1. Sickle Cell Disease Martin H. Steinberg Department of Medicine, Boston University School of Medicine, Boston, MA (07/18/13)

2. Sickle Cell Disease: General Points

3. Globin Gene Mutations are Autosomal Co-dominant (Recessive) Traits

4. Pathophysiology of Sickle Cell Disease, 2013

5. Laboratory Diagnosis family study, clinical symptoms, exam, blood morphology separation of hemoglobin proteins by HPLC DNA-based Dx by PCR and sequencing

6. Many Genotypes Comprise the Phenotype of Sickle Cell Disease

7. Sickle Cell Trait • Sickle cell trait is not a disease • Normal blood counts (PCV, MCV, reticulocytes) • Normal blood film • 60% HbA, 40% HbS, normal HbA2 and HbF • Normal lifespan; few medical problems hyposthenuria; hematuria; ? increased UTI in pregnancy; 2x increased risk of thromboembolic disease and pulmonary embolism(4x); increased risk of death from exertional heat illness

8. Pathophysiology Complexity suggests sites for intervention

9. Irreversibly Sickled Cells (ISCs) Result of membrane damage Hemoglobin may be in solution Do NOT signify acute sickle cell-related events

10. Vascular Complications Little affected by HbF concentration; less prevalent with co-incident α thalassemia; sometimes a mortality risk

11. Other Complications HbF affects the incidence of many of these complications

12. HbSC Disease

13. Necrotic Bone Marrow Embolization and ACS 46 y.o. man,HbSC disease, chest and leg pain, weakness, SOB. Acute severe anemia, leukocytosis, hypoxia, obtundation, liver and renal failure, death.

14. Pain in Sickle Cell Disease Acute painful episode-most frequent Acute chest syndrome-often presents as acute pain Others Osteonecrosis Leg ulcers Acute Chronic opioid induced, secondary to acute pain Neuropathic (

15. Prerequisites of EffectiveAcute Pain Management

16. Acute Painful Episodes

17. Diagnosis of the Acute Painful Episode (Ballas and Smith, Blood, 1992)

18. Acute Sickle Cell Pain: Management

19. Acute Sickle Cell Pain: Management

20. Acute Sickle Cell Pain: Management

21. Burning Tingling Shooting Lancinating Numb Paroxysmal Emotional distress Behavioral dysfunction Neuropathic Pain Damage or dysfunction of the nervous system Associated with dysesthesia and allodynia Continuous and/or episodic Rx: antidepressants, anticonvulsants, opioids, others

22. Causes of Persistent Severe Pain

23. "Difficult" Patients

24. Complications of the Acute Painful Episode: Days 1-5

25. Chronic Opioid Treatment

26. Hydroxyurea in Sickle Cell Disease

27. Benefits of Hydroxyurea After 17.5 years, ↓deaths; 87% of deaths occurred in patients who never took hydroxyurea or took it for <5 years. Long-term use of hydroxyurea in adults is safe. (Steinberg et al, 2003, Steinberg et al, 2010, Voskaridou et all, 2009)

28. Transfusion

29. Stem Cell Transplantation Myeloablative transplantation in children: ~85% disease free survival (Lucarelli, 2012) Nonmyeloablative HLA matched transplants in 10 adults: stable mixed chimerism and "cure" in 9 of 10 cases (Hsieh, 2009) Related haploidentical transplants in adults and children (Bolanos-Meade, 2012; Dallas, 2013)

30. Summary