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 A single point mutation in HBB causes sickle hemoglobin (HbS) Sickle cell trait is innocuous HbS homozygotes and some compound heterozygotes, like HbSC disease and HbS-β thalassemia have a severe disease Pathophysiology is complex and suggests multiple Rx targets The clinical features are heterogeneous; life is shortened Acute painful episodes are the major clinical issue and their treatment can be very difficult

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 Sickle cell anemia: HbS homozygote (1/600 African Americans) HbSC: compound heterozygote (1/800) HbS-β thalassemia: β +, β 0 thalassemia compound heterozygotes (1/1600) HbSE: compound heterozygote, Asian ancestry Many rarer compound heterozygotes; e.g., HbSD, HbSO Arab

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 HbA 2 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. HbS polymerization Sickle cell membrane damage Hemolysis of sickle cells (anemia) Intracellular adherence Reperfusion injury, NO scavenging, oxidant injury, inflammation Complexity suggests sites for intervention Pathophysiology

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

10. Leg ulcers Cholelithiasis Priapism ↓Renal function/albuminuria Stroke, ↑TCD, silent cerebral infarction TRV and pulmonary hypertension Vascular Complications Little affected by HbF concentration; less prevalent with co-incident α thalassemia; sometimes a mortality risk

11. Other Complications Clinical manifestations are very heterogeneous Acute painful episode-most patients, most frequent Acute chest syndrome- ~½ of patients; can be lethal Osteonecrosis-crippling, painful Retinopathy; splenomegaly in HbSC disease Multiorgan failure HbF affects the incidence of many of these complications

12. HbSC Disease Proliferative retinopathy Splenomegaly: infarction, sequestration Acute chest syndrome: half the rate of HbSS Stroke: age-adjusted prevalence 0.84% (4% in HbSS) Osteonecrosis: ~1/2 the prevalence as HbSS Leg ulcers: rare Renal failure: 2.4% (4.2% in HbSS) Pain: 0.4 episodes/patient y (0.8 in HbSS) Priapism: uncommon

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 Neuropathic opioid induced, secondary to acute pain

15. Prerequisites of Effective Acute Pain Management Know & understand the patient Know the types and patterns of pain Know the pharmacology of a few analgesics Patient education Non-pharmacological, alternative and complementary therapeutics

16. Acute Painful Episodes Most common complication: some patients always in pain; others rarely have pain; most have 2-3 episodes/year Most pain is managed at home Etiology unclear: unrelated to "sickling," blood film is not diagnostic Pain distribution variable Physical findings limited Duration variable High incidence of pain is a bad prognostic sign Directly related to PCV/indirectly related to HbF

17. Diagnosis of the Acute Painful Episode (Ballas and Smith, Blood, 1992) History Hematological changes are not diagnostic Other laboratory not useful RBC deformability and density change but measurement not clinically practical

18. Acute Sickle Cell Pain: Management Short-acting Parenteral Opioids Morphine Hydromorphone (Dilaudid) Fentanyl Avoid Meperidine (Demerol)

19. Acute Sickle Cell Pain: Management Assessment Analgesic choice; type, dose, route, PCA vs. bolus dosing Titration Adjuvants; antidepressants, NSAIDs, antihistamines Maintenance Manage side-effects

20. Acute Sickle Cell Pain: Management Adjustment for tolerance/rotation Tapering Switch to oral agents

21. Neuropathic Pain Burning Tingling Shooting Lancinating Numb Paroxysmal Emotional distress Behavioral dysfunction 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 Progressive tissue damage Inadequate treatment Tolerance Hyperalgesia Changes at receptors Maladaptive behavior

23. "Difficult" Patients Often alienate the entire health care team No single cause severe sickle cell disease severe psychosocial disease poor treatment excessive or ineffective opioid use

24. Complications of the Acute Painful Episode: Days 1-5 Acute chest syndrome Acute multiorgan failure Sudden death Relapse/hospital readmission

25. Chronic Opioid Treatment Develop a formal Rx plan and prescribe judiciously Use an opioid contract and evaluate often Be careful of dose escalation Use a single long- and short-acting agent Interruption of Rx can mimic acute pain episode High doses make acute pain Rx difficult

26. Hydroxyurea in Sickle Cell Disease Almost all patients should take HU Dose must be titrated for maximum effect HbF, blood counts and MCH and MCV should be followed

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) Reduced pain and ACS Mortality reduced 40% Less hemolysis (improved anemia) Fewer hospitalizations Reduced medical costs Improved physical capacity

28. Transfusion Beneficial Severe anemia Prevention of CVA Preoperative Some acute chest syndrome Sometimes Needed Pregnancy Renal failure Major problems: iron storage, alloimmunization, venous access

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 Correct diagnosis important especially for genetic counseling Disease phenotype is very variable HU in adults reduces pain, prolongs life and should be used in nearly all patients Pain management often difficult Transfusions should be used cautiously Transplantation can help some patients