treatment for hemolytic disorders
TRANSCRIPT
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Treatmen t of
Hemolyt ic Anem ias
Felicia L. Wilson, M.D.
Professor of Pediatrics
Director, Division of Hematology/Oncology
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Normal Red Blood Cells
(RBCs)
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Normal RBCs
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Red Cell Metabolism 2,3-DPG is the most
abundant RBC phosphate
Important in maintaining theposition of the O2dissociation curve.
The higher the content in
RBCs, the more easilyoxygen is liberated fromhemoglobin.
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Hemolytic Anemias Increased RBC destruction
shortened survival
Hereditary (intracorpuscular) defects ofmembrane
enzymes
globinAcquired (extracorpuscular) causes
Immune
Nonimmune
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Physical Features Pallor
Jaundice
Tachycardia
Heart murmur
Splenomegaly
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Laboratory Features Reticulocytosis
Increased Bilirubin
LDH
AST
Hemoglobinuria
Hemoglobinemia
Hemosiderinuria
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Case # 1 A 18 month old African-American male
presents to the emergency room withlow-grade fever, decreased appetite andpainful swelling of his hands. Hereceived a dose of Tylenol at home butdid not get any relief.
On physical examination, he is fussy,but consolable and is tachycardic with aIII/VI systolic ejection murmur. Thespleen is palpable 2 cm below the left
costal margin.
The CBC reveals a hemoglobin of 8.3gm/dl, hematocrit 24%, MCV 78, RBC of3.2 MIL/l and a retic count of 8%.
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100,000 cases
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RBC Function
One RBC contains ~ 250 million hemoglobin molecules and eachhemoglobin can bind 4 molecules of oxygen. During each circuit of
the body, a single RBC carries ~ one billion molecules of oxygen.
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Deoxygenated Sickle
Hemoglobin
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Sickling and Membrane Injury
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Manifestations of Sickle Cell Disease
Vaso-occlusion
Sickled Erythrocytes Endothelial Cells
Vascular injury
Hemolytic anemia
vesselocclusion
normalRBC
vesselocclusion
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Complicat ions in Sickle Cel l Disease
Bones
Spleen
Lungs
Liver
CNS/Eyes
GU
Complication
(%)
Organ
Vaso-occlusive
Episodes
Pain/Infarcts (1-2 events/yr
> 70%)
Infarction (90)
Sequestration (11)
Infection (15)
Acute chest syndrome (40)
Gallstones (42)
Sequestration
Strokes (10)
Proliferative retinopathy (12)
Hypostenuria (50)
Renal failure (3)
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Dactylitis
Often the 1stmanifestation of SCD
Jaundice 35%
HSM 50-75%
Ischemic necrosis ofsmall tubular bones
of the hands &/orfeet
Often bilateral
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Hand-foot
Syndrome
Characterized by
soft tissue swelling,
heat & tenderness
Peak age 2 years
(6 months 8 years)
Dactylitis
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Destructive Bone Lesions ofDactylitis
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Unequal Growth of Digits
Pain is an indication of tissue damage.
Most common reason for hospitalization and ER visits.
Recurrent pain is known to be associated with early death.
Pain crisis is a diagnosis of exclusion!
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World Health Organization3-Step Ladder
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Cooperative Study ofSickle Cell Disease
Initiated in 1978 by NIH to gather dataprospectively on the natural history of
SCD Cohort of 2824 patients registered,
followed, and managed (4007registered)
23 clinical centers in the US
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CSSCD Mortality Data
Infection - major cause of morbidity & mortality
S. pneumoniae - most common during early childhoodEnteric organisms emerge as important pathogens in older patientsLeinken et al. Pediatrics. 1989;84:500.
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Cell mediated immunity and humoral immunity
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Immune Dysfunction
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Penicillin Prophylaxis StudyPROPS - I
NEJM, 1986 314:1593-9
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Infections,
3 deaths
2/105Infections,
No deaths
Study was
terminated
8 months
early
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IMMUNIZATION
as recommended by the AAP PCV13 (conjugated pneumococcal vaccine)
pneumococcal vaccine
23-valent polysaccharide vaccine
Age 2 years
Booster age 5 years
meningococcal vaccine
influenza vaccine
HPV (human papilloma virus) vaccine
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STREPTOCOCCUS PNEUMONIAE
Deaths continue to occurdespite PCN prophylaxis
Non-compliance
Inappropriate outpatientmanagement
400 fold above normalpopulation
Septicemia
Meningitis
Pneumonia Septic Arthritis
Resistance
22-25% - penicillin
15% - cephalosporin
50% - macrolide
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Transfusion Therapy in SCD
Episodic Transfusions
Symptomatic Anemia ASSC
Aplastic crisis Stroke or acute neurological event ACS Multiorgan failure Preoperative management
Chronic Transfusions Primary and secondary stroke prevention Recurrent ACS not improved by hydroxyurea Progressive organ failure Recurrent ASSC
Complicated Pregnancy
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Modulators of SCDSeverity
Fetal Hemoglobin 1948Dr. Janet Watson
SCD babies rarely have problems in 1st
yr of life High Hb F levels protects the infant
1975Stamatoyannopoulos et al.
HPFH > 20% F in all cells Fetal Hb disrupts polymerization
Few pts with SCD have F > 10% in some cells
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Multicenter National Trial1991FDA approved 199550% reduction in pain crises, ACS and need for transfusion40% reduction in deaths
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To date, > 300Bone MarrowTransplants have been
performed around theworld forSickle Cell Disease.
The Cure
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Outcome After Transplantation
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BMT Patient with SCD & AML
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Case #2
One of your friends went on amission trip in the Mediterranean
She adopted this little boy froman orphanage and doesnt knowanything about his PMH or FH
Since arriving in America heseems tired and depressed and
doesnt want to do much
She wants you to be his primarycare provider and recommend agood dentist
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Peripheral Smear
Abnormal shapes, red cell rigidity
& fragmentation
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Thalassemia Major
Results from inheritance of two impaired globingenes
Profound anemia secondary to ineffectiveerythropoiesis with impaired production of Hb A
Presents in early infancy with anemia, paleness,weakness, failure to thrive, splenomegaly
Transfusions are necessary for survival
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Oliveri,N. NEJM 1999;341(18):1407 200 Mutations Causing Thalassemia
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Adult Hemoglobin
Globin chains
- alpha - beta
- delta - gamma
Hemoglobin
A1 - 22A2 - 22 F - 2 2
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- Thalassem ia
Decreased synthesis of chains
Relative excess of chains
Increased Synthesis
chains 2 2 (Hb A2)
chains 22 (Hb F)
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Age 4low transfusion Age 11high transfusion
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Treatment for-Thalassemia Major
Transfusions are the mainstay of therapy
Goal is to maintain Hg >9.5g/dl
Requires transfusions every 2 to 4 weeks
Advantages include: Improved physical and psychologic well being
Decreased cardiomegaly Decreased hepatosplenomegaly
Fewer bony changes and orthodontic problems
Normal or near normal growth until adolescence
However, patients become severely iron overloaded
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Case # 3
18 month old
Fever
Stuffy nose
Decreased activity
Sleeping more
Rash
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Peripheral Smear
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Hereditary Spherocytosis
Most common cause of non-immune hemolytic anemia
Autosomal dominant transmission
25-30% sporadic mutations
Loss of membrane surface area relative to intracellularvolume spheres and decreased deformability
Extravascular hemolysis in the spleen
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HS
Abnormalities of spectrin and/or ankyrin, andless commonly Protein 4.2 or Band 3
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Clinical Manifestions of HS
Hemolytic anemia Degree of anemia varies with different mutations 25% with compensated hemolysis and no anemia
Pallor, fatigue Jaundice
Neonatal jaundice in first 24 hours of life Splenomegaly
Gallstones Positive family history
May present with parvovirus associated aplasia
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Laboratory Manifestations of HS
Spherocytes onperipheral blood smear
Reticulocytosis Increased incubated
osmotic fragility
Negative DAT
Increased MCHC > 36%due to relative cellulardehydration
Increased bilirubin, LDH
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Incubated Osmotic FragilityTesting Red cells are incubated in varying
concentrations of saline (00.9%) for up to 48 hours
As concentration of salinedecreases, cells take on water andare hemolyzed
Normal cells around 0.5%
HS cells at higher NaCl concentrations
Degree of hemolysis is detected byspectrophotometry
Not reliable < 6-12 months of age
Normal Osmotic Fragility
Increased Sensitivity to Lysis
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Treatment
Folic acid supplementation
Transfusion if anemia is severe
Splenectomy
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Indications for Splenectomy
Controversy re: need for and timing of splenectomy
Splenectomy typically leads to marked improvement in RBCsurvival and laboratory parameters
Risk of gallstones is reduced (but not gone)
Complications include local infection, bleeding,postsplenectomy sepsis, thrombosis, cardiovascular disease,pulmonary HTN
Pneumococcal, meningococcal vaccines preop
Indications: growth failure, skeletal changes, transfusiondependence, massive splenomegaly
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Case #4
3 yo WM
Playing hide and seekwith the baby sittersgrandson
Mom noticed peculiarsmell, dark urine andfound these in his pocket
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Hemoglobinuria
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G-6-Phosphate Dehydrogenase
Regenerates NADPH, allowingregeneration of glutathione
Protects against oxidativestress
Oxidative stress leads to Heinzbody formation &extravascular hemolysis
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G6PD Deficiency
Most common red cell enzymopathy
X linked inheritance
Decreased production of NADPH with inability to
maintain reduced glutathione levels Hemolysis occurs in response to oxidative stresses such
as infections, drugs, fava beans (favism), naphthalene(moth balls)
Anemia may be low grade and chronic (CNSHA) or acuteafter exposure to oxidant
Denatured hemoglobin seen as Heinz bodies on bloodsmear; also with blister cells on smear
Reticulocytes have 5X higher G6PD, so assay after
resolution of hemolytic crisis
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Treatment for G-6-PD
Avoid precipitatingfactors
Infections
severe stress
certain foods (suchas fava beans) andcertain drugs
Rest during episodes
Transfuse ifnecessary
Antimalarial drugs
Aspirin
Nitrofurantoin Nonsteroidal anti-
inflammatory drugs(NSAIDs)
Quinidine
Quinine
Sulfa drugs
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RBC Enzyme Disorders
RBC enzymes are importantfor: Energy production through
glycolysis and the pentosephosphate shunt
Maintaining cation gradient
Protecting from oxidative damage
Production of 2,3 DPG
Maintenance of ferrous 2+ iron Nucleotide salvage
Abnormalities result in diversephenotypes
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Pyruvate Kinase Deficiency
Autosomal recessive enzymedysfunction leading to anemia that is
chronic rather than episodic
Transfusion is the mainstay of therapy
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Case #5
14 yo WF at UMS track meet Wednesdaynight
It was the first day of spring so shethought it would be warm, instead she
was freezing
Yesterday she noticed tea colored urine
and got concerned
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Autoimmune Hemolytic Anemia
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Treatment Cold AIHA
Treat underlying cause
Causes: Mycoplasma, EBV, HIV, CLL
Avoid cold triggersreact at 28-31 degrees C
Steroids/splenectomy/IVIG
Rituximab
Try to avoid transfusions
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Treatment for Warm AIHA
Causes: Lupus, Rheumatoid Arthritis, CLL,methyldopa
IgG reacts at 37 degrees C
Steroids & folic acid, IVIG - frontline
Splenectomy, rituximab2ndline
Immunosuppressioncyclophosphamide,imuran, MMF
Try to avoid transfusions
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Treatment for PCH
Causes: Measles, Mumps, EBV, CMV,Mycoplasma, syphilis, HIV
Self limited
Treat underlying cause
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Case #6
15 yo WM
Vomiting, bloody diarrhea started 1 week ago
Now 1 week later c/o weakness
Hemoglobin is 9 and pt referred to USACWH EC
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T t f
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Treament ofHemolytic Uremic Syndrome
E. coli bacteria O157:H7 toxin
Also linked to shigella & salmonella
Dialysis
Steroids
Transfusion of pRBCs and platelets
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