Phys final review -- sickle cell anemia .pdf

Sickle cell anemia Disease summary ○ Definition: Blood disorders classified as hemolytic anemias are characterized by: Premature destruction of red blood cells Retention in the body of iron Bilirubin...

Sickle cell anemia Disease summary ○ Definition: Blood disorders classified as hemolytic anemias are characterized by: Premature destruction of red blood cells Retention in the body of iron Bilirubin Other products of hemoglobin breakdown An increase in erythropoiesis ○ The term sickle cell disease refers to a group of three inherited blood disorders characterized by: The presence of an abnormal form of hemoglobin– hemoglobin S (HbS) – within erythrocytes HbS, the so-called “sickle hemoglobin”, reacts to dehydration and deoxygenation by distorting RBCs into an elongated sick or crescent-moon shape This structural change in the RBC has a variety of pathophysiological consequences, including hemolytic anemia ○ Sickle cell anemia is a chronic, autosomal recessive disease and the most serious type of SCD and results in: hemolytic anemia Severe pain, organ failure Pain and organ failure result from: Blood vessel obstruction, sluggish blood flow, poor oxygen delivery from the abnormally shaped RBCs ○ The first account of SCA in the medical literature appeared in 1910. James B. Herrick, a Chicago physician, described the symptoms of 20 year old black male student from west indies ○ The patient’s clinical manifestations included: Shortness of breath, anemia, palpitations, episodes of icterus ○ Dr. Herrick described the patient’s peripheral blood smear as showing “think, sickle-shaped and crescent shaped red cells” Distortion of red blood cells is most commonly causes by: Deoxygenation, dehydration, acidosis, and cold temperature ○ The incidence of SCA among latin Americans in the United states is 1 in 1,000-1,400 ○ In eastern africa where malaria is endemic, the frequency of the sick cell gene is among the highest in the world and approaches 45% ○ As a result, SCA is associated with considerable economic loss and disability The mortality rate of the disease to 18 years of age is significant (15%) and life expectancy is often reduced A complication that often occurs between 6 months and 3 years of age is foot-hand syndrome This condition is characterized by inflammation of the periosteum of the metacarpal and metatarsal bones and painful swelling of the dorsal surface of the hands and feet Joint inflammation with pain and limited range of motion may accompany this condition  Occasionally, in the latter part of the first year of life, blood pools in the liver and spleen and both organs undergo a sudden, very painful enlargement known as acute sequestration crisis ○ Strokes are no uncommon in children, often occur around 8 years of age, and tend to be recurrent ○ Repeat strokes occur in ⅔ of patients within 3 years of the first stroke ○ A common serious complication of SCA during adult life is vaso-occlusive crisis ○ Approximately half of all patients experience a vaso-occlusive crisis, which accounts for 90% of hospital admissions among adults with SCA ○ Excurtiation and unrelenting pain is present in extremities, abdomen and sometimes the face ○ The person in crisis is in extreme discomfort and requires hospitalization and narcotic meds for relief ○ Recurrent episodes of vaso-occlusive crisis can cause: irreversible organ damage and acute chest syndrome ○ Acute chest syndrome is a medical emergency characterized by chest pain, difficulty breathing, fever, and hemoptysis ○ If not treated immediately, the patient may develop life threatening acute respiratory distress syndrome ○ Acute chest syndrome is the second leading cause most hospitalization in patients with SCA and a leading cause of death associated with the disease ○ Aplastic crisis consists of profound anemia caused by reduced erythropoiesis despite an increased demand for new RBCs ○ This serious complication occurs when the ability of the bone marrow to compensate for the hemolysis is compromised by a viral infection or folate deficiency ○ Marked tachycardia and high–output heart failure can result ○ Priapism is a serious and common complication in males (occurs in up to 40% of all males with SCA) and tends to occur repeatedly ○ Priapism is an abnormal condition of prolonged penile erection, often painful, and seldom associated with sexual arousal ○ In extreme cases, priapism can lead to impotence ○ Pregnancy represents a special area of concern ○ A high rate of fetal loss results from poor oxygen delivery to the developing infant ○ At birth, the infant often is premature and has a low birth weight Causes and risk factors ○ The cause of SCA is a single nucleotide base change (Thymine for adenine) in DNA (i.e., a point mutation) that leads to an amino acid substitution of valine for glutamic acid in the 6th position of the B-globin chain of the hemoglobin molecule ○ Under normal circumstances, the body produces healthy hemoglobin known as hemoglobin A ○ The abnormal B chain is designated BS and the tetramer of a2B2S is designated sickle hemoglobin or HbS ○ The apparently minor change in the molecular structure of hemoglobin causes profound abnormalities in both the stability and solubility of the protein  ○ The gene for HbS is transmitted by autosomal recessive inheritance and can manifest as sickle cell trait in heterozygotes with one HbS gene or as SCA in homozygotes with two HbS genes ○ In the heterozygote or “carrier”, only 40% of the total amount of hemoglobin is HbS Pathophysiology ○ All of the clinical manifestations of SCA are related to the pathophysiology of sickle RBCs ○ Sickling is an occasionally phenomenon that can be triggered and sustained by the following stressors: Low oxygen tension (PaO2) of the blood (i.e., hypoxemia) High hydrogen ion concentration in the blood (i.e., decreased plasma pH or acidosis) High plasma osmolality Low plasma volume Cold temperature Deoxygenation of erythrocytes is one of the most important variables that cases sickling In patients with SCA, erythrocytes survive only 10-20 days in contrast to normal cells that survive approximately 120 days ○ Anemia and its resulting hypoxemia trigger erythropoiesis in the bone marrow and in extreme cases also in the liver ○ A compensatory increase in RBC production (5-8 times normal) replaces cells lost by premature hemolysis ○ As true for most hemolytic anemias, hyperbilirubinemia (i.e., elevated serum bilirubin level) from the breakdown of hemoglobin often leads to jaundice and the production of pigment stones (composed of calcium bilirubinate) in the gallbladder ○ Sickling usually is not permanent ○ Most sickled RBCs regain their normal biconcave disk-like shape after reoxygenation or rehydration. ○ After repeated episode of deoxygenation and reoxygenation (or dehydration and rehydration) however RBCs remain permanently sickled ○ Irreversible sickling is caused by injury to the plasma membrane of the erythrocyte, an effect that may be related to the loss of active membrane transport and the influx of calcium ions ○ Up to one half of erythrocytes may be irreversibly injured at one time in a patient with SCA. ○ Laboratory features are distinctive ○ The hematocrit usually ranges between 18% and 30%. ○ The peripheral blood smear is characteristically abnormal with irreversibly sickled cells comprising up to 50% of all RBCs. ○ The white blood cell count is characteristically elevated and the platelet count may also be high (i.e., thrombocytosis). ○ Indirect serum bilirubin concentrations are also higher than normal. ○ Other typical findings include:  an elevated reticulocyte count the presence of nucleated RBCs in the peripheral blood hallmarks of reduced splenic function in the peripheral blood, such as target cells. ○ The reticulocyte is a type of immature erythrocyte characterized by a mesh-like pattern of tangles at the former site of the nucleus. ○ Reticulocytes normally account for 2% of all circulating erythrocytes. ○ A greater proportion reflects an increased rate of erythropoiesis. ○ Target cells are abnormal RBCs characterized by a densely stained center surrounded by a pale unstained ring that is encircled by a dark, irregular band. ○ A carrier of sickle cell gene will demonstrate HbS that is 35-40% of total hemoglobin and HbA equal to 60-65% ○ Present on chest x-rays in patients with acute chest syndrome ○ Radiographs of the vertebral column may reveal the typical “fish mouth appearance” of vertebrae suggesting expansion of the bone marrow from increased erythropoiesis ○ Abdominal ultrasound can be used to assess liver and spleen size and locate gallstones Head CT (i.e., computed tomography) or MRI (i.e., magnetic resonance imaging) is used in cases of neurologic crisis ○ Bone scans and MRIs are helpful in distinguishing bone injury due to recurrent vaso-occlusive crises from osteomyelitis. ○ Radiographs of the hands and feet from pediatric patients who previously presented with hand-foot syndrome show dramatic changes within 5 weeks of the onset of swelling: thinning of cortical bone and destruction of metacarpal and metatarsal bones. ○ Septicemia and meningitis develop in as many as 10% of children with SCA during the first 5 years of life, with a mortality rate of 25%. ○ Survival time is unpredictable and many young adults die in their twenties. ○ The average age of death for male patients with SCA is 42 years, and is 48 years for female patients. ○ However, the average life expectancy is increasing as a result of improved supportive care and there are now reports of patients living past the age of 70. ○ People with the sickle cell trait generally remain well and have a normal life expectancy. ○ Rare reports exist, however, of deaths occurring under extreme conditions—such as military basic training in which strenuous exertion was a key factor. ○ Similarly, isolated reports exist of organ damage and crises under unusual circumstances. ○ Progress toward successful gene therapy, which has the potential to cure the disease, has been slow. Acute chest syndrome is managed with analgesics, oxygen, antibiotics, and blood transfusion. ○ The major objective of a blood transfusion is to decrease the serum concentration of HbS to 30% or less of total hemoglobin. ○ Aplastic crisis and hemolytic crisis are also treated with a transfusion. ○ Leg ulcers are treated with debridement, antibiotics, zinc oxide occlusive dressing, and elevation of the leg. ○ Skin grafting may be necessary for poorly healing ulcers ○ Priapism can be treated with analgesics and hydration. Priapism that does not resolve within 6 hours, however, may require surgical drainage of the corpora cavernosa.  ○ Gallstone surgery may necessary ○ Gallstones may necessitate a cholecystectomy. ○ For a pain crisis that is resistant to all other treatments, an exchange transfusion is an option. ○ Exchange transfusions introduce whole blood in exchange for 75–85% of the patient’s total blood volume that is repeatedly withdrawn in small amounts and replaced with equal amounts of donor blood. ○ Bone marrow and stem cell transplantation have the potential to cure children with SCA and are the treatments of choice. ○ However, these options are available only to a small minority of patients, primarily because of the high risk for adverse effects (e.g., graft-versus host disease) and the difficulty in finding suitable donors. ○ Furthermore, drugs required for a successful transplantation are highly toxic and procedures are very expensive.