Splenic Sequestration Crisis

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](A1)

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]