Continuing Education Activity

Young children with sickle cell anemia are at risk for acute splenic sequestration crises. These occur when an excessive amount of blood becomes trapped in the spleen, causing a dangerous drop in the circulating blood volume. This activity outlines the etiology, evaluation, and management of acute splenic sequestration crises and highlights the role of the interprofessional team in managing patients with this condition.

Objectives:

• Identify the etiology and epidemiology of splenic sequestration crises.
• Describe the appropriate history and physical examination of a patient with a splenic sequestration crisis.
• Summarize the appropriate treatment options available for a patient with a splenic sequestration crisis.
• Review interprofessional team strategies for improving care coordination and outcomes for patients with splenic sequestration crises.

Introduction

Splenic sequestration is a feared complication of sickle cell anemia that primarily affects young children. It is an acute drop in hemoglobin of 2 g/dL accompanied by splenomegaly. The spleen is at particular risk for complications from sickle cell anemia due to its role as a filter of the blood. The spleen is composed of three areas; white pulp, red pulp, and a transitional zone, and each plays a role in the immune system. A minority of blood flow entering the spleen (approximately 10%) is directed outside of the vessels into the parenchyma of the red pulp, where the red blood cells (RBCs) become exposed to reticuloendothelial cells such as macrophages which clear away abnormal cells or other pathogens.[1] To re-enter the vascular system, the RBCs must squeeze through narrow slits in the endothelium of the venous sinuses. The organization of the white pulp of the spleen is predominantly T-cell periarteriolar sheaths and follicles, consisting of B cells. These B cells are critical in the production of IgM antibodies capable of opsonizing encapsulated bacteria such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenza type B. Among children with sickle cell anemia, the spleen gradually loses function and size over the first five years of life due to repeated episodes of autoinfarction and scarring.[2] Children with less severe variants of sickle cell disease such as hemoglobin SC disease or sickle cell-beta thalassemia may have preserved some splenic function into adulthood, and studies have shown that treatment with hydroxyurea can preserve and even result in some recovery of splenic function.[2]

Etiology

Adult type hemoglobin, the oxygen-carrying molecule contained within RBCs, consists of two alpha and two beta-globin chains. Mutations in the structure of the beta-globin can result in abnormal polymerization and aggregation of the beta-globin chains when they are in a deoxygenated state, rendering the RBC stiff and deformed into a sickled shape.[3] Sickle cell disease refers to a group of disorders in which both globin chains are abnormal, and at least one has the sickling mutation, while sickle cell anemia refers to those who are homozygous for the sickle cell mutation. In utero, fetal hemoglobin is produced, which has a higher affinity for oxygen and does not contain a beta-globin chain. Over the first few months of life, the infant’s predominant hemoglobin transitions into adult-type hemoglobin, and the downstream effects of the mutated beta-globin chain begin to develop. The classic manifestation of sickle cell disease is vaso-occlusive events that occur in the small capillary beds, leading to sequelae such as pain crises, stroke, and acute chest syndrome. Within the spleen, the blood, which is directed to the red pulp flows slowly in a concentrated state as it becomes exposed to the reticuloendothelial cells of the immune system.[4] This situation promotes a deoxygenated state within the RBC that leads to polymerization and aggregate formation of deoxygenated beta-globin. These RBCs, now sickled, are unable to pass through the small endothelial slits of the venous sinuses and rejoin the intravascular system.[1][5] Typically these events self-resolve or lead to isolated areas of congestion and fibrosis, which, over time, contribute to the autoinfarction of the spleen. However, in some cases, the obstruction may spread, causing the spleen to rapidly fill with RBCs which cannot flow out. A large percentage of the body’s blood volume may become acutely trapped within the spleen, leading to a sequestration crisis.

Epidemiology

Splenic sequestration crises are one of the first serious manifestations of sickle cell anemia and typically occur from age six months to 5 years, after which the spleen has typically undergone autoinfarction. However, a case series of acute sequestration events in adults demonstrated continued risk for those with variant hemoglobinopathies such as HbSC disease and sickle cell beta-thalassemia.[6] Reports exist of splenic sequestration as a presenting complaint in up to 20% of patients with sickle cell disease.[7]

The median age of children with sequestration crises is 1.4 years, with 75% of episodes occurring before age 2.[1] Due to the variation in mutations among children with sickle cell disease within a particular geographic region, prevalence estimates are difficult to quantify, but reports are between 7 to 30%.[8] Recurrence rates among children with one sequestration crisis are 50% to 78% and are higher among those who have their first event before age 1.[9]

Pathophysiology

Splenic sequestration crises are thought to occur when an area of sickled cells within the red pulp of the spleen obstructs a larger draining vein.[1] This mechanical obstruction quickly propagates as more RBCs sickle in response to sluggish flow and low oxygen tension. As more RBCs become trapped in the spleen, the hemoglobin level drops quickly, and the spleen rapidly enlarges. It is unclear what causes these small occlusive events to spread quickly rather than self-resolve, though studies have suggested an association between sequestration crises, infection, and vaso-occlusive pain events.[9][8]

Histopathology

Children with sickle cell disease have a disordered architecture of the white pulp of the spleen characterized by reduced and indistinct follicles and varying levels of fibrosis and RBC congestion within the red pulp.[10]

History and Physical

Splenic sequestration crises characteristically demonstrate the abrupt onset of pallor, weakness, and tachycardia.[11] Young children with sickle cell disease frequently have baseline splenomegaly of 1 to 2 cm below the left costal margin but with a sequestration crisis typically present with a dramatic splenic enlargement beyond their baseline splenomegaly. Massive splenomegaly can lead to significant abdominal pain and distention. In a large case series, half of the sequestration crises showed correlations with hemodynamic instability upon initial presentation.[9]

Evaluation

The diagnosis of an acute splenic sequestration crisis is primarily clinical and can usually be accomplished by a careful history and focused physical exam.[1] The severity of the anemia should undergo an assessment with a complete blood count with differential, and a reticulocyte count is necessary to rule out other causes of acute anemia such as an aplastic crisis. Imaging of the spleen is generally not needed for diagnosis provided splenomegaly can be appreciated on exam. Ultrasound imaging of the spleen can be considered but is often limited by patient discomfort. A contrasted computed tomography (CT) of the abdomen is also an option if the diagnosis is in question.[12]

Treatment / Management

Immediate management of acute splenic sequestration episodes consists of restoring the circulating blood volume, typically accomplished by the transfusion of RBCs, which improves the hemoglobin level directly and promote the release of trapped RBCs by the spleen. The usual recommended dose for transfusion is 5-10 ml/kg. Initial transfusions should target a post-transfusional hematocrit of less than 35%. This is to avoid complications from excessive RBC release and subsequent hyperviscosity syndrome.[1] The lower border of the spleen can be marked on the belly for follow-up. In the majority of cases, spleen size starts decreasing within 6 to 12 hours.  Multiple transfusions might be required. Care should be taken to avoid increasing hb > 100-110g/l[13]. IV fluids may also be given unless the underlying anemia is too severe. Long-term management to prevent the recurrence of sequestration events is controversial as most children will undergo autosplenectomy by age five and no longer be at risk.[14] Splenectomy is effective at preventing recurrent sequestration events but does place the child at greater risk for infectious complications.[15] For this reason, partial splenectomy has been a proposed means of preserving some immune function while still reducing the risk of recurrent sequestration.[16] Scheduled transfusion therapy until the spleen autoinfarcts can also be used to reduce the proportion of sickled cells in the body and raise the baseline hemoglobin but carries with it the risk of iron overload and alloimmunization.[3] Expectant management without transfusion is another viable option for some families, as demonstrated in a comprehensive case review.[2]

Differential Diagnosis

An acute aplastic crisis may present with sudden onset pallor, fatigue, and anemia but is typically associated with a low reticulocyte count and lack of splenomegaly.[17] Hypersplenism is a more chronic condition characterized by increased splenic phagocytic activity, which leads to splenomegaly along with anemia, leukopenia, and thrombocytopenia. There are no known triggers for hypersplenism, but it can occur after an acute sequestration event.[1] Other etiologies of acute abdominal pain, such as a vaso-occlusive pain crisis, pancreatitis, and pyelonephritis, should be considered among children with sickle cell disease.

Prognosis

Although historically splenic sequestration was the second leading cause of death among young children with sickle cell anemia, mortality rates have dropped dramatically over the past forty years.[14] Initial research from the 1980s described mortality rates from 12% to 44%; more recent case studies report mortality from acute splenic sequestration as less than 1%.[11][2][18][8]

Complications

Acutely, children with a sequestration crisis are at risk for severe anemia and cardiovascular collapse. Many of the long-term complications of acute splenic sequestration crises arise from efforts to prevent its recurrence. The spleen plays an important role in optimizing antibody production against encapsulated organisms such as Streptococcus pneumoniae, and children who undergo splenectomy have lower circulating IgM levels and are at increased risk of sepsis from encapsulated bacteria.[19][4][14] Despite the decrease in invasive bacterial infections that occurred after widespread vaccination against streptococcal pneumoniae and Hemophilus influenza type b, asplenic children, particularly those younger than age 5, have an increased risk of bacteremia.[1] Chronic RBC transfusion therapy increases the risk of alloimmunization, which makes finding future suitable blood donors difficult. Excessive iron deposition from repeated RBC transfusions is manageable with concomitant chelation therapy, but the long-term effects of chronic chelation therapy are unknown.[3]  

Postoperative and Rehabilitation Care

Daily penicillin prophylaxis is the recommended intervention for all children with sickle cell anemia starting at two months of age, and children who undergo splenectomy to prevent future sequestration crises must be maintained on this antibiotic to lessen their risk of sepsis from encapsulated organisms. Asplenic children must also receive the pneumococcal conjugate vaccine series as well as the Hemophilus influenzae type b series and a yearly influenza vaccine.

Deterrence and Patient Education

The use of hydroxyurea, a medication that stimulates the production of non-sickling fetal hemoglobin, has resulted in a marked reduction in the number of vaso-occlusive events among young children with sickle cell anemia. However, it has not demonstrated a reduction in the risk of splenic sequestration crises, and primary prevention remains an unresolved goal.[20] However, widespread neonatal screening for hemoglobinopathies has given parents and physicians the ability to prepare for the early complications of sickle cell disease. Parents should learn to perform daily spleen checks in which they palpate the left upper quadrant of the abdomen; if parents are concerned that the spleen has increased significantly in size, they should promptly seek evaluation by their primary care physician or hematologist. Parents also need to monitor their child for the development of symptoms such as sudden pallor, abdominal pain, and fatigue, which would raise suspicion of a sequestration crisis.

Pearls and Other Issues

Splenic sequestration crises are medical emergencies that must be diagnosed and managed promptly to prevent hemodynamic collapse. Children with sickle cell anemia are most at risk before age 5, after which the spleen is rendered minimally functional through the process of autoinfarction. Sequestration events are primarily a clinical diagnosis when an acute enlargement of the spleen accompanies signs of anemia such as pallor, fatigue, and tachycardia. The evaluation consists of a careful physical exam and a CBC to assess the degree of anemia. Emergent management should focus on the restoration of circulating blood volume and is typically accomplished through the use of RBC transfusions. Long-term prevention of recurrent sequestration events is controversial and may involve watchful waiting, chronic transfusion therapy, or splenectomy.

Enhancing Healthcare Team Outcomes

Sickle cell disease affects nearly every organ system, and the management of patients with this condition depends on effective interprofessional communication. Splenic sequestration crises are managed primarily in the emergency department setting. However, many children may first present to their primary care provider who must be able to recognize this potentially fatal condition quickly. The emergency department must have nursing protocols in place to promptly triage and evaluate children with sickle cell disease. After triage and initial evaluation are complete, emergency physicians should communicate closely with the patient's primary hematologist, who can provide consultation and assist with the coordination of care. In the case of sequestration crises, the blood bank staff must be available to type and crossmatch blood for transfusion if necessary quickly. Long-term management of children with splenic sequestration crises may include splenectomy, which would require consultation from a surgeon as well as the child's primary hematologist. Overall care coordination for children with sickle cell disease is complex and should be led by the child's primary hematologist in conjunction with their primary care provider. Nursing will assist the team by providing ongoing monitoring, and assist in the event of surgical intervention, counseling parents, and assessing compliance. With interprofessional collaboration, children with splenic sequestration can achieve optimal outcomes. [Level 5]