Table of contents
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General Approach
- Increased destruction anemia.
- Many patients with hereditary hemolysis have low-grade compensated hemolysis, and often decompensate when a production issue is introduced (i.e. Pavrovirus B19 infections).
Etiology
- Hereditary
- Abnormal Membrane (Spherocytosis, elliptocytosis)
- Abnormal Enzymes (Pyruvate kindase def, G6PD def)
- Abnormal Hemoglobin (thalessemias, hemoglobinopathies, sickle cell)
- Acquired
- Immune
- Hemolytic transfusion reaction (AHTR)
- Autoimmune hemolytic anemia (AIHA)
- Warm AIHA
- Cold AIHA
- Drugs (i.e. penicillin)
- Cold agglutinins
- Non-Immune
- Microangiopathic HA (MAHA) (thrombus in blood vessel shears cell)
- DIC, HUS/TTP, pre-eclampsia/HELLP, vasculitides, malignant HTN.
- Others:
- PNH, hypersplenism, etc… mechanical heart valves
- Immune
Diagnosis
- Symptoms:
- Anemia (Exertional dyspnea, fatigue, etc...)
- Jaundice, scleral icterus, gall stones (usually chronic congenital), splenomegaly.
- Suspect:
- Rapid Hb drop, no bleeding, increased retics, Plasma free Hb incr, elevated bilirubin (unconj), incr urobilinogen, AST (and not ALT), LDH, low or absent haptoglobin, urinary hemosiderinuria, coombs test
- Labs:
- 4 Cardinal Labs:
- 1. High LDH
- 2. High Bilirubin (indirect)
- 3. Low haptoglobin
- NOTE: LDH + Haptoglobin are 90% sensitive for hemolysis
- 4. Morphologic Changes in Erythrocytes on Peripheral Smear
- DAT (Direct Antiglobulin Test)
- Used to evaluate immune-mediated hemolysis (one of many).
- Often part of initial workup.
- Includes Ig, and 3rd component complement on RBCs
- Direct Coombs’ Test (aka DAT - Direct Antiglobulin Test
- Detects antibodies or complement on the surface of RBCs
- Indications: (Hemolytic Disease of Newborn, Warm AIHA, Hemolytic Tfsn Reaction)
- Indirect Coombs' Test
- Detects antibodies in patient's serum (mix patient's serum + donor RBCs, check with Coumbs' Anti-Ig Ab)
- Indications: Crossmatching, Atypical Blood Groups, AIHA, Blood Antibodies in Pregnant Women.
- (detects IgG or complement on surface of RBC)
- High Reticulocytes
- 4 Cardinal Labs:
-
Intravascular
Extravascular
Hemoglobinemia
+
- (+ in severe cases)
Hemoglobinuria
+ (free Hb in blood)
- (+ in severe cases)
Haptoglobin
Absent
Reduced(absent if severe)
Hemosiderinuria
Present
Absent
LDH
Grossly Elevated
Elevated
Jaundice
Present
Present
Splenomegaly
Absent
Present
Blood film
SchIstocytes (helmets)
SphErocytes
DAT
Usually -
Often +
Treatment
- Based on underlying disorder.
- All pts with Chronic Hemolysis
- Folic Acid Supplementation (1mg/day).
- Make patient aware their Hb can rapidly drop if get BM suppression (i.e. classically Pavrovirus B19 infection).
Hereditary Hemolytic Anemia
Hereditary Spherocytosis
- Most common congenital chronic hemolytic anemia (1 in 2000 in North European descent).
- Pathology:
- Autosomal dominant, but can be sporatic with variable penetrance.
- Unstable membrane due to mutations (i.e. Ankyrin and other ankoring proteins lead to spectrin deficiency --> results in cytoskeleton dysfunction and loss of erythrocyte area).
- Destabilizes the erythrocyte membrane/structure --> spherocytic shape.
- Reduced deformibility --> trapping and destruction in the spleen.
- Symptoms:
- Hemolysis symptoms (anemia, jaundice, splenomegaly, gall stones).
- Suspect if relatives also have this history.
- Range from severe neonatal jaundice to aplastic crisis from Pavrovirus B19 infection.
- Many diagnosed in late adulthood with enlarged spleen (mildly anemic and asymptomatic).
- Hemolysis symptoms (anemia, jaundice, splenomegaly, gall stones).
- Labs:
- Classically Osmotic Fragility Testing --> only tells you there are spherocytes (does not help with cause)
- Put RBCs into hypotonic solutions, as water rushes in, biconcave shapes can sustain more water influx, and spherocytosis already inflated can burst.
- MCH (Mean Cellular Hemoglobin Concentration)
- Goes up with spherocytosis, sometimes used to help diagnosis.
- Need to have negative DAT.
- Peripheral Blood Smear: See spherocytes (loss of biconcave shape).
- Can also get this with warm hemolytic anemia
- Classically Osmotic Fragility Testing --> only tells you there are spherocytes (does not help with cause)
- Treatment:
- If asymptomatic:
- No treatment.
- Sometimes replace folic acid, and counsel on looking out for pigment gallstones.
- If symptomatic:
-
Indications for Treatment of Hereditary Spherocytosis:
1. Symptomatic anemia
2. Painful splenomegaly
3. Recurrent billiary stones
4. Failure to thrive
- Require treatment.
- Laparoscopic splenectomy
- Then VACCINATE gainst encapsulated organisms including pneumococcus, H.influenzae, Meningogoccus, etc.. !!!
-
- If asymptomatic:
G6PD Deficiency
- G6PD is an enzyme, and most common RBC enzyme defect --> affecting >200 million people worldwide.
- Glucose-6-phosphate dehydrogenase.
- X-linked (see almost exclusively in men)
- Disease caused by various G6PD mutations on the X-chromosome
- Different mutations = different G6PD activity.
- X-linked, so more common in males.
- More often african american descent.
- Mutations thought to protect against Plasmodium falciparum (malaria).
- RBC cannot generate NADPH and maintain glutathione in reduced state --> causes hemolytic anemia.
- Two main variants:
- African American Variant (more common)
- causes episodic hemolysis in response to oxidant stressors (drugs!).
- Big Three that trigger hemolytic anemias:
- Dapsone
- Trimethoprim Sulfa
- Nitrofurantoin
- Others (less common)
- Phenazopyridine - used as urinary anesthetic
- Rasburicase - metabolizes uric acid.
- Big Three that trigger hemolytic anemias:
- causes episodic hemolysis in response to oxidant stressors (drugs!).
- Mediterranian Variant (less common)
- Leads to chronic hemolysis.
- Worsens after ingestion of fava beans (can be fatal hemolytic anemia).
- African American Variant (more common)
- Labs:
- Can measure G6PD level (elevated?).
- In African American (AA) variant, elevated levels of G6PD found in young reticulocytes --> hence can be falsely normal during hemolytic episode.
- When hemolyzing will destroy older cells, so will measure normal levels.
- Hence: In AA variant wait several months after a hemolytic event before measuring G6PD.
- **Peripheral Smear**:
- See bite cells! aka helmet cells DURING ACUTE HEMOLYTIC EPISODE.
- Brilliant cresyl blue stain reveals heinz bodies (denatured oxidized hemoglobin)
(Brillian cresyl blue generally used for counting erythrocytes).
- Can measure G6PD level (elevated?).
- Treatment:
- Once diagnosed:
- Counsel not to receive drugs that cause oxidative hemolysis (Big Three):
- Dapsone
- Trimethoprim Sulfamethoxazole
- Nitrofurantoin
- Counsel not to receive drugs that cause oxidative hemolysis (Big Three):
- During hemolytic crisis:
- Supportive (avoid/withdraw from responsible drug)
- Treat underlying infection (oxidative stress).
- NOTE: when AA variant has hemolytic episode, begins to retic. AA variant retics have high G6PD levels --> improves hemolysis even if offending drug is continued.
- Once diagnosed:
Acquired Hemolytic Anemias
- Must do family history and personal history to avoid missing a hemolytic anemia.
Intro Autoimmune Hemolytic Anemia (AIHA)
- Most common is IgG (80%) and IgM (20%)
- Causes:
- Idiopathic
- Autoimmune
- Lymphoproliferative
- Malignant
- Infectious
- Drug-Related.
- Classified by the temperature at which autoantibodies bind RBCs.
Warm AIHA
- Caused by IgG antibodies
- Bind RBC Rh antigens close to body temperature.
- Antibody-coated RBCs are bound to Fc receptors in splenic macrophages, which causes partial phagocytosis of RBCs creating spherocytes.
- Warm AIHA --> See spherocytes (NOT schistocytes).
- Looks identical to hereditary spherocytosis, but not congenital.
- Clinical Features
- Jaundice, mild splenomegaly.
- Peripheral smear: spherocytes.
- Diagnosis: DAT (aka Direct Coombs Test) is positive for IgG on RBC surface.
- 10% negative, if still suspect do a more sensitive Coombs ("super coombs").
- (negative or weakly positve for complement)
-
- Peripheral Smear: Spherocytes (extravascular hemolysis)
- Coombs Test (DAT) --> Positive for IgG, +/- complement
- Treatment
- Corticosteroids
- Interfere with antibody production and macrophage clearance.
- Prednisone usually 1mg/kg/day + prolonged 2-4w taper.
- 2/3 respond.
- Splenectomy
- Indications: non-responders, or relapse or chronic steroids.
- 1/3 develop normal Hb, 1/3 have acceptable Hb, and 1/3 don't respond.
- Others:
- Rituximab (Monoclonal CD-20 antibody)
- Beneficial in non-randomized trials for refractory Warm AIHA.
- Danazol (Synthetic androgen - immunedeficient).
- Rituximab (Monoclonal CD-20 antibody)
- Corticosteroids
Cold AIHA
- Caused by IgM antibodies
- Usually binds I or i antigen (big I, little i)
- Bind occurs at temperatures <37°C, with max activity ~4°C
- Pathology:
- When exposed to cold - tip of nose/finger --> causes cold agglutinin disease.
- Efficiently fix complement --> RBC clearance by direct intravascular hemolysis or binding macrophages in liver (Kupffer Cells)
- Reverses with rewarming.
- Clinical Features:
- Anemia --> mild-to-mod, chronic, worse in cold temperatures.
- EBV and mycoplasma can trigger.
-
- Peripheral Smear: clumping/agglutination of RBC's
(... as slides are kept at low temperature.)- Clumping = astronomically high MCV.
- Coombs Test (DAT) --> Negative for IgG, positive for complement.
- (IgM doesn't stay on RBCs very long, so instead of IgM, just look for complement)
- Peripheral Smear: clumping/agglutination of RBC's
- Most have clonality, and have underlying lymphoma.
- Treatment:
- Avoid cold temperature.
- When infusing blood products or fluids (use warm solutions)
- Wear gloves, mittens, etc..
- Move to warm environments
- Other:
- Chlorambucil, cyclophosphamide, rituximab
- If severe, use plasmapheresis to clear IgM (large, stays in blood stream, does not diffuse out)
- NOTE: corticosteroids and splenectomy are ineffective (complement mediated hemolysis, in liver)
- Transfusion:
- Challenging, difficult to cross-match. Only transfuse when necessary
- But do not hold back for angina and CNS symptoms.
- High risk of acute or delayed hemolytic transfusion reaction.
- Communicate with blood bank, use blood warmer, most compatible
- NOTE: even patient's own blood won't be compatible.
- Avoid cold temperature.
Drug-Induced Hemolytic Anemia
- Caused by drug or drug metabolite or induced antibody interaction with RBC membrane.
- Typically days or weeks after drug initiation.
- Identify causative agent difficult (drugs, herbals etc..)
- Many drugs can cause this:
- 2nd + 3rd gen cephalosporins (MOST COMMON)
- chemo drugs
- MANY kinds
- Clinical Features:
- Testing for drug-induced antibodies is suboptimal
- Sometimes DAT positive for IgG, C3, both or neither. (positive DAT in 1-2% of hospitalized pts)
- Treatment:
- Stop the drug
- Usually hemolysis resolves after stopping drug, but can prolong with certain agents like fludarabine.
- Stop the drug
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