Splenectomy in the Elderly

Splenectomy in the Elderly COLONEL WILLIAM H. CROSBY, MC, U. S. ARMY (RET.)* COLONEL THOMAS J. WHELAN, MC, U. S. ARMY** LIEUTENANT GENERAL LEONARD D. HEATON, MC, U. S. ARMY***

Almost every treatment of disease involves risk to the patient. The informed physician knows the risk; the wise physician weighs the risk against the anticipated benefits of therapy or the consequences of no treatment. Age is one of the factors which modifies risk, and advanced age tends to diminish anticipated benefits. An elective operation which is strongly recommended at the age of 40 may be pointless at 80. Age may be a deterrent, yet the problems of treatment for the elderly cannot be resolved by all-inclusive generalities. Individual judgment must determine the recommendation in every case. Advanced age should not become an excuse for doing nothing, nor should severe illness in the aged preclude procedures which may involve considerable therapeutic risk. The hope for improvement and for the prolongation of life remains the guide. With elderly patients the problems are essentially the same as with the young, only they are more complicated. 5 Splenectomy is now a procedure which, in competent hands, carries little risk. Careful attention to the hematologic problems, such as the correction of thrombocytopenia and the control of postoperative thrombocytosis, has done much to reduce morbidity and mortality. However, the indications for splenectomy are not yet entirely clear.16 It is known to cure From the Departments of Medicine and Surgery, WaIter Reed General Hospital, Washington, D. C. * Formerly Chief, Hematology Service, WaIter Reed General Hospital, Washington, D. C. Present address: New England Medical Center Hospitals, Boston, Massachusetts ** Formerly Chief, General Surgical Service, Walter Reed General Hospital, Washington, D. C. Present address: Tripler General Hospital, Honolulu, Hawaii *** The Surgeon General, United States Army. Formerly the Commanding General, Walter Reed General Hospital, Washington, D. C.

1533

1534

WILLIAM H. CROSBY, THOMAS J. WHELAN, LEONARD D. HEATON

several varieties of hemolytic anemia and a high proportion of well selected cases of thrombocytopenia and granulocytopenia. Large spleens are sometimes removed because of the sheer encumbrance of their bulk. N ot-so-large spleens may be removed in order to learn whether or not splenectomy is of value in rare or unexplored conditions. In this way, for example, splenectomy for myeloid metaplasia has become an acceptable procedure even though one cannot hope to cure the underlying myeloproliferative disease. After a number of years of trial we have come to believe that our patients with Hodgkin's disease do better if splenectomy is done at the first sign of hypersplenism, rather than waiting until the patient is a hematologic cripple. We have also studied the effects of splenectomy in elderly patients with hematologic problems. Since 1954 we have had experience of 20 such cases. The present report concerns the problems and results of splenectomy in these patients, all of whom were past 59 when the operation was performed. IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)

The cure rate of ITP following splenectomy is gratifyingly high. In large series of cases it is reported to be 80 to 85 per cent.4, 17 The disease is more common in younger people than old, and although the response to splenectomy is thought to be better in the young, cures and improvement in the not-so-young are commonplace. The cases in this group illustrate our convictions concerning the handling of this disease. When the possibility of a drug reaction has been eliminated, corticosteroids are prescribed. If the platelet count does not increase significantly within two weeks, splenectomy is recommended. But if the count does increase, the dose of steroid is promptly but gradually reduced. If it is not possible to withdraw the drug without precipitating a relapse, prompt splenectomy is recommended. In view of the potential for damage possessed by steroid therapy (Case II), it is not advisable to defer the decision. These three cases of ITP demonstrate a spectrum of response to splenectomy. All were considered to be failures of corticosteroid therapy: one was completely refractory, one had only a flicker of response and one responded well but relapsed when attempts were made to withdraw the drug. The response to splenectomy was also divergent: one failed to respond, but her thrombocytopenia was thereafter amenable to steroids; one had a delayed response after splenectomy; and the third had an immediate cure. Splenectomy for ITP in the elderly is not a hopeless gesture. CASE 1. A white woman in her 60th year (b. 1889)* was admitted to WaIter Reed General Hospital in October, 1958 after conization of the cervix in another hospital had yielded a carcinoma in situ. Her initial complaint was of vaginal bleeding beginning in mid-September. Physical examination revealed nothing of significance. * The age stated in each report is the age at the time of splenectomy.

SPLENECTOMY IN THE ELDERLY

1535

Hemoglobin concentration was 10 gm.; leukocyte count 3,600 with 60 per cent polymorphonuclears. One week after admission an abdominal hysterectomy was performed with an estimated loss of 3.5 liters of blood which was replaced by transfusion. Transfusions were continued after the operation for the correction of circulatory instability. During the first postoperative week, a hematoma formed in the wound and the patient vomited some blood. It was necessary to continue transfusions. On November 5, a platelet count was 5000 and aspirated sternal marrow was moderately hyperplastic with normal numbers of megakaryocytes which appeared to be "not producing platelets." The myeloerythroid ratio was altered in the direction of erythroid hyperplasia. A choluric jaundice developed. On November 15 when corticosteroid therapy (60 mg. of prednisone per day) was begun, the platelet count was 1000, the leukocyte count 2300 and hemoglobin 9 gm. The platelet count did not respond to steroids and, on December 8, splenectomy was done. Generalized oozing continued during the operation. The spleen weighed 81 gm. and showed reticuloendothelial hyperplasia and siderosis. The postoperative course was without incident. Although steroids were continued, platelet count by December 29 was only 13,000. The patient was transferred to the hospital from which she had come. During the month of January, 1959, the patient improved. Her platelet count was as high as 160,000 on 60 mg. of prednisone per day, and at the time of her discharge to home in February it was 62,000 when she was receiving 5 mg. of prednisone. She was given a transfusion for anemia (hemoglobin 7 gm.). In June, 1959, because of renal colic, she returned to the hospital. Hematologic studies: platelet count 143,000, leukocyte count 7000 with 80 per cent polymorphonuclears, hemoglobin 11 gm. Pyelolithotomy was performed without difficulty. In January, 1965, the patient was reported to be in good health.

Comment. It should be axiomatic that unexplained uterine bleeding is an indication for a platelet count.l5 In this case, it might have saved both the patient and her surgeons considerable distress. From the point of view of therapy of ITP, this patient was refractory to corticosteroids. However, splenectomy was followed by a slow response but ultimate cure of the purpura. CASE 2. A 68 year old white woman (b. 1891) was admitted to WaIter Reed General Hospital in January, 1959 with a history of bruising for several years. In February, 1958, the tourniquet test was positive; but the platelet count was 185,000, and other tests of hemostasis and coagulation were normal. At the time of admission spontaneous purpura had been present for a month, but except for the bruises the physical examination was normal. The platelet count was less than 1000. Leukocyte count was 5100 and hemoglobin concentration 12.3 gm. Aspirated marrow appeared normal. The patient was treated with 80 mg. per day of prednisone. Within 2 weeks her platelet count had risen to 29,000 and then almost immediately while steroid therapy continued the count subsided once again to 1000. The spleen was removed on January 26, 1959. During the operation the patient received 1000 ml. of freshly drawn blood as a source of platelets, and there was no untoward bleeding. The operation and postoperative course were uncomplicated. The patient received prednisolone during and after surgery. The platelet count went to 300,000 and attempts were made to reduce the dose of corticosteroids. However, it was not possible to maintain her platelet count and thereby prevent severe purpura with less than 20 mg. per day of prednisone; on several occasions thrombocytopenia and bleeding developed in spite of it. In August she sustained compression fracture of the body of vertebra T6. Congestive heart failure also developed with atrial fibrillation and acute pancreatitis of unknown etiology but probably related to a duodenal ulcer. She died of bronchopneumonia on Sep-

1536

WILLIAM H. CROSBY, THOMAS J. WHELAN, LEONARD D. HEATON

tember 25, 1959. With 20 to 30 mg. per day of prednisone the patient's platelet count had remained at reasonable levels, around 100,000, during the final phase of her illness. The leukocyte count was around 5000 and the hemoglobin concentration around 13 gm.

Comment. This case illustrates some of the side effects of corticosteroid therapy, peptic ulcer and demineralization of the skeleton, which one tries to avoid by performing splenectomy when it proves impossible to maintain a reasonably safe platelet count without steroids. In this patient's case such a number of platelets was obtained only with the combination of splenectomy and steroid therapy. Fairly rapid deterioration was the consequence of the necessity to continue steroid therapy. CASE 3. A 65 year old retired officer (b. 1897) was admitted to WaIter Reed General Hospital in July, 1962 because of thrombocytopenia with increased megakaryocytes. History was negative for purpura, except easy bruising since childhood. Physical examination revealed no hepatosplenomegaly. There was evidence of hypertensive, arteriosclerotic heart disease and prostatic hypertrophy. Platelet count was 21,000; leukocyte count 9100 with 50 per cent polymorphonuclears; hemoglobin 16 gm.; reticulocyte count 0.5 per cent. Reserpine and chlorothiazide (Diuril) were discontinued without benefit, and treatment was begun with prednisone 60 mg. per day. By July 30 the platelet count was 208,000. The drug was tapered off beginning on July 27. At 30 mg. daily, the platelet count was 30,000; at 20 mg. it fell in the 20,OOO's. When the drug was increased to 40 mg. per day the count rose again to about 100,000; when the dose was decreased the count fell again. The patient's spleen was removed on September 11. During the operation he was given an adequate dose of steroid and his platelet count was normal. A sclerotic section of rectosigmoid colon was also removed because of diverticulitis. The 125-gm. spleen demonstrated no significant pathology. Two weeks after splenectomy the platelet count crested at 1 million, then subsided to normal levels within the next 2 weeks. On October 17, without incident, a transurethral prostatectomy was performed because of obstructive hypertrophy. A saccular aneurysm of the abdominal aorta discovered during splenectomy was replaced by prosthesis in May, 1963, and in June, 1964, an incisional hernia was repaired. In January, 1965, the patient was well and teaching school. On each of these latter 3 occasions the patient's platelet count was about 300,000, hemoglobin 16 gm., and leukocyte count about 10,000 with 60 per cent polymorphonuclears.

Comment. This case represents a situation in which one is tempted to temporize. The patient was old, his cardiovascular system demonstrated obvious degenerative changes and his response to steroid therapy was prompt and adequate. However, the response was not sustained when the steroid dose was reduced. The choice, therefore, lay between maintaining the patient on a steroid regimen that would certainly have provoked physiological deterioration and removing his spleen while he was a fairly good operative risk.

HEREDITARY SPHEROCYTOSIS (HS) Hereditary spherocytosis is the only hematologic disease which can be cured by splenectomy in virtually every case. Of course the hereditary fault

SPLENECTOMY IN THE ELDERLY

1537

of the red cell is not corrected, but the hemolytic mechanism provided by the spleen is removed. The only cases in which splenectomy has not been followed by permanent cure of hemolytic anemia are those few in which residual splenic tissue was of sufficient amount to cause a resumption of abnormal hemolysis. 7 A large accessory spleen (in excess of 100 gm.), splenosis (multiple small implantations of splenic tissue in the peritoneum following rupture of the spleen), splenic remnants left on the abdominal wall because of adhesion, and, presumably, the failure to identify and remove one of the halves of a bifed spleen: these are the accidents whereby splenectomy may fail to cure the hemolytic disease of HS. What is the justification for removal of the spleen from a patient 60 years of age who has lived with hereditary anemia all his life? In the first place, the danger of the aregenerative crisis is greater in the old than in the young. The abrupt, severe anemia which appears when the marrow is temporarily wiped out in patients with short-lived red cells is catastrophic in the elderly. This is a complication of chronic hemolytic disease, probably related to viral infection, which may develop at any time without warning. ll In the second place, many elderly patients become less tolerant of even moderate anemia. The disease which, as youngsters, they tolerated without discomfort becomes less and less tolerable. Correction of the anemia restores their well-being. This indication for elective splenectomy was well demonstrated by the result in both cases. CASE 4. A 66 year old retired officer (b. 1897) was admitted to WaIter Reed General Hospital on April 4, 1963, for an elective splenectomy. He complained of symptoms of anemia. Hemoglobin concentration was 10 gm., hematocrit 33 per cent, and reticulocyte count ranged from 2 to 6 per cent. Platelets were 280,000 and leukocytes 4600 with a normal differential count. Bone marrow aspirate showed erythroid hyperplasia and the presence of "reactive plasma cells." Plasma bilirubin concentration was 2 mg. per 100 ml. and total protein was 7 gm. with a normal albumin-globulin ratio. Urine was normal. Osmotic fragility tests of the patient's red cells indicated spherocytosis; morphologic examination demonstrated the cells to the elliptical.2 6 On April 8 an uneventful splenectomy was performed without any transfusion. The spleen weighed 525 gm. and its microscopic appearance was characteristic of hereditary spherocytosis. After the operation the platelet count increased above 1 million, so the patient was given coumadin as prophylaxis against thrombotic complications. He was discharged from the hospital on April 26. Anticoagulant therapy was discontinued when his platelet count returned to a level below 500,000. His hematocrit increased to 44.5 per cent and the reticulocyte count became normal. In August, 1964, the patient returned to the hospital and died of myelomatosis.

Comment. The cure of this patient's hemolytic disease was a shortlived satisfaction. Even in retrospect, however, it was not possible to make a diagnosis of myelomatosis prior to the operation. The plasma cells in the marrow were the only sign, but their number was small and they did not appear abnormal. CASE 5. A 75 year old white woman (b. 1883) was admitted to WaIter Reed General Hospital on June 16, 1958 for an elective splenectomy for hereditary

1538

WILLIAM H. CROSBY, THOMAS

J.

WHELAN, LEONARD

D.

HEATON

spherocytosis. She had been anemic and slightly jaundiced since childhood, with continual feeling of being "washed out" or "unable to keep up." At age 27 cholecystectomy was performed for gallstones. She had one child and became eclamptic at the time of delivery. At age 65 she was told she had pernicious anemia and was given liver injections and 6 blood transfusions without benefit. At age 70 she was told she had hemolytic anemia and was given corticosteroids and althOl.:gh without benefit this treatment had been continued. At age 75 because of ankle edema she was given digitalis until she developed nausea and vomiting and discontinued the drug on her own initiative. In the spring of 1958 she appeared at the WaIter Reed General Hospital outpatient clinic: hemoglobin 8 gm.; reticulocyte counts about 18 per cent. Bone marrow showed erythroid hyperplasia. Splenectomy was recommended. On her admission to the hospital the physical examination revealed a slight icterus and spleen palpable on inspiration; normal vital signs and a soft systolic murmur. Weight was 57 kg.; leukocytes 11,700; the blood smear showed obvious spherocytosis; hemoglobin 10.6 gm., mean corpuscular volume (MCV) 109 p.3; mean corpuscular hemoglobin (MCH) 34 p.pg.; mean corpuscular hemoglobin concentration (MCHC) 37 per cent; reticulocytes 15 per cent; platelets 324,000; Coombs test negative. Serum bilirubin 2 mg. with 0.3 mg. direct, proteins 7.3 gm. with 4.4 gm. albumin per 100 ml. Osmotic fragility of the patient's red cells was considerably increased. Red cell mass measured with 5lCr-tagged red cells was 15.2 ml. per kg. body weight; total was 709 ml. Blood volume was computed to be 62 ml. per kg. T->-2 of the patient's 5lCr-tagged red cells was 5.5 days. Splenectomy was performed on July 9 without incident. One unit of blood was transfused during the operation. The spleen weighed 185 gm., and the microscopic examination revealed the red-pulp congestion which is characteristic of spherocytosis. Before her discharge from the hospital on July 28, the patient's hemoglobin was 13.9 gm. and the reticulocyte count 1.7 per cent. Leukocytes were 14,000, polymorphonuclears 65 per cent. In October the counts were essentially the same. Following the operation the patient felt quite well and noted that for the first time in her life she was sleeping all night; a persistent, repeated nocturia which she had had all her life disap peared. The patient became and remained hematologically normal. She died in 1961 of metastasis from a cancer of the breast.

Comment. This patient's experience demonstrates how a lifetime of discomfort and illness might have been prevented by early splenectomy. Even at the age of 75 this sprightly old lady had much to gain from the correction of anemia which had been increasingly troublesome to her over the preceding ten years. The case also demonstrated the futility of treating hereditary anemia by inappropriate means such as liver extract, transfusion, and corticosteroid.

LYMPHOMA WITH SPLENOMEGALY AND HYPERSPLENISM It is well known that splenomegaly associated with the malignant lymphomas and Hodgkin's disease may cause hypersplenism, sometimes of a serious degree. Whether or not splenectomy is indicated in this situation has been a subject of debate. 23 In view of the malignant nature of the primary disease the question concerning splenectomy is properly asked, is it worth it? In most cases we believe that it is. In fact, it has become our

SPLENECTOMY IN THE ELDERLY

1539

policy to recommend splenectomy as soon as the earliest discernible evidence of hypersplenism appears. We have learned that, once hypersplenism manifests itself it remains a complication. While it may improve temporarily with treatment of the lymphoma, relapse is inevitable and the hypersplenism seems to become more severe as the patient's condition deteriorates and his marrow is injured by chemotherapy, x-irradiation and the disease itself. The time comes when cytopenias are serious, the patient is ill and in need of chemotherapy and the physician hesitates to assault the marrow even though hypersplenism may be the principal pathogenic factor in the cytopenia. Splenectomy at such a time is desirable but the patient is a risky candidate for surgery. The spleen should have been removed the year before when it first became enlarged and the granulocytopenia (or thrombocytopenia or hemolytic anemia) was mild, not even a problem but only a threat. In the first of the following cases we did not recommend splenectomy in 1954, but we would do so today. The patient took the matter into her own hands and had the operation done elsewhere. The problem as she saw it was the size of the spleen, but it is noteworthy that there was evidence of hypersplenism which splenectomy corrected. In the second case a serious transfusion problem was corrected by splenectomy. Thereafter for most of the patient's life transfusion was not needed. He was pleased with this and so were his physicians even though the time was not long. CASE 6. The patient was a 74 year old white woman Cb. 1888) whose illness, giant follicle lymphoma, appeared as an enlargement of the abdomen in mid-1951. This proved to be due to massive splenomegaly. There was a mild anemia and leukopenia and a normal platelet count. The splenomegaly responded rapidly and completely to x-irradiation. The enlargement recurred and once again responded to irradiation. In January, 1954, there was yet another recurrence. The patient requested that the spleen be removed because of its inconvenience which had something to do with the fit of her dresses. Because the tumor responded well to irradiation, this treatment was used again. The patient was a strong-willed woman and when her spleen enlarged the next time, in July, 1954, she sought surgical help elsewhere and a splenectomy was performed. For the next 3 years she felt well and all of her blood counts were normal. Then in February, 1957, while skiing in New England, she had an attack of renal colic caused by ureteral obstruction by tumor tissue. Generalized lymphadenopathy rapidly appeared together with evidence of intracranial involvement. The patient was admitted to WaIter Reed General Hospital on March 1 in serious condition. Hematologic studies at that time: hemoglobin 13 gm., leukocytes 7600 with 80 per cent polymorphonuclears, platelets 430,000. The red cells showed the usual evidence of an absent spleen plus burr cells. Moderate uremia was controlled with ureteral catheters. The tumors disappeared after treatment with 20 pg. of nitrogen mustard and radiation directed at the ureteral area, but the tumors promptly reappeared. She died on March 30 and postmortem examination revealed widespread lymphoblastic lymphosarcoma involving lymph nodes, lungs, liver, and kidneys.

Comment. This was a lively, handsome woman who resented her illness to the extent of attempting to have it cut out. Her action demonstrated

1540

WILLIAM H. CROSBY, THOMAS J. WHELAN, LEONARD D. HEATON

the value of splenectomy when there is evidence of hypersplenism but no serious problem. She remained free of symptoms and dependence upon doctors for about three years. Such a case supports the policy of splenectomy early in the course of malignant lymphoma when the spleen is hyperactive or uncomfortably enlarged. CASE 7. A 72 year old white retired soldier (b. 1896) was in good health until January, 1958, when progressive symptoms of anemia appeared. In March he was hospitalized with a hemoglobin concentration of 3 gm. and during several weeks received 6 units of transfused blood. There was no evidence of bleeding or hemolytic disease. He was given injections of vitamin B12 and iron-dextran without benefit. On May 5, he was transferred to Waiter Reed General Hospital. Examination revealed edema of the legs and enlarged lymph nodes (1 to 3 cm.) in the neck, axillae, and groins. Liver and spleen were moderately enlarged. The patient was afebrile. Hematologic data: hemoglobin 3.4 gm., reticulocytes 2.5 per cent, platelets 321,000, leukocytes 7700 with 56 per cent polymorphonuclears and no abnormal cells. Bone marrow aspirate contained a preponderance of abnormal young cells characteristic of lymphosarcoma. A lymph node was described as "reactive." Blood transfusion was followed by disappearance of the edema, but the hemoglobin concentration increased for a short time only: the T-72 of autotransfused MCr-tagged red cells was 10 days. The patient's red cell mass at that time (late June) was 877 ml. or 13 ml. per kg. of body weight. (Hematocrit 25 per cent, weight 68 kg.). The patient was treated with chlorambucil and his condition improved. The spleen grew smaller and the hemoglobin increased. The drug was discontinued in late June after 150 mg. By July the patient maintained his hemoglobin at 10 gm. Reticulocyte counts of 7 to 10 per cent were recorded. It was decided to remove the spleen while the patient was in good condition, and splenectomy was performed on July 16 without transfusion. Recovery was uncomplicated. The spleen weighed 208 gm. and was reported to show no evidence of malignant disease. He was discharged from the hospital on August 1. Thereafter he did well with normal hemoglobin concentration and platelet counts, but the leukocyte count gradually increased. When he was readmitted to the hospital in March, 1960, for shortness of breath his leukocyte count was 36,000 with 50 per cent lymphoeytes, many of them abnormal and 7 per cent were blasts; hemoglobin 14 gm., platelets 295,000. The lung fields showed mottled infiltration ("snowstorm"), but the sputum contained no pathogens. Fifteen per cent of the bone marrow cells were atypicallymphocytes and blast cells. Daily treatment with 6 mg. of chlorambucil was begun and the leukocyte count dropped to normal and then abruptly rose to levels around 150,000. The drug was increased to 12 mg. per day and the patient was discharged to outpatient status on May 3. The appearance of the lung fields was unchanged, but the shortness of breath had disappeared with diuresis and salt restriction. He did not respond further to chlorambucil and was readmitted on May 16 for a trial of cyclophosphamide (Cytoxan). He did not respond to this or to nitrogen mustard. Generalized lymphadenopathy increased; the number of blasts in the blood increased; anemia returned but without evidence of hemolysis. Platelet counts remained normal. The patient developed bronchopneumonia and died on June 16, 1960.

Comment. In Case 7, the patient survived 11 months following splenectomy which cured the hemolytic anemia complicating a documented lymphosarcoma. For 10 of the 11 months he was free of anemia even though he developed a refractory leukosarcoma prior to his death. His care during

SPLENECTOMY IN THE ELDERLY

1541

this terminal illness would have been greatly complicated had hypersplenism been allowed to persist. BANTI SYNDROME

The Banti syndrome is an association of splenomegaly and cirrhosis of the liver, often with hematologic evidence of hypersplenism. The simultaneous existence of hypersplenism and portal hypertension poses a problem of therapeutic judgment in which the following factors should be taken into account: 1. Which condition is the more serious threat to the patient? With large esophageal varices and a history or likelihood of bleeding therefrom, decompression of the portal hypertension is the primary consideration. At present a portacaval shunt is the procedure of choiceY If, however, the portal hypertension is not severe in its manifestations and the hypersplenism is serious or progressive, primary consideration is given to removal of the spleen. At the same time it may be advisable to construct a splenorenal shunt. 2. Hypersplenism is not cured by portal decompression. In less than half the cases the blood counts may revert to normaPO but it has not been established that the life span of the blood cells also becomes normal. Hemolytic disease may persist even when the hypersplenism is no longer severe enough to cause hemolytic anemia. 3. In over two-thirds of cases the cytopenia persists after successful decompression of portal hypertension if the spleen is not removed. 22 Because these patients are subject to hematologic crises they must be followed carefully, and consideration should be directed to removal of the spleen before progression of the cirrhosis has made the patient a poor surgical risk. 4. Splenomegaly is not cured by decompression in most cases. Portal hypertension is responsible for only part of the enlargement of the spleen. It has been shown experimentally that the spleen transplanted away from the portal circulation still enlarges when the liver becomes cirrhotic. 3 5. Removal of the spleen at the time of construction of a portal shunt does increase somewhat the possibility of thrombosis: thrombosis may develop at the site of the shunt or a thrombus may propagate from the stump of the splenic vein. For this reason, the platelet count should be followed closely; when in doubt use anticoagulants. Moderate anticoagulation does not compromise hemostasis, even during surgery.25 The following cases illustrate some of the problems which may be encountered in the Banti syndrome complicated by hypersplenism in elderly patients. CASE 8. A 62 year old white woman Cb. 1900) was found on a routine physical examination in 1959 to have a moderate hepatosplenomegaly. She stated that she had had gallstones for almost 30 years but had refused surgery. During the next

1542

WILLIAM H. CROSBY, THOMAS J. WHELAN, LEONARD D. HEATON

two years, both liver and spleen enlarged still more with a progressive thrombocytopenia suspected to be a consequence of hypersplenism. A presumptive diagnosis of cirrhosis with congestive splenomegaly was made. There was no evidence or history of alcoholism. The leukocyte count was 5200 but had been as low as 2300; hemoglobin was 12.5 gm. and platelet count was 60,000. Bone marrow showed erythroid hyperplasia, normal granulopoiesis and adequate megakaryocytes. Moderate varices were found on esophagoscopy. Liver function tests were abnormal; BSP retention 22 per cent, alkaline phosphatase 58 King-Armstrong units, cephalin flocculation 3 plus in 49 hours; prothrombin activity was 70 per cent of normal; serum albumin 2.6 gm. of total protein, 7.7 gm. per 100 ml.; total bilirubin 1.5 mg. with 0.6 mg. direct. On February 2,1962 the patient's spleen was removed and a splenorenal shunt was established. Splenoportogram demonstrated "evidence of severely increased portal pressure." The portal blood pressure was 375 mm. H 20; with the shunt it became 260 mm. The patient received 3 units of blood during an uncomplicated surgical procedure. Biopsied liver tissue showed biliary cirrhosis with portal fibrosis. The spleen weighed 485 gm. and showed "chronic congestion" with GamnaGandy nodes. At the time of discharge from the hospital 2 weeks after the operation the leukocyte count was 12,000 with 72 per cent polymorphonuclears, hemoglobin 13 gm., and platelets 258,000. In February 1964, cholecystectomy was performed without incident. Portal pressure was normal. When re-examined in August, 1964, the patient was hem atologically normal; hematocrit 43, leukocytes 8700, platelets 365,000. The liver function tests were abnormal as before.

Comment. Elective splenectomy was performed at a time when the patient was in good condition. The procedure and convalescence were uneventful and the patient remains hematologically normal and in reasonably good health three years after the operation. Indication for splenectomy was a gradually increasing hypersplenism in which thrombocytopenia was the most serious threat. Splenorenal shunt was performed because of the high portal pressure and the presence of esophageal varices. To judge from the liver function tests there has been no improvement of the cirrhosis, but it has not become worse. CASE 9. A 60 year old retired officer (b. 1895) was admitted to WaIter Reed General Hospital in April, 1955, with a 4-year history of hepatomegaly and 1 year's history of splenomegaly. The patient had always been a nondrinker. Several bleeding episodes had occurred during the preceding 3 years; once he was hospitalized after he cut himself shaving; another time he bled profusely during an epididymectomy, but there was no history of purpura. Both liver and spleen were palpable 10 cm. and there were large esophageal and gastric varices. Platelet counts ranged from 30,000 to 90,000; leukocyte counts about 5000 and hemoglobin 14 gm. Aspirated bone marrow showed increased numbers of megakaryocytes and an increased proportion of erythroid cells. Some liver function tests were abnormal: bilirubin 1.3 mg.; prothrombin activity 75 per cent; cephalin flocculation 3 plus at 48 hours; BSP retention 25 per cent. The spleen, weighing 900 gm., was removed on May 25, 1955 and a splenorenal shunt was constructed. Splenic vein pressure was reduced from 330 mm. of water to 210 mm. Two weeks later the platelet count was 500,000; the leukocyte count 10,000 and hemoglobin 12 gm. Esophagoscopy showed the varices 75 per cent reduced. Liver function tests were normal except the BSP retention which was unchanged. The spleen showed fibrosis. Tissue from the liver was severely fibrotic without the

SPLENECTOMY IN THE ELDERLY

1543

lobular disorganization of cirrhosis. Six months later the platelet count was 395,000; leukocyte count 5200; hemoglobin concentration 14 gm. The shrunken varices were unchanged; 1 fingerbreadth of the liver edge was palpable. The patient's condition remained essentially unchanged until May, 1964, when he suffered a perforated gastric ulcer. In December, 1964, he died during a severe hemorrhage from a gastric ulcer. Except for anemia he was hematologically normal. Postmortem examination revealed only the ulcer and the cirrhosis.

Comment. In cirrhosis of the liver the platelet count may be marginal, the plasma clotting factors reduced and fibrinolysin may be active. None of these alone may be severe enough to cause a bleeding dyscrasia, but in combination they may result in a critically compromised hemostatic system. The bleeding episodes in this case may have been a result of such a combination of disorders. In sueh a situation, improvement of the platelet count to normal may restore hemostatic competence. CASE 10. A 72 year old retired officer (b. 1886) was admitted to Waiter Reed General Hospital in April, 1958. In 1937, during cholecystectomy a diagnosi~ of cirrhosis was established and was manifested by ESP retention thereafter. Blood counts as late as 1957 were normal. In 1958 the patient began to complain of upper abdominal distress. On examination there was tenderness over the liver and a palpable spleen. Esophagoscopy revealed varices of the distal third of the esophagus. Hemoglobin concentration was 14.5 gm., reticulocyte count 3 per cent, leukocyte count 3600 with 60 per cent polymorphonuclears, platelet count 17,000. Aspirated marrow demonstrated relative erythroid hyperplasia. Liver function tests showed abnormal retention of ESP, reversal of albumin-globulin ratio and 1 mg. of bilirubin. Alkaline phosphatase was normal. Splenectomy with construction of a splenorenal shunt was performed in June 10, 1958; operation and convalescence were uncomplicated. The spleen demonstrated congestion, fibrosis, and mild siderosis; the diagnosis of postnecrotic cirrhosis of the liver was confirmed. Leukocyte and platelet counts became normal. Re-examination in July permitted the patient to be classified as a "good response to splenorenal shunt," but he did not feel well. He complained of weight loss and low-grade fever. Serious gastrointestinal bleeding began in September. Surgical intervention (subtotal gastrectomy with gastrojejunostomy) was in vain. The patient died November 4 and necropsy revealed diffuse hepatoma (liver cell carcinoma) extending into the portal vein forming large tumor thrombi.

Comment. The patient survived splenectomy by three months when he died of hepatoma, an unsuspected complication of cirrhosis. The primary indication for splenectomy was severe thrombocytopenia. Result of the operation was a correction of the hematologic abnormalities and reduction of portal pressure. When the presence of hepatoma is known, splenectomy is not indicated. Survival is too short to justify the operation. CASE 11. An 84 year old officer (b. 1880) entered Waiter Reed General Hospital in March, 1964, with a history of many years of self-imposed medical neglect. Four years prior to the present admission he had had a transurethral prostatectomy, but only after he had become uremic. For at least 10 years he had had massive bilateral inguinal hernias for which he had refused surgery. Episodes of jaundice and upper abdominal pain had occurred over the preceding 12 years but he had declined adequate diagnostic procedures. During this time his liver and spleen gradt:ally enlll,rged. The present admission was preceded by an episode of jaundice during

1544

WILLIAM H. CROSBY, THOMAS

J.

WHELAN, LEONARD

D.

HEATON

which the patient lost 20 pounds of weight, passed tarry stools, and developed severe pruritus. Because of this last complaint he finally consented to hospitalization. Physical examination of this lifelong teetotaler revealed emaciation, spider telangectasia on the upper torso and distended veins across the abdomen, hepatomegaly (4 cm.), splenomegaly (3 cm.) and bilateral inguinal hernias which could not be reduced. Laboratory studies indicated the presence of parenchymalliver disease, renal insufficiency and hypersplenism. Bilirubin was 17 mg., BUN 41 mg., alkaline phosphatase 52 King-Armstrong units, transaminase (SGOT) 224, prothrombin activity 50 per cent, hemoglobin 9.4 grams, reticulocytes 3.5 per cent, leukocytes 5700 (50 per cent polymorphonuclears and 12 per cent bands), platelets 87,000. The patient was given 2 blood transfusions and vitamin K which elevated the hemoglobin concentration to 10.7 gm. and prothrombin activity to 90 per cent. With adequate hydration and osmotic diuretics the BUN promptly returned to normal. A small, fibrous gallbladder was removed and many stones were taken from the bile ducts. The liver was enlarged with biliary cirrhosis secondary to obstruction. Two units of blood were given during surgery. Following the operation the patient improved for 2 weeks until a massive hemorrhage occurred from a ruptured varix high in the esophagus. Splenectomy and a splenorenal shunt were performed. A Sengstaken tube was used to control the bleeding. Before and during the operation a massive transfusion was required for replacement and to stabilize the circulatory system. Following splenectomy, the leukocyte count was in the range of 40,000 and the platelets 150,000. Six days after the second operation the jejunum in the left inguinal hernial sac became obstructed and perforated. Intestinal resection was performed but hepatic and renal insufficiency supervened and the patient died one week after the operation. At postmortem examination the patient was found to have large and extensive esophageal varices.

Comment. It is evident that definitive care of several remediable disorders was too long deferred. With regard to the splenomegaly and hypersplenism, one can only speculate as to whether the hemorrhagic catastrophe might have been prevented by earlier decompression of the portal hypertension. The size and extent of the varices were not revealed by preoperative x-ray studies. The case also illustrates an important attitude toward surgery in the elderly and other classes of patients with increased risk but with some salvageable life expectancy: therapy should not be withheld even though the risks are high, when the alternative is death. MYELOID METAPLASIA Myeloid metaplasia is a proliferation of blood-forming tissueerythroid, myeloid, and megakaryocytic-in organs other than the bone marrow, an abnormal situation in extra-uterine human existence. It is one of the group of so-called myeloproliferative syndromes,14 indeed, it may be sequentially associated with other diseases of the group as in Case 15, where it followed polycythemia vera and preceded granulocytic leukemia. Although "myeloid metaplasia" is always present in chronic granulocytic

SPLENECTOMY IN THE ELDERLY

1545

leukemia, the syndrome referred to is usually a nonleukemic disease associated with myelofibrosis or myelosclerosis. Because of the fibrotic replacement of the marrow, myeloid metaplasia is often assumed to be a reactive response to the requirement for blood cells. The relation is probably not so simple as this. Sometimes, as in Case 12, we see the onset of myeloid metaplasia before there is detectable myelofibrosis and the marrow is, in fact, generally hyperplastic. On the other hand, in Case 17, the liver, usually heavily involved by the metaplasia, contained only a few megakaryocytes and was itself, like the marrow, severely fibrotic. Myeloid metaplasia is usually a disease of the elderly, and the requirement for splenectomy must often be considered against a background of degenerative changes. However, the splenic complications of myeloid metaplasia are serious: 1. Progressive splenomegaly becoming massive and producing symptoms of intra-abdominal pressure: there may be immobilization of the left diaphragm, compression of the urinary bladder, and especially the small-stomach syndrome which interferes with the patient's nutrition. 2. Hypersplenism may also be progressive. The thrombocytopenia or the anemia may be severe enough to threaten the patient's life. 3. Infarction of the spleen and perisplenitis produce adhesions, thereby increasing risk of splenectomy. Because the progression of these complications increases the danger and debilitates the patient at a time when age may also be taking its toll of cardiac, pulmonary, and renal reserves, we have come to believe that splenectomy should not be deferred. In the absence of contraindications remove the spleen as soon as the diagnosis is established. Contraindications to splenectomy in myeloid metaplasia relate to the patient's general condition and not to the value of the spleen. For many years it was suspected that removal of the spleen would be disastrous, because it was assumed to be the principal source of blood cells. This suspicion was put to the test by Green and Conley,18 who demonstrated the value of splenectomy. By now it has become apparent that no patient's hematologic values are diminished by splenectomy and most of the patients are hematologically improved. 2 • 21 In every case, of course, the progression of the splenic complications is halted. Preparation for surgery should take into special account the platelet problems in myeloid metaplasia. In most kinds of thrombocytopenia a level of 20,000 platelets is sufficient for normal hemostasis, and a patient with this count or better need not be given supportive platelet transfusions. In the myeloproliferative syndromes, however, the platelets often are abnormal and surgical hemostasis may be difficult, even when the platelets are numerically adequate (Cases 15 and 16). One should therefore be prepared to support these patients with transfused platelets. This is not the only problem. However inadequate they may be for hemostasis, the platelets in myeloid metaplasia are liable to precipitate thrombotic complications when

1546

WILLIAM H. CROSBY, THOMAS J. WHELAN, LEONARD D. HEATON

their numbers become increased. When the platelet count is abnormally high before splenectomy, one can expect a great increase afterward. It is advisable to avoid this thrombocytosis by preoperative myelosuppressive chemotherapy. Should thrombocytosis or thromboembolic complications develop unexpectedly after splenectomy, anticoagulants should be employed immediately. Effective amounts of heparin or coumarin do not interfere with normal hemostasis and may be employed even during surgery.26 The routine use of anticoagulant therapy for a period of four to six weeks after operation may be advisable in this disease, but the problem needs further study. CASE 12. A 70 year old retired officer Cb. 1890) was admitted to WaIter Reed General Hospital in April, 1960, when, during an outpatient evaluation of chronic bursitis, he was found to have a buccal hematoma and ecchymosis of the palate. Physical examination was otherwise unremarkable; there was no splenomegaly. The platelet count was 2500; hemoglobin and leukocytes were normal. Bone marrow showed moderate megakaryocytic hyperplasia. During 2 weeks' hospitalization the platelet count rose to 167,000, but at home it gradually fell to 6000 and in August he was again admitted to the hospital. The platelet count began to rise and he was discharged; however, it crested at 35,000 and fell. He was readmitted with a platelet count of 6000. Leukocyte count was 7200 with 46 per cent polymorphonu clears and 1 myelocyte; hemoglobin 14 gm. Aspirated bone marrow at this time showed a generalized hyperplasia. The spleen was removed on September 13; it was of normal size and demonstrated myeloid metaplasia. The platelet count rose to 620,000 and promptly subsided to normal levels. A leukocyte count of 14,000 was associated with a subphrenic abscess which was evacuated through the drain left in the surgical wound and gradually healed without further difficulty. Seven weeks after the operation the patient died of a severe anteroseptal myocardial infarction. The coronary occlusion was the consequence of subintimal hemorrhage in an area of atherosclerotic plaques. The platelet count was normal at the time. CASE 13. A 74 year old retired officer Cb. 1884) dated the onset of progressive symptoms of anemia from 1953. During 1956 and 1957 he was under observation in the outpatient clinic of the Waiter Reed General Hospital. The spleen edge was 2 cm. below the costal margin, but otherwise the physical examination was unremarkable except for a ruddiness of the complexion which belied the patient's anemia. Biopsy of bone marrow revealed myelofibrosis. His hemoglobin was 8 to 10 gm. with poikilocytosis and an occasional erythroblast; MCV 95 jJ.3, MCH 32 jJ.jJ.g. MCHC 30 per cent. In October, 1957, red cell mass was 14 ml. per kg.; and half-life radioactivity of autogenous red cells tagged with 5lCr was 28 days. Leukocyte count was around 4000 with 60 per cent polymorphonuclears. His platelet count fell: for example in February, 1956, it was 1,067,000; in May, 1956, it was 136,000 and on admission to the hospital for splenectomy it was 145,000. At this time his hemoglobin was 10 gm. and the leukocyte count, 4500. After splenectomy the platelet count increased to 450,000 and the leukocyte count to 10,350. The spleen weighed 370 gm. and showed myeloid metaplasia. Since that time the patient's hematologic condition has remained essentially unchanged. Presently his hemoglobin is 10 to 11 gm., the leukocyte count 10,000 with 35 per cent polymorphonuclears and 20 per cent nucleated red cells, and the platelet count is 230,000. Since November, 1960, he has received 7.5 mg. per day of prednisone and 200 mg. per week of testosterone. Without these steroids his hemoglobin is about 9 gm. and he does not feel so well. As he approached 80 he gave up horseback riding.

SPLENECTOMY IN THE ELDERLY

1547

Comment. This is an example of splenectomy performed in anticipation of trouble. After the diagnosis of myelofibrosis with myeloid metaplasia was established and after evidence of hypersplenism appeared, but before the spleen had become massively enlarged or severely hypersplenic, the operation was performed. The patient was in good condition. Surgery and convalescence were uncomplicated. CASE 14. A 60 year old white woman (b. 1897) was admitted to WaIter Reed General Hospital on April 17, 1957, from another hospital. In 19461eukopenia has been noted but hematologic studies including examination of bone marrow were otherwise normal. Splenomegaly was not found. Since about 1952, the patient had noted easy bruising. During the winter of 1956-1957 symptoms of anemia progressed in severity but she finally came into the hospital because of left upper quadrant distress which began about March 1. Physical examination revealed an enlarged spleen which, on inspiration, crossed the umbilicus. The liver was 10 cm. below the rib margin. There were not other significant findings. The hemoglobin concentration ranged between 8 and 10 gm., the leukocyte count between 1000 and 2000 with 88 per cent lymphocytes and an occasional nucleated red cell; platelet count was about 130,000. Bone marrow biopsy revealed myelofibrosis. Liver biopsy showed erythroblasts and megakaryocytes in the sinusoids and no evidence of leukemia. Reticulocyte count was 3 per cent and the half-life of autologous red cells labeled with [lCr was 16 days, indicating a moderate hemolytic disease. Splenectomy was performed on May 6. The spleen weighed 2000 gm. and microscopic examination revealed considerable myeloid metaplasia with many eosinophilic myelocytes, nucleated red cells, and megakaryocytes. The operation and convalescence were uncomplicated. When the patient left the hospital at the end of May the hemoglobin concentration was 14 gm., leukocyte count about 4000 with 15 per cent polymorphonuclears, and the platelet count was about 500,000. At her home in the Midwest she was in good health for about a year when she caught cold, and from then on her condition gradually deteriorated. She was hospitalized frequently for treatment of infections. In May, 1958, marrow aspirated from her sternum was hyperplastic (sic) and demonstrated a great increase in myeloid-erythroid ratio and a shift to the left of the granulocytic series; at the same time there was an almost complete agranulocytosis of the blood: 1 per cent polymorphonuclears. During her final febrile episode in November, 1958, there was an almost complete leukopenia, the leukocyte count being 300 without polymorphonuclears, but no ancmia (Hb. 12.5 gm.) and no thrombocytopenia. Partial autopsy (abdomen only) confirmed the diagnosis of myelofibrosis. There was no evidence of leukemia in liver or lymph nodes.

Comment. Splenectomy corrected the patient's anemia and thrombocytopenia, but the longstanding granulocytopenia persisted and grew worse. Aspiration of hyperplastic, heavily granulocytic marrow in May, 1958, is surprising on two counts: (1) it demonstrated granulopoiesis in the presence of agranUlocytosis in the blood; (2) it demonstrated that the myelofibrosis was not uniform throughout the bone marrow. CASE 15. A retired medical officer (b. 1883) was admitted for the last time to WaIter Reed General Hospital in June, 1960. At the time of his retirement from active service in 1945 he was found to have polycythemia vera with a red cell count of 10 million. He refused treatment, except for a single phlebotomy every 8 to 10 months; but he was in good condition until gout developed in 1951. Meanwhile,

1548

WILLIAM H. CROSBY, THOMAS

J.

WHELAN, LEONARD

D.

HEAToN

the hemoglobin concentration of his blood declined to 12 gm. but his leukocyte count was 21,000 with 95 per cent polymorphonuclears. In 1953, he received his first transfusion when his hemoglobin was about 11 gm. In November, 1954, he appeared at the Hematology Clinic, WaIter Reed General Hospital. The spleen was enlarged to the iliac crest. Leukocyte count was 20,000, hemoglobin 11 gm., platelets 106,000. Aspirated bone marrow revealed normal cellularity with abnormally heavy preponderance of granulocytic cells, relative hypoplasia of erythroid tissue, and decreased numbers of megakaryocytes. During the next 2 years the anemia became gradually worse although the leukocyte and platelet counts remained essentially the same. In 1956, the patient underwent transurethral resection of the prostate and following the operation blood and clots drained from his bladder for a week until he was given a platelet transfusion, upon which bleeding ceased abruptly. A biopsy of the sternum in 1957 revealed only cortical bone: myelosclerosis. In the spring of 1957, the patient developed a refractory ulcer of the right cornea which finally required enucleation of the eye in October, 1957. Meanwhile in August, 1957, splenectomy was performed because of the great size of the spleen (2540 gm.). Microscopy demonstrated myeloid metaplasia. Postoperatively the patient bled repeatedly from his wound, necessitating many transfusions, and finally 3 weeks after the operation the wound was reopened to achieve mechanical hemostasis. The patient's platelet count increased temporarily to 300,000 and then subsided to around 90,000. The leukocyte count increased and stayed around 100,000 with 10 per cent nucleated red cells. The anemia was unchanged after the splenectomy, and over the next several years as the disease progressed it became somewhat worse. Early in 1959, the leukocyte count began a gradual upward drift with increasing numbers of granulocytes and nucleated red cells. The patient was admitted to the hospital in January, 1960 with a total nucleated cell count of 500,000, half being erythroblasts and the rest showing a pattern consistent with chronic granulocytic leukemia. Platelet count was 180,000. Bone marrow biopsy revealed myelofibrosis. The patient was given 6-mercaptopurine but he discontinued the drug on leaving the hospital. He returned in June, 1960, quite ill. His hemoglobin was 8.7 gm., platelets 37,000. The leukocyte count was 320,000 with myeloblasts 60 per cent, and only 3 per cent erythroblasts. The leukocyte count increased to 600,000 and the hemoglobin fell to 6.7 gm. He died in a week. Autopsy was not permitted.

Comment. This case provides a classic example of the natural history of the progression of myeloproliferative disease: polycythemia vera to myelofibrosis and myeloid metaplasia to granulocytic leukemia, first with the picture of chronic leukemia but terminating as acute. The case also demonstrates that patients with such a disease may have platelets in numbers adequate for hemostasis and still have bleeding which can be stopped by administration of normal platelets. In myeloproliferative disease the platelets may be numerically sufficient but functionally inadequate. Splenectomy rid the patient of the symptoms of his massive spleen. The operation should have been done earlier; indeed, the operation might have spared his eye. We were unaware of Hutt's observations in Felty's syndrome in which indolent ulcer of the cornea promptly healed following removal of the spleen. 20 In the present case the ulcer did not heal, but at the time of splenectomy the central portion of the cornea was completely destroyed.

SPLENECTOMY IN THE ELDERLY

1549

CASE 16. A 66 year old officer Cb. 1898) was admitted to WaIter Reed General Hospital for splenectomy on June 8, 1964. He had been well until 1954 when he began to have episodes of rectal bleeding. This occurred 6 times until spring, 1962, when his physician performed proctoscopy and referred him to WaIter Reed General Hospital because of a bleeding rectal polyp. The patient was found to have splenomegaly and a leukocyte count of 47,000 with 90 per cent polymorphonuclears and a rare nucleated red cell. Hemoglobin concentration was 10 gm. and the platelet count was 120,000. Alkaline phosphatase reaction of the granulocytes was strongly increased. Serum vitamin Bl2 was 980 'Y'Y per ml. Serum iron was 85 'Y and total iron-binding capacity 295 'Y per 100 ml. Bone marrow could not be obtained by aspiration. The patient was discharged from the hospital with a presumptive diagnosis of myelofibrosis and myeloid metaplasia and referred to the Hematology Clinic. Both diagnoses were confirmed later. The patient refused splenectomy. During the next two years the patient's leukocyte count increased to 80,000, his hemoglobin declined to 8 gm. and the platelet count remained around 125,000. Symptoms of anemia became oppressive. The spleen enlarged to the pelvic brim; the patient complained of pain in the left upper abdomen and the small-stomach syndrome. There was no recurrence of bleeding nor evidence of purpura. Splenectomy was performed on June 17, 1964. The spleen was densely adherent to the diaphragm and the posterior abdominal wall. There was serious bleeding which was finally controlled, and the loss was replaced by transfusion. The spleen weighed 1700 gm. and demonstrated myeloid metaplasia. The patient was in good condition for 24 hours after the operation when he became febrile, hypotensive, and oliguric. Treatment was prompt, appropriate, and continuous. It succeeded in correcting the circulatory instability and urinary output, but the patient died on June 27 of a gram-negative pneumonitis. Autopsy was not permitted.

Comment. Splenectomy was performed in this case before the patient was in any serious hematologic difficulty but not before he had become a poor operative risk because of the great size of his spleen and its adhesion to walls of the abdomen. Such an experience inclines us to a policy of earlier intervention in this syndrome of myeloid metaplasia. This is a progressive, incurable disease in which the complications become more numerous and severe as the patient becomes sicker and older. The spleen becomes massive, often with a tendency to infarction and perisplenitis, and often associated with hypersplenism. At the present time there seems to be no valid reason why splenectomy should not be performed as soon as the diagnosis is established. CASE 17. A 73 year old white woman Cb. 1885) was admitted to WaIter Reed General Hospital on July 22, 1958, complaining of symptoms of anemia gradually worsening over a period of 1 month. In 1950, she had been found to have polycythemia vera which was treated by phlebotomy. In 1954 while in England she developed a malignant melanoma requiring removal of the left eye. At that time her hemoglobin concentration was 13.5 gm., erythrocytes 7.5 million, hematocrit 47 per cent. Leukocyte count was 13,700 with 84 per cent polymorphonuclears; platelet count 1,000,000. She was treated with 32p, a total of 13 mc. There was no further treatment until February, 1957, when she received an additional 4 mc. because her hematocrit was 64 per cent, leukocyte count 10,600 and platelets 530,000. In October, 1957, she had pancytopenia and was told she had leukemia; she was treated with repeated whole blood transfusions. The patient appeared at WaIter Reed in July, 1958. Physical examination

1550

WILLIAM H. CROSBY, THOMAS

J.

WHELAN, LEONARD

D.

HEAToN

revealed hepatosplenomegaly (both organs 10 cm. below the rib margin) and signs of anemia. Hemoglobin concentration was 7 gm., leukocyte count 2000 with 25 per cent polymorphonuclears, a few myelocytes and 8 nucleated red cells; reticulocytes 1.2 per cent; platelets 75,000. Bone marrow biopsy revealed myelofibrosis. Red cell mass was 8.8 ml. per kg. Half-life of autologous red cells tagged with 51Cr was 16 days. The patient was prepared for surgery with blood transfusions, and the spleen was removed on September 3, 1958; it weighed 640 gm. and demonstrated myeloid metaplasia. The operation and convalescence were uncomplicated. The patient was discharged on September 20. Her hemoglobin concentration was 10 gm., leukocyte count 7600 with 50 per cent polymorphonuclears and platelet count 240,000. She continued to have anemia and to require 2 units of blood every month or two to maintain her hemoglobin at a level of 8 or 9 gm., and this kept her reasonably comfortable. Her leukocyte and platelet counts remained at normal levels and there were about 5 nucleated red cells.

Comment. At the time of her death in June, 1962, this patient had received in excess of 200 units of blood. Her leukocyte count at that time was 12,300 with 75 per cent polymorphonuclears and 1 metamyelocyte. There were 70 nucleated red cells per 100 leukocytes. Platelets were noted to be "large and slightly decreased in number." Death resulted from slowly progressing central nervous system disease, and postmortem examination revealed this to have been multifocalleukoencephalopathy secondary to vascular changes of arteriosclerosis. There was severe siderosis of liver, lymph nodes and pancreas, with cirrhosis and severe fibrosis of the liver but none in the pancreas. There was little, if any, myeloid metaplasia. Marrow was fibrotic in all areas. There was no evidence of melanoma. The patient was apparently not benefited by splenectomy. However, during her last four years, she was not beset by the increasing problems of splenomegaly which are characteristic of the progression of myeloid metaplasia. Of tangential interest are the fibrosis of the liver and the almost complete absence of myeloid metaplasia in that organ-a pattern which duplicates the destruction of the marrow in this disease where fibrosis replaces hematopoietic tissue.

SPLENECTOMY OF NO VALUE

The absolute contraindications for splenectomy-situations in which removal of the spleen is severely detrimental-have disappeared with expanding knowledge and experience. Exacerbation of malaria and other infections with intra-erythrocytic organisms such as Hemobartonella may be prevented with appropriate chemotherapy. The injurious flood of platelets which follows removal of the spleen in essential thrombocytosis and sometimes in other myeloproliferative diseases may be controlled by myelosuppressive drugs or anticoagulants. The spleen of myeloid metaplasia is known not to be essential as it was once regarded. Nevertheless, there are diseases in which splenectomy, while not dangerous per se, is of no value. Acute leukemia, myelomatosis, and chronic granulocytic leukemia

SPLENECTOMY IN THE ELDERLY

1551

are good examples. Unless there is good evidence of hypersplenism-and this is rare-or unless the spleen is ruptured or seriously infarcted, splenectomy is useless. In fulminating aplasia of the marrow, removal of the spleen is a futile gesture, and it serves no purpose in mild degrees of aplasia when the small gains which may result from splenectomy would not be important. In aplastic anemia we recommend splenectomy for chronic cases when a modest improvement of the platelet count or hematocrit can make the difference between danger and safety or even survivaU 9 There are other conditions, not so common or well known, in which we believe splenectomy to be of no value. The following cases illustrate the futility of splenectomy in acute myeloproliferative syndromes and the chronic Di Guglielmo syndrome. CASE 18. The patient, a 67 year old white woman (b. 1889), was admitted to WaIter Reed General Hospital in July, 1956, after having been treated elsewhere for anemia for about 2 years. Symptoms of anemia dated from March, 1954. In October, 1954, the bone marrow was examined and a diagnosis of pernicious anemia was made. However, she failed to improve after treatment with vitamin B 12 , folic acid, liver extract, iron, and multivitamin preparations. She received during these years blood transfusions every 4 to 6 weeks. Physical examination July 19, 1956, was negative except for signs of anemia. Hemoglobin was 7.2 gm. with normal indices, 1 per cent reticulocytes, a rare erythroblast, and marked poikilocytosis and anisocytosis. Leukocyte count was 2500 with 15 per cent polymorphonuclears and 80 per cent lymphocytes. Platelet count was 170,000. Bone marrow aspiration demonstrated "megaloblastic" disease. Serum iron was 214 'Y and the iron-binding capacity was completely saturated. Red cell mass was 5.4 ml. per kg. (285 ml./53 kg.); hematocrit 17 per cent. During further attempts to treat her anemia as a deficiency state, the hemoglobin declined to 5 gm. Following transfusion of her own red cells tagged with 61Cr, only 40 per cent of the radioactivity remained in the blood after 6 days. On August 13,1956, a spleen weighing 155 gm. was removed; it was histologically unremarkable. Following splenectomy the patient's condition was essentially unchanged. During the autumn her hemoglobin ranged between 6 and 9 gm.; reticulocytes 2.5 per cent, platelet count between 170,000 and 470,000; leukocyte count 4000 to 6000 with 7 to 15 per cent polymorphonuclears and an occasional myelocyte. Monocytes were increased up to 30 per cent, but at no time was there recorded an eosinophil. In December she developed thrombosis of the right renal vein and the kidney was removed. There was an abscess in the kidney. During this time the leukoeyte count went as high as 96,000 with 90 per cent polymorphonuclears. The platelet count fell to 75,000. When she recovered, her counts returned to previous levels. During this critical time she developed atrial fibrillation and congestive heart failure. Thereafter it was necessary to use digitalis and to restrict sodium for the rest of her life. In February, 1957, she moved out of the Washington area. Her anemia continued to require an occasional transfusion. In July, 1957, there were 30 nucleated red cells per 100 leukocytes in her blood, some of them very immature. The bone marrow continued to show erythroid hyperplasia with some giant forms in the erythroid series. In March, 1958, following a blood transfusion she developed acute pulmonary edema and quickly died. Necropsy revealed only pulmonary edema as the cause of

death.

1552

WILLIAM H. CROSBY, THOMAS J. WHELAN, LEONARD D. HEATON

Comment. This dyscrasia, characterized by erythroid hyperplasia, anemia without reticulocytosis, resembling pernicious anemia but failing to respond to any form of treatment, has been called the Di Guglielmo syndrome.1 3 Di Guglielmo has described giant forms of erythroblast which may prove to be diagnostic of this disorder.16 Sometimes the disease terminates as acute granulocytic leukemia.13 It is becoming evident that splenectomy is of no value in the treatment of anemia of the Di Guglielmo syndrome; the patient described above was not benefited. It is possible that thrombocytopenia might be associated with secondary hypersplenism, and if this were severe enough to threaten the patient's life, splenectomy would be indicated. Care must be taken to discriminate between this disease and the varieties of acquired hemolytic anemia which may be cured by splenectomy. This patient's death following a compatible blood transfusion illustrates one of the hazards of transfusion therapy in elderly patients with borderline cardiac status. This is a strong reason to correct the cause of anemia, where possible, rather than continue transfusion existence. CASE 19. A 64 year old clergyman (b. 1900) was admitted to WaIter Reed General Hospital in April, 1964, because of pancytopenia and splenomegaly. He had had symptoms of anemia for 1 month. The case is to be reported in detail elsewhere.1 In brief, liver and spleen were enlarged 4 cm. below the costal margin, but there was no lymph node enlargement. The patient's marrow was extremely hyperplastic, demonstrating abnormal proliferative and bizarre forms in all 3 blood cell forming elements; erythroid tissue was megaloblastoid with binucleated cells; myeloid series was shifted to the left with myeloblasts increased in number and containing multiple nucleoli; megakaryocytes were abundant, large and definite in outline. Iron stores were increased. In the blood the hemoglobin concentration was 6 gm. with 4 per cent reticulocytes; MCV 90 J.L3 MCH 25 J.LJ.Lg. and MCRC 28 per cent. Leukocyte count was 2000 with 50 per cent polymorphonuclears, 1 per cent myeloblasts, 2 per cent myelocytes and 40 per cent lymphocytes. There were 100 nucleated red cells per 100 leukocytes. Platelet count was 9500. Leukocyte alkaline phosphatase was normal. It was recommended that splenectomy not be done. The patient returned to his home where splenectomy was performed on June 2 without benefit. The patient also received corticosteroid and 6-mercaptopurine without benefit. His leukocyte count, which remained low after splenectomy (3800 on June 28) was found in September to be in excess of 200,000 with blasts predominating. There were signs of thrombocytopenic purpura and platelet counts around 25,000 were recorded. The patient died on September 28 of a massive intracerebral hemorrhage. Postmortem examination revealed leukemic infiltrates in almost every organ.

Comment. This is an acute myeloproliferative disease involving abnormalities of all the blood-forming elements of the marrow. In spite of a hyperactive, hyperplastic marrow, pancytopenia prevails in the blood. In polycythemia vera there is overproduction of all three cellular elements, but production is effective so the blood counts-red cell, white cell and platelet-are all increased. This present syndrome has been called the acute analogue of polycythemia vera,6 with ineffective proliferation of all three cellular elements. Splenectomy was not recommended because hypersplenism plays little or no part in the pathogenesis of the pancytopenia and,

1553

SPLENECTOMY IN THE ELDERLY

as in this case, removal of the spleen does not alter the course of the marrow's disease. It is not uncommon for any myeloproliferative disease to terminate with the picture of acute leukemia predominating. 14 CASE 20. A 74 year old retired soldier (b. 1889) reported to his clinic when shortness of breath necessitated curtailing to 2 miles his daily 4-mile walk. His hemoglobin concentration was 6 gm., which was one facet of a pancytopenia. Because of the patient's keen mentality and regular habits one could accurately date the onset of symptoms to mid-June, 1963. The patient was thought to have acute granulocytic leukemia. Several blood transfusions provided only temporary benefit. He was admitted to WaIter Reed General Hospital on August 20, one day after he developed left chest pain, malaise, and fever. On physical examination signs of anemia and left pleural effusion were noted. Hemoglobin concentration was 8 gm., reticulocyte count 0.2 per cent, leukocyte count 2000 with 60 per cent polymorphonuclear:-; and platelet count 5000. Biopsy of the patient's marrow revealed myelofibrosis. Tuberculosis was suspected and treatment therefor was begun on the presumptive diagnosis because of the seriousness of the patient's condition. He developed a severe hematoma which formed an ulcer at the site of streptomycin injection. As this improved, splenectomy was performed on October 4. The operation was supported by transfusions of freshly drawn blood and was completed without complication. The spleen weighed 230 !l;m.; it had nothing to suggest either leukemia or myeloid metaplasia. The patient did well for several days, but the leukocyte and platelet counts did not change. Immediately after the operation, the hemoglobin was 13 gm. and the platelet count 30,000 because of the transfusions, but the platelet count was 5000 on October 7. Leukocyte count remained at 2500. Then the patient developed lobar pneumonia and died on October 8. Necropsy revealed no evidence of tuberculosis, only left lower lobar pneumonia.

Comment. In acute myelofibrosis splenectomy is probably of no benefit. We have seen modest, temporary improvement of the platelet count, but lasting only several weeks; hardly worth it. DISCUSSION

The indications for splenectomy in the elderly are the same as in the young. Splenic catastrophe such as rupture, torsion, or infarction usually requires immediate intervention, and massive splenomegaly may become so uncomfortable that the patient demands relief. In most cases, however, hypersplenism is the indication. How is a detrimental increase in splenic activity recognized? Dameshek's postulates, with certain exceptions, are generally accepted: 12 (1) splenomegaly (but the spleen may be of normal size in ITP), (2) cytopenia of the blood (but there may be no anemia in HS), (3) hyperplastic marrow (but there may be a hypersplenic component in aplastic anemia), and (4) the cytopenia is improved or corrected after splenectomy. To this final postulate there is no exception; if the patient is not better off without his spleen he had no hypersplenism. It is too bad that this last criterion reveals itself after the fact. While we have learned from experience whieh diseases may be associated with hypersplenism, we cannot yet predict which patients will be cured. An 80 per cent cure rate in ITP

1554

H.

WILLIAM

c1

CROSBY, THOMAS

J.

WHELAN, LEONARD

c1

69 AHA-IOYRS

D.

78 AHA-6YRS

10

10 HEMOGLOBIN GM

5

HEATON

•.....•....•..•....

..................

:1·······..······• :.

.........

·....i

................. 34

.....······.3.0 DIED

5

DIED

or--------------------------------l,r---------------------~O

*

TRANSFUSIONS 500ML

ttt

=

.

tt

Htttttttt

PLAN FOR SPLENECTOMY ABANDONED

JULY

TRANSFUSIONS NONE

FEVER

AUG

1

DISCHARGED TO HOME LIVER IRON VITAMINS

SEPT

ACTH

I5MG

OCT

APR

PER OAr

MAY

Figure 1. Autoimmune hemolytic anemia in 2 elderly men. R A, A 69 year old man had been ill with hemolytic anemia for 10 years. In July, 1949, he became abruptly worse and was admitted to a hospital with hemoglobin concentration of 5 gm., reticulocytes 21 per cent. He was given a number of transfusions with little improvement of the anemia. Because of anemia the proposed splenectomy was abandoned and the patient was sent home. He returned to the hospital in October with hemoglobin of 3.5 gm. Two more transfusions provoked febrile reactions. Therefore no more transfusions were given and the patient died of anemia. B, A 78 year old man had been ill with acquired hemolytic anemia for 6 years with crises in January and June, 1949, and a last crisis in April, 1951. He was admitted to a hospital with a hemoglobin concentration of 6 gm., retieulocytes 7 per cent. No transfusions were given because abnormal warm agglutinins interfered with the cross-match. The patient died of anemia. In both cases there is evidence of a lack of understanding of the principles of good transfusion practice.24 Furthermore splenectomy, even years before the final crisis, would have been amply justified in each case and might have cured the hemolytic disease.

means that 20 per cent of patients are subjected to splenectomy without benefit. Hypersplenism ean be divided into three categories: the self-limited, the indeterminate, and the chronic or progressive. When hypersplenism is clearly related to a curable infection, the condition is self-limited and splenectomy is pointless. However, in most eases of idiopathic hypersplenism it is impossible to predict whether or not the disease is to be self-limited. In this situation one protects the patient and waits for a reasonable interval. If there is no improvement or if the patient remains in danger, splenectomy is indicated. In the permanent or progressive diseases, splenectomy may be justified as soon as the diagnosis is established, even before the patient is in imminent danger from his disease. Hypersplenism in the elderly patient is complicated by the problems of

SPLENECTOMY IN THE ELDERLY

1555

advancing age. At the present time the increasing number of elderly people and the expanding knowledge of the role of splenectomy indicate that more and more often we will be confronted with the question of whether or not to perform the operation. 5 The decision should be based upon the nature of the disease and the condition of the patient. Some hypersplenic diseases involve so great a risk to the patient that the risk of splenectomy seems mild by contrast. Idiopathic thrombocytopenia is such a disease. The older the patient the greater the risk of cerebral hemorrhage, while the possibility of cure after splenectomy is a very good one. Autoimmune hemolytic anemia (AHA) is another severe disease which is often cured by splenectomy. iD Several years ago, Crosby and Rappaport8 reviewed the cases of acquired hemolytic anemia which had been accessioned at the Armed Forces Institute of Pathology-cases which had been submitted from many hospitals, military and civilian. Seven* patients in the group of 34 with idiopathic hemolytic anemia were age 60 or above. Splenectomy was performed in four of the seven, two died of uremia at six and eight months; the other two had good remissions. The three who were not treated by splenectomy died of the circulatory complications of severe anemia. One died in an acute hemolytic crisis, but two of the patients had chronic anemia; there had been several years of opportunity for surgical intervention before increasing severity reduced these old men to a critical condition (Fig. 1). Their cases demonstrate a hopeless attitude which should not prevail in the management of elderly patients. These patients were permitted to die of severe anemia, almost as though an attempt to cure was judged to involve a more serious risk than the certainty of death. Corticosteroids may correct the cytopenia in ITP and AHA, but unless the improvement is prompt and endures after the drug is discontinued, the decision for splenectomy should not be delayed. Corticosteroid has destructive side effects and patients who continue its use may be severely injured (Case 2). Splenectomy should not be delayed until, as a last resort, it is done in desperation. The patient's best interest is not served by such a policy. When hypersplenism is a complication of a permanent or progressive disease, there is usually nothing to be gained by deferring splenectomy once the diagnosis has been established. Especially in the aged, if one waits until the indications for splenectomy are urgent, the patient may have become an almost unacceptable surgical risk. Our present attitude toward splenectomy in the syndrome of myelofibrosis with myeloid metaplasia is based upon these considerations. Granted, the patient may live for years with spleen intact but meanwhile1. The spleen enlarges, produces intra-abdominal symptoms and becomes a more cumbersome surgical problem because of its size and adhesions. 2. The hypersplenic complications of anemia and thrombocytopenia

* Patient 29 was age 67, not 57 as reported.

1556

WILLIAM H. CROSBY, THOMAS

J.

WHELAN, LEONARD

D.

HEATON

do not improve spontaneously and tend to become more important as the marrow becomes more fibrotic and its output diminishes. The patient thereby becomes a poorer surgical risk. 3. The steroid therapy which is often employed has side effects whereby the patient may become a poorer surgical risk. 4. The patient grows older. The same attitude is appropriate with regard to hypersplenism in the Banti syndrome or complicating malignant lymphoma. Hereditary spherocytosis, while not progressive, is certainly permanent, and the hemolytic anemia is cured by splenectomy. In these varieties of hypersplenism, splenectomy should be considered as soon as the diagnosis is established. Unless there is some contraindication, the operation is recommended. The contraindications are usually not related to the hypersplenism. A patient terminally ill with cirrhosis or lymphoma is not a candidate for splenectomy. A patient with multiple myeloma should not have his spleen removed for treatment of hereditary spherocytosis (Case 4). Other progressive and life-limiting diseases should be weighed in a similar manner: uremia, congestive heart failure, or emphysema. The risk of splenectomy must be weighed against the likelihood of benefit. There are several hematologic diseases associated with splenomegaly in which splenectomy is of no benefit and the operation, therefore, is not recommended. Case 20 of this series was of acute, rapidly progressing fibrosis of the marrow. Case 18 was of abnormal proliferation of the erythroid elements of the marrow, megaloblastoid in nature, described by some as chronic Di Guglielmo syndrome. Case 19 involved a megaloblastoid proliferation of the erythroid marrow, while the megakaryocytes and the granulopoietic tissue were also involved in fruitless proliferation. In these cases splenectomy was of no value. To such diseases one must add acute leukemia, chronic granulocytic leukemia, myelomatosis, and severe aplastic anemia. The pathogenicity of accessory spleens has been much debated. In the hypersplenic syndromes it may be said, in general, that bigness equates with badness; it is the large spleen which is hypersplenic.1 2 Review of the problem has led to the conclusion that accessory spleens may be regarded as of no significance unless they are unusually large. 7 While it is advisable to remove them when removal is easy, one should not increase the operative risk by removal of small accessory spleens from difficult sites such as the pancreas or the wall of a hollow viscus. SUMMARY

During the past ten years we had the experience of splenectomy for hematologic disease in 20 elderly patients. The problems are the same as in other age groups, except for the complications of aging.

1557

SPLENECTOMY IN THE ELDERLY

When it is determined that hypersplenism is on the basis of a permanent or progressive disease, it is recommended that the spleen be removed promptly even though the patient is not very ill. The policy of waiting until he becomes ill is not in the patient's best interest. In this category of disease are included the Banti syndrome and malignant lymphoma with hypersplenism. In myeloid metaplasia splenectomy is recommended as soon as the diagnosis is established, whether or not there is overt hypersplenism. With idiopathic thrombocytopenic purpura and autoimmune hemolytic anemia, splenectomy is recommended as soon as the chronicity of the disease has been established, as a rule within six weeks of onset. With hereditary spherocytosis splenectomy is indicated when the diagnosis is made. Splenectomy as a "last resort" is not recommended. In conditions in which splenectomy is known to be beneficial, the decision should be made and the spleen removed before the patient has deteriorated to the state of last resort. ACKNOWLEDGMENT

The authors are indebted to Lt. Colonel Paul W. Palmer, MC, Pathology Service WaIter Reed General Hospital, for his thorough review of several of the more difficult cases.

REFERENCES 1. Bergin, J. J., and Crosby, W. H.: Acute polycythemia vera. In preparation. 2. Bouroncle, B. A., and Doan, C. A.: Myelofibrosis. Clinical, hematologic and patho-

logic study of 110 patients. Am. J. M. Sci. 243: 697, 1962. 3. Cameron, G. R., and de Saram, G. S. W.: A method for permanently dissociating the spleen from the portal circulation (the "marsupialized" spleen) and its use in the study of experimental liver cirrhosis. J. Path. Bact. 48: 41, 1939. 4. Carpenter, A. F., Wintrobe, M. M., Fuller, E. A., Haut, A., and Cartwright, G. E.: Treatment of idiopathic thrombocytopenic purpura. J.A.M.A. 171: 1911, 1959. 5. Case, T. C., and Giery, R. A.: Surgery in patients between 80 and 100 years of age. J. Am. Geriat. Soc. 12: 345, 1964. 6. Crosby, W. H.: El equivalenta agudo de la policitemia vera. Sangre 2: 44,1957. 7. Crosby, W. H.: Hypersplenism. Ann. Rev. Med. 13: 127,1962. 8. Crosby, W. H., and Rappaport, H.: Autoimmune hemolytic anemia. I. Analysis of hematologic observations with particular reference to their prognostic value. A survey of 57 cases. Blood 12: 42, 1957. 9. Curtis, G. M., and Movitz, D. Splenectomy for patients past sixty. J. Geront.1: 303, 1946. 10. Dacie, J. V.: The Haemolytic Anaemias. Part I. The Congenital Anaemias. 2nd Ed. New York, Grune & Stratton, 1960, p. 110. 11. Dacie, J. V.: The Haemolytic Anaemias. Part 11. The Autoimmune Haemolytic Anaemias. 2nd Ed. New York, Grune & Stratton, 1962, p. 666. 12. Dameshek, W.: Hypersplenism. Bull. New York Acad. Med. 31: 113,1955. 13. Dameshek, W., and Baldini, M.: The Di Guglielmo syndrome (Editorial). Blood 13: 192, 1958. 14. Dameshek, W., and Gunz, F.: Leukemia. 2nd Ed. New York, Grune & Stratton, 1964, p. 392.

1558

WILLIAM H. CROSBY, THOMAS

J.

WHELAN, LEONAIW

D.

HEATON

15. Dameshek, W., and Rheingold, J. J.: Idiopathic thrombocytopenic purpura and menorrhagia mistakenly treated for local disease: Report of four cases. J.A.M.A. 139: 993, 1949. 16. Di Guglielmo, G.: Le Malattie Eritremiche ed Eritroleucemiche. Rome, Il Pensiero Scientifico Editore, 1962. 17. Doan, C. A., Bouroncle, B. A., and Wiseman, B. K.: Idiopathic and secondary thrombocytopenic purpura: Clinical study and evaluation of 381 cases over a period of 28 years. Ann. Intern. Med. 53: 861, 1960. 18. Green, T. W., Conley, C. L., Ashburn, L. L., and Peters, H. R.: Splenectomy for myeloid metaplasia of the spleen. New England J. Med. 248: 211, 1953. 19. Heaton, L. D., Crosby, W. H., and Cohen, A.: Splenectomy in the treatment of hypoplasia of the bone marrow. With a report of twelve cases. Ann. Surg. 146: 637, 1957. 20. Hutt, M. S. R., Richardson, J. S., and Staffurth, J. S.: Felty's Syndrome. A R?port of Four Cases Treated by Splenectomy. Quart. J. Med. 20: 57, 1951. 21. Jensen, M. K.: Splenectomy in Myelofibrosis. Acta Med. Scand. 175: 533, 1!J!i4. 22. Rousselot, L. M., Panke, W. F., Bono, R. F., and Moreno, A. H.: Experiences with Portacaval Anastomosis. Analysis of 104 End-to-Side Shunts. Amer. J. Med. 34: 297, 1963. 23. Schultz, J. C., Denny, W. F., and Ross, S. W.: Splenectomy in Leukemia and Lymphoma: Report of 24 Cases. Amer. J. Med. Sci. 247: 30, 1964. 24. Strumia, M. M. et al.: General Principles of Blood Transfusion. Philadelphia, J. B Lippincott Co., 1963, p. 29. 25. Sturm, 0.: Anticoagulant Protection in Surgery. Thromb. Diath. Haemorrh. 2: 484, 1958. 26. Weiss, H. J.: Hereditary Elliptocytosis with Hemolytic Anemia. Amer. J. Med 35: 455, 1963. 27. Wratten, G. P., Jahnke, E. J., and Whelan, T. J.: Portosystemic Shunts: Five- and Ten-Year Follow-Ups of 68 Cases. Amer. J. Gastroent. 41: 519,1964.

Address requests for reprints to: Department of Hematology WaIter Reed Army Institute of Research Washington, D. C. 20012