# Presentation: 017569

## Sickle Cell Anemia

- Jeffrey Keefer MD, PhD

- 	“Peculiar elongated and sickle-shaped red corpuscles in a case of severe anemia”
- JB Herrick describing disease in a West Indian student
- Archives of Internal Medicine in 1910

- Sickle cell anemia is one of the most prevalent genetic disorders world-wide
- Results from a variant of the Beta Globin gene on chromosome 11
- a glutamic acid at the 6th position is replaced by a valine resulting in formation of Hemoglobin S

## Slide 4

## Hemoglobin S

## Sickle cell disease genotypes

- Hemoglobin SS disease (homozygous sickle cell disease)
- Both Beta Globin alleles with the S mutation
- Most common and most severe form
- Hemoglobin SC disease
- One Beta Globin with the S mutation
- One Beta Globin with the C mutation (lysine at position 6)
- Patients sickle and have disease-typically milder than SS

## Sickle cell disease genotypes

- Hemoglobin S Beta 0 (null) Thalassemia
- One Beta Globin gene with the S mutation
- One Beta Globin Gene with a severe thalassemia mutation (No production of normal beta globin)
- Similar to SS disease
- Hemoglobin S Beta Plus Thalassemia
- One Beta Globin with the S mutation
- One Beta Globin Gene with a mild thalassemia mutation (decreased but finite production of normal beta globin)
- Typically milder than SS disease

## Non-sickling HbS genotypes

- Sickle cell trait
- One normal Beta globin allele
- One beta globin allele with the S mutation
- HbS HPFH
- One beta globin cluster with HPFH mutation
- One beta globin allele with the S mutation

##  Frequency of beta globin gene variants in California

| Ethnicity | Hb SSb | Hb AS | Hb S/beta+thal | Hb SC |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Asian | 0/207551 | 1/1336 | 0/207551 | 0/207551 |   |   |
| Asian Indian | 0/15843 | 1/725 | 1/15843 | 0/15843 |   |   |
| Black | 1/700 | 1/14 | 1/4056 | 1/1297 |  |  |
| Hispanic | 1/45622 | 1/183 | 1/729953 | 1/364976 |  |  |
| Middle Eastern | 0/21677 | 1/360 | 0/21677 | 0/21677 |   |   |
| Native American | 1/16529 | 1/176 | 0/16529 | 0/16529 |   |   |
| White | 1/158127 | 1/625 | 1/553447 | 0/1106895 |   |   |

- aSource: Lorey et al (1996)bHbSS includes HbS/beta0-thalassemia

## Hemoglobin S:  What’s the big deal?

- 1927 Hahn and Gillespie showed sickling with deoxygenation of red cells in a patient

## Hemoglobin S polymer formation

|                                           |
| --- |
|   |

- The hydrophobic valine is exposed in the deoxy conformation and burrows within a hydrophobic pocket of neighboring Beta chains

## Hemoglobin 

- Hemoglobin
- polymers

## Simple pathology-complex disease 

- Presence of HbS leads to a variety of clinical manifestations- Cool pathophysiology at work!
- Infection				painful crises
- chest crises			priapism
- strokes 				pulmonary htn
- splenic sequestration 	         avascular necrosis
- renal failure

## Simple pathology-complex disease

- Disease severity variable and difficult to predict
- Genotype (SS vs SC vs Sthal)
- Beta globin gene cluster haplotype
- Senegal most benign, central african republic most severe
- Fetal hemoglobin levels-Higher is better
- BAD as infant: dactylitis, severe anemia, leukocytosis
- Steinberg MH. Predicting clinical severity in sickle cell anaemia.Br J Haematol. 2005 May;129(4):465-81.

## Incidence of sickle cell complications in the US, based on genotype

| Complication | HbSS(per 100 pt-years) | HbSC(per 100 pt-years) | HbS/beta0-thalassemia (per 100 pt-years) | HbS/beta+-thalassemia(per 100 pt-years) |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Acute Chest Syndrome | 12.8 | 5.2 | 9.4 | 3.9 |  |  |
|  |  |  |   |   |  |  |
| Bacteremia | 6.5 | 5.8 |   |   |  |  |
|  |  |  |   |   |  |  |
| Stroke | 0.61 | 0.17 | 0.10 | 0.11 |  |  |
|  |  |  |  |  |  |  |
| Pain crisis | 24.0 | 8.5 |   |   |  |  |
|  |  |  |   |   |  |  |

- A.J. Epidemiology May 2000

## Survival by genotype in 1980s

| Sex and Genotype | Median Survival |
| --- | --- |
| Males with Hb SS | 42 years |
| Females with Hb SS | 48 years |
| Males with Hb SC | 60 years |
| Females with Hb SC | 68 years |

-  In 1973 mean survival with SS disease was 14 years!

- Care for sickle cell patients has begun to focus on screening and prevention in addition to symptom management

## Early Diagnosis

- Maryland has universal newborn hemoglobin screening
- Big step in decreasing mortality in sickle cell disease
- Identify babies to prophylax against infection
- Isoelectric focusing
- Electrophoresis in a pH gradient
- HPLC column chromatography to quantify
- Molecular diagnostics-sequencing the beta globin gene

## IEF Gel

- 1         2         3

- Reported by intensity:  SFA
- Hemoglobin S beta plus thalassemia

## TRAIT on HPLC

- Report is ASFA2
- Sickle cell trait

## SICKLE CELL DISEASE IN CHILDREN AND ADOLESCENTS: DIAGNOSIS, GUIDELINES FOR COMPREHENSIVE CARE,AND PROTOCOLS FOR MANAGEMENT OF ACUTEAND CHRONIC COMPLICATIONS©

**SICKLE CELL DISEASE IN CHILDREN AND ADOLESCENTS: DIAGNOSIS, GUIDELINES FOR COMPREHENSIVE CARE,AND PROTOCOLS FOR MANAGEMENT OF ACUTEAND CHRONIC COMPLICATIONS©**
**Mid-Atlantic Sickle Cell Disease Consortium (MASCC) Practice Guidelines Workgroup**
**sponsored by the Mid-Atlantic Regional Human Genetics Network (MARHGN)**

## Preventative Medicine

- All patients need a medical home
- Primary pediatrician + hematology care
- Q3month visits here in the first year then q6month-yearly depending
- Patient/family education
- State educator meets with each family at home or in the clinic for detailed teaching
- Assess fever, respiratory distress, splenomegaly and jaundice at a minimum
- Management of febrile events

## Prevention

- Prophylactic Penicillin (PROPS study, NEJM1986)
- Shown to reduce mortality from pneumococcal sepsis (84% decrease in bacteremia)
- Start by 2 months of age (or at first visit)
- 125mg BID until age 3
- 250mg BID until ???

## Penicillin—When to stop?

- We historically have stopped 1 year after 2nd 23 valent pneumococcal vaccine (age 6)
- PROPS II showed no advantage of continuing after 5yo but many centers do
- Immunology division does lifelong PCN for asplenic patients-why don’t we?
- Recent death from pneumococcal sepsis 1 week after stopping PCN at age 7
- Our management strategy is in flux
- considering longer term therapy

## Prevention

- Immunizations
- Routine immunizations including H. flu and Prevnar, the 7 valent pneumococcal conjugate
- 23 valent polysaccharide conjugated pneumococcal vaccine at age 2 and 5
- Booster schedule unclear and no formal recs
- Immunology does q5-10 years
- Influenza vaccine yearly
- Meningococcal vaccine
- Have not been giving to kids routinely
- Definitely for college

## Prevention	

- Health screening
- Transcranial Doppler Ultrasound for stroke risk
- At age 2, for SS patients, begin TCD ultrasound screening on a yearly basis
- Measures flow velocity in CNS vasculature
- “garden hose analogy”
- <170cm/sec is normal
- 170-200-repeat frequently to assure no progression to abnormal
- >200 abnormal-repeat to confirm and begin chronic transfusions if abnormal

## STOP: Stroke prevention in Sickle Cell Anemia Trial (NEJM 1998)

- Trial showed that stroke risk is elevated (10% per year) in patients with abnormal TCD
- Chronic transfusions in kids with abnormal TCDs decreases stroke risk by 6 months on therapy
- Recent California data show study suggest 5-6 fold decrease in stroke pre versus post TCD (Fullerton,Blood 2004)
- When to stop???

## STOP II trial

- Randomized kids after 3 years of transfusion to
- Continue transfusion
- Stop transfusion
- Monitor TCD and clinical parameters
- Study halted secondary to high rate of conversion to abnormal TCD and stroke in several patients
- For now abnormal TCD = prolonged transfusional therapy

## Other preventative measures

- CNS
- Neurocognative testing and education intervention
- MRI for silent stroke-unsure of treatment plan-needs study!!
- Lungs
- Pulmonary function testing-especially with RAD or post ACS
- Sleep study for snoring/sleep apnea
- Pulmonary Hypertension screening late adolescents/adults
- Renal
- Screening for proteinuria—microalbumin
- Use of ACE inhibitors to prevent renal disease-some data
- Eyes
- Yearly optho exams especially in SC patients
- General
- Prophylactic use of Hydroxyurea to prevent organ damage
- BABY HUG STUDY

- “My baby has a fever”
- “I am in pain all over”
- “My hand is numb”
- “I can’t catch my breath”
- “My baby has a huge spleen”
- “My privates are swollen”

## Fever

- Infection is the most immediate risk for infants with SCA
- All sickle cell patients with t>38.5 or recurrent low grade temps should be seen immediately
- PE, CBC with retic, blood culture, chest x-ray, UA and urine culture
- Admit for antibiotics (48 hr rule-out) and observation
- Young Kids (under 3?, no right answer)
- Sick kids (temp>40, low BP etc, petechiae etc)
- Indwelling catheters
- Elevated white counts or low platelet counts
- Alarming Urinalysis
- Infiltrates
- Toxic smears
- Social concerns-no phone, transportation etc

## Outpatient fever management

- DISCUSS WITH YOUR FRIENDLY ATTENDING PLEASE
- Older kids
- Not ill
- Good family for follow-up
- Get blood cultures
- GIVE ceftriaxone
- Observe after antibiotics in ED (4 hours recommended)
- Follow-up next day for evaluation and 2nd ceftriaxone dose pending culture results

## Pain

- Dactylitis in infants—usually ok with NSAIDs
- Mild pain
- NSAIDs and/or oral narcotics-many families have a “home regimen” for early pain
- Rest and fluids
- Local measures-warm compresses, massage, distraction
- Failing home meds: ED VISIT
- Aggressive upfront pain management is key
- Morphine sulfate IV large doses repeating as needed
- Tordol IV
- Hydration (not hyperhydration)

## Inpatient Pain Management

- Hematology manages pain of sickle cell patients on our service
- PCA is typical starting point (some exceptions)
- Morphine versus Dilaudid
- Orders are on D drive on public workstations-PCA folder
- Residents will write these from Excel spread sheet-requires 2 signatures-Dosing ranges are included in orders
- Orders include Tordol dosing and other prn meds such as senekot, benedryl etc
- Both basal and bolus are given-Bolus use is an indicator of pain control
- Remember typical pain crisis is 5-7 days

## Pain

- Transition to oral
- Add daily IV dose from basal and bolus together and convert this to a daily oral dose
- IV to Oral conversions vary-usually 3X for MSO4-see the Lane or other reference for conversion
- Leave bolus on while initially transitioning
- Don’t need to be pain-free to leave
- Be sure patients can fill their narcotics before leaving the hospital

## Pain

- For atypical pain think of other causes
- Myalgias-Influenza
- Point tenderness with fevers-osteomyelitis
- Joint pain-rheumatologic issues
- Consult pain service
- Prolonged/chronic pain
- Multiple pain meds
- Use of Epidurals
- Don’t work outside your own comfort zone with these drugs!!!

## Acute Chest Syndrome	

- Definition:
- New infiltrate + (fever or chest pain or hypoxia)
- Causes (Vichinsky,NEJM 2000)
- Fat emboli from necrotic marrow
- Chlamydia pneumoniae, Mycoplasma
- S.pneumo, Staph aureus
- Parvo

## ACS Management

- Antibiotics
- Ceftriaxone + Biaxin
- Incentive spirometry/pulmonary toilet
- Albuterol if needed
- Transfusion therapy
- Simple transfusion for low hemoglobin (maybe)
**BE CAREFUL** —Stroke assoication with simple transfusion especially with hct over 30% (Strouse in progress)
- Exchange transfusion
- Some would argue this is best in almost all cases
- Certainly indicated for ill children or for clinical deterioration

## ACS Management

- Steriods anyone? (Buchanan Blood 1998)
- 0.3mg/kg of dexamethasone q12hrX 4 doses
- Lots of improvement but 27% readmitted within 72 hours vs 4% no steriods
- Our experience is even worse with “rebound effects” primarily prolonged hospitalization for pain
- Conclusion:  No steroids for ACS
- Treat asthma however if necessary

## Stroke	

- 10-12% of children with SCA will have a symptomatic stroke (large vessel disease)
- Additional 20% have asymptomatic infarcts by MRI scanning
- RAPID action can reverse deficits associated with acute stroke
- For any suspicious CNS event
- EXHANGE TRANSFUSION (Don’t delay for imaging)
- Goal is HbS < 30%
- Manual exchange in PICU
- Erythrocytopheresis team (Need large lines for this)
- Page on call aphoresis attending for help setting this up
- Long term management with chronic transfusion

## Stroke

**Exchange transfusion ASAP for CNS symptoms**
- Don’t wait 2 days for MRI slot
- Don’t wait until morning so everyone can sleep
- Don’t wait to discuss with your team on rounds with a full notebook of articles to impress the attending
- Of course nothing is every easy or straight forward!!

## Splenic Sequestration

- Occurs in infants and young kids with SS dz
- Rapid onset of fatigue, listlessness and pallor
- Can progress quickly to shock
- SC patients sequester as older kids/adolescents and tend to be less severe
- Admit and closely monitor spleen size and hemoglobin-q2-4 hours in some cases
- Therapy is red cell transfusion/fluid management or emergent splenectomy in extreme cases
- Recurrent episodes may be indication for elective splenectomy

## Aplastic Crisis

- Low reticulocyte counts with no hemoglobin drop deserve close outpatient follow-up
- Patients with Hemoglobin 1.5-2g less than baseline with low reticulocyte count need admission with observation
- PRBCs for symptomatic/exaggerated anemia
- Slow infusion
- Isolation and send Parvovirus studies

## Priapism

- Painful persistent erection due to vaso-occlusive obstruction of the venous drainage
- 89% of males will have at least one episode by adulthood
- Episodes classified as
- Stuttering: frequent intermittent episodes with mild tenderness that resolves spontaneously
- Often in younger prepubertal kids
- Persistent: severe/painful often seen in pubescent or older teens
- Both stuttering and persistent episodes can lead to impotence but persistent painful erection is a medical emergency

## Priapism management

- Stuttering
- Typically resolves on its own
- Ensure adequate hydration
- Oral analgesia if necessary
- Attempt to urinate
- Gentle exercise: walking stairs etc
- Treat any underlying UTI if present

## Priapism management

- Persistent
- All of the therapies for stuttering are appropriate as initial therapy (can be started at home)
- Analgesia, hydration, exercise, urination
- If these don’t work patients need to be seen ASAP
- Next steps are really not well defined:
- “There is no evidence for the benefits or risks of the different treatments for both stuttering and fulminant priapism in sickle cell disease. This systematic review has clearly identified the need for well-designed, adequately-powered, multicentre randomised controlled trials assessing the effectiveness of specific interventions for priapism in sickle cell disease” _[Chinegwundoh](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Chinegwundoh+F%22%5BAuthor%5D)__[ F](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Chinegwundoh+F%22%5BAuthor%5D)_, _[Anie](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Anie+KA%22%5BAuthor%5D)__[ KA](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Anie+KA%22%5BAuthor%5D)_ Cochrane Database Syst Rev. 2004 Oct 18;(4):CD004198.

## Priapism management

- Many therapies have been utilized
- IV narcotics and hydration is standard
- Transfusion-exchange and simple
- No good data, simple exchanges have been reported to worsen in some situations
- Vasoactive agents-oral or injected into corpora cavernosa
- Terbutaline
- Hydralazine
- Epinephrine

## Priapism management

- Penile aspiration (Buchanan Blood 2000)
- Aspiration with epinephrine irrigation in ED within 6 hours of onset
- Successful in 37/39 cases
- Our urologists have much less faith in this procedure
- Often want “maximal medical therapy” (exchange) before attempting this
- Our approach : dialogue with urology early
- Typically kids ultimately get exchange and/or aspiration but order is variable-I push for aspiration up front
- Prevention
- Antiandrogen therapy has been successful
- Oral pseudoephrine

## Therapy for Sickle Cell Anemia

- Chronic Transfusion
- Hydroxyurea
- Bone Marrow Transplant

## Chronic Transfusion

- Monthly transfusion to suppress reticulocytosis with HbS < 25%
- Indications
- Prevention of recurrent stroke
- Prevention of first stroke (abnormal TCD)
- Recurrent ACS
- Recurrent severe pain crises
- Renal failure and heart failure
- Not studied in children

## Transfusion Complications

- Iron overload
- No specific data in kids on effects of this
- In adult SS disease overload+ increased mortality and organ failure (Ballas 2001)
- Defining iron status is important
- Liver biopsy
- Where iron is deposited: RES versus organs
- Desferal therapy is standard therapy
- Erythrocytopheresis as a transfusion method may decrease need for chelation
- Allo-immunization: Anti K, E, C most common
- Transfusion reactions
- Potential transfusion mediated infections

## Hydroxyurea

- Causes increase in fetal hemoglobin production
- HbF inhibits polymerization of HbS
- Myelosuppressive effects may also be important
- In adults HU decreases
- Pain crises
- ACS events
- Need for Red cell transfusions
- Mortality***  (Steinberg,JAMA 2003)
- 40% reduction in mortality in patients on HU
- Initial publication NEJM 1995 Multicenter Study of HU (MSH) Drs. Charache and Dover

## HU in Children

- Now several studies published:  as young as 6 months of age
- To summarize
- HU increases HbF levels (and F cells) in kids
- Higher baseline=better effect
- Higher dose+better effect
- Toxicity
- Myelosuppression, N/V, rashes,
- No severe effects reported-no obvious malignancy link
- No effect on growth or development noted
- Clinical efficacy
- Decrease in pain, ACS and transfusions
- Use in stroke prevention still not definative

## Hydroxyurea

- Indications are bad disease
- Frequent pain or ACS are most common
- Start low and escalate every 2-3 months
- 15mg/kg to start
- Close followup for counts (myelosuppression)
- Follow HbF response
- Follow clinical course
- May have response at less than MTD that is sufficient

## Bone Marrow Transplant

- It is curative
- Standard matched sib versus non-myeloablative (mini-transplant)
- Our non-myeloablative protocol
- Initial trials failed to induce stable engraftment in 3 patients
- Now adding cytoxan post infusion to help  prevent graft failure

## Nice reference on line 

- http://www.pitt.edu/~marhgn/guide.pdf

**SICKLE CELL DISEASE IN CHILDREN AND ADOLESCENTS: DIAGNOSIS, GUIDELINES FOR COMPREHENSIVE CARE, AND PROTOCOLS FOR MANAGEMENT OF ACUTE AND CHRONIC COMPLICATIONS©**
**Mid-Atlantic Sickle Cell Disease Consortium (MASCC) Practice Guidelines Workgroup**
**sponsored by the Mid-Atlantic Regional Human Genetics Network (MARHGN)**

## THE END