sickle cell (hemoglobin SS) disease

Etiology

• point mutation in gene for hemoglobin beta chain*

* first molecular disease identified

Pathology

• precipitation of hemoglobin SS under low oxygen tension resulting in loss of erythrocyte structure & deformability
  • sickling & hemolysis due to polymerization of sickle hemoglobin upon deoxygenation
• microvascular occlusion & infarction
• overactivity of SLC12A4 may contribute to erythrocyte dehydration
• P-selectin may play a role in painful crises
  • it is released from endothelial cells & from platelets activated by inflammation or trauma
  • it mediates binding of erythrocytes & leukocytes to the endothelial cell surface
  • adherent masses of sickled red cells & leukocytes contribute to occlusive pain crises

Genetics

• point mutation in gene for hemoglobin beta chain
• both allelles are affected (homozygous state)
• mutation results in amino acid substitution of valine for glutamate at residue 6 of the beta chain

Clinical manifestations

• symptomatic chronic anemia
• sickle cell vaso-occlusive crisis or "painful crises"
  • may be very painful & debilitating for the patient
  • there are no objective findings to confirm the presence of pain
• splenic atrophy in all patients by late adolescence
• bone pain

Laboratory

• complete blood count (CBC)
  • anemia (Hgb 7-10 g/dL) normocytic
  • leukocytosis
  • thrombocytosis
• peripheral smear - sickle cells
• reticulocyte count
  • usually elevated, especially during hyperhemolytic crisis
  • diminished during aplastic crisis despite hemolytic anemia
• hemoglobin electrophoresis establishes diagnosis
  • Hgb S (80-98%), Hgb F (2-20%), Hgb A 0%
• solubility testing
• sickle cell disease genotyping
  • beta globin gene mutation
• urinalysis for microalbuminuria
• serum ferritin to assess iron status

Diagnostic procedures

• echocardiography to assess pulmonary hypertension

Radiology

• transcranial Doppler ultrasound annually for children 2-16 years of age
  • lifelong for patients with history of stroke

Complications

• vaso-occlusive painful crises, aplastic crises, hyperhemolytic crisis
  • may be due coexisting infection, especially parvovirus B19
  • number of painful crises is inversely related to life expectancy
• complications of transfusion
  • iron overload
  • transfusion reactions (alloimmunization)
    • delayed hemolytic transfusion reactions 5-10 days after RBC transfusion result in jaundice, fever, & worsening painful crisis
  • transfusion-associated infections
• ischemic stroke
  • exchange transfusion or hydroxyurea
  • IV alteplase can be helpful for adults
• bone marrow fat embolism
• pulmonary complications
  • acute chest syndrome with progressive respiratory failure
    • incentive spirometry in hospital to reduce risk
  • pneumonia
    • children: Streptococcus pneumonia is most common
    • adults:
      • Staphylococcus aureus & Haemophilus influenzae
      • majority of suspected pneumonias are due to pulmonary embolism
  • pulmonary embolism
  • pulmonary infarction
  • pulmonary hypertension
• renal complications (chronic renal failure)
  • impaired urine concentrating ability (hyposthenuria)
  • polyuria & nocturia
  • microscopic & gross hematuria
  • renal medullary ischemia resulting in infarction, necrosis, interstitial fibrosis & papillary necrosis
  • focal segmental glomerulosclerosis
  • nephrotic syndrome
• cardiac complications
  • cardiomyopathy
  • mitral regurgitation
  • cardiac arrhythmias
  • heart failure
• splenic sequestration*
• hepatobiliary
  • gallstones (pigmented) 70%, cholecystitis
  • choledocholithiasis
  • hepatic crisis
  • viral hepatitis
• visual
  • retinopathy
  • blindness
• skeletal (bone)
  • bone infarcts
  • avascular osteonecrosis
    • analgesics & physical therapy
  • oseomyelitis
  • osteopenia/osteoporosis
• skin (dermatologic) - ankle ulcers, foot ulcers
• increased susceptibility to bacterial infections due to autosplenectomy*
• priapism
• multiorgan failure

* hypersplenism & splenic sequestration may occur in children (> 5 years) prior to autosplenectomy from splenic infarction

Management

• vaso-occlusive crisis (painful crisis)
  • parenteral opioids for pain
    • therapeutic management of the pain is a frequent source of conflict between the physician & patient or patient's family
    • do not use meperidine for treatment of painful crisis
  • general management principles include:
    • hydration with 3-4 L of oral fluid/day
    • intravenous fluids for dehydration or acute illness
    • avoid iatrogenic fluid overload in patients with renal, cardiac or hepatic insufficiency
    • incentive spirometry to avoid acute chest syndrome
    • pregnant patients treated similarly to non-pregnant patients
  • agents used in combination with analgesics
    • antihistamines: diphenhydramine, hydroxyzine
    • tricyclic antidepressants
    • phenothiazines for nausea (ondansetron may be of benefit for nausea)
  • nitric oxide of no benefit
  • systemic glucocorticoids increase risk for hospitalization due to vaso-occlusive crisis 4-fold
• aggressive evaluation is required for:
  • fever > 38.5 C
  • severe abdominal pain
  • acute pulmonary complaints
  • acute neurological events
  • intractable pain unrelieved by oral medications
• analgesia for chronic pain:
  • non-steroidal anti-inflammatory agents (NSAIDs)
  • acetaminophen
  • relaxation, massage, biofeedback
  • P-selectin inhibitor crizanlizumab (2.5-5 mg/kg q4 weeks) can decrease frequency of sickle cell painful crises
  • glutamine can also reduce frequency of painful crises
• avascular necrosis
  • analgesics & physical therapy
• renal complications
  • ACE inhibitor for microalbuminuria
• ophthalmology referral for retinopathy
• other pharmceuticals
  • hydroxyurea
    • indications
      • > 2 painful crisis/year
      • acute chest syndrome
      • symptomatic anemia
      • pain or chronic anemia interfering with activities
      • not for ischemic stroke or prophylaxis for ischemic stroke - chronic exchange transfusions treatment of choice
    • contraindicated in renal failure & pregnancy
    • increases hemoglobin F
    • reduces frequency of acute chest syndrome, painful crises, hospitalizations, & blood transfusions
    • as effective as chronic transfusion therapy for preventingstroke
    • effective, but underused
    • improves mortality & decreases painful crisis
    • some patients may not respond favorably to hydroxyurea
  • glutamine powder (Endari)
    • FDA-approved for treatment of sickle cell disease
    • 0.3 g/kg BID alone or with hydroxyurea reduces number of painful crisis
  • voxelotor reduces polymerization of hemoglobin upon deoxygenation thus sickling of erythrocytes
  • folic acid can reduce need for transfusions
  • iron only for documented iron deficiency
    • deferasirox (Exjade) for iron overload
  • oxygen for all hypoxemic patients pO2 < 60-70 mm Hg
  • erythropoietin for severe anemia, low reticulocyte count & chronic renal failure especially when cross-match compatible blood is difficult to find
  • aliphatic butyrate salts increase hemoglobin F
  • prasugrel of no benefit
  • metformin use in patients with sickle cell disease & diabetes mellitus associated with fewer emergency deparment visits & fewer in-hospital adverse events
• blood transfusion/exchange transfusion
  • indications
    • ischemic stroke (erythrocyte exchange transfusion)
      • history of ischemic stroke, history of transient ischemic attack, acute stroke
      • monthly transfusions reduce risk of recurrent stroke in children
    • acute chest syndrome
    • surgery requiring anesthesia:
      • target blood hemoglobin = 10 g/dL
      • exchange tranfusion with target of 30% Hgb S exposes patient to more blood products than transfusion
    • reduces vaso-occlusive crisis
    • fat embolism
    • priapism
    • no role for routine RBC transfusion during pregnancy
  • contraindications
    • uncomplicated pregnancy
    • routine painful episodes
    • minor surgery not requiring anesthesia
    • asymptomatic anemia
  • RBC should be phenotypically matched whenever possible for
    • K antigen (Kell)
    • C antigen
    • E antigen
    • other antigens to which they have developed alloantibody
  • erythrocyte exchange
    • more effectively decreases hemoglobin S in blood than does packed RBC
    • goal: hemoglobin S < 30% of total hemoglobin
    • greater exposure to blood & higher risk of transfusion reaction than target blood hemoglobin = 10 g/dL
    • history of ischemic stroke, history of transient ischemic attack, acute stroke
• chelation therapy for iron overload
• prophylaxis
  • Pneumovax is indicated for all patients with Hemoglobin SS disease
  • penicillin prophylaxis for children <= 5 years of age
    • 125 mg PO BID < 3 years of age, then 250 mg PO QD
  • ACE inhibitor for microalbuminuria
• stem cell transplantation
  • allogeneic hematopoietic stem cell transplantation from HLA-matched sibling (without myeloablation) for severe sickle cell phenotype
  • indications:
    • overt stroke or abnormal transcranial Doppler
    • frequent pain with an inadequate response to standard therapies
    • recurrent acute chest syndrome
  • for patients without a matched sibling donor, transplant from an alternative donor is suggested
  • immunosuppression can be discontinued after 1 year in many patients
• gene therapy
  • antisickling beta-globin variant inserted into a lentivirus vector & transduced into bone marrow-enriched CD34+ cells followed by bone marrow ablation with busulfan & stem cell transplantation

More general terms

• hemoglobinopathy
• hemolytic anemia

More specific terms

• sickle cell disease during pregnancy

Additional terms

• acute sickle cell chest syndrome; chest crisis; pulmonary sickle crisis
• hemoglobin S
• hemoglobin S/beta thalassemia +
• hemoglobin S/beta thalassemia 0
• hemoglobin SC disease
• sickle cell
• sickle cell trait; hemoglobin S trait
• sickle cell vaso-occlusive crisis

Patient information

sickle cell disease patient information