Acquired Hemolytic Anemias Flashcards
1. Explain the mechanisms of red blood cell hemolysis and acquired hemolytic anemias. (MKS, 1b) 2. Describe the pathologic mechanism of immune-mediated red blood cell hemolysis. (MKS, 1b) 3. List the basic approach to the treatment of hemolytic anemias (MKS, 1e) 4. Describe the laboratory tests used in the diagnosis of hemolytic anemias. (MKS, 1d)
1
Q
What is the role of measuring reticulocytes in diagnosis? What do these measurements suggest?
A
- Reticulocytes are immature RBCs, that no longer contain a nucleus but retain some RNA
- Reticulocytes are indicators of increased bone marrow production of RBCs but are not specific for hemolysis
- They can also be increased in acute blood loss or bone marrow disorders
- The reticulocyte response is assessed by either the absolute reticulocyte count or the reticulocyte production index (RPI)
- When the reticulocytes are reported as a percentage, the RPI should be calculated
- The RPI takes into account the degree of anemia and the reticulocyte maturation time in the circulation (1-2 days)
- RPI = (Reticulocyte percentage/2) x (Patient’s HCT ÷ 45[normal hematocrit])
- An appropriate bone marrow response to anemia is suggested by a corrected RPI over 2% or an absolute reticulocyte count of over 100,000/μl
2
Q
What are the broad categories of hemolytic anemias? What are the findings in each?
A
- Hereditary vs. Acquired or
- Intracorpuscular vs. Extracorpuscular (refers to site of the defect)
- Extravascular vs. Intravascular
3
Q
What are some common etiologies of hemolytic anemias? Are these intracorpuscular or extracorpuscular? Hereditary or acquired?
A
-
Abnormalities of RBC interior
- Enzyme defects (ex. G-6-PD) - IC, H
- Hemoglobinopathies (ex. sickle cell) - IC, H
-
RBC membrane abnormalities
- Hereditary spherocytosis - IC, H
- Paroxysmal nocturnal hemoglobinuria - IC, A
- Spur cell anemia - IC, A
-
Extrinsic factors
- Hypersplenism - EC, A
- Immunologic hemolysis - EC, A
- Microangiopathic hemolysis - EC, A
- Infectious (ex. malaria, babesiosis) - EC, A
4
Q
What distinguishes extravascular from intravascular hemolysis?
A
- Extravascular hemolysis: destruction of the red blood cells occurs in the reticuloendothelial system (mononuclear phagocytes), particularly in the spleen and liver
- Intravascular hemolysis: direct mechanical damage to red blood cells or can be immune-mediated
5
Q
What are hematologic lab findings that suggest hemolytic anemia? What differentiates the intravascular and extravascular forms?
A
-
Routine blood film
- extravascular - polychromatophilia
- intravascular - polychromatophilia
-
Reticulocyte
- extravascular - increased
- intravascular - increased
-
Bone marrow exam
- extravascular - erythroid hyperplasia
- intravascular - erythroid hyperplasia
6
Q
What are the plasma lab findings that suggest hemolytic anemia? What are the differences between the extravascular and intravascular variants?
A
-
Bilirubin
- extravascular - increased unconjugated
- intravascular - increased unconjugated
-
Haptoglobin
- extravascular - decreased or absent
- intravascular - absent
-
Plasma hemoglobin
- extravascular - normal to slightly increased
- intravascular - greatly increased
-
Lactate dehydrogenase
- extravascular - slightly increased (variable)
- intravascular - greatly increased (variable)
7
Q
What are the urine lab findings that suggest hemolytic anemia? What are the differences between the intravascular and extravascular variants?
A
-
Bilirubin
- extravascular - 0
- intravascular - 0
-
Hemosiderin
- extravascular - 0
- intravascular - +
-
Hemoglobin
- extravascular - 0
- intravascular - + in severe cases
8
Q
What are the major categories of immune-mediated hemolytic anemia?
A
- More common in women
-
Warm antibody or cold antibody type
- Can be associated with a variety of disorders
- Warm reactive antibodies are more common than cold
- About 50-70% are idiopathic, while the rest are secondary to other disorders or medications
- The antibodies are directed against certain antigens on the RBC
- Antibodies can be of either IgG, IgM or IgA subtype
- Can have the ability to fix complement
- Tissue macrophages, particularly in the spleen, interact with RBCs coated with IgG or complement and result in clearance of the RBC
9
Q
What is the direct Coomb’s test?
A
-
Direct antiglobulin test (DAT): detects immunoglobulins or fragments of complement that have adhered to the patient’s red cells
- Anti-immunoglobulin or anti-complement antibodies are incubated with patients RBCs
- If patient RBCs have immunoglobulin or complement bound to them then agglutination of the RBC will occur
10
Q
What is the indirect Coomb’s test?
A
-
Indirect Coomb’s: detects antibodies to red blood cells present in the patient’s plasma
- The patient’s serum (which includes any circulating antibodies) is incubated with normal RBCs
- Anti-immunoglobulin antibodies are then added.
- Agglutination of RBCs will result if the patient’s serum contained any antibodies which recognized antigens on the normal RBCs
- May be positive in the presence of an alloantibody or autoantibody
- A positive test does not necessarily mean active hemolysis for either the direct or indirect test
11
Q
What is the pathophysiology, presentation, and management of warm-antibody hemolytic anemia?
A
-
Pathophysiology
- Most commonly IgG antibody, can be IgM or IgA
- Antibodies lead to clearance of RBC by the splenic macrophages
- Also can have complement mediated lysis of the membrane
- Microspherocytes are formed when only part of the RBC membrane is removed by the splenic macrophages
-
Clinical
- Primarily adults – more common in women and older adults
- 25% have an underlying disease
- Patients may present with:
- jaundice
- pallor
- splenomegaly
- Evan’s syndrome is hemolytic anemia with immune thrombocytopenia
-
Laboratory Features
- Microspherocytes, anemia and elevated reticulocytes
- Increased bilirubin, primarily indirect
- Decreased haptoglobin
- Positive direct Coomb’s test
-
Therapy
- Cessation of drugs known to cause hemolysis
- Folate
- Corticosteroids – first line choice
- Other immunosuppressive therapy
- Splenectomy in refractory cases
- RBC transfusions for significant symptoms only
12
Q
What is the pathophysiology, presentation, and management of cold-antibody hemolytic anemia?
A
-
Pathophysiology
- These RBC autoantibodies bind at lower temperatures, ex. 4º C
- Also called cold agglutinins
- Usually are IgM antibodies
- Hemolysis occurs through complement fixation
- Many patients without active hemolysis can have cold-reacting antibodies
- May arise due to neoplasm (monoclonal antibody) or infection (polyclonal antibody)
- Neoplasms – often in the elderly. Can be a monoclonal gammopathy, lymphoma, and rarely solid tumors.
- Infections associated with cold agglutinins include mycoplasma and infectious mononucleosis
-
Clinical
-
Acrocyanosis – purple extremities, due to lack of oxygenation
- Occurs when the blood gets cold enough to cause RBC agglutination and improves on warming
-
Hemolysis – the degree depends on several factors
- Antibody titer – more agglutination with higher titer
- Thermal amplitude – higher amplitude react more in vivo
- Environmental temperature – cold outside = more agglutination
-
Acrocyanosis – purple extremities, due to lack of oxygenation
-
Laboratory
- RBC agglutination on peripheral smear
- Hemoglobinemia, hemoglobinuria, hemosiderinuria
- DAT is positive with complement
- Antibody testing is done with fetal (i) and with adult (I) RBCs
- anti-I – react more strongly against the adult cells; seen in monoclonal gammopathy and mycoplasma
- anti-i – react more strongly against the fetal cells, seen in lymphomas and mononucleosis
-
Therapy
- Keep the patient warm
- Transfusion can make the hemolysis worse
- Treat the underlying disorder
- Corticosteroids are ineffective, Rituximab can be effective
13
Q
What are the major types of drug-induced immune hemolytic anemia?
A
-
Hapten/drug adsorption, ex. Penicillin
- Drug binds to red cell membrane, antibody attaches to drug without interacting with the red cell
- Occurs in a minority of patients exposed; usually with high-dose of drug
- Red cells are removed by splenic macrophages; anemia develops gradually
- Direct Coomb’s is positive, indirect antiglobulin test would be positive only with drug-coated red cells
- Hemolysis stops when medication is discontinued
-
Neoantigen (Immune-complex), ex. Quinidine
- Antibody develops to a combined antigen, neoantigen, formed by the drug and the red cell membrane.
- Only small dose of drug is required
- Complement-mediated lysis
-
Autoimmune mechanism, ex. a-methyldopa, levodopa, procainamide
- Causes production of an antibody which is directed against a red cell antigen
- only a minority of patients develop hemolysis
- Features very similar to autoimmune hemolytic anemia
- Causes production of an antibody which is directed against a red cell antigen
14
Q
What is paroxysmal cold hemoglobinuria?
A
- Formation of Donath-Landsteiner antibodies
- IgG directed against the P antigen which can cause hemolysis
- Associated with syphilis
-
Transient attacks after exposure to cold with:
- fever
- chills
- back, leg, abdominal pain
- headache
- malaise
- Coombs may be negative
- Test for the specific antibody
15
Q
What are some causes of traumatic RBC lysis?
A
-
Microangiopathic hemolytic anemia
- Thrombotic thrombocytopenic purpura (TTP)
- Hemolytic-uremic syndrome (HUS)
- Disseminated intravascular coagulation (DIC)
- Malignant hypertension
- Preeclampsia, eclampsia, HELLP syndrome
- Cavernous hemangioma (Kasabach-Merritt syndrome)
- March hemoglobinuria – traumatic red cell destruction after long marches
- Cardiac valvular disease
