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in the clinic

Sickle Cell Disease

Common Genotypes of Sickle Cell Disease



Sickle cell trait (“HbAS”)



Person carries sickle hemoglobin gene (HbS) and also has some normal hemoglobin (HbA)



HbS ≤40% total hemoglobin; usually no symptoms



Cells don’t deform when deoxygenated



Sickle cell anemia (sickle cell disease, “HbSS”)



HbS homozygosity; most / all HbA replaced with HbS



Most common + most severe of sickle cell variations



Complications due to sickled cells shape + thickness

Other Common Genotypes of Sickle Cell Disease



HbSC disease



Compound heterozygosity for HbS and HbC genes



HbSE disease



Compound heterozygosity for HbS and HbE genes



HbS β-thalassemia disease



Compound heterozygosity for HbS and a β 0 - or β + thalassemia gene



HbSO Arabia



Compound heterozygosity for HbS and HbO Arabia



HbSD Los Angeles (Punjab)



Compound heterozygosity for HbS and HbD

Who should be screened for sickle cell anemia and sickle cell trait?

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All U.S. newborns



Test also detects sickle cell trait carriers



At risk individuals pregnant or planning pregnancy



Determining who is at risk can be difficult



Maternal & paternal family history: best guide for determining individual HbS screening



Individuals with hyphema or hematuria

What screening and diagnostic tests are available?

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To detect HbS: high-performance liquid chromatography



In newborns, children, adults



Some labs use isoelectric focusing



When genetic counseling needed: DNA-based test

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Establishes parental globin gene mutations



If positive: DNA-based testing of chorionic villus samples or amniotic fluid cells



Before considering prenatal Dx, counsel parents:

 

On risks of procedure and consequences of positive Dx On likelihood of affected fetus and options for termination



Pathophysiology includes:



Abnormal erythrocyte volume regulation

 

Impaired nitric oxide bioavailability Reperfusion injury

 

Inflammation and oxidant damage Abnormal intercellular interactions

 

Endothelial injury Leukocyte and platelet activation



HbS gene most prevalent in persons of African, Arabian, and Asian-Indian ancestry

CLINICAL BOTTOM LINE: Screening…



Screening can lead to prompt diagnosis



Screening helps prevent serious complications



Screening provides information for family planning

What should prompt consideration of undiagnosed sickle cell disease?



Suspicious symptoms

    

Frequent, unexplained pain Splenomegaly Stroke at young age Pneumonia with anemia requiring transfusion Osteonecrosis in femur heads and humerus



Rare complications



Leg ulcers, priapism, nephropathy+renal failure, severe anemia



Complications occurring with advancing age

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Sickle retinopathy, liver disease



Infections



Major cause of death in children and adults

What should be looked for on the physical exam when sickle cell disease is suspected?

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Swelling and tenderness over affected areas and low-grade fever (in acute, painful episodes)

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Consolidation, rales, rhonchi, wheezing (acute chest syndrome)

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Cardiac enlargement and systolic murmurs (common)

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Enlarged liver

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Asplenia, no splenic dullness on percussion

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Splenomegaly (in HbSC disease and HbS –β-thalassemia)

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Sickle retinopathy

What lab tests should be ordered in the evaluation of possible sickle cell disease?



In untreated sickle cell anemia



Erythrocytes (normocytic or macrocytic); microcytosis

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Sickle solubility test

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High-performance liquid chromatography



After diagnosis established



Baseline CBC and reticulocyte counts

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Red cell antigen phenotyping

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Blood urea nitrogen, creatinine, urine albumin, electrolytes, bilirubin, lactate dehydrogenase, serum ferritin, alanine transaminase, aspartate transaminase, alkaline phosphatase



Chest radiographs and pulmonary function tests

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Pulse oximetry

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Echocardiography to estimate the TRV

What are complications of sickle cell trait?

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Most carriers can’t concentrate urine normally



Due to renal medullary abnormalities

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Important to hydrate adequately



Increased risk hematuria



Due to papillary necrosis (usually benign and self-limited)

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2-fold higher risk thromboembolic disease

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4-fold higher risk pulmonary embolism

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Splenic infarction rare

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Preop screen: needed w/ open-heart or complicated intra thoracic procedures where hypoxia intrinsic to procedure

Which patients with sickle cell disease should be referred to a specialist?

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General internist, pediatrician, or family physician can manage routine maintenance + common complications

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Consult appropriate specialists as needed

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All patients with sickle cell disease: hematologist with expertise in hemoglobinopathies (annually)



Pulmonary complications:

pulmonologist or cardiologist



Severe acute chest syndrome:

care specialist hematologist and critical



Pregnancy: high-risk obstetrician and hematologis t

CLINICAL BOTTOM LINE: Diagnosis and evaluation…



Suspicious symptoms: undiagnosed sickle cell disease

    

Frequent, unexplained pain Splenomegaly Stroke at young age Pneumonia with anemia requiring transfusion Osteonecrosis in femur heads and humerus



H&P and lab tests used to confirm diagnosis and evaluate patient

What drugs should be considered for the primary treatment of sickle cell anemia?



Hydroxyurea



Only FDA-approved drug for primary Rx



Begin early, before irreversible vasculopathy and organ damage develop



Reduces of acute painful events and acute chest syndrome



Reduces mortality 40% and reduces hemolysis



Fewer hospitalizations, reduced medical costs



Improved physical capacity

What is the role of blood transfusion?



Simple transfusions reduce HbS levels more gradually



Require only peripheral venous access and rapidly available



Lower alloimmunization risk; greater hyperviscosity risk



Exchange transfusions reduce HbS levels more rapidly



Take more time to start and more complicated venous access



Lower hyperviscosity risk; higher alloimmunization risk



Preop: simple transfusion can reduce postop complications



Stroke: exchange transfusion can reduce recurrence



Acute chest syndrome

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Patient may not need transfusion if no hypoxia + chest infiltrates minor, fever minimal, blood count changes small



Don’t use repeated transfusion to manage routine crisis

What is the role of bone marrow transplantation in sickle cell anemia?

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Transplantation mortality rate: ≈5%



Event-free survival: 84%



Rejection or disease recurrence: ≈10%

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When successful, disease is “cured”



Patient no longer anemic



Long-term, stable engraftment sufficiently eliminates the phenotype of sickle cell disease



Myeloablative stem cell transplantation largely limited to children <16 yrs old with severe disease

What are the features of sickle cell anemia over a patient's lifetime?



Major clinical features in the first decade…



Severe life-threatening infection



Acute chest syndrome



Splenic sequestration

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Stroke; pain; dactylitis



Major clinical features in young adulthood and beyond…



Sickle vasculopathy likely to progress despite few symptoms



Chronic organ damage leads to pulmonary vasculopathy



Deteriorating pulmonary function and renal failure



Late effects of cerebrovascular disease

How does pain manifest in sickle cell disease?

Clinical Features of the Acute Painful Episode



Some patients always in pain; others rarely



Pain distribution and duration varies



Pain most often occurs in back, chest, extremities, joints



Cause unclear: unrelated to “new sickling”; blood film unhelpful



Physical findings limited



Frequent episodes associated with poor prognosis



Directly related to packed cell volume; indirectly related to HbF

How should pain be managed?



Most pain successfully managed at home



Many patients can sense the beginning of an episode



Use nonopioid analgesics, then oral opioids if needed



Up fluid intake, use rest, warm baths, heating pads, massage



Pain requiring medical intervention



Usually treated in the hospital ED

  

Initiate parenteral opioids and adjust dosage as needed Individualize Rx (analgesic doses can vary considerably) Monitor for oversedation, hypoxia, and low respiratory rate

How are episodes requiring further treatment and continuously increased use and dose of opioids managed?



Decision to initiate long-term opiate therapy



Define cause of pain



Determine pain intensity + effect on functioning, QOL

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Document evaluation and treatment plan



Monitor closely Causes of Persistent Severe Pain



Progressive tissue damage

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Inadequate treatment



Tolerance

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Hyperalgesia

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Changes at receptors

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Maladaptive behavior

How common is the acute chest syndrome in sickle cell disease?



Affects >50%

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Mortality higher in adults than children (<10% cases fatal)



Second most common reason for hospitalization



Features: fever, chest pain, cough, and lung infiltrates



Causes: infarction, pulmonary infection, atelectasis, embolism, in situ thrombosis



Frequent postop complication, even after preop transfusion



Fat embolism from necrotic bone marrow causes most severe acute chest events

How is the acute chest syndrome in sickle cell disease managed?

   

Transfusions

 

Antibiotics Hydration (avoid overhydration)

 

Respiratory therapy with bronchodilators Incentive spirometry Maintenance of tissue oxygenation Oxygen: if hypoxic or tachypneic; in respiratory distress Opioids: balance pain relief w/ respiratory suppression risk



Patients who deteriorate rapidly: admit to ICU

What other conditions complicate sickle cell anemia?



Pulmonary vasculopathy & abnormal pulmonary function

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Infection

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Retinopathy

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Anemia

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Leg ulcers

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Priapism

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Renal disease

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Digestive system disease



Neurocognitive dysfunction

As patients with sickle cell disease live longer, what new health issues are emerging?



Cardiomegaly and heart murmurs



Contractility usually normal and overt CHF uncommon



Hypertension



Cause of ventricular hypertrophy and HF



May contribute to sickle nephropathy and renal failure



Chest pain



Very common but MI unusual

Is pregnancy more complicated in women with sickle cell disease?



Most managed without regular transfusions



Identify red cell phenotype & alloantibodies: so pheno typically matched blood can be used if needed



Multiple-birth pregnancies benefit from transfusion



Obstetric complications and C-section more common



Prenatal testing needed



Establish Hb phenotype and HbF level



Blood counts; serum chemistries; hepatitis A,B,C; HIV testing



Urinalysis; urine culture; rubella antibody titer; serum ferritin

Are patients with sickle cell disease at particularly high risk during surgery?



Surgery and anesthesia safe but not complication-free



Blood transfusion: major issue preoperatively



Preparation: hydration; optimization of pulmonary status



Be vigilant toward detecting acute chest syndrome Prevent acute chest syndrome after surgery with…



Rapid mobilization



Incentive spirometry and bronchodilators



Close monitoring of oxygen saturation

How should end organ damage be monitored, treated, and prevented?



If patient stable



follow every 4 to 6 months



Perform blood counts



Monitor renal and liver function



Test for baseline pulmonary function



Obtain baseline and periodic estimation of TRV



Periodically evaluate for sickle retinopathy



Ophthalmologist visit

CLINICAL BOTTOM LINE: Treatment and management…



Sickle cell disease has protean manifestations



Optimum care consists of:



Direct drug therapy with hydroxyurea



Prompt diagnosis



Prompt treatment of complications

What should patients be taught about preventing disease complications?



Good self-management can help prevent complications



Awareness of acute pain episode beginning



Use rest, hydration, warm baths to arrest development



Avoidance extremes of temperature



Cold, windy conditions associated with painful episodes



Maintenance of good hydration



Lower legs: protect from trauma, keep well moisturized



To avoid leg ulcers

What should patients be taught about prenatal screening and management of pregnancy?



Discuss prenatal screening and its implications



Preferably during planning



At least in the first weeks of pregnancy



Manage pregnancies in a high-risk obstetrics clinic



Consult with a hematologist

CLINICAL BOTTOM LINE: Patient education…



Teach patients to recognize the early signs of an acute crisis



Encourage regular medical follow-up from a primary care provider with access to a sickle cell center