Chronic intravascular coagulation associated with chronic myelocytic leukemia

Chronic Intravascular Coagulation Associated with Chronic Myelocytic Leukemia Use of Heparin in Connection with a Surgical Procedure

HAROLD J. GERMAN, M.D. JEANNE A. SMITH. M.D. JOHN LINDENBAUM, M.D. New York, New York

From the Medical Service, Harlem Hospital Center; and the Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York. Requests for reprints should be addressed to Dr. John Lindenbaum, Medical Service, Harlem Hospital Center, Lenox Avenue and 135th Street, New York, New York 10037. Manuscript accepted December31, 1975.

A woman with Philadelphia chromosome-positive chronic myelocytic leukemia lived nearly 12 years from the time of diagnosis. During most of this period she received no therapy, and marked cyclic oscillations in the whtte blood cell count were documented. The last two years of her illness were marked by a hemorrhagic disorder associated with hypofibrtnogenehtia, thrombocytopenia, increased plasma fibrinopeptide A concentration and markedly elevated serum levels of fibrin degradation products. The coagulation disorder was rapidly reversible on several occasions with heparin therapy. After treatment with heparin and platelet transfusions, the patient underwent successful resection of a large ovarian cyst with excellent hemostasis during the procedure. Postoperatively, the administration of heparin and platelets was dtscontinued and a large wound hematoma developed. After resumption of therapy with heparin and platelets, the remainder of her postoperative course was uneventful. The literature on the subject is reviewed and tentative guidelines are offered concerning the management of patients with intravascular coagulation who require diagnostic or therapeutic surgical procedures. In recent years increasing numbers of patients have been described to have a chronic state of intravascular coagulation associated with underlying malignancies, hemangiomas, aortic aneurysms, vasculitides and liver disease [l-4]. Such patients may require diagnostic or therapeutic surgical procedures, which may be complicated by disastrous operative or postoperative hemorrhage [S-10]. The defibrination syndrome has frequently been encountered in the acute leukemias [ 111, but it is not a recognized complication of chronic myelocytic leukemia (CML). We describe a patient with CML in whom a coagulation disorder developed consistent with intravascular coagulation and who also required surgical excision of an enlarging pelvic mass. Based on our experience with this patient and that of others described in the literature, we have attempted to develop guidelines which may be useful in the management of other patients with chronic intravascular coagulation who may require surgery or invasive diagnostic procedures. CASE REPORT In September 1962, at age 35, a previously healthy Puerto Rican housewife was found to have CML when she presented to another hospital with painful

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splenomegaly. The white blood cell count was 364,OOO/pl, with 43 per cent neutrophils, 15 per cent band forms, 17 per cent metamyelocytes, 14 per cent myelocytes, 3 per cent promyelocytes, 1 per cent myeloblasts, 3 per cent basophils, 3 per cent eosinophils and 1 per cent monocytes. The hemoglobin value was 6.4 g/dl and the platelet count 49O,OOO/pl. A bone marrow aspirate was hypercellular with increased myelopoiesis. She was treated with busulfan. By March 1963 she felt well, the spleen was no longer palpable, the white blood cell count was 6,9OO/u1,and the hemoglobin value and platelet count were normal. The patient did well without further therapy until July 1967, when she was admitted to Bellevue Hospital with acute tuberculous pericarditis. At that time the spleen was not palpable. The white blood cell count was 13,8OO/pl with a normal differential, the hematocrit value was 35 per cent, and the platelet count 36O,OOO/pl. She had an uneventful recovery on antituberculous therapy and was subsequently followed at 1 to 2 month intervals in the hematology clinics of Bellevue and Harlem Hospitals from October 1967 to April 1972; during this period she remained asymptomatic and received no antileukemic therapy. Her peripheral blood values fluctuated markedly during this period. In April 1972 she noted the onset of multiple ecchymoses on both legs, and evaluation at that time showed an increase in the size of the spleen to 5 cm below the left costal margin, a more marked leukocytosis, thrombocytopenia and evidence of a disorder in blood coagulation. Results of liver function tests were within normal limits. Over the next several months she was treated with prednisone and busulfan, with lowering of the white blood cell count to 31,OOO/pl but no change in her coagulation abnormalities and a slight diminution in the purpuric tendency. In December 1972, she noted the onset of menorrhagia, and a 10 by 15 cm nontender lower abdominal mass was noted on pelvic examination. She was admitted to Harlem Hospital and after further evaluation and heparin therapy, underwent resection of a benign mucous cyst of the left ovary weighing 1,200 g. Her postoperative course was complicated by the development of a wound hematoma which caused a superficial dehiscence, requiring operative incision and drainage, and by pulmonary infection. She was discharged in May 1973. During the last year of her life she had multiple admissions to Harlem Hospital Center for recurrent episodes of gout, massive splenomegaly with splenic infarction, generalized lymphadenopathy due to infiltration with immature leukocytes, and a severe peripheral neuropathy. The peripheral blood showed a worsening anemia, and advancing leukocytosis with increasing numbers of promyelocytes and blast cells. Transient responses to therapy with vincristine, prednisone, splenic irradiation and hydroxyurea were documented. In May 1974, the patient had convulsive seizures, congestive heart failure, ascites and worsening liver function test results associated with the presence of hepatitis B antigen in her serum. She died 11 213 years after her initial presentation. Permission for postmortem examination was denied. HEMATOLOGIC

FINDINGS

Cells. The patient had a complete blood count with platelet and reticulocyte counts and 200 to 500 cell differ-

White

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entials on 171 occasions during the period 1967-1974. Review of these findings revealed certain trends. Between 1967 and 1972 the white blood cells fluctuated in a cyclic fashion, with a periodicity of approximately two to three months, between 9,000 and 98,OOO/pl. At the time of the cyclic white blood cell peaks, there were higher percentages of immature myeloid cells in the peripheral blood, with 2 to 4 per cent promyelocytes and 0 to 1 per cent blast forms. At the nadirs of the white blood cell cycles, when counts were below 25,000, no blast forms and 0 to 1 per cent promyelocytes were seen. The spleen was palpable at 1 to 2 cm below the left costal margin at the time of peak leukocytosis, but it could not be felt during the white blood cell nadirs. The percentage of basophils remained at 1 per cent or less. In April 1972, at the time of development of her coagulation disorder, the white blood cell count had risen to 88,OOO/yl with 6 per cent promyelocytes and 1 per cent myeloblasts. A bone marrow aspirate was hypercellular with 15 per cent promyelocytes and 5 per cent myeloblasts. The promyelocyte granules showed no unusual morphologic features. Over the next month (before therapy), the white blood cell count rose to 194,OOO/~l with 10 to 11 per cent promyelocytes and 1 to 4 per cent myeloblasts. A bone marrow aspirate was hypercellular with 15 per cent myeloblasts. A basophilia of 2 to 7 per cent was noted from April 1972 until her death two years later. The cycling of the white blood cells was interrupted by multiple courses of chemotherapy and irradiation during her last two years, but during a 10 month period without any therapy in 1973, the white blood cells cycled between 17,000 and 374,OOO/pl. The percentage of blast cells in the peripheral blood was approximately 16 per cent in late 1973 (at which time the bone marrow showed more than 90 per cent myeloblasts) and increased to 44 per cent during the month before her death in 1974. The Philadelphia chromosome was present in bone marrow cultures obtained in 1969 and 1970. Leukocyte alkaline phosphatase determinations were low in 1967 and 1969, but rose to well within the normal range in late 1970 and were again normal in 1972 and 1973, at times of marked leukocytosis. Erythrocytes. Rare nucleated red blood cells and mild anisocytosis and poikilocytosis with occasional ovalocytes and tear drop shaped red blood cells were noted in the peripheral blood in 1968 and 1969. The morphologic abnormalities gradually became more severe until April 1972, after which time marked anisopoikilocytosis was present, with 3 to 10 nucleated red blood cells/l00 white blood cells. The hematocrit value remained in the 30 to 35 per cent range until April 1972 when it declined to 15 to 20 per cent, where it remained (except after transfusions) during the last two years of her life, associated with a 6 to 20 per cent reticulocytosis. On several occasions, the serum bilirubin and haptoglobin levels, plasma hemoglobin and urinary hemosiderin were within normal limits. No myelofibrosis could be demonstrated on connective tissue stains of bone marrow biopsy specimens obtained in 1972 and 1973. Platelets. During 1967 to 1971, the platelet count varied between 134,000 and 480,000/& cyclic oscillations appeared to be present which were out of phase with the fluctuations in white blood cells. Significant thrombocytopenia was noted for the first time in April 1972, when the platelet

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count fell to 34,OOO/pl in association with her coagulation disorder. During the previous two years the platelet count had been in the range of 150,000 to 480,000/~1. Increased numbers of megathrombocytes were noted in the peripheral blood as early as 1969. Bone marrow biopsy specimens in 1972 and 1973 showed decreased numbers of megakaryocytes. The platelet count remained at 25,000 to 75,000/~1, except after platelet transfusions, during the last two years of her life. Coagulation Studies. When the onset of ecchymoses and severe thrombocytopenia occurred in April 1972, a coagulation profile (Table I) showed marked hypofibrinogenemia, with minimal prolongations of the prothrombin time, activated partial thromboplastin time and thrombin time. The staphylococcal clumping titer was markedly elevated, and the euglobulin lysis time (performed on a I:1 mixture of the patient’s plasma and normal plasma) was 3 hours (normal 2 to 4 hours). A cryofibrinogen could not be demonstrated. The coagulation profile was essentially unchanged when repeated on 18 occasions when she was not receiving heparin during the last two years of her life, except for a marked prolongation of the thrombin time, that was not corrected by the addition of normal plasma, on one occasion in May 1973. The fibrinogen concentration fluctuated between 34 and 175 mg/dl except on two occasions when it rose to 234 to 262 mg/dl in association with acute gouty arthritis and splenic infarction in October 1973 and in the week before her death in May 1974. The fluctuations in the fibrinogen concentration could not be correlated with variations in the platelet or white counts. The fibrinogen remained low following various courses of therapy with busulfan, vincristine and prednisone, which resulted in temporary depressions of the white blood count to normal or near normal levels and regression of splenomegaly. Effects of Heparin Therapy. Since the only clinical manifestations of the patient’s coagulation disorder were occasional recurrent ecchymoses over the lower extremities, it was initially elected to withhold any therapy directed specifically at the hypofibrinogenemia. In February 1973, when exploratory abdominal surgery for diagnosis and treatment of the pelvic mass was under consideration, a trial of heparin therapy was undertaken. Following two intravenous injections of heparin, 5,000 U (75 U/kg), separated by a 6 hour interval, the plasma fibrinogen concentration rose to normal (Table II). An initially elevated plasma fibrinopeptide A level fell to within normal limits within an hour of the first heparin injection (Table II). Two weeks later, the patient was prepared for surgery by being given intravenous injections of 5,000 U of heparin, 12 and 6 hours preoperatively. The fibrinogen concentration rose from 91 mg/dl before the administration of heparin to 147 mg/dl at the time of surgery. Twenty units of platelet concentrates were infused during the operation. The surgeons noted no excessive bleeding during resection of the large ovarian cyst. Immediately after the operation, the platelet count was 198,OOO/~l, and the fibrinogen concentration 139 mg/dl. Heparin and platelet transfusions were not given during the first six postoperative days. On day 7, a large wound hematoma was noted. The fibrinogen concentration was 131 mg/dl, thrombin time 18 seconds (control, 12 seconds), platelet count 59,000//*1, and staphylococcal clumping titer 1: 1024. Heparin therapy was resumed, the patient was given

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Coagulation Studies TABLE I ..-.-. ~~.~_ .-~- ..~~~--__~___ --_ Patient Range* Normal 1972-1974 4/11/12 Test Range ______.__~__~~_ -__11-13

13.8

12.7-I

37-41

46.9

31 .o-47

11-13

15.1

11.6->I20

[361

200-400

52

34-262

fmg/dl) Staphylococcal clumping titer


Prothrombin

time

(sac) Partial thromboplastin time (secl Thrombin time fsec) Fibrinogen

I:1024

[371

6.3 .o

1:64-1:1024

___

Range of 18 determinations when patient heparin, between April 1972 and May 1974. l

was not receiving

platelet transfusions, and the wound was opened and drained in the operating room. Twelve hours after heparin therapy was resumed, the fibrinogen level rose to 223 mg/dl. Intravenous heparin, 5,000 U every 8 hours, was given over the remaining seven weeks in the hospital, which were uncomplicated except for an episode of pneumonia. The fibrinogen level measured on nine occasions while the patient was receiving heparin was between 208 and 352 mg/dl except for one value of 156 mg/dl. No definite effect of heparin therapy on the platelet count or the staphylococcal clumping titer was apparent. Heparin therapy was discontinued at the time of discharge in April 1973, and one month later in the clinic the fibrinogen concentration was 87 mg/dl. During the two years between the discovery of the coagulation disorder and the patient’s death, the fibrinogen level was measured on 19 occasions when she was not receiving heparin (mean & 1 SE, 126 f 14 mg/dl) and 10 times when she was receiving heparin (mean, 257 f 20 mg/dl, p
TABLE

Effects of Heparin Therapy

II

Time After First Heparin Injection (hour) 0” 0.5 1 6” 12 28 * Heparin,

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Plasma Fibrinogen (mgldl)

Plasma Fibrinopeptide A WI1 (nglml) ~_______

Platelet Count (cellslpl)

87

11 .4 3.8 1 .7

46,000

I54 306 138 5,000

U given intravenously

66,&O at 0 and 6 hours.

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nopeptide A level, and prompt response of the abnormalities in fibrinogen and fibrinopeptide A concentrations to heparin therapy. At the time of discovery of the hypofibrinogenemia, there were no abnormalities in liver function; surgical removal of the ovarian cyst had no effect on the coagulation abnormalities. In the absence of other underlying causes associated with chronic intravascular coagulation, such as an aortic aneurysm, hemangioma, carcinoma, vasculitis or severe liver disease [i-4], we suspect that the defibrination syndrome in this patient was in some way related to the presence of CML. Defibrination has been reported to be a common complication of the various acute leukemias, and it is especially common in the acute promyelocytic variety [ 111. Hypofibrinogenemia appears to be an unusual complication of CML. Normal fibrinogen concentrations were found in all of 26 patients studied with CML [ 121. Fibrinogen and platelet survival times were reported to be normal or increased in six patients with CML who also had normal fibrinogen levels and platelet counts [ 131. Low fibrinogen concentrations have been recorded in four previously described patients with CML [ 14-171. In two, hypofibrinogenemia was clearly associated with blastic transformation [ 14,151, and in a third it was first noted at a time of busulfan resistance in the sixth year of illness, two weeks before the death of the patient [ 171. In the fourth patient, an eight year old child with CML, the disease was still responsive to busulfan therapy, and the patient was reported well after 14 months of follow-up, although no subsequent coagulation data were presented [ 161. In none of the reported cases was therapy with heparin attempted: in one of the patients, fibrin degradation products were measured and found to be slightly increased [ 171. Our patient survived more than two years after the appearance of the defibrination syndrome, but even at that time evidence of impending blastic transformation [ 18,191 was present, including increased percentages of myeloblasts and promyelocytes in the peripheral blood and bone marrow, basophilia, worsening anemia, decreased marrow megakaryocyte numbers, and an increase to within the normal range of a previously depressed leukocyte alkaline phosphatase level. Subsequently unequivocal evidence of myeloblastic transformation developed. Intravascular coagulation may therefore have been a harbinger of the accelerated phase of her disease, and may have been related to the increased numbers of promyelocytes in the blood, bone marrow and spleen. Increased procoagulant or “tissue factor” activity has been reported in the promyelocytes of patients with promyelocytic leukemia, and it has been postulated that tissue factor present on the promyelocyte cell membranes or released from these cells is responsible for initiating intravascular coagulation 1111.

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Subsequent to the development of the coagulation disorder, an enlarging pelvic mass was noted in our patient. Since the underlying cause for the intravascular coagulation was not established, and defibrination has been reported in association with ovarian carcinoma [20], pelvic surgery was deemed to be of both diagnostic and potentially curative value. There are no guidelines in the literature regarding the surgical management of patients with underlying intravascular coagulation. Several cases have been published in which the coagulation disorder was due to disease in the spleen (such as the presence of splenic hemangiomas), and splenectomy in the absence of heparin therapy resulted in cure of the coagulation disorder, followed by an uneventful postoperative course [21-241. In other patients with inoperable hemangiomas who were not prepared for surgery by heparinization, severe, even fatal, operative or postoperative bleeding occurred, or massive wound hematomas developed [5-10,25,26], as in our patient. Two patients have been described who received heparin in preparation for surgery [27,28]. In one an above-elbow amputation of an arm bearing a large hemangioma was successfully performed during a continuous intravenous infusion of heparin; administration of the anticoagulant was gradually discontinued postoperatively after the wound had healed [28]. In a patient with metastatic colonic carcinoma associated with defibrination, heparin was given preoperatively, omitted on the day of surgery, and resumed 24 hours later [27]. Fibrinogen levels remained normal until anticoagulation was discontinued on the fifth postoperative day. Hypofibrinogenemia recurred within 24 hours of heparin withdrawal and promptly responded to reinstitution of therapy [27]. In two other patients with multiple hemangiomas that were not resected, heparin treatment was instituted on the fifth [26] and ninth [25] postoperative days in order to control profuse bleeding from the operative site. In our patient, heparin was administered immediately prior to surgery and platelet infusions were given during the operation. A large ovarian cyst was removed without excessive operative hemorrhage. The administration of heparin was discontinued postoperatively, and platelets were withheld to determine whether resection of the ovarian tumor would cure the defibrination. A massive wound hematoma developed and therapy with these measures was resumed, enabling an uneventful second operative procedure and postoperative course. From our experience and that reported in the literature, we would suggest that patients with intravascular coagulation who require surgical procedures be managed in the following fashion: (1) Heparin therapy should be given preoperatively using a dosage shown in that patient to be adequate to reverse hypofibrinogenemia. (2) Platelet concentrates can be infused immediately

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before and during the procedure, if heparinization has not resulted in a normal platelet count. (The platelet count is slow to respond to heparin therapy in patients with defibrination [2]. In our patient, decreased platelet production was an additional cause 6f the thrombocytopenia). (3) On the basis of the limited experience in our patient and that of Merskey and colleagues [27], heparin does not need to be given during the operative procedure, unless hemostasis proves to be unsatisfactory. (4) The administration of heparin should be resumed 24 hours after the operation and continued (for at least one week) until excellent wound healing has occurred. Platelet transfusions should be given for thrombocytopenia noted during this period. (5) Daily monitoring of fibrinogen and platelet levels during the postoperative period is advisable. Two other features of our patient’s course are worthy of comment: the cyclic leukocytosis and prolonged survival. Cyclic oscillations of the white blood cell count have been well documented in certain patients with treated or untreated CML [ 29-321. Periodic increases in the numbers of immature cells in the peripheral blood and in the size of the spleen at the time of the peaks of the white blood cell cycles were noted in our patient and

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have been reported by others [32]. The relationship of these phenomena to elevations in urinary white cell colony stimulating factor levels is presently uncertain [31,32]. Our patient survived for nearly 12 years after her first presentation with marked leukocytosis. After an initial remission following busulfan administration, she did well for more than nine years without any antileukemic therapy. The average survival time in CML is in the order of three to four years [33]; however, approximately 2 per cent of patients live more than IO years after the onset of symptoms [ 341, and several well documented cases have been reported in which survival lasted from 16 to 19 years [35]. There is too little information in the literature published to date to determine whether long survival is more likely to occur in those patients with marked cyclic fluctuations in the circulating white blood cell count. ACKNOWLEDGMENT We thank Drs. Hymie L. Nossel and Harold S. Ballard for their assistance and advice. Dr. Nossel and Dr. Ian Yudelman performed the fibrinopeptide A assays.

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