Sickle Cell Disease & Acute Pain Crises

Sickle Cell Anemia (SCA): review of the pathophysiology

Hg S: substitution of valine for glutamic acid in the 6th amino acid of the beta globin chainàhemoglobin tetramer (alpha2/beta S2), which is poorly soluble when deoxygenated
Polymerization of deoxyhemoglobin S takes an elongated rope-like formation, which distorts the RBCs into crescent or “sickle” shapes, and decreases the RBC deformability
Polymerization is affected by the presence of other hemoglobin mutations (ie. HgSC disease or Sickle-Beta Thal etc.) and concentration of fetal hemoglobin
Hb F percentage accounts for much of the clinical heterogeneity in patients with sickle cell anemia, normal adults levels are <1%, levels of 10 to 20% can significantly decrease clinical severity
In addition to polymerization of HgS, the pathophysiology of sickle cell disease is also affected by chances in the RBC membrane, cell volume and increased adherence to the vascular endothelium
Sickle cell disease (SCD) refers to all the conditions associated with sickling (ie. includes Hg SC disease or sickle cell trait), whereas sickle cell anemia refers to homozygosity for Hg S

Laboratory findings in SCA:

chronic hemolysis causes: mild mod anemia (Hct 20-30); reticulocytosis (3-15%), which can also cause a high/nl MCV and high RDW; unconjugated hyperbilirubinemia; elevated LDH; low serum haptoglobin
peripheral smear: sickled red cells, polychromasia, Howell-Jolly bodies (reflects hyposplenism from repeated splenic infarcts)
rbcs are usually normochromic unless there is a concomitant thalassemia or iron deficiency
iron deficiency is present in approx 20% of pts with SCD, but this can be obscured by an elevated serum iron in the setting of chronic hemolysis, but low ferritin and transferin levels (also often not detected b/c of high MCV)
anemia can also result from low epo (often w/ CRI) and low folate (increased folate utilization)
level of hemoglobin F is often slight elevated, and there is no Hemoglobin A

Major Complications from Sickle Cell Anemia: Generally can be thought of in two categories--vaso-occlusive phenomena and hemolysis

splenic sequestration crisis: vaso-occlusive events within the spleen (pooling of RBCs in spleen), risk is in pts who have not yet undergone splenic fibrosis from recurrent splenic infarcts. Can be fatal if transfusions are not given early; recommendation is for splenectomy after first acute event
aplastic crisis: transient arrest of erythropoiesis, leading to a decrease in the retic count. Most commonly w/ parvovirus B19 infection, also w/ strep pneumo, salmonella and EBV
hyperhemolytic crisis: increased destruction, associated w/ a high retic count. Etiology is unclear, but can be associated with multiple transfusions.

most common vaso-occlusive event, can occur in any body part, but especially in the back/chest and extremities
more frequent episodes are associated with higher mortality
frequency correlates with high hemoglobin levels (>8.5g/dl is a risk factor) and low fetal hemoglobin levels
Can be triggered by infection, stress, dehydration, etc., but often there is no identifiable cause
Clinical signs can include fever, TTP, swelling, tachycardia, HTN, n/v
Generally last from 2-7 days

Generally with encapsulated organisms (strep pneumo, HIB etc.) due to functional asplenia
Atypical pneumonia (chlamydia, mycoplasma)
Gram neg bacteremia (esp in children)
Osteomyelitis (difficult to distinguish from vaso-occlusive dz)

Cerebrovascular events: TIA, ischemic or hemorrhagic CVAs; more likely with low hemoglobin levels (there is a role for prophylactic transfusion in children at high risk—identified by transcranial doppler)
Bone complications:

accelerated hematopoiesis (painful expansile lesions)
bone infarction--AVN can occur with equal frequency (as Bimpe pointed out) in the humoral and femoral heads, but progressive deformity requiring joint replacement is more common in the hip due to weight bearing
pulmonary fat emboli (from osteonecrosis)
chronic hemolysis can also causes bossing of the forehead and fish-mouth deformity of the vertebrae)

Acute chest syndrome
Chronic interstitial fibrosis (often related to recurrent acute chest synd)
Mild hypoxemia (avg O2 sats 93-95%)
Pulmonary HTN (most associated with chronic hemolysis, but can also be 2/2 chronic embolic phenomena and interstitial lung disease)—see link to review article

Renal complications: primarily due to chronic occlusion of the vasa-recta capillaries in the renal medulla . Can develop hematuria, proteinuria, HTN, FSGS
CV complications: MI in the absence of CAD, due to microvascular damage and increased oxygen demands
Pripapism
Liver/GB complications: pigment stonesàcholelithiasis, iron-overload syndromes
Dermatologic (mostly leg ulcers)
Retinopathy

Treatment of Acute Pain Crises:

Mostly includes pain control and hydration (maintaining euvolemia)
Can be managed in the outpatient setting in some circumstances
Exchange transfusion (as we discussed in this case) is not a standard therapy for acute pain episodes, but can be considered when pain is refractory to other treatment modalities
Exchange transfusion involves “bleeding” the patient and replacing with an equal volume of isotonic fluids and donor RBCs to decrease % of HgS (ideally <30%). There is data to support the use of exchange transfusion to improve mortality in acute chest syndrome and sometimes perioperatively (esp cardiac surgery)
hydroxyurea is the only agent that has been shown to decrease mortality and frequency of pain crises in SC anemia is (primarily by increasing production of Hg F, thereby decreasing viscosity and vaso-occlusive events; also increases NO, which can help mediate the relative decrease in NO as free hemoglobin binds to it in chronic hemolysis)
See link to article on management of acute pain crises

(Victoria Kelly MD, 10/1/10)