SICKLE CELL DISEASE

JOHN M KAUFFMAN JR DOASSOCIATE DEAN FOR POSTGRADUATE AFFAIRS

VIA COLLEGE OF OSTEOPATHIC MEDICINE

Goals and Objectives

• At the conclusion of this program, the attendee will have a better understanding of:

• The genetics and transmission of Sickle Cell Disease• The Diagnosis and pathophysiology of Sickle Cell

Disease• The management of the complications of Sickle Cell

Disease• The current treatment of Sickle Cell Disease

Sickle Cell Disease: A Case

• A 22yo AA woman is transferred to your hospital with respiratory failure. You are asked to see her in the emergency department. In the ED the patient is in obvious distress with a RR of 45 and an O2sat of 72%. Her ABG revealed 7.34/44/59/23/76% on 3 liters O2 by nasal canula.

Sickle Cell Disease: A Case

• The patient had been diagnosed with Sickle Cell Anemia at age 6 and was hospitalized for a sickle cell crisis at age 12. 24 hours prior to admission in your hospital she was seen in another ED with severe pain (10/10) in her back thighs and knees. She was nauseated and had vomited once. She denied chest pain, SOB, fever, chills, abdominal pain, dysuria, constipation or diarrhea.

Sickle Cell Disease: A Case

• Within 10 hours of admission to your hospital, the patients O2 sat dropped to 40% and she was intubated. Her ABG revealed: 7.35/44/80/22/94% on the vent with 100% O2 TV=350, and 22cm of peep.

• What is your diagnosis?

Definitions

• Sickle-Cell Disease: A group of blood disorders caused by a mutation in the hemoglobin gene.

• Common Sickle Cell Diseases Include:• Sickle Cell Anemia• Hemoglobin SC Disease• Sickle Beta Thalasemia

• Sickling and sickle cell disease also confer some resistance to malaria

Definitions

• Sickle-Cell Anemia : Sickle-cell anemia is the name of a specific form of sickle-cell disease in which the individual is homozygous for the mutation that causes HbS. Normal hemoglobin is called hemoglobin A, but people with sickle cell anemia have only hemoglobin S, which in the homozygous form, turns normal, round red blood cells into abnormally curved (sickle) shapes. Sickling decreases the cells' flexibility and predisposes the carrier to potentially serious complications. Sickle-cell anemia is also referred to as "HbSS", "SS disease", "hemoglobin S" etc.

Sickle Cell Anemia

Definitions

• Sickle Cell Trait: condition in which a person has one abnormal allele of the hemoglobin beta gene ( heterozygous), but does not display the severe symptoms of sickle cell disease that occur in individuals who have two copies of the abnormal Hb S allele ( homozygous)

• About 2 million Americans have sickle cell trait. The condition occurs in about 1 in 12 African Americans.

Sickle Cell Disease

• Sickle cell disease (SCD) is the most common genetic disorder identified in African Americans,

• Also found in people from South and Central America, the Mediterranean and the Middle East.

Sickle Cell Disease

• In the United States, it’s estimated that sickle cell anemia affects around 50,000 people, mainly African Americans. The disease occurs in about 1 out of every 700 African American births.

• Before the era of Hydroxyurea, the average life expectancy was in the 40’s

Clinical Hallmarks of Sickle Cell Disease (SCD)

• Vaso-occlusion

• Hemolysis

Diagnostic Testing:

• Cellulose acetate electrophoresis is a standard method of separating Hb S from other hemoglobin variants. However Hb S, G, and D have the same electrophoretic mobility with this method.

Diagnostic Testing:

• Citrate agar electrophoresis seperates Hb S from Hb D and G

• Thin-layer isoelectric focusing and high performance liquid chomatography (HPLC) are highly accurate tools for the diagnosis of sickle or other hemoglobin variants

Diagnostic Testing

• In Summary: Cellulose acetate electrophoresis with either citrate agar electrophoresis or a solubility test allows a definitive diagnosis of sickle cell syndrome

• Alternatively, thin layer isoelectric focusing will separate Hb S, D, and G and can replace the two electrophoretic methods.

• However, thin-layer isoelectric focusing still requires a confirmatory solubility test for Hb S

Newborn Screening

• Mandated in all 50 states and the District of Columbia.

• Most states use either thin-layer isoelectric focusing (IEF) or high performance liquid chromatography (HPLC) as the initial screening test.

• Both methods have extremely high sensitivity and specificity for sickle cell anemia. Specimens must be drawn prior to any blood transfusion (false negative)

• Extremely premature infants may have false positive results when adult hemoglobin is undetectable

Screening Programs

• Selective screening of infants of high-risk parents

• Universal testing of newborns

• Selective screening misses up to 20% of AA newborns with SCD

• sickle cell diagnoses doubled when screening was changed from targeted to universal

Hemoglobin Patterns

Laboratory Findings in Sickle Cell Disease

• Chronic Hemolysis with mild to moderate anemia (Hct 20-30%)

• Reticulocytosis of 3-15% (.5-1.85% RBCs)• Unconjugated hyperbilirubinemia• Sickled RBCs on peripheral smear• Low serum erythropoietin secondary to

progressive renal disease• Folate and Iron deficiency secondary to increased

utilizaton of folate and urinary excretion of iron

Peripheral Blood Smear

• Sickled red cells• Polychromasia indicative of reticulocytosis• Howell-Jolly bodies secondary to splenic

infarcts• Normochromic, normocytic RBCs

Findings in Sickle Cell Disease

• The Cooperative Study of Sickle Cell Disease looked at Lab Data in 2600 people with SCD

• Mean WBC counts elevated especially in children < age 10

• Thrombocytosis seen individuals < age 18• Serum Alk Phos elevated until puberty

TIMING OF SCREENING

• Test all newborns at the time of birth

• Verify screening results at first office visit

• Perform confirmatory tests no later than 2 months of age.

Most common types of sickle cell disease

• Hemoglobin SS disease (also called Sickle Cell Anemia)

• Hemoglobin Sickle-C disease

• Sickle Beta-Thalassemia.

Hemoglobin

• Hemoglobin: Definition and Structure • Hemoglobin carries oxygen from the lungs to tissues

and CO2 from the tissues to the lungs for excretion. • Hemoglobin molecule consists of two parts: • Porphyrin group or heme• Protein or globin portion. • Globin is made up of four polypeptide chains

attached to the porphyrin ring • Four types: alpha, beta, delta and gamma.

Hemoglobin Molecule

Sickle Cell Hemoglobin

• In normal Hemoglobin A, glutamic acid is on the 6th position of the beta chain, while in sickle-cell disease, this glutamic acid is replaced by valine (point mutation) leading to the formation of sickle cells.

• Polymerization: the two beta chains fit into each other forming a longitudinal polymer (or lock and key) causing the cell to become deformed and very rigid leading to vessel occlusion.

• Polymerization: activated by infections, hypoxia, acidosis, physical exercise, vasoocclusion due to cold as well as dehydration.

Sickle Cell Hemoglobin

In sickle cell hemoglobin (HbS) glutamic acid in position 6 (in beta chain) is mutated to valine. This change allows the deoxygenated form of the hemoglobin to stick to each other.

Normal Adult Hemoglobin

• Primarily Hemoglobin A• 2 alpha chains and 2 beta chains • Beta chain synthesis begins early in fetal

development• Sixth week of gestation, hemoglobin A composes

about 7% of the total hemoglobin; the percentages slowly increase throughout the pregnancy

• Thirtieth week there is a switch from gamma chain to beta chain production.

Fetal Hemoglobin

• At birth babies have mostly fetal or F hemoglobin

• falls to the normal level of less than 3 to 5% by the time the infant is 5-6 months of age

• Adults have less than 2% fetal hemoglobin. • Fetal hemoglobin is made up of two alpha and

two gamma chains.

STRUCTURAL FORMULA FOR NORMAL HEMOGLOBIN

• A Major Adult Hemoglobin 2 Alpha Chains + 2 Beta Chains • F Fetal Hemoglobin 2 Alpha Chains + 2 Gamma Chains • A2 Minor Adult Hemoglobin 2 Alpha Chains + 2 Delta Chain

HEMOGLOBINOPATHIES

• Hemoglobinopathy: disease or trait caused by a defect in the genetic code for hemoglobin synthesis

• Over 600 known hemoglobin variants reported

• Vast majority of abnormal hemoglobin result from the mutation of a single polypeptide chain.

Genetics of Sickle Cell Trait

• Heterozygous subject (sickle cell trait (A/S), an abnormal gene is inherited from one parent and it directs the formation of abnormal hemoglobin.

• A normal gene is inherited from the other parent and it directs the formation of normal hemoglobin.

Example of an Inheritance Pattern for Sickle Cell Trait

Genetics of Sickle Cell Disease

• Homozygous subject, identical abnormal genes are inherited; one from each parent, and the majority of the hemoglobin is abnormal, such as in sickle cell anemia (S/S).

Example of an Inheritance Pattern for Sickle Cell Trait

HEMOGLOBIN A/S SICKLE CELL TRAIT

• GENOTYPE: AS • Beta chain variant• Each red cell contains a mixture of A (60%)

and S (40%). • Amount of A in each cell is enough to prevent

sickling under most physiological conditions.

POPULATIONS AFFECTED

• African Americans: 8-10% • Hispanic Americans: 2% • Occurs frequently in Greeks, Italians, Saudi

Arabians, East indians and Middle Easterners

CLINICAL SYMPTOMS of Sickle Cell Trait

• NOT associated with anemia. • Offers some protection against malaria. • Occasional hematuria and hyposthenia (impaired renal

concentrating ability)• Splenic infarction reported to occur at altitudes greater

than 7,000 feet • Greater risk for sudden death under extreme conditions

such as those that might occur during basic training in the military.

• severe dehydration, malnutrition, physical overexertion and exhaustion. This risk though increased, is small.

PRECAUTIONS

• Avoid hypoxic situations: deep sea diving, flying in unpressurized aircraft, strenuous physical activity over a prolonged period of time.

COUNSELING POINTS TO BE MADE

• Person is a healthy carrier• Person is not sick. • Sickle cell trait is not a disease. • Sickle cell trait will not cause you to be anemic. • There is a small amount of hemoglobin S, but not

enough to change the shape of the red blood cell. • The red blood cells of a person with sickle cell trait

remain round and flexible.

SICKLE CELL ANEMIA

• GENOTYPE: S/S • Hemoglobin S (90-100%) • Hemoglobin F may be slightly elevated

SICKLE CELL ANEMIA

• Most common form of sickle cell disease identified in African Americans

SICKLE CELL ANEMIAClinical Symptoms

• Most severe form of sickle cell disease • Clinical course variable • Severe anemia • Vaso-occlusion, pain episodes, organ damage • Aplastic episode, splenic sequestration, increased risk

for infection • If HbF is greater than 10% there is a decreased risk of

stroke

SICKLE CELL ANEMIAPRECAUTIONS

• Genetic counseling and screening to clarify risk for child born with sickle cell disease

• Referral to High Risk OB Clinic for pregnancy. • Avoid Hypoxia, dehydration

Clinical Manifestations of Sickle Cell Disease

• Vasoocclusion and hemolysis are the hallmarks of sickle cell disease

• Vasoocclusion results in recurrent painful episodes (sickle cell crisis)

• Dactylitis (acute pain in the hands and feet) is the most common initial symptom

Most Common Complications of Sickle Cell Disease

• Acute Painful Crisis (Sickle Cell Crisis)• Acute Chest Syndrome• Stroke• Chronic Lung Disease• Avascular Necrosis• Leg Ulcers

Clinical Manifestations of Sickle Cell Disease

• Hemoglobin S (HbS) results results form the substitution of a valine for glutamic acid as the sixth amino acid of the beta globin chain, that produces a hemoglobin tetramer (alpha 2/beta S2) that is poorly soluble when deoxygenated.

Clinical Manifestations of Sickle Cell Disease

• Sickle Cell Disease is used to describe those conditions associated with “ Sickling”

• Patients who are homozygous for HbS have the most severe form of the disease

Pathophysiology of Vasoocclusion

• Sickle cells (Hb SS) lose deformability when deoxygenated

• Causes vascular obstruction and ischemia• Critical factor underlying painful crises, acute

chest syndrome, functional asplenia, and stroke

Pathophysiology of Vasoocclusion

• Membrane damage shortens the lifespan of RBCs

• Causing chronic intravascular and extravascular hemolysis

• Intravascular hemolysis causes:• Decreased nitric oxide, Increased vascular

tone, and pulmonary artery hypertension

Pathophysiology of Vasoocclusion

• Damaged RBCs have irregular surfaces that cause them to adhere to the vascular endothelium

• promotes acute vascular occlusion leading to a proliferative “lesion” made up of WBCs, platelets, smooth muscle cells and coagulation proteins

• Leading to strokes and possibly Pulm HTN

Gladwin and Vichinsky n engl j med November 20, 2008 359 (21): 2254

Acute Painful Crisis (Sickle Cell Crisis)

• Acute pain (previously know as “sickle cell crisis”)

• Most common type of vasoocclusive events• First symptom noted in over 25% of patients• Most frequent symptom after the age of two

Clinical Manifestations of Sickle Cell Disease

• Dactylitis (acute pain in the hands and feet) most common symptom before the age of two

• Pain was the most common symptom after the age of two

• Splenic sequestration is the third major symptom

Clinical Manifestations of Sickle Cell Disease

• Significant predictors of adverse outcome• Dactylitis before the age of 1• Hemoglobin level <7 g/dl• Leukocytosis in the absence of infection

Pulmonary Complications

• Acute Chest Syndrome• Bronchoconstriction/Asthma• Pneumonia• Pulmonary hypertension• Chronic lung disease

Acute Chest Syndrome

• Presentation: Chest pain, pulmonary infiltrate and fever

• Most common form of acute pulmonary disease in Sickle Cell Disease

• Most common cause of death in SCD• Etiology: pneumonia, infarction/thrombosis,

fat embolus

Acute Chest Syndrome

• Presentation: Chest pain, pulmonary infiltrate and fever

• Most common form of acute pulmonary disease in Sickle Cell Disease

• Most common cause of death in SCD• Etiology: pneumonia, infarction/thrombosis,

fat embolus

Gladwin and Vichinsky n engl j med November 20, 2008 359 (21): 2254

Acute Chest Syndrome

• The Acute Chest Syndrome occurs in the majority of patients with sickle cell disease at least once during their lives

• Second most common cause of hospital admission after “painful vaso-occlusive crises”

Acute Chest Syndrome

• The Acute Chest Syndrome is a life-threatening disorder

• Leading cause of death in people with sickle cell anemia.

• Defined as the presence of a new pulmonary infiltrate on Chest Xray, with chest pain, fever, cough, dyspnea, or an elevated WBC count in a patient with sickle cell anemia.

Acute Chest Syndrome

• Caused by occlusion of the pulmonary vessels by sickled red cells. Since hypoxia is the chief stimulus for polymerization of hemoglobin S, lung disease of any type poses a particular threat to the patient with sickle cell anemia.

Four Major Precipitants of Acute Chest Syndrome

• Infection• Bone Marrow Emboli• Thromboembolism• Atelectasis

Acute Severe Anemia

• Splenic Sequestration Crisis• Aplastic Crisis• Hyperhemoytic Crisis

Splenic Sequestration Crisis

• Vaso-occlusion within the spleen and pooling of RBCs leads to a marked fall in Hg and an increase in reticulocytes

Aplastic Crisis

• Transient cessation of erythropoiesis secondary to infection with parvovirus

• Can also occur after infection with Strep pneumoniae, salmonella, and EBV

Hyperhemolytic Crisis

• Associated with multiple transfusions• Also associated with certain drugs, infections

and glucose-six-phostate dehydrogenase deficiency

Growth and Development

• Growth retardation and delayed puberty are common in children with SCD

Infection

• Impairment of the spleen• Patients are susecptable to encapsulated

organisms such as Strep pneumo, and H flu• Bacteremia• Meningitis• Pneumonia• Osteomyelitis

Fever

• Medical emergency requiring immediate attention and treatment with antibiotics

Cerbrovascular/ Neurologic Disease

• Stroke/ TIA• Intracranial Bleed• Spinal Cord Infarction/ Compression• Vestibular dysfunction• Sensory hearing loss

Bone Complications

• Bone infarction and necrosis• Osteomyelitis• Osteoporosis• Osteonecrosis (avascular or ischemic necrosis)• Bone marrow infarction• Pulmonary fat embolism (secondary to bone

marrow infarction)

Cardiac Complications

• Increased Cardiac Output (secondary to chronic anemia)

• Myocardial Infarction (caused by increased oxygen demand that cannot be met due to the anemia and decreased oxygen carrying capacity of the RBCs)

Dermatolgic Complications

• Leg Ulcers (secondary to vasoocclusion in the skin

Hepatobiliary Complications

• Acute Hepatic Ischemia• Cholestasis• Hepatic sequestration crisis• Iron overload secondary to multiple

transfusions• Acute and chronic cholelithiasis secondary to

pigmented gallstones• Hepatitis C secondary to blood transfusion

Obstetrical Complications

• Fetal complications: Spontaneous abortion, intrauterine growth retardation, fetal demise, low birth weight secondary to compromised placental blood flow

• Maternal complications: acute chest syndrome, UTI, pyelonephritis, endometritis, preeclampsia, thromboembolic events, which occur in up to 50% of pregnancies

Renal Complications

• Hematuria• Proteinuria• Hypertension• Renal Infarction, Papillary necrosis• Nephrogenic DI• Focal Glomerulosclerosis• Renal Medullary carcinoma, seen in black

patients with sickle cell trait

Retinopathy

• Proliferative retinopathy• Retinal artery occlusion• Retinal detachment and hemorrhage

TREATMENT

• COMPREHENSIVE CARE — • Upon diagnosis of SCD implement a Comprehensive

Care program for the affected child and his\her family

• Because of the many manifestations of the acute and chronic complications of SCD

• Critical to involve specialists with expertise • Multidisciplinary teams: social workers,

psychologists, nurses, genetic counselors, and nutritionists.

TREATMENT

• Universal screening of newborns• Prophylactic Penicillin• Improved medical care• Have reduced the mortality of Sickle Cell

Disease from 25% to less than 3%

TREATMENT

• Begin prophylactic penicillin 125mg BID by 2-3 months of age and continue until two to three years of age. At this time increase dose to 250mg BID until the age of 5.

• After age 5 some clinicians elect to stop the penicillin prophylaxis

• Immunize against, Streptococcus pneumoniae, Haemophilus influenza,Hepatitis B and influenza

TREATMENT

• Folic Acid 1mg daily• Children 16 or younger should be evaluated

with transcranial doppler (TCD) to identify those children at risk for cerebrovascular accidents.

• Begin TCDs at age two and continue every 12 to 24 months.

• The risk of stroke can be reduced

TREATMENT

• Hydroxyurea

• Hematopoietic Stem-cell Transplantation

• Long Term Transfusion Therapy

Treatment

• Hydroxyurea: Only FDA approved therapy to prevent episodes of pain in SCD. Interferes with the sickle hemoglobin polymerization process by increasing the production of fetal hemoglobin

Cure

• Hematopoietic stem cell transplant. Limited to individuals less than 16 years of age

Hydroxyurea

• Cytotoxic drug that can bind metals. Used in polyc ythemia vera to decreas the elevated Hct and platelet count

• Inhibits ribonucleotide reductase by bindings its 2 main iron molecules and inactivating a critical tyrosyl radical that reduces the production of RBCs with a high level of HbSS

• Favors production of fetal Hb which arises from precursor cells that divide at a slower rate

Hydroxyurea

• A major breakthrough that shifts hemoglobin production from sickle hemoglobin to fetal hemoglobin by altering the bone marrow to favor fetal hemoglobin production

Hydroxyurea

Hydroxyurea

• Dose: Single daily oral dose 15 mg/kg (adjust for decreased creatinine clearance)

• Monitor CBC every 2 weeks• Contraindicated in: pregnancy, breast feeding,

severe anemia, leukopenia and thrombocytopenia

• Discontinue if CBC counts drop below the acceptable range

Hydroxyurea

Hematopoietic Stem-cell Transplantation

• Still under careful investigation in the US• Currently the only potential cure for SCD

SICKLE CELL DISEASE

• THE LITERATURE

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Dew, A., & van Besien, K. (2010). Stem-cell transplantation for sickle cell disease. The New England Journal of Medicine, 362(10), 955-956.

Feld, J. J., DeBaun, M. R., & Vichinsky, E. P. (2009). Overview of the management of sickle cell disease. UpToDate. Retrieved from www.uptodate.com

 

Firth, P. G. (2009). Pulmonary complications of sickle cell disease. The New England Journal of Medicine, 360(10), 1044-1045.

 

Gladwin, M. T., Sachdev, V., Jison, M. L., Shizukuda, Y., Plehn, J. F., Minter, K., … Ognibene, F. P. (2004). Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. The New England Journal of Medicine, 350(9), 886-895.

 

Gladwin, M. T., & Vichinsky, E. (2010). Pulmonary complications of sickle-cell disease. The New England Journal of Medicine, 359(21), 2254-2265.

 

Khan, S., & Rodgers, G. P. (2010). Hematopoietic cell transplantation in sickle cell disease.UpToDate. Retrieved from www.uptodate.com

 

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ReferencesMedoff, B. D., Shepard, J. O., Smith, R. N., & Kratz, A. (2005). Case 17-2005: A 22-year-old woman with back and leg pain and respiratory

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National Guideline Clearinghouse. (2007). Hemoglobinopathies in pregnancy. Retrieved from http://www.guideline.gov

National Guideline Clearinghouse. (2007). Screening for sickle cell disease in newborns: U.S. Preventive Services Task Force recommendation.

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Platt, O. S. (2008). Hydroxyurea for the treatment of sickle cell anemia. The New England Journal of Medicine, 358(13), 1362-1369

 

Rodgers, G. P. (2010). Specific therapies for sickle cell disease. UpToDate. Retrieved from www.uptodate.com

 

Strouse, J. J., Takemoto, C. M., Keefer, J. R., Kato, G. J., & Casella, J. F. (2008). Corticosteroids and increased risk of readmission after acute chest syndrome in children with sickle cell

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Vinchinsky, E. (2009). Overview of the clinical manifestations of sickle cell disease. UpToDate. Retrieved from www.uptodate.com

Virginia Department of Health. (2005). Sickle cell anemia (Hb SS Disease). Retrieved from http://www.vahealth.org/genetics

Virginia Department of Health Division of Women’s and Infant Health. (n.d.). A counseling guide for sickle cell and other hemoglobin variants. The Virginia Sickle Cell Awareness Program. Retrieved from www.vaheatlh.org/sicklecell/

 

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