Hemolytic Anemia Flashcards
Elevated Reticulocytes Indicate..
Hemoglobinopathies
• RBC Membrane
Defects
• Enzyme deficiencies
Decreased Recitulocytes indicate…
Fe deficiency • Lead poisoning • Inflammation • Bone marrow failure syndromes
Two definitions of Hemolytic Anemia
Increased RBC destruction
• Premature death, accelerated destruction
Increased RBC production
• Fully or partially compensated anemia
• Can have hemolysis without being anemic if the rate of red cell
production is brisk enough to keep up with the rate of destruction
Two types of etiology of hemolytic anemia
Intrinsic abnormalities ( most often congenital) Membrane, enzymes, hemoglobin
Extrinsic forces ( most often acquired) Antibodies, toxins, mechanical stress
Two types of hemolysis
Intravascular
Extravascular
Hemolytic Anemia History (Hx): look for:
- Sex: G6PD (enzyme disorder) is X-linked
- Race/Ethnicity: Hemoglobinopathies
- Personal and Family History: Previous counts, Neonatal jaundice, History of required transfusion, Early gallstones, Splenomegaly/Splenectomy
- Drugs
- Infections/Illnesses: AIHA, Parvovirus B19—aplastic event
Hemolytic Anemia Signs/Sx:
Pallor, fatigue
Jaundice, dark urine
Splenomegaly, gallstones
Hemolytic Anemia Lab Findings
Reticulocytosis, Anemia Elevated bilirubin Elevated AST > ALT Elevated LDH
Hemolytic Anemia Intrinsic Causes:
Membrane disorders: Spherocytosis, Eliptocytosis, Pyropoikilocytosis
Enzyme disorders: G6PD Deficiency, Pyruvate Kinase Deficiency
Hemoglobin disorders
Hereditary Spherocytosis (HS) Characteristics
Spherocytes: smaller, loss of central pallor
Congenital hemolytic anemia • Most common inherited anemia in individuals of northern European descent • Autosomal Dominant Inheritance • ~1/3 are spontaneous mutations
Mutations affect RBC membrane
• Spectrin, ankyrin
• Loss of membrane surface area relative to intracellular
volume
Hereditary Spherocytosis Clinical Signs/Sx
Neonatal jaundice
• First 24 hours of life
• Exaggerated, prolonged physiologic nadir
Outside the newborn period:
• Incidental Laboratory findings
• Acute aplastic event (Parvovirus B19)
• Jaundice, Splenomegaly, early gallstones
Parvovirus B19 infection Characteristics
- “5th Disease”
- Clinical manifestations: URI/pharyngitis, rash (“slapped cheeks”), Very mild anemia
- Infects RBC precursors for 7-10 days so rapid decrease in red calls daily
- Dx: serology (IgM)
Hereditary Spherocytosis Levels of Infection
Depends on Spectrin Content:
Mild HS: 20-30% of cases, No anemia, sight Reticulocyte increase, Mild jaundice
Moderate HS: 65-75% of cases, + anemia, +Reticulocytes, + Bilirubin, ± splenomegaly, Occasional transfusions
Severe HS: 5% of cases, ++ anemia, ++Reticulocytes, ++ Bilirubin, Marked splenomegaly, Regular transfusions
Hereditary Spherocytosis Lab Findings
Anemia
Reticulocytosis
*MCHC typically > 36%
Wide RDW (small spheres and large reticulocytes)
Often elevated bilirubin, LDH, AST>ALT
*Presence of spherocytes on peripheral blood smear
Hereditary Spherocytosis Diagnostic Test results
Negative Direct Antiglobulin Test (DAT/Coombs)
Positive Osmotic Fragility Testing: decreased surface area means no room to swell so burst.
Osmotic Fragility Testing:
*Tests RBC integrity with varying osmotic loads
Endpoint is in vitro hemolysis
Difficulties in interpretation Transfused cells, high reticulocyte count Young age (< 6 - 12 months)
Does not differentiate congenital vs. acquired
spherocytes
Hereditary Elliptocytosis (HE) Characteristics:
- Elliptical, cigar shaped, erythrocytes
- Normochromic, normocytic, may or may not be anemic
- Defect in spectrin
- African and Southeast Asian Variants: 1:100 in parts of Africa
- Autosomal Dominant
- Many asymptomatic: RBC lifespan decreased by only ~10%
Hereditary Pyropoikilocytosis (HPP) Characteristics:
• Newborns with severe hemolytic anemia:
– Anemia, jaundice
– Poikilocytosis, elliptocytosis, and spherocytosis
– Fragments of cells so intra & extravascular lysis
• Gradually evolves into mild HE
Normal RBC Metabolism Characteristics
Absence of nucleus, mitochondria, ribosomes
Anaerobic metabolism: Glycolysis for ATP production
- Facilitated transfer of glucose
- Embden-Meyerhof pathway for energy (ATP)
- Rapoport-Luebering clutch (2,3 DPG)
- HMP shunt for reducing power (NADPH, glutathione)
Energy needs and Enzymatic activities decline with time
- Maintenance of cation gradients (Na/K pump)
- Protection from oxidative damage
- Maintenance of 2+ ferrous iron (NADH)
- Production of 2,3 DPG for oxygen unloading
- Nucleotide salvage and conservation
RBC Enzyme Disorders Characteristics:
Inherited defects in the metabolic pathway
Effects on the erythrocytes:
- Shortened in vivo lifespan,
- Congenital non-spherocytic hemolytic anemia
- Intravascular versus extravascular hemolysis
Effects other cells: Leukocytes, liver, brain
Two Kinds of Genetics of RBC Enzyme Disorders
Autosomal recessive inheritance: Majority of congenital RBC enzyme disorders
X-linked inheritance
- Glucose 6 Phosphate (G6PD) Deficiency
- Phosphoglycerate kinase (PGK) deficiency
Pyruvate Kinase Deficiency Characteristics:
Autosomal recessive disorder affecting RBC, WBC, liver
Non-spherocytic hemolytic anemia with:
- Hemolysis
- Reticulocytosis
- Elevated LDH, Bili, hemoglobinuria
- Polychromasia, ecchinocytes, acanthocytes
Decreased synthesis of ATP
-Increased 2,3 DPG levels cause O2 release at low hemoglobin concentrations
Partial response after splenectomy
G6PD Deficiency Characteristics
Most common human genetic mutation: X-linked
High prevalence re malaria protection
> 400 missense Genetic mutations:
A- variant most common among African descent
Mediterranean variant more severe
Effects of G6PD deficiency
Incomplete protection against oxidative stress
Acute hemolytic anemia after exposure to oxidative stress: Infections Sulfa drugs Naphthalene (moth balls) Fava beans
G6PD Deficiency Signs/Sx:
Acute fatigue, jaundice, pallor,
dark urine (intravascular hemolysis),
+/- history of known trigger
G6PD Deficiency Diagnostic Lab findings:
• Normocytic, normochromic anemia
• Reticulocytosis
• Elevated LDH, Bilirubin
** Hemoglobinuria (+ for blood, no RBCs on microscopic urine)
** Blister cells, anisocytosis on blood smear
**Assay G6PD activity after resolution of a hemolytic crisis
Medical Management of Congenital
Hemolytic Anemia
Periodic medical visits
Education re: signs/symptoms of anemia and hemolysis
Examination for growth (children), icterus, splenomegaly
Blood counts for hemoglobin, reticulocytes
Anticipatory guidance for gallstones, splenomegaly, and
parvovirus B19 infection
Therapeutic intervention
Folic acid supplementation (+/-)
Erythrocyte transfusions BUT can cause poor growth,
cardiovascular compromise
Consider full/partial Splenectomy risk/benefits
Splenectomy For Hemolytic Anemia Considerations:
Indications: Splenomegaly, hypersplenism, gallstones, jaundice, Growth, transfusion dependence
Methods
Partial versus total splenectomy procedure
Open versus laparoscopic procedure
**Pre-operative immunizations
Outcomes:
Laboratory improvement
Alleviation of transfusion dependence
Prevention of gallstone formation
Post-Splenectomy Complications:
Overwhelming post-splenectomy infection (OPSI)
• Typically encapsulated organisms
• Immunizations, Antibiotic prophylaxis
• Fever precautions
Resistant pneumococcal and meningococcal
disease
Thrombotic Events
Pulmonary Hypertension
DDX: Erythrocyte Membrane Disorders vs Enzyme Disorders
Erythrocyte Membrane Disorders: Spherocytes, Autosomal Dominant, Osmotic Fragility, Splenectomy: Complete response
Erythrocyte Enzyme Disorders: No Spherocytes,
Autosomal Recessive, No Osmotic Fragility, Splenectomy: Partial response
Hemolytic Anemia Extrinsic Etiologies:
Erythrocyte Alloantibodies:
Neonatal alloimmune hemolysis
Post-transfusion exposure
Erythrocyte Autoantibodies:
Warm-reactive IgG antibodies
Cold-reactive IgG antibodies (PCH)
Cold agglutinin disease
External forces:
Schistocytic anemia,
Drugs, toxins, burns
Complement (PNH)
Autoimmune Hemolytic Anemia (AIHA) characteristics:
Incidence: 1 - 3/100,000, children and adults
Variable clinical course: self-limited, short illness, waxing and waning, chronic illness
Prognosis typically good: Morbidity from treatment, Mortality <10%
Erythrocyte autoantibodies: IgG, IgM, Complement fixation
Types: Warm vs. Cold
Lab Test: Direct Antiglobulin Test (Coombs test)
Warm-Reactive AIHA characteristics:
IgG autoantibody mediated RBC destruction
(G for Georgia = Warm)
• Bind RBC surface at warmer temperatures
* Extravascular hemolysis—Fc Receptors in the spleen
• Occasionally fix complement leading to lysis
Types:
- Idiopathic
- Immunodeficiency
- Secondary: EBV infection
Direct Antiglobulin Test (DAT)
AKA “Coombs Test”: How does it work?
Sensitized Erythrocytes \+ Coombs reagent (anti-IgG, anti-C3) = Visual RBC Agglutination (1+ to 4+)
Warm-Reactive AIHA Signs/Sx:
- Typically rapid onset anemia
- Can be life threatening
- Fatigue, dyspnea, heart failure
- Scleral Icterus, Jaundice, +/- dark urine (hemoglobinuria)
- Splenomegaly
Warm-Reactive AIHA Labs:
• Anemia and reticulocytosis • Spherocytes on peripheral blood smear • Positive DAT \+ IgG, ± Complement (C3)
Warm-Reactive AIHA
Transfusion will not be 100% compatible but may be necessary (Least Incompatible)
Glucocorticoids: Once remission has been achieved, wean steroids SLOWLY and mimic physiologic dosing as much as possible (AM dosing)
Splenectomy
Rituximab: Monoclonal antibody directed against CD20 on B-cell surface
Problems with Long-term Steroids:
Weight gain Diabetes Osteoporosis and fracture Osteonecrosis of the femoral head Cataracts
Cold Agglutinin Disease
(Cold Reactive AIHA)
Characteristics:
IgM-mediated RBC destruction (M for Minnesota = Cold)
• Agglutinins, Hemolysins
Pathophysiology: IgM binds and fixes complement to red cell in areas with cooler circulation, red cell returns to warmer circulation, then IgM dissociates but leaves complement (C3) leading to cell lysis
Kupffer cells in the liver have receptor for C3b
Etiology: Most idiopathic, some after mycoplasma or viral infection
Cold Agglutinin Disease
(Cold Reactive AIHA)
Signs/Sx:
Erythrocyte agglutination upon exposure to cold
• Mottled or numb fingers and toes
• Acrocyanosis (blue extremities)
Cold Agglutinin Disease
(Cold Reactive AIHA)
Labs:
• Mild anemia with reticulocytosis
** Red cell agglutination on PBS made at room temperature (but not at 37 C)!
** DAT (Coombs) will be positive for complement (C3) only
Cold Agglutinin Disease
(Cold Reactive AIHA)
Treatment
Largely symptomatic–Avoid cold!
Rituximab re active or relapsing symptomatic hemolysis
Splenectomy and corticosteroids ineffective so avoid
If transfusion is needed—Warm the RBCs!
DDX re Warm-Reactive AIHA vs Cold-Reactive AIHA
Warm-Reactive AIHA: IgG, DAT result: +IgG, ± C3 (C3 fixation Variable) Thermal reactivity 37C, RBC destruction: Spleen, Tx: Steroids, Splenectomy
Cold-Reactive AIHA: IgM Thermal reactivity: 4C \+C3 (C3 fixation) RBC destruction: Liver Common therapy: Avoid cold, Rituximab
Treatment Takeaways re Hemolytic Anemias
- NEVER withhold RBC transfusions if needed
- Corticosteroid therapy must be weaned slowly
- Limited utility of IVIG
- Immunizations before splenectomy
- Increasing use of rituximab therapy
