Myeloproliferative Disorders SEYMOUR 1. SCHWARTZ, M.D.*
Forty-three operative procedures were performed on a population of 250 patients with myeloproliferative disorders, including polycythemia vera, myeloid metaplasia (MM) and chronic myelogenous leukemia (CML). The overall operative mortality was approximately 7% and the incidence of excessive bleeding which could be related to coagulopathy was 5%. Twenty-one patients with MM or CML underwent splenectomy for palliation of symptoms related to the enlarged spleen or hematologic problems. Eighty-four percent of the latter group were improved. Adverse hematologic effects which could be attributed to splenectomy in these patients were confined to two patients who developed marked thrombocytosis. Among the 23 patients with MM, 9 had portal hypertension. Three underwent portacaval shunt and one a splenorenal shunt for bleeding varices. One of the patients died of hepatic necrosis. Estimated hepatic blood flow determinations (EHBF) in 4 patients with portal hypertension demonstrated a marked absolute increase and an increase in the ratio of EHBF/Cardiac Index. Absence of any evidence of intrahepatic or extrahepatic obstruction in these patients and the demonstration that splenectomy relieved portal hypertension defined at surgery in 4 patients, suggests that augmented adhepatic flow contributes to portal hypertension in some cases. The review leads to the conclusions that: 1) Operative procedures in prepared patients with myeloproliferative disorders are not associated with prohibitive mortality and morbidity rates. 2) Splenectomy is indicated for patients with increasing transfusion requirements and symptomatic splenomegaly or hypersplenism and should be performed early in the course of disease. 3) When associated portal hypertension and bleeding varices are present, hemodynamic studies should be carried out to define if splenectomy alone, or a portal systemic decompressive procedure is indicated.
THE MYELOPROLIFERATIVE DISORDERS include a spec-
s trum of diseases, each of which may be due to a different disturbance in proliferation and/or maturation of the hematopoietic stem cell of marrow. Polycythemia Presented at the Annual Meeting of the American Surgical Association, Quebec City, Quebec, May 7-9, 1975. *The University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642.
From the University of Rochester School of Medicine and Dentistry, and Strong Memorial Hospital, Rochester, New York
Vera (PV), Acute and Chronic Myelogenous Leukemia (AML and CML), Myeloid Metaplasia (Myelofibrosis, Myelosclerosis) (MM) and Essential Thrombocythemia all have been included within the general category of myeloproliferative disorders. Surgical consideration of patients with myeloproliferative disorders relates to: 1) a general appreciation of the operative risk for any surgical procedure in these patients; 2) the application of splenectomy as a palliative procedure in patients with MM and CML; and 3) the management of portal hypertension and variceal bleeding in patients with MM. Material and Methods The records of 250 patients with myeloproliferative disorders seen at the Strong Memorial Hospital between 1955 and 1974 were reviewed. Included were 90 patients with PV, 64 patients with MM and 96 patients with CML. Some of these patients have progressed from PV to MM. Each patient was assigned to the more advanced category, unless an operative procedure was performed, in which case he or she was considered in that category during which the operation was carried out. All patients had the diagnosis established by blood counts, peripheral blood smears, bone marrow aspirates or biopsies. In patients subjected to splenectomy and/or portal decompressive procedures, histologic evaluation of the spleen and/or liver contributed to the diagnosis. Operative mortality was considered as that occurring during the hospitalization for the procedure or within 30 days. Excessive bleeding related to an hemostatic defect was defined as that associated with a 5% reduction in
464
A
Vol. 182
*
MYELOPROLIFERATIVE DISORDERS
No. 4
465
hematocrit, requirement for a number of transfusions OPERATIVE PROCEDURES IN PATIENTS WITH significantly greater than that usually associated with the MYELOPROLIFERATIVE DISORDERS procedure, reexploration at which a single bleeding site TOTAL could not be defined, or a combination of the above. CASES 250 TOTAL Portal pressures were measured during the operative procedure in either the portal vein itself, or in an omental OPERATIVE CASES vein with the portal vein as a reference level, using a MORTALIT-Y spinal manometer filled with saline. Central venous pressures (CVP) were determined simultaneously. Hemodynamic studies were performed on awake paCHRONIC tients who were not premedicated. Hepatic blood flow MYELOGENOUS POLYCYTHEMIA LEUKEMIA (EHBF) during the postabsorptive state was carried out VERA according to the method of Leevy et al.12 employing 96 MYELOFIBROSIS indocyanine green dye. Pressure measurements in these patients were made using Statham P-23 AA strain gauges and a Sanborn direct writing recorder. Cardiac output l77 = ZZ determinations were made from the standard indocyanine green indicator dilution curves. Body surface area estiI I OX ,mates were derived from a Du Bois normogram. 10 9U 25X% Results I. Operative procedures in all categories Forty-five operative procedures were performed in 41 ,patients. Twelve procedures were carried out in patients with PV, 29 were performed in patients with MM, and four procedures were performed in patients with CML (Table I). There were 4 deaths related to the operative procedure, resulting in an overall mortality rate of 9o. None of the patients with PV died; one of the patients with CML died, while in the group with MM, the mortality rate was 10%o (Fig. 1). In the MM group, a patient died following splenectomy
with ensuing subphrenic abscess and sepsis. Another patient died due to hepatic necrosis following an end-to-side portacaval anastomosis. The third death in the MM group occurred in a 48-year-old woman who had a 4,950 gram spleen removed because of symptomatic splenomegaly on 5-18-72 without intraoperative or postoperative transfusional requirement. On 2-28-73 she underwent trans-
PERCENT MORTALITY FIG. 1. Mortality Associated with Operative Procedures in patients with Myeloproliferative Disorders.
thoracic subclavian endarterectomy. Her preoperative hematocrit was 35, WBC 50,000 and platelets 160,000/ mm.3 Postoperatively she developed an hemothorax which required three reexplorations. She subsequently developed aspiration pneumonia, respiratory failure and died 6 weeks after the first thoracotomy. One patient who underwent splenectomy for hypersplenism associated with CML died following discharge but within one month of surgery. At autopsy there were extensive thromboses of the renal veins and mesenteric veins. In the group of patients with PV, there was no excessive bleeding, and only one significant postoperative infection; a subphrenic abscess following cholecystectomy for acute cholecystitis. In one of the patients, the preoperative platelet count was 843,000/mm3 while in all others this was in the normal range. One patient was
TABLE 1. Operative Procedures in Patients With Myeloproliferative Disorders PV
Arterial Reconstructions Amputations 'Lumbar Sympathectomy Aortic Valve Replacement Pericardial Poudrage Nephrectomy Mastectomy Drainage Subphrenic Abscess Cholecystectomy Total: Deaths: *Excessive bleeding + Death
MM 3 2
12 0
CML
Splenectomy (With Splenorenal shunt 1) Portacaval Shunt Subclavian Endarterectomy Cholecystectomy Vagotomy & Pyloroplasty Hernia Repair Total: Deaths:
22 (1*, 1+)
Splenectomy Vagotomy & Antrectomy
3 (1+)
3 (1+) 1 (1+)
29 3
Total: Deaths:
4
TABLE 2. Indications for SplenectomylEffects
Primary
Symptomatic Splenomegaly/ Hypermetabolism Anemia/ Hemolysis Thrombocytopenia Leukopenia Total:
Ann. Siurg.
SCHWARTZ
466
8 (2+)
Improvement Improvement In Survivors Secondary In Survivors
6/6
10
7/10
6
5/6
4 2
3/4 2/2
8
7/8
24
19/22 (86%)
12/14 (86%)
+ Death
operated on with a hematocrit of 63, while in the remainder the hematocrit was less than 52%. Ten of the 12 patients had been treated with busulfan, 32P, multiple phlebotomies or a combination of these modalities. In the 6 patients requiring an operation for peripheral arterial disease, neither hematocrit nor platelet count were significantly increased. Among the 27 patients with MM undergoing 29 procedures, excessive bleeding occurred in 3 cases; in the subclavian endarterectomy described above and in two of the 21 splenectomies. In none of these three could the bleeding be attributed to a specific bleeding site, and none of these patients had platelet counts less than 70,000/mm.3 In both splenectomy cases, reexploration and evacuation of the clot from the left subphrenic space resulted in cessation of bleeding. There was no excessive bleeding in the two patients with platelet counts greater than 350,000/mm.3 At the operative procedure in patients with MM, no patient had a hematocrit greater than 52. Two of the three deaths in the group of patients with MM were related to sepsis. The three splenectomies in the CML group were performed in patients with mild anemia; two had thrombocytopenia, and one mild thrombocytosis. There were no immediate postoperative complications, but one patient had a slightly elevated platelet count and died within a month of surgery from extensive visceral venous thromboses and a blastic crisis. II. Splenectomy as a Palliative Procedure Twenty-four splenectomies were performed as palliative procedures in patients with MM or CML. The indications are listed in Table 2. In 8 patients the major indication was symptomatic splenomegaly in which the spleen was of such magnitude as to be uncomfortable or to interfere with alimentation, or in which multiple episodes of painful splenic infarcts occurred. In some patients there was associated hypermetabolism. In 10 patients, a significantly increased transfusion requirement or hemolysis was the major indication, while in 4 patients
-
October 1975
thrombocytopenia with clinical manifestations constituted the major indication. In two patients leukopenia interfering with the defense mechanism toward an infection, prompted splenectomy. All patients had received medical therapy, usually from months to years prior to the operation. The regimen varied and consisted of phlebotomies, prednisone, :'2P, busulfan, cyclophosphamide or a combination of these. The mean weight of the spleens which were removed for symptomatic splenomegaly was about 3,150 gm, range of 2,250-7,650 gm. There were two patients with an accessory spleen. Five of the patients had platelet counts of 70,000/mm:3 or less. The left subphrenic space was drained in 7 patients. Reexploration for continued bleeding was required in 2 patients, one of whom had thrombocytopenia, and one was a patient in whom the space was not drained. One of the patients developed a subphrenic abscess and died of sepsis a month after the second procedure. The other death occurred in the patient with CML described above. The 6 remaining patients had symptomatic improvement, and in no instance was there an adverse hematologic effect, i.e., more profound anemia, thrombocytopenia or leukopenia. Two of the patients have died, years after the operative procedure for CML. In 16 patients, the major indication was hypersplenism, with anemia, thrombocytopenia or leukopenia the factor prompting the operative procedure (Table 2). The mean weight of the spleens in these patients was 2,250 gm (range 675 gm-3,150 gm). There were three patients in whom small, accessory spleens were also removed. The subphrenic space was drained in 14 patients. The hematologic defect which constituted the prime indication for surgery was improved in 12 patients for an overall therapeutic effect of 75% (Fig. 2). Seven of the 10 patients with an increase in transfusion requirements had this significantly reduced for months to years following splenectomy. Five of the 6 patients in whom anemia was a contributory factor, had some increase in the hematocrit following splenectomy. Three of the 4 patients with symptomatic thrombocytopenia as the major factor, improved following splenectomy. Platelets were not adX PALLIATION
INDICATION 6 CASES SPLENOMEGALY ^ ANEMIA/HEMOLYSIS
10 CASES I 4 CASES
100%
66 % 75 %
THROMBOCYTOPENIA 2 CASES
100 %
LEUKOPENIA
FIG. 2. Results with Spienectomy in Patients with Myeloproliferative Disorders.
Vol. 1 8
No() 4
\o
MYELoPROLIFERATIVE DISORDERS
ministered preopei-atively in these patients but 10 to 20 packs were given intraoperatively to 2 of the patients following splenectomy. In one of these. there was significant postoperative bleeding requiring evacuation of a hematoma. but the platelet count increased significantly from 1 ,000/mm' to 60.000/mmT;3 the week after surgery and was maintained above 70.000/mm: for 5 years. The patient in whom no improvement occurred, has a platelet count which has persisted at 18,000/mm' and has had no bleeding since surgery for the past 4 years. In the 8 patients with thrombocytopenia as a contributory factor, an increase in the count of at least 20,000/mm' has been maintained in 7 patients since splenectomy. The two patients subjected to splenectomy for uncontrollable pulmonary infection related to white blood counts of 800/mm' and 1200/mm:', had spleen weights of 675 gm and 1,350 gm respectively. There were no accessory spleens. In both instances, the infection came under control postoperatively with continuance of preoperative antibiotic therapy which had previously been ineffective. In one patient. the initial increase in white blood count was minimal, i.e., 800/mm3 to 1600/mm3, and the white blood count has been sustained at about 3,000/mm3 with no subsequent infections for the past month. In the second patient, the white blood count increased to 6,000/ mm3 and has been maintained for 6 months at that level without evidence of further infection. There were two significant postoperative infections; both subphrenic abscesses. One of these patients died of uncontrollable sepsis. The other developed gram negative sepsis due to Se1rra(ati inar(cescens following drainage of an infected subphrenic hematoma. This responded to gentamycin and the patient did well for 41/2 years. There was no instance of worsening of the hematologic profile subsequent to splenectomy in ant patients who underwent splenectomy for palliation. The WBC increased in the immediate postoperative period in 84% of the patients. In I I there was marked leukocytosis preoperatively. and this persisted postoperatively. In two patients there were platelet counts of 480,000/mm3 and 380,000/ mm3 preoperatively. In the former, the count increased temporarily to 843.000/mm' with no adverse effects. The one death which may have been related to thrombocytosis occurred one month after surgery in a patient with CML. His maximum platelet count was 420,000/ mm3, but at autopsy there were thromboses and multiple mesenteric and renal veins. Three of the patients with MM and one of the CML patients have died of their disease 3 to 7 years following splenectomy. In two of these, infection, in one a case of Crvptococcus neof o'rnanls, contributed to the demise.
467
TABLE 3. Portal Decompressii'e Procedures In Patients With Myeloid Metaplasia
Procedure
Sex. Age Cirrhosis
Splenorenal Shunt
F, 60
+
End-to-Side Portacaval shunt
F. 41
-
Result Died 3 years later-pneumonia Mild recurrent encephalopathy
Died 36 hours later Massive
hepatic necrosis it
M, 77
+
F. 74
-
Died 6 years later-M.I. Mild Recurrent encephalopathy Died 3 years later-? Etiology Mild recurrent encephalopathy
cedures for portal hypertension, esophagogastric varices and a history of recurrent upper gastrointestinal bleeding (Table 3). One 60-year-old woman who had been treated for pernicious anemia at age 38 and who had been diagnosed at age 50 as having MM, underwent splenectomy and splenorenal anastomosis in 1966. In the 10 antecedent years she had had multiple phlebotomies, splenic irradiation and several courses of busulfan. At surgery the liver biopsy revealed portal cirrhosis in addition to minor foci of extramedullary hematopoiesis. Since splenectomy alone affected only a minor reduction in portal pressure, a splenorenal shunt was carried out and the blood pressure reduced to near caval pressure. Her three year postoperative course was complicated by several episodes of encephalopathy which responded to protein restriction and neomycin. She died of pneumonia, and at autopsy there was no evidence of varices. In the group subjected to end-to-side portacaval shunts, one patient developed hepatorenal failure due to massive hepatic necrosis, and died on the second postoperative day. In addition to the acute necrosis, the liver revealed foci of extramedullary hematopoiesis but no cirrhosis. The second patient, a 77-year-old man, had no recurrent bleeding post shunt, but did experience mild recurrent encephalopathy and died from cardiac problems 6 years subsequent to his shunting procedure. At the operative procedure, his liver demonstrated both extramedullary hematopoiesis and cirrhosis. The remaining patient who received an end-to-side portacaval shunt for bleeding varices was the subject of a previous case report.16 She survived two years and her course was complicated by several episodes of mild recurrent encephalopathy. This 74-year-old woman had portal hypertension, bleeding varices and no evidence of cirrhosis or regenerative nodules. Small foci of extramedullary hematopoiesis were present in the liver. The presence of portal hypertension unassociated with any hepatic lesion which could be indicted as a cause of outflow obstrucIII. Myeloid Metaplasia and Portal Hypertension tion, led to a consideration of increased flow through the Four patients with MM underwent decompressive pro- splenoportal system as a factor in the production of portal
468
Ann. Surg. * October 1975
SCHWARTZ
TABLE 4. Correlation of Intraoperative Pressures (MM Patients With Suspected Portal Hypertension)
Portal Pressure (mm saline) Before After
Spleen
Patient
Ascites
Varices
Splenectomy
Splenectomy
I
+
2 3
-
+
110 370 170 270
140
110 130 120 320 290
90 110 80 70 90
4
5 6 7 8
+
-
+ -
+ + + + +
+ +
360
480 390 320
hypertension in the patient with MM and associated marked splenomegaly. In 8 patients with MM in whom portal hypertension was anticipated due to the presence of varices or ascites, portal pressures were determined at the operative procedure, before and after splenectomy (Table 4). Two patients revealed normal pressures in the portal system, while in 6 an elevation was demonstrated. In 4 of the 6 patients, splenectomy effected a marked reduction in portal pressure to levels within the range of normal but still slightly elevated in reference to CVP. All 4 of these patients showed only small foci of extramedullary hematopoiesis in the liver, and there was no evidence of cirrhosis. In two of these patients, the varices gradually disappeared months after splenectomy. Two patients with significant cirrhosis experienced only a slight reduction in portal pressure associated with splenectomy. One of these was subjected to a concomitant splenorenal shunt. The findings of hemodynamic studies in 4 patients with MM and suspected portal hypertension are shown in Table 5. The hepatic venous wedge pressure was greater than normal in all patients and more than twice normal in
CVP
Cirrhosis
Weight (gm.)
-
-
80
-
1840 3850
-
3630 2200 4950 2250 3150
+
+ +
two. Similarly, the EHBF was significantly increased in all patients and more than twice normal in two. In only one of these patients did liver biopsy reveal cirrhosis.
DiSCUSSlOi The presently reported experience with major surgical procedures in patients with a variety of myeloproliferative disorders is encouraging in regard to mortality and morbidity rates as compared to previous publications. Hemorrhage has been the most commonly reported complication, occurring in 75% of the complicated cases, and leading to 69% of the death.1521 Venous or arterial thrombosis and infection rank second and third on the complication list, both in patients with PV and MM. The hemostatic abnormalities in these patients are complex, multifaceted, and not precisely defined. The increased viscosity associated with a high hematocrit is thought to lead to tissue hypoxia and consequent interference with vascular integrity. Quantitative platelet abnormalities in the form of thrombocytopenia may contribute to a compromise of hemostasis, while the less common thrombocytosis may be a factor in thrombosis, bleeding, or a combination of the two. A variety of qual-
TABLE 5. Hemodynamic Findings in Patients With Suspected Portal Hypertension*
Measurement Rt. Atrium Inferior Vena Cava Free Hepatic Vein Hepatic Venous Wedge
Cardiac Output (L/min) Cardiac Index (L/min/m2) Estimated Hepatic Blood Flows (ml/min/m2) EHBF/C I Varices Ascites Cirrhosis *Some data previously published.14
Normal
Case 1
Pressures (mm Hg) Case 2
0-5 2-7 4- 10 6- 13
4 8 10 26
2 5 9 15
5 13 14 21
4 12 15 30
2.7 - 5.0
4.97 3.23
5.83 4.10
8.28 3.97
5.92 3.92
480 (±+150) 0.20
1485 0.46
853 0.21
1100
1640
0.28
0.42
+
+
+
+
-
+
-
+
-
+
Case 3
Case 4
Vol. 182 * No. 4
MYELOPROLIFERATIVE DISORDERS
itative platelet abnormalities has been reported.2'1421 These include: viscous metamorphosis, reduced dendrite formation and abnormal fragility, all contributing to a defective platelet fibrin network. Abnormal clot retraction, abnormal platelet aggregation and deficiency of platelet factor 3 have all been demonstrated and may further contribute to disorganization of the platelet fibrin network. In addition, the serotonin carrying capacity of platelets may be reduced, interfering with the hemostatic process of vasoconstriction.21 Abnormalities of plasma coagulation factors have also been defined in some cases of PV and MM. These include: a moderate reduction of fibrinogen, decrease in factor 5, 7 and prothrombin with a consequent prolongation of prothrombin time, and rarely fibrinolysis. The mortality and morbidity rates reported in this series are in keeping with those presented by Wasserman and Gilbert,21 since all patients were prepared and none were markedly erythremic. It has been shown that reducing the hematocrit to less than 52% is associated with a reduction in the incidence of complications in PV and MM cases from 79o to 28%, and a reduction in mortality from 36% to 5%. An extended period of control, i.e., greater than 4 months, has been associated with a mortality rate that is 1/3 that present when the period of control ranged between 1 week to 4 months.21 The need for meticulous surgery merits emphasis since technical and mechanical causes represent the most common factors in postoperative hemorrhage. The therapy of MM and CML, including the hematologic manifestations, is generally based on transfusions, androgens, alkylating agents and 32P. Although splenectomy may not alter the natural history of the disease, it is applicable as a palliative procedure to alleviate symptoms attributable to massive splenomegaly or multiple painful splenic infarcts, to reduce transfusion requirements or to correct significant thrombocytopenia and/or leukopenia. In 1937 Hickling8 emphasized a high mortality following splenectomy in patients with MM. Jackson et al.10 reinforced this concept and suggested that a major deterent was that splenectomy removed an important organ of blood formation. However, Green et al.7 in 1953, presented a collective review in which they could demonstrate no support for this concept. As recently as 1966 a partial resection of the spleen for massive incapacitating splenomegaly in a patient with MM was carried out in an attempt to preserve an important site of extramedullary hematopoiesis.13 in reference to the palliative effective of splenectomy in patients with MM, Bouroncle and Doan1 reported 14 of 24 patients had good results, while 5 could not be evaluated completely. Jensen9 reported on 5 patients with MM who underwent splenectomy for hemolytic anemia, and in each instance there was a rise in hemoglobin and in
469
4 of the 5, the platelet count was elevated. None of the patients developed an exacerbation of the hematologic condition. Fishman and Ballinger0 reported a similar experience with 5 patients in that a significant rise in platelets, neutrophiles and hemoglobin occurred in each instance. Recently, Silverstein and ReMine18 reviewed their experience with 29 MM patients in whom splenectomy was performed for hemolytic anemia, thrombocytopenia, splenomegaly and portal hypertension. When compared with medical management for major hemolysis or radiation therapy for massive splenomegaly, their data suggested a better course for the splenectomy group. An increase in mortality and morbidity was noted in men, but the groups were not similar in that women tended to be younger when splenectomized and had a longer duration of illness before splenectomy. Our own experience and an extrapolation of the experience of others fail to reveal this suggested difference related to sex.
In order to distinguish cases where the role of the spleen is primarily that of an organ of red cell destruction
from those cases where the spleen is a major organ of
erythrocyte production, erythrokinetic studies using 51Cr
for red cell survival, 99Fe for identifying the site of erythropoetic activity and 99mTc for measuring splenic red cell mass have been applied. Since it is now appreciated that the spleen is rarely, if ever a significant organ of extramedullary hematopoiesis in these patients and an adverse hematologic effect related to splenectomy has yet to be encountered, these studies are not carried out routinely in our institution preemptive to splenectomy in order to provide a basis for patient selection. Increased portal pressure in patients with MM and massive splenomegaly may result from increased hepatic resistance due to cirrhosis or diffuse extramedullary hepatic foci. Another proposed cause of the increased portal pressure is increased portal flow, either unassociated with or superimposed upon increased hepatic resistance. Previous publications have reported that splenectomy alone in patients with MM has reduced portal pressure to normal levels,4'9 and resulted in the disappearance of varices two months after splenectomy.20 A number of cases have been reported in which splenic arteriovenous aneurysms unaccompanied by hepatic portal venous obstruction caused portal hypertension.3 A case of variceal bleeding has been related to intrasplenic AV shunt, and after splenectomy, the varices disap-
peared.19 Evaluation, on theoretical gounds, of the increased portal venous flow necessary to increase portal pressure
to levels greater than normal suggests that forward blood flow increases in physiologically possible ranges may result in hypertension in a low resistance portal venous system.'6 The presently reported intraoperative pressure
470
SCHWARTZ
determinations demonstrating reduction of portal pressure with splenectomy alone in patients with MM, coupled with the hemodynamic studies defining significant increases in estimated hepatic blood flow indicate that patients with MM, massive splenomegaly and portal hypertension should be thoroughly investigated in order to define that group for which splenectomy alone may correct the portal hypertension and its clinical manifestations. References 1. Bouroncle, B. A. and Doan, C. A.: Myelofibrosis. Clinical, Hematologic and Pathologic Study of 110 Patients. Am. J. Med. Sci., 243:697, 1962. 2. Cardamone, J. M., Edson, J. R., McArthur, J. R. and Jacob, H. S.: Abnormalities of Platelet Function in Myeloproliferative Disorders. JAMA, 221:270, 1972. 3. Cassel, W. G., Spittel, J. A., Ellis, F. H. and Bruwer, A. J.: Arteriovenous Fistula of the Splenic Vessels Producing Ascites. Circulation, 16:1077, 1957. 4. Dagradi, A. E., Siemsen, J., Brook, J. et al.: Bleeding Esophageal Varices in Myelofibrosis. Am. J. Gastroenterol., 44:536, 1967. 5. Damashek, W.: Some Speculations on the Myeloproliferative Syndromes. Blood, 6:372, 1951. 6. Fishman, N. and Ballinger, W. F., II.: Splenectomy for Agnogenic Myeloid Metaplasia and Myelofibrosis. Arch. Surg., 90:536, 1967. 7. Green, T. W., Conley, C. L., Ashburn, L. L. and Peters, H. R.: Splenectomy for Myeloid Metaplasia of the Spleen. N. Engl. J. Med., 248:211, 1953. 8. Hickling, R. A.: Chronic Nonleukemic Myelosis. Quart. J. Med., 6:253, 1937.
DISCUSSION DR. WALTER F. BALLINGER. 11 (St. Louis): The subject of splenectomy from myeloproliferative disorders continues to have many controversial aspects. Dr. Schwartz has convincingly demonstrated in this presentation that splenectomy is indicated for palliation in some of these conditions such as myeloid metaplasia with myelofibrosis, but leaves the question unresolved for others. His breakdown of indications for splenectomy is quite similar to ours. Furthermore, our morbidity and mortality data are almost identical to those presented by Dr. Schwartz today. Opportunity for long term survival in our hands seems somewhat less optimistic and might perhaps reflect a difference in referral patterns in that patients may be seen earlier in the course of their disease by Dr. Schwartz and his group. Two somewhat minor controversial points in reviewing the manuscript about the surgical management might be emphasized. The first, an old chestnut, is whether or not to drain the subphrenic space. Our attitude seems to be somewhat different from that expressed by Dr. Schwartz, not on the podium today, but in his manuscript. We would rather not drain the space following splenectomy unless there is significant oozing from divided adhesions between the spleen and the diaphragm or unless there is a suspected or actual injury to the tip of the pancreas. A second unsettled issue is related to the anticipation and management of post-splenectomy thrombocytosis. There is increasing evidence of thrombotic episodes, particularly in patients with myeloid metaplasia and chronic myelogenous leukemia, occurring not infrequently after splenectomy. The seriousness of this has been emphasized by the reports of mesenteric vein occlusions as reported by Boss this year and one such case included in the manuscript of Dr. Schwartz. We think the use of acetylsalicylic acid as the antiplatelet agent has several appealing aspects. The mechanism of its action has been thoroughly well worked out by
Ann. SLrg.
October t197s
9. Hunt, A. H.: Portal Hypertension. London. E and S Livingstone Ltd., 1958. 10. Jackson, J., Jr., Barker, F. and Lemon. H. M.: Agnogenic Myeloid Metaplasia of the Spleen. N. EngI. J. Med. . 222:985, 1940. 11. Jensen, M. K.: Splenectomy in Myelofibrosis. Acta Med., Scand., 175:533, 1964. 12. Leevy, C. M. and Gliedman, M. L.: Practical and Research Value of Hepatic Vein Catheterization. N. Engl. J. Med., 258:696. 1958. 13. Morgenstern, L., Kahn, F. H. and Weinstein, 1. M.: Subtotal Splenectomy in Myelofibrosis. Surgery, 60:336, 1966. 14. Neemeh, J. A., Bowie, E. J. W., Thompson, J. H., Jr.. et al.: Quantitation of Platelet Aggregation in Myeloproliferative Disorders. Am. J. Clin. Pathol., 57:336. 1972. 15. Neubart, S. and Siegman, F.: Hemorrhagic Tendency in Polycythemia Vera. Arch. Surg., 70:257. 1955. 16. Oishi, N., Swisher, S. N., Stormont. J. M. and Schwartz. S. I.: Portal Hypertension in Myeloid Metaplasia. A.M.A Arch. Surg.. 81:80, 1960. 17. Rosenbaum, D. L., Murphy. G. W. and Swisher. S. N.: Hemodynamic Studies of the Portal Circulation in Myeloid Metaplasia. Am. J. Med., 41:360, 1966. 18. Silverstein, M. N. and ReMine, W. H.: Sex. Splenectomy. and Myeloid Metaplasia. JAMA, Vol 227, 4:422, 1974. 19. Stener, B.: Arterio-Venous Shunt in the Spleen Diagnosed Before Operation. Acta. Chir. Scand., 108:344, 1955. 20. Sullivan, A., Rheinlander, H., Weintraub. L. R.: Esophageal Varices in Agnogenic Myeloid Metaplasia. Disappearance After Splenectomy. Gastroenterology, 66:429, 1974. 21. Wasserman, L. R. and Gilbert, H. S.: Polycythemia Vera and Myeloid Metaplasia. In Surgical Bleeding (Ed: Ulin. A. W. and Gollub, S. S.) New York, McGraw-Hill, 1966. 22. Wetherley-Mein, G., Jones, N. F. and Pullan. J. M.: Effects of Splenectomy on Red-cell Production in Myelofibrosis. Br. Med. J., 84:1, 1961.
Roth and Majares. It seems that very low doses of aspirin. as little as 300 mg will significantly alter platelet aggregation probably by inactivating an enzyme necessary for synthesis of prostoglandin E-2. As long as there are no bleeding tendencies or abnormalities of coagulation factors. aspirin should be taken in these doses. Furthermore, by stopping aspirin, the effects can be completely reversed within one to two weeks with normal bone marrow producing normal platelets. Clinical studies of prophylactic aspirin, although not conclusive. show a definite benefit in possible prevention of thrombosis. as de-' scribed recently in England. Whether it will help the post-splenectomy thrombosis in these situations is unknown. DR. PAUL C. KIERNAN (Washington. D.C.): President Hardy. a small r group of patients substantiate Dr. Schwartz's thesis so beautifully presented. One of chronic myelogenous leukemia and two of myeloid t metaplasia. A 45-year-old man with myelogenous leukemia and evidence or hypersplenism with splenomegaly required daily' multiple transfusions to maintain a hematocrit of 28. An estimated 6000 gm spleen with huge vascular splenoperitoneal adhesions precluded splenectomy, at least in this person's hands. andl suggested splenic artery ligation with resultant massive infarction and rapid decrease in the splenic size and marked improvement in all segments of the blood, a sharp drop in the need for transfusion and good palliation. A 40-year-old man with extensive myelofibrosis of the marrow and pancytopenia required frequent blood transfusions because of the pancytopenia. An 1800 gm spleen was removed and since then normal blood counts have been maintained. A 73-year-old male with pancytopenia required frequent transfusions. There was an absolute white count of less than 500 and platelets of 15,000-20,000. He survived an ailp/la wtrepto(cocc(us and E. (oli sepsik,
Forty-three operative procedures were performed on a population of 250 patients with myeloproliferative disorders, including polycythemia vera, myeloid metaplasia (MM) and chronic myelogenous leukemia (CML). The overall operative mortality was approximately 7% and the incidence of excessive bleeding which could be related to coagulopathy was 5%. Twenty-one patients with MM or CML underwent splenectomy for palliation of symptoms related to the enlarged spleen or hematologic problems. Eighty-four percent of the latter group were improved. Adverse hematologic effects which could be attributed to splenectomy in these patients were confined to two patients who developed marked thrombocytosis. Among the 23 patients with MM, 9 had portal hypertension. Three underwent portacaval shunt and one a splenorenal shunt for bleeding varices. One of the patients died of hepatic necrosis. Estimated hepatic blood flow determinations (EHBF) in 4 patients with portal hypertension demonstrated a marked absolute increase and an increase in the ratio of EHBF/Cardiac Index. Absence of any evidence of intrahepatic or extrahepatic obstruction in these patients and the demonstration that splenectomy relieved portal hypertension defined at surgery in 4 patients, suggests that augmented adhepatic flow contributes to portal hypertension in some cases. The review leads to the conclusions that: 1) Operative procedures in prepared patients with myeloproliferative disorders are not associated with prohibitive mortality and morbidity rates. 2) Splenectomy is indicated for patients with increasing transfusion requirements and symptomatic splenomegaly or hypersplenism and should be performed early in the course of disease. 3) When associated portal hypertension and bleeding varices are present, hemodynamic studies should be carried out to define if splenectomy alone, or a portal systemic decompressive procedure is indicated.
THE MYELOPROLIFERATIVE DISORDERS include a spec-
s trum of diseases, each of which may be due to a different disturbance in proliferation and/or maturation of the hematopoietic stem cell of marrow. Polycythemia Presented at the Annual Meeting of the American Surgical Association, Quebec City, Quebec, May 7-9, 1975. *The University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642.
From the University of Rochester School of Medicine and Dentistry, and Strong Memorial Hospital, Rochester, New York
Vera (PV), Acute and Chronic Myelogenous Leukemia (AML and CML), Myeloid Metaplasia (Myelofibrosis, Myelosclerosis) (MM) and Essential Thrombocythemia all have been included within the general category of myeloproliferative disorders. Surgical consideration of patients with myeloproliferative disorders relates to: 1) a general appreciation of the operative risk for any surgical procedure in these patients; 2) the application of splenectomy as a palliative procedure in patients with MM and CML; and 3) the management of portal hypertension and variceal bleeding in patients with MM. Material and Methods The records of 250 patients with myeloproliferative disorders seen at the Strong Memorial Hospital between 1955 and 1974 were reviewed. Included were 90 patients with PV, 64 patients with MM and 96 patients with CML. Some of these patients have progressed from PV to MM. Each patient was assigned to the more advanced category, unless an operative procedure was performed, in which case he or she was considered in that category during which the operation was carried out. All patients had the diagnosis established by blood counts, peripheral blood smears, bone marrow aspirates or biopsies. In patients subjected to splenectomy and/or portal decompressive procedures, histologic evaluation of the spleen and/or liver contributed to the diagnosis. Operative mortality was considered as that occurring during the hospitalization for the procedure or within 30 days. Excessive bleeding related to an hemostatic defect was defined as that associated with a 5% reduction in
464
A
Vol. 182
*
MYELOPROLIFERATIVE DISORDERS
No. 4
465
hematocrit, requirement for a number of transfusions OPERATIVE PROCEDURES IN PATIENTS WITH significantly greater than that usually associated with the MYELOPROLIFERATIVE DISORDERS procedure, reexploration at which a single bleeding site TOTAL could not be defined, or a combination of the above. CASES 250 TOTAL Portal pressures were measured during the operative procedure in either the portal vein itself, or in an omental OPERATIVE CASES vein with the portal vein as a reference level, using a MORTALIT-Y spinal manometer filled with saline. Central venous pressures (CVP) were determined simultaneously. Hemodynamic studies were performed on awake paCHRONIC tients who were not premedicated. Hepatic blood flow MYELOGENOUS POLYCYTHEMIA LEUKEMIA (EHBF) during the postabsorptive state was carried out VERA according to the method of Leevy et al.12 employing 96 MYELOFIBROSIS indocyanine green dye. Pressure measurements in these patients were made using Statham P-23 AA strain gauges and a Sanborn direct writing recorder. Cardiac output l77 = ZZ determinations were made from the standard indocyanine green indicator dilution curves. Body surface area estiI I OX ,mates were derived from a Du Bois normogram. 10 9U 25X% Results I. Operative procedures in all categories Forty-five operative procedures were performed in 41 ,patients. Twelve procedures were carried out in patients with PV, 29 were performed in patients with MM, and four procedures were performed in patients with CML (Table I). There were 4 deaths related to the operative procedure, resulting in an overall mortality rate of 9o. None of the patients with PV died; one of the patients with CML died, while in the group with MM, the mortality rate was 10%o (Fig. 1). In the MM group, a patient died following splenectomy
with ensuing subphrenic abscess and sepsis. Another patient died due to hepatic necrosis following an end-to-side portacaval anastomosis. The third death in the MM group occurred in a 48-year-old woman who had a 4,950 gram spleen removed because of symptomatic splenomegaly on 5-18-72 without intraoperative or postoperative transfusional requirement. On 2-28-73 she underwent trans-
PERCENT MORTALITY FIG. 1. Mortality Associated with Operative Procedures in patients with Myeloproliferative Disorders.
thoracic subclavian endarterectomy. Her preoperative hematocrit was 35, WBC 50,000 and platelets 160,000/ mm.3 Postoperatively she developed an hemothorax which required three reexplorations. She subsequently developed aspiration pneumonia, respiratory failure and died 6 weeks after the first thoracotomy. One patient who underwent splenectomy for hypersplenism associated with CML died following discharge but within one month of surgery. At autopsy there were extensive thromboses of the renal veins and mesenteric veins. In the group of patients with PV, there was no excessive bleeding, and only one significant postoperative infection; a subphrenic abscess following cholecystectomy for acute cholecystitis. In one of the patients, the preoperative platelet count was 843,000/mm3 while in all others this was in the normal range. One patient was
TABLE 1. Operative Procedures in Patients With Myeloproliferative Disorders PV
Arterial Reconstructions Amputations 'Lumbar Sympathectomy Aortic Valve Replacement Pericardial Poudrage Nephrectomy Mastectomy Drainage Subphrenic Abscess Cholecystectomy Total: Deaths: *Excessive bleeding + Death
MM 3 2
12 0
CML
Splenectomy (With Splenorenal shunt 1) Portacaval Shunt Subclavian Endarterectomy Cholecystectomy Vagotomy & Pyloroplasty Hernia Repair Total: Deaths:
22 (1*, 1+)
Splenectomy Vagotomy & Antrectomy
3 (1+)
3 (1+) 1 (1+)
29 3
Total: Deaths:
4
TABLE 2. Indications for SplenectomylEffects
Primary
Symptomatic Splenomegaly/ Hypermetabolism Anemia/ Hemolysis Thrombocytopenia Leukopenia Total:
Ann. Siurg.
SCHWARTZ
466
8 (2+)
Improvement Improvement In Survivors Secondary In Survivors
6/6
10
7/10
6
5/6
4 2
3/4 2/2
8
7/8
24
19/22 (86%)
12/14 (86%)
+ Death
operated on with a hematocrit of 63, while in the remainder the hematocrit was less than 52%. Ten of the 12 patients had been treated with busulfan, 32P, multiple phlebotomies or a combination of these modalities. In the 6 patients requiring an operation for peripheral arterial disease, neither hematocrit nor platelet count were significantly increased. Among the 27 patients with MM undergoing 29 procedures, excessive bleeding occurred in 3 cases; in the subclavian endarterectomy described above and in two of the 21 splenectomies. In none of these three could the bleeding be attributed to a specific bleeding site, and none of these patients had platelet counts less than 70,000/mm.3 In both splenectomy cases, reexploration and evacuation of the clot from the left subphrenic space resulted in cessation of bleeding. There was no excessive bleeding in the two patients with platelet counts greater than 350,000/mm.3 At the operative procedure in patients with MM, no patient had a hematocrit greater than 52. Two of the three deaths in the group of patients with MM were related to sepsis. The three splenectomies in the CML group were performed in patients with mild anemia; two had thrombocytopenia, and one mild thrombocytosis. There were no immediate postoperative complications, but one patient had a slightly elevated platelet count and died within a month of surgery from extensive visceral venous thromboses and a blastic crisis. II. Splenectomy as a Palliative Procedure Twenty-four splenectomies were performed as palliative procedures in patients with MM or CML. The indications are listed in Table 2. In 8 patients the major indication was symptomatic splenomegaly in which the spleen was of such magnitude as to be uncomfortable or to interfere with alimentation, or in which multiple episodes of painful splenic infarcts occurred. In some patients there was associated hypermetabolism. In 10 patients, a significantly increased transfusion requirement or hemolysis was the major indication, while in 4 patients
-
October 1975
thrombocytopenia with clinical manifestations constituted the major indication. In two patients leukopenia interfering with the defense mechanism toward an infection, prompted splenectomy. All patients had received medical therapy, usually from months to years prior to the operation. The regimen varied and consisted of phlebotomies, prednisone, :'2P, busulfan, cyclophosphamide or a combination of these. The mean weight of the spleens which were removed for symptomatic splenomegaly was about 3,150 gm, range of 2,250-7,650 gm. There were two patients with an accessory spleen. Five of the patients had platelet counts of 70,000/mm:3 or less. The left subphrenic space was drained in 7 patients. Reexploration for continued bleeding was required in 2 patients, one of whom had thrombocytopenia, and one was a patient in whom the space was not drained. One of the patients developed a subphrenic abscess and died of sepsis a month after the second procedure. The other death occurred in the patient with CML described above. The 6 remaining patients had symptomatic improvement, and in no instance was there an adverse hematologic effect, i.e., more profound anemia, thrombocytopenia or leukopenia. Two of the patients have died, years after the operative procedure for CML. In 16 patients, the major indication was hypersplenism, with anemia, thrombocytopenia or leukopenia the factor prompting the operative procedure (Table 2). The mean weight of the spleens in these patients was 2,250 gm (range 675 gm-3,150 gm). There were three patients in whom small, accessory spleens were also removed. The subphrenic space was drained in 14 patients. The hematologic defect which constituted the prime indication for surgery was improved in 12 patients for an overall therapeutic effect of 75% (Fig. 2). Seven of the 10 patients with an increase in transfusion requirements had this significantly reduced for months to years following splenectomy. Five of the 6 patients in whom anemia was a contributory factor, had some increase in the hematocrit following splenectomy. Three of the 4 patients with symptomatic thrombocytopenia as the major factor, improved following splenectomy. Platelets were not adX PALLIATION
INDICATION 6 CASES SPLENOMEGALY ^ ANEMIA/HEMOLYSIS
10 CASES I 4 CASES
100%
66 % 75 %
THROMBOCYTOPENIA 2 CASES
100 %
LEUKOPENIA
FIG. 2. Results with Spienectomy in Patients with Myeloproliferative Disorders.
Vol. 1 8
No() 4
\o
MYELoPROLIFERATIVE DISORDERS
ministered preopei-atively in these patients but 10 to 20 packs were given intraoperatively to 2 of the patients following splenectomy. In one of these. there was significant postoperative bleeding requiring evacuation of a hematoma. but the platelet count increased significantly from 1 ,000/mm' to 60.000/mmT;3 the week after surgery and was maintained above 70.000/mm: for 5 years. The patient in whom no improvement occurred, has a platelet count which has persisted at 18,000/mm' and has had no bleeding since surgery for the past 4 years. In the 8 patients with thrombocytopenia as a contributory factor, an increase in the count of at least 20,000/mm' has been maintained in 7 patients since splenectomy. The two patients subjected to splenectomy for uncontrollable pulmonary infection related to white blood counts of 800/mm' and 1200/mm:', had spleen weights of 675 gm and 1,350 gm respectively. There were no accessory spleens. In both instances, the infection came under control postoperatively with continuance of preoperative antibiotic therapy which had previously been ineffective. In one patient. the initial increase in white blood count was minimal, i.e., 800/mm3 to 1600/mm3, and the white blood count has been sustained at about 3,000/mm3 with no subsequent infections for the past month. In the second patient, the white blood count increased to 6,000/ mm3 and has been maintained for 6 months at that level without evidence of further infection. There were two significant postoperative infections; both subphrenic abscesses. One of these patients died of uncontrollable sepsis. The other developed gram negative sepsis due to Se1rra(ati inar(cescens following drainage of an infected subphrenic hematoma. This responded to gentamycin and the patient did well for 41/2 years. There was no instance of worsening of the hematologic profile subsequent to splenectomy in ant patients who underwent splenectomy for palliation. The WBC increased in the immediate postoperative period in 84% of the patients. In I I there was marked leukocytosis preoperatively. and this persisted postoperatively. In two patients there were platelet counts of 480,000/mm3 and 380,000/ mm3 preoperatively. In the former, the count increased temporarily to 843.000/mm' with no adverse effects. The one death which may have been related to thrombocytosis occurred one month after surgery in a patient with CML. His maximum platelet count was 420,000/ mm3, but at autopsy there were thromboses and multiple mesenteric and renal veins. Three of the patients with MM and one of the CML patients have died of their disease 3 to 7 years following splenectomy. In two of these, infection, in one a case of Crvptococcus neof o'rnanls, contributed to the demise.
467
TABLE 3. Portal Decompressii'e Procedures In Patients With Myeloid Metaplasia
Procedure
Sex. Age Cirrhosis
Splenorenal Shunt
F, 60
+
End-to-Side Portacaval shunt
F. 41
-
Result Died 3 years later-pneumonia Mild recurrent encephalopathy
Died 36 hours later Massive
hepatic necrosis it
M, 77
+
F. 74
-
Died 6 years later-M.I. Mild Recurrent encephalopathy Died 3 years later-? Etiology Mild recurrent encephalopathy
cedures for portal hypertension, esophagogastric varices and a history of recurrent upper gastrointestinal bleeding (Table 3). One 60-year-old woman who had been treated for pernicious anemia at age 38 and who had been diagnosed at age 50 as having MM, underwent splenectomy and splenorenal anastomosis in 1966. In the 10 antecedent years she had had multiple phlebotomies, splenic irradiation and several courses of busulfan. At surgery the liver biopsy revealed portal cirrhosis in addition to minor foci of extramedullary hematopoiesis. Since splenectomy alone affected only a minor reduction in portal pressure, a splenorenal shunt was carried out and the blood pressure reduced to near caval pressure. Her three year postoperative course was complicated by several episodes of encephalopathy which responded to protein restriction and neomycin. She died of pneumonia, and at autopsy there was no evidence of varices. In the group subjected to end-to-side portacaval shunts, one patient developed hepatorenal failure due to massive hepatic necrosis, and died on the second postoperative day. In addition to the acute necrosis, the liver revealed foci of extramedullary hematopoiesis but no cirrhosis. The second patient, a 77-year-old man, had no recurrent bleeding post shunt, but did experience mild recurrent encephalopathy and died from cardiac problems 6 years subsequent to his shunting procedure. At the operative procedure, his liver demonstrated both extramedullary hematopoiesis and cirrhosis. The remaining patient who received an end-to-side portacaval shunt for bleeding varices was the subject of a previous case report.16 She survived two years and her course was complicated by several episodes of mild recurrent encephalopathy. This 74-year-old woman had portal hypertension, bleeding varices and no evidence of cirrhosis or regenerative nodules. Small foci of extramedullary hematopoiesis were present in the liver. The presence of portal hypertension unassociated with any hepatic lesion which could be indicted as a cause of outflow obstrucIII. Myeloid Metaplasia and Portal Hypertension tion, led to a consideration of increased flow through the Four patients with MM underwent decompressive pro- splenoportal system as a factor in the production of portal
468
Ann. Surg. * October 1975
SCHWARTZ
TABLE 4. Correlation of Intraoperative Pressures (MM Patients With Suspected Portal Hypertension)
Portal Pressure (mm saline) Before After
Spleen
Patient
Ascites
Varices
Splenectomy
Splenectomy
I
+
2 3
-
+
110 370 170 270
140
110 130 120 320 290
90 110 80 70 90
4
5 6 7 8
+
-
+ -
+ + + + +
+ +
360
480 390 320
hypertension in the patient with MM and associated marked splenomegaly. In 8 patients with MM in whom portal hypertension was anticipated due to the presence of varices or ascites, portal pressures were determined at the operative procedure, before and after splenectomy (Table 4). Two patients revealed normal pressures in the portal system, while in 6 an elevation was demonstrated. In 4 of the 6 patients, splenectomy effected a marked reduction in portal pressure to levels within the range of normal but still slightly elevated in reference to CVP. All 4 of these patients showed only small foci of extramedullary hematopoiesis in the liver, and there was no evidence of cirrhosis. In two of these patients, the varices gradually disappeared months after splenectomy. Two patients with significant cirrhosis experienced only a slight reduction in portal pressure associated with splenectomy. One of these was subjected to a concomitant splenorenal shunt. The findings of hemodynamic studies in 4 patients with MM and suspected portal hypertension are shown in Table 5. The hepatic venous wedge pressure was greater than normal in all patients and more than twice normal in
CVP
Cirrhosis
Weight (gm.)
-
-
80
-
1840 3850
-
3630 2200 4950 2250 3150
+
+ +
two. Similarly, the EHBF was significantly increased in all patients and more than twice normal in two. In only one of these patients did liver biopsy reveal cirrhosis.
DiSCUSSlOi The presently reported experience with major surgical procedures in patients with a variety of myeloproliferative disorders is encouraging in regard to mortality and morbidity rates as compared to previous publications. Hemorrhage has been the most commonly reported complication, occurring in 75% of the complicated cases, and leading to 69% of the death.1521 Venous or arterial thrombosis and infection rank second and third on the complication list, both in patients with PV and MM. The hemostatic abnormalities in these patients are complex, multifaceted, and not precisely defined. The increased viscosity associated with a high hematocrit is thought to lead to tissue hypoxia and consequent interference with vascular integrity. Quantitative platelet abnormalities in the form of thrombocytopenia may contribute to a compromise of hemostasis, while the less common thrombocytosis may be a factor in thrombosis, bleeding, or a combination of the two. A variety of qual-
TABLE 5. Hemodynamic Findings in Patients With Suspected Portal Hypertension*
Measurement Rt. Atrium Inferior Vena Cava Free Hepatic Vein Hepatic Venous Wedge
Cardiac Output (L/min) Cardiac Index (L/min/m2) Estimated Hepatic Blood Flows (ml/min/m2) EHBF/C I Varices Ascites Cirrhosis *Some data previously published.14
Normal
Case 1
Pressures (mm Hg) Case 2
0-5 2-7 4- 10 6- 13
4 8 10 26
2 5 9 15
5 13 14 21
4 12 15 30
2.7 - 5.0
4.97 3.23
5.83 4.10
8.28 3.97
5.92 3.92
480 (±+150) 0.20
1485 0.46
853 0.21
1100
1640
0.28
0.42
+
+
+
+
-
+
-
+
-
+
Case 3
Case 4
Vol. 182 * No. 4
MYELOPROLIFERATIVE DISORDERS
itative platelet abnormalities has been reported.2'1421 These include: viscous metamorphosis, reduced dendrite formation and abnormal fragility, all contributing to a defective platelet fibrin network. Abnormal clot retraction, abnormal platelet aggregation and deficiency of platelet factor 3 have all been demonstrated and may further contribute to disorganization of the platelet fibrin network. In addition, the serotonin carrying capacity of platelets may be reduced, interfering with the hemostatic process of vasoconstriction.21 Abnormalities of plasma coagulation factors have also been defined in some cases of PV and MM. These include: a moderate reduction of fibrinogen, decrease in factor 5, 7 and prothrombin with a consequent prolongation of prothrombin time, and rarely fibrinolysis. The mortality and morbidity rates reported in this series are in keeping with those presented by Wasserman and Gilbert,21 since all patients were prepared and none were markedly erythremic. It has been shown that reducing the hematocrit to less than 52% is associated with a reduction in the incidence of complications in PV and MM cases from 79o to 28%, and a reduction in mortality from 36% to 5%. An extended period of control, i.e., greater than 4 months, has been associated with a mortality rate that is 1/3 that present when the period of control ranged between 1 week to 4 months.21 The need for meticulous surgery merits emphasis since technical and mechanical causes represent the most common factors in postoperative hemorrhage. The therapy of MM and CML, including the hematologic manifestations, is generally based on transfusions, androgens, alkylating agents and 32P. Although splenectomy may not alter the natural history of the disease, it is applicable as a palliative procedure to alleviate symptoms attributable to massive splenomegaly or multiple painful splenic infarcts, to reduce transfusion requirements or to correct significant thrombocytopenia and/or leukopenia. In 1937 Hickling8 emphasized a high mortality following splenectomy in patients with MM. Jackson et al.10 reinforced this concept and suggested that a major deterent was that splenectomy removed an important organ of blood formation. However, Green et al.7 in 1953, presented a collective review in which they could demonstrate no support for this concept. As recently as 1966 a partial resection of the spleen for massive incapacitating splenomegaly in a patient with MM was carried out in an attempt to preserve an important site of extramedullary hematopoiesis.13 in reference to the palliative effective of splenectomy in patients with MM, Bouroncle and Doan1 reported 14 of 24 patients had good results, while 5 could not be evaluated completely. Jensen9 reported on 5 patients with MM who underwent splenectomy for hemolytic anemia, and in each instance there was a rise in hemoglobin and in
469
4 of the 5, the platelet count was elevated. None of the patients developed an exacerbation of the hematologic condition. Fishman and Ballinger0 reported a similar experience with 5 patients in that a significant rise in platelets, neutrophiles and hemoglobin occurred in each instance. Recently, Silverstein and ReMine18 reviewed their experience with 29 MM patients in whom splenectomy was performed for hemolytic anemia, thrombocytopenia, splenomegaly and portal hypertension. When compared with medical management for major hemolysis or radiation therapy for massive splenomegaly, their data suggested a better course for the splenectomy group. An increase in mortality and morbidity was noted in men, but the groups were not similar in that women tended to be younger when splenectomized and had a longer duration of illness before splenectomy. Our own experience and an extrapolation of the experience of others fail to reveal this suggested difference related to sex.
In order to distinguish cases where the role of the spleen is primarily that of an organ of red cell destruction
from those cases where the spleen is a major organ of
erythrocyte production, erythrokinetic studies using 51Cr
for red cell survival, 99Fe for identifying the site of erythropoetic activity and 99mTc for measuring splenic red cell mass have been applied. Since it is now appreciated that the spleen is rarely, if ever a significant organ of extramedullary hematopoiesis in these patients and an adverse hematologic effect related to splenectomy has yet to be encountered, these studies are not carried out routinely in our institution preemptive to splenectomy in order to provide a basis for patient selection. Increased portal pressure in patients with MM and massive splenomegaly may result from increased hepatic resistance due to cirrhosis or diffuse extramedullary hepatic foci. Another proposed cause of the increased portal pressure is increased portal flow, either unassociated with or superimposed upon increased hepatic resistance. Previous publications have reported that splenectomy alone in patients with MM has reduced portal pressure to normal levels,4'9 and resulted in the disappearance of varices two months after splenectomy.20 A number of cases have been reported in which splenic arteriovenous aneurysms unaccompanied by hepatic portal venous obstruction caused portal hypertension.3 A case of variceal bleeding has been related to intrasplenic AV shunt, and after splenectomy, the varices disap-
peared.19 Evaluation, on theoretical gounds, of the increased portal venous flow necessary to increase portal pressure
to levels greater than normal suggests that forward blood flow increases in physiologically possible ranges may result in hypertension in a low resistance portal venous system.'6 The presently reported intraoperative pressure
470
SCHWARTZ
determinations demonstrating reduction of portal pressure with splenectomy alone in patients with MM, coupled with the hemodynamic studies defining significant increases in estimated hepatic blood flow indicate that patients with MM, massive splenomegaly and portal hypertension should be thoroughly investigated in order to define that group for which splenectomy alone may correct the portal hypertension and its clinical manifestations. References 1. Bouroncle, B. A. and Doan, C. A.: Myelofibrosis. Clinical, Hematologic and Pathologic Study of 110 Patients. Am. J. Med. Sci., 243:697, 1962. 2. Cardamone, J. M., Edson, J. R., McArthur, J. R. and Jacob, H. S.: Abnormalities of Platelet Function in Myeloproliferative Disorders. JAMA, 221:270, 1972. 3. Cassel, W. G., Spittel, J. A., Ellis, F. H. and Bruwer, A. J.: Arteriovenous Fistula of the Splenic Vessels Producing Ascites. Circulation, 16:1077, 1957. 4. Dagradi, A. E., Siemsen, J., Brook, J. et al.: Bleeding Esophageal Varices in Myelofibrosis. Am. J. Gastroenterol., 44:536, 1967. 5. Damashek, W.: Some Speculations on the Myeloproliferative Syndromes. Blood, 6:372, 1951. 6. Fishman, N. and Ballinger, W. F., II.: Splenectomy for Agnogenic Myeloid Metaplasia and Myelofibrosis. Arch. Surg., 90:536, 1967. 7. Green, T. W., Conley, C. L., Ashburn, L. L. and Peters, H. R.: Splenectomy for Myeloid Metaplasia of the Spleen. N. Engl. J. Med., 248:211, 1953. 8. Hickling, R. A.: Chronic Nonleukemic Myelosis. Quart. J. Med., 6:253, 1937.
DISCUSSION DR. WALTER F. BALLINGER. 11 (St. Louis): The subject of splenectomy from myeloproliferative disorders continues to have many controversial aspects. Dr. Schwartz has convincingly demonstrated in this presentation that splenectomy is indicated for palliation in some of these conditions such as myeloid metaplasia with myelofibrosis, but leaves the question unresolved for others. His breakdown of indications for splenectomy is quite similar to ours. Furthermore, our morbidity and mortality data are almost identical to those presented by Dr. Schwartz today. Opportunity for long term survival in our hands seems somewhat less optimistic and might perhaps reflect a difference in referral patterns in that patients may be seen earlier in the course of their disease by Dr. Schwartz and his group. Two somewhat minor controversial points in reviewing the manuscript about the surgical management might be emphasized. The first, an old chestnut, is whether or not to drain the subphrenic space. Our attitude seems to be somewhat different from that expressed by Dr. Schwartz, not on the podium today, but in his manuscript. We would rather not drain the space following splenectomy unless there is significant oozing from divided adhesions between the spleen and the diaphragm or unless there is a suspected or actual injury to the tip of the pancreas. A second unsettled issue is related to the anticipation and management of post-splenectomy thrombocytosis. There is increasing evidence of thrombotic episodes, particularly in patients with myeloid metaplasia and chronic myelogenous leukemia, occurring not infrequently after splenectomy. The seriousness of this has been emphasized by the reports of mesenteric vein occlusions as reported by Boss this year and one such case included in the manuscript of Dr. Schwartz. We think the use of acetylsalicylic acid as the antiplatelet agent has several appealing aspects. The mechanism of its action has been thoroughly well worked out by
Ann. SLrg.
October t197s
9. Hunt, A. H.: Portal Hypertension. London. E and S Livingstone Ltd., 1958. 10. Jackson, J., Jr., Barker, F. and Lemon. H. M.: Agnogenic Myeloid Metaplasia of the Spleen. N. EngI. J. Med. . 222:985, 1940. 11. Jensen, M. K.: Splenectomy in Myelofibrosis. Acta Med., Scand., 175:533, 1964. 12. Leevy, C. M. and Gliedman, M. L.: Practical and Research Value of Hepatic Vein Catheterization. N. Engl. J. Med., 258:696. 1958. 13. Morgenstern, L., Kahn, F. H. and Weinstein, 1. M.: Subtotal Splenectomy in Myelofibrosis. Surgery, 60:336, 1966. 14. Neemeh, J. A., Bowie, E. J. W., Thompson, J. H., Jr.. et al.: Quantitation of Platelet Aggregation in Myeloproliferative Disorders. Am. J. Clin. Pathol., 57:336. 1972. 15. Neubart, S. and Siegman, F.: Hemorrhagic Tendency in Polycythemia Vera. Arch. Surg., 70:257. 1955. 16. Oishi, N., Swisher, S. N., Stormont. J. M. and Schwartz. S. I.: Portal Hypertension in Myeloid Metaplasia. A.M.A Arch. Surg.. 81:80, 1960. 17. Rosenbaum, D. L., Murphy. G. W. and Swisher. S. N.: Hemodynamic Studies of the Portal Circulation in Myeloid Metaplasia. Am. J. Med., 41:360, 1966. 18. Silverstein, M. N. and ReMine, W. H.: Sex. Splenectomy. and Myeloid Metaplasia. JAMA, Vol 227, 4:422, 1974. 19. Stener, B.: Arterio-Venous Shunt in the Spleen Diagnosed Before Operation. Acta. Chir. Scand., 108:344, 1955. 20. Sullivan, A., Rheinlander, H., Weintraub. L. R.: Esophageal Varices in Agnogenic Myeloid Metaplasia. Disappearance After Splenectomy. Gastroenterology, 66:429, 1974. 21. Wasserman, L. R. and Gilbert, H. S.: Polycythemia Vera and Myeloid Metaplasia. In Surgical Bleeding (Ed: Ulin. A. W. and Gollub, S. S.) New York, McGraw-Hill, 1966. 22. Wetherley-Mein, G., Jones, N. F. and Pullan. J. M.: Effects of Splenectomy on Red-cell Production in Myelofibrosis. Br. Med. J., 84:1, 1961.
Roth and Majares. It seems that very low doses of aspirin. as little as 300 mg will significantly alter platelet aggregation probably by inactivating an enzyme necessary for synthesis of prostoglandin E-2. As long as there are no bleeding tendencies or abnormalities of coagulation factors. aspirin should be taken in these doses. Furthermore, by stopping aspirin, the effects can be completely reversed within one to two weeks with normal bone marrow producing normal platelets. Clinical studies of prophylactic aspirin, although not conclusive. show a definite benefit in possible prevention of thrombosis. as de-' scribed recently in England. Whether it will help the post-splenectomy thrombosis in these situations is unknown. DR. PAUL C. KIERNAN (Washington. D.C.): President Hardy. a small r group of patients substantiate Dr. Schwartz's thesis so beautifully presented. One of chronic myelogenous leukemia and two of myeloid t metaplasia. A 45-year-old man with myelogenous leukemia and evidence or hypersplenism with splenomegaly required daily' multiple transfusions to maintain a hematocrit of 28. An estimated 6000 gm spleen with huge vascular splenoperitoneal adhesions precluded splenectomy, at least in this person's hands. andl suggested splenic artery ligation with resultant massive infarction and rapid decrease in the splenic size and marked improvement in all segments of the blood, a sharp drop in the need for transfusion and good palliation. A 40-year-old man with extensive myelofibrosis of the marrow and pancytopenia required frequent blood transfusions because of the pancytopenia. An 1800 gm spleen was removed and since then normal blood counts have been maintained. A 73-year-old male with pancytopenia required frequent transfusions. There was an absolute white count of less than 500 and platelets of 15,000-20,000. He survived an ailp/la wtrepto(cocc(us and E. (oli sepsik,
