Sickle Cell Anemia

What is Sickle Cell Anemia (SCA)?

First described in Chicago in 1910 by James Herrick as an inherited condition that results in a decrease in the ability of red blood cells to carry oxygen throughout the body

Sickle red blood cells become hard and irregularly shaped (resembling a sickle) Become clogged in the small blood vessels and therefore do not deliver oxygen to the tissues. Lack of tissue oxygenation can cause excruciating pain, damage to body organs and even death.

Mechanism
Red blood cells (RBC)
Contain a special protein called haemoglobin (Hb) Hb is the component that carries oxygen from the lungs to all parts of the body Most people have only hemoglobin type Hb A within RBC (normal genotype: Hb AA)

Sickle Cell: HbS

S similar to A, but one structural change Other types: HbC, HbD, and HbE

Mechanism -HbS

When sickle haemoglobin (HbS) gives up its oxygen to the tissues, HbS sticks together

Forms long rods form inside RBC RBC become rigid, inflexible, and sickle-shaped Unable to squeeze through small blood vessels, instead blocks small blood vessels Less oxygen to tissues of body Normally 120 days Chronic state of anaemia

RBCs containing HbS have a shorter lifespan

Genetics

2 copies of the gene for Hb (each parent)

HbS Recessive S=Sickle A=Normal

Pathophysiology

HgbS fibers are rigid Hgb S fibers deform RBC membranes Membrane disruption exposes transmembrane proteins and lipids that are proinflammatory Progressive sickling makes cells dense and inflexible

Factors that Promote Hgb S polymerization:

Low pO2 / Hypoxia Prolonged Delay Time time RBC spends in microcirculation Low pH High Hgb S concentration Genotype-dependent
Cellular Dehydration

Low Hgb F concentration 2S: gamma globin chains bind Hgb S chains and inhibit Hgb S
polymerization, thus countering sickling process

Vaso-occlusion: A Multifactorial Process

Mechanical Obstruction sickle cell aggregation RBC - Endothelial Adherence expression adhesion molecules high # pro-adhesive reticuloctes Intimal thickening

Impaired vascular tone responsiveness to NO

Vaso-occlusion: A Multifactorial Process

Inflammation
Chronic Leukocytosis -- characteristic of sickle cell disease WBC > 15,000 is independent risk factor for early death Risk Factor for acute chest syndrome and stroke
Repetitive Vaso-occlusion episodes Chronic ischemiareperfusion injury granulocytic oxygen burst reactive oxygen species tissue damage Up-regulation of pro-inflammatory cytokines (TNF-, IL1-B) Activation of PMNs and Monocytes release cytokines , chemotactic factors PMN endothelium adhesion extravasation of PMNs into interstitial tissues ( L-selectin / 2-selectin)

Vaso-occlusion: A Multifactorial Process

Endothelial Cell Activation
Endothelial Cell contraction exposure of pro-inflammatory subendothelial matrix expression of adhesion molecules for RBCs and leukocytes ICAM, VCAM, E-selectin Expression of cytokines (IL-6) and chemotactic factors (IL-8) Multiple Protrhrombotic Effects: Release of high-multimer Von-Willibrand Factor Depletion of anticoagulants (thrombomodulin, heparan sulfate) plasminogen activator inhibitor platelet activating factor expression of tissue factor

Vaso-occlusion: A Multifactorial Process

Nitric Oxide and Dysregulation of Vascular Tone NO is potent vasodilator NO is produced from Arginine by Nitric Oxide Synthase NO is consumed by hemoglobin NO + oxyhemoglobin methemoglobin and nitrate NO + deoxyhemoglobin iron nitrosylnitrate SCD patients: High serum free oxy- and deoxyhemoglobin from RBC lysis Decreased vascular responsiveness to NO High serum arginase due to release by ruptured sickle RBCs High levels of ROS consume NO Low serum arginine due to excessive NO production and arginase activity

Sickle Cell Trait:

Prevalence 8-14% in African Americans

Usually asymptomatic and without anemia Pathology usually limited to renal and splenic vascular beds Increased risk of: UTI in women Hematuria (4X risk) Hyposthenuria Splenic sequestration / infarction at high altitude (>10,000 ft) Exertional Heat Illness / Sudden Death (40 X increased risk) Renal Medullary Carcinoma

Three common types of Sickle Cell Disorders

1. Sickle Cell Anemia

Sickle haemoglobin (HbS) + Sickle haemoglobin (HbS)

Most Severe No HbA

Other Sickling Disorders

Other types of Hb combine with sickle Hb
2. Hemoglobin S-C disease

Sickle haemoglobin (HbS) + (HbC) Beta thalassaemia gene reduces the amount of HbA that can be made Sickle haemoglobin (HbS) + reduced HbA Milder form of Sickle Cell Disorder than sickle cell anemia

3.

Hemoglobin S-Beta thalassemia

Some Genetic History

The error in the hemoglobin gene results from a genetic mutation that occurred many thousands of years ago in people in parts of Africa, the Mediterranean basin, the Middle East, and India.
A deadly form of malaria was very common at that time Malaria epidemics caused the death of many In areas where malaria was a problem, children who inherited one sickle hemoglobin gene and who, therefore, carried the sickle cell trait - had a survival advantage. Unlike the children who had normal hemoglobin genes, they survived the malaria epidemics they grew up, had their own children, and passed on the gene- for sickle hemoglobin.

Sickle Cell Gene

Severe Malaria

History
As populations migrated, the sickle cell-mutation spread to other Mediterranean areas, further into the Middle East and eventually into the Western Hemisphere. In the United States and other countries where malaria is not a problem, the sickle hemoglobin gene no longer provides a survival advantage. Instead, it may be a serious threat to the carrier's children, who may inherit two abnormal sickle hemoglobin genes and have sickle cell anemia.

Who is at risk?
Most common in Africans and African Americans. East Asia, Southern Italy, Saudi Arabia, India, Egypt, South and Central American, Cuba, the Caribbean, Greece, and Iran, and Eastern Jews have also been found to have a form of this illness.

Prevalence
More than 2.5 million Americans have the trait 70,000 or more Americans have sickle cell disease About 1,000 babies are born with the disease each year in America
In Nigeria, 1/3 population of U.S., 45,000-90,000 babies with sickle cell disease are born each year

Among African - Americans

1 in 12 have Sickle Cell Trait (Hb SA) 1 in 600 have Sickle Cell Anemia (Hb SS) 1 in 1500 have Sickle C Disease (Hb SC) 1 in 350 have Sickle Cell Disease (Hb SS, SC, S-BetaThal)

Among Latinos
1 in 172 have Sickle Cell Trait (Hb SA) 1 in 1,000 have Sickle Cell Disease (Hb SS, SC, SBeta-Thal)

Screening
1. Haemoglobin Electrophoresis
Simple Blood test Routine screening in high risk groups During pregnancy Before anaesthesia

2. Prenatal Testing Amniocentesis

16 and 18 weeks of the pregnancy small risk of causing a miscarriage (1 in 100) 9th or 10th week of pregnancy very small amount of material from the developing placenta slightly higher chance of miscarriage

Chorionic villus sampling (CVS)

Early Symptoms and Complications

Typically appear during infant's first year 1st symptom: dactylitis and fever (6 mo-2 yrs) Pain in the chest, abdomen, limbs and joints Enlargement of the heart, liver and spleen nosebleeds Frequent upper respiratory infections Chronic anemia as children grow older
Over time Sickle Cell sufferers can experience damage to organs such as liver, kidney, lungs, heart and spleen Can result in death

Medical Complications
1. pain episodes 2. strokes 3. increased infections 4. leg ulcers 5. bone damage 6. yellow eyes or jaundice 7. early gallstones 8. lung blockage 9. kidney damage and loss of body water in urine 10. painful erections in men (priapism) 11. blood blockage in the spleen or liver (sequestration) 12. eye damage 13. low red blood cell counts (anemia) 14. delayed growth

Complications
Infectious complications Prominent early in life Leading cause of morbidity and mortality Susceptibility to encapsulated organisms due to functional asplenia Streptococcus pneumoniae and Haemophilus influenzae Great improvement in the prognosis related to newborn screening for sickle cell disease, vaccination for childhood illnesses, the use of prophylactic antibiotics, and aggressive diagnosis and treatment of febrile events Acute splenic sequestration Episodes of rapid increase in splenic size and decrease in hemoglobin Potential source of morbidity and mortality early in life for children with sickle cell anemia and at any age for those with Hb SC disease and sickle thalassemia

Manifestations of Renal Disease:

Glomeruli: Proteinuria (20-30%) Nephrotic syndrome (~5%) FSGS / MPGN (without mesangial antibody/antigen deposits)

Medulla: Isothenuria ~100% (max urine OsM 400-450 mOsm/kg) Papillary necrosis 15-36% Hematuria Medullary Carcinoma ( risk in Sickle Cell Trait only!)
Distal Tubule Incomplete distal RTA (only in setting of renal insufficiency) Impaired potassium secretion

Serious Complications
Strokes Up to 15% of children may have overt or silent strokes during childhood Chronic transfusion therapy reduces the recurrence rate of overt stroke which may approach 75% without intervention Bone disease Early risk is primarily from osteomyelitis

Infectious usually painful inflammatory disease of bone often of bacterial origin and may result in bone tissue death

Avascular necrosis of the femur and humerus Death of bone tissue due to disrupted blood supply Marked by severe pain in the affected region and by weakened bone that may flatten and collapse

 Leg ulcers

Seen in patients older than 10 years of age Resistant to therapy and cause significant morbidity

Ophthalmic complications

Proliferative retinopathy, vitreous hemorrhage, & retinal detachment

Priapism

Distressing complication that occurs at all ages Difficult to treat Causes a high incidence of impotence

Chronic Anemia

Associated with fatigue, irritability, jaundice, pain, delayed puberty, leg sores, eye problems, gum disease

Cardiac Disease:
Increased cardiac output Cardiomegaly, enlarged ventricular size Cardiomyopathy unusual Increased risk of non-atherogenic MI (~10% in one autopsy series)

Priapism Retinal Disease Leg Ulcers Growth Retardation Delayed Cognitive Development

Serious Complications: PAIN Recurrent Pain Episodes or Sickling Crises

Occur at any age but appear to be particularly frequent during late adolescence and early adult life

Unpredictable Red Blood Cells get stuck in the small veins and prevent normal blood flow Characterized by severe pain in the back, chest, abdomen, extremities, and head Highly disruptive to life Most common reasons for individuals to seek health care

Danger Signs of a Crisis

1. Fever 2. Chest pain 3. Shortness of Breath 4. Increasing tiredness 5. Abdominal swelling 7. Any sudden weakness or loss of feeling 8. Pain that will not go away with home treatment 9. Priapism (painful erection that will not go down)

6. Unusual headache

10. Sudden vision change

Crises
During a crisis severe pain in the fingers, toes, arms, joints,legs, back, abdomen, and bones. Decrease in oxygen to the chest and lungs May lead to acute chest syndrome Damage to the lungs Severe pain and fever Lungs' airways narrow, further reducing O2 Leads to an increased risk of potentially fatal infections

Triggers of Pain

Infections Thirst and dehydration caused by not drinking enough even if thirst is not felt Over-exertion Over-excitement Cold weather and cold drinks and swimming Bangs, bumps, bruises and strains Stress triggers pain in adults, but does not seem to do so in children.

Predicting Pain
Children and families can often tell when a severe sickle pain is coming on by

Thirst
Eyes turning yellow (jaundice),

Sufferer being more irritable or tired than usual.

Alleviating Pain
Warmth: increases blood flow Massaging and rubbing Heat from hot water bottles and deep heat creams Bandaging to support the painful region Resting the body Cognitive Behavioral Therapy Getting the sufferer to relax deep breathing exercises distracting the attention by other psychological methods. Pain-killing medicines (analgesics): paracetamol, codeine non-steroidal anti-inflammatory, morphine if necessary

Daily Preventative Measures

1. Taking the folic acid (folate) daily to help make new red cells 2. Daily penicillin until age six to prevent serious infection

3. Drinking plenty of water daily (8-10 glasses for adults)

4. Avoiding too hot or too cold temperatures 5. Avoiding over exertion and stress

6. Getting plenty of rest

7. Getting regular check-ups from knowledgeable health care providers

Treating Complications

Pain-killing drugs and oral and intravenous fluids To reduce pain and prevent complications.
Transfusions Correct anemia Treat spleen enlargement in children before the condition becomes life-threatening Regular transfusion therapy also can help prevent recurring strokes in children at high risk of crippling nervous system complications.

Psychosocial Issues
Require regular medical attention
Especially before and after operations, dental extraction and during pregnancy.

Adherence to medical regimen

Vitamins, antibiotics, fluid intake, activity level

Schools must be involved Family planning

Suitable types of employment

Air travel Increased fluids, pain killers or oxygen may be recommended

Psychosocial Issues
Child should be encouraged to participate in sports, but not pushed passed their limitations If they are in pain or feel tired they should be allowed to rest and keep warm. They should have access to drinks. Strenuous exercise, dehydration and cold can induce a crisis. Strenuous outdoor activities should be avoided in cold or wet weather Should only swim if the water is warm and care is taken to keep warm when leaving the water
If develops a crisis despite these precautions he or she should avoid swimming all together

Psychosocial Issues
Child Specific Issues: Coping with Pain
Pain happens more often Lasts longer

Generally all day, even if not continuously all day

Associated with great tiredness about half the time Causes them to spend significant time in bed

Psychosocial Issues

No easily overt detectable signs of sickle pain So children known to have sickle cell disorder who say they are in pain must be trusted If they can rely on the adults around them to take them seriously, they are less likely to take advantage of their condition to seek attention or avoid distasteful tasks. Boys at risk for priapism May be too embarrassed to mention to parents Severe sickling can lead to impotence

Treatments
Hydroxyurea The first effective drug treatment for adults with severe sickle cell anemia reported in early 1995

Daily doses of the anticancer drug, hydroxyurea, reduced the frequency of painful crises, acute chest syndrome, needed fewer blood transfusions
Increases production of fetal hemoglobin in the blood

Fetal hemoglobin seems to prevent sickling of red cells

cells containing fetal hemoglobin tend to survive longer in the bloodstream

Therapy
Acute Vaso-occlusive Pain Crisis
Identify and Treat Underlying Infections

Achieve Pain Control IV Fluid Resuscitation Folic Acid Supplementation

Assess Patient and Identify Etiology of Crisis

Identify all sources of pain Assess oxygenation Suppl O2 to keep SaO2 > 92% Assess volume status Consider reversible causes Review previous pain crises Look for signs / symptoms of infection Assess for acute chest syndrome Labs: CBC, retic index, CMP, ABG INR/aPTT CXR

Pain Management Assessment

Rapid Acute Crises
Focus on pain intensity, promt tx, and relief Identify sources, quality, severity, related signs/symptoms

Comprehensive Chronic pain assessment

Outpatient setting Involves pt, family, health care team Address physiologic, sensory, affective, cognitive, behavioral, and sociocultural factors

Therapy
Acute Pain Management

Determine usual analgesics used during acute crises,

dosages, and side effects Identify home maintenance regimen Identify meds taken since onset of crisis

Acute Pain Management NIH guidelines

Initiate analgesic therapy within 15 minutes
Pt with known crisis history use opioid and dose known to be effective for that pt Otherwise, give loading dose of IV morphine 5 to 10mg or IV hydromorphone 1.5mg

Reassess and Re-dose Q 15-30 min prn with to loading dose until pain relieved
Start scheduled opioid dosing with breakthrough prn or PCA pump Co-administer scheduled NSAIDs

Pain management for sickle cell disease

1 study: IV ketorolac vs meperidine for severe pain. Ketorolac was superior in reducing pain in first 150 minutes. 1 study: Morphine SR po vs IV morphine. No significant difference in pain scores, dosing frequency, adverse effects 2 studies: Adjunctive use of corticosteroids: single-dose methylprednisolone 15mg/kg vs placebo 2 days dexamethasone 0.3mg/kg Q12h vs placebo Result: Both Steroid arms duration of analgesic tx (41.3 vs 71.3 P 0.03 for single dose) and (36.2 vs 48.4 P=0.04 for multiple dose)

Pain management in acute Vaso-occlusion crisis

Summary:
Begin analgesic tx within 15 to 30 minutes Titrate Q15 minutes until pain relieved Convert to scheduled + breakthrough vs PCA pump Consider early conversion to po analgesics Start concurrent NSAIDS (IV or PO) Consider 2-day corticosteroid pulse Convert to long-acting po meds Consider addition of anxiolytics

Acute Chest Syndrome Oxygen supplementation, goal SaO2 > 92 - 95%

Aggressive pain management IVF support Serial ABGs, monitor A-a gradient Daily CBC w/ diff, renal and liver function labs Blood exchange or transfusion if PaO2 < 70mm Hg or Hgb >1 g/dL below baseline Blood / sputum / urine cultures Empiric Broad-Spectrum Abx: 3rd gen Cephalosporin and macrolide Bronchodilator therapy Incentive spirometry

Hydroxyurea Dosing: NIH guidelines as defined by MSH

Initiation of Treatment: Hydroxyurea 10-15mg/kg/day in single daily dose X 6-8 weeks Check CBC Q 2wks, Hgb F Q 6-8 wks, serum chem Q 2-4 wks

Tx Continuation: If no major toxicity, escalate dose Q 6-8wks until desired endpoint reached
Treatment Endpoints: Decreased pain / pain crises Hgb F 15-20% Acceptable myelotoxicity: <2500 neutrophils / ul < 90,000 platelets / ul Hgb < 5.3 g/dL

Hydroxyurea: To Treat or not To Treat?

Very few randomized controlled trials MSH is only large trial, and only included adults Hydroxyurea only approved by FDA for adults with SCD

Pros: Promising benefits in reducing frequency of pain crises, ACS Promising benefit in reducing mortality Potential major cost benefits Cons: Uncertain benefit in preventing other major complications of SCD (stroke, avascular necrosis, priapism) Uncertain effects on pregnancy Application to other sickle cell variants? Uncertain long-term toxicity risks: Cancer? Leukemia?

Other Hgb F inducing Agents

Short-chain fatty acids (sodium butyrate) Mechanism: Histone deacetylation Baboons: Hgb F Phase II study (N=15): 11 responders, Increased Hgb F 7% 21% 5-Azacytidine and 5-Aza-2deoxycytidine Mechanism: Demethylation of DNA 9-month Phase I/II study (N=7): Increased Hgb F 3.1% 13.9%

Erythropoietin

Developing Treatments
Bone marrow transplantation Shown to provide a cure for severely affected children with sickle cell disease

Only about 18 percent of children with sickle cell anemia are likely to have a matched sibling.

The Ultimate Cure? Gene Therapy

1. Correcting the defective gene and inserting it into the bone marrow
2. Turning off the defective gene and simultaneously reactivating another gene that turns on production of fetal hemoglobin. No real cure for Sickle Cell Anemia at this time.

In the past 30 years, the life expectancy of people with sickle cell anemia has increased. Many patients with sickle cell anemia now live into their mid-forties and beyond.