“Sickle Cell Disease in the Emergency Department: Atypical Complications and Management”

Abstract

Sickle cell disease is the most common inherited blood disorder in the United States. This disorder of hemoglobin structure leads to a chronic hemolytic anemia and complex chronic disease manifested by sudden, severe, and life-threatening complications. These acute complications can occur in any organ system beginning in early childhood and lasting throughout life. The intermittent nature and acuity of these complications lend the emergency department to be an important site of care. The hallmark of sickle cell disease is the vasoocclusive painful event. Other more “typical” complications include fever, acute chest syndrome, priapism, and ischemic stroke. Children with sickle cell disease can also present with other “atypical” complications that can have devastating consequences if they are unrecognized. Detailed discussion of these “atypical” sickle cell disease complications, organized by organ system involved, will be the focus of this article.

Sickle Cell Disease (SCD) is the most common inherited blood disorder in the United States affecting about 89,000 Americans or 1 in 400 African Americans.(1) SCD is caused by inheritance of the sickle β globin gene, either in the homozygous form (hemoglobin SS) or in combination with hemoglobin C (hemoglobin SC), β-thalassemia (hemoglobin Sβ-thalassemia) or several less common hemoglobin variants.(2) This disorder of hemoglobin structure leads to a complex disease in which patients have a chronic hemolytic anemia and can suffer from sudden, severe, and life-threatening complications caused by the acute sickling of red cells with resultant pain or organ dysfunction. Repetitive sickling events can result in irreversible organ damage. Thus, SCD is a chronic multi-organ system debilitating disease with complications beginning in early childhood and lasting throughout life. Currently, all 50 states in the United States screen every newborn infant for a hemoglobinopathy on the newborn screen allowing the diagnosis of a sickle cell disorder to be readily made at birth in most cases. (3)

Currently, the only cure for SCD is bone marrow transplantation; however, this is limited by the need for a human leukocyte antigen (HLA) matched sibling donor and treatment-related toxicity.(4) A current clinical trial is evaluating the role of unrelated bone marrow transplantation or alternative donors for children with SCD.(5) Preventative measures for SCD-related complications include chronic red blood cell transfusions and hydroxyurea. Although effective, regular transfusions may be associated with development of iron overload. Hydroxyurea, an oral drug taken once daily, decreases vaso-occlusive painful events and acute chest syndrome and is safe for use in children.(6–10)

Emergency Department Utilization by Patients with Sickle Cell Disease

The intermittent nature and acuity of SCD complications lend the emergency department (ED) to be an important site of acute care for patients with SCD. In a recent study, Brousseau et al. described acute care utilization for patients with SCD based on an analysis of the Healthcare Cost and Utilization Project State Inpatient Databases and State ED Databases.(11) ED visits among patients with SCD in eight states over a two year period totaled 97,578, of which 52,107 required hospitalization and the remainder were “treat-and-release” visits. The acute care utilization rates varied by age with the highest rate, 3.61 encounters per patient per year, in the 18–30 year old age group. Children and adolescents in the 10–17 year old age group had 2.04 encounters per patient per year. Rates of return to acute care were also high with almost 40% of hospital discharges for patients with SCD resulting in a return visit for acute care within 30 days of discharge and a quarter of discharges resulting in a return visit within 14 days.(11) These data affirm that the ED is likely the initial point of entry for many patients with SCD presenting with both typical and atypical complications, making recognition and treatment of these complications in the ED vital.

Acute Complications of SCD Presenting to the Emergency Department

Since SCD is a multi-organ system disease, any organ system can theoretically become involved. The hallmark of SCD is the vaso-occlusive painful event, which is the leading cause of ED visits and hospitalizations for children with SCD and is associated with mortality in adults.(11–13) Sickle cell pain may involve any part of the body, the onset is often unpredictable and the severity, location, and duration of the pain vary among patients. In addition, objective signs of pain on physical examination are usually absent. In a subset of patients with SCD, acute pain can be superimposed on chronic pain. In addition to pain, patients may present to the ED with other more typical SCD-related complications, including fever, acute chest syndrome, priapism, and ischemic stroke. Other less common or “atypical” complications can occur that providers in the ED should be familiar with. A summary of “typical” and “atypical” SCD complications organized by organ system is displayed in Table 1. A detailed discussion of the “atypical” SCD complications will be the focus of the remainder of this review.

Table 1.

Typical and atypical acute complications of sickle

Organ System Involved	Typical Complication	Atypical Complication
Eyes	Proliferative retinopathy	Orbital wall infarction
		Orbital compression syndrome
		Central retinal artery occlusion
Central nervous system	Ischemic stroke	Subarachnoid hemorrhage
		Cerebral aneurysms
Pulmonary	Acute chest syndrome	Pulmonary embolism
	Asthma
Abdominal	Vaso-occlusive abdominal pain	Splenic sequestration
		Splenic infarct
		Acute cholecystitis
		Acute hepatic crisis (sickle cell hepatopathy)
		Hepatic sequestration
Hematologic	Hyperhemolysis	Delayed hemolytic transfusion reaction
		Aplastic crisis

cell disease presenting in the emergency department.

Ophthalmologic Emergencies

Orbital Wall Infarction and Orbital Compression Syndrome

Case Presentation

A 3-year-old female with hemoglobin SS disease presented to the ED with a 2-day history of extremity pain. On exam she was noted to have periorbital edema with normal visual acuity and no fevers or eye pain. Her periorbital swelling was initially thought to be due to an allergy. Due to the extent of the swelling, however, computerized tomography (CT) imaging of the orbits was obtained, which revealed bilateral periorbital soft tissue edema and two intraorbital lesions associated with subperiosteal fluid collection: one in the inferolateral aspect of the left orbit and another in the superolateral aspect of the right orbit displacing the lateral rectus muscle inferomedially (Figure 1). Bone windows were normal without deformity or bony involvement and the optic nerves were normal. Due to the CT findings and lack of infectious symptoms, a diagnosis of orbital wall infarction with associated hematomas was made.

Figure 1.

Orbital CT scan findings of a patient with orbital wall infarction revealing bilateral periorbital soft tissue edema and two intraorbital lesions: one in the inferolateral aspect of the left orbit with an associated subperiosteal fluid collection and one in the superolateral aspect of the right orbit displacing the lateral rectus muscle inferomedially with an associated subperiosteal fluid collection. The subperiosteal fluid collections are likely hematomas.

Discussion

Orbital wall infarction, caused by vaso-occlusion related infarction of the orbital bones, is an unusual complication of SCD due to the limited amount of marrow space in the facial bones.(14) This complication primarily presents in younger patients because developmentally, children have a greater amount of marrow space within their facial bones.(14) The clinical signs and symptoms include eye pain, periorbital and/or orbital edema, proptosis, visual acuity changes, fever, and headache. Bone and/or bone marrow infarction results in sterile inflammation and hemorrhage leading to subperiosteal hematomas.(14, 15) The inflammation may be severe enough to compromise structures in the orbit and in the most severe cases, may lead to optic nerve compression. Left untreated, this optic nerve compression may result in irreversible vision loss. The differential diagnosis includes periorbital or orbital cellulitis, orbital abscess or allergic reaction, especially if there is bilateral involvement.(14–18) The diagnosis of orbital wall infarction, which is bilateral in one-fourth of cases,(16) is made by CT or magnetic resonance imaging (MRI).(18) Treatment involves supportive measures with intravenous hydration and pain control as well as consultation with ophthalmology. If there is concern for true compression, steroids are given to decrease inflammation and the risk of irreversible vision loss.(14, 17) In the most severe cases, surgery may relieve compression from an associated orbital hematoma. Antibiotics should be given if there is a high index of suspicion for infection based on history, clinical and imaging findings.

Central Retinal Artery Occlusion

Case Presentation

A 14-year-old male with hemoglobin SS disease presented to the ED with vaso-occlusive pain requiring admission for pain control. While on the floor, he developed fever and an increase in his pain. He also developed hypotension during his first dose of parenteral antibiotics, after which he complained of blurry vision and headache. He was transferred to the pediatric intensive care unit for observation and further management, which included a simple transfusion. Although his blurry vision improved, he woke up several hours later with complete bilateral vision loss. He underwent emergent exchange transfusion after being diagnosed by ophthalmology with bilateral central retinal artery occlusion.

Discussion

Central retinal artery occlusion is a rare devastating cause of macular ischemia and acute vision loss in SCD, first described in the 1970s,(19–21) and occurring primarily in individuals with homozygous disease. The hallmark of the complication is sudden, painless loss of vision in one or both eyes, which may be permanent. In the general population, central retinal artery occlusion is seen in the setting of systemic vasculitis, ocular trauma, systemic coagulopathy or major surgery. Risk factors for its development in SCD, however, are not clear. Although vaso-occlusive pain episodes, infection and acute chest syndrome have all been described in separate cases to precede the development of retinal artery occlusion in individuals with SCD, the lack of preceding symptoms or concomitant complications is equally common.(22) Acute thrombus formation or embolization is presumed to be the pathophysiologic process responsible for central retinal artery occlusion. In SCD, the eye may be especially susceptible to vaso-occlusion since the retinal vasculature is small in caliber and prone to low oxygen tension, which may increase red blood cell sickling. Sudden hypotension and decreases in intravascular volume, which also increase sickling, may be especially pertinent in SCD.(23) The optimal treatment of retinal artery occlusion in SCD, including the role of simple or exchange transfusion, is not known. Early consultation with ophthalmology, however, is essential. General strategies should aim to optimize retinal oxygen delivery, increase blood flow and prevent further ischemia. Interventions to reduce ocular pressure as well as hyperbaric oxygen or thrombolytic therapy are unproven. Prognosis overall is grim in the general and sickle cell population,(22) in which the majority of affected individuals will have no or only partial recovery of vision.

Central Nervous System Emergencies

Subarachnoid Hemorrhage

Case Presentation

A 16-year-old male with hemoglobin SS disease presented to the ED with complaints of severe headache and vomiting. While being evaluated in the ED, he became confused, delirious, and combative. His heart rate dropped to 56 beats per minutes and his blood pressure increased to 147/87 mmHg. CT of the head revealed a large subarachnoid hemorrhage (Figure 2). Subsequent imaging with a cerebral angiogram revealed multiple large cerebral aneurysms (Figure 3). His clinical course progressed and he was declared brain dead 5 days after admission.

Figure 2.

Head CT findings of a patient with hemoglobin SS disease depicting acute subarachnoid hemorrhages.

Figure 3.

Cerebral angiogram depicting multiple cerebral aneurysms from a patient with hemoglobin SS disease who suffered a subarachnoid hemorrhage.

Discussion

Although ischemic strokes comprise the vast majority of cerebrovascular events in children with SCD, other complications of the central nervous system should be considered in the child with SCD who presents with neurologic complaints. Children with SCD are at increased risk of developing cerebral aneurysms, which may rupture and result in subarachnoid hemorrhage. The signs and symptoms of subarachnoid hemorrhage are no different from that seen in the general population and include sudden severe headache, focal headache with progression, nausea, vomiting, symptoms of meningeal irritation, photophobia, visual changes, behavior changes, or loss of consciousness.(24) Several differences in presentation, however, exist between sickle cell patients and the general population with cerebral aneurysms and subarachnoid hemorrhage. In SCD, subarachnoid hemorrhage occurs in younger patients, with a mean age of 25–30 years, compared to the general population, in which only 10% occurs in patients less than 35 years.(25–28) Patients with SCD more commonly present with multiple aneurysms compared to what is observed in the general population.(26, 27) In addition, aneurysms in SCD have a higher predilection for both the posterior circulation and the vertebrobasilar location when compared to the general population.(26) The cause of cerebral aneurysms in SCD is not entirely known; however, it is thought to be the result of chronic endothelial damage and subsequent development of vasculopathy.(26–28) Cerebral aneurysms and subarachnoid hemorrhage are more commonly seen in patients with hemoglobin SS disease,(28) and may have a female predominance.(26) Management of sickle cell patients presenting with subarachnoid hemorrhage does not differ from that recommended for the general population. Prompt consideration and recognition of subarachnoid hemorrhage in any patient with SCD presenting to the ED with a severe headache is critical. If neurosurgical intervention is required, a simple transfusion of packed red blood cells should be given to minimize the risks of anesthesia.

Pulmonary Emergencies

Pulmonary Embolism

Case Presentation

A 15-year-old female with hemoglobin SS disease presented to the ED with a 2 day history of worsening right sided chest pain not responding to oral narcotics and shortness of breath. Upon initial evaluation, she was noted to be hypoxic with pulse oximetry of 85% on room air, respiratory rate of 35 breaths per minute, and heart rate of 130 beats per minute. She did not have fever. Exam revealed significantly decreased breath sounds at the right base and reproducible right-sided pleuritic chest pain. Her chest X-ray was normal. Due to her clinical presentation and normal chest X-ray, a helical CT of her chest was obtained that revealed a large pulmonary embolism in the right pulmonary artery.

Discussion

SCD is associated with multiple perturbations in the hemostatic system that collectively result in a hypercoagulable state.(29, 30) Present at baseline, this hypercoagulable state may worsen during acute sickle-cell related complications(30) and put a patient at a higher risk of developing thromboembolism, including deep venous thrombosis and pulmonary embolism. To date, there are no comprehensive studies assessing the incidence and prevalence of this complication in SCD. Much of the data have come from autopsies of patients who have died from fatal embolisms.(31, 32) In the National Discharge Hospital Survey administrative dataset, the proportion of patients with a discharge diagnosis of SCD and pulmonary embolism was 0.44%, compared to 0.12% in African Americans with a diagnosis of pulmonary embolism without SCD.(33) The mean age of patients with SCD and pulmonary embolism in this study was 28 years.(33) A case series of autopsies of patients with SCD who suffered sudden death found 38.1% of patients had evidence of pulmonary embolism.(31) Given the lack of data regarding the utility of prophylactic anticoagulation in SCD, anticoagulation has not been adopted as standard practice in this population. Differentiating pulmonary embolism from acute chest syndrome in a patient with SCD requires a high index of suspicion by providers in the ED in order to make a correct diagnosis. Reasons to consider a helical chest CT in a sickle cell patient with hypoxia, chest pain, and respiratory distress might include lack of fever and a normal chest X-ray. The diagnosis of acute chest syndrome requires the presence of a pulmonary infiltrate on chest X-ray, without which other etiologies for the patient's symptoms should be investigated. Treatment of pulmonary embolism in SCD is not different than that in other patients and should involve emergent anticoagulation with heparin (low molecular weight or unfractionated heparin). Thrombolytic therapy is reserved for patients with hemodynamic compromise.(34)

Abdominal Emergencies

Abdominal pain is not an unusual complaint for children with SCD. Patients with SCD may develop vaso-occlusive abdominal pain or vaso-occlusive events within the organs of the abdomen. These events may present with acute pain that is indistinguishable from other causes of an acute abdomen. However, the differential diagnosis of abdominal pain in a patient with SCD, when compared to that in the general pediatric population, should be expanded to include specific SCD-related abdominal pathology.

Splenic Sequestration

Case Presentation

A 10-month-old male with hemoglobin SS disease presented to the ED with a 1 day history of fever, pallor, decreased activity, decreased oral intake and increased fussiness. His vital signs revealed a temperature of 39°C, heart rate of 170 beats per minute, respiratory rate of 40 breaths per minute, blood pressure of 90/40 mm Hg and pulse oximetry of 99% on room air. The physical exam revealed a listless infant with conjunctival and palmar pallor, tachycardia, abdominal distension, diffuse abdominal tenderness, a spleen palpable 7 cm below the left costal margin and cool extremities. Laboratory studies revealed a hemoglobin of 3.2 g/dL, reticuloctye count of 12%, white blood cell count of 12 ×10³/μL and platelet count of 100 ×10³/μL. The diagnosis of splenic sequestration was made based on the severe anemia, splenomegaly, reticulocytosis, and mild thrombocytopenia.

Discussion

Splenic sequestration is a life-threatening complication associated with a hyperacute fall in hemoglobin secondary to red blood cell sickling and pooling within the spleen. The hemoglobin may fall by half of its baseline value within a few hours of onset of the sequestration crisis. Infants manifest signs and symptoms of impending hypovolemic shock, while older patients may complain of diffuse or left sided abdominal pain. On exam, the spleen is moderately to markedly enlarged, often very tender and the reticulocyte count is usually elevated. Thrombocytopenia and leukopenia can also be seen in the setting of acute splenic sequestration and can aid in the diagnosis. Patients with acute sequestration crisis require an urgent simple packed red blood cell transfusion, and most will have rapid clinical improvement within a few hours. Care must be taken not to transfuse too much blood as subsequent release of pooled red cells from the spleen may result in hyperviscosity. If the patient is clinically unstable, uncrossmatched type O-negative blood should be given and may be life-saving in this circumstance. Recurrent episodes are common and may be addressed by splenectomy. Importantly, the risk of splenic sequestration varies by age and genotype of the patient. The majority of patients with hemoglobin SS disease are functionally asplenic by 12 months of age,(35) and have auto-infarcted their spleen by 6 years of age,(36) making sequestration less likely in older children. In contrast, patients with less severe sickle cell genotypes (hemoglobin SC, hemoglobin Sβ⁺-thalassemia) maintain some splenic function throughout life and thus may continue to be at risk for splenic sequestration. Less commonly, hepatic sequestration can occur and presents with right upper quadrant pain and hepatomegaly.(37) Laboratory findings are similar to that described for splenic sequestration but also include mild to moderate elevation of liver transaminases. Treatment is also similar and usually results in rapid resolution of the hepatomegaly and clinical symptoms.

Acute Splenic Infarct

Case Presentation

A 14-year-old male with hemoglobin SC disease presented to the ED with abdominal, back and leg pain. He has a history of chronic splenomegaly. His exam revealed a palpable spleen 5 cm below the left costal margin that was extremely tender to palpation and reproducible tenderness diffusely over his back and extremities. His laboratory studies revealed a hemoglobin of 11.7 g/dL (baseline is 14 g/dL) and platelet count of 63 ×10³/μL (baseline is 250 ×10³/μL). He was treated with intravenous morphine and his leg pain improved; however, due to the extreme and persistent left-sided tenderness and splenomegaly, an abdominal CT was obtained that revealed a large splenic infarct (Figure 4).

Figure 4.

Abdominal CT findings of a patient with hemoglobin SC disease who suffered an acute splenic infarct.

Discussion

Chronic damage to the spleen due to recurrent microinfarcts leaves children and adults with SCD functionally asplenic. However, patients with sickle cell genotypes other than hemoglobin SS disease can maintain some splenic function and thus are at risk for the development of larger splenic infarcts.(38) Rarely, large splenic infarcts have been reported in patients with hemoglobin SS disease.(39) Patients usually present with severe left upper quadrant pain, tender splenomegaly, fever, thrombocytopenia and worsening anemia.(38) A CT scan of the abdomen will reveal this diagnosis. Conservative management of a large acute splenic infarct includes intravenous fluids and pain control. Antibiotics may be required if a patient is febrile since large splenic infarcts are a nidus for infection and may result in development of a splenic abscess. Splenectomy may result in dramatic resolution of unremitting pain.(39–41)

Acute Cholecystitis

Case Presentation

A 13-year-old male with hemoglobin SS disease presented with a 3 day history of worsening abdominal pain and vomiting and a 1 day history of increased jaundice and fever. Pain was significantly worse on the day of presentation after a meal in a fast food restaurant. Although the pain was reported to be diffuse, it localized to the right upper quadrant on exam. Her exam was also significant for scleral icterus and a fever of 38.8°C. Laboratory studies revealed a hemoglobin of 7.9 g/dL, reticuloctye count of 10%, white blood cell count of 30 ×10³/μL, platelet count of 450 ×10³/μL, and bilirubin of 14.6 mg/dL (conjugated bilirubin of 3.2 mg/dL, unconjugated of 11.4 mg/dL). Abdominal ultrasound revealed calculi within the gallbladder, thickening and edema of the gallbladder wall, and sludge within the gallbladder lumen. A diagnosis of acute cholecystitis was made.

Discussion

Children and adults with SCD are at increased risk for development of bilirubin gallstones due to chronic hemolysis. The prevalence of cholelithiasis in SCD ranges from 26–58%.(42) Cholelithiasis, which appears to correlate with degree of hemolysis and occurs most commonly in hemoglobin SS disease, presents at a much younger age in individuals with SCD than in the general population. Bilirubin stones are more likely to migrate outside of the gallbladder due to their small size. Thus, it is not uncommon for patients with SCD to present with complicated cholecystitis, including choledocolithiasis or pancreatitis.(42) The presence of fever in an ill-appearing patient should raise suspicion for ascending cholangitis and the need to initiate empiric antibiotic therapy. Symptoms of cholecystitis in SCD do not differ from those in the general population and include abdominal pain, nausea, vomiting, worsening jaundice, and fever. Prompt recognition of the potential for cholecystitis in a patient presenting with these symptoms should be followed by evaluation with ultrasound. Surgical removal of the gallbladder is curative. If needed, prior to surgery, patients with SCD should be transfused to achieve a hemoglobin of at least 10 g/dL to minimize the risk of post-op complications.(43) Consultation with a hematologist for peri-operative care is recommended. Prophylactic cholecystectomy for patients with asymptomatic gallstones is not currently recommended in children with SCD.

Acute Hepatic Crisis (Sickle Cell Hepatopathy)

Case Presentation

A 4-year-old female with hemoglobin SS disease presented to the ED with a 2 day history of severe abdominal pain, fever, worsening jaundice and vomiting. Her vital signs revealed temperature of 39.8° C, pulse of 130 beats per minute, respiratory rate of 28 breaths, and blood pressure of 100/60 mm Hg. Upon examination she was noted have severe jaundice and hepatomegaly (8 cm below left costal margin) that was exquisitely tender. Laboratory studies revealed a total bilirubin of 40 mg/dL with conjugated bilirubin of 32 mg/dL, aspartate aminotransferase (AST) of 220 IU/L, alanine transaminase (ALT) of 175 IU/L, prothrombin time (PT) of 16.2 seconds, and partial thromboplastin time (PTT) of 50 seconds. Abdominal ultrasound revealed a normal gallbladder without stones, normal common bile duct, no biliary ductal dilation, and hepatomegaly with a homogenous liver. Based on extreme conjugated hyperbilirubinemia, tender hepatomegaly, transaminitis, liver synthetic dysfunction, and the absence of extrahepatic biliary obstruction, the diagnosis of acute hepatic crisis was made.

Discussion

Acute hepatic crisis, also known as sickle cell hepatopathy, is thought to be the result of acute intrasinusoidal sickling with subsequent obstruction and hepatocyte ischemia. This leads to an increase in liver transaminases and a conjugated hyperbilirubinemia.(37, 42, 44, 45) The complication occurs most commonly in patients with hemoglobin SS disease. Total bilirubin values in sickle cell hepatopathy usually range from 13–80 mg/dL, but values over 100 mg/dL have been reported.(44, 45) In a review of their own experience and the existing literature, Ahn et al. found that while some cases of sickle hepatopathy were associated with a milder, self-limited course, others resulted in fulminant liver failure, encephalopathy, hepato-renal syndrome and ultimately death.(45) Initial evaluation of a child with suspected acute hepatic crisis should include a complete blood count, liver profile (including fractionated bilirubin, AST, ALT, albumin), serologic testing for hepatitis A, B, and C, an abdominal ultrasound or CT, and a coagulation panel to evaluate for liver synthetic dysfunction. The diagnosis of acute hepatic crisis is made based upon the presence of severe hyperbilirubinemia unexplained by hemolysis, viral hepatitis or hepatic sequestration as well as tender hepatomegaly, elevated transaminases, and evidence of liver dysfunction. Extrahepatic obstruction (i.e. cholelithiasis, choledocolithiasis) also needs to be excluded. Treatment varies based on the severity of the process. A simple red blood cell transfusion and supportive care may be adequate for mild cases. In severe cases, red cell exchange transfusion may be required in addition to management aimed at addressing liver dysfunction.(37, 44, 45) Liver biopsy does not appear to aid in the diagnosis and can cause significant bleeding due to the degree of liver insufficiency.(46) Once a patient has suffered from an acute hepatic crisis, recurrences have been reported and subsequent death is not uncommon.(45)

Hematologic Emergencies

Delayed Hemolytic Transfusion Reaction

Case Presentation

A 14-year-old female with hemoglobin SS disease on chronic monthly transfusions for history of stroke was last transfused 7 days ago. She presents to the ED with a 2-day history of increasing jaundice, back pain, abdominal pain, fever, chills, and dark urine. Her exam reveals temperature of 39.6° C, heart rate of 140 beats per minute, respiratory rate of 25 breaths per minute, blood pressure of 100/60 mm Hg, prominent scleral icterus, conjunctival pallor, and reproducible back pain localized to her lower thoracic/lumbar region. Diagnostic studies revealed a hemoglobin of 4.6 g/dL, reticuloctye count of 22%, unconjugated bilirubin of 10.4 mg/dL, lactate dehydrogenase (LDH) of 2545 IU/L, direct and indirect Coombs tests were positive, and urinalysis revealed large blood and bilirubin. The diagnosis of delayed hemolytic transfusion reaction (DHTR) was made.

Discussion

Although a DHTR presents similarly to an acute hemolytic transfusion reaction, the hemolysis associated with a DHTR occurs approximately 6–10 days after a packed red blood cell transfusion rather than immediately.(47–49) DHTRs have been reported in 4–11% of patients with SCD who have received a packed red blood cell transfusion.(49) Patients typically present with fever, jaundice, back pain, abdominal pain, leg pain, hemoglobinuria, and laboratory evidence of severe hemolysis including hyperbilirubinemia and elevated LDH.(47–49) Importantly, since the signs and symptoms of a DHTR can mimic an acute vaso-occlusive pain event, the history of a recent transfusion should be elicited from any child with SCD presenting to the ED with pain. A positive Coombs test is highly suggestive of a DHTR but may be negative in 50–75% of cases.(47–50) Severe hemolysis from a DHTR may rapidly progress to life-threatening anemia, hypovolemic shock and death if unrecognized as well as complications such as acute chest syndrome, renal failure and pancreatitis.(47, 48) The hemolysis is caused by red cell alloimmunization, which occurs in 5–36% of transfused patients with SCD and is defined by the development of red blood cell antibodies due to differences in minor red cell antigens between donor and recipient.(47–49) Increased exposure to red blood cell transfusions increases the risk of alloimmunization. Alloimmunized patients who experience DHTRs may have negative antibody screens at baseline due to low antibody titers. However, re-exposure to the responsible antigen during transfusion may result in an anamnestic response associated with an acute increase in alloantibody titer and subsequent hemolysis of donor cells.(47) Suppression of erythropoiesis can also occur and results in reticulocytopenia that further contributes to the anemia.(47–49) Treatment of a DHTR is directed at supportive care, decreasing the antibody production with steroids and/or intravenous immunoglobulin (IVIG) and promotion of red cell production with erythropoietin if there is evidence of reticulocytopenia.(47–49) Packed red blood cell transfusion should be avoided as this can cause life-threatening exacerbation of the hemolysis. In patients who have had a DHTR, future transfusions should be avoided and are reserved only for potential life-threatening SCD-related complications. Consideration for extended red cell phenotyping should also be given for these patients. The implementation of extensive red blood cell phenotyping for patients with SCD requiring transfusion has been shown to decrease the development of alloimmunization.(47, 51)

Aplastic Crisis

Case Presentation

A 3-year-old female with hemoglobin SS disease presented to the ED with a 2 day history of worsening fatigue, pallor, rash, and 1 day history of fever to 38.9° C. Her parents report she had been sleeping significantly more over the past 2 days and had not been eating or drinking. Vital signs revealed temperature of 39.1° C, heart rate 140 beats per minute, respiratory rate 24 breaths per minute, blood pressure 90/40 mmHg and pulse oximetry of 99% on room air. Physical examination revealed lethargy, conjunctival and palmar pallor, no scleral icterus, no evidence of splenomegaly, and a diffuse lacy rash on her arms, legs, and chest. Labs revealed a hemoglobin of 3.3 g/dL, reticuloctye count of <0.1%, white blood cell count of 17×10³/μL, and a platelet count of 250×10³/ μL. Based on these findings, a diagnosis of aplastic crisis was made, likely secondary to parvovirus B19 infection.

Discussion

Parvovirus B19 infects red cell precursors in the bone marrow and may induce transient red cell aplasia.(52) Since patients with SCD have shortened red cell survival, with an estimated red cell life span of approximately 10 days, the concomitant shut down of red cell synthesis in the marrow may result in a significant fall in hemoglobin and occasionally, hypovolemic shock in the most severe cases.(53) Affected children may present with gradual onset of pallor, fatigue, lethargy, and headache and occasionally with a “viral syndrome”. In general, spleen size and reticulocyte count may help to differentiate a sequestration crisis from an aplastic crisis. In sequestration crisis, the spleen is enlarged and reticulocyte count appropriately elevated, whereas in aplastic crisis, the spleen is unchanged in size and the reticulocyte count is low, often <0.1 %. Rarely, the presence of splenic enlargement with reticulocytopenia in the setting of severe anemia may suggest the simultaneous development of both complications.(54) Most affected patients will require a simple transfusion administered slowly with careful monitoring for the development of congestive heart failure. Appropriate isolation measures should be taken for patients with SCD and suspected aplastic crisis, especially in the presence of pregnant and immunocompromised caregivers.

Summary

The ED is the primary point of entry for the majority of children with SCD seeking treatment for acute disease related complications. Thus, ED clinicians are charged with the initial evaluation and management of both typical and atypical complications of SCD. As such, the index of suspicion of these complications needs to be high for physicians in the ED so that a comprehensive evaluation may be performed, the correct diagnosis made, and the most prudent management initiated. When available, hematology consultation is indicated to assist in the diagnosis and management of these complications.