Sickle Cell Disease

Martin H. Steinberg

Department of Medicine, Boston University School of Medicine, Boston, MA

(07/18/13)

Sickle Cell Disease: General PointsA 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

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

Pathophysiology of Sickle Cell Disease, 2013

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B

C

Laboratory Diagnosis

family study, clinical symptoms, exam, blood morphology

separation of hemoglobin proteins by HPLC

DNA-based Dx by PCR and sequencing

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+, β0 thalassemia compound heterozygotes (1/1600)

HbSE: compound heterozygote, Asian ancestry

Many rarer compound heterozygotes; e.g., HbSD, HbSOArab

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

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

Irreversibly Sickled Cells (ISCs)

Result of membrane damage

Hemoglobin may be in solution

Do NOT signify acute sickle cell-related events

Leg ulcersCholelithiasisPriapism↓Renal function/albuminuriaStroke, ↑TCD, silent cerebral infarctionTRV and pulmonary hypertension

Vascular Complications

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

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

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

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.

Pain in Sickle Cell Disease

Acute painful episode-most frequent

Acute chest syndrome-often presents as acute pain

Others

Osteonecrosis

Leg ulcers

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Acute

Chronic

Neuropathicopioid induced, secondary to acute pain

Prerequisites of EffectiveAcute 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

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

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

Acute Sickle Cell Pain: Management

Short-acting Parenteral Opioids

Morphine

Hydromorphone (Dilaudid)

Fentanyl

Avoid Meperidine (Demerol)

Acute Sickle Cell Pain: Management

Assessment

Analgesic choice; type, dose, route, PCA vs. bolus dosing

Titration

Adjuvants; antidepressants, NSAIDs, antihistamines

Maintenance

Manage side-effects

Acute Sickle Cell Pain: Management

Adjustment for tolerance/rotation

Tapering

Switch to oral agents

Neuropathic Pain

• Burning

• Tingling

• Shooting

• Lancinating

• Numb• Paroxysmal• Emotional distress• Behavioral dysfunction

Damage or dysfunction of the nervous systemAssociated with dysesthesia and allodynia Continuous and/or episodic

Rx: antidepressants, anticonvulsants, opioids, others

Causes of Persistent Severe Pain

Progressive tissue damage

Inadequate treatment

Tolerance

Hyperalgesia

Changes at receptors

Maladaptive behavior

"Difficult" Patients

Often alienate the entire health care team

No single causesevere sickle cell diseasesevere psychosocial diseasepoor treatmentexcessive or ineffective opioid use

Complications of the Acute Painful Episode: Days 1-5

Acute chest syndromeAcute multiorgan failureSudden deathRelapse/hospital readmission

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

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

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

Transfusion

Beneficial Severe anemia Prevention of CVA Preoperative Some acute chest syndrome

Sometimes Needed Pregnancy Renal failure

Major problems: iron storage, alloimmunization, venous access

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)

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