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Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005. Case A. HPI: A 14 year old Nigerian boy, who is visiting the bay area, presented to the ED with severe chest pain, fever, and shortness of breath for 2 days.

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Hematology: Inherited blood disorders, case histories and review Michael R. Jeng, MD Tuesday, August 2, 2005

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  1. Hematology: Inherited blood disorders, case histories and reviewMichael R. Jeng, MDTuesday, August 2, 2005

  2. Case A • HPI: A 14 year old Nigerian boy, who is visiting the bay area, presented to the ED with severe chest pain, fever, and shortness of breath for 2 days. • Past Medical History: This boy has been admitted to the hospital in the past for pain of the arms and legs, but there is no diagnosis. He is on no current medications.

  3. PE: 40.0 C, 100, 40, 120/76 • Mild respiratory distress, uncomfortable • Mildly icteric eyes • Resp: Crackles at LLL • CV: 3/6 SM at LLSB • Abd: unremarkable. No HSM

  4. Labs: • Chemistry Panel: T Bili: 2.5 mg/dL • WBC: 10.5 K/uL, Plts: 594 K/uL • Hgb: 8.5 gm/dL, Retic: 15%, ARC: 485 K/uL • HPLC: SF, Hgb S: 96%:, Hgb F: 4% • CXR: LLL and RLL infiltrates

  5. Peripheral Blood Smear

  6. Normal Smear Sickle Smear

  7. SCD: Pathophysiology • Most common mutation is the substitution of a valine for glutamine at the 6-position. • The resulting abnormal hemoglobin, (Hb S), easily precipitates and crystallizes. When this occurs, the red blood cells change shape, into a sickle shape. • Dehydration, low PH, deoxygenation, stress can lead to crystallization/precipitation. • This change in conformation causes occlusion of blood vessels, which leads to the complications of sickle cell disease.

  8. Normal disc-Shaped soft(like a bag of jelly) easily flow through small blood vessels lives for 120 days Sickle sickle-Shaped hard (like a piece of wood) often gets stuck in small blood vessels lives for < 20 days SCD: PathophysiologyNormal vs. Sickle Hemoglobin

  9. SCD: Diagnosis • Types of screening: • Sickle Prep / morphology • Hemoglobin electrophoresis • HPLC (gas chromatography) • DNA testing • Electrophoresis/HPLC: • AS trait: 55-65% A, 40-45% S, 1-2% A2 • SS disease: 80-100% S, 0-20% F • SC disease: 50% S, 50% C • S – Thal: 75-100% S, 0-20% F: 3-6% A2, some 1-15% A

  10. Epidemiology • Sickle cell disease is an inherited disease. • It is the most common genetic (inherited) disease due to a single amino acid substitution in the USA. • 1 in 10 African Americans carry the gene, and approx. 1 in 300 have the disease. • Most common mutation is the substitution of a valine for glutamine at the 6-position. • Heterozygotes with this mutation are thought to have a selective advantage due to protection from cerebral malaria.

  11. Epidemiology • There are about 50,000 - 70,000 persons with sickle cell disease in the USA. • More rare, Indian, Middle Eastern, Latin American, and Caucasian persons may be affected. • 48 states have newborn screening for hemoglobinopathies. 2 states do not screen for sickle cell disease: Idaho, South Dakota. (?Montana-pilot program) • The current lifespan for people with sickle cell disease is about 45-50 years for men, and 50-55 years for women in the USA.

  12. Probability of Survival to Age 20 years in Patients with Hb SS, Hb SC, and All Others entered in Cooperative Study of Sickle Cell Disease at <20 years of age 1.00 .95 .90 Proportion Surviving .85 SS SC .80 ALL .75 1Y 3Y 6Y 10Y 2M 20Y Age

  13. 1.0 0.9 0.8 0.7 0.6 Probability of Survival 0.5 0.4 0.3 0.2 0.1 0 0 10 20 30 40 50 60 70 Age (Years) Females with SS Males with SS Black females Black males Probability of Survival for Male and Female Patients with SS Compared with Black Males and Females

  14. Medical Complications – Acute Management • Although there are many different complications, classically there are 4 crises: • Vaso-occlusive Crisis: Dactylitis, Priapism, CVA • Acute Chest Syndrome/Crisis • Aplastic Crisis • Splenic Sequestration Crisis • Fever/Infections • Other Clinical Issues: Fever, Gallstones, Ocular damage

  15. Vaso-occlusive Crisis • Usually begin at 8-10 months of age • Dactylitis if often first symptom (Hand-foot) ** • Priapism – emergency • Pain • Stroke – emergency (most serious complication)

  16. Vaso-Occlusive Crisis • Pain Episodes: Most common VOC. • Treat with fluids, pain medications, warm compresses, time. . . . • Try to avoid transfusions • Stroke: 11% of patients by 18 years of age, most serious complication • Treat with exchange transfusion with goal of Hb around 10 gm/dL, and %Hb S at less than 30% • Rehabilitation

  17. Aplastic Crisis • Usually associated with Parvo B19 infection • Sudden drop in Hgb, no reticulocytosis • Often contagious (family) • Phenomenon due to shortened red cell half life • DX: severe anemia, low reticulocyte, parvovirus B19 titers • RX: Close observation or simple transfusion, monitor family members with SCD

  18. Splenic Sequestration Crisis • Acute drop in hemoglobin • Sickling in efferent venules can cause balloon like phenomenon • All patients taught to monitor spleen size • DX: clinical - May be associated with fever, pain, respiratory symptoms, sudden trapping of blood within the spleen • Circulatory collapse and death can occur in less than thirty minutes. • Usually occurs in 1st 5yrs of life • RX: follow serial hgbs, simple transfusions, follow-up

  19. Acute Chest Syndrome • Fever • Chest Pain • Increased work of breathing • Shortness of breath • Decreased oxygen saturation • DX: new infiltrate on CXR with above symptoms • RX: antibiotics, oxygen, bronchodilators, transfusion, incentive spirometry, close monitoring

  20. Other Clinical Issues:FEVER/Infections • By age 5 years, 84% without spleen • Infections are a common complication of SCD • Patients begin prophylactic PCN by age 2-3 months • All patients with fever need evaluation • Esp. prone to encapsulated organisms (S. pneumoniae, H. influenzae, Salmonella (osteomyelitis), mycoplasma • Need all Pneumococcal vaccines, H. Flu • RX: antibiotics, follow blood cultures

  21. Case B • 5 week old infant was referred because of a hemoglobin F pattern noted on the neonatal screen. • History: 5 week old baby boy born to Vietnamese parents. Birth history = unremarkable. • Growing on his home regimen of breast milk and formula. • You have seen him twice since being discharged from the hospital with no complications or problems at any of these visits. There have been no fevers; abnormal bleeding or bruising; vomiting or diarrhea.

  22. Expected PE • What other history? • Family History? • WHAT TO DO NOW?

  23. Lab evaluation: • WBC: 11; hemoglobin of 14.4; and platelets of 497. • Reticulocyte count was 0.98. He had a total bilirubin of 9.3. MCV: 51 fL • Repeat HPLC: Showed Hb F pattern

  24. Thalassemias: • The thalassemias are a diverse group of genetic blood diseases characterized by absent or decreased production of normal hemoglobin, resulting in a microcytic anemia of varying degree. • The thalassemias have a distribution concomitant with areas where P. falciparum malaria is common.

  25. Affected Populations Southeast Asian (Vietnamese, Laotian, Thai, Singaporean, Filipino, Cambodian, Malaysian, Burmese, and Indonesian) Chinese East Indian African Middle Eastern Greek Italian Transcaucasian (Georgian, Armenian, and Azerbaijani)

  26. Malaria Belt

  27. Two main types: alpha or beta thalassemia • Alpha Thalassemia: • 4 copies of the alpha globin genes on Chromosome 16 • Thus, there are 4 genotypes possible

  28. Alpha Thalassemia • aa/aa: normal • a-/aa: silent carrier • a-/a- (aa/--): alpha thal trait minor anemia, microcytosis • a-/--: HbH disease: anemia and microcytosis, occ. transfusions, high bili • --/--: Hydrops fetalis

  29. Beta Thalassemia • Beta Thal Minor/ Beta Thal Trait • Asymptomatic, carriers. • Mild anemia, and microcytosis

  30. Beta Thal Major/Beta Thalassemia (Cooley’s anemia) • Transfusion Dependent, usually about 10 – 12 months of age • At risk for bony deformities, gall stones, splenomegaly • Long term transfusions are used to treat these patients • Eventually, suffer from iron overload

  31. Case C • A 1 day old newborn is noted to be icteric and jaundiced. • Maternal history: Born to a 32 year old G3P1 > 2 Caucasian woman, by NSVD. Uncomplicated delivery. Little prenatal care • PE: normal vital signs, healthy appearing except for jaundice and minimal pallor. No congenital defects, normal appearing male.

  32. What other history? • Labs?

  33. Review of labs: • Mother: Rh negative, Anti-Rh antibodies present • CBC: WBC: 12 Hgb: 10, with spherocytes, reticulocyte count: 16%, Platelets – 242 • Coombs positive

  34. RH disease

  35. Hemolytic Disease of the Newborn (HDN) • Rh Alloimmune hemolytic disease • This disorder is called erythroblastosis fetalis when it occurs in the fetus and HDN when it occurs in the newborn. • Rarely seen now with anti-Rh antibody (Rhogam). If prenatal care~! • Wide range of clinical presentation

  36. For Prenatal Care • In the Rh negative patient, initial testing, if negative, is usually followed up with another antibody screen at 28 weeks, just prior to administration of antenatal Rh(D) immune globulin and after delivery. (300 mcg) • Usually give after any procedures • May monitor antibody titers

  37. For Prenatal Care • Test for Fetal-Maternal Hemorrhage • Rosette Test • Kleihauer-Betke Test

  38. Treatment of infant, or known HDN • If antibodies present, monitoring of the infant for signs of anemia: • Hgb/hct (by amnio/cordocentesis sampling) • Liver size by U/S • Doppler U/S for fetal MCA flow • Possible intrauterine transfusions, and early delivery may be necessary • Postpartum monitoring and possible transfusions

  39. TREATMENT of Sensitized Mother: Of mother: If there is anti-D in the maternal serum, and the mother did NOT receive antenatal Rh immune globulin, then she would NOT be a candidate for Rh immune globulin postpartum, since she has apparently already been sensitized to the Rh(D) factor.

  40. Case D • A 5-year, 9-month-old male was previously healthy, was seen in the Emergency Room yesterday for jaundice and emesis. The parents say that he had been recently well, with no recent upper respiratory symptoms or diarrhea. • Yesterday, he developed emesis, which they report as being approximately five times, a yellow-greenish color, no blood and no diarrhea. • They also noticed that his eyes were yellow, and his skin was yellow, and therefore, they brought him into the emergency room.

  41. ROS: Dark-colored urine since yesterday • History of ingesting fava beans (2 days prior to on Friday presentation). • PMH: full-term at birth, with neonatal hypobilirubinemia with T-bili up to 24.3, for which he required phototherapy for two days. H • History of iron deficiency anemia in 1998 with a hemoglobin down to 9.8 and an MCV down to 74. • Other than this, he has had no hospitalizations or surgeries and no prior instances of jaundice outside of the neonatal period.

  42. MEDICATIONS: None. • ALLERGIES: No known drug allergies. • FAMILY HISTORY: There are no bleeding problems, no members with jaundice, no • members with autoimmune diseases, such as SLE or rheumatoid arthritis. • There is no known family history of G6PD deficiency.

  43. Physical Exam: Pallor, scleral icterus, jaundice, 3/6 systolic heart murmur. No HSM. No other findings. • Initial lab studies: • Hemoglobin = 6.8 gm/dL • Total bilirubin = 6.1 mg/L • Reticulocyte count of 1%. • Repeat laboratory studies: • Hemoglobin = 5.1 gm/dL LDH: 2429 u/L (900) • Reticulocyte count = 18% TBili: 8.2 mg/L (<1.4) • Coombs test = negative **

  44. G6PD: 2.5 u/gm Hg (5.5 – 8.8) • PK: 13.8 (3.2 – 6.5) ** • What other causes?

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