This Knowledge Check reviews the topics in Module 8 and is formative in nature. It is worth 20 points where each question is worth 1 point. You are required to submit a sufficient response of at least 2-4 sentences in length for each question. Scenario 1: Acute Lymphoblastic Leukemia (ALL) A ten-year-old boy is brought to clinic by his mother who states that the boy has been listless and not eating. She also notes that he has been easily bruising without trauma as he says he is too tired to go out and play. He says his bones hurt sometimes. Mother states the child has had intermittent fevers that respond to acetaminophen. Maternal history negative for pre, intra, or post-partum problems. Child’s past medical history negative and he easily reached developmental milestones. Physical exam reveals a thin, very pale child who has bruises on his arms and legs in no particular pattern. The APRN orders complete blood count (CBC), and complete metabolic profile (CMP). The CBC revealed Hemoglobin of 6.9/dl, hematocrit of 19%, and platelet count of 80,000/mm3. The CMP demonstrated a blood urea nitrogen (BUN) of 34m g/dl and creatinine of 2.9 mg/dl. The APRN recognizes that the patient appears to have acute leukemia and renal failure and immediately refers the patient to the Emergency Room where a pediatric hematologist has been consulted and is waiting for the boy and his mother. The diagnosis of acute lymphoblastic leukemia (ALL) was made after extensive testing. Question 1 of 2: What is ALL? Acute lymphoblastic leukemia (ALL) is a malignant clonal disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. ALL is the most common type of cancer and leukemia in children in the United States. The malignant cells of acute lymphoblastic leukemia (ALL) are lymphoid precursor cells (ie, lymphoblasts) that are arrested in an early stage of development. This arrest is caused by an abnormal expression of genes, often as a result of chromosomal translocations or abnormalities of chromosome number. These aberrant lymphoblasts proliferate, reducing the number of the normal marrow elements that produce other blood cell lines (red blood cells, platelets, and neutrophils). Consequently, anemia, thrombocytopenia, and neutropenia occur, although typically to a lesser degree than is seen in acute myeloid leukemia. Lymphoblasts can also infiltrate outside the marrow, particularly in the liver, spleen, and lymph nodes, resulting in enlargement of the latter organs. 2 Question 2 of 2: How does renal failure occur in some patients with ALL? Renal failure occurs in some patients with ALL as a result of hyperuricemia. Uric levels rise as an end product of purine metabolism from cellular destruction. Because the major excretory pathway is through the kidneys, urates can precipitate in renal tubules or ureters and can lead to oliguria and acute renal failure. Scenario 2: Sickle Cell Disease (SCD) A 12-year-old female with known sickle cell disease (SCD) present to the Emergency Room in sickle cell crisis. The patient is crying with pain and states this is the third acute episode she has had in the last nine months. Both parents are present and appear very anxious and teary eyed. A diagnosis of acute sickle cell crisis was made. Appropriate therapeutic interventions were initiated by the APRN and the patient’s pain level decreased, and she was transferred to the pediatric intensive care unit (PICU) for observation and further management. Question 1 of 2: What is the pathophysiology of acute SCD crisis and why is pain the predominate feature of acute crises? The pathogenesis of sickling includes erythrocyte derangement, chronic hemolysis, microvascular occlusions, and tissue damage. Deoxygenation is probably the most important variable in determining the occurrence of sickling. Other significant variables that affect sickling include interaction of Hbs with other types of hemoglobin in the cell, mean cell hemoglobin concentration (MCHC), intracellular pH, and transit times of erythrocytes through the microcirculation. The intense pain of an acute crisis is due to lack of oxygen to major organs and bones. The lack of oxygen leads to ischemia and organ death. Question 2 of 2: Discuss the genetic basis for SCD. SCD denotes all genotypes containing at least one sickle gene, in which HbS makes up at least half the hemoglobin present. Major sickle genotypes described so far include the following: • HbSS disease or sickle cell anemia (the most common form) - Homozygote for the S globin with usually a severe or moderately severe phenotype and with the shortest survival • HbS/b-0 thalassemia - Double heterozygote for HbS and b-0 thalassemia; clinically indistinguishable from sickle cell anemia (SCA) • HbS/b+ thalassemia - Mild-to-moderate severity with variability in different ethnicities • HbSC disease - Double heterozygote for HbS and HbC characterized by moderate clinical severity • HbS/hereditary persistence of fetal Hb (S/HPHP) - Very mild or asymptomatic phenotype 3 Sickle cell trait or the carrier state is the heterozygous form characterized by the presence of around 40% HbS, absence of anemia, inability to concentrate urine (isosthenuria), and hematuria. Under conditions leading to hypoxia, it may become a pathologic risk factor. Sickle cell disease produces illness, while sickle cell trait usually does not. People who inherit two genes for sickle hemoglobin (one from each parent) have sickle cell disease. With a few exceptions, a child can inherit sickle cell disease only if both parents have one gene for sickle cell hemoglobin. Scenario 3: Hemophilia The parents of a 9-month boy bring the infant to the pediatrician’s office for evaluation of a swollen right knee and excessive bruising. The parents have noticed that the baby began having bruising about a month ago but thought the bruising was due to the child’s attempts to crawl. They became concerned when the baby woke up with a swollen knee. Infant up to date on all immunizations, has not had any medical problems since birth and has met all developmental milestones. Pre-natal, intra-natal, and postnatal history of mother noncontributory. Family history negative for any history of bleeding disorders or other major genetic diseases. Physical exam within normal limits except for obvious bruising on the extremities and right knee. Knee is swollen but no warmth appreciated. Range of motion of knee limited due to the swelling. The pediatrician suspects the child has hemophilia and orders a full bleeding panel workup which confirms the diagnosis of hemophilia A. Question 1 of 2: Explain the genetics of hemophilia Deficiencies in factor VIII, IX, and XI are associated with 90% of hemorrhagic bleeding disorders. Hemophilia A and hemophilia B are inherited in an X-linked recessive pattern. The genes associated with these conditions are located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is enough to cause the condition. A son inherits his mother's other X chromosome, he will have normal blood clotting. A carrier's son has a 50% chance of having hemophilia. A baby girl will inherit an X chromosome with a dominant gene for normal blood clotting from her father. Therefore, the daughter will not have hemophilia. Question 2 of 2: Briefly describe the pathophysiology of Hemophilia Hemophilia A is caused by an inherited or acquired genetic mutation that results in dysfunction or deficiency of factor VIII, or by an acquired inhibitor that binds factor VIII. Of genetic cases, up to approximately one third are the result of de novo mutations not present in the mother's X chromosome. Inadequate factor VIII results in the insufficient generation of thrombin by the FIXa and FVIIIa complex by means of the intrinsic pathway of the coagulation cascade. This mechanism, in combination with the effect of the tissue-factor pathway inhibitor, creates an