hemolytic anemias * Pathophysiology: * Lab diagnosis: * Unique clinical features:

Answer 26

* Pathophysiology: **RBC autoantibodies** that react at **37º** causing intravascular coating of RBCs and **extravascular lysis in spleen** * Lab diagnosis: Smear review for spherocytes; **DAT** * Unique clinical features: **Splenomegaly**; seen in **association with B-cell lymphoproliferative disorders**

Question 27

Cold autoimmune hemolytic anemia * Pathophysiology: * Lab diagnosis: * Unique clinical features:

Answer 27

* Pathophysiology: **RBC IgM autoantibodies** that react at **\<30º** and may lead to **extravascular hemolysis in the spleen or liver** * Lab diagnosis: Smear review for **spherocytes**; **DAT** * Unique clinical features: **Rarely clinically significant**; Raynaud phenomenon associated with **Mycoplasma infections and EBV infections**

Question 28

Microangiopathic hemolytic anemia * Pathophysiology: * Lab diagnosis: * Unique clinical features:

Answer 28

* Pathophysiology: **Traumatic shearing** and subsequent lysis of RBCs due to **malfunctioning heart valve** or **vascular obstruction by microthrombi** * Lab diagnosis: Smear review for **schistocytes**; **ADAMTS-13 activity**; **coagulation tests** * Unique clinical features: **DIC**; **TTP** (thrombotic throbocytopenia purpura); **Metastatic carcinoma**; **malignant hypertension**

Question 29

Malaria/Babesia * Pathophysiology: * Lab diagnosis: * Unique clinical features:

Answer 29

* Pathophysiology: **Intracellular parasites** infect the RBC and cause lysis * Lab diagnosis: Smear review (**thick and thin**); **PCR** for parasites * Unique clinical features: **Cyclic fever**; **cerebral malaria**; **Blackwater fever**

Question 30

What are spherocytes?

Answer 30

* Normal sized RBCs with increased hemoglobin concentration * Less flexible, trapped in the spleen * Shortened life span

Question 31

What are three causes of spherocytes in the blood?

Answer 31

* Thermal injury * Intrinsic abnormalities * Immune hemolysis

Question 32

What protein most commonly has a defect in Hereditary spherocytosis?

Answer 32

Ankyrin (though most patients have deficiencies in both ankyrin AND spectrin)

Question 33

How is Hereditary spherocytosis managed?

Answer 33

* Removal of gallbladders in younger patients * Folate supplementation in aplastic crisis * Splenectomy: Complete (in adults) and partial (in children \< age 6)

Question 34

Warm-autoantibody type represents \_\_\_% of the autoimmune hemolytic anemias

Answer 34

80%

Question 35

What are some secondary causes of Warm autoantibody type hemolytic anemia?

Answer 35

* Lymphoproliferative disorders * Autoimmune disorders * Non-hematopoietic neoplasms (Ovarian cancer) * Drugs (methyldopa; cephalosporins)

Question 36

What are some secondary causes of cold-autoantibody type hemolytic anemias?

Answer 36

* Postinfectious (Infectious mononucleosis) * Lymphoproliferative disorders

Question 37

What type of immunoglobulin is associated with cold AIHA? What is the mechanism?

Answer 37

* IgM - RBC agglutination impedes blood flow in superficial distant vessels * Igm and complement mediate RBC injury (intravascular hemolysis)

Question 38

What immune cells are associated with Warm AIHA?

Answer 38

IgG or Complement mediated (extravascular hemolysis)

Question 39

Blood smear findings in Warm/Cold AIHA?

Answer 39

Spherocytes Polychromatisa Agglutinins (Cold)

Question 40

Acute vs Chronic Cold AIHA?

Answer 40

* Acute form occurs 2-3 weeks into infectious illness (EBV/Mycoplasma) * Chronic form is associated with lymphoproliferative disorders

Question 41

A G6PDH deficiency results in decreased _______ production and an inability to reduce _______ \_\_\_\_\_\_\_

Answer 41

glutathione; oxidant stressors

Question 42

What are heinz bodies (in G6PDH deficiency)?

Answer 42

Denatured hemoglobin that directly damages the RBC causing intravascular hemolysis Heinz bodies are removed in the spleen

Question 43

What are oxidant stressors in a G6PDH deficiency?

Answer 43

Infection Fava beans Drugs (Dapsone, sulfonamides, primaquine, nitrofuantoin, quinolones)

Question 44

What are the differences between the following G6PD variants in terms of hemolysis and population affected? * G6PD A (normal): * G6PD B (normal): * G6PD A-: * G6PD^MED: * G6PD^CANTON:

Answer 44

* G6PD A (normal): No hemolysis; Blacks (20% AA) * G6PD B (normal): No hemolysis; All races * G6PD A-: Moderate hemolysis; Blacks (11% AA) * G6PD^MED: Severe hemolysis; Whites * G6PD^CANTON: Moderate hemolysis; Asian

Question 45

In G6PD A-, what is the difference between new RBCs and old RBCs due to an unstable enzyme?

Answer 45

100% acitivity in new RBCs 5-15% activity in "old" RBCs (120 day lifespan normally)

Question 46

How are G6PDH deficiencies screened for today? How are they measured?

Answer 46

NADPH fluorescence Normal, Deficient (intermediate), and Grossly deficient (Low) In Males: Low OR Normal (during hemolytic rxns) In Female carriers: Normal, intermediate, or low dependent (on X-inactivation)

Question 47

Paroxysmal Nocturnal Hemoglobinuria is an acquired mutation in the ____ gene

Answer 47

PIGA (X chromosome)