INTRODUCTION — Although relatively rare, hereditary spherocytosis (HS) is the most common cause of hemolytic anemia due to a red cell membrane defect. It is a result of heterogeneous alterations in one of five genes that encode red blood cell (RBC) membrane proteins involved in vertical associations that link the membrane cytoskeleton to the lipid bilayer.
The genetics, pathophysiology, clinical features, diagnosis, and treatment of HS will be reviewed here. Other inherited RBC membrane disorders, including hereditary elliptocytosis (HE), Southeast Asian ovalocytosis (SAO), hereditary pyropoikilocytosis (HPP), and hereditary stomatocytosis (HSt), are discussed separately, as are general approaches to the evaluation of hemolytic anemia.
●HE, HPP, and SAO – (See "Hereditary elliptocytosis and related disorders".)
●HSt – (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)
●Hemolytic anemia, child – (See "Overview of hemolytic anemias in children".)
●Hemolytic anemia, adult – (See "Diagnosis of hemolytic anemia in adults".)
PATHOPHYSIOLOGY — HS is a heterogeneous group of disorders caused by variants in certain genes that encode proteins of the red blood cell (RBC) membrane and cytoskeleton (figure 1); specifically, HS involves alterations in the vertical associations linking the RBC inner membrane skeleton to the outer lipid bilayer (figure 2). These defects impair the elastic deformability that is essential to the normal RBC lifespan, and they are responsible for the spherocytic (rather than biconcave disc) shape of HS RBCs. (See "Red blood cell membrane: Structure, organization, and dynamics".)
Genetics
Overview of gene variants — HS can be caused by variants in genes that encode the following RBC membrane/cytoskeletal proteins [1]:
●Spectrin – Erythrocyte spectrin is composed of alpha, beta heterodimers; the proteins are encoded by the SPTA1 and SPTB genes, respectively.
●Ankyrin – Erythrocyte ankyrin is encoded by the ANK1 gene.
●Band 3 (the anion exchanger AE1) – This anion channel is encoded by the solute carrier family 4 anion exchanger (SLC4A1) gene.
●Band 4.2 (previously called pallidin) – Band 4.2 is encoded by the EPB42 gene.
The relative frequencies of these mutations have been illustrated in surveys of affected individuals. Examples include the following:
●A 2008 study that evaluated 300 patients with HS using protein-based methods (SDS-PAGE on RBC ghosts) found that band 3 and spectrin deficiencies were most common (54 and 31 percent, respectively) [2]. Ankyrin or combined spectrin and ankyrin deficiencies were seen in 3 percent, band 4.2 deficiency was seen in 1 percent, and no abnormality was detected in 11 percent.
●A 1996 study that evaluated 166 independent HS families in Portugal using protein-based methods combined with single nucleotide polymorphism (SNP) analysis of band 3 found that spectrin deficiency or combined spectrin and ankyrin deficiency were most common (60 percent), followed by band 3 deficiency (23 percent) and band 4.2 deficiency (2 percent) [3]. No abnormality was detected in 15 percent.
●A 1996 study that evaluated 46 HS families using DNA-based methods (sequencing of coding and promoter regions) of ANK1 (gene for ankyrin) and SLC4A1 (gene for band 3) found mutations in ANK1 to be more common [4].
The reason for the different frequency of mutations in the cited studies is not completely clear, but several factors may be involved. These include population differences (eg, variants in EPB42 [gene for protein 4.2, also called "band 4.2" because of the location of the band on the SDS-PAGE gel] are largely found in individuals of Japanese ancestry) and different techniques of ascertainment (eg, protein- or DNA-based testing).
Variants affecting band 4.1, encoded by the EPB41 gene, have not been reported in HS, although they are known to cause hereditary elliptocytosis (HE). Variants affecting the Rh-associated glycoprotein, encoded by the RHAG gene, cause hereditary stomatocytosis. (See "Hereditary elliptocytosis and related disorders" and "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)
The studies that have evaluated specific gene variants have generally found that pathogenic variants in these genes tend to be distributed throughout the gene rather than localized to specific "hotspots"; this is illustrated in the figure (figure 1) [3-5].
Most (approximately three-fourths) of HS variants act in an autosomal dominant fashion (ie, a single variant allele is sufficient to confer disease). This includes variants in SPTB, ANK1, SLC4A1, and EPB42. However, autosomal recessive transmission also occurs, particularly with SPTA1 and EPB42 variants [6,7]. De novo mutations are often described, although the relative frequency has not been determined [8-13].
The roles of these variants in causing spherocytosis has been studied in several genetically engineered animal models (transgenic mice) and in naturally occurring variants in mice and cattle [14-18]. In the neonatal anemia (Nan) mouse, a variant in another gene that encodes the transcription factor KLF1 results in deficiencies of multiple membrane proteins (alpha spectrin, beta spectrin, ankyrin, band 3, and band 4.1) and clinical features of HS (spherocytic anemia), but variants in KLF1 have not been reported in patients with HS [19,20].
Additional information about the assembly of these proteins is presented separately. (See "Red blood cell membrane: Structure, organization, and dynamics", section on 'Composition of the membrane/cytoskeleton'.)
Ankyrin and spectrin deficiencies — Ankyrin is the major protein responsible for the mechanical coupling between the RBC plasma membrane and the underlying cytoskeleton. Spectrin is a flexible, rod-like protein that binds ankyrin (figure 2). Spectrin maintains the composition of other proteins and lipids in the RBC membrane, confers the biconcave disc shape of the cell, and allows RBCs to undergo reversible deformations without alterations in surface area as they traverse the microvasculature.
●When ankyrin deficiency is accompanied by spectrin deficiency, the usual cause is an ANK1 mutation with secondary loss of spectrin from the RBC membrane due to reduced incorporation of spectrin into the membrane; this occurs because ankyrin is the principal binding site for spectrin in the membrane [17]. Over 60 ANK1 variants have been described, most of them private (ie, found in only a single kindred) [21,22].
ANK1 disease variants typically act in an autosomal dominant fashion, but autosomal recessive presentations have also been reported. One study found that missense mutations in the coding region and a variant in the promoter region were typically associated with recessive HS, whereas frameshift and nonsense mutations were more likely to cause autosomal dominant HS [4]. Another study found a frameshift mutation, designated Ankyrin Florianópolis, in three independent families with severe autosomal dominant HS [23]. Patients with a deletion of the short arm of chromosome 8, which contains the ANK1 gene, have been described; these individuals have HS, intellectual disability, and other congenital anomalies [24].
●A smaller proportion of cases of isolated spectrin deficiency may be caused by variants affecting the SPTA1 or SPTB genes, which encode alpha and beta spectrin, respectively. In cases caused by spectrin variants, beta spectrin (SPTB) variants tend to act in an autosomal dominant fashion and alpha spectrin (SPTA1) variants tend to act in an autosomal recessive fashion [25-33]. This is because beta spectrin is rate limiting for assembly of the alpha-beta tetramer, whereas alpha spectrin is synthesized in excess. However, missense mutations affecting beta spectrin with autosomal recessive inheritance have also been reported; these are presumed to have a milder clinical presentation because they do not completely abolish beta spectrin production.
Some individuals may have more severe disease when an HS spectrin variant is inherited together with a low-expression alpha spectrin allele such as alpha-spectrin Bughill, alpha spectrin Lepra, or possibly alpha spectrin low-expression Lyon (Lely) [32,34]. These alpha spectrin alleles are discussed separately. (See "Hereditary elliptocytosis and related disorders", section on 'Spectrin variants'.)
As noted above, ankyrin deficiency (or combined spectrin and ankyrin deficiency) caused by disease variant in the ANK1 gene accounts for a large proportion of cases of HS. (See 'Overview of gene variants' above.)
Band 3 deficiency — Band 3 has two major functions. It provides cohesion between the RBC plasma membrane and the underlying cytoskeletal proteins, preventing membrane surface loss, and it exchanges bicarbonate for chloride ions, maintaining RBC water content and preventing cellular dehydration.
SLC4A1 variants typically act in an autosomal dominant fashion and typically cause mild, compensated hemolytic anemia. Documented pathogenic variants include frameshift, missense, splicing, or nonsense mutations [3,5,35-40]. Hemolysis may be aggravated by compound heterozygosity for pathogenic variant in SLC4A1 plus a low-expression band 3 allele [41,42].
SLC4A1 variants can also cause secondary band 4.2 deficiency [3]. (See 'Band 4.2 deficiency' below.)
Variants in SLC4A1 affecting band 3 can cause other disorders besides HS:
●A distinct variant affecting band 3 causes Southeast Asian ovalocytosis (SAO) (picture 1). Details are discussed separately. (See "Hereditary elliptocytosis and related disorders", section on 'Differential diagnosis'.)
●Individuals with certain variants affecting band 3 can present with an autosomal dominant distal renal tubular acidosis (RTA) related to loss of anion exchanger function; these individuals may have HS or SAO but not all do [36,43-49]. (See "Etiology and clinical manifestations of renal tubular acidosis in infants and children", section on 'Genetic causes' and "Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Distal (type 1) RTA'.)
As noted above, band 3 deficiency caused by disease variant in the SLC4A1 gene accounts for a large proportion of cases of HS. (See 'Overview of gene variants' above.)
Band 4.2 deficiency — Band 4.2 (also called protein 4.2) strengthens the linkage between band 3 and ankyrin. The typical patient with band 4.2 deficiency is of Japanese ancestry with an autosomal recessive transmission of an EBP42 variant [50]. A number of missense and splicing mutations have been reported [51-55]. Other cases of band 4.2 deficiency may be secondary to a variant in SLC4A1 (encodes band 3) that alters the stability of the band 4.2 protein and/or its interactions with the cytoskeleton [56-60].
As noted above, deficiencies of band 4.2 are rare causes of HS. (See 'Overview of gene variants' above.)
Changes in the RBC membrane — As noted above, most of the pathogenic HS variants reduce the level of one or more RBC membrane proteins that link the cytoskeleton to the overlying plasma membrane. It is also possible for HS variants to affect protein-protein binding rather than protein abundance. (See 'Genetics' above.)
Studies from animal models suggest that one of the mechanisms of secondary cytoskeletal protein deficiencies involves aberrant sorting of these proteins during the enucleation stage of RBC maturation (ie, when the nucleus is extruded, certain proteins are expelled with the extruded cell nucleus) [61].
The loss of these proteins results in reduced vertical associations between the cytoskeleton and membrane, which in turn leads to microvesiculation and progressive membrane loss, the central abnormality that defines HS [62-64]. Loss of membrane reduces the ratio of RBC surface area to volume, in turn creating progressively more spherical cells (picture 2). (See "Red blood cell membrane: Structure, organization, and dynamics", section on 'Surface area to volume ratio (SA/V)'.)
There is evidence that membrane loss is present as early as the reticulocyte stage; this distinguishes HS from autoimmune hemolytic anemia (AIHA), in which only mature RBCs become spherocytic due to membrane loss [65].
Two hypotheses have been advanced to explain how deficiencies or qualitative defects in these membrane proteins lead to vesiculation and membrane loss. In the first, spectrin deficiency acts directly on the bilayer to create areas of weakness that allow membrane loss. In the second, band 3 deficiency or dispersion causes vesiculation by reducing the integrity of the lipid bilayer [66].
Some individuals with HS have abnormal RBC ion transport, the severity of which may depend on the degree of band 3 deficiency (band 3 is the anion transporter) [67]. On the other hand, all spherocytes demonstrate increased passive permeability to monovalent cations (sodium and potassium) [67,68]. (See "Control of red blood cell hydration", section on 'Passive gradient-driven systems'.)
Mechanisms of hemolysis — Spherocytes are prone to hemolysis. The mechanisms include reduced deformability, which impairs passage through constricted regions of the microcirculation, and phagocytosis by splenic macrophages, which occurs in response to splenic trapping. Loss of spectrin appears to be especially correlated with the severity of hemolysis [69].
Once RBCs become spherocytic, successive phagocytosis during repeated passages through the splenic cords (a process termed splenic conditioning) promotes further membrane loss and a progressively more spheroidal shape (picture 2). This in turn further impairs passage through the narrow fenestrations of the splenic cords [70,71]. The mechanics of passage through the splenic cords and the effect on spherocytes has been simulated using a two-component RBC model [72]. In severe cases, reduced membrane stability may contribute to mechanical RBC destruction.
In addition to phagocytosis, the spleen also exposes RBCs to an acidotic, oxidizing, metabolically unfavorable environment. RBCs may also become depleted of 2,3-bisphosphoglycerate (2,3-BPG; previously called 2,3-diphosphoglycerate [2,3-DPG]), and in certain cases, there may be methylation of membrane proteins (in spectrin deficiency but not in band 3 deficiency) [73].
Case reports have described individuals with the same familial variant who have different severities of hemolysis (ie, variable clinical penetrance). In some cases, this variability has been due to concomitant variants in other genes that affect RBC function. As an example, in a family with mild autosomal dominant HS due to partial band 3 deficiency, one family member had more severe clinical features than others, and this was attributed to an exacerbating effect of a pyruvate kinase (PK) gene (PKLR) mutation [74]. It was speculated that low ATP levels from his partial PK deficiency increased the osmotic fragility of his RBCs. A study from Germany found that PK activity in RBCs from patients with HS were relatively low, particularly in reticulocytes [75]. It was speculated that loss of membrane-associated PK was responsible and might contribute to the severity of HS. Further studies are needed.
As discussed below, splenectomy virtually eliminates hemolysis and anemia in moderately severe cases of HS and partially corrects the anemia in severe cases. However, it has been reported that splenectomy is more effective in reducing hemolysis when HS is due to spectrin/ankyrin deficiency than when HS is due to band 3 deficiency, perhaps due to different degrees of reticuloendothelial clearance as a mechanism of hemolysis in different individuals. Elegant studies have demonstrated that this may be related to greater opsonization (binding of naturally occurring antibodies) with spectrin/ankyrin-deficient RBCs [76]. The role of splenectomy in HS management is discussed below. (See 'Splenectomy' below.)
Hemolysis may transiently lessen if an individual with HS develops obstructive jaundice [77]. This is thought to be because transient hepatic obstruction produces an abnormal plasma lipid profile that increases RBC membrane surface area and partially corrects the reduced surface area to volume (SA/V) ratio characteristic of spherocytes. (See "Red blood cell membrane: Structure, organization, and dynamics", section on 'Surface area to volume ratio (SA/V)'.)
EPIDEMIOLOGY — HS is seen in all populations but appears to be especially common in people of northern European ancestry. In these individuals, HS affects as many as 1 in 2000 to 1 in 5000 (prevalence, approximately 0.02 to 0.05 percent) [6,7,63,78].
The frequency is thought to be lower in individuals from other parts of the world such as Africa and Southeast Asia, although comprehensive population survey data are unavailable.
In a 2006 study that tested 402 severely jaundiced neonates (requiring phototherapy), four (1 percent) were ultimately diagnosed with HS (ie, approximately 20 times more prevalent than in the general population; approximately one-fifth as prevalent as acquired, immune-mediated spherocytosis) [79]. Other causes of neonatal jaundice and the evaluation of a neonate suspected to have HS are presented below. (See 'Neonates' below and 'Differential diagnosis' below.)
CLINICAL PRESENTATION
Disease severity and age of presentation — HS can present at any age and with any severity, with case reports describing a range of presentations, from hydrops fetalis in utero through diagnosis in the ninth decade of life [63,66,80-82].
The majority of affected individuals have mild or moderate hemolysis or hemolytic anemia and a known family history, making diagnosis and treatment relatively straightforward [64]. Individuals with significant severe hemolysis may develop additional complications such as jaundice/hyperbilirubinemia, folate deficiency, or splenomegaly.
Hemolytic anemia — A classification for HS has been developed based on the severity of anemia and markers of hemolysis (reticulocyte count and bilirubin) [64,83]; it characterizes patients as having one of the following:
●HS trait – Normal hemoglobin, bilirubin, and reticulocyte count
●Mild HS (20 to 30 percent of cases) – Hemoglobin 11 to 15 g/dL; reticulocytes 3 to 6 percent; bilirubin 1 to 2 mg/dL (from 17 to 34 micromol/L)
●Moderate HS (60 to 75 percent of cases) – Hemoglobin 8 to 12 g/dL; reticulocytes >6 percent; bilirubin >2 mg/dL (>34 micromol/L)
●Severe HS (5 percent of cases) – Hemoglobin 6 to 8 g/dL; reticulocytes >10 percent; bilirubin >3 mg/dL (>51 micromol/L)
Neonates may have a relatively normal hemoglobin level at birth that is followed by development of severe anemia, especially during the first three weeks and, in some cases, the first year of life, when the erythropoietic response may not be adequate [84,85]. According to one review, more than half of neonates with HS are not anemic during the first week of life [86]. However, anemia can develop after several days, and is most likely to be severe during the second or third week of life. Some infants require chronic transfusions during the first year; however, transfusion dependence beyond the first year of life is unusual. Red blood cell (RBC) indices are described below. (See 'Initial testing' below.)
In older children and adults, the presentation may be that of an incidental finding of hemolysis, hemolytic anemia, or spherocytes on the blood smear (picture 2), or the individual may be symptomatic from anemia, splenomegaly, pigment gallstones, or jaundice. Jaundice due to severe hemolysis is less common after the newborn period. (See 'Older children and adults' below.)
In some cases, co-inheritance of another disorder affecting RBC survival such as sickle cell disease or thalassemia can influence the severity of anemia and make diagnosis more challenging [83]. (See 'Evaluation' below.)
Exacerbations of anemia may also occur in certain settings:
●Infections – Infections that impair RBC production in the bone marrow and thus diminish the capacity to compensate for chronic hemolysis may lead to a period of aplasia.
A commonly cited cause of transient aplastic crisis is parvovirus B19 infection; other viral or bacterial infections may also cause transient aplasia. This is because individuals with chronic hemolysis are highly dependent on the accelerated production of new RBCs by the bone marrow, and they can experience a rapid drop in hemoglobin level when the bone marrow is unable to compensate for hemolysis.
In a series of individuals with hereditary hemolytic anemias who presented to the hospital with acute parvovirus infection, common manifestations included fever, musculoskeletal pains, and pancytopenia [87]. Individuals with HS were more likely than those with other underlying anemias to have acute kidney injury, severe hyperbilirubinemia, lymphadenopathy, and skin rashes.
If an individual with HS develops a precipitous decline in hemoglobin level or reticulocyte count, testing for parvovirus infection is appropriate. (See "Clinical manifestations and diagnosis of parvovirus B19 infection".)
●Splenomegaly – Conditions that increase the size of the spleen, such as infectious mononucleosis (table 1), may cause increased splenic pooling of RBCs and/or increased hemolysis. (See "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Splenomegaly'.)
●Nutrient deficiencies – Individuals who develop folate, vitamin B12, or iron deficiency may be unable to produce sufficient RBCs to compensate for those lost by hemolysis. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency" and "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Iron requirements and iron deficiency in adolescents" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)
●Pregnancy – Anemia may worsen during pregnancy, as the RBC mass and plasma volume expand to meet the physiologic needs of the pregnancy. Attention to folic acid supplementation and iron stores are also important so as not to impair RBC production. (See 'Overview of treatment' below.)
Individuals who experience a decline from their baseline hemoglobin level and/or reduction in baseline reticulocyte count are likely to require more frequent monitoring and/or additional testing, details of which will depend on the associated symptoms and laboratory findings.
Complications of hemolysis — Common complications of hemolysis in individuals with HS include neonatal jaundice, splenomegaly, and pigment gallstones, which are discussed in the sections that follow. (See 'Neonatal jaundice' below and 'Splenomegaly' below and 'Pigment gallstones' below.)
Rarely, hemolysis may be severe enough to cause extramedullary hematopoiesis and/or growth delay [88,89]. A small subset of these children may be at risk for iron overload due to increased iron absorption and/or transfusions, although the majority of patients with HS do not develop iron overload [63].
Other rare complications that have been reported include leg ulcers, priapism, neuromuscular disorders, cardiac disease, and gout; in some cases, these may represent coincidental rather than causal associations [63,90,91].
Neonatal jaundice — HS may present in the neonatal period with jaundice and hyperbilirubinemia, and the serum bilirubin level may not peak until several days after birth. Some experts have proposed that HS is underdiagnosed as a cause of neonatal jaundice [92]. A requirement for phototherapy and/or exchange transfusion during this period is common [63,84]. (See 'Neonates' below.)
Hyperbilirubinemia may be exacerbated by concomitant Gilbert syndrome. (See "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia".)
Splenomegaly — Splenomegaly is rare in neonates, but can often be seen in older children and adults with HS [86]. Early reports of family studies found palpable spleens in over three-fourths of affected members, but this may reflect a skewed population with the most severe disease. In these studies, the relationship between disease severity and splenic size was not linear [93].
There is no evidence of an increased risk of splenic rupture.
Indications for splenectomy in HS and possible complications are discussed below. (See 'Splenectomy' below.)
Pigment gallstones — Pigment (bilirubin) gallstones are common in individuals with HS and may be the presenting finding in adults. Gallstones are unlikely before the age of 10 years but are seen in as many as half of adults, especially those with more severe hemolysis [94]. Gallstones appear to be more common in individuals with Gilbert syndrome (inherited disorder of bilirubin glucuronidation) [95]. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction", section on 'Bilirubin overproduction'.)
Obstructive jaundice or cholecystitis is treated similarly to that in individuals without HS. If cholecystectomy is performed, it may be worthwhile to discuss whether splenectomy was also planned, as the procedures could be combined; however, splenectomy should not be routinely performed during cholecystectomy [96].
EVALUATION
When to suspect HS — The diagnosis of HS should be suspected in an individual with Coombs-negative (ie, non-immune) hemolytic anemia and spherocytes on the peripheral blood smear. A positive family history of HS or negative testing for other inherited hemolytic anemias increases suspicion for HS. Severe disease can present in the neonatal period, whereas mild or compensated HS may not present until adulthood.
Typical findings of hemolytic anemia include low hemoglobin level, high reticulocyte count, high lactate dehydrogenase (LDH) and bilirubin, and low haptoglobin. (See "Diagnosis of hemolytic anemia in adults", section on 'Laboratory confirmation of hemolysis'.)
HS is a non-immune form of hemolysis; thus, the Coombs test (also called direct antiglobulin test [DAT]) is negative. (See "Overview of hemolytic anemias in children", section on 'Intrinsic hemolytic anemias' and "Diagnosis of hemolytic anemia in adults", section on 'Immune versus non-immune'.)
If hemolysis is severe, the patient may have jaundice (including neonatal jaundice). If compensation is insufficient (ie, if the bone marrow cannot produce new red blood cells [RBCs] with sufficient rapidity to compensate for hemolyzed RBCs), there may be symptoms of anemia. (See "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia", section on 'Increased production'.)
Findings that suggest an alternative diagnosis include prior normal complete blood counts and hemolysis markers or obvious RBC abnormalities that suggest a different type of hemolytic anemia (eg, stomatocytes, ovalocytes, target cells, sickle cells). (See "Evaluation of the peripheral blood smear", section on 'Permutation in shape'.)
Initial testing
All patients — Some aspects of the initial evaluation differ in neonates versus older children and adults since affected neonates tend to have more severe disease and less useful laboratory parameters. (See 'Neonates' below.)
However, the following are appropriate in virtually all individuals:
●CBC and RBC indices – All individuals with suspected HS based on family history, neonatal jaundice, or other findings should have a complete blood count (CBC) with reticulocyte count and red blood cell (RBC) indices. The mean corpuscular hemoglobin concentration (MCHC) is often the most useful parameter for assessing spherocytosis; an MCHC ≥36 g/dL is consistent with spherocytes. A low mean corpuscular volume (MCV) is also helpful in some cases, especially in neonates, but variable degrees of reticulocytosis make the MCV less useful in older children and adults.
●Blood smear review – All individuals with suspected HS should have a blood smear reviewed by an experienced individual. RBC parameters to be assessed include the presence and abundance of spherocytes, other abnormal RBC shapes, and the degree of polychromatophilia, which reflects reticulocytosis.
●Hemolysis testing – Testing for hemolysis is also appropriate in all patients. This includes lactate dehydrogenase (LDH), indirect bilirubin, haptoglobin, and reticulocyte count. Findings consistent with hemolysis include increased LDH and indirect bilirubin, decreased or absent haptoglobin, and an elevated reticulocyte count.
●Coombs testing – If hemolysis is present, Coombs testing (also called direct antiglobulin testing [DAT]) is usually done to eliminate the possibility of immune-mediated hemolysis, which may be due to hemolytic disease of the fetus and newborn (HDFN) in neonates or autoimmune hemolytic anemia (AIHA) in older children and adults. The results of testing may also be useful to the transfusion service if transfusion is indicated. Coombs testing in HS is negative.
Our approach to the evaluation is consistent with a 2011 guideline (published in 2012) from the British Committee for Standards in Haematology (BCSH) on the diagnosis of HS and a 2015 guideline from the International Council for Standardization in Haematology (ICSH) on non-immune hereditary RBC membrane disorders [83,97].
Neonates — As noted above, neonates with severe hemolysis due to HS may present with neonatal jaundice. The evaluation of a neonate with suspected HS depends on whether a parent is known to have HS.
●If an infant with hyperbilirubinemia or other findings of non-immune hemolytic anemia has a known family history of HS, then the likelihood of HS is high, and we rely heavily on the RBC indices. As noted above, an MCHC ≥36 g/dL is highly suggestive of HS. (See 'Clinical presentation' above.)
●If an infant with hyperbilirubinemia or hemolytic anemia does not have a known family history of HS, then a number of other possible diagnoses must be considered (see 'Differential diagnosis' below). Appropriate therapy should not be delayed while determining the underlying cause; likewise, the importance of making the diagnosis of HS should be emphasized regardless of the management interventions needed. Hemolytic anemia with a negative Coombs test and a high MCHC (eg, ≥36 g/dL) is consistent with HS but must be considered in the context of the entire clinical picture. (See 'Confirmatory tests' below and "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia" and "Screening for hyperbilirubinemia in term and late preterm newborn infants".)
Neonates with HS tend to have an elevated MCHC (typical range in HS, 35 to 38 g/dL) [86]. This is a useful discriminator between HS and hemolytic disease of the fetus and newborn (HDFN) because HDFN RBCs tend to have MCHC in the range of 33 to 36 g/dL [92].
Spherocytes on the blood smear are helpful if present, but up to one-third of neonates with HS do not have prominent spherocytes, and some neonates without HS have spherocytes [86]. In addition, it may be difficult to assess spherocytes on the peripheral blood smear in a neonate, either because neonates with HS may have fewer spherocytes or because spherocytic cells are often present after birth in neonates without HS [97]. If the infant is well, it is reasonable to postpone testing until approximately six months of age or older, at which time the RBC morphology will be easier to assess [83]. If there is greater urgency to establish a diagnosis (eg, severe anemia or hyperbilirubinemia), specialized testing may be used. (See 'Confirmatory tests' below.)
Older children and adults — As noted above, HS may be suspected in a patient of any age who has evidence of hemolysis (eg, elevated serum LDH, elevated indirect bilirubin, reduced haptoglobin, increased reticulocyte count) or hemolytic anemia that is Coombs-negative and not explained by another condition.
HS may also be suspected in an individual who presents with a complication of hemolysis, such as splenomegaly, pigmented gallstones, or an abrupt drop in hemoglobin level when the bone marrow cannot compensate for hemolysis (eg, during a viral illness, pregnancy, or other condition). In such cases, a CBC will be obtained and RBC indices will be available; the reticulocyte count should also be measured if not done already.
Evidence consistent with HS as the likely diagnosis in an older child or adult include the following:
●Positive family history of HS, although this is not always present as some cases arise as de novo mutations and not all individuals will have a complete family history available.
●Chronic hemolytic anemia, although in mild cases, there may be chronic compensated hemolysis without anemia.
●Jaundice and/or splenomegaly, although these may be absent if the hemolysis is mild.
●Spherocytes (picture 2) on the peripheral blood smear. The percentage of spherocytes is variable. The typical reticulocyte count in older children and adults with HS is approximately 5 to 20 percent, but it may be as high as 20 to 30 percent in severe cases. Certain genetic defects have been associated with specific spherocyte morphologies, although the diagnostic value of these findings has not been rigorously tested [3,25,28,98,99] (see 'Genetics' above):
•Pincered or notched spherocytes – Band 3 deficiency
•Acanthocytic spherocytes – Spectrin deficiency
•Dense and irregularly shaped cells – Spectrin/ankyrin deficiency
•Elliptocytic spherocytes – Spherocytic elliptocytosis
●RBC indices consistent with spherocytosis (eg, MCHC >36 g/dL; normal to slightly low MCV). The MCV and red cell distribution width (RDW) may be increased by greater degrees of reticulocytosis in older children and adults; thus, the MCHC is the most useful of the RBC indices. The combination of increased MCHC and increased RDW further improves diagnostic performance [100]. If reticulocyte indices are available, a higher-than-average reticulocyte MCHC and a low reticulocyte MCV are also consistent with HS (table 2) [83].
As noted below, in the appropriate clinical setting, this testing is sufficient to establish a diagnosis of HS. (See 'Diagnosis' below.)
In cases that are unclear or if additional diagnostic confirmation is needed, specialized testing can be pursued. (See 'Confirmatory tests' below.)
Confirmatory tests — A number of tests are available for confirming the diagnosis of HS. We perform confirmatory testing in all cases of suspected HS, although some experts may omit this testing, especially in resource-limited settings and/or if there are classic clinical findings in an individual with a known family history of HS.
EMA binding is our preferred test, and it is widely available. We generally order EMA binding. If the results are equivocal, the osmotic fragility test or osmotic gradient ektacytometry (if available) can be added.
Available tests include the following:
●EMA binding – If specialized testing is indicated, EMA binding is our preferred test. EMA (eosin-5-maleimide) is an eosin-based fluorescent dye that binds to RBC membrane proteins, especially band 3 and Rh-related proteins [101]. The mean fluorescence of EMA-labeled RBCs from individuals with HS is lower than controls, and this reduction in fluorescence can be detected in a flow cytometry-based assay, as illustrated in the figure (figure 3). The reduction in EMA binding is observed in RBCs when HS is due to band 3 deficiency or to deficiencies in other proteins such as ankyrin or spectrin, possibly due to long-range effects on the RBC membrane [102]. Two case series of individuals with HS have found the EMA fluorescence in individuals with HS to be approximately two-thirds that of controls [101,103]. Samples can be stored and tested; one of the studies also analyzed the effect of delayed testing and found that samples stored for 24 hours in the darkness gave similar results to those tested immediately [101].
Advantages of EMA binding include its high sensitivity and specificity; rapid turnaround time (approximately two hours); and need for only a minimal amount of blood (a few microliters), which is especially advantageous for testing neonates [104-106]. In addition, EMA testing can be used to identify HS in a patient who has recently received a transfusion [107]. In various studies, the sensitivity and specificity of the test appear to be in the ranges of 93 to 96 and 93 to 99 percent, respectively [104,108-110]. It is important in testing neonatal RBCs to compare the results of EMA binding to control samples from age-matched controls [111].
EMA binding may also be positive in some forms of hereditary elliptocytosis (HE; eg, hereditary pyropoikilocytosis [HPP]) and in Southeast Asian ovalocytosis (SAO), in individuals with congenital dyserythropoietic anemia (CDA) type II, and/or in autoimmune hemolytic anemia [103,108]. False negative results may be seen in mild cases of HS.
●Osmotic fragility – If EMA binding is not available, osmotic fragility testing (OFT) is another useful specialized test for HS. In this test, fresh RBCs are incubated in hypotonic buffered salt solutions of various osmolarities, and the fraction of hemoglobin released (due to hemolysis) is measured. The test takes advantage of the increased sensitivity of spherocytes to hemolysis, which is due to their reduced surface area to volume (SA/V) ratio (figure 4). Incubation of patient samples for 24 hours prior to testing may accentuate osmotic fragility and improve diagnostic yield.
The OFT has relatively low sensitivity and specificity. It fails to identify a significant number of individuals with HS, and, particularly in the newborn, it may be positive in other conditions including immune hemolytic anemia, hemolytic transfusion reactions, RBC enzyme defects such as glucose-6-phosphate dehydrogenase (G6PD) deficiency, and unstable hemoglobin variants [97]. In one series of 86 individuals with HS, only 57 (66 percent) had positive osmotic fragility testing [112].
●Osmotic gradient ektacytometry – Osmotic gradient ektacytometry is an alternative assay that generates a profile of osmotically induced RBC shape change (deformability) across an osmotic gradient [113]. An example of ektacytometry in HS versus hereditary elliptocytosis is shown in the figure (figure 3). Although more informative than the traditional osmotic fragility test, this test is not routinely available. Patient results can be compared with profiles of deformability gradients associated with various conditions [97,114]. Laser-assisted optical rotational cell analyzer (LORCA) is a related test under investigation.
●Glycerol lysis – The glycerol lysis test (GLT) and the acidified GLT (AGLT) are modifications of the OFT that add glycerol (in the GLT) or glycerol plus a sodium phosphate (to lower the pH to 6.85, in the AGLT) to the hypotonic buffered salt solutions in which the patient's RBCs are incubated [78,97]. Like the OFT, these tests may also be positive in acquired spherocytosis conditions such as AIHA.
The "pink test" is a modification of the GLT in which the final extent of hemolysis is measured in a blood sample incubated in the glycerol solution at pH 6.66 [115]. A further modification has been proposed (the direct pink test) in which the test sample is obtained from fingerprick (or heel puncture in newborns), rather than venipuncture, and incubated directly in the glycerol solution; this requires only a few microliters of blood [116].
●Cryohemolysis – In the cryohemolysis test, RBCs are suspended in a hypertonic solution, briefly heated to 37°C, then cooled to 4°C for 10 minutes [117]. Ease of performance and the wide separation in degree of hemolysis between spherocytes and normal cells are two attractive features of this test [118]. This test has limited availability in the United States.
The relative performance of these tests was evaluated in a 2012 study that tested samples from 150 individuals known to have HS [103]. Test sensitivities were as follows:
●AGLT – 95 percent
●EMA binding – 93 percent
●Pink test – 91 percent
●Osmotic fragility, incubated – 81 percent
●Osmotic fragility, fresh – 68 percent
●GLT – 61 percent
Combined testing with EMA binding and AGLT had a sensitivity of 100 percent; combined testing with EMA binding and pink test had a sensitivity of 99 percent; and EMA binding plus osmotic fragility (incubated or fresh) had a sensitivity of 95 percent [103].
These results demonstrate that no one test reliably identifies all individuals with HS, and in certain cases, diagnostic yield may be improved by using two tests. Test results should be compared with results of a normal control of the same age, coupled with a thorough examination of the peripheral blood smear and red cell indices.
These tests can also be positive in other conditions, and the results cannot be interpreted in isolation. If a positive test is not consistent with the clinical picture or findings on the peripheral blood smear, laboratory personnel or a consulting hematologist with expertise in interpreting these tests should be consulted [83].
Specialized testing for selected cases — In certain atypical cases in which further characterization of the RBC cytoskeletal/membrane proteins is needed, gel electrophoresis can be done using RBC ghosts, or DNA sequencing can be performed. These approaches may require a specialized laboratory. Identifying the deficient protein is mainly of research interest and generally does not affect management. Identifying a familial disease variant may be useful in some cases for genetic testing and counseling (see 'Prenatal testing, family testing, and genetic counseling' below). Resources for genetic testing are listed on the Genetic Testing Registry website.
Certain academic laboratories have a special interest or ability in performing this testing and may be contacted for further discussions. As examples:
●Cincinnati Children's Molecular Genetics Laboratory
•Website – www.cincinnatichildrens.org/moleculargenetics
•Phone – (513) 636-4474
●Blood Disease Reference Laboratory Program at Yale University
•Website – www.medicine.yale.edu/pathology/clinical/mdx/
•Phone – (203) 737-1349
●Mayo Clinic's Mayo Medical Laboratories
•Website – https://www.mayomedicallaboratories.com/customer-service/contacts.html
•Phone – (800) 533-1710
•Email – mml@mayo.edu (United States) or mliintl@mayo.edu (international)
Diagnosis — The diagnosis of HS is made in an individual who presents with Coombs-negative hemolysis, an increased MCHC, a positive family history for HS, and/or spherocytes on the peripheral blood smear, by finding a positive result from one or more confirmatory tests such as AGLT, EMA binding, or osmotic fragility. Specialized testing is especially important if splenectomy is being considered. Specialized testing may be omitted if definitive diagnosis is unlikely to alter management (eg, if hemolysis is mild and childbearing is not planned) or in resource-limited areas of the world [83]. (See 'Confirmatory tests' above.)
For an individual with a strong suspicion of HS and negative or equivocal testing by EMA binding, for whom accurate diagnosis was especially important (eg, due to a previous affected child), positive results from genetic testing is confirmatory for HS. Genetic testing is available in several specialized laboratories. (See 'Specialized testing for selected cases' above.)
This testing is similar to that described in published guidelines [83,97]. However, we are more likely to order confirmatory testing in all patients except those in resource-limited settings or those who do not have access to specialized testing for other reasons, as treatment for HS may differ from other conditions (eg, splenectomy is often used in HS but is typically avoided in hereditary stomatocytosis). (See 'Splenectomy' below.)
Differential diagnosis — The differential diagnosis of HS includes a number of other hemolytic anemias with spherocytes on the peripheral blood smear:
●Other inherited hemolytic anemias – Other inherited RBC membrane disorders include hereditary elliptocytosis (HE) (picture 3) and elliptocytosis variants (hereditary pyropoikilocytosis [HPP]) (picture 4), hereditary stomatocytosis (HSt), and hereditary xerocytosis (HX) (figure 5). RBC enzyme disorders include glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase (PK) deficiency, and other rarer metabolic disorders. Like HS, these present with variable degrees of anemia and hemolysis and can be diagnosed at any age. Unlike the other disorders, G6PD deficiency typically presents with more discrete episodes of hemolysis after exposure to oxidant drugs. Unlike the other membrane disorders, which each have distinctive morphologies on the blood smear, and the enzyme disorders, which typically have nonspecific findings (eg, mild reticulocytosis), HS is characterized by spherocytosis as the predominant morphology. (See "Overview of hemolytic anemias in children", section on 'Intrinsic hemolytic anemias' and "Diagnosis of hemolytic anemia in adults", section on 'Intracorpuscular'.)
It is especially important to distinguish between HS and HSt because HS is generally helped by splenectomy, whereas in HSt, splenectomy is generally avoided. (See 'Decision to pursue splenectomy' below.)
●Hemolytic disease of the fetus and newborn (HDFN) – Neonates may present with severe HDFN (also called neonatal alloimmune hemolytic anemia), which is caused by maternal antibodies that cross the placenta and recognize foreign fetal RBC antigens, leading to alloimmune hemolysis. Like HS, neonates can present with severe jaundice and anemia requiring aggressive treatment, and like HS, HDFN can be associated with abundant spherocytes on the blood smear. Unlike HS, HDFN is a transient condition that resolves after the maternal antibodies are cleared, and HDFN is characterized by positive Coombs testing, which typically reveals the alloantibodies on fetal RBCs, as well as evidence of an immunologically significant discordance between maternal and neonatal blood type. (See "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management".)
●Infantile pyknocytosis – Infantile pyknocytosis is a disorder of unknown etiology in which RBCs become hyperdense and dehydrated [119]. Like HS, this condition presents in neonates with anemia and an increased mean corpuscular hemoglobin concentration (MCHC). Unlike HS, the RBCs have irregular borders and varying numbers of projections, and the condition resolves spontaneously during the first year of life (typically, six to nine months after birth) without intervention.
●Congenital dyserythropoietic anemia (CDA) – CDA type II is a group of inherited anemias caused by one of several gene variants that results in abnormal RBC production in the bone marrow. Like HS, some individuals may have significant hemolysis and/or splenomegaly, and like HS, some specialized tests such as EMA binding may be positive. Unlike HS, individuals with one of the CDAs are likely to have characteristic morphology of RBC precursors in the bone marrow, and the reticulocyte count is usually lower in the CDAs [83]. (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Congenital dyserythropoietic anemia'.)
●Autoimmune hemolytic anemia (AIHA) – AIHA, in which autoantibodies directed against self-RBC antigens lead to hemolysis, is a common cause of hemolysis and/or anemia, especially in adults. Warm AIHA associated with an underlying disorder such as systemic lupus erythematosus (SLE) or without an underlying disorder is more common than cold AIHA, which is typically triggered by an infection such as infectious mononucleosis. Like HS, patients can have anemia and/or hemolysis of variable severity and abundant spherocytes on the peripheral blood smear. Unlike HS, in AIHA, the Coombs test is typically positive, there is not family history of hemolytic anemia, and prior complete blood counts (CBCs) will show a normal hemoglobin level and reticulocyte count. (See "Autoimmune hemolytic anemia (AIHA) in children: Classification, clinical features, and diagnosis" and "Warm autoimmune hemolytic anemia (AIHA) in adults" and "Cold agglutinin disease".)
MANAGEMENT
Overview of treatment — As with most inherited hemolytic anemias, treatment is directed at preventing or minimizing complications of chronic hemolysis and anemia. There are no specific treatments directed at the underlying red blood cell (RBC) membrane defect.
If a neonate is suspected of having HS (eg, based on positive family history and neonatal jaundice), treatment can be initiated for HS without awaiting diagnostic confirmation. This may include therapy for hyperbilirubinemia and, in severe cases, transfusion or even exchange transfusion [86]. Treatment of hyperbilirubinemia is discussed separately. (See "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns".)
The frequency of patient monitoring depends on disease severity and symptoms (see 'Disease severity and age of presentation' above). Once a baseline has been established, an annual visit is sufficient for a child with mild hemolysis, with closer monitoring during viral or other infections that might cause more severe anemia [83]. Growth should be monitored, and patients and/or families should be informed about the possible risk of transient aplastic crisis, including the symptoms and the need to seek medical attention. Adults with mild disease may receive routine medical and preventive care; those with more severe hemolysis may require more frequent monitoring, with the interval depending on their specific needs. (See 'Hemolytic anemia' above.)
General supportive measures may include the following, depending on disease severity:
●Folic acid – Folic acid supplementation is appropriate for those with moderate to severe hemolysis and/or during pregnancy. This is based on an increased requirement for folate in RBC production. There are no clinical trials investigating the role of folic acid treatment. However, observational studies that documented megaloblastic anemia in a small number of patients with HS were performed before the institution of routine folic acid supplementation of grains and cereals [64]. This, coupled with the low cost and minimal toxicity of folic acid, make it an attractive and simple therapy to recommend. The typical dose for those with moderate to severe hemolysis is 1 to 2 mg/day, while those who have HS of any severity and are pregnant should receive doses as high as 4 to 5 mg/day, as discussed separately. (See "Folic acid supplementation in pregnancy".)
For individuals with mild hemolysis who have normal intake of fresh fruits and vegetables (or folic-acid-supplemented grains), daily folic acid is not required, but for those who place a high value on avoiding folate deficiency, which could cause worsening anemia, taking daily folic acid (typical dose, 1 to 2 mg daily) is safe and inexpensive, and there are essentially no side effects or contraindications.
●Transfusions – Blood transfusion is often required in severely affected infants and may be needed during certain times in other settings (eg, aplastic crisis, pregnancy). However, transfusions usually are not required on a chronic basis or for a long enough time to cause iron overload.
Typical hemoglobin thresholds for transfusion depend on the age of the patient, symptoms, and comorbidities.
•Some infants may require transfusions for anemia and/or hyperbilirubinemia. Older children may be able to tolerate a hemoglobin level of 5 to 6 g/dL without transfusions. (See "Red blood cell transfusion in infants and children: Indications".)
•Adults may require transfusions for anemia, with thresholds determined by their clinical status, as discussed in detail separately. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult".)
•Individuals with an aplastic crisis due to parvovirus infection or other bone marrow insult may require transfusions if they have a decreasing hemoglobin level without a robust reticulocytosis. The usual course of parvovirus-associated anemia is spontaneous resolution within a few days or weeks. Infected individuals are monitored with twice-weekly complete blood counts (CBCs) and reticulocyte counts to determine the expected hemoglobin nadir and the need for transfusion. (See "Treatment and prevention of parvovirus B19 infection", section on 'Transient aplastic crisis'.)
Consideration of transfusional iron overload typically occurs after transfusion of more than 15 to 20 units of RBCs (more than 10 units in smaller children). Adults with mild hemolysis may have a slight increase in iron absorption, and if this occurs in the setting of hereditary hemochromatosis, which is common, iron overload may occur. Screening for iron overload, management, and related subjects are discussed separately. (See "Approach to the patient with suspected iron overload", section on 'Transfusional iron overload'.)
●Erythropoietin – Erythropoietin (EPO) may be helpful in reducing the need for transfusion in some infants [83]. Typically, this can be discontinued around the age of nine months. In one study, the use of recombinant human EPO (1000 international units/kg per week) with iron supplementation obviated the need for transfusion in 13 of 16 infants with severe HS [120]. As the infants grew and began to mount an adequate erythropoietic response, the EPO dose could be tapered and discontinued before the age of nine months.
●Splenectomy and/or cholecystectomy – For those with relatively severe hemolysis, splenectomy is effective at improving anemia. Ideally, this is delayed until the individual is older than six years to reduce the likelihood of sepsis due to absent splenic function. Simultaneous cholecystectomy can be performed if gallstones are also present.
Individuals with symptomatic gallstone disease who require cholecystectomy should be evaluated for the possible role of simultaneous splenectomy, but this should only be pursued if clinically indicated (eg, symptomatic hemolytic anemia and/or severe complications of hemolysis). (See 'Splenectomy' below.)
●Considerations related to splenomegaly – There are no special restrictions (eg, no activity limitations) on children with splenomegaly due to HS [83]. However, those with an unusually large spleen should be made aware of the risk of splenic rupture during contact sports.
●Other therapies – Allogeneic hematopoietic cell transplantation (HCT) is not used in HS due to an unfavorable risk-benefit ratio, but a case was reported in which an individual with both HS and chronic myelogenous leukemia (CML) underwent allogeneic HCT, which cured both disorders [121].
Splenectomy
Decision to pursue splenectomy — Decisions regarding splenectomy must take into account the severity of hemolysis, age of the patient, and the complications of the procedure [83,122,123]:
●For children with HS who remain transfusion-dependent or severely symptomatic from anemia after one year of age, we suggest splenectomy. Partial splenectomy may be preferable in those who are under six years of age; compared with total splenectomy, partial splenectomy reduces the risk of sepsis from encapsulated bacteria. Total splenectomy, if necessary, can be delayed until after the age of six years.
●The use of splenectomy in individuals with moderate disease is individualized. We are more likely to advise splenectomy for individuals with more severe hemolysis and/or greater symptoms (eg, abdominal symptoms related to splenomegaly, distress related to jaundice) or for those with growth delays or skeletal changes related to extramedullary hematopoiesis.
●Some individuals with mild hemolysis may pursue splenectomy as a means of reducing gallstone formation, but for most individuals, the risks of splenectomy (see 'Complications' below) exceed the possible benefit [124]. One decision-support model concluded that combined prophylactic splenectomy and cholecystectomy provided a substantial gain in quality-adjusted life expectancy for patients with mild HS under the age of 39 who had asymptomatic gallstones and for patients under the age of 52 with gallstones accompanied by occasional episodes of biliary colic [125]. The analysis was sensitive to compliance with post-splenectomy infection prophylaxis.
●We typically defer splenectomy in children until at least six years of age if possible due to the risk of sepsis [83]; partial splenectomy is an option if such a delay is not possible. (See "Clinical features, evaluation, and management of fever in patients with impaired splenic function" and 'Operative techniques' below.)
Our approach is consistent with a 2011 guideline from the British Committee for Standards in Haematology (BCSH) and a 2017 guideline form the European Hematology Association (EHA) [83,123].
There are no randomized trials comparing splenectomy with expectant management. Observational evidence to support the efficacy of splenectomy includes the following:
●A 2016 series followed 79 individuals with HS after undergoing partial splenectomy at a single institution in France [126]. The indications for splenectomy were transfusion dependence or severe anemia in 39 and other symptoms (fatigue, gallstones, icterus) in 40. The mean age for splenectomy was 4.3 years for those who were transfusion-dependent and 11 years for those with symptoms of anemia. The procedure involved removal of 85 to 95 percent of splenic tissue using an open approach, with concurrent cholecystectomy if gallstones were present.
At a mean of 11 years of follow-up, all patients but one had a significant improvement in hemoglobin level (mean increase, 0.97 g/dL) and reduction in number of transfusions (from 3.1 to 0.2 per patient per year), a benefit that remained stable or continued to improve over the course of 10 years. A composite endpoint of no symptoms from anemia was documented in 69 of the children (87 percent) and 65 were transfusion-free.
Regrowth of the splenic remnant was common, and 21 patients (27 percent) underwent reoperation with total splenectomy, approximately half for a significant decrease in hemoglobin and half for other symptoms related to splenomegaly or hemolysis. The typical interval between the initial partial splenectomy and the subsequent total splenectomy was 7 to 9 years. Of the 46 who did not undergo concomitant cholecystectomy, 16 (35 percent) developed gallstones, typically several years after splenectomy. There were no severe infections requiring hospitalization and no thrombotic complications.
●Two reports from 2015 and 2016 described outcomes in a consortium registry of patients with a variety of congenital hemolytic anemias (Splenectomy in Congenital Hemolytic Anemia [SICHA]) that included 61 children and adolescents with HS [127,128]. Procedures were evenly divided between total and partial splenectomy; most were performed laparoscopically. Hemoglobin increased in all of the children with HS (mean increase, 4.1 g/dL; greater increases with total than partial splenectomy), and transfusion dependence in the group as a whole decreased from 22 to 4 percent [128].
●A 2001 series of 48 individuals with HS reported that those who had undergone splenectomy had a mean hemoglobin of approximately 15 g/dL, and those who had not undergone splenectomy had a mean hemoglobin of approximately 12 g/dL (table 2) [65].
Additional smaller series have reported similar findings, although some have observed more concerning complications such as post-splenectomy sepsis [129-134]. (See 'Complications' below.)
In our experience, the typical post-splenectomy course includes an increase in hemoglobin, a decrease in reticulocyte count, and a decrease in serum bilirubin levels, all of which occur over the course of several days. Often, the hemoglobin and bilirubin become normal or near normal, although RBC survival remains shorter than normal and the reticulocyte count may remain mildly elevated. In individuals with severe disease, the risk of life-threatening anemia and the need for regular transfusions is often eliminated, although some degree of anemia may persist; adverse effects on growth and development and pain due to splenomegaly will also be ameliorated. This is consistent with observations published by other experts [83,122,123,135]. The likelihood of requiring cholecystectomy for gallstone disease may also be reduced, as noted above; however, reducing the need for cholecystectomy is rarely an indication for splenectomy.
In patients for whom splenectomy is appropriate but surgery is refused or contraindicated, partial splenic embolization has been employed, with anecdotal reports of success [136].
Presplenectomy considerations — For individuals considering splenectomy (total or partial), it is prudent to ensure that all immunizations for encapsulated organisms have been administered with sufficient time to develop an antibody response (typically approximately two weeks before the surgery). Specific recommendations vary based on patient age and number of vaccine doses previously received. (See "Prevention of infection in patients with impaired splenic function", section on 'Children'.)
For children two years or older who have received all recommended routine vaccinations, the following is appropriate:
●Pneumococcal disease – If standard four doses of PCV13 have not previously been administered, one or two doses should be given to complete the series. A single dose of PPSV23 should also be given before splenectomy (but not within eight weeks of PCV13 administration).
●Haemophilus influenzae – A single dose of Hib should be administered.
●Meningococcal disease – Two doses of meningococcal conjugate vaccine (either Menactra or Menveo) should be administered.
Children younger than two years or those who have not received routine vaccinations should be vaccinated on a catch-up schedule.
For individuals with gallstones, it may be advantageous to perform simultaneous cholecystectomy at the time of splenectomy. This decision takes into account the size and symptoms of the stones as well as other operative factors. The use of cholecystectomy in individuals with asymptomatic gallstones is controversial; patient values and preferences should be factored into this decision. (See "Approach to the management of gallstones".)
As noted separately, it is important to confirm that the diagnosis is HS rather than another inherited hemolytic anemia such as hereditary stomatocytosis (HSt), for which outcomes with splenectomy are considerably worse. (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)", section on 'Management'.)
Operative techniques — Splenectomy was traditionally performed as a total splenectomy via laparotomy, which allows a search to be made for accessory splenic tissue, which may be located at other sites within the abdomen. If not removed, an accessory spleen may grow and result in the recurrence of symptomatic anemia [137].
However, laparoscopic splenectomy is increasingly used by surgeons with expertise in this technique. There are no randomized trials comparing open versus laparoscopic splenectomy in HS; however, observational studies in broader pediatric populations and case series have observed that, when performed properly, laparoscopic splenectomy is associated with lower complication rates and shorter hospital stays [138-143]. Laparoscopic splenectomy appears to be equally effective in locating and removing an accessory spleen if present [141]. Thus, laparoscopic splenectomy is used when there is appropriate institutional and surgical expertise [83,144]. In rare cases with a very large spleen, it may be necessary to extend the incision. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Surgical approach'.)
For younger children who cannot delay splenectomy until after six years of age, we suggest partial splenectomy (also called subtotal or near-total splenectomy). There are no randomized trials comparing partial splenectomy with total splenectomy in HS, and the decision between total and partial splenectomy is made on a case-by-case basis. Compared with total splenectomy, partial splenectomy is likely to be effective in reducing hemolysis while maintaining splenic immune function, although it is probably less effective than total splenectomy in reducing hemolysis [129,130,145-154].
Following partial splenectomy, the spleen eventually regrows and regains part or all of its previous size, and a second (complete) splenectomy may be required. In many cases, this is performed at a time when the patient is considerably older, with a reduced risk of sepsis. Some individuals who undergo near-total splenectomy may have less regrowth of the splenic remnant [148]. Partial/subtotal splenectomy should be accompanied by all of the precautions regarding potential sepsis risk (eg, vaccinations, antibiotics) in case of secondary necrosis of the splenic remnant [145].
Complications — Splenectomy has a number of known risks of which patients (or parents) should be aware [123].
General information about operative and postoperative risks is presented separately. (See "Elective (diagnostic or therapeutic) splenectomy", section on 'Postoperative risks'.)
Evidence regarding postoperative risks specific to HS includes:
●Operative risks – Operative risks such as infection, bleeding, or injury to adjacent organs such as the stomach or tail of the pancreas; these are relatively infrequent.
●Infections – Infections including overwhelming sepsis, from encapsulated organisms (eg, Streptococcus pneumoniae, Neisseria meningitidis, H. influenzae) that can no longer be removed by normal splenic clearance mechanisms, as well as certain other microorganisms including plasmodia, Babesia, Bordetella, and Capnocytophaga species (from animal bites) [123]. These risks are thought to be highest in the first year following splenectomy and in individuals undergoing splenectomy before five to six years of age.
•A 1973 review evaluated 850 patients, mostly infants and children, who had undergone splenectomy for HS; 3.5 percent developed sepsis and 2.2 percent died of infection [155].
•A 1995 review evaluated 226 patients with HS who underwent splenectomy up to 45 years earlier [156]. Four deaths from sepsis occurred 2, 18, 23, and 30 years after splenectomy, and the estimated mortality from overwhelming sepsis was 0.73 per 1000 patient-years. The mortality rates for the 35 children who underwent splenectomy prior to six years of age and for the 191 individuals who underwent splenectomy at an older age were 1.12 and 0.66 per 1000 years, respectively, both of which were far higher than those seen in the general population.
•A 1999 review of 264 children who underwent splenectomy at a single medical center reported that 10 (3.8 percent) developed post-splenectomy sepsis within a mean period of two years [157]. Nine of the 10 episodes occurred in patients whose surgery was performed between the ages of zero and five years.
However, risks of sepsis are likely to have declined with improved options for preoperative vaccinations and postoperative prophylactic penicillin. This was illustrated in a 1991 study from the Danish National Patient Registry that demonstrated a dramatic reduction in serious S. pneumoniae infections following pneumococcal vaccination [158]. Individuals who did not receive appropriate presplenectomy vaccinations should have a thorough review of their immunization history and should receive vaccinations as discussed separately. (See "Prevention of infection in patients with impaired splenic function".)
●VTE – Venous thromboembolic (VTE) complications including thromboses of the deep veins, pulmonary emboli, splenic or portal vein thrombosis, as well as thrombosis in other unusual sites [159,160]. VTE events appear to be more common in individuals with HS who undergo splenectomy than in those who do not, but the individuals who undergo splenectomy may have had more severe underlying disease, making direct comparisons difficult [161]. Thromboprophylaxis at the time of surgery should be based on standard practices; there is no indication for extended thromboprophylaxis beyond the usual duration [83]. This subject is discussed in detail separately:
•Children – (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Approach to VTE prophylaxis'.)
•Adults – (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)
●Arterial thrombosis – Arterial thrombotic events may also be increased relative to individuals with HS who do not undergo splenectomy, with the same caveat that applies to VTE (patients who undergo splenectomy may have more severe underlying disease) [161,162].
●Pulmonary hypertension – It is not clear whether pulmonary artery hypertension (PAH) is a complication of splenectomy in HS. A case report described an individual with HS who underwent splenectomy at the age of 15 years and then developed PAH 32 years later [163]. Retrospective studies have suggested that individuals who have undergone splenectomy for HS and other hemolytic anemias are at greater risk of PAH than those who have not undergone splenectomy; however, it is not clear whether the increased risk is due to the underlying disorder, the splenectomy, or the combination [164-168]. In some cases, affected individuals also had hypercoagulable states, potentially further confounding a possible association [165,169]. If PAH occurs, it may take many years. In a study that evaluated 26 children with HS at a median of 4.5 years after splenectomy, none had evidence of PAH [170].
In a 2009 administrative database review that included 1657 children and adolescents under age 18 with a diagnosis of HS who underwent splenectomy, no adverse event occurred in more than 1 percent of the cases [171].
Prenatal testing, family testing, and genetic counseling — If one child is born with HS, there may be concern about HS in a sibling. Thus, if HS is diagnosed in a child, we obtain a full family history and obtain a CBC, reticulocyte count, and examination of the peripheral blood smear on each parent and sibling in order to determine whether the spherocytic gene variant is dominant or recessive. Appropriate counseling can be performed once this information has been obtained. It is especially important to test a newborn sibling for HS, as this may be associated with severe degrees of hyperbilirubinemia and anemia during this period.
For individuals of childbearing age with HS, review of the familial gene variant and its mode of transmission (autosomal dominant or recessive) may be useful for informing discussions of the likelihood of HS in children. If the familial variant is known to act in an autosomal dominant fashion, it is important to make this information clear in the prenatal record and to make the information available to the pediatrician before delivery [86]. Some individuals who had HS as a child and were treated with splenectomy may have forgotten about the condition or may not realize the implications for their child.
It is also important to test newborns of affected parents for HS, as affected newborns may have severe hyperbilirubinemia and anemia. This may be done by a clinician with expertise in hemolytic anemias or by a genetic counselor. It is possible for an individual with no hemolysis, no spherocytes on the blood smear, and a normal reticulocyte count to be a carrier of HS, which may be relevant in certain families [83]. (See "Genetic counseling: Family history interpretation and risk assessment".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults".)
SUMMARY AND RECOMMENDATIONS
●Genetics and pathophysiology – Hereditary spherocytosis (HS) is a heterogeneous group of disorders caused by variants in certain genes that encode proteins of the red blood cell (RBC) membrane and cytoskeleton, most commonly spectrin (SPTA1 and SPTB genes), ankyrin (ANK1 gene), and band 3 (SLC4A1 gene). These abnormalities decrease the levels of proteins that link the RBC inner membrane skeleton to the outer lipid bilayer (figure 2), which in turn leads to membrane vesiculation, progressive spherocyte formation, and hemolysis. Approximately three-fourths of these variants act in an autosomal dominant manner, with the remainder autosomal recessive. (See 'Pathophysiology' above.)
●Prevalence – HS is seen in all populations but appears to be especially common in people of northern European ancestry. In these individuals, HS affects as many as 1 in 2000 to 1 in 5000 (prevalence, approximately 0.02 to 0.05 percent). HS may account for as many as 1 percent of infants with neonatal jaundice. (See 'Epidemiology' above.)
●Clinical findings – HS can present at any age and with any severity. The majority of affected individuals have mild or moderate hemolytic anemia. Neonates with HS often present with jaundice and hyperbilirubinemia; the serum bilirubin level may not peak until several days after birth. In older children and adults, the presentation may be that of an incidental finding of hemolytic anemia or spherocytes on the blood smear (picture 2), or the individual may be symptomatic from anemia, splenomegaly, or pigment gallstones. Exacerbations of anemia may occur in certain settings such as parvovirus infection, mononucleosis, or pregnancy. (See 'Clinical presentation' above.)
●Evaluation – All individuals suspected of having HS based on a known family history and/or clinical findings should have complete blood count (CBC) with reticulocyte count and RBC indices, review of the blood smear by an experienced individual, testing for hemolysis, and Coombs testing. In neonates or infants, a mean corpuscular hemoglobin concentration (MCHC) ≥36 g/dL is highly suggestive of HS. Spherocytes and reticulocytosis are less reliable indicators in infants but are important in older children and adults. (See 'Initial testing' above.)
●Diagnostic confirmation – A number of tests are available for confirming the diagnosis of HS in individuals in whom the disorder is suspected based on the history, examination, and results of initial laboratory testing. Of these, EMA (eosin-5-maleimide) binding is our preferred test because of its high sensitivity and specificity, as shown in the figure (figure 3); this test is widely available. Other options include osmotic fragility, osmotic gradient ektacytometry, glycerol lysis and modifications (acidified glycerol lysis, pink test), and cryohemolysis. In atypical cases, two tests can be combined, and if the diagnosis remains in question, DNA testing can be performed. (See 'Confirmatory tests' above and 'Specialized testing for selected cases' above and 'Diagnosis' above.)
●Differential diagnosis – The differential diagnosis of HS includes a number of other hemolytic anemias with spherocytes on the blood smear (figure 5). Other inherited RBC membrane disorders include hereditary elliptocytosis (HE) and hereditary stomatocytosis (HSt). Other possible diagnoses in neonates include hemolytic disease of the fetus and newborn (HDFN), infantile pyknocytosis, and congenital dyserythropoietic anemia (CDA) type II. Other possible diagnoses in adults include autoimmune or drug-induced hemolytic anemias. (See 'Differential diagnosis' above.)
●Management – Treatment of HS is directed at minimizing complications of chronic hemolysis and anemia. Neonates may require therapy for hyperbilirubinemia and in severe cases, transfusion or even exchange transfusion. Erythropoietin may be used in some infants to reduce transfusion requirements. For those with moderate to severe hemolysis, we suggest folic acid supplementation (Grade 2C); a typical dose is 1 to 2 mg/day. Pregnant women with HS require higher doses of folic acid, as presented separately. (See 'Overview of treatment' above and "Folic acid supplementation in pregnancy".)
●Splenectomy – For children with HS whose disease remains transfusion dependent or who are severely symptomatic from anemia after one year of age, we suggest splenectomy (Grade 2B). For children who are under six years of age, we suggest partial rather than total splenectomy (provided there is adequate surgical expertise) (Grade 2C); total splenectomy, if necessary, can be delayed until after the age of six years to reduce the risk of sepsis. Some children closer to six years may reasonably elect to have a total splenectomy rather than partial splenectomy as the initial procedure. Observational data demonstrate a dramatic reduction in transfusion requirements after splenectomy. The use of splenectomy in individuals with moderate disease is individualized based on symptoms (eg, discomfort from splenomegaly, distress from jaundice). (See 'Decision to pursue splenectomy' above.)
●Splenectomy risks – For individuals considering splenectomy, it is prudent to ensure that all immunizations for encapsulated organisms have been administered with sufficient time to develop an antibody response. For individuals with gallstones, it may be possible to perform simultaneous cholecystectomy at the time of splenectomy. Patients should be aware of different operative techniques available (partial versus total splenectomy; open versus laparoscopic procedures) and potential complications of splenectomy, which include potentially life-threatening sepsis, venous thromboembolism (VTE), and possibly arterial thromboembolic events or pulmonary hypertension. It is important to confirm that the patient does not have HSt, for which outcomes with splenectomy are considerably worse. (See 'Presplenectomy considerations' above and 'Operative techniques' above and 'Complications' above and "Elective (diagnostic or therapeutic) splenectomy", section on 'Postoperative risks'.)
●Family members – Family testing, prenatal testing, and/or genetic counseling may be useful in family members of affected children, children of affected parents, and individuals of childbearing age. (See 'Prenatal testing, family testing, and genetic counseling' above.)
ACKNOWLEDGMENT — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.
