1. Sickle Cell Disease

2. Introduction
Vaso-occlusive phenomena and hemolysis are the clinical hallmarks of Sickle Cell Disease (SCD)
Inherited disorder due to homozygosity for the abnormal hemoglobin, hemoglobin S (HbS)

3. HbS results from substitution of valine for glutamic acid as sixth amino acid of the beta globin chain, which produces a hemoglobin tetramer that is poorly soluble when deoxygenated.
Polymer assumes elongated rope-like fiber form in the classic sickle shape

5. Sickle cell shape results in decrease cell deformability.
Changes also occur in red cell membrane structure and function, disordered cell volume control and increase adherence to vascular endothelium.

6. Overview
Disorder most severe in patients with SCD (homozygosity for HbS), of intermediate severity in hemoglobin SC disease (HbSC, combined heterozygosity for hemoglobin S & C), and generally benign in those with sickle cell trait (heterozygosity for Hbs).

7. Patients with homozygous SCD are typically anemic and often lead a life of painful episodes.
Clinical signs and symptoms begin at an early age.

8. Prevalence of symptoms at age
Six month of age - 6%
Twelve months of age - 32%
Two years of age - 61%
Six years of age - 92%
eight years of age - 96%

9. Predictors of adverse outcome
Dactylitis before age one
Hemoglobin concentration < 7 g/dl
Leukocytosis in absence of infection
An adverse outcome, defined as stroke, frequent episodes of pain, recurrent acute chest syndrome or death occurred in 18% with these predictors,(392 infants/10yrs).

10. Laboratory findings Moderate anemia Reticulocytosis 3-15% High MCV
Unconjugated hyperbilirubinemia
Elevetaed LDH
Low haptoglobin
Folate & iron deficit
Peripheral smear shows sickle cells
Polychromasia
Howell-jolly bodies
Elevated WBC
Elevated Platelets
Low than after 18 yrs high creatinine

14. Acute Severe Anemia Acute fall in haptoglobin.
Patients present with pallor, weakness and lethargy.
Fatalities not uncomon.
Due to the Splenic sequestration crisis, aplastic crisis or hyperhemolytic crisis.

15. Splenic sequestration crisis
Vaso-occlusion in the spleen and pooling of blood in the spleen produce fall in hemoglobin, reticulocytosis and rapidly enlarging spleen.
Risk of hypovolemic shock and 10-15% mortality.
Recurrent in 50% of survivors.

16. Aplastic crisis
Arrest of erythopoiesis with falling hemoglobin levels and absence of reticulocytes.
Associated with infection namely Parvo-B19, EBV, Streptococcus and salmonella.
Reticulocytes usually reappear in 2-14 days.

17. Hyperhemolytic crisis
Sudden exacerbation of anemia with reticulocytosis.
Cause unknown.
Rare

18. Major Clinical Manifestations
Acute painful episodes
Multiorgan failure
Psychosocial issues
Growth & development
Infection
Bacteremia
Meningitis
Bacterial pneumonia
Osteomyelitis
CVA
Bone complcations
Infarct and necrosis
Marrow infarct
Orbital compression
Arthritis

19. Major Clinical Manifestations
Cardiac complications
Myocardial infarct
Dermatologic complications
Leg ulcers
Hepatobiliary complications
Cholelithiasis
Chronic liver disease
Acute hepatic episodes
Pregnancy complications
Fetal complications
priapism
Pulmonary complications

20. Major Clinical Manifestations
Renal complications
Retinopathy
Take a deep breath!

21. Acute painful crisis
Precipitated by cold, infection, dehydration, infection, stress, menses, hypoxemia, alcohol or no identifiable cause.
Can affect any area, but back, chest, extremities and abdomen most frequent.
Usually last 2-7 days.
Frequency- 1/3 rarely, 1/3 2-6yr, 1/3>6yr

22. Acute chest syndrome
Due to pneumonia, infarct due to in situ thrombosis and embolic phenomena due to fat embolism and bone marrow infarct.
Manifestations are chest pain, infiltrate on CXR and fever.
Treat with O2, antibiotics, and exchange transfusion to lower HbS to below 30%.

23. Management
Treatment and prevention of the acute manifestations of SCD.
Therapies designed to interfere with the polymerization process at different levels

24. General principals Regular Physician follow up.
Establish base line labs and Physical findings.
Education regarding nature of disease, genetic counseling and psychosocial assessment.
Immunize for Strep, influenza and Hep B

25. Prophylactic penicillin until five years.
Folic acid 1md/day
TCD
Retinal evaluation
BCP
Hydroxyurea

26. Hdroxyurea Increases production of hemoglobin F.
Reduces median crisis rate by 50%, decreased acute chest syndrome and transfusion.
40% reduction in mortality.
Mild increase in acute myeloid leukemia

27. Pain management Narcotics - Morphine or dilaudid Toradol
Inhaled nitric oxide
anticoagulation low dose INR 1.5
Poloxamer 188

28. Management of infection
Prophylactic fever - Ceftriaxone
Acute chest syndrome - Cefuroxime & Erythromycin.
Osteomyelitis - Cover salmonella and staph until cultures available.

29. Transfusion therapy Aplastic crisis Acute chest syndrome or sepsis CVA
Priapism
Perioperative
Simple vs exchange
Do not raise Hgb > 10

30. Prophylactic preoperative transfusion
Increase hemoglobin to 10g/dl
Reduces serious complications
Orthopedic surgery still has 67% serious complications and 17% sickle-related Complications ( acute chest syndrome and vaso-occlusive crises )

31. Transfusion complications
Alloimmunization
Iron overload
Infection

32. Prognosis
Median age of death for SCD in males is 42 for men and 48 for women
Median age of death for Hb SC is 60 for men and 68 for females

33. Causes of death Infection - 48% Stroke - 10%
Complications of therapy - 7 %
Splenic sequestration - 7 %
Thromboembolism - 5%
Renal failure - 4 %
Pulmonary hypertension - 3 %

34. The future Gene therapy Increase expression of Hb F RNA repair
Hematopoietic cell transplantation