BRIEF CLINICAL OBSERVATIONS
Figure 1. Atypical plasma cells in the pleural effusion (Wright-Giemsa stain; original magnification X400, reduced by 10%).
visible on serum protein electrophoresis. Long-term follow-up of the patient was subsequently performed on an outpatient basis. Cyclophosphamide was continued orally, at a dosage ranging from 50 to 100 mg daily, until January 1, 1985. She has currently survived 11 years since the diagnosis of myeloma and four years since discontinuing her medication, and has no evidence of disease. Protein electrophoresis, immunoelectrophoresis, and immunofixation of the serum and urine have shown normal results, the most recent series of tests being in January 1989. Repeated bone marrow aspirations have revealed no evidence of multiple myeloma. The bone surveys remain unchanged, with minimal evidence of recalcification of the lytic lesion. A few patients with symptomatic multiple myeloma have survived for 10 years or longer, Kyle [4] reported that 19 (2.2%) of a series of 870 patients with overt multiple myeloma survived for longer than 10 years. In a series of 305 patients, Alexanian [5] reported 13 (4.3%) who survived longer than 10 years. Most patients with overt myeloma who survive 10 years or longer have persistent symptoms requiring chemotherapy, and only occasionally do patients with multiple myeloma become asymptomatic after they respond to chemotherapy. However, even these patients still tend to have evidence of residual myeloma after many years. Only two patients with symptomatic multiple myeloma (one with IgG
myeloma, the other with IgD myeloma) have ever been reported who showed a complete response to treatment with alkylating agents and had no evidence of multiple myeloma more than 10 years after diagnosis [6,7]. Although patients with multiple myeloma usually survive only two to three years, it is important for physicians to realize that some patients can show an impressive response to chemotherapy, resulting in long survival and even cure. However, the following problems remain to be solved before this fact becomes clinically significant: (1) Are there any characteristics common to patients in whom longterm, disease-free survival is possible with the appropriate therapy? (2) Can the prognosis of the subgroup of patients defined by these characteristics be improved by the use of aggressive treatment? HIROSHI KAMESAKI, M.D. HIROYUKI AMANO,M.D. SHI~EMI TOYODA, Ph.D. YOHICHIRO OHNO, M.D. TAKANOBU IMANAKA, M.D. YUTAKA TAKAHASHI, M.D. Tenri Hospital Mishima 200 Tenri, Nara, Japan 1. Alexanian R, Balcerzak S, Bonnet JD, et a/; Prognosticfactors In multiple myeloma. Cancer 1975: 36: 1192-1201. 2. Hughes JC, Votaw ML: Pleural effusion in multiple myeloma. Cancer 1979; 44: 1150-1154. 3. Hansen OP, Jessen B, Videbaek A: Prognosis of myelomatosis on treatment wtth prednisone and cytostatics. Stand J Haematol 1973; 10: 282-290. 4. Kyle RA: Long-term survival in multiple myeloma. N Engl J Med 1983: 308: 314-316. 5. Alexanian R: Ten-year survival in multlple myeloma. Arch Intern Med 1985; 145: 2073-2074. 6. Dutcher JP, Wiernik PH: Long-term survival of a
February
1990
patient with multiple myeloma-a cure? Cancer 1984; 53: 2069-2072. 7. Kyle RA: IgD multiple myeloma: a cure at 21 years. Am J Hematol 1988; 29: 41-43. Submitted
July 13. 1989, and accepted in revised form September 7, 1989
CHRONIC MYELOGENOUS LEUKEMIA COMPLICATED BY fJJ;;MUNE HEMOLYTIC Autoimmune hemolysis is a frequent complication of certain diseases with abnormal immunologic reactivity. Systemic lupus erythematosus and malignant lymphoproliferative disorders are the most common entities associated with autoimmune hemolysis. Autoimmune hemolytic anemia is a rare feature of chronic myelogenous leukemia and is even denied by some authors [l]. However, a few cases have been reported [2,3], and we herein report another one. The patient was a 55-year-old black man who in January 1985 sought medical attention because of heartburn after spicy foods. His white blood cell count was 109,000/ mm3 and he had an enlarged spleen. The leukocyte alkaline phosphatase score was 5 (normal, 16 to 120), and the result of a bone marrow examination was compatible with the diagnosis of chronic myelogenous leukemia. The patient was treated with busulfan intermittently. The patient was first seen in our Hematology Unit in September 1985. The white blood cell count was 85,000/mm3, and busulfan
The American
Journal
of Medicine
Volume
88
197
Figure 1. The patient’s karyotype was 47,XY,t(9;22)(q34;ql1),+22q-. All cells analyzed had two Phl chromosomes. One of the Phl chromosomes is translocated to one of the chromosomes of pair 9. The other Phl chromosome is either translocated to the same 9 or the piece of the 22 is deleted.
treatment was resumed. The patient’s condition remained stable until August 1988, when he developed progressive shortness of breath. The spleen was palpable 2 cm below the costal margin even though the white blood cell count was only 29,000/mm3. Pulmonary function tests showed a restrictive lung disease pattern, and the possibility of pulmonary fibrosis due to busulfan was considered. The drug was discontinued and the patient was admitted on August 25, 1988, for further evaluation. On that admission, the hemoglobin level decreased from 14 g/dL to 8 g/dL. The reticulocyte count increased to 10.6%, the haptoglobin level was 4 mg/dL, the total bilirubin value was 1.1 mg/dL with a direct fraction of 0.2 mgldL, and the lactic dehydrogenase level was 375 U/L. A direct Coombs’ test result was strongly positive for IgG (4+). Treatment with prednisone was begun. Respiratory symptoms improved and the hemolytic process was halted. The reticulocyte count decreased to 2.3%, the hemoglobin level stabilized around 10 g/dL, and the spleen became nonpalpable. Prednisone had to be discontinued five weeks later because of side effects. Cytogenetic studies performed at this time showed a trisomy 22 with two Philadelphia (Ph’) chromosomes (Figure 1). At the time of this report, the patient is in stable condition and
he is being treated with 6-mercaptopurine. The respiratory status is almost back to baseline, the hemoglobin level is stable around 14 g/ dL, the reticulocyte count is 0.5%, and the total bilirubin value is 0.4 mg/dL. The result of a direct Coombs’ test remains positive for IgG (3+). We have presented a typical case of chronic myelogenous leukemia. The association of this type of leukemia with autoimmune hemolysis is very unusual. Maldonado et al [2] reported a similar case. Their patient had unusual sensitivity to busulfan (gastrointestinal symptoms after the drug was taken) and they mentioned that fact as a possible initiating factor. Videbaek [3] reported two other cases in which the hemolytic process was associated with moderately and weakly positive Coombs’ test results. Although red blood cell survival might be slightly decreased in chronic myelogenous leukemia, usually in the presence of splenomegaly, the Coombs’ test does not give positive results [4,5]. All three aforementioned patients and our own patient responded to prednisone as treatment for their hemolytic process. It is important to point out that the first three patients died shortly after the diagnosis of the hemolytic event, either because of blast crisis (one patient) or secondary to infections. This suggests that the occurrence of
198
of Medicine
February
1990 The American
Journal
Volume
88
autoimmune hemolytic anemia in a patient with chronic myelogenous leukemia is a poor prognostic sign. Our patient, though, is still alive and in clinically stable condition 10 months after the diagnosis. However, the presence of a double Ph’ chromosome is considered a poor prognostic finding [6]. Also, we would like to point out that in the cases previously reported and in our case, prednisone seemed to stop the hemolytic process. In the two cases reported by Videbaek [3], results of Coombs’ tests, which were moderately and weakly positive initially, became negative. In the case reported by Maldonado et al [2] and in our patient, the finding on Coombs’ testing remained positive. It is difficult to make any final conclusion from a single case, but it is our intention to increase the awareness that autoimmune hemolytic anemia may complicate cases of Ph’ chromosome-positive chronic myelogenous leukemia. A decrease in the hemoglobin level in such patients should be investigated with that fact in mind. YAMILM. ARBAJE,M.D. GERMANBELTRAN,M.D. Tulane
University
New Orleans,
School of Medicine Louisiana
ACKNOWLEDGMENT We thank Emmanuel Shapira. M.D., and Maria Varela, M.D.. for the cytogenetics studies.
BRIEF CLINICAL OBSERVATIONS 1. Rundles RW: Chronic myelogenous leukemia. In: Williams WJ, et al. Hematology, 3rd ed. New York: McGraw-Hill, 1983; 200-201. 2. Maldonado N, Haddock J, Perez-Santiago E: Autoimmune hemolytic anemia in chronic granulocytic leukemia. Blood 1967; 30: 518-521. 3.Videbaek A: Auto-immune hemolytic anemia in some malignant systemic diseases. Acta Med Stand 1962; 171: 463-476. 4. Cline M, Berlin N: Patterns of anemia in chronic myelocytic leukemia. Cancer 1963; 16: 624-632. 5. Pengelly CDR. Wilkinson JF: The frequency and mechanism of haemolysis in the leukaemias. reticuloses and myeloproliferative diseases. Br J Haematol 1962; 8: 343-357. 6. Rowley JD. Testa JR: Chromosome abnormalities in malignant hematologic diseases. Adv Cancer Res 1982; 36: 103-148. Submitted
August 3, 1989, and accepted in revised form September 7, 1989
(NOTE: This work was supported kins Leukemia Fund.)
in part by the Per-
DEFICIENT TISSUE PLASMINOGEN ACTIVATOR RELEASE AND NORMAL TISSUE PLASMINOGEN ACTIVATOR INHIBITOR IN A PATIENT WITH RECURRENT DEEP VEIN THROMBOSIS Venous thrombosis may be caused by several interacting factors, such as stasis of the blood, hypercoagulability, or deficient fibrinolysis [l]. Recent studies in patients with idiopathic deep venous thrombosis have shown that deficient fibrinolysis is increasingly diagnosed as the underlying mechanism for the propensity for the development of abnormal thrombosis [2]. In principle, defective fibrinolysis might be due to (1) a decreased synthesis of vessel wall tissue plasminogen activator (t-PA) or defective release of activators, or both; or (2) inactivation of t-PA by inhibitors. In this report, we describe a patient who presented with recurrent spontaneous deep vein thrombosis and no known organic disorders commonly associated with hypercoagulability. Laboratory determinations of the fibrinolytic response demonstrated low values for both t-PA activity and t-PA antigen concentration, and normal concentrations of t-PA inhibitor (t-PAD. A 21-year-old black man presented with a five-day history of fever, right lower extremity pain, and edema. His medical history was significant for three previous hospitalizations since age 17 for recurrent episodes of deep femoral system venous thrombosis complicated on one occasion by the onset of pul-
monary embolus. He had no family history of thrombotic disorders and no known risk factors associated with a hypercoagulable state. Extensive search to demonstrate an underlying malignancy was undertaken twice with negative results. Computed tomography of the abdomen revealed complete occlusion of the inferior vena cava and iliac veins with development of collateral circulation in the superficial venous system of the pelvis and abdomen. During his most recent hospitalization in February 1989, he was initially treated with sodium heparin in a continuous infusion at an average dose of 1,400 units/hour for 10 days, and long-term oral anticoagulation with warfarin at 7.5 mg/day was resumed. In addition, a therapeutic trial with stano~0101, 12 mglday, was begun in an attempt to enhance plasminogen activator release [3]; however, the patient was lost to follow-up for several months and exhibited poor compliance with his prescribed medications. On admission, the hemoglobin level was 10.7 g/dL, the hematocrit was 34 volume %, the white blood cell count was 6,500/ PL (69 polymorphonuclear leukocytes, two bands, 26 lymphocytes, three monocytes), and the platelet count was 36O,OOO/pL. Blood from the antecubital vein was collected into O.l-volume trisodium citrate (final concentration 0.01 mL), after a 12-hour fast. For the coagulation and fibrinolytic studies, the heparin infusion was temporarily discontinued and the titrated blood was immediately cooled on ice. Platelet-poor plasma obtained by centrifugation at 4°C for 15 minutes at 3,000 G was quick-frozen in aliquots and stored at -7O”C, until
used. The venous occlusion test was carried out with a sphygmomanometer pressure at the midpoint between systolic and diastolic blood pressure for 20 minutes [4]. Blood samples were obtained before and at the end of venous occlusion from the occluded arm. All assays were performed in duplicate and the results are shown in Table I. A distinct abnormality was noted in the expected enhancement of the t-PA activity and antigen after 20 minutes of venous occlusion; in addition, the t-PA1 activity was determined not to be increased and similar to that measured in normal individuals. Various abnormalities of the blood coagulation and fibrinolytic system have been identified in persons with thromboembolic disease. Since the initial reports of subjects with congenital deficiencies of antithrombin-III, protein C, or protein S, a significant number of families with these disorders have been described. Dysfunctional molecules of antithrombin-III, fibrinogen, and protein C have also been reported as predisposing to venous or arterial thrombosis [5]. Disturbances in the fibrinolytic system are also considered to play an important role in the development of thromboembolic diseases. Thus, increased fibrinolysis inhibition or decreased vein wall fibrinolysis activity has been found in patients with venous thrombosis [l]. This system is activated by various agents, an important one being the t-PA localized to the vessel wall where it is synthesized and stored. The activator is continuously released from the endothelial cells into the bloodstream and its baseline concentration is now measured
TABLE I Coagulation Assay and Effect of Venous Occlusion (VO) on Fibrinolytic Parameters Patient Before VO After Vd Prothrombin time (seconds) Activated partial thromboplastin time (seconds) Antithrombin-Ill activity (%) Protein C activity (%) Protein C antigen (U/mL) Protein S antigen (U/mL) Plasminogen activity(%) t-PA activity (IU/mL) t-PA antigen (ng/mL) t-PA inhibitor activity (IU/mL)
12.8 30.3 113 130 1.23 1.12 113 0.07 3.7 2.3
0:9 4.2
Control Subjects (n = 18) Before VO After VO (range) 10.5-13.0 29.1-38.6
-
82-115 61-132 0.67-1.40 0.67-1.25 80-120 0.02-0.09 1.3-8.5 0.4-3.0
x 0.33-0.73 3.5-25 -
-PA = tissue plasminogen activator.
February
1990
The American
Journal
qf Medicine
Volume
88
199
Figure 1. Atypical plasma cells in the pleural effusion (Wright-Giemsa stain; original magnification X400, reduced by 10%).
visible on serum protein electrophoresis. Long-term follow-up of the patient was subsequently performed on an outpatient basis. Cyclophosphamide was continued orally, at a dosage ranging from 50 to 100 mg daily, until January 1, 1985. She has currently survived 11 years since the diagnosis of myeloma and four years since discontinuing her medication, and has no evidence of disease. Protein electrophoresis, immunoelectrophoresis, and immunofixation of the serum and urine have shown normal results, the most recent series of tests being in January 1989. Repeated bone marrow aspirations have revealed no evidence of multiple myeloma. The bone surveys remain unchanged, with minimal evidence of recalcification of the lytic lesion. A few patients with symptomatic multiple myeloma have survived for 10 years or longer, Kyle [4] reported that 19 (2.2%) of a series of 870 patients with overt multiple myeloma survived for longer than 10 years. In a series of 305 patients, Alexanian [5] reported 13 (4.3%) who survived longer than 10 years. Most patients with overt myeloma who survive 10 years or longer have persistent symptoms requiring chemotherapy, and only occasionally do patients with multiple myeloma become asymptomatic after they respond to chemotherapy. However, even these patients still tend to have evidence of residual myeloma after many years. Only two patients with symptomatic multiple myeloma (one with IgG
myeloma, the other with IgD myeloma) have ever been reported who showed a complete response to treatment with alkylating agents and had no evidence of multiple myeloma more than 10 years after diagnosis [6,7]. Although patients with multiple myeloma usually survive only two to three years, it is important for physicians to realize that some patients can show an impressive response to chemotherapy, resulting in long survival and even cure. However, the following problems remain to be solved before this fact becomes clinically significant: (1) Are there any characteristics common to patients in whom longterm, disease-free survival is possible with the appropriate therapy? (2) Can the prognosis of the subgroup of patients defined by these characteristics be improved by the use of aggressive treatment? HIROSHI KAMESAKI, M.D. HIROYUKI AMANO,M.D. SHI~EMI TOYODA, Ph.D. YOHICHIRO OHNO, M.D. TAKANOBU IMANAKA, M.D. YUTAKA TAKAHASHI, M.D. Tenri Hospital Mishima 200 Tenri, Nara, Japan 1. Alexanian R, Balcerzak S, Bonnet JD, et a/; Prognosticfactors In multiple myeloma. Cancer 1975: 36: 1192-1201. 2. Hughes JC, Votaw ML: Pleural effusion in multiple myeloma. Cancer 1979; 44: 1150-1154. 3. Hansen OP, Jessen B, Videbaek A: Prognosis of myelomatosis on treatment wtth prednisone and cytostatics. Stand J Haematol 1973; 10: 282-290. 4. Kyle RA: Long-term survival in multiple myeloma. N Engl J Med 1983: 308: 314-316. 5. Alexanian R: Ten-year survival in multlple myeloma. Arch Intern Med 1985; 145: 2073-2074. 6. Dutcher JP, Wiernik PH: Long-term survival of a
February
1990
patient with multiple myeloma-a cure? Cancer 1984; 53: 2069-2072. 7. Kyle RA: IgD multiple myeloma: a cure at 21 years. Am J Hematol 1988; 29: 41-43. Submitted
July 13. 1989, and accepted in revised form September 7, 1989
CHRONIC MYELOGENOUS LEUKEMIA COMPLICATED BY fJJ;;MUNE HEMOLYTIC Autoimmune hemolysis is a frequent complication of certain diseases with abnormal immunologic reactivity. Systemic lupus erythematosus and malignant lymphoproliferative disorders are the most common entities associated with autoimmune hemolysis. Autoimmune hemolytic anemia is a rare feature of chronic myelogenous leukemia and is even denied by some authors [l]. However, a few cases have been reported [2,3], and we herein report another one. The patient was a 55-year-old black man who in January 1985 sought medical attention because of heartburn after spicy foods. His white blood cell count was 109,000/ mm3 and he had an enlarged spleen. The leukocyte alkaline phosphatase score was 5 (normal, 16 to 120), and the result of a bone marrow examination was compatible with the diagnosis of chronic myelogenous leukemia. The patient was treated with busulfan intermittently. The patient was first seen in our Hematology Unit in September 1985. The white blood cell count was 85,000/mm3, and busulfan
The American
Journal
of Medicine
Volume
88
197
Figure 1. The patient’s karyotype was 47,XY,t(9;22)(q34;ql1),+22q-. All cells analyzed had two Phl chromosomes. One of the Phl chromosomes is translocated to one of the chromosomes of pair 9. The other Phl chromosome is either translocated to the same 9 or the piece of the 22 is deleted.
treatment was resumed. The patient’s condition remained stable until August 1988, when he developed progressive shortness of breath. The spleen was palpable 2 cm below the costal margin even though the white blood cell count was only 29,000/mm3. Pulmonary function tests showed a restrictive lung disease pattern, and the possibility of pulmonary fibrosis due to busulfan was considered. The drug was discontinued and the patient was admitted on August 25, 1988, for further evaluation. On that admission, the hemoglobin level decreased from 14 g/dL to 8 g/dL. The reticulocyte count increased to 10.6%, the haptoglobin level was 4 mg/dL, the total bilirubin value was 1.1 mg/dL with a direct fraction of 0.2 mgldL, and the lactic dehydrogenase level was 375 U/L. A direct Coombs’ test result was strongly positive for IgG (4+). Treatment with prednisone was begun. Respiratory symptoms improved and the hemolytic process was halted. The reticulocyte count decreased to 2.3%, the hemoglobin level stabilized around 10 g/dL, and the spleen became nonpalpable. Prednisone had to be discontinued five weeks later because of side effects. Cytogenetic studies performed at this time showed a trisomy 22 with two Philadelphia (Ph’) chromosomes (Figure 1). At the time of this report, the patient is in stable condition and
he is being treated with 6-mercaptopurine. The respiratory status is almost back to baseline, the hemoglobin level is stable around 14 g/ dL, the reticulocyte count is 0.5%, and the total bilirubin value is 0.4 mg/dL. The result of a direct Coombs’ test remains positive for IgG (3+). We have presented a typical case of chronic myelogenous leukemia. The association of this type of leukemia with autoimmune hemolysis is very unusual. Maldonado et al [2] reported a similar case. Their patient had unusual sensitivity to busulfan (gastrointestinal symptoms after the drug was taken) and they mentioned that fact as a possible initiating factor. Videbaek [3] reported two other cases in which the hemolytic process was associated with moderately and weakly positive Coombs’ test results. Although red blood cell survival might be slightly decreased in chronic myelogenous leukemia, usually in the presence of splenomegaly, the Coombs’ test does not give positive results [4,5]. All three aforementioned patients and our own patient responded to prednisone as treatment for their hemolytic process. It is important to point out that the first three patients died shortly after the diagnosis of the hemolytic event, either because of blast crisis (one patient) or secondary to infections. This suggests that the occurrence of
198
of Medicine
February
1990 The American
Journal
Volume
88
autoimmune hemolytic anemia in a patient with chronic myelogenous leukemia is a poor prognostic sign. Our patient, though, is still alive and in clinically stable condition 10 months after the diagnosis. However, the presence of a double Ph’ chromosome is considered a poor prognostic finding [6]. Also, we would like to point out that in the cases previously reported and in our case, prednisone seemed to stop the hemolytic process. In the two cases reported by Videbaek [3], results of Coombs’ tests, which were moderately and weakly positive initially, became negative. In the case reported by Maldonado et al [2] and in our patient, the finding on Coombs’ testing remained positive. It is difficult to make any final conclusion from a single case, but it is our intention to increase the awareness that autoimmune hemolytic anemia may complicate cases of Ph’ chromosome-positive chronic myelogenous leukemia. A decrease in the hemoglobin level in such patients should be investigated with that fact in mind. YAMILM. ARBAJE,M.D. GERMANBELTRAN,M.D. Tulane
University
New Orleans,
School of Medicine Louisiana
ACKNOWLEDGMENT We thank Emmanuel Shapira. M.D., and Maria Varela, M.D.. for the cytogenetics studies.
BRIEF CLINICAL OBSERVATIONS 1. Rundles RW: Chronic myelogenous leukemia. In: Williams WJ, et al. Hematology, 3rd ed. New York: McGraw-Hill, 1983; 200-201. 2. Maldonado N, Haddock J, Perez-Santiago E: Autoimmune hemolytic anemia in chronic granulocytic leukemia. Blood 1967; 30: 518-521. 3.Videbaek A: Auto-immune hemolytic anemia in some malignant systemic diseases. Acta Med Stand 1962; 171: 463-476. 4. Cline M, Berlin N: Patterns of anemia in chronic myelocytic leukemia. Cancer 1963; 16: 624-632. 5. Pengelly CDR. Wilkinson JF: The frequency and mechanism of haemolysis in the leukaemias. reticuloses and myeloproliferative diseases. Br J Haematol 1962; 8: 343-357. 6. Rowley JD. Testa JR: Chromosome abnormalities in malignant hematologic diseases. Adv Cancer Res 1982; 36: 103-148. Submitted
August 3, 1989, and accepted in revised form September 7, 1989
(NOTE: This work was supported kins Leukemia Fund.)
in part by the Per-
DEFICIENT TISSUE PLASMINOGEN ACTIVATOR RELEASE AND NORMAL TISSUE PLASMINOGEN ACTIVATOR INHIBITOR IN A PATIENT WITH RECURRENT DEEP VEIN THROMBOSIS Venous thrombosis may be caused by several interacting factors, such as stasis of the blood, hypercoagulability, or deficient fibrinolysis [l]. Recent studies in patients with idiopathic deep venous thrombosis have shown that deficient fibrinolysis is increasingly diagnosed as the underlying mechanism for the propensity for the development of abnormal thrombosis [2]. In principle, defective fibrinolysis might be due to (1) a decreased synthesis of vessel wall tissue plasminogen activator (t-PA) or defective release of activators, or both; or (2) inactivation of t-PA by inhibitors. In this report, we describe a patient who presented with recurrent spontaneous deep vein thrombosis and no known organic disorders commonly associated with hypercoagulability. Laboratory determinations of the fibrinolytic response demonstrated low values for both t-PA activity and t-PA antigen concentration, and normal concentrations of t-PA inhibitor (t-PAD. A 21-year-old black man presented with a five-day history of fever, right lower extremity pain, and edema. His medical history was significant for three previous hospitalizations since age 17 for recurrent episodes of deep femoral system venous thrombosis complicated on one occasion by the onset of pul-
monary embolus. He had no family history of thrombotic disorders and no known risk factors associated with a hypercoagulable state. Extensive search to demonstrate an underlying malignancy was undertaken twice with negative results. Computed tomography of the abdomen revealed complete occlusion of the inferior vena cava and iliac veins with development of collateral circulation in the superficial venous system of the pelvis and abdomen. During his most recent hospitalization in February 1989, he was initially treated with sodium heparin in a continuous infusion at an average dose of 1,400 units/hour for 10 days, and long-term oral anticoagulation with warfarin at 7.5 mg/day was resumed. In addition, a therapeutic trial with stano~0101, 12 mglday, was begun in an attempt to enhance plasminogen activator release [3]; however, the patient was lost to follow-up for several months and exhibited poor compliance with his prescribed medications. On admission, the hemoglobin level was 10.7 g/dL, the hematocrit was 34 volume %, the white blood cell count was 6,500/ PL (69 polymorphonuclear leukocytes, two bands, 26 lymphocytes, three monocytes), and the platelet count was 36O,OOO/pL. Blood from the antecubital vein was collected into O.l-volume trisodium citrate (final concentration 0.01 mL), after a 12-hour fast. For the coagulation and fibrinolytic studies, the heparin infusion was temporarily discontinued and the titrated blood was immediately cooled on ice. Platelet-poor plasma obtained by centrifugation at 4°C for 15 minutes at 3,000 G was quick-frozen in aliquots and stored at -7O”C, until
used. The venous occlusion test was carried out with a sphygmomanometer pressure at the midpoint between systolic and diastolic blood pressure for 20 minutes [4]. Blood samples were obtained before and at the end of venous occlusion from the occluded arm. All assays were performed in duplicate and the results are shown in Table I. A distinct abnormality was noted in the expected enhancement of the t-PA activity and antigen after 20 minutes of venous occlusion; in addition, the t-PA1 activity was determined not to be increased and similar to that measured in normal individuals. Various abnormalities of the blood coagulation and fibrinolytic system have been identified in persons with thromboembolic disease. Since the initial reports of subjects with congenital deficiencies of antithrombin-III, protein C, or protein S, a significant number of families with these disorders have been described. Dysfunctional molecules of antithrombin-III, fibrinogen, and protein C have also been reported as predisposing to venous or arterial thrombosis [5]. Disturbances in the fibrinolytic system are also considered to play an important role in the development of thromboembolic diseases. Thus, increased fibrinolysis inhibition or decreased vein wall fibrinolysis activity has been found in patients with venous thrombosis [l]. This system is activated by various agents, an important one being the t-PA localized to the vessel wall where it is synthesized and stored. The activator is continuously released from the endothelial cells into the bloodstream and its baseline concentration is now measured
TABLE I Coagulation Assay and Effect of Venous Occlusion (VO) on Fibrinolytic Parameters Patient Before VO After Vd Prothrombin time (seconds) Activated partial thromboplastin time (seconds) Antithrombin-Ill activity (%) Protein C activity (%) Protein C antigen (U/mL) Protein S antigen (U/mL) Plasminogen activity(%) t-PA activity (IU/mL) t-PA antigen (ng/mL) t-PA inhibitor activity (IU/mL)
12.8 30.3 113 130 1.23 1.12 113 0.07 3.7 2.3
0:9 4.2
Control Subjects (n = 18) Before VO After VO (range) 10.5-13.0 29.1-38.6
-
82-115 61-132 0.67-1.40 0.67-1.25 80-120 0.02-0.09 1.3-8.5 0.4-3.0
x 0.33-0.73 3.5-25 -
-PA = tissue plasminogen activator.
February
1990
The American
Journal
qf Medicine
Volume
88
199
