Splenectomy

Splenectomy INDICATIONS, TECHNIC A2CD COMPLICATIONS

W A L T E R F. B A L L I N G E R , II ALLAN J. E R S L E V

T A B L E OF C O N T E N T S HISTORICAL NOTE

3

ANATOMY

6

White Pulp.

9

Marginal Zone.

9

Red Pulp

9

NORMAL AND ABNORMAL FUNCTIONS

10

The Spleen as a Filter .

11

The Spleen as a Reticuloendothelial Organ

17

DIAGNOSIS OF SPLENOMEGALY AND HYPERSPLENISM

20

Splenomegaly

20

Hypersplenism .

21

Classification of Potential Hypersplenic Disorders

26

RUPTURE OF THE SPLEEN

34

MISCELLANEOUS CONDITIONS OF THE SPLEEN

41

OPERATIVE TECHNIC.

42

COMPLICATIONS OF SPLENECTOMY

46

is Associate Professor of Surgery, Johns Hopkins University School of Medicine. He received his M.D. degree from the University of Pennsylvania, and served his internship and took his residency training in surgery at the Columbia Division of Bellevue Hospital and the Columbia-Presbyterian Medical Center. Dr. Ballinger's investigative interests include gastrointestinal, metabolic and hematologic problems applied to surgery.

is Thomas Martinez Cardeza Research Professor of Medicine and Director of the Cardeza Foundation for Hematologic Research, Jefferson Medical College. He is a graduate of the University of Copenhagen and served his internship in that city. His residency training was gained at Memorial Hospital in New York and at Grace-New H a v e n Hospital. Dr. Erslev's work has been primarily in the field of hematology, and he is particularly interested in the control of red cell production under normal and abnormal conditions.

HISTORICAL NOTE ERASISTRATUS (310-250 B.c.) was primarily concerned with describing the functions, as opposed to the appearance, of the organs of the body and came close to the discovery of the circulation. He studied the abdominal viscera and was of the opinion that the spleen was of no use whatever. Some 350 years later, Galen described the spleen as "an organ full of mystery." The ancients preferred to assign various roles to the spleen in an attempt to explain some of the theologic and physiologic mysteries of the day. One of the theories bruited about the Graeco-Roman littoral during the last few centuries B.C. was that the presence of the spleen decreased the speed of running. Shakespeare commented in King John: I am scalded with my violent motion and spleen of speed to see your Majesty. (V, vii, 49) Although the evidence is not conclusive, a rather rugged and probably incomplete splenectomy was performed with the hot iron upon marathon contestants in order to improve their running. A more pleasant function of the spleen was reported by Pliny and was a popular belief

of the time. It was thought that the spleen was in some way connected with mirth. Thus, loss of the spleen resulted in loss of laughter and, contrariwise, those who laughed a lot had large spleens. Shakespeare was also aware of this ancient function of the spleen as noted in

Measure for Measure: Such fantastic tricks as make the angels weep; who, with our spleens, would all themselves laugh mortal. (II, ii, 121) Again, in Twelfth Night, Shakespeare observed: If you desire the spleen and will laugh yourself into stitches, follow me. (III, ii, 72) Splenomegaly of massive proportions caused by malarial and other parasitic infections was not uncommon in ancient Greece and Rome. It is difficult to ascribe much mirth to a huge spleen that reached the pelvis and occupied much of the abdomen and was associated with repeated attacks of malaria. A favorite method of dispensing with an enemy was a sudden blow to the left subcostal region. There were, however, anatomic investigations. Aretaeus of Cappadocia (c. 150 A.D.) assigned to the spleen the role of straining black blood, or black bile. This was opposed to the function of the liver, which produced yellow bile. Thus, enlargement of the spleen indicated a derangement in this hypothetically important fluid. Galen was of the opinion that black bile was formed in the liver and was, somehow, attracted to the spleen. Man's inhumanity to man has produced many surgical advances. The earliest splenectomies following the Renaissance were undoubtedly necessitated by posttraumatic splenic eviscerations, the surgeon merely completing the delivery. The first such record of a splenectomy was that by Leonardo Fioraventi in 1549, but the veracity of this has been doubted. However, as bands of soldiers throughout Europe joyously attacked each other with spears and axes, crossbows and arquebuses, musketry and grape, such cases of posttraumatic splenectomy began to be reported. Among the earliest were those described by Baillon in 1578 and by Rousset in 1581 (53). A number of these had been performed by the next century and concern was voiced regarding the effects of splenectomy. In other words, it was time to enter the laboratory. Malpighi was the first to study the microscopic anatomy of the spleen (1659) and to discover the corpuscles which bear his name, mistakenly assuming them to be endocrine glands. Although Barbette performed the first experimental splenectomy in dogs in the latter half of the 17th century (50), Clarke

reported a series in 1776 and questioned whether the animals became fatter, lost their fertility or changed somehow in manners or disposition (53). Morgagni repeated the experiments and studied the dogs for 5 years after. He noted no changes whatever in the animals. At about this time it was recalled that Aristotle, many centuries before, had noted that the spleen was not absolutely necessary for life since there were rare examples of congenital absence of the organ. The full circle of history was thus completed, and it became established that removal of the spleen did not seriously impair life. In fact, it was agreed that removal of the normal spleen apparently did not even impair good health. Thus, the way was paved both for physiologic experiments to determine the function of the spleen and also for splenectomy as a therapeutic measure which would eventually be utilized in a variety of conditions. The first splenectomy in the modem era was performed in 1826 by Quittenbaum of Rostock. It was carried out in a female patient who was suffering from cirrhosis with ascites. Little is known of this poor woman except that she died 6 hours after operation. Sporadic reports of splenectomy continued to appear. In the mid 1850's, a bitter controversy broke out in Germany following the death of a patient due to postoperative hemorrhage after removal of an enlarged malarial spleen. It was questioned whether the operation was ever justified and the argument raged throughout the learned societies of the Continent. In England, in 1876, splenectomy was first performed for massive enlargement by a surgeon of impeccable reputation, Spencer Wells. Although the patient died of an infection and the surgeon recognized that he had injured the pancreas, his reputation was so great that the operation was not questioned. It was not until the sixth patient was operated on that survival was achieved. Of the first 5, 3 died of hemorrhage and 2 of peritonitis. The first collective review appeared in 1882, detailing 29 splenectomies ( 15 ). Of these, 13 were performed for "various enlargements" and there were 8 recoveries. It is assumed that recoveries meant leaving the hospital; longevity was not discussed. The remaining 16 were performed for leukemia and there were no survivals, even from the initial effects of the operation itself. It was concluded that the operation should not be performed for leukemia because of the disastrous hemorrhage that always ensued. Following this report, the operation was performed principally for mechanical problems, such as trauma or rotation of the pedicle, and massive enlargement due to cysts and occasionally for miscellaneous, poorly understood causes. Thirty-five years later, as technic improved, splenectomy for various hematologic diseases again became more acceptable. Moynihan, in 1908, wrote an extensive chapter on surgery of the spleen in Kcen's Surgery, the most complete text of the day

(54). He devoted only a few paragraphs to an ill-defined "splenic anemia," the rest to injuries and tumors. The same author wrote a monograph on splenectomy in 1921 and most of this book was devoted to diseases of a hematologic nature (53). Since that time changes in technic have not been as significant as have advances in understanding of anatomy, function and theory of hematologic diseases; therefore, most of this discussion will be devoted to these subjects.

ANATOMY The question in modern anatomy has become not What, but Why.-MACALASTER.

At approximately the 8 mm. stage several small swellings develop in the embryo just beneath the epithelial cells of the future peritoneum, on the left side of the dorsal mesogastrium. These masses project more and more above the omental surface and, at the same time, merge. The point where this future spleen joins the dorsal mesogastrium, or greater omentum, gradually narrows and becomes the gastrosplenic ligament. By the third month of development, the spleen has almost reached its adult form, although somewhat more lobulated. During fetal life, especially from the fifth to the eighth month, there is active hematopoiesis of both red and white cells (1). Accessory spleens probably form as a result of: 1. failure of union of the tiny subepithelial swellings of the dorsal mesogastrium; 2. an unusually distant location of their formation from the main splenic buds; or, 3. a pinching off of splenic tissue from the main mass by temporary incisures or fetal lobulations. The adult spleen is a highly vascular organ located in the left upper quadrant of the abdomen. In the adult it weighs approximately 150 Gm. and is about the size of a human fist. Essentially, it is a specialized capillary bed lying between the splenic artery and its portal venous drainage system. It may act upon all known cellular and noncellular elements of the blood. The numerous suspensory ligaments of the spleen, of considerable surgical importance, are composed of peritoneal folds containing, in some cases, vessels, lymphatics and nerves (Fig. 1). The normally avascular phrenosplenic, splenocolic and a portion of the splenorenal ligaments are the site of collateral venous channels in congestive splenomegaly. The gastrosplenic omentum contains the short gastric vessels, and the medial portion of the splenorenal ligament contains the splenic artery and vein and their branches at the hilum. In humans, the capsule of the spleen is several millimeters thick 6

FIG. 1.---Ligaments of the spleen.

and can become much thicker when diseased. It is composed of dense connective tissue covered on the outside by a closely adherent peritoneum. The peritoneum may form dens~ adhesions to surrounding structures, especially the diaphragm. The peritoneum and capsule are indented at the hilum which lies in the medial aspect of the organ where it is penetrated by its blood vessels, lymphatics and nerves. From the inner surface of the capsule, branches of connective tissue subdivide the organ into smaller and smaller compartments, the smallest being several millimeters in size, which communicate with each other. In humans, the capsule of the spleen contains very little smooth muscle, differing from the highly muscular capsule of the spleen of dogs and cats. An abundant muscular sheath in these animals permits the spleen to store blood and to release it to the circulation in response to appropriate stimuli. The arteries and veins follow the course of the trabeculae as they run into or drain from the pulp or parenchyma. The lymphatics, on

the other hand, are restricted to the trabeculae and the capsule. There are sympathetic nerves associated with the blood vessels of the spleen. The compartments between the trabeculae are composed of a concentration of reticuloendothelial elements. This is known as the splenic pulp and is subdivided into the red and white pulp and the marginal zone between the two. The arterial supply to these areas is highly specialized and not completely understood (Fig. 2). Knowledge of their general structure, however, is an aid in understanding splenic function. Branches of the splenic artery are known as trabecular arteries. After passing through the white pulp, small arterial vessels pass to the marginal zone and to the red pulp to vascular spaces, terminating in the corresponding veins. It is the exact distribution of the micro-circulation within the spleen, known as its intermediate circulation, about which there is still considerable disagreement (75). A very fine and delicate reticular network is also present in the small compartments formed by the minor subdivisions of the trabeculae. This mesh-work is open in most of the splenic pulp, particularly in the red pulp where its numerous fenestrations are of special significance and will be described below.

M~

S~nu~ FIG. 2.--Microcirculation of the spleen. (From Weiss, L.: The Spleen, in Greep, R. L. (ed.), Histology [New York: McGraw-Hill Book Company, 1965].)

WHITE PULP An aggregation of lymphocytes, plasma cells, macrophages and other cells lying in a network of reticulum is known as the white pulp of the spleen. These masses of cells surround the central arteries as thin coats of lymphatic tissue or as actual follicles. The endothelium of the central artery is unusual in that it is cuboidal or even columnar, so that the lumen may be effaced when examined in tissue sections. Most probably, muscular contractions may close the lumen permitting redistribution of blood from one vessel to another. Most branches of the central artery run through the white pulp into the marginal zone, but some terminate as capillaries in the white pulp itself, and others enter the red pulp. MARGINAL ZONE This portion of the spleen is ill-defined, yet important. It may vary in size and is essentially a vascular space in a reticular network. Sometimes it contains only plasma and, at other times, many cellular elements of the blood are noted. Its importance lies in the fact that foreign material is preferentially sequestered here. RED PULP The red pulp is comprised almost entirely of splenic cords and sinuses. The cords are really a network of reticular cells which are continuous and form a regular partition (74). Thus, the sinuses and the cords form a honeycomb throughout the red pulp. The cords are somewhat similar to the marginal zone in that there is considerable sequestration of cells, and a remarkable diversity of cells and other foreign material may be seen within them. This is particularly true in diseases in which damaged cells are sequestered in the spleen. In such situations, the cells of the cords may undergo transformation into macrophages. The sinuses of the red pulp may be several hundred microns in length. They fit into the irregular honeycombed pattern of the red pulp, branching and following the distribution of the cords. They are usually about 35 to 40 microns in diameter but contain frequent gaps of 2 to 3 microns. Blood cells may be seen to traverse these gaps and become deeply indented or constricted as they pass through. The cords and the sinuses may communicate with each other from the lumen of the sinus through its lining cell and its basement membrane, which contains gaps, through the lining cells of the cord and into the vascular spaces of the cord. The sinuses eventually become the smallest tributaries of the splenic vein.

The central arteries become considerably smaller after coursing through the white pulp. As they advance into the red pulp, they become slender arteriolar vessels, called penicillar arteries, which end in small capillaries of either high or flat endothelium. Some of them are terminal vessels which end in the cords, others open into the cord by a funnel-shaped opening or through a tiny narrow orifice. Tremendous variation occurs in the arteriolar capillaries as they communicate with the sinuses and cords in the red pulp. Some of the capillaries are sheathed with phagocytic cells and it is significant that these capillaries have no basement membranes, so that the phagocytic cells lie directly beneath the endothelium. This accounts for the remarkable ability of the areas to concentrate foreign particulate matter. Thus, it may be seen that blood may flow through the spleen through several different routes (67). Such patterns of flow have been extensively studied and it has been determined that there can be a remarkable variation in the flow of erythrocytes through the spleen. In particular, it can be demonstrated, using erythrocytes tagged with radioactive chromium, that although normal cells flow promptly through the spleen, abnormal cells or normal cells in abnormal streams are considerably retarded. The importance of the variations in the pathways of the elements of the blood through the spleen probably lies in the differentiation of function of different portions; namely, the ability of the spleen to entrap as well as to produce elements of blood, and its association with the functions of lymphatic tissue, including the production of lymphocytes and monocytes as well as antibodies.

NORMAL AND ABNORMAL FUNCTIONS The normal adult human spleen is a large reticuloendothelial filter, daily sifting 350 liters of blood for defective cells or foreign bodies. Despite this seemingly vital mission, splenectomy is followed by remarkably few functional problems. After a brief period of postoperative equilibration, other organs take over its reticuloendothelial functions and its filtering capacity does not appear to be missed (18). In young children there may be decreased resistance to blood-borne infections, but even this danger has been discounted by some. In fetal life, however, the spleen may contribute significantly to physiologic homeostasis. It is a hematopoietic organ before birth and its production of cells of potential immunologic competence has recently linked it to the thymus and to the processes involved in immunologic defense and self-recognition. Information about the normal physiologic function of the spleen is primarily gained from studies of the animal spleen and from studies of the effect of splenectomy and splenomegaly in humans. It has to be 10

realized, however, that these experimental models have serious shortcomings. The spleen in some species, such as the cat or the dog, is anatomically and functionally a storage organ; the spleen in the rabbit is so small that it appears almost vestigial; and the enlarged or ruptured human spleen removed at operation is obviously not normal. These shortcomings have led to considerable differences in opinion regarding the functions of the normal spleen, differences which are still not resolved. As mentioned, anatomically the spleen is a sophisticated filter and biologically it is a reticuloendothelial organ. Although filtration and reticuloendothelial functions frequently overlap, they do represent different entities and are best described separately. THE SPLEEN AS A FILTER

The normal spleen removed, for example, during a gastrectomy contains no more than 20 to 30 ml. of red blood cells (59). This is far less than the relative content of blood in the spleen of some animals in which the organ serves as a reservoir. In the dog, during sleep or anesthesia, the spleen may sequestrate up to 35% of the red cell mass (29) and epinephrine-induced splenic contraction both in dogs and cats will lead to significant changes in the circulating blood volume. The lack of contractile muscle fibers in the capsule and trabeculae of the human spleen, along with its small content of blood, rule it out as a physiologically important storage organ. The absence of a large red cell pool in the human spleen also indicates that under normal conditions its filtering and sequestering capacity is largely unused. This conclusion is supported by in vivo studies by Harris (33) and Prankerd (59) of the rate of red cell mixing in the spleen. When red cells labeled with radioactive chromium are infused, there is a rapid increase in splenic radioactivity with complete equilibration in less than 2 minutes. This indicates that there is no significant pool of sequestered red cells in the spleen and that blood flows rapidly from artery to vein. Consequently, under normal conditions, only a few cells are filtered, probably reflecting the efficiency with which the normal bone marrow produces cells of standard size and shape. Nevertheless, splenic filtration must contribute in policing the circulating blood because splenectomy is followed by the appearance of a considerable number of abnormal cells. In the presence of defective functioning of the bone marrow, the filtering capacity of the spleen assumes major significance. NORMAL SPLENIC FILTRATION OF NORMAL CELLS.--The invariable presence of Howell-Jolly bodies, Heintz bodies, siderocytes and target cells after splenectomy and in patients with agenesis of the spleen 11

suggests that the normal spleen screens and removes these cells from the circulation (18). Howell-Jolly bodies.----Bits of nuclear material in otherwise normal red blood cells are called Howell-Jolly bodies. They are, presumably, formed during abnormal mitosis and represent fragments of chromosomes which have become detached and isolated. These bodies are seen in many diseases associated with strained and abnormal bone marrow function, but they are particularly characteristic of the splenectomized state. They appear within hours after removal of the spleen and can thereafter be found indefinitely. Presumably, they are removed by extrusion and it appears that this extrusion occurs in the splenic pulp. How the spleen "recognizes" cells with these inclusions and screens them and why the extrusion does not occur in the bone marrow in the same manner as the extrusion of normoblastic nuclei is not known. Siderocytes.---These are red cells containing clusters of iron-protein particles. During cellular maturation, iron is contributed in excess of needs and deposited in the form of ferritin or hemosiderin. Under normal conditions it appears that the spleen can retrieve these particles without injury to the cell. Following splenectomy in an otherwise normal patient, 1 to 2% of circulating red cells will contain siderocytic granules. If, in addition, the bone marrow is abnormal, as in Cooley's anemia, 50 to 100% of red cells may become siderocytic. The removal of intracellular residues without hurting the cell is a feat believed to be accomplished by reticuloendothelial cells. In a series of studies using the electron microscope, Bessis showed that ferritin crystals are exchanged between nucleated red cells and reticulum cells (8). He interpreted this sequence as representing a transfer of iron from reticulum cells to nucleated red cells. However, in vitro studies of bone marrow suspensions and studies of children suffering from atransferrinemia have led to the conclusion that all iron used for intracellular hemoglobin synthesis is contributed by circulating transferrin. Consequently, it has been suggested that the phenomenon observed by Bessis represents removal of excess intracellular iron rather than donation (32). It seems likely that some cells are released from the bone marrow before they have been properly rid of intracellular "debris," and that these cells are trapped in the spleen for final inspection and cleaning. Heintz bodies.--These are red cell inclusions representing oxidized, denatured hemoglobin. Their appearance in circulating blood after splenectomy suggests that there is a low-grade, but continuous, oxidative injury to red cells and that the normal spleen filters out these damaged cells. It seems probable that such cells are damaged beyond repair and are eliminated by the spleen. Crosby has intro12

duced the term "culling" to describe the capacity of the spleen to recognize and destroy abnormal cells. Target cells.---These cells appearing after splenectomy indicate that the spleen has a so far completely unexplained effect on the red cell surface. In the process of maturation of reticulocytes both volume and surface are lost, and it is believed that target cells may result from a disproportionately greater shrinkage in volume than in surface. One has to assume that the many, although brief, sojourns in the spleen have an effect on the maturation and shrinkage of the reticulocyte surface. Reticulocytes.---The presence of postsplenectomy target cells in humans brings up the question of the role of the normal spleen in reticulocyte maturation. A significant trapping and pooling of blood occur in the spleen of dogs and rats, and reticulocytes seem to spend some time here, presumably in an environment less crowded than the bone marrow, but equally conducive to maturation (38). Splenic blood has been found to have relatively more reticulocytes than circulating blood and splenectomy will result in a moderate reticulocytosis. In man, however, there is no significant pooling and splenectomy does not usually result in a reticulocytosis. In hemolytic anemia there is released from the bone marrow a large number of immature reticulocytes, and Berendes (7) has found an increased content of these cells in the spleen. These young reticulocytes often clump on smears and appear to be sticky. Jandl (38) has suggested that the stickiness is caused by a coat of transferrin on red cells engaged in iron uptake and active hemoglobin synthesis. The stickiness of this protein coat may be responsible for the normal retention of reticulocytes in the bone marrow until maturation has almost been finished, and for the temporary sequestration in the spleen of cells released too early from their natural bone marrow environment. It may also explain the persistent reports that the Coombs test is positive in some cases of congenital hemolytic anemia (65). Aged cells.--The spleen undoubtedly recognizes and removes some aged cells. However, the daily removal of about 20 ml. of dying cells in man is accomplished by the whole reticuloendothelial system. Splenectomy will not prolong the normal red cell life span, and other parts of the reticuloendothelial system not endowed with a specialized filtering apparatus can obviously substitute for the spleen. Rate of red cell production.--In humans, the removal of a normal spleen is not followed by anemia or polycythemia. It has been emphasized that the normal spleen contains only a small amount of blood and it would not be anticipated that its removal would interfere with the homeostatic mechanism which keeps the red cell mass at a constant level. In animals in which the spleen serves as a reservoir, splenectomy is followed by a readjustment in the homeostatic balance. 13

A normochromic normocytic anemia occurs regularly after splenectomy in dogs and subsides gradually in a few months (72). The rate of red cell production must decrease after the removal of a large vascular compartment or a polycythemia would ensue. The development of a splenectomy anemia is certainly not very compatible with the venerable, but somewhat tenuous, hypothesis that the spleen suppresses bone marrow formation. At present all data support the conclusion that the spleen will trap and sequester red cells, but that it will not interfere with rate of red cell production and hemoglobin synthesis. Leukocytes.----A modest, temporary leukocytosis is observed after splenectomy. It is primarily made up by an increased number of lymphocytes and it appears to be higher and more prolonged than after other surgical intervention. It is of no known clinical significance except that it may confuse the picture in a postoperative infection, such as a subphrenic abscess. Platelets.--Postsplenectomy thrombocytosis is a regularly occurring phenomenon observed not only in animals with large sequestering spleens, but also in normal humans as well. The platelet count will start to rise a few days after splenectomy and may reach 1 million cells or more per cubic millimeter. It has been suggested that there is a corresponding increase in the number of marrow megakaryocytes, but the quantification of megakaryocytes is notoriously imprecise. More than any other postsplenectomy observation, this phenomenon has led to the hypothesis that the spleen suppresses bone marrow function (23). It has been proposed that the spleen releases a humoral substance which decreases the production or release of platelets. Despite many attempts, this hypothesis has not yet received convincing experimental support. An alternative hypothesis is that the bone marrow is geared to maintain the circulating platelet mass at a constant size. If splenectomy removes a considerable fraction of the vascular platelet-containing compartment, an unchanged bone marrow output of platelets will lead to thrombocytosis in the remaining compartment (3). After a few weeks a new homeostatic balance is established between the bone marrow and a diminished vascular compartment, explaining the return to normal in platelet count which occurs 2 to 3 weeks after splenectomy. It is difficult to imagine that the normal spleen, containing about 20 to 30 ml. of blood, contains a major fraction of the platelet pool. However, the attractive feature of this hypothesis is that it deals with platelet dynamics in terms which have been used quite successfully in explaining the pathogenesis of many red cell disorders. N O R M A L SPLENIC FILTRATION OF ABNORMAL CELLS.--Red cells.The introduction of abnormal cells into the circulation will immediately "activate" the dormant filtering capacity of the human spleen. 14

Spherocytes, either obtained from a patient with hereditary spherocytosis or produced by heating normal cells to 50 C. for 60 minutes, are particularly vulnerable to splenic sequestration. In fact, most changes in physical structure or surface composition will result in red cell pooling and in an impeded transit through the spleen (59). From an anatomic point of view it can be understood that spheroid red cells may be trapped in the splenic red pulp. The slit-like communications between cords and sinuses are narrow, of the order of 2 to 3 ~ in diameter, and will retain starch granules with a diameter of 5 ~ or more (74). This geometric explanation has been questioned by Crosby who demonstrated that although red cells from patients with a combination of hereditary spherocytosis and iron deficiency were microcytic, they were still trapped in the spleen (21). However, even microcytes can become spheroid enough to be sequestered and Crosby's observation does not rule out the basic pathogenetic hypothesis that the spleen serves as a filter, with a mesh small enough to impede the transit of spheroid cells. Other abnormally shaped cells, such as sickle cells, macrocytes from patients with pernicious anemia or poikilocytes from patients with thalassemia, may also be screened out by the normal spleen. Recent studies have emphasized the importance of surface alterations or surface changes in the splenic recognition and sequestration of red ceils. Cells treated with a nonhemolyzing and nonsphering amount of an agent which blocks membrane sulfhydryl groups were found to be removed rapidly by the spleen (36). It also seems likely that the specific splenic sequestration of cells coated with small amounts of an incomplete antibody, like anti-D, but neither exhibiting agglutination nor sphering, must be related to antibodyinduced membrane changes (42). It is possible that cells, such as siderocytes, or cells containing Heintz bodies or Howell-Jolly bodies, have associated membrane changes permitting them to be recognized and retained. The sequestration of cells does not necessarily mean the destruction of cells. Most sequestered cells spend only a short time in the splenic pulp and, as is true in dogs, normal red cells kept in the splenic reservoir are not hurt by this visit. The temporary sequestration, however, gives the reticuloendothelial tissue time to phagocytose abnormal cells, remove siderocytic granules and further weaken an aged or defective cell membrane. Each delayed transit will expose the cells to a vicious circle in which close red cell packing leads to glucose deprivation, to a reduction in phosphate energy necessary to the maintenance of a potassium-sodium gradient, to unopposed influx of sodium and water, to sphering, to slower transit time, and so on. Leukocytes.-- The normal leukocyte spends 6 to 12 hours in the circulation before it is marginated and removed. This margination occurs throughout the vascular system and the final removal and de15

struction do not appear to be specifically linked to any one reticuloendothelial organ, such as the spleen. Leukopenias associated with leukocyte antibodies, either drug-induced or idiopathic, are generally not related to increased splenic sequestration of coated cells, but rather to a generalized reticuloendothelial removal of clumps of agglutinated cells. However, in the rare case of "splenic neutropenia," splenectomy has such a strikingly beneficial effect that it must be assumed that the spleen is the major sequestering site. Thrombocytes.--Antibodies presumably specific for platelets can be demonstrated in drug-induced purpura, in posttransfusion purpura and in idiopathic thrombocytopenic purpura. The coating of platelets with such antibody may lead to agglutination and platelet sequestration in all reticuloendothelial areas. Recent studies by Aster and Jandl (4) have shown that, in the same way as with red cells, platelets coated with small amounts of isoantibodies are removed specifically by the spleen, while platelets containing large amounts of antibody are removed chiefly by the liver and other reticuloendothelial areas. Platelets heavily damaged by ethylene diamine tetracetic acid (EDTA) are also chiefly removed by extrasplenic reticuloendothelial tissue, presumably because of its greater mass. Platelets coated by the agglutinating antibody found in many cases of idiopathic thrombocytopenic purpura were shown by body scanning to be sequestered preferentially by the spleen. This is consistent with the clinical remission seen frequently after splenectomy. Microorganisms and foreign bodies.--Bacteria, carbon particles or macromolecular colloids are removed by the reticuloendothelial system, including its splenic component. A specific filtering contribution by the spleen seems to be made in Bartonella infestations of dogs and rats. In these animals, splenectomy results in the transformation of a latent infection to a fulminant disease (25). The role of the human spleen in infections is not clear, but the fear of septicemia in young children after splenectomy seems to be exaggerated. ABNORMAL SPLENIC FILTRATION OF NORMAL CELLS.--nypersplenism is a term used to denote inappropriate sequestration and destruc-

tion of blood cells by the spleen. At present, it does not seem warranted to include bone marrow inhibition in this definition since it has never been proved satisfactorily that the spleen releases inhibiting humoral factors. Hypersplenism can be classified as primary and secondary. Primary hypersplenism is a condition in which abnormal cells are removed so efficiently by a normal hyperplastic spleen, that the resulting cytopenia becomes of greater concern than the presence of abnormal cells. Secondary hypersplenism is a condition in which a spleen, enlarged because of a constitutional disorder, becomes destructive to normal cells. Primary hypersplenism.---The spleen will become hypertrophic as 16

will other organs in response to a sustained and heavy "work load." In hemolytic anemia, idiopathic thrombocytopenic purpura or splenic neutropenia, the spleen will increase in size and become increasingly efficient in filtering out abnormal cells. Although the removed cells are abnormal, they are better than no cells and at a certain point the patient would be "hematologically better off without his spleen" (19) and can be considered to suffer from primary hypersplenism. In the hyperfunctioning spleen there is, in addition, an increase in the number of red cells within the spleen, with stasis and a slow cellular transit time. This will eventually damage all cellular elements, and secondary hypersplenism with sequestration and destruction of normal cells may follow. Secondary hypersplenism.mSplenomegaly caused by a number of pathologic conditions may lead to excessive destruction of circulating blood cells. The splenic enlargement can be caused by primary hypersplenism, by inflammation, by congestion, by ingestion of macromolecular colloids or by infiltration of normal or abnormal cells. In all these conditions there is splenic pooling of red cells and splenic stasis. Consequently, conditions are ripe for splenic sequestration of blood cells and hypersplenic pancytopenia. However, splenomegaly is not always associated with hypersplenism and, conversely, pancytopenia may be associated with splenomegaly without being caused by it. Many diseases involve bone marrow and spleen, and it is of importance in patients with blood cytopenia and splenomegaly to establish a diagnosis of hypersplenism before splenectomy is considered. THE SPLEEN AS A RETICULOENDOTHELIAL ORGAN The reticuloendothelial system is distributed throughout the body with the liver, bone marrow and spleen being the major sites. Its total mass appears to be kept fairly constant, with hyperplasia in one organ counter-balanced by hypoplasia in others. In particular, splenomegaly has been found to be associated with decreased reticuloendothelial activity in the liver and splenectomy is followed by rapid compensatory hyperplasia of distant reticuloendothelial sites (39). It seems that phagocytosis of particulate matter directly stimulates the division of reticuloendothelial cells and that the size of the reticuloendothelial system and, specifically, the size of the spleen, is regulated by its "work load," the amount of phagocytosis it has to perform. In addition to phagocytosis, the splenic reticuloendothelial cells are involved in antibody production and in hematopoiesis. PHAGOCYTOSIS.---The cellular uptake and destruction of defective or worn-out cells, of pathologic microorganisms and of particulate substances are of great importance, but still poorly understood. Karnovsky (43) has reviewed the metabolic basis for phagocytosis 17

and pinocytosis. These are presumably triggered by the physical attachment of a particle to the surface of the cell. The associated membrane changes are energy-dependent and appear to derive the necessary energy from direct oxidation of glucose-6-phosphate. The intracellular destruction and digestion are related to enzymes in the specific granules in phagocytosing granulocytes and probably in related structures in the reticuloendothelial cells. As mentioned previously, the reticuloendothelial cells appear to have the capacity to remove certain intracellular inclusions, like hemosiderin particles, without destroying the integrity of the cell, aptly referred to by Crosby as the pitting function (20). In the reticuloendothelial cells, phagocytosed red cells will be destroyed and the hemoglobin broken down to polypeptides which are reutilized, bilirubin which is excreted and iron which is temporarily deposited as ferritin until released to circulating transferrin. In approximate figures, the destruction of 1 ml. of packed red cells will result in the release of 10 mg. of bilirubin and 1 mg. of iron. An impairment in the release of reticuloendothelial iron to transferrin resulting in a defective reutilization of iron may be of pathogenetic importance in the anemias of chronic infection and chronic disease (3O). ANTIBODY PRODUCTION.--Gamma globulins with antibody function are produced by plasma cells in the spleen, cells which are closely related to lymphocytes and to phagocytosing reticuloendothelial cells. Dameshek has coined the names immunoblasts and immunocytes, and he envisions the interrelation and functional mission of these cells as outlined in Figure 3 (22). The capacity of the spleen to produce antibodies will obviously lead to a slight temporary reduction in antibody production after splenectomy. In acquired hemolytic anemia, splenic neutropenia and idiopathic thrombocytopenic purpura, antibodies to specific cellular elements are produced and splenectomy will both reduce antibody production and abolish an organ designed to sequester antibody coated cells. Whether the antibody produced is a true autoantibody, or is an antibody directed at an unknown antigen but by chance is capable of coating blood cells, has not been resolved (64). Many recent studies have taken exception to the popular concept of autoimmune diseases and one ought to be careful in equating an agglutinating substance in blood with a true, pathogenetically important autoantibody (69). EXTRAMEDULLARY HEMATOPOIESIS.----Thereticuloendothelial cells in the spleen are involved in the normal production of monocytes, lymphocytes and plasma cells. Recent studies employing skin windows, tissue cultures and histochemical examination of single cells ]8

/ I'~t"'q"q,.m,~,/~R,E. . CtrLL

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D HEYLPAEYRESDENSITIVITY have indicated the close interrelation between these cells without having established firmly their evolution or fate (60). From the third to the sixth fetal month the human spleen is also involved in the production of erythroid, myeloid and thrombocytoid cellular elements. After that, splenic blood cell production ceases but the stem cells responsible for hematopoietic activity persist, possibly in a dormant state. They can be reactivated after a prolonged and intense demand for blood cell formation. This so-called extramedullary hematopoiesis occurs not because of unsatisfied demand, but more likely because of "neoplastic" transformation of the stem cells (28). The relation between these stem cells and the reticuloendothelial system is not clear. Yoffey's theory that mature circulating lymphocytes can be transformed into stem cells (81 ) is probably not correct, but no convincing alternative hypothesis of the source and identity of stem cells has been proposed. It has also been suggested that splenic hematopoiesis merely represents trapping of immature bone marrow cells, with the final divisions and maturation occurring here. However, suspensions of splenic cells definitely contain hematopoietic stem ceils since they will recolonize bone marrow and establish new blood cell formation when infused 19

into lethally radiated animals. Similarly, shielding of the spleen will protect lethally radiated animals presumably by the release from the spleen of stem cells capable of producing new bone marrow (16). Judging from cases of agnogenic myeloid metaplasia, blood cell formation in the spleen appears to be carried out in a less favorable environment than in the bone marrow cavity (80). There is ineffective erythropoiesis with cell death in situ and premature release of early erythroid and myeloid cells. The mature red cells are characterized by a great deal of anisocytosis and poikilocytosis. Megakaryocyte fragments and giant platelets are often observed. However, it is possible that this dyshematopoiesis is related to the disease process causing myeloid metaplasia rather than to extramedullary hematopoiesis per se. There are no good studies of the quality of blood cell production from compensatory extramedullary hematopoietic foci. DIAGNOSIS OF SPI.ENOMEGALY AND HYPERSPLENISM The spleen may become enlarged and hyperfunctional in a great variety of diseases. However, the degree of red cell pooling, the sinusoidal or extrasinusoidal site of congestion, the extent of cellular infiltration and the activity of reticuloendothelial cells differ substantially, and the degree of hypersplenism may have little direct relation to the size of the spleen. Consequently, the decision to perform a therapeutic splenectomy rests on an accurate assessment of both the size of the spleen and the degree of hypersplenism. SPLENOMEGALY PHYSICAL EXAMINATION.--Under normal conditions, percussion in the left mid-axillary line should not disclose any significant dullness, since the pulmonary resonance blends into the tympanic sound over the colon at the splenic flexure. The first physical evidence of an enlarging spleen may be a dull percussion note in this area at or above the ninth intercostal space. As the spleen grows, hi-manual examination with careful positioning of the patient will give a rough estimate of spleen size and will usually differentiate an enlarged spleen, with its typical notch, from the left lobe of the liver, from a pancreatic cyst or from a large left kidney. X-RAY EXAMINATION.--On flat film of the abdomen the splenic shadow can be visualized immediately below the left leaf of the diaphragm, medially bordering on the fundus of the stomach and with its lower pole impinging on the colon. Enlargement of the spleen results in the displacement of the stomach bubble medially and down, and of the colonic air bubble posteriorly and down. The presence of a

20

FIG. 4.-~can of normal adult spleen. (Wagner, H. N., Jr., et al.: Arch. Int. Med. 109:673, 1962.)

distinct subdiaphragmatic air pocket is unusual in patients with splenomegaly. The outline of the spleen can be accentuated by introducing air into the stomach (carbonated drinks), into the colon (rectal tube) or into the peritoneum (pneumoperitoneum with CO2). Tomograms may also be of help in outlining an atypical spleen. RADIOISOTOPE SCANNING.--Elythrocytes heated to 50 C. for 1 hour become spheroid and will be trapped and destroyed by the spleen. If, in addition, the red cells are labeled with Cr ~1, the spleen becomes radioactive and can be visualized by scintillation scanning (Fig. 4) (71). This procedure is of value in the differential diagnosis of left upper quadrant masses, in the diagnosis of splenic cysts or metastatic replacement of the spleen, in the demonstration of accessory spleens and in making a diagnosis of agenesis or of previous surgical removal of the spleen. Similar results can be obtained by using labeled Rh positive cells coated with anti-Rh antibodies (41). However, the heated cells are always autologous and are easier to produce and handle. HYPERSPLENISM Splenic hypersequestration and destruction of blood cells can be evaluated indirectly by measuring the rate of cellular destruction or the degree of compensatory production, and directly by measuring splenic sequestration of labeled cells. DESTRUCTION OF ERYTHROCYTES.----An increased rate of red cell destruction will lead to a reduction in hemoglobin concentration 21

which, in turn, will cause a compensatory increase in the rate of red cell production. The hemoglobin concentration will stabilize at a level at which it generates a production of red cells sufficient to balance the destruction. In hereditary spherocytosis and occasionally in other hemolytic anemias, a compensated hemolytic process is observed. In these cases, there is no reduction in the hemoglobin concentration. Nevertheless, an accelerated red cell production is maintained despite the absence of an anemic stimulus. Red cell life span.--The normal red cell life span is 120 days (halflife, 60 days). A number of methods have been used to measure life span, but at present only technics utilizing Cr 51 tagged cells are in common use (32). Because of continuous elution of Cr ~1 from labeled cells, the apparent half-life of normal cells is about 30 days rather than 60, and a T / 2 of Cr ~1 tagged cells of more than 25 days must be considered normal. Red cell destruction.--Under normal conditions, about 20 ml. of red cells is destroyed every day (Blood volume x Hematocrit • 1 45 1 lifespa~ or, in a 70 kg. man, 5000 • ~ • 1 2 0 - 2 0 m l . ) . In 10 days this will amount to about 200 ml. of red cells, or about one unit of blood with a hematocrit of 40%. As a rough guide, it can be assumed that any transfusion need in excess of one unit of blood per 10 days means shortened red cell life span with accelerated destruction. Splenic sequestration of red cells usually produces a chronic hemolytic anemia characterized by bilirnbinemia, increased fecal urobilinogen and the accumulation of gallstones. The bilirubin released from the reticuloendothelial cells is bound to serum albumin and readily conjugated to glucuronic acid and excreted by the normal liver. Calculations of the velocity constant of bilirubin excretion indicate that the normal liver is capable of excreting 200 to 400 mg. of bilirubin a day, at a serum bilirubin of about 1 mg. per cent (44). Since each milliliter of broken down red cells will produce 10 mg. of bilirubin, this excretory capacity will easily take care of the daily destruction of about 20 ml. of red cells. When the rate of red cell destruction increases (red cell life span decreases), bilirubin will be retained. However, the amount of pigment excreted by the liver increases proportionately to the square of its concentration in serum, and the rise in bilirubin, even in severe hemolytic disease, will be small. Actually, if the bilirubin in hemolytic anemia is higher than 4 to 5 mg. per cent, the patient probably has some degree of hepatocellular dysfunction. The conversion of bilirubin into gallbladder stones is common in some congenital hemolytic anemias, but the mechanism is poorly understood. In Macpherson's studies of hereditary spherocytosis (51 ), 22

66% of patients older than 30 years had gallstones, compared to 12% of patients less than 30. Compensatory red cell production.--Accelerated red cell production is reflected by increases in reticulocyte counts, erythroid-myeloid ratio of the bone marrow and serum iron turnover. The bone marrow is capable of increasing its productive rate 6 to 10 times and, if the supply of metabolic "building blocks" is adequate, maintains such rates indefinitely. Aplastic crises with reticulocytopenia and a rapid fall in hemoglobin concentration are seen occasionally in chronic hemolytic anemias and several studies have strongly suggested that a temporary I00. w =,- 9 0 . o t~ 80. z 70. o

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1956.) 23

deficiency in the metabolic building block, folic acid, may be responsible (58). Site of red cell destruction.--In a patient with hemolytic anemia, it is possible to evaluate the relative role of the spleen in the over-all destruction of red cells. Labeling of autologous cells with Cr 51 followed by daily isotope scanning over the spleen, liver and precordium will provide an estimate of the degree of red cell sequestration in the spleen and in the liver (Figs. 5-7) (39). If the red cell life span is less than half normal ( T / 2 Cr51--red cells ~ 15 days) and there is a progressive rise in splenic radioactivity, it is believed that splenectomy may be of definite therapeutic value. In 50 cases reported, a beneficial effect of splenectomy was correctly predicted in about 90% by this method (70). However, it must be emphasized that a thorough clinical evaluation in a patient with hemolytic anemia and splenoI00. ,,,,

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24

megaly most often will lead to an accurate prediction of the value of splenectomy. DESTRUCTION OF LEUKOCVTEs.--Granulocytopenia with myeloid bone marrow hyperplasia characterizes hypersplenic neutropenia. The normal half-life of circulating granulocytes can be measured, but is so short (6 to 8 hours) that no satisfactory clinical method of assessing a further shortening is available (17). The bone marrow will show an increase in early myeloid cells. This has incorrectly been called "maturation arrest," but it merely indicates that the more mature myeloid cells have been swept into the circulation leaving the early and rapidly proliferating promyelocytes and myelocytes. The metabolic effects and the place of increased destruction cannot be demonstrated by any clinically available methods. The leukocytic response to endotoxin or epinephrine will relate to the size of the marginated pool of leukocytes, but will not give any information as to the relative importance of the spleen in the destruction of leukocytes. DESTRUCTION OF PLATELETS.--In the same manner as with other cytopenias, a thrombocytopenia can be caused by a production defect or by increased destruction. The most accurate way to differentiate these conditions is to measure the platelet life span. Practical methods for such measurements are slowly being introduced into clinical medicine. Normal platelets labeled with Cr 51 have a half-life of about 7 to 10 days and pronounced shortening has been demonstrated in some cases of splenomegaly (14). In thrombocytopenia due to destruction, the bone marrow smear will usually be of help by disclosing a compensatory increase in early, immature forms. Dameshek has emphasized that the margin of these megakaryocytes is smooth and that they lack cytoplasmic granular accumulation, so-called Wright's figures. However, this does not necessarily indicate a production defect but merely a shift to the left, with the majority of megakaryocytes in a preplatelet-producing state, similar to the significance of the situation seen in hemolytic anemia and splenic neutropenia. In several cases observed by the authors, excessive destruction of platelets in rapidly growing thrombi was associated with the same smooth megakaryocytes as observed in hypersplenic thrombocytosis. An increase in platel~t destruction should be expected to cause a release of platelet constituent into the circulation. A search for free clot-accelerating phospholipids has not been successful, but Oski and coworkers (56) have reported that peripheral platelet destruction results in an increase in circulating acid phosphatase, a platelet enzyme. Similar to methods used for the localization of red cell sequestration, surface scanning has been used to localize the site of destruction of platelets, labeled with Cr ~1 (4). This method is still experimental but may eventually provide the physician with an additional clue in predicting the value of splenectomy. 25

CLASSIFICATION OF POTENTIAL HYPERSPLENIC DISORDERS In Table 1, potential hypersplenic disorders are listed and divided into primary and secondary hypersplenism. TABLE 1.--CLASSIFICATIONOF POTENTIAL HYPERSPLENIC DISORDERS Primary Hypersplenism Congenital hemolytic anemia:

Hereditary spherocytosis Hereditary elliptocytosis Pyruvate-Kinase deficiency Hemoglobinopathies (sickle cell anemia, etc.) Thalassemia Porphyria hematopoietica "Autoimmune"

Acquired hemolytic anemia: Idiopathic thrombocytopenic purpura Primary splenic neutropenia Primary splenic pancytopenia Secondary Hypersplenism Inflammation: Acute: Typhoid fever, rubella, chicken pox, etc. Septicemia, subacute bacterial endocarditis Chronic: Tuberculosis Syphilis Boeck's sarcoid Beryllium disease Rheumatoid arthritis (Felty's syndrome) Disseminated lupus erythematosus Malaria Trypanosomiasis Schistosomiasis Leishmaniasis Echinococcosis Histoplasmosis Cryptococcosis Lymphopathia venereum Congestion: Cirrhosis of liver Portal vein obstruction Splenic vein obstruction Congestive heart failure Ingestion: Gaucher disease Niemann-Pick disease Amyloidosis Hyperlipemia Infiltration: "Benign": Compensatory hematopoiesis Infectious mononucleosis "Neoplastic": Leukemia Lymphoma Histiocytosis (Hand-Schiiller-Christian; Letterer-Siwe) Hodgkin's disease Macroglobulinemia Polycythemia vera Agnogenic myeloid metaplasia 26

PRIMARY HYPERSPLENISM.--Congenital hemolytic anemias.--Hereditary spherocytosis is caused by an autosomal dominant defect of the red blood cells. On blood smears, a fraction of the red cells can clearly be seen to be small, dense and spheroid, and osmotic fragility tests will show that this fraction is excessively sensitive to osmotic hemolysis. It is presumed that spheroid or nearly spheroid cells will be temporarily sequestered by the spleen and become further altered in this congested, glucose-poor environment. There is a progressive conditioning of the cells and after a number of passages through the spleen they eventually will be permanently trapped and destroyed. The metabolic defect responsible for their shape and their sensitivity to the splenic environment is now believed to reside in the red cell membrane. The red cell membrane contains energy-dependent sodium pumps which clear the red cell interior of excess sodium. Recent studies have suggested that these sodium pumps are defective in hereditary spherocytosis and that they demand an excessive amount of phosphate energy to keep going (35). The source of the energy, glucose, is readily available in circulating blood but is in short supply in the tightly packed sinusoids of the spleen. This combination of splenic trapping and splenic hypoglycemia leads to hypersplenism and, hence, to the excellent clinical results of splenectomy. It seems likely that further studies of this condition may change the current working hypothesis, since the spherocytes are not merely swollen red cells but are actually abnormal cells with an excessive content of hemoglobin, the mean corpuscular hemoglobin concentration (MCHC) often being in excess of 36% (26). As pointed out earlier, compensated hemolytic anemia with an accelerated red cell production despite normal hemoglobin concentration is another still unexplained feature of many cases of hereditary spherocytosis. The diagnosis is usually self-evident because of family history, splenomegaly, characteristic blood smear and abnormal osmotic fragility tests. After the diagnosis has been established, splenectomy should be performed. Even in cases with compensated hemolytic anemia, aplastic crises and gallbladder stones arc frequent enough complications to warrant removal of the spleen and of the gallbladder, if it contains stones. Smith and his group (66) have emphasized that splenectomy in children less than 4 years of age may be followed by severe infections and have recommended the prophylactic use of penicillin. Other authors (45,27) however, have not been convinced that splenectomy leads to an increased susceptibility to infections, and the question remains unsettled. Hereditary elliptocytosis is caused by a concomitant autosomal red cell defect. It is usually a harmless blemish but occasionally it is associated with hypersplenic hemolysis. The presence of oval- and rod-

27

shaped cells in blood smears from the patient and from family members establishes the diagnosis. Splenectomy should only be considered in patients with anemia, reticulocytosis and hyperbilirubinemia (46). Pyruvate-Kinase (P-K) deficiency is a nonspherocytic hemolytic anemia caused by an autosomal recessive defect in the production of high energy phosphate (ATP) from glucose (11). The homozygous victims have a severe macrocytic hemolytic anemia with splenomegaly, impaired physical development and high infant mortality. The autohemolysis test is of importance in separating this disorder from hereditary spherocytosis, and from glucose-6-phosphate dehydrogenase deficiency, another of the nonspherocytic hemolytic anemias. In pyruvate-kinase deficiency, glucose will not abolish autohemolysis but adenosine triphosphate will. This is in contradistinction to hereditary spherocytosis, in which both glucose and ATP will decrease hemolysis. It also may be differentiated from glucose-6phosphate deficiency in which the defect does not involve ATP and, consequently, there is a less than normal inhibition of autohemolysis when the involved erythrocytes are incubated with glucose or ATP (Table 2). Although the defect in P-K deficiency is so severe that it T A B L E 2.--AUTOHEMOLYSIS TEST--PER CENT HEMOLYSIS, 37 C., 48 HOURS RED CELLS

Normal Hereditary spherocytosis Pyruvate-Kinase deficiency Glucose-6-phosphate dehydrogenase deficiency

WITHADENOSINE

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jeopardizes survival of red cells anywhere in the circulation, splenectomy will ameliorate the hemolytic anemia moderately and may make life more tolerable. There are also certain hemoglobinopathies. For example, in patients with sickle cell anemia, nature performs a highly beneficial "autosplenectomy" which results in a significant prolongation of the life span of sickled cells. It is a slow procedure lasting many years and involving many painful crises, and it can be frustrating to compare this natural process with a swift and efficient surgical splenectomy. In young children, severe hypersplenism with hemolytic crises and excessive transfusion requirements may occur and make surgical splenectomy the definite treatment of choice (Fig. 7) (32). In general, all patients with hemoglobinopathies with a marked shortening in red cell life span are apt to improve after splenectomy. Cr51-1abeled cells that can be localized in the spleen will provide additional indication for surgical intervention. 28

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FIG. 7.--Autosurvival of CPLlabeled erythrocytes in a child with sickle cell anemia and splenomegaly, before and after splenectomy. (From Harris, J. W.:

The Red Cell: Production, Metabolism, Destruction, Normal and Abnormal [Cambridge, Mass.: Harvard University Press, 1963]. Published for the Commonwealth Fund. )

Thalassemia major is characterized by an ineffective production of abnormal red cells and by a splenomegaly which eventually will cause trouble, both functionally and mechanically. Splenectomy will decrease transfusion requirements and it is indeed rare to see patients in their teens suffering from this disease who have not had a splenectomy. It is important, however, to realize that thalassemia is primarily a bone marrow disorder and that splenectomy is merely palliative. Porphyria hematopoietica is an extremely rare disease which is only mentioned because splcnectomy may be of significant therapeutic benefit ( 6 1 ) . In this disease there is an abnormal production of Type 29

1 porphyrins in the nucleated red cells. Since red cells with this defect are destroyed prematurely by the spleen, a hypersplenic syndrome with accelerated red cell production and accelerated production of Type 1 porphyrins will ensue. The ultimate effect of this accelerated production and destruction is photosensitivity and severe mutilating bullous dermatitis. Splenectomy will result in a slow-down of the vicious feedback mechanism between destruction and production and may result in a lasting improvement. Acquired hemolytic anemia.--This condition is associated with protein coating of the red cells which leads to premature cellular destruction in the reticuloendothelial system. Large amounts of complement fixing or agglutinating gamma globulins will cause red cell destruction throughout the reticuloendothelial system, but small amounts appear to lead to splenic destruction alone, presumably because the pooling and stagnation in the spleen provide additional hazards (42). The Coombs test is of importance in establishing that red cells are coated by a protein, but it does not, as was believed previously, prove the presence or absence of a true "autoantibody." Recent studies of druginduced cytopenias have demonstrated that there is, first, a specific antigen-antibody union and, second, a nonspecific absorption onto blood cells (64). It is suggested that at least some of the so-called autoimmune hemolytic anemias are caused by nonrecognized antigens, and that the coating of red cells and eventual destruction are fortuitous rather than specific. Transfusions and steroids are of help and may help the patient until a spontaneous remission has occurred. Transfusion involves a difficult problem of typing and cross matching. Although careful cell washing and the use of potent saline active antisera will give the correct blood type, accurate cross matching is often impossible and may have to be dispensed with. If steroids do not maintain an adequate remission or if serious side effects of the hormones occur, splenectomy must be tried. It can be anticipated that about 50% of patients will respond to splenectomy with a significant and gratifying reduction in hemolysis. However, the basic disorder responsible for the production of proteins which coat the red cells is rarely altered and relapses are frequent. In the resistant cases, immunosuppressive agents, such as 6-mercaptopurine (63), can be tried but the results are erratic, and a significant number of patients with acquired hemolytic disease eventually will succumb from uncontrollable red cell destruction. Idiopathic thrombocytopenic purpura (ITP).--ITP is characterized by thrombocytopenia despite an increase of mcgakaryocytes. It is distinguished from secondary thrombocytopenic purpura by the absence of a preceding infection, by the lack of exposure to potential toxins and by the absence of splenomegaly. The acute cases occur 30

primarily in children and it seems reasonable to believe that they may represent responses to inapparent viral infections. The chronic cases can occur at any age, but are more frequent in young adult women. Platelet agglutinin and complement fixing antibodies have been demonstrated in a large proportion of tested cases, but these tests are still in the experimental stage. The clot retraction inhibition test, however, is of practical importance in separating drug-induced from idiopathic cases (73). The presence of platelet "antibodies" in ITP was most convincingly demonstrated by Harrington who transfused ITP blood into normal recipients. In 16 out of 26 patients, thrombocytopenia ensued (31). The presence of "antibodies" is also evident from the fact that children born to mothers with ITP may be born with a temporary neonatal purpura. Quotation marks have been put around platelet "antibodies" because it is not certain that these are true autoantibodies. In some cases, at least, the antibodies appear to be directed at a foreign antigen, while the platelets are involved only as nonspecific absorbents for the antigen-antibody complex (64). If the thrombocytopenia is severe (less than 50,000 platelets per cubic mm.) and if it causes serious bleeding, the immediate treatment of choice is steroid hormones. These will cause a decrease in hemorrhagic manifestations and, in about half the cases, an increase in platelets. If fresh blood and plastic or siliconized equipment are used, transfusion of blood from polycythemic patients with high platelet counts can be of help in an emergency. Transfusions of separated fresh or frozen platelets are encouraging prospects, but the platelet "antibodies" are apt to decrease their effectiveness (6). Although some investigators advocate almost immediate splenectomy (24), most workers prefer to give the steroids a few months' chance either to induce a remission or to help the patient until spontaneous remission occurs. Splenectomy is unquestionably extremely effective and will, in almost every patient, be followed by a rise in platelet count. This rise begins within 24 to 48 hours after splenectomy, probably a reflection of the large number of potential or actual platelet-producing megakaryocytes in the bone marrow. The platelet count may exceed one or even two million, but unless the patient is immobilized because of postoperative complications, prophylactic anticoagulants are usually not indicated. The gratifyingly immediate response to splenectomy should not make one forget that the underlying disorder has not been changed. Platelet "antibodies" can be demonstrated in many patients after a successful splenectomy. Indeed, a significant proportion of patients will relapse; figures range from 20 to 40%. The search for an accessory spleen has been made easier by the employment of body scanning after the administration of heated, Cr~l-labeled red ceils (71). However, the hope that an accessory 31

spleen is responsible for a relapse is not realized often, and in most cases of failure one must postulate that the spleen did not play a major role in the manifestation of the disease. The hazards of postsplenectomy infections in children and of activation of a dormant lupus erythematosus appear to be overrated and should not influence the decision to remove the spleen (2).

Primary splenic neutropenia and primary splenic pancytopenia.-These are rare conditions in which a neutropenia or a pancytopenia is benefited or cured by splenectomy. The bone marrows are characteristically hyperplastic with evidence of a shift to the left and "autoantibodies" can occasionally be demonstrated. The relation of these syndromes to arthritis and Felty's syndrome is of interest, but poorly understood. SECONDARYnYPERSPLENISM.--Inflammations.--Generalized infections are usually accompanied by a decreased rate of red cell production but in rare cases a hemolytic component may dominate the clinical signs. This complication is seen primarily when reticuloendothelial overactivity has led to splenomegaly with red cell pooling and stasis (40). This "acute splenic tumor" may also lead to thrombocytopenic purpura, but most postinfectious thrombocytopenias are related in an unknown manner to viral infections, such as rubella and chicken pox. Chronic infections and chronic inflammatory states are most likely to be associated with reticuloendothelial hyperplasia, splenomegaly and hypersplenism. Splenectomy is rarely indicated but should be considered in leishmaniasis (kala-azar) if the spleen becomes mechanically troublesome and in Boeck's sarcoid or rheumatoid arthritis if the hypersplenic manifestations become severe. Splenectomy in disseminated lupus erythematosus has been frowned on because it has been claimed that it would make the disease worse. Indeed, it has been suggested that idiopathic thrombocytopenic purpura may be a prodromal phase of disseminated lupus and that splenectomy can activate an otherwise dormant serious illness. This fear appears to be unsubstantiated and should not be an important consideration in the decision (9). Congestion.--Banti's disease, or Banti's syndrome, is a term still used to describe congestive splenomegaly with hypersplenic cytopenia. This disorder is no longer believed to originate in the splenic parenchyma, but rather in the portal vascular bed causing back pressure and splenic congestion. Studies of red cell sequestration have established the congested spleen as the site of red cell destruction, but studies of platelet life span have not been consistent (14). Both normal and reduced platelet life spans have been reported in patients with congestive splenomegaly and the possibility that the congested spleen in some way inhibits platelet production has not been ruled out. Splenectomy is of value in correcting the cytopenias but a splenorenal 32

or mesenterocaval venous anastomosis may be necessary in order to reduce portal pressure and to relieve the congestion in other areas of the portal bed. In portal hypertension, splenectomy alone should reduce the influx of blood into the obstructed venous bed since almost 40% of portal blood is contributed via the splenic artery. Hunt (34) has reported increased portal pressure in patients with myelosclerosis and splenomegaly and has also reported dramatic lowering of the portal pressure after splenectomy. However, the application of this finding to the treatment of the usual causes of portal hypertension, such as Laennec's cirrhosis or thrombosis of the portal vein, has been unsuccessful compared with the results in lowering portal tension and in reducing the incidence of variceal hemorrhage using various types of portosystemic venous shunts. Ingestion.--The presence of macromolecular "foreign" substances leads to reticuloendothelial phagocytosis, reticuloendothelial hyperplasia, splenomegaly, blood cell pooling and stasis, and to the inevitable hypersplenic cytopenias. The hypersplenic syndrome produced by macromolecular substances, such as cerebrosides (Gaucher disease) or sphingomyelin (Niemann-Pick disease) has been duplicated experimentally by feeding rats methyl cellulose (57). The resulting splenomegaly has served as a useful experimental model for studies of hypersplenism. Although the results have been somewhat conflicting, they have, in general, supported the theory that hypersplenism is caused by excessive cellular sequestration rather than by bone marrow suppression. Splenectomy may be necessary to relieve the manifestations of hypersplenism or to produce comfort by removing the occasionally huge spleen. Infiltration.--Cellular infiltration will produce splenomegaly but will not necessarily produce pooling, stasis or destruction. Since diseases in this category often produce bone marrow failure, it is important to use red cell life span measurements, transfusion requirements and in vivo scanning for splenic sequestration as guides in deciding whether to perform splenectomy. It is also of importance to consider whether a patient already doomed by a diagnosis such as lymphoma or Hodgkin's disease, should be subjected to major surgery. However, worthwhile symptomatic improvement may make the last years or months more tolerable and justify an active approach (62). At present, the splenomegaly in agnogenic myeloid metaplasia is not considered compensatory but, rather, part of the disease process. Splenectomy is often of assistance by removing a destructive focus and by ridding the patient of a mechanically distressing abdominal mass. However, careful preoperative evaluation of the bone marrow potential (bone marrow aspiration and biopsy) and of the splenic destructive function (red cell life span, transfusion requirements, platelet and white cell counts) have to be carried out before a deci33

sion to perform a splenectomy is made (77). Erythrokinetics are of limited value because of ineffective red cell production, premature cellular release and the huge, but unknown, volume of the spleen (28). RUPTURE OF THE SPLEEN

The spleen is a relatively small organ and, in man, is tucked high and posteriorly under the left hemidiaphragm, protected by the ribs and muscular parietes. Nevertheless, the spleen is commonly injured and such injury should never be considered trivial. This extremely friable, vascular organ, surrounded by an adherent capsule and suspended by several ligaments, bleeds profusely when injured. Avulsion of portions of the capsule from the splenic substance results in inevitable hemorrhage. Furthermore, the ligaments maintaining the spleen in its upper abdominal position may themselves aid in tearing the capsule from the spleen when a blunt force is applied from without. Whitesell (78) has demonstrated smooth muscle fibers in the upper portion of the gastrosplenic omentum where the spleen is separated from the greater curvature of the stomach by a distance of only 1 to 2 cm. Also, several of the upper vasa brevia, which are large but thinwalled vessels, run through this fold and may be lacerated at the time of blunt trauma. That splenic injury is serious is attested by the numerous reports over many years of approximately 10% mortality in patients with ruptured spleens who have been operated on. The mortality in patients in whom there are other serious concomitant injuries is between 15 and 25%. Perhaps the major factor responsible for this excessive mortality is delayed diagnosis; failure to deal properly with concomitant injuries accounts for many other deaths. When proper treatment is instituted early and carried out effectively, the mortality rate should drop sharply in patients with isolated injuries to the spleen. Although the incidence of multiple injuries in association with ruptured spleen appears to be the same in children and adults, the mortality rate in children is less than that in adults (76). This may be explained by the fact that diagnosis is often easier in children because of earlier manifestation of abdominal tenderness. Children also seem to tolerate complete avulsion of the spleen from its pedicle better than adults, possibly because of the ability of the splenic artery to enter into an intense spasm and seal itself off, at least temporarily, with a thrombus. Many classifications have been devised to categorize various types of ruptured spleens. These classifications take advantage of anatomic differences, causative factors and the time interval between injury and its obvious manifestations. The authors prefer the following classifica34

tion simply because certain clinical features are more easily categorized, analyzed and explained: A. Penetrating trauma 1. transabdominal 2. transthoracic B. Nonpenetrating trauma 1. immediate rupture 2. delayed rupture C. Operative trauma D. Spontaneous rupture PENETRATING TRAUMA.--Although wounds of the spleen have been classified in a fashion similar to other wounds of the body (contused, incised, lacerated, etc.), such a distinction seems academic. There is one notable exception--puncture wounds of the spleen of iatrogenic origin. Splenic puncture is utilized with increasing frequency for the measurement of pressures in the portal vein and for the injection of radiopaque material into the portal venous system. Although not commonly used in this country, splenic biopsy is performed in some European clinics with a reportedly low incidence of complications (52). The patients must remain apneic during this procedure to avoid tears in the splenic capsule, with subsequent hemorrhage. Penetrating wounds may be large and gaping, resulting from blast injuries, or small, pinpoint punctures from stab wounds. Bullets and other high-speed missiles, such as from rotary lawn mowers, account for most of the remaining penetrating injuries to the spleen. Transthoracic penetrating injuries almost always penetrate the lung, pleura and diaphragm and there is an associated hemopneumothorax. Transthoracic exploration permits evacuation of the blood in the pleural space together with repair of the diaphragm which may itself be a source of significant hemorrhage. Splenectomy is accomplished without difficulty through the diaphragm. Exploration of the remainder of the abdomen may be indicated and, if so, either a separate abdominal incision or a combined thoracoabdominal incision may be necessary to correct other abdominal injuries. Associated intra-abdominal injuries are most likely to involve the greater curvature of the stomach, the left kidney, the pancreas, and the vascular structures at the root of the mesentery. NONPENETRATING TRAUMA.--This may result in contusions with bleeding into splenic parenchyma and eventual rupture through the capsule, thus explaining one form of delayed rupture. Such subcapsular hematomas may dissect through the trabeculae, along the subcapsular plane and then extend between the peritoneal folds of the splenic ligaments to the retroperitoneal space and present as an ccchymosis on the abdominal wall or flank. Other forms of injury result in

35

tears of the capsule at the time of the blow, fragmentation of the spleen or complete avulsion of the spleen from its pedicle. Automobile-pedestrian accidents are by far the most common cause of nonpenetrating splenic injury; reported series are remarkably constant in this respect. This is true in both adults and children despite the oft-repeated comment that sledding injuries represent the typical nonpenetrating trauma leading to rupture of the spleen in children. Other commonly described injuries are direct blows during fights and bicycle injuries (10). Approximately 15 % of nonpenetrating injuries to the spleen result in delayed rupture. Thus, patients may be discharged from the hospital accident room with a false sense of security only to return hours, days or weeks later following sudden rupture and a near exsanguinating hemorrhage. Seventy-five per cent of these delayed ruptures become manifest in the first 2 weeks after injury. It is important to note that when the patients are returned to the hospital, the initial injury may have been forgotten because of its triviality or be overshadowed by the profound shock due to blood loss. If this possibility is kept in mind, however, the diagnosis should be made and confirmed in time for laparotomy and splenectomy. Spontaneous rupture of the spleen is rare, and it is difficult to prove that there was no antecedent trauma. An enlarged, diseased spleen is more prone to rupture than a normal spleen following trauma and the rupture is presumed to be secondary to the splenic disorder itself. Spontaneous rupture of the diseased spleen is most frequently noted in the tropics where malaria is endemic and spleens may become tremendously enlarged. Other conditions in which spontaneous rupture has been described are typhoid fever, typhus and acute generalized infections. Spontaneous rupture has also been noted in pregnancy and parturition, and in the newborn. Infectious mononucleosis is probably the most common nonmalarial cause for splenomegaly and spontaneous rupture. Lymphomas and leukemias involving the spleen have also resulted in splenic rupture. Spontaneous rupture of a presumably normal spleen has been reported rarely. Orloff and Peskin, in a review of this condition, stated that in order to qualify for this diagnosis, no antecedent history of trauma, however slight, can be uncovered on repeated questioning (55). Nevertheless, it seems apparent that normal spleens do not rupture spontaneously, although the patient may steadfastly deny any history of trauma over the preceding weeks. A slight and forgotten injury is undoubtedly the cause for such events. There may be other, as yet unidentified, influences permitting minor trauma to result in rupture of the spleen. Such an injury may result in a delayed rupture since a small tear may be sealed off by a clot or by omentum with little or no intraperitoneal bleeding. Subsequently, lysis of a clot or 36

enlargement of a hematoma with extensive bleeding into the peritoneal cavity may occur with the production of typical symptoms of a ruptured spleen but with no detectable history of trauma. OPERATIVE TRAUMA.----Brownand his associates collected 40 cases ( 2 % ) of operative injury to the spleen in almost 2,000 operations involving the viscera of the left upper quadrant of the abdomen (12). Such injuries usually occur as a result of retractors placed directly against the spleen in the performance of vagotomy or subtotal gastrectomy, or in the undue traction exerted against the spleen during removal of the splenic flexure of the colon. Traction resulting in capsular tears may also occur during manipulation of the diaphragm. The importance of recognition of such an injury is obvious and the surgeon should inspect the area of the spleen not only for the presence of free blood, but also for subcapsular injuries after operations of this nature. The clinical signs of ruptured spleen.--The spleen may be completely avulsed or fragmented and the patient may be moribund from this and other injuries upon arrival in the hospital. The majority of patients, however, appear either completely well or in various stages of development of the typical signs of a ruptured spleen. The signs and symptoms will vary according to the severity and rapidity of hemorrhage, the presence of other injuries and the time between injury and examination. The injury may have been so trivial as to be overlooked by the patient. This is particularly true in children, whose history can be particularly confusing; they are more frequently involved in small episodes of physical trauma, most of which are forgotten. Nevertheless, such a minor episode may result in a deep laceration of the spleen, producing severe blood loss and the rapid development of hemorrhagic shock. An average, or "typical," patient usually complains of generalized abdominal pain. He is slightly nauseated and may give a history of having vomited. Approximately one third of these patients localize their pain in the left upper quadrant. It has been emphasized that the best approach to the diagnosis of a ruptured spleen, either immediate or delayed, is by repeated thorough clinical examination (79). Such an examination usually reveals some muscle spasm in the left upper quadrant of the abdomen. Some observers describe a doughy feel when examining the abdomen, but this is probably related to massive bleeding into the peritoneal cavity and must be considered a late sign. Rebound tenderness is usually greater than direct tenderness in this area. A tender mass is rarely felt, but many observers have described an area of fixed dullness (Ballance's sign) in the left upper quadrant, indicating the presence of a large extra- or subcapsular hcmatoma or a mass of omentum surrounding an injured spleen. Shifting dullness 37

over the abdomen may occasionally be detected, but this also is a late sign and is caused by the presence of a large quantity of blood in the free peritoneal cavity. Kehr's sign is the presence of pain at the tip of the left shoulder in patients with rupture of the spleen. Some observers have noted that this sign was positive only in approximately 15% of their patients, whereas others have elicited it in over 75 % of examinations of patients with ruptured spleen. The incidence of positive response probably rises not only with the degree of interest in looking for it, but also with the use of a slight Trendelenburg position during the examination. After several minutes in this position, gentle bimanual compression of the left upper quadrant usually produces the typical shoulder tip pain. Obviously, the vital signs vary tremendously. A tachycardia is by far the commonest derangement and appears before the development of hypotension. The red blood cell count or the hematocrit level are not particularly reliable early in the progression of the disease because of rapid fluid shifts or hemoconcentration. However, the white blood cell count rises rapidly after splenic injury and a leukocytosis of at least 12,000 with a shift left is the rule shortly after injury. Within a short period, the white count may exceed 20,000 and occasionally rises above 30,000. This is perhaps one of the most important diagnostic signs. Many patients with ruptured spleens pass through a latent period during which casual examination will reveal little. Nevertheless, with painstaking and repeated examinations, most patients will demonstrate tenderness below the left costal margin on compression and one or more of the following: (1) left shoulder pain on assumption of the Trendelenburg position; (2) tenderness in the left flank; (3) muscle guarding in the left flank; or, (4) slight abdominal distention. Delay in diagnosis is usually because the examiner does not recognize the possibility that trauma to the spleen could have occurred with a history of a trivial injury. The apparent well-being of the patient during the examination, failure to realize that classic signs or hemorrhage may not be present, or failure to demonstrate some of the finer points of diagnosis, such as Kehr's sign, are also causes of delay in diagnosis. X-ray examination is usually not helpful early in the diagnosis of a ruptured spleen. However, a plain film of the abdomen should always be obtained after any penetrating or nonpenetrating injury and the following signs may, on occasoin, be noted. The splenic outline may not be easily discerned or there may be an increase in the size of the splenic shadow. There may be a loss of the usual outline of the left kidney or of the left psoas shadow. The left half of the transverse colon may also be displaced downward in response to the expanding left upper quadrant mass. Rib fractures are present in approximately 38

20% of these patients and, if observed, should increase suspicion of the diagnosis of a ruptured spleen. An interesting roentgen sign is the presence of serration of the greater curvature of the stomach with medial displacement of this organ. This irregularity is probably caused by blood from a splenic tear dissecting through the gastrosplenic ligament and producing indentations in the wall of the greater curvature of the stomach. The left hemidiaphragm may be less mobile or even fixed in position when examined fluoroscopically. A rare finding on x-ray examination is the development of an acute scoliosis in response to splenic bleeding. An x-ray of the chest should also be obtained to determine whether any concomitant injuries may be observed in the left hemithorax. The diagnosis of intraperitoneal bleeding may be confirmed by peritoneal tap using a no. 18 or no. 20 needle and a 10 ml. syringe. Such taps should not be performed in the presence of dense peritoneal adhesions with fixation of bowel loops, or in the presence of distention. The needle should be inserted into each of four quadrants, care being taken to avoid an enlarged liver or spleen. An alternative method is to insert a needle through the peritoneum of the left lower quadrant and thread a small polyethylene catheter through this needle into the pelvis. The needle may then be withdrawn and the catheter aspirated at intervals for blood. Although a negative tap does not eliminate the diagnosis of ruptured spleen, the presence of blood does much to confirm it. Treatment.--Patients should be prepared for operation by the administration of whole blood. Operation should not be delayed, however, either for unnecessary diagnostic examinations or for a period of watchful waiting if suspicion is high that a ruptured spleen exists. A longitudinal upper abdominal incision, midline or, preferably, left paramedian, has the advantage of rapidity and also of permitting extension to manage other intra-abdominal injury when present. It is difficult to explore the abdomen as carefully and to handle other contingencies through a left subcostal incision. After the peritoneal cavity is entered, the source of bleeding may be quickly determined and if profuse bleeding is occurring in the spleen its pedicle may be clamped between the thumb and forefinger. If the left hand is used for this maneuver, the right hand can then palpate the spleen confirming the diagnosis by the presence of a mushy softness in the enlarged organ. The spleen can then be rapidly delivered into the wound. It has often been noted that the spleen removed because of trauma is more mobile than when it is removed for hematologic disease. Thus, a splenectomy can be performed fairly rapidly, minimizing further hemorrhage. Although some older texts mention repair of small splenic lacerations, it is generally conceded today that total splenectomy is necessary if any damage is present, be it either a capsular tear or subcap39

sular injury. It is important to dissect the tail of the pancreas carefully from the hilum of the spleen and this may be slightly more difficult because of extravasation of blood in this area. It is advisable to obtain an occasional serum amylase report during the postoperative period in order to rule out an associated pancreatic injury, unrecognized at the time of operation or caused by a rapid and inaccurate clamping of the splenic pedicle. After the splenectomy has been completed, the entire abdomen should be carefully explored again to rule out other injuries. Approximately one third of patients operated on for splenic trauma have other associated intra-abdominal injuries, most commonly involving the kidney, the bladder, the intestinal tract or the liver. Results.--Although approximately 25% of patients with splenic injuries die, this figure is misleading because most of these deaths are caused by associated severe cranioeerebral, thoracic, or other abdominal injury. Of those patients that live long enough to be operated on, approximately 10% die. However, if the group with isolated splenic injuries is considered separately, operative mortality is below 1%, particularly in children. It is only necessary to repeat that the chief problem in splenic injury is making the diagnosis correctly and early. Late manilestations of splenic injury.---Traumatic pseudocysts and old, well-organized hematomas of the spleen have been noted either coincidentally, at laparotomy, or when the spleen has been removed for undiagnosed enlargement (47). Although these findings are rare, they provide ample evidence that occasionally the spleen must sustain injury without diagnosis. Their occurrence should not, under any circumstances, encourage delay in operation once the diagnosis of ruptured spleen has been made or is strongly suspected. Before the turn of the century, nodules of splenic tissue had been found scattered in the peritoneal cavities of patients at operation or autopsy and the significance of these bits of apparently normal spleens was poorly understood. Kuttner, in 1907, operated on a patient for a gunshot wound of the spleen, performing a splenectomy. The patient died three years later and, at autopsy, almost 100 splenic nodules were found attached to both parietal and visceral peritoneal surfaces. It was suggested that these were implants resulting from fragmentation of the spleen at the time of the gunshot wound. Such a condition of autotransplantation of splenic tissue is known as splenosis. Although it has been suggested that these bits of splenic tissue represent accessory spleens, this theory has never been seriously accepted. The nodules are scattered throughout the peritoneal cavity and do not lie in proximity to where pinched off primordia of the main splenic bud would normally occur. True accessory spleens have hilar structures; implanted splenic nodules do not. Today, it is generally accepted that, following trauma which fragments the spleen, numerous bits of splenic tissue parasitize upon various peritoneal surfaces, resulting in this 40

condition. Splenosis is of some clinical significance because the implants may produce symptoms of intestinal obstruction or, more commonly, present as undiagnosed nodules during laparotomy (68).

MISCELLANEOUS CONDITIONS OF THE SPLEEN NEOPLASMS.--Although many benign and malignant, primary and metastatic tumors of the spleen have been reported, they represent a wide variety and are relatively uncommon. Classifications of these tumors is useful, but it should be remembered that in most instances, the diagnosis is established only at operation performed for undiagnosed splenomegaly. Benign tumors may arise from any of the elements of splenic tissues. Furthermore, hamartomas, similar to those seen in liver and lung, have been described. Usually, the benign tumors are diagnosed by the presence of a left upper quadrant mass, occasionally tender, indistinguishable clinically from many other diseases producing splenic enlargement and confirmed only at operation. Those benign tumors of vascular origin, angiomas and endotheliomas, may produce the typical picture of hypersplenism with pancytopenia. They are particularly susceptible to mild degrees of trauma, rupturing with massive hemorrhage. A third complication of these tumors is that of malignancy. Examination of the excised spleen will often reveal areas of apparent benign tumor adjacent to areas of obvious malignancy. All primary malignant tumors of the spleen are sarcomatous in origin. They are usually of fairly rapid growth, may be accompanied by a persistent pain in the left upper quadrant or intracapsular area, by cachexia and occasionally by a pleural effusion and ascites. They spread rapidly to the liver, regional nodes and pancreas. Often they are not localized, but are part of a generalized sarcomatous process throughout the reticuloendothelial system of the entire body. Thus, although splenectomy is the only treatment currently effective, cure is uncommon. Metastatic malignant tumors of the spleen have been reported to be rare. This is undoubtedly true if reference is being made to a hitherto unestablished diagnosis, made at laparotomy for a splenic tumor. However, autopsy series have indicated the spleen to be a common site of metastases in far advanced malignancies, especially of lung and breast. CYsTs.--These are also relatively rare in the spleen and are classified as those elsewhere, into parasitic and nonparasitic. The parasitic are practically always ecchinococcic in origin. The nonparasitic are subdivided into three classifications (dermoid, epidermoid and endothclial) and the pseudocysts. These are often diMcult to differentiate since the lining of a true cyst may be destroyed. Pseudocysts of the 41

spleen result most commonly from trauma and, therefore, may contain old blood or venous fluid with cholesterol crystals. Rarely, such cysts may result from breakdown of a splenic infarct. The diagnosis is usually based upon gross and histologic findings and splenectomy is the treatment of choice. ECTOPIC SPLEEN.--This condition is occasionally reported and is thought to be caused by congenital or acquired deficiencies or lengthening of the ligaments of the spleen. Extreme mobility of the spleen may result in acute torsion of the pedicle, requiring emergency surgical intervention. Otherwise, the spleen may present as a mobile or fixed mass as low as the pelvis, being confused with an ovarian cyst or a fibroid tumor of the uterus. ANEURYSMS OF THE SPLENIC ARTERY.--These, although found in approximately 1 in 1,000 autopsies, occasionally rupture in life producing massive hemorrhage. They are usually noted as asymptomatic masses on abdominal x-ray and are characterized by an eggshell rim of calcification in the left upper quadrant. They are more prevalent in women. Symptoms attributable to the aneurysm are an ominous sign of impending rupture and include pain, nausea and vomiting. Most surgeons advise splenectomy and excision of the aneurysm, whether symptomatic or not. ABSCESS OF THE SPLEEN.---This is a rare condition which is usually encountered as an unexpected finding. Preoperative diagnosis depends upon the presence of an enlarged spleen, possibly irregular in contour, and a septic course. If possible, splenectomy should be performed. However, in the presence of a dense inflammatory mass, especially involving the pancreas, simple drainage is safer and will suffice.

OPERATIVE TECHNIC Numerous authors have described favorite technics for splenectomy. There are, perhaps, as many incisions described for this operation as for any other. Various abdominal, thoracic and combined abdominothoracic incisions have been utilized. Although the technic may vary according to the local findings and the need for speed, it is only rarely necessary to employ an incision other than a left subcostal, which may be extended well into the flank, or a left paramedian incision. Situations which may require changes in the usual technic of splenectomy are decreased coagulability of the blood, extension of the tail of the pancreas well into the hilum of the spleen, the presence and location of accessory spleens and the presence of adhesions between the spleen and diaphragm. PREOPERATIVE PREPARATION.---The conditions for which splenectomy are indicated have been detailed and it becomes apparent that, 42

except for rupture, there is little need for emergency splenectomy today. Thus, the patient can usually be brought into optimal condition, depending upon his disease. This implies the use of whole blood together with the use of steroids, if indicated. It is often advantageous to use whole blood which has been freshly obtained, using siliconized and plastic equipment in order that critical components, such as platelets, can be preserved as long as possible (5). ANESTHESIA.--Splenectomy is considerably simplified by adequate relaxation of the abdominal wall. With such relaxation, it becomes far easier to approach the diaphragmatic surface of the spleen in order to divide adhesions and to control bleeding. Furthermore, the spleen may be more easily delivered onto the anterior abdominal wall prior to removal. Spinal anesthesia is generally considered undesirable as an anesthetic for splenectomy because blood flow is increased and the spleen enlarged in size. This makes the organ more bulky to remove and possibly sequesters a significant portion of the blood volume. Ether produces a significant decrease in the size of the spleen and, for this reason, is the anesthetic of choice, if other unrelated factors do not contraindicate its use. OPERATIVE PROCEDURE.---Aleft subcostal incision is made approximately l to 2 inches below and parallel to the costal margin. If the spleen is not enlarged, incision can begin at the midline and extend laterally only a short distance into the oblique musculature. On the other hand, if the spleen is enlarged, the incision should be carried medially to the right costal margin or even curved downward to the right, in order to gain more exposure in this direction. Of greater importance is the extension of the incision laterally well into the flank in the presence of an enlarged spleen. Every inch of incision laterally allows considerably greater freedom in exposing the lienorenal and lienocolic ligaments, permitting the first stages of mobilization of the spleen and more easy dissection along the diaphragm from the lateral side. If a hemorrhagic diathesis is present, it is usually better to use a midline or left paramedian incision which is faster and transects fewer blood vessels. On the other hand, the left rectus muscle may be divided between clamps quite rapidly and a better exposure obtained. The clamps may be left in place until after the spleen has been removed and a better state of coagulability achieved. Once the peritoneal cavity is entered, the left hand is placed over the diaphragmatic surface of the spleen, gently retracting it downward. If adhesions are present, this maneuver is not possible. As the thumb and forefinger sweep posteriorly and caudally, the splenocolic ligament is grasped and brought anteriorly. It is usually unnecessary to place clamps across it or across the splenorenal and splenophrenie 43

folds. These structures are relatively avascular and may be quite easily divided. In the presence of congestive splenomegaly or portal hypertension, numerous vessels may traverse these peritoneal folds requiring division between clamps and ligation. After the ligaments have been divided, the spleen may be rotated forward and medially, exposing the hilum and tail of the pancreas. This rotation is impossible when the spleen is bound to the undersurface of the diaphragm by adhesions. Enough mobility has been achieved, however, to begin this dissection. It is important to divide the adhesions without entering or tearing the capsule of the spleen. Hemostasis may be difficult and electrocoagulation may be helpful. Once this dissection is complete, the spleen may be delivered into the wound. Occasionally, a large pack behind the spleen may be of use in maintaining the spleen in the wound, facilitating further dissection and providing hemostasis beneath the diaphragm. At this juncture, the short gastric vessels are divided between clamps and ligated. There is considerable variation in the anatomy of the tail of the

FiG. 8.---The spleen just before removal. Usual incisions for splenectomy are shown at upper left. Only a few short gastric branches need be divided before the spleen is freed of all its attachments. 44

pancreas, the splenic vessel and the hilum of the spleen. The surgeon must assure himself that the pancreas will not be injured as the vessels are individually dissected, clamped, divided and ligated (Fig. 8). The spleen is now removed and a search for accessory spleens conducted, if this is indicated. This is best accomplished by following an orderly plan so that likely areas are not overlooked. The remnant of the splenic pedicle is examined first and then the course of the splenic artery and vein is traced over the superior border of the pancreas. Next, a search is made behind the tail of the pancreas and along its inferior border. Occasionally, accessory spleens may be found in the remnants of the divided splenic ligaments, in the mesentery of the small intestine and high along the greater curvature of the stomach. It is helpful to know that if an accessory spleen is found, the likelihood of additional accessory spleens in other locations is low. Over 85 % of accessory spleens occur in the location of the first one found. Thus, they are often multiple but usually found in the same general area. Adhesions between the spleen and the diaphragm, massive splenomegaly and decreased coagulability of the blood are factors which, when combined, convert a relatively simple operation into one which may be exceptionally difficult. If fresh blood has been used preoperatively and during the initial stages of the operation, adequate clotting may be achieved. In such situations, the surgeon may prefer to approach the spleen transthoracically or through a thoracoabdominal incision, splitting the diaphragm and dissecting the splenophrenic adhesions under more advantageous exposure (Fig. 9). However, if the transabdominal route is preferred, extension of the incision well into the left flank permits excellent exposure of the inferior lateral pole of the spleen. Once the splenocolic and splenorenal attachments have been divided, this tip provides an excellent point at which to begin dissection upward through the adhesions. Before closing the wound, it is important to inspect the undersurface of the diaphragm in order to insure complete hemostasis. The splenic pedicle should be carefully inspected to insure adequacy of the ligatures on the splenic vessels and to control any small venous tributaries which may cause troublesome oozing in the area. If considerable oozing is expected from the diaphragm or because of clotting abnormalities, a drain may be placed deep in the splenic fossa and brought out through an anterolateral stab wound. However, with careful hemostasis and flushing of the splenic fossa with sterile normal saline to remove clots and devitalized fat, the wound is best closed without drainage. Occasionally, ligation of the splenic artery preliminary to splenic disseetion is of great aid, particularly in the prcscncc of a massively enlarged and adherent spleen. This may produce a slight reduction in 45

FIG. 9.----Thoracoabdominal exposure permits a more direct approach to the splenophrenic adhesions which are vascular and difficult to dissect without tearing the capsule of the spleen. the size of the spleen but, of more importance, it helps to control hemorrhage during the subsequent dissection about the spleen. Ligation of the splenic artery as a first step may best be accomplished by division of the gastrocolic omentum and on approach to the superior border of the pancreas, where the artery may be seen or felt posteriorly. It is carefully freed from the pancreas. Simple ligation without division is usually sufficient for the purposes of splenectomy since it is necessary to divide the splenic hilum later in the procedure and to ligate the vessels individually at this time.

COMPLICATIONS OF SPLENECTOMY Complications peculiar to splenectomy itself are, fortunately, relatively few. Perhaps the most common complication is that of atelec46

tasis or hypostatic pneumonia. Dissection of the left upper quadrant, especially with division of adhesions between the spleen and the diaphragrn, results in limitation of motion or even temporary paralysis of the left hemidiaphragm with decreased ventilation of the left lung. It is important to encourage deep breathing and coughing in the immediate postoperative period. Retained secretions should be treated by nasotracheal or bronchoscopic aspiration if the patient is unable to raise the secretions. Pleural effusions are also occasionally seen following splenectomy. Dissection on the undersurface of the left hemidiaphragm also may result in the loss of plasma or blood into the left subphrenic space in the early postoperative period. Such subphrenic collections may become manifest several days later and eventually form an abscess requiring drainage. In the presence of a large collection, needle aspiration may confirm the diagnosis before surgical drainage, but small collections may be difficult to find by aspiration. Severe hemorrhage may occur from the splenic arteries or veins or the short gastric vessels which have been inadequately ligated. Division and ligation of the short gastric vessels too close to the stomach may result in injury to the gastric wall, and perforations of the greater curvature of the stomach in the postoperative period have been reported on rare occasions. A more common injury to a contiguous organ occurs in the tail of the pancreas. This is particularly prone to happen when splenectomy is being performed in the presence of hemorrhage. Blood may emanate from the splenic hilum along the vessels and surround the entire tail of the pancreas in a huge hematoma. Ligatures in this area producing unrecognized trauma to the pancreas result in a localized pancreatitis which usually subsides, but which may occasionally progress and involve the entire gland in a fulminating and fatal process. In the past, the danger of postoperative thrombocytosis has been discussed frequently. Although this complication has undoubtedly been overemphasized, it should not be ignored. An increase in platelets is most prone to occur following splenectomy for trauma or congenital spherocytosis. Recent evidence suggests that this thrombocytosis may be more serious after splenectomy in agnogenic myeloid metaplasia with myelofibrosis (49) and may be not infrequently associated with thrombosis. Rises in platelet count to 800,000 or so should produce no cause for alarm, but a platelet count of over 1,000,000 should suggest the need for temporary anticoagulation with heparin. Many believe that rises in platelets over 1,000,000 increase the likelihood of splenic vein thrombosis with extension of this process into the portal vein. Such a complication was far more frequently reported in the past than today, and may very well have been related to infection or contiguous trauma at the time of splenectomy. 47

A n o t h e r c o m p l i c a t i o n of s p l e n e c t o m y is recurrence of disease o r failure to a m e l i o r a t e a disease due to the presence of accessory spleens which were not r e m o v e d at operation. This has b e e n most c o m m o n l y r e p o r t e d after splenectomy for congenital spherocytosis o r idiopathic thrombocytopenic purpura. T h e question of increased susceptibility to infection in infants and children has b e e n m u c h d e b a t e d in recent years ( 6 6 ) . It was suggested that the i m m u n o l o g i c defenses of the individual were transgressed, p e r m i t t i n g serious and often o v e r w h e l m i n g infections to occur. H o w ever, recent evidence suggests that an increase in infection is m o s t p r o b a b l y m o r e a p p a r e n t t h a n real (45, 2 6 ) . T h e r e is inconclusive evidence of little change in the a n t i b o d y response to certain antigen challenges in the s p l e n e c t o m i z e d individual ( 13 ). REFERENCES 1. Arey, L. B.: Developmental Anatomy (Philadelphia: W. B. Saunders Company, 1942). 2. Ashby, W. F., and Ballinger, W. F., II: Indications for splenectomy. Changing concepts as a result of advances in hematology, Arch. Surg. 85:913, 1962. 3. Aster, R. H.: Effect of anticoagulant, ABO incompatibility and spleen size on recovery and survival of transfused human platelets, Clin. Res. 12:219, 1964. 4. Aster, R. H., and Jandl, J. H.: Platelet sequestration in man. II. Immunological and clinical studies, J. Clin. Invest. 43:856, 1964. 5. Ballinger, W. F., II, and Cohn, H. E.: The preservation of blood, Surg., Gynec. & Obst. 112:411, 1961. 6. Ballinger, W. F., II, et al.: In vivo and in vitro survival of glycerolized frozen platelets, J.A.M.A. 179:148, 1962. 7. Berendes, M.: The proportion of reticulocytes in the erythrocytes of the spleen as compared with those of circulating blood, with special reference to hemolytic states, Blood 14:558, 1959. 8. Bessis, M. C., and Breton-Gorius, J.: Iron metabolism in the bone marrow as seen by electron microscopy: A critical review, Blood 19:635, 1962. 9. Best, W. R., and Darling, D. R.: A critical look at the splenectomy-S.L.E. controversy, M. Clin. North America 46: 19, 1962. 10. Boley, S. J., McKinnon, W. M. D., and Schwartz, S. S.: Traumatic rupture of the spleen in children, Surg., Gynec. & Obst. 109:78, 1959. 11. Bowman, H. S., and Procopio, F.: Heredity non-spherocytic hemolytic anemia of the pyruvate-kinase deficient type, Ann. Int. Med. 58:567, 1963. 12. Brown, M. J., Woodward, B., and Mehnart, I. H.: Surgical trauma to the spleen, Ann. Surg. 29:710, 1963. 13. Carlisle, H. N., and Saslaw, S.: Properdin levels in splenectomized persons, Proc. Soc. Exper. Biol. & Med. 102:150, 1959. 14. Cohn, P., Gardner, F. H., and Barnett, G. O.: Reclassification of the thrombocytopenias by the Cr~l-labeling method for measuring platelet life span, New England J. Med. 264:1294, 1961. 15. Collier, H.: Splenectomy: A justifiable operation in leucocythaemia, Lancet 1:219, 1882. 16. Congdon, C. C.: Recovery from radiation injury with special consideration of the use of bone marrow transplantation, in Tocantins, L. M. (ed.), Progress in Hematology (New York: Grune & Stratton, Inc., 1959). 48

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