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CHAPTER 60 HYPERSPLENISM AND HYPOSPLENISM

CHAPTER 60 HYPERSPLENISM AND HYPOSPLENISM
Williams Hematology

CHAPTER 60 HYPERSPLENISM AND HYPOSPLENISM

ALLAN J. ERSLEV

Hypersplenism

History and Definition

Etiology and Pathogenesis

Clinical Features

Laboratory Features

Therapy, Course, and Prognosis
Hyposplenism

Definition

Etiology and Pathogenesis

Clinical Features

Laboratory Features

Therapy, Course, and Prognosis
Chapter References

The normal spleen shares with other tissues a number of functions, such as the formation, storage, and destruction of blood cells and the production of antibodies, but the spleen has one unique function, that of filtering blood and removing abnormal or foreign material. From an evolutionary point of view, this latter function is no longer vital, but it determines the clinical consequences of hyper- or hyposplenism.
Hypersplenism occurs when the size of the spleen is increased by cells or tissue components or by vascular engorgement. This augments its filtering function, and even normal blood cells experience a delayed transit and temporary sequestration. The sequestration of granulocytes and platelets causes neutropenia and thrombocytopenia, but these cells appear to tolerate their prolonged stay in the spleen. The trapped red cells on the other hand are usually destroyed causing a hemolytic anemia. Splenectomy is called for if the hypersplenic cytopenias are severe enough to demand intervention or if the enlarged spleen causes pain and discomfort. To eliminate the surgical trauma and maintain some splenic functions, partial destruction of the spleen by embolization can be accomplished by the intraarterial infusion of gel particles.
Hyposplenism occurs when splenic function is reduced in certain illnesses or eliminated by splenectomy. It may be well tolerated but demands prevention or vigorous treatment of all suspected bacterial infections.

HYPERSPLENISM
HISTORY AND DEFINITION
The size and function of the spleen have intrigued physicians and philosophers since ancient times.1 Many mysterious powers have been assigned to the spleen, but it was not until the turn of the century that it was related to destruction of blood cells. In 1899, Chauffard proposed that increased splenic activity causes hemolysis.2 This proposal provided the impetus for therapeutic splenectomy, which was carried out first in 1910 by Sutherland and Burghard3 in a patient with hereditary spherocytosis and then in 1916 by Kaznelson4 in a patient with idiopathic thrombocytopenic purpura. Since then, normal and abnormal functions of the spleen have been identified and assigned to two basic mechanisms: filtration and macrophage surveillance of blood in the red pulp and antibody synthesis in the white pulp (see Chap. 5).
Hypersplenism occurs when these functions are appropriately increased (as in hereditary spherocytosis or idiopathic thrombocytopenic purpura) or inappropriately increased (as in portal hypertension).5 As enunciated by Dameshek,6 hypersplenism is usually associated with splenomegaly, causes cytopenias with compensatory marrow hyperplasia, and is most often corrected by splenectomy.
ETIOLOGY AND PATHOGENESIS
The normal spleen is an important component of the mononuclear phagocyte system and participates in antigen processing and antibody synthesis. Speculation exists that the spleen is the principal producer of autoantibodies aimed at circulating blood cells, but firm support for this proposal exists only for antiplatelet antibodies.9 The main mission of the spleen, however, is to serve as a filter, retaining defective blood cells and foreign particles in a bed of phagocytic cells.10 This is accomplished by having part of the splenic blood supply (about 5 to 10 percent) diverted into the red pulp, where it slowly percolates through a nonendothelialized mesh studded with macrophages.11 The blood then reenters the circulation through narrow slits, measuring 1 to 3 microns, in the endothelium of the venous sinuses. The bulk of the blood supply is rapidly channeled through regular endothelialized vessels, linking the arterioles with the venous sinuses and is not filtered or modified.12 In many animals, such as the dog and the horse, the red pulp serves as a reservoir for red cells, and splenic contraction can provide the red cell volume with a functionally important boost.13 In humans, however, the splenic capsule is poorly contractile and red cells are not stored to any significant degree in the spleen.14 On the other hand, a large fraction of the circulating neutrophil pool is marginated in the spleen,14 and about one-third of platelets are sequestered temporarily by this organ.15
The slow transit of blood through the red pulp permits the macrophages to recognize and destroy antibody- or complement-coated cells and microorganisms and to poorly deformable cells or particles retained mechanically by the narrow exit slits in the venous sinuses (see Chap. 5).
This appropriate filtration and elimination of aged and defective cells becomes excessive and harmful in patients with hereditary abnormalities of the red cell membranes or with antibody-coated blood cells. These cells may be functionally intact, but, since they are retained and destroyed in the spleen, symptomatic cytopenias may ensue. The spleen becomes moderately enlarged due to overwork hypertrophy and may, in addition to the elimination of the abnormal cells, sequester and destroy normal blood cells.
Splenomegaly due to a variety of causes usually increases the proportion of blood channeled through the red pulp, causing inappropriate hypersplenic sequestration of both normal and abnormal blood cells.16 The causes of such splenomegaly are many and various (Table 60-1), with a few diseases associated with massive splenic enlargement (Table 60-2). However, the increase in the size of the filtering bed is more pronounced when the splenomegaly is caused by congestion (as in portal hypertension) than when it is caused by cellular infiltration (as in leukemias, thalassemias, or amyloidosis). Nevertheless, even infiltrative disorders such as Gaucher disease and myelofibrosis may be associated with severe hypersplenic sequestration of normal cells.

TABLE 60-1 CLASSIFICATION AND THE MOST COMMON CAUSES OF SPLENOMEGALY WITH HYPERSPLENISM

TABLE 60-2 CAUSES OF MASSIVE SPLENOMEGALY*

The platelets are especially likely to be sequestered by an enlarged spleen, and up to 90 percent of the total number of platelets in blood may be found there.15 However, both sequestered white cells and platelets survive almost normally in the spleen and may be available, although slowly, when needed to combat infections or vascular damage.14,15,17 The red cells, on the other hand, are metabolically less self-sufficient and may be destroyed prematurely in the red pulp.18
It has been proposed that anemia in patients with splenomegaly is in part due to dilution of red cells in an expanded plasma volume.19 However, it appears that this expansion, as measured by radiolabeled albumin or fibrinogen, is due more to an increase in the splenic pool of protein rather than to an increase in circulating plasma volume.20
The increased blood flow from an enlarged spleen tends to overload the splanchnic vasculature and increase portal pressure. This initiates a vicious cycle, with portal hypertension causing splenomegaly, which in turn increases portal pressure. In a few cases splenectomy has alleviated some of the problems of portal hypertension.21
CLINICAL FEATURES
A slight to moderate enlargement of the spleen is usually asymptomatic and is first found during a routine examination of the abdomen. Even massive splenomegaly can be well tolerated, but the patients may complain of abdominal discomfort, early satiety, and trouble sleeping on one or the other side. Pleuritic-like pain in the left upper quadrant with or without a rub may accompany a splenic infarct. In children with sickle cell anemia or malaria and in adults with red cell abnormalities such as spherocytosis, the spleen may become acutely enlarged and painful due to a sudden increase in red cell pooling and sequestration. These hemolytic or sequestration crises often follow infections and are characterized by a sudden aggravation of the anemia.
The size of an enlarged spleen is difficult to assess by manual palpation. Youngsters and thin patients with low diaphragms may have a palpable spleen tip without splenomegaly.22 In general, however, a palpable spleen signifies splenomegaly and is measured by the number of centimeters it protrudes below the costal margin. Such an enlargement can be verified and more accurately measured by abdominal scanning after the injection of colloid particles labeled with radioactive technetium or of heat-damaged red cells tagged with radioactive chromium. However, these tests have almost all been replaced by the use of ultrasound for the assessment of splenic size. CT scans and magnetic resonance imaging are used primarily to provide structural information in order to identify cysts, tumors, and infarcts.23
LABORATORY FEATURES
Cytopenia associated with splenomegaly and hyperplasia of the corresponding cellular element in the marrow constitute the characteristic triad of hypersplenism. The cellular morphology is usually normal, although a few spherocytes may be present due to metabolic conditioning of red cells during the slow transit through the red pulp.24 A compensatory increase in red cell production usually is evident by an increase in the reticulocyte count. However, since the spleen preferentially sequesters reticulocytes, the reticulocytosis may not be as prominent as otherwise expected. The presence of a compensatory increase in granulocyte or platelet production is more difficult to identify, and tests such as the epinephrine mobilization tests have been used to distinguish sequestration from ineffective cellular production. Epinephrine will release neutrophils and platelets from the spleen, but since it also will release the cells from marginal pools, the test may be difficult to interpret.25
THERAPY, COURSE, AND PROGNOSIS
TOTAL SPLENECTOMY
Total splenectomy is indicated as an emergency procedure after abdominal trauma and partial rupture of the spleen. It is also indicated when splenic size or infarcts causes sustained left upper abdominal pain or discomfort. Splenectomy also is considered when there is pathologic splenic sequestration of circulating blood cells resulting in potentially dangerous cytopenias (see Table 60-1). In such circumstances, splenectomy may result in dramatic restoration of blood counts to normal levels within weeks after surgery.
Hereditary spherocytosis and idiopathic thrombocytopenic purpura are the most common responsive causes, but other congenital or autoimmune cytopenias frequently are treated with splenectomy. The hemolytic anemia of thalassemia major is usually aggravated and complicated by hypersplenic cytopenias. In such cases, splenectomy may improve the response to transfusion. Patients with sickle cell anemia may benefit if repeated sequestration crises and abdominal pains occur before autosplectomy renders the spleen inactive.27 In autoimmune neutropenias and acquired hemolytic anemias, splenectomy may not only remove an inappropriate sequestration site but also decrease the production of autoantibodies.
Since splenectomy will reduce the volume of blood flowing into the portal circulation, it often is used to alleviate portal hypertension.28 However, since intra- or extrahepatic portal-systemic shunts can reduce both excessive blood flow and congestive hypersplenic sequestration, they may be preferable.29,30,31 and 32
In patients with infiltrative splenomegaly and hypersplenism, it is often difficult to decide what to do. In some diseases, such as Gaucher disease, the spleen serves a useful function as a sink for indigestible glycocerebosides. In others such as agnogenic myeloid metaplasia or chronic leukemias, it participates in not only the destruction but also the production of blood cells. Various tests have been designed to evaluate how much splenic enlargement is due to cellular sequestration versus useful cellular production.33 However, such tests have had limited clinical utility. Partial splenectomy has become popular because it may minimize the risks for immediate postsplenectomy surges in the platelet count or systemic infections due to complete absence of protective splenic filtering.34,35 and 36
PARTIAL SPLENECTOMY
Partial surgical removal of the spleen37 often is performed with ligation of some of the splenic arteries38 or the intra-arterial infusion of gel-foam particles.39 These latter procedures result in the induction of large splenic infarcts and a reduction in the active splenic mass. These procedures can be performed percutaneously or transvascularly, but the patients have to be observed closely for a number of days to weeks to detect signs of intra-abdominal rupture of the splenic infarcts. The results have been encouraging as testified by a number of long-term follow-ups.40,41,42,43 and 44
Partial ablation by X-ray radiation, especially in poor surgical risk patients, is a popular alternative to more invasive procedures.45 Although supported by some enthusiastic reports, the results have not been too encouraging.
HYPOSPLENISM
DEFINITION
Hyposplenism occurs when splenic functions are reduced by disease or are absent after splenectomy.7 It may or may not be associated with a reduction in splenic size. Impaired filtering function usually causes a mild thrombocytosis and an increased risk of severe bloodstream infections.8 The filtering and immunogenic functions of the spleen are reduced to a varying degree in a number of illnesses (Table 60-3) and of course are absent after splenectomy.26

TABLE 60-3 HYPOSPLENISM

ETIOLOGY AND PATHOGENESIS
The normal neonate46,47 as well as the aged individual48,49 may demonstrate findings suggestive of impaired splenic function. These include occasional Howell-Jolly bodies and erythrocyte pits (see “Laboratory Features,”). However, the clinical significance of such functional hyposplenism is uncertain.
Congenital asplenia may be found in infants with situs inversus and other developmental abnormalities.50 Autoimmune disorders, such as glomerulonephritis,51 systemic lupus erythematosus,52,53 and 54 or rheumatoid arthritis,54 have been associated with both laboratory evidence (Howell-Jolly bodies and erythrocyte pits, increased white cell and platelet counts) and the clinical manifestations (impaired clearance of sensitized cells, overwhelming sepsis with encapsulated bacteria) of functional hyposplenism. The same is true for chronic graft-versus-host disease,56,57 sarcoidosis,58 alcoholic liver cirrhosis,59,60 or hepatic amyloidosis.61,62 Hyposplenism occurs in 30 to 50 percent of patients with celiac disease63,64 and also commonly occurs in inflammatory bowel disease.65,66 The mechanisms for this are unknown.
The presence of space-occupying lesions such as cysts or tumors may cause hyposplenism. However, in many cases compensatory hypertrophy of the remaining normal tissue prevents this complication. Splenic replacement by neoplastic cells, as in lymphomas and leukemias, does not usually cause hyposplenism, although splenic sequestration may be less than anticipated in view of the extent of splenic enlargement. Splenic irradiation67 and vascular obstruction68 also may lead to functional hyposplenism. However, among all these possibilities, sickle cell anemia and surgical splenectomy are the most common causes of clinically significant hyposplenism.
Although the presence of an enlarged spleen usually suggests hypersplenism, the size of the spleen is not a reliable index of splenic function. Complete splenic replacement by cysts, neoplastic tissues, or amyloid is an example of hyposplenic splenomegaly.69 In addition, acute sequestration crises, which occur occasionally in patients with malaria70 and essential thrombocythemia71 and regularly in infants with sickle hemoglobinopathies,72 may clog the red cell pulp with cellular debris and result in hypersplenic sequestration being replaced temporarily or permanently by hyposplenism.
CLINICAL FEATURES
In most patients with hyposplenism, reductions in the filtering of blood and immunologic handling of antigens are of little or no clinical consequence, and the diagnosis when made is based exclusively on laboratory findings.
If the spleen is totally destroyed or removed, however, serious infections may ensue. Since the spleen is a major component of the mononuclear phagocyte system, hyposplenism or splenectomy will reduce antibody synthesis at least temporarily. This rarely causes a problem and may actually be beneficial in autoimmune disorders. However, the removal of an efficient filtering bed in which opsonized organisms are exposed to macrophages may lead to an overwhelming sepsis. The responsible organism is usually an encapsulated bacterium, such as Pneumococcus or Haemophilus influenzae. Unrestrained in vivo proliferation of such microorganisms may cause fatal septicemia.73,74 and 75 The risk is greatest among the very young whose general immunologic tolerance has not matured enough to counteract bacterial infections. For this reason, splenectomy in young children should be deferred until after the fourth year of life. The risk is lower in adults, but even healthy adults whose normal spleens have been removed after accidental rupture are at increased risk.
LABORATORY FEATURES
The reduction or absence of normal splenic function can be recognized by certain hematologic changes. Some of these are nonspecific, such as a slight to moderate increase in the white cell count and platelet count. However, the finding of Howell-Jolly bodies, pitted erythrocytes, and target cells in the blood smear is of greater diagnostic significance. For still unknown reasons the red cell surface area is increased, causing buckling and target cell formation.76 Nuclear fragments that normally are removed in the spleen are present in circulating red cells and are termed Howell-Jolly bodies.77 They are almost always present in the asplenic state, but only 1 of 100 to 1000 red cells is affected.77 A sensitive indication of hyposplenism is the appearance of pits or pocks on the cell surface.78,79 They consist of submembraneous vacuoles and can be seen only in wet preparations of red cells using direct interference-contrast microscopy.
Oxidative drugs may produce Heinz bodies even in normal individuals, but those red cell inclusions are effectively removed by the spleen. After splenectomy they may be observed in supravitally stained blood films. Nucleated red cells are, on the other hand, only rarely seen on blood films after splenectomy (except in patients with hemolytic disorders, in whom their number may increase dramatically). The reticulocyte count remains within normal values, and the life span of red cells is unchanged as other organs take up the function of removing senescent red cells.
Ultrasound, MRI, or CT scan can measure the actual size of the spleen. The clearance of 51Cr-labeled heat-damaged red cells has been used as a measure of splenic function, but this is a difficult test to evaluate. Technetium 9mTc sulfur colloid particles are now more commonly used for scanning, a reliable measure of the capacity of the spleen to clear particulate matter from the bloodstream.80
THERAPY, COURSE, AND PROGNOSIS
Immunization with a polyvalent pneumococcal vaccine81 should be carried out in all patients with hyposplenism, preferably before splenectomy.82 No revaccination is needed according to present recommendations. In children, a vaccine against H. influenzae should also be administered. Some pediatricians prescribe penicillin as prophylaxis for every asplenic child.83 Other physicians advise all asplenic patients that no febrile infection should be considered trivial. They instruct these patients to take penicillin upon the onset of symptoms and not to wait for office visits or culture results. Also, dental work, especially tooth extraction, should always be covered with broad-spectrum antibiotics, such as clindamycin or amoxicillin.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology

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