Treatment for Hemolytic Disorders

8/9/2019 Treatment for Hemolytic Disorders

1/87

Treatmen t of

Hemolyt ic Anem ias

Felicia L. Wilson, M.D.

Professor of Pediatrics

Director, Division of Hematology/Oncology


2/87

Normal Red Blood Cells

(RBCs)


3/87

Normal RBCs


4/87


5/87

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.


6/87

Hemolytic Anemias Increased RBC destruction

shortened survival

Hereditary (intracorpuscular) defects ofmembrane

enzymes

globinAcquired (extracorpuscular) causes

Immune

Nonimmune


7/87

Physical Features Pallor

Jaundice

Tachycardia

Heart murmur

Splenomegaly


8/87

Laboratory Features Reticulocytosis

Increased Bilirubin

LDH

AST

Hemoglobinuria

Hemoglobinemia

Hemosiderinuria


9/87

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%.


10/87


11/87

100,000 cases


12/87

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.


13/87


14/87

Deoxygenated Sickle

Hemoglobin


15/87

Sickling and Membrane Injury


16/87

Manifestations of Sickle Cell Disease

Vaso-occlusion

Sickled Erythrocytes Endothelial Cells

Vascular injury

Hemolytic anemia

vesselocclusion

normalRBC

vesselocclusion


17/87

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)


18/87

Dactylitis

Often the 1stmanifestation of SCD

Jaundice 35%

HSM 50-75%

Ischemic necrosis ofsmall tubular bones

of the hands &/orfeet

Often bilateral


19/87

Hand-foot

Syndrome

Characterized by

soft tissue swelling,

heat & tenderness

Peak age 2 years

(6 months 8 years)

Dactylitis


20/87

Destructive Bone Lesions ofDactylitis


21/87

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!


22/87


23/87

World Health Organization3-Step Ladder


24/87

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


25/87

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.


26/87

Cell mediated immunity and humoral immunity


27/87

Immune Dysfunction


28/87


29/87

Penicillin Prophylaxis StudyPROPS - I

NEJM, 1986 314:1593-9

13/110

Infections,

3 deaths

2/105Infections,

No deaths

Study was

terminated

8 months

early


30/87

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


31/87

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


32/87

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


33/87

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


34/87


35/87

Multicenter National Trial1991FDA approved 199550% reduction in pain crises, ACS and need for transfusion40% reduction in deaths


36/87


37/87


38/87

To date, > 300Bone MarrowTransplants have been

performed around theworld forSickle Cell Disease.

The Cure


39/87

Outcome After Transplantation


40/87

BMT Patient with SCD & AML


41/87

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


42/87


43/87

Peripheral Smear

Abnormal shapes, red cell rigidity

& fragmentation


44/87

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
http://content.nejm.org/content/vol341/issue2/images/large/07f2.jpeg


45/87

Oliveri,N. NEJM 1999;341(18):1407 200 Mutations Causing Thalassemia


46/87

Adult Hemoglobin

Globin chains

- alpha - beta

- delta - gamma

Hemoglobin

A1 - 22A2 - 22 F - 2 2


47/87

- Thalassem ia

Decreased synthesis of chains

Relative excess of chains

Increased Synthesis

chains 2 2 (Hb A2)

chains 22 (Hb F)


48/87


49/87


50/87


51/87


52/87

Age 4low transfusion Age 11high transfusion


53/87

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


54/87


55/87

Case # 3

18 month old

Fever

Stuffy nose

Decreased activity

Sleeping more

Rash


56/87

Peripheral Smear


57/87

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


58/87

HS

Abnormalities of spectrin and/or ankyrin, andless commonly Protein 4.2 or Band 3


59/87

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


60/87

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


61/87

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


62/87

Treatment

Folic acid supplementation

Transfusion if anemia is severe

Splenectomy


63/87

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


64/87

Case #4

3 yo WM

Playing hide and seekwith the baby sittersgrandson

Mom noticed peculiarsmell, dark urine andfound these in his pocket


65/87


66/87


67/87

Hemoglobinuria


68/87

G-6-Phosphate Dehydrogenase

Regenerates NADPH, allowingregeneration of glutathione

Protects against oxidativestress

Oxidative stress leads to Heinzbody formation &extravascular hemolysis


69/87

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


70/87

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


71/87

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


72/87

Pyruvate Kinase Deficiency

Autosomal recessive enzymedysfunction leading to anemia that is

chronic rather than episodic

Transfusion is the mainstay of therapy


73/87

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


74/87


75/87


76/87


77/87


78/87


79/87


80/87

Autoimmune Hemolytic Anemia


81/87

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


82/87

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


83/87

Treatment for PCH

Causes: Measles, Mumps, EBV, CMV,Mycoplasma, syphilis, HIV

Self limited

Treat underlying cause


84/87

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


85/87

T t f


86/87

Treament ofHemolytic Uremic Syndrome

E. coli bacteria O157:H7 toxin

Also linked to shigella & salmonella

Dialysis

Steroids

Transfusion of pRBCs and platelets


87/87

Documents

Treatment for Hemolytic Disorders