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Reversible Portal Vein Thrombosis Complicating Induction Therapy of Acute Promyelocytic Leukemia
Thrombosis Research 101 (2001) 101 ± 103
LETTER TO THE EDITORS IN CHIEF
Reversible Portal Vein Thrombosis Complicating Induction Therapy of Acute Promyelocytic Leukemia
Ï olovicÂ1, P. MiljicÂ1, N. C Ï olovicÂ1, G. JankovicÂ1 and M. StojkovicÂ2 M. C 1 Institute of Hematology, Clinical Center of Serbia, Koste TodorovicÂa 2, 11000 Belgrade, Yugoslavia, and 2Institute of Digestive Diseases, Clinical Center of Serbia, Koste TodorovicÂa 6, 11000 Belgrade, Yugoslavia (Received 11 September 2000 by Editor BlombaÈck; revised/accepted 25 September 2000)
D
isseminated intravascular coagulation (DIC) and/or fibrinolysis commonly complicates the course of acute promyelocytic leukemia (APL) with massive hemorrhages as a primary cause of early mortality [1]. Thromboembolic events occasionally develop in patients with APL treated with all-transretinoic acid (ATRA) and complication of such treatment, known as ``retinoic acid syndrome'' that primarily consists of fever and respiratory distress. It has been also observed that administration of chemotherapy in patients with hyperleukocytic form of APL may be associated with the occurrence of thromboembolic complications. We have recently successfully treated two patients with APL who developed a complication of reversible portal vein thrombosis following chemotherapy and combination of ATRA and chemotherapy, respectively.
1. Case 1 A 34-year-old professional tennis coach presented with malaise, cough and fever in November 1999. On examination, a pronounced Ï olovicÂ, PhD, Institute of Corresponding author: Prof. Dr. M. C Hematology, Clinical Center of Serbia, Koste TodorovicÂa 2, 11000 Belgrade, Yugoslavia. Tel: +381 (11) 361 5564; Fax: +381 (11) 361 5564; E-mail:.
hemorrhagic syndrome with petechiae, hematomas, high pyrexia (39.3°C) and right hemophtalmus were found. Laboratory data showed hemoglobin 91 g/l, RBC 2.6 1012/l, platelets 19 109/l, MCV 93, hematocrit 23% and WBC 61 109/l with promyelocytes 97%. Bone marrow aspirate showed hypercellularity with 87% of atypical promyelocytes of hypergranular type with rare Auer rods and bilobed nuclei. On immunophenotyping, it was found positivity with CD13 and CD33, HLA-DR and negative for CD34. Cytogenetic analysis disclosed t(15;17)(q22;12) in all mitoses. A diagnosis of hyperleukocytic, hypergranular APL with typical t(15;17) was diagnosed. Biochemical analyses showed LDH 1880 u/l, normal renal and liver function tests. Coagulation tests were as follows: PT, 112%; PTT, 32.7 s; fibrinogen, 2.64 g/l; D-dimer, 1827 mg/l (normal < 375 mg/l); factor II, 96%; factor V, 144%; factor X, 89%. Chemotherapy (Adriblastine 70 mg 3 days, cytosine-arabinoside 200 mg in continuous intravenous infusion 7 days) was immediately administered with a platelet, fresh frozen plasma and antibiotic support. After termination of chemotherapy laboratory data were as follows : Hb, 67 g/l; WBC, 1.0 109/l; platelet, 15 109/l; PT, 70%; PTT, 40 s; fibrinogen, 3.25 g/l; D-dimer, 3778 mg/l. In the period of bone marrow aplasia, a septic temperature with bilateral bronchopneumonia appeared. After
0049-3848/01/$ ± see front matter D 2001 Elsevier Science Ltd. All rights reserved. PII S0049-3848(00)00371-6
102
Ï olovic et al./Thrombosis Research 101 (2001) 101± 103 M. C
10 days of treatment with antibiotics (tienam, teicoplanin, tazocin) and an antimycotic (amphotericin B) complete resolution of bronchopneumonia was achieved. On the 17th day following chemotherapy repeated upper gastro-intestinal (G-I) bleeding, melena and hematemesis accompanied by rectal bleedings that reoccurred 3 days later. Urgent panendoscopy disclosed grade III oesophageal and cardial varices from which patient bled. Partial sclerozation of bleeding sites was done. Doppler flow ultrasonography showed an 85% obstruction of the portal vein with thrombotic masses, with splenic vein dilatation and pronounced reduction in blood flow. In that phase the patient was treated with stilamin. Concentrate of antithrombin (Kybernin1, Behring, Germany) in dose of 1500/U was administered. Symptoms and laboratory data of obvious DIC were not present in the patient when diagnosis of portal vein thrombosis was established. After treatment with Kybernin control ultrasonography showed the recanalized portal vein with restored blood flow parameters. Control upper G-I endoscopy documented a complete disappearance of oesophageal varices. The patient achieved complete remission.
2. Case 2 A 35-year-old man was diagnosed with APL in April 2000. On physical examination diffuse hemorrhagic syndrome was found. Initial laboratory showed Hb 95 g/l, platelet count 18 l09/l, WBC 5.4 109/l with 55% of promyelocytes, PT 54%, PTT 41s, fibrinogen 0.1 g/l and D-dimer 2841 mg/l. The bone marrow aspirate showed hypercellularity with 84% hypergranular promyelocytes. Karyotype studies demonstrated a classic balanced translocation between chromosome 15 and 17, t(15;17)(q22;12) in all metaphases. The patient was treated with ATRA 45 mg/m2/day orally, infusions of fresh frozen plasma and kryoprecipitate. On Day 4, the patient developed bilateral pulmonary infiltrates and the number of WBC rose to 26.4 109/l, PT 98%, PTT 32 s, fibrinogen 2.8 g/l and D-dimer 2421 mg/l. ATRA therapy was discontinued, patient received steroid therapy and doxorubicin
in a total dose of 300 mg. Pulmonary symptoms worsened in the next week with increased bilateral infiltrates, dyspnea and hemoptoe. DIC was worsened with D-dimer 3097 mg/l, fibrinogen 1.82 g/l, PT 74% and PTT 38.2 s. On Day 18th, acute renal failure developed with urea 25.3 mmol/l, creatinine 525 mmol/l and acid uric 508 mmol/l. Abdominal ultrasonography showed splenomegaly (156 74 mm), enlargement of both kidneys with edema of the cortex, with thrombotic masses in portal vein. Patient was treated with LMW heparin, antibiotics, saline hyperhydration and diuretics. On this treatment general condition improved after 10 days, renal function tests became normal, on control abdominal ultrasonography confirmed complete patency of portal vein. He achieved complete remission. APL is a distinct form of acute myelogenous leukemia (AML) characterized by the balanced reciprocal translocation between chromosomes 15 and 17. It is associated with life-treating hemorrhagic syndrome [1,2]. The bleeding diathesis was suggested to be caused by DIC resulting from the release of procoagulants or enzymes from abnormal promyelocytes. Infrequently, thromboembolic events such as arterial occlusion and hepatic and portal vein thrombosis were diagnosed [2±5]. Postmortal examination show widespread thromboses in 15% to 20% of patients [2,3]. A large Italian study showed absence of any clearly beneficial role of heparin in the treatment of coagulopathy in APL (receiving platelet transfusion alone, platelet transfusion + heparin and platelet transfusions + an antifibrinolytic agent) [1]. So, we rarely use heparin in the treatment of DIC in patients with APL in our institution. By contrast, intensive platelet support seems to be a crucial element in preventing fatal bleeding accompanying chemotherapy in APL. In the GIMEMA study 2 out of 268 patients treated with chemotherapy died from thrombotic events [1]. In the MD Anderson Cancer Center study group (Houston, TX) of patients with APL, thrombotic complications following ATRA therapy were noted in 3 out of 31 newly diagnosed patients. Two of three patients died from thrombotic complications. Patients with APL treated by the same study group with chemotherapy alone resulted in only 1 thrombo-
Ï olovic et al./Thrombosis Research 101 (2001) 101± 103 M. C
tic complication out of 25 patients treated [2,5]. The implication is that ATRA might be responsible for a higher rate of thrombotic events in alltrans-retinoic treated patients. Thrombotic complications in our patients may be partly caused by platelet therapy without concomitant anticoagulation. Septic complications in the aplastic period of the disease may have contributed [6]. With modern intensive blood component therapy, the reduction in hemorrhagic complications in APL with or without ATRA treatment is expected, but as this communication shows, even in the absence of signs of DIC, thrombotic events may occur.
3.
4.
References
5.
1. Rodighiero F, Avvisati G, Castman G, Barbui T, Mandelli F. Early deaths and anti-haemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study in 268 consecutive patients. Blood 1990;11: 2112±7. 2. Escudier SM, Kantarjian HM, Estey EH.
6.
103
Thrombosis in patients with acute promyelocytic leukemia treated with and without all-trans retinoic acid. Leuk Lymphoma 1996;20(5±6): 435±9. Runde V, Aul C, Heyll A. Schneider W. Alltrans retinoic acid: not only a differentiation agent, but also an inducer of thromboembolic events in patients with M3 leukemia (Letter). Blood 1992;79:534. Assouline D, Negrier C, Coguard I, Archimbaud E, Fiere D, Bret M, Bodnar D. Successful systemic thrombolysis of hepatic vein thrombosis in a patient with promyelocytic leukemia treated with all-trans retinoic acid. Am J Hematol 1995;48(4):291±2. Kantarjian H, Keating M, Walters R, Estey E, McCredie K, Smith T, Dalton A, Trujillo J, Reireich E. Acute promyelocytic leukemia. MD Anderson hospital experience. Am J Med 1986;80:789±97. Tallman MS, Hakimian D, Kwaan HC, Rickles FR. New insights into pathogenesis of coagulation dysfunction in acute promyelocytic leukemia. Leuk Lymphoma 1993;11(1±2):27±36.
LETTER TO THE EDITORS IN CHIEF
Reversible Portal Vein Thrombosis Complicating Induction Therapy of Acute Promyelocytic Leukemia
Ï olovicÂ1, P. MiljicÂ1, N. C Ï olovicÂ1, G. JankovicÂ1 and M. StojkovicÂ2 M. C 1 Institute of Hematology, Clinical Center of Serbia, Koste TodorovicÂa 2, 11000 Belgrade, Yugoslavia, and 2Institute of Digestive Diseases, Clinical Center of Serbia, Koste TodorovicÂa 6, 11000 Belgrade, Yugoslavia (Received 11 September 2000 by Editor BlombaÈck; revised/accepted 25 September 2000)
D
isseminated intravascular coagulation (DIC) and/or fibrinolysis commonly complicates the course of acute promyelocytic leukemia (APL) with massive hemorrhages as a primary cause of early mortality [1]. Thromboembolic events occasionally develop in patients with APL treated with all-transretinoic acid (ATRA) and complication of such treatment, known as ``retinoic acid syndrome'' that primarily consists of fever and respiratory distress. It has been also observed that administration of chemotherapy in patients with hyperleukocytic form of APL may be associated with the occurrence of thromboembolic complications. We have recently successfully treated two patients with APL who developed a complication of reversible portal vein thrombosis following chemotherapy and combination of ATRA and chemotherapy, respectively.
1. Case 1 A 34-year-old professional tennis coach presented with malaise, cough and fever in November 1999. On examination, a pronounced Ï olovicÂ, PhD, Institute of Corresponding author: Prof. Dr. M. C Hematology, Clinical Center of Serbia, Koste TodorovicÂa 2, 11000 Belgrade, Yugoslavia. Tel: +381 (11) 361 5564; Fax: +381 (11) 361 5564; E-mail:
hemorrhagic syndrome with petechiae, hematomas, high pyrexia (39.3°C) and right hemophtalmus were found. Laboratory data showed hemoglobin 91 g/l, RBC 2.6 1012/l, platelets 19 109/l, MCV 93, hematocrit 23% and WBC 61 109/l with promyelocytes 97%. Bone marrow aspirate showed hypercellularity with 87% of atypical promyelocytes of hypergranular type with rare Auer rods and bilobed nuclei. On immunophenotyping, it was found positivity with CD13 and CD33, HLA-DR and negative for CD34. Cytogenetic analysis disclosed t(15;17)(q22;12) in all mitoses. A diagnosis of hyperleukocytic, hypergranular APL with typical t(15;17) was diagnosed. Biochemical analyses showed LDH 1880 u/l, normal renal and liver function tests. Coagulation tests were as follows: PT, 112%; PTT, 32.7 s; fibrinogen, 2.64 g/l; D-dimer, 1827 mg/l (normal < 375 mg/l); factor II, 96%; factor V, 144%; factor X, 89%. Chemotherapy (Adriblastine 70 mg 3 days, cytosine-arabinoside 200 mg in continuous intravenous infusion 7 days) was immediately administered with a platelet, fresh frozen plasma and antibiotic support. After termination of chemotherapy laboratory data were as follows : Hb, 67 g/l; WBC, 1.0 109/l; platelet, 15 109/l; PT, 70%; PTT, 40 s; fibrinogen, 3.25 g/l; D-dimer, 3778 mg/l. In the period of bone marrow aplasia, a septic temperature with bilateral bronchopneumonia appeared. After
0049-3848/01/$ ± see front matter D 2001 Elsevier Science Ltd. All rights reserved. PII S0049-3848(00)00371-6
102
Ï olovic et al./Thrombosis Research 101 (2001) 101± 103 M. C
10 days of treatment with antibiotics (tienam, teicoplanin, tazocin) and an antimycotic (amphotericin B) complete resolution of bronchopneumonia was achieved. On the 17th day following chemotherapy repeated upper gastro-intestinal (G-I) bleeding, melena and hematemesis accompanied by rectal bleedings that reoccurred 3 days later. Urgent panendoscopy disclosed grade III oesophageal and cardial varices from which patient bled. Partial sclerozation of bleeding sites was done. Doppler flow ultrasonography showed an 85% obstruction of the portal vein with thrombotic masses, with splenic vein dilatation and pronounced reduction in blood flow. In that phase the patient was treated with stilamin. Concentrate of antithrombin (Kybernin1, Behring, Germany) in dose of 1500/U was administered. Symptoms and laboratory data of obvious DIC were not present in the patient when diagnosis of portal vein thrombosis was established. After treatment with Kybernin control ultrasonography showed the recanalized portal vein with restored blood flow parameters. Control upper G-I endoscopy documented a complete disappearance of oesophageal varices. The patient achieved complete remission.
2. Case 2 A 35-year-old man was diagnosed with APL in April 2000. On physical examination diffuse hemorrhagic syndrome was found. Initial laboratory showed Hb 95 g/l, platelet count 18 l09/l, WBC 5.4 109/l with 55% of promyelocytes, PT 54%, PTT 41s, fibrinogen 0.1 g/l and D-dimer 2841 mg/l. The bone marrow aspirate showed hypercellularity with 84% hypergranular promyelocytes. Karyotype studies demonstrated a classic balanced translocation between chromosome 15 and 17, t(15;17)(q22;12) in all metaphases. The patient was treated with ATRA 45 mg/m2/day orally, infusions of fresh frozen plasma and kryoprecipitate. On Day 4, the patient developed bilateral pulmonary infiltrates and the number of WBC rose to 26.4 109/l, PT 98%, PTT 32 s, fibrinogen 2.8 g/l and D-dimer 2421 mg/l. ATRA therapy was discontinued, patient received steroid therapy and doxorubicin
in a total dose of 300 mg. Pulmonary symptoms worsened in the next week with increased bilateral infiltrates, dyspnea and hemoptoe. DIC was worsened with D-dimer 3097 mg/l, fibrinogen 1.82 g/l, PT 74% and PTT 38.2 s. On Day 18th, acute renal failure developed with urea 25.3 mmol/l, creatinine 525 mmol/l and acid uric 508 mmol/l. Abdominal ultrasonography showed splenomegaly (156 74 mm), enlargement of both kidneys with edema of the cortex, with thrombotic masses in portal vein. Patient was treated with LMW heparin, antibiotics, saline hyperhydration and diuretics. On this treatment general condition improved after 10 days, renal function tests became normal, on control abdominal ultrasonography confirmed complete patency of portal vein. He achieved complete remission. APL is a distinct form of acute myelogenous leukemia (AML) characterized by the balanced reciprocal translocation between chromosomes 15 and 17. It is associated with life-treating hemorrhagic syndrome [1,2]. The bleeding diathesis was suggested to be caused by DIC resulting from the release of procoagulants or enzymes from abnormal promyelocytes. Infrequently, thromboembolic events such as arterial occlusion and hepatic and portal vein thrombosis were diagnosed [2±5]. Postmortal examination show widespread thromboses in 15% to 20% of patients [2,3]. A large Italian study showed absence of any clearly beneficial role of heparin in the treatment of coagulopathy in APL (receiving platelet transfusion alone, platelet transfusion + heparin and platelet transfusions + an antifibrinolytic agent) [1]. So, we rarely use heparin in the treatment of DIC in patients with APL in our institution. By contrast, intensive platelet support seems to be a crucial element in preventing fatal bleeding accompanying chemotherapy in APL. In the GIMEMA study 2 out of 268 patients treated with chemotherapy died from thrombotic events [1]. In the MD Anderson Cancer Center study group (Houston, TX) of patients with APL, thrombotic complications following ATRA therapy were noted in 3 out of 31 newly diagnosed patients. Two of three patients died from thrombotic complications. Patients with APL treated by the same study group with chemotherapy alone resulted in only 1 thrombo-
Ï olovic et al./Thrombosis Research 101 (2001) 101± 103 M. C
tic complication out of 25 patients treated [2,5]. The implication is that ATRA might be responsible for a higher rate of thrombotic events in alltrans-retinoic treated patients. Thrombotic complications in our patients may be partly caused by platelet therapy without concomitant anticoagulation. Septic complications in the aplastic period of the disease may have contributed [6]. With modern intensive blood component therapy, the reduction in hemorrhagic complications in APL with or without ATRA treatment is expected, but as this communication shows, even in the absence of signs of DIC, thrombotic events may occur.
3.
4.
References
5.
1. Rodighiero F, Avvisati G, Castman G, Barbui T, Mandelli F. Early deaths and anti-haemorrhagic treatments in acute promyelocytic leukemia. A GIMEMA retrospective study in 268 consecutive patients. Blood 1990;11: 2112±7. 2. Escudier SM, Kantarjian HM, Estey EH.
6.
103
Thrombosis in patients with acute promyelocytic leukemia treated with and without all-trans retinoic acid. Leuk Lymphoma 1996;20(5±6): 435±9. Runde V, Aul C, Heyll A. Schneider W. Alltrans retinoic acid: not only a differentiation agent, but also an inducer of thromboembolic events in patients with M3 leukemia (Letter). Blood 1992;79:534. Assouline D, Negrier C, Coguard I, Archimbaud E, Fiere D, Bret M, Bodnar D. Successful systemic thrombolysis of hepatic vein thrombosis in a patient with promyelocytic leukemia treated with all-trans retinoic acid. Am J Hematol 1995;48(4):291±2. Kantarjian H, Keating M, Walters R, Estey E, McCredie K, Smith T, Dalton A, Trujillo J, Reireich E. Acute promyelocytic leukemia. MD Anderson hospital experience. Am J Med 1986;80:789±97. Tallman MS, Hakimian D, Kwaan HC, Rickles FR. New insights into pathogenesis of coagulation dysfunction in acute promyelocytic leukemia. Leuk Lymphoma 1993;11(1±2):27±36.