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766 Part VI: The Erythrocyte Chapter 49: Disorders of Hemoglobin Structure: Sickle Cell Anemia and Related Abnormalities 767

127
TABLE 49–2. Pathophysiologic Mechanisms and Potential commonly in the liver. Splenic sequestration is typically seen in chil-
dren (younger than 5 years of age) prior to autoinfarction of the spleen,
Therapeutic Targets in Sickle Cell Disease
but can be seen in adults with HbSC disease or HbS–β-thalassemia with
Pathophysiology/ persisting splenomegaly. 128–130 A minor sequestration episode is usually
Complication Therapeutic Interventions accompanied by a Hb of more than 7 g/dL, and a major episode usually
Sickle hemoglobin (HbS) Fetal hemoglobin (HbF) is one in which the Hb is less than 7 g/dL or the Hb has decreased by 3
polymerization induction g/dL from baseline. 131
Cellular dehydration Gardos channel inhibition Acute splenic and hepatic sequestration crises can present with
rapidly enlarging spleen or liver, pain, hypoxemia, and hypovolemic
Potassium-chloride cotransport shock. Treatment consists of red cell transfusion. Transfusion carries
channel inhibition
the risk of hyperviscosity when the sequestration crisis resolves and
Adhesion to endothelium the sequestered red cells are returned to the general circulation. Splenic
Red blood cell Antiselectin sequestration crisis has a high rate of recurrence, especially in children.
Splenectomy to prevent recurrence is debated in very young children.
Antiintegrin Some report chronic red cell exchange transfusion as a means of delay-
White blood cell Antiselectin ing splenectomy until the child is older while others did not see any
Intravenous immunoglobulin benefit to this treatment. Patients younger than 2 years of age can be
placed on chronic transfusion until they are older, at which time sple-
Hydroxyurea (HU) nectomy should be considered. Splenectomy is recommended after the
Inflammation Nuclear factor-κB inhibition first episode of life-threatening splenic sequestration crisis or chronic
Immunomodulatory drugs hypersplenism. Partial splenectomy and emergency splenectomy during
a crisis is not recommended. Parental education is important for early
HU recognition of the problem so they can seek medical care promptly. 126
Statins Hyperhemolytic Crisis The term hyperhemolytic crisis is used
Nitric oxide (NO) scavenging NO donor (NO, HU, to describe the occurrence of episodes of accelerated rates of hemo-
tetrahydrobiopterin) lysis characterized by decreased blood Hb, increasing reticulocytes,
and other markers of hemolysis (hyperbilirubinemia, increased LDH).
Phosphodiesterase 5 inhibition Hyperhemolysis can occur during resolution of a VOE, at which time
Modulation of hemolysis irreversibly sickled and dense red cells are rapidly destroyed, as well as
Coagulation Tissue factor inhibition from an acute or delayed hemolytic transfusion reactions. 126,132
Antiplatelet therapy Pain Control
Anticoagulation Patients with SCD have acute pain, chronic pain, or both. As a symp-
Hyposplenism/infection Penicillin prophylaxis tom, pain is often underrated in its intensity and undertreated by care-
Ischemia–reperfusion Xanthine oxidase inhibition givers, especially inexperienced physicians. Patients are often perceived
as drug-seekers or drug addicts, when in fact less than 10 percent of
Myeloperoxidase inhibition patients are addicted, a number comparable to other disease states.
Iron overload Chelation Unsatisfactory relief of pain drives patients to behaviors that appear to
healthcare givers as signs of addiction—a state termed pseudoaddiction.
A study comparing sickle cell anemia patients who use the emergency
department frequently or infrequently found significant impairment in
The characterization of crisis phases has implications for clinical quality of life and increased markers of disease severity in those who
research, especially in pain management, wherein interventions early in use the emergency department frequently, dispelling the myth that
the course of a crisis could result in better outcomes for patients. frequent emergency department use indicates narcotic-addicted indi-
Aplastic Crises Aplastic crises in sickle cell anemia result when viduals when, in fact, they may have more severe disease. 3,133–137 The
there is a marked reduction in red cell production in the face of ongoing landmark Pain in Sickle Cell Epidemiology Study revealed that adult SCD
hemolysis, causing an acute, severe drop in Hb level. The characteristic patients have pain at home approximately 55 percent of the time, which
laboratory finding is a reticulocyte count less than 1 percent. The most contrasts sharply to pain studies in children, who report at-home pain
common causative agent is parvovirus B19, which attaches to the P anti- approximately 9 percent of the time. 138,139
gen receptor on erythroid progenitor cells, causing a temporary arrest in Acute pain is managed with opioids, nonsteroidal antiinflamma-
red cell production (Chap. 36). Recurrent aplastic crises by parvovirus tory drugs, acetaminophen, or a combination of these medications.
B19 are rare because of the development of protective antibodies. Other Immediate pain assessment and frequent reassessment with appropri-
rare complications associated with parvovirus B19 include acute splenic ate application of medications until pain relief is obtained is important.
and/or hepatic sequestration, acute chest syndrome, marrow necrosis, For adults and children weighing more than 50 kg, morphine can be
and renal dysfunction. Patients usually recover within 2 weeks; how- started at a dose of 0.1 to 0.15 mg/kg. The hydromorphone dose should
ever, those with severe symptomatic anemia need red cell transfusion. be 0.015 to 0.020 mg/kg intravenously. These are recommended doses
Siblings of SCD patients with parvovirus infections should be moni- for opioid-naïve patients and are at the lower end of the dosing range.
tored closely for aplastic crisis given high secondary attack rates (>50 123,140,141 The use of meperidine has declined because of neurologic side
percent). Patients need to be isolated from pregnant individuals given effects, especially in patients with renal failure, who are at risk for the
increased risk of hydrops fetalis with parvovirus B19 infection. 126 serotonin syndrome in conjunction with use of other medications. 142–144
Sequestration Crises This type of crisis is characterized by However, the use of morphine is not benign and concerns of increased
sudden, massive pooling of red cells, typically in the spleen and less association of acute chest syndrome, dysphoria, and neuroexcitatory

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