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Sickle Cell Disease. Martin H. Steinberg. Department of Medicine, Boston University School of Medicine, Boston, MA. (07/18/13). Sickle Cell Disease: General Points. Globin Gene Mutations are Autosomal Co-dominant (Recessive) Traits.

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Sickle cell disease

Sickle Cell Disease

Martin H. Steinberg

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

(07/18/13)



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


Pathophysiology of Sickle Cell Disease, 2013 Co-dominant (Recessive) Traits


Laboratory Diagnosis Co-dominant (Recessive) Traits

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 Trait Phenotype of Sickle Cell Disease

  • 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


Pathophysiology Phenotype of Sickle Cell Disease

Complexity suggests sites for intervention


Irreversibly Sickled Cells (ISCs) Phenotype of Sickle Cell Disease

Result of membrane damage

Hemoglobin may be in solution

Do NOT signify acute sickle cell-related events


Vascular Complications Phenotype of Sickle Cell Disease

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


Other Complications Phenotype of Sickle Cell Disease

HbF affects the incidence of many of these complications


HbSC Disease Phenotype of Sickle Cell Disease


Necrotic Bone Marrow Embolization and ACS Phenotype of Sickle Cell Disease

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 Phenotype of 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

(


Prerequisites of effective acute pain management
Prerequisites of Effective Phenotype of Sickle Cell DiseaseAcute Pain Management


Acute Painful Episodes Phenotype of Sickle Cell Disease


Diagnosis of the Acute Painful Episode Phenotype of Sickle Cell Disease

(Ballas and Smith, Blood, 1992)


Acute sickle cell pain management
Acute Sickle Cell Pain: Management Phenotype of Sickle Cell Disease


Acute sickle cell pain management1
Acute Sickle Cell Pain: Management Phenotype of Sickle Cell Disease


Acute sickle cell pain management2
Acute Sickle Cell Pain: Management Phenotype of Sickle Cell Disease


Neuropathic pain

Burning Phenotype of Sickle Cell Disease

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


Causes of persistent severe pain
Causes of Persistent Severe Pain Phenotype of Sickle Cell Disease


"Difficult" Patients Phenotype of Sickle Cell Disease



Chronic Opioid Treatment Phenotype of Sickle Cell Disease


Hydroxyurea in Sickle Cell Disease Phenotype of Sickle Cell Disease


Benefits Phenotype of Sickle Cell Disease 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)


Transfusion Phenotype of Sickle Cell Disease


Stem cell transplantation
Stem Cell Transplantation Phenotype of Sickle Cell Disease

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 Phenotype of Sickle Cell Disease


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