Sickle Cell Disease Core Concepts for the Emergency Physician and Nurse Epidemiology, Genetics, Pathophysiology Spring 2013 Paula Tanabe, PhD, RN, FAEN, FAAN Associate Professor Duke University, Schools of Nursing and Medicine

Objectives Identify the genotype associated with the most severe form of SCD. Identify the median lifespan for individuals with SCD.

Pre-test Which genotype is associated with the most severe symptoms? SC SB0 SB+

Pre-test 2. What is the median lifespan for most individuals with SCD?

Epidemiology of SCD SCD is a genetic disease affecting 70,000 – 100,000 Americans, primarily of African descent (Hassell, 2010) Most common genetic disease among blacks SCD occurs in 1 of every 500 black births 1:1,100 Hispanics (eastern states) 1:32,000 Hispanics (western states) SCD occurs in many other ethnic groups, including Northern Europeans and those that live in the Middle Eastern Countries 1:12 African-Americans are carriers (trait) for the disorder While considered a rare disease SCD still affects approximately 100,000 individuals in the United States. It is a genetic disease, babies are born with it. SCD is most prevalent in the United States among African Americans, but not exclusively. Sickle cell trait is very common among African Americans. Two parents with trait have a 25% change of having a child with sickle cell disease.

Comparison of Life Expectancy US Population vs. Sickle Cell Disease Persons with SCD continue to experience a shortened life expectancy of approximately 30 years when compared to the general population.

Changes in Life Expectancy National Center for Health Statistics (CDC) Compared 1999-2007 with 1979-1998 Largest declines in ages 0-4 Smaller but significant declines up to age 19 Due to prophylactic treatment with penicillin and vaccinations Transcranial doppler screening identifies children at risk of stroke; placed on chronic transfusion therapy to prevent stroke No differences in the 20-24 age group Increase in death rate ages: 45-54, 55-65, and 65-75 Significant improvement in childhood mortality has occurred since the advent of newborn screening. All newborns are now screened for SCD. Babies with SCD are placed on penicillin until age 5 and receive pneumococcal vaccination. This prevents sepsis and death. Transcranial doppler screening is also performed to identify children at high risk of stroke. These children are placed on a monthly chronic transfusion program to prevent stroke.

What is the pathophysiology? Sickle cells have many abnormal properties and change shape under conditions of de-oxygenation. Cells are sticky and begin to form long polymers and obstruct blood flow and oxygen delivery. All tissues and organ systems require oxygen. Over the lifespan, organ damage can occur to all organ systems. During an acute vaso-occlusive crisis, oxygen delivery is compromised and severe pain results.

Normal Vs. Sickle Red Cells Sickle-shaped Rigid Live for 20 days or less Sticky surface, abnormal properties Normal Biconcave disc-shaped Deformable Life span of 120 days Sickle cells have many, many abnormal properties. Persons with sickle cell have chronic anemia. It is important to know an individual patients’ baseline hemoglobin before determining whether transfusion is needed, and to identify aplastic crisis, a life-threatening condition.

Prolonged Sickling of RBC’s After recurrent episodes of sickling membrane damage occurs cells not capable of resuming biconcave shape upon re-oxygenation Deformed sickle cells adhere to endothelium & macrophages induces hemolytic process Over time, blood vessel and organ damage occurs.

Hemolysis and Vaso-occlusion ▪ Anemia in SCD is caused by red cell destruction, or hemolysis ▪ The degree of anemia varies widely between patients ▪ Red cell production by the bone marrow increases dramatically, but is unable to keep pace with the destruction Vaso-occlusion: Complex process initiated by rigid and abnormally shaped sickled RBC’s Abnormal adhesion occurs to the endothelium Activation of WBC’s, RBC’s and the endothelial surface which enhances the VOC process Results in tissue damage, hypoxia, necrosis and organ dysfunction The primary pathophysiologic processes of SCD are hemolysis and vaso-occlusion.

Acute and Chronic Manifestations Acute Manifestations: Bacterial sepsis or meningitis* Recurrent vaso-occlusive pain (dactylitis, musculo-skeletal or abdominal pain) Splenic sequestration* Aplastic crisis* Acute chest syndrome* Stroke* Priapism Hematuria, including papillary necrosis Chronic Manifestations: Anemia Jaundice Splenomegaly Functional asplenia Cardiomegaly and functional murmurs Hyposthenuria and enuresis Proteinemia Cholelithiasis Delayed growth and sexual maturation Restrictive lung disease* Pulmonary hypertension* Avascular necrosis Proliferative retinopathy Leg ulcers Transfusional hemosiderosis* Persons with SCD experience a wide variety of both acute and chronic complications. The bolded starred complications are causes of mortality. All of these complications contribute to the severely shortened lifespan. *Potential cause of mortality

Sickle Cell Disease (SCD) Common Genotypes Approximate % of US Patients Genotype Sickle cell anemia (SS, most severe form) Sickle/Hb C disease (SC, lesser severity, but can still have pain episodes, and life-threatening complications) Sickle/Beta plus thalassemia (Sβ+ thalassemia, similar to SC) Sickle/Beta zero thalassemia (Sβ° thalassemia, similar to SS) 65 % 25 % 8 % 2 % The term sickle cell disease describes a group of complex, chronic disorders, not simply Sickle Cell Anemia (SS) SS is the most common and severe form of the disease. SC disease is considered to be a less severe form of the disease. However, patients with SC disease more frequently experience retinopathy and blindness, and avascular necrosis of the hips and shoulders. In some persons, a sickle gene combines with a gene for beta thalassemia is inherited from the other. SB0 is the more severe form and similar to SS disease. SB+ is less severe and more similar to SC disease. Persons without the disease, but with trait typically do not have symptoms. However, no research has been done to determine if patients with trait have symptoms. It is important that persons with trait receive reproductive counseling.

References Hassell KL. Population estimates of sickle cell disease in the U.S. Am J Prev Med. 2010;38(4S):S512-S521. Platt et al. Mortality in sickle cell disease, life expectancy and risk factors for early death. NEJM 1994. 330: 1639-44. Hamideh, D. Trends in Mortality Among Patients with SCD in the United States. Is there any change in the past 10 years? 2012. 6th Annual Sickle Cell Disease Research and Educational Symposium & Annual National SCD Scientific Meeting http://wonder.cdc.gov/controller/datarequest/D79

Post-Test Which genotype is associated with the most severe symptoms? SC SB0 SB+

Post-Test 2. What is the median lifespan for most individuals with SCD? 20’s 30’s 40’s 50’s