Original Papers © 1991 S. Karger AG, Basel 0301-0147/91 /0212-006 5$2.75/0
Haemostasis 1991;21:65-67
Antithrombin III Activity Is Not Related to Plasma Homocysteine Concentrations T. Bienvenua, B. Chadefauxa, A. Ankrib, V. Leblondb, M. Coude*, B. Salehianb, J.L. Binetb, P. Kamoun a 3 Laboratoire de Biochimie Génétique, Hôpital Necker-Enfants-Malades, et bDépartement d’Hématologie, Hôpital de la Salpêtrière, Paris. France
Key Words. Thrombosis • Antithrombin III • Homocysteine • Bone marrow transplantation
Arterial and venous thromboembolic events represent frequent and life-threaten ing complications in homocystinuric pa tients and are responsible for their early deaths [1]. Palaretti and Coccheri [2] have recently reported reduced levels of anti thrombin III activity in homocystinuric pa tients. During pyridoxine and folate treat ment, antithrombin III activity rapidly re turned to normal. So, high plasma L-homocysteine concentration could play a role in
the low antithrombin III activity level. Bone marrow transplantation (BMT) is associated with a decrease of vitamin B,2 absorption and folic acid deficiency [3, 4], Deficiencies in vitamin B12, folic acid may result in vary ing degrees of homocysteinemia. So, we have studied the relationship between total plasma L-homocysteine concentrations and inhibitors of blood coagulation levels in 16 patients with malignancies, who received al logeneic or autologous bone marrow grafts.
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Abstract. Arterial and venous thromboembolic events represent frequent and life-threat ening complications in homocystinuric patients and are responsible for their early deaths. Reduced levels of antithrombin III activity in homocystinuric patients have recently been reported. So, high plasma L-homocysteine concentration could play a role in the low anti thrombin III activity level. In the present study, we have studied the relationship between total plasma homocysteine and inhibitors of blood coagulation levels in 16 patients with malignancies who received bone marrow grafts. There were no correlations between homo cysteine values and inhibitors of blood coagulation levels. So, while the defect in amino acid transsulfuration that is responsible for homocystinuria can directly affect the synthesis or activity of some clotting factors, homocysteine concentration is not responsible for this effect.
Bienvenu/Chadefaux/Ankri/Leblond/Coude/Salehian/Binet/Kamoun
66
Patients
Diagnosis
Day after graft
1 REN. 2 LEN. 3 DEL.
Myeloma AML AML
4 REZ. 5 KOU. 6 DOR.
Myeloma Myeloma ALL
7 SAN.
CML
8 PAS. 9 DER.
CML CML
0 0 6 39 50 56 68 20 21 22 77 89 22 29 39 50 68 94 135 106 210 117 270 300 180 200 426 438 450 510 540 497 540 570 750
10 JOL.
CML
11 KAR.
AML
12 GRE.
AML
13 FOR.
CML
14 JAQ.
CML/AML
15 VAU.
CML
16 LEG.
CML
Antithrombin III/homocysteine Protein C/homocysteine Protein S/homocysteine
ND
Hey pmol/1 6.8 6.2 49.2 17.8 22.3 16.7 11.9 11.9 87.7 37.1 22.5 30.4 31.9 25.9 97.3 161.9 13.4 18.3 10.8 5.2 9.8 6.3 8.1 6.2 9.0 7.8 16.9 19.7 16.1 12.8 18.6 8.9 7.2 7.2 8.6
ATI 11 %
Prot. C %
Prot. S %
88 90 109 114 150 131 121 89 121 101 160 115 150 150 ND 114 163 116 130 113 86 123 100 95 116 140 134 112 110 124 126 101 106 111 105
86 85 78 104 180 154 123 69 74 79 180 175 80 83 ND 95 135 136 166 90 92 86 62 85 158 150 144 165 91 99 101 107 110 108 119
110 91 105 100 120 140 110 110 145 91 160 120 100 110 ND 85 120 145 120 100 160 110 110 150 150 160 140 130 98 110 200 70 80 82 110
r = 0.075 r = -0.154 r = -0.114
NS NS NS
y = 0.052x+116.9 y = -0 .1 7 8 x + 120.5 y - -0.1 lOx+121.3
ALL = Acute lymphoblastic leukemia; AML = acute myeloid leukemia; CML = chronic myeloid leukemia; = not done; NS = not significant.
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Table 1. Plasma total L-homocysteine concentration, protein C and antithrombin III activity and protein S antigen in 16 patients with malignancies who received allogeneic or autologous grafts at different times after transplantation, and correlation and linear regression equation between total homocysteine and inhibitors of coagulation plasma concentrations
Antithrombin III Activity and Homocysteinemia
References 1 Mudd, S.H.; Skovby, F.; Levy, H.L.; Pettigrew, K.D.; Wilcken, B.; Pyeritz, R.E.; Andria, G.; Boers, G.H.J.; Bromberg, I.L.; Cerone, R.; Fowler, B.; Grobe, H.; Schmidt, H.; Schweitzer, L.: The natural history of homocystinuria due to cysta thionine B-synthase deficiency. Am. J. hum. Ge net. 37: 1-31 (1985). 2 Palaretti, G.; Coccheri, S.: Lowered antithrombin III activity and other clothing changes in homo cystinuria: effects of a pyridoxine folate regimen. Haemostasis 19: suppl. 1, pp. 24-28 (1989). 3 Milligan, D.W.; Quick, A.; Barnard, D.L.: Vita min Bi 2 absorption after allogeneic bone marrow transplantation. J. clin. Pathol. 40: 1472-1474 (1987). 4 Link, H.; Blaurock, M.; Wernet, P.; Niethammer, D.; Wilms, K.; Ostendorf, P.: Acute folic acid defi ciency after bone marrow transplantation. Klin. Wschr. 64: 423-432 (1986). 5 Storb, R.; Deeg, H.J.; Whitehead, J.; Appelbaum, F. ; Beatty, P.; Bensinger, W.; Buckner, D.; Clift, R.; Doney, K.; Farewell, V.; Hansen, J.; Hill, R.; Lum, L.; Martin, P.; Me Guffin, R.; Sanders, J.; Stewart, P.; Sullivan, K.; Witherspoon, R.; Yee, G. ; Donnall Thomas, E.: Methotrexate and cyclo sporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. New Engl. J. Med. 314: 729-735 (1986). 6 Chadefaux, B.; Coude, M.; Hamet, M.; Bienvenu, T.; Fraigne, P.; Aupetit, J.; Kamoun, P.: Dosage radioisotopique de la ¿-homocystéine totale dans le plasma et l’urine: application à des dosages en séries. Annls Biol. Clin. 48: 33-36 (1990). Received: July 20, 1990 Accepted: August 29, 1990 by Prof. Tobelem T. Bienvenu Laboratoire de Biochimie Génétique Hôpital Necker-Enfants-Malades F-75743 Paris (France)
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The age of the recipients ranged from 24 to 59 years (median 37.5 years). CCNU, VP 16, melphalan and total body irradiation (TBI) was given to 6 patients with acute myeloid leukemia or acute lymphoblastic leukemia, CCNU, VP 16, cyclophosphamide, mel phalan and TBI to 3 with myeloma, and cyclophosphamide and TBI to 7 patients with chronic myeloid leukemia. To prevent acute graft-versus-host disease, all patients received ciclosporin from day 1 before BMT to day 180 after BMT and a short course of methotrexate [5], Total plasma ¿-homocys teine concentrations were determined by a radioisotopic assay [6]. Antithrombin III and protein C plasma concentrations were determined by a chromogenic assay with an automatic device (Chromotimer, Behring) using commercial reagents (Behring). Pro tein S antigen was determined by electroim munodiffusion using a commercial reagent (Assera-plate protein S. Diagnostica Stago). Results of the natural anticoagulants were expressed as a percentage of a mixed adult normal serum pool. The following normal ranges were estab lished for these assays: protein C (70-120%), protein S (70-120%), antithrombin III (70120%). The results are reported in table 1. There was no correlation between ¿-ho mocysteine concentrations and inhibitors of blood coagulation levels. So, if the defect in amino acid transsulfuration that is responsi ble for homocystinuria can directly affect the synthesis or activity of some clotting factors, homocysteine concentration is not responsi ble for this effect.
67
Haemostasis 1991;21:65-67
Antithrombin III Activity Is Not Related to Plasma Homocysteine Concentrations T. Bienvenua, B. Chadefauxa, A. Ankrib, V. Leblondb, M. Coude*, B. Salehianb, J.L. Binetb, P. Kamoun a 3 Laboratoire de Biochimie Génétique, Hôpital Necker-Enfants-Malades, et bDépartement d’Hématologie, Hôpital de la Salpêtrière, Paris. France
Key Words. Thrombosis • Antithrombin III • Homocysteine • Bone marrow transplantation
Arterial and venous thromboembolic events represent frequent and life-threaten ing complications in homocystinuric pa tients and are responsible for their early deaths [1]. Palaretti and Coccheri [2] have recently reported reduced levels of anti thrombin III activity in homocystinuric pa tients. During pyridoxine and folate treat ment, antithrombin III activity rapidly re turned to normal. So, high plasma L-homocysteine concentration could play a role in
the low antithrombin III activity level. Bone marrow transplantation (BMT) is associated with a decrease of vitamin B,2 absorption and folic acid deficiency [3, 4], Deficiencies in vitamin B12, folic acid may result in vary ing degrees of homocysteinemia. So, we have studied the relationship between total plasma L-homocysteine concentrations and inhibitors of blood coagulation levels in 16 patients with malignancies, who received al logeneic or autologous bone marrow grafts.
Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 1:04:01 AM
Abstract. Arterial and venous thromboembolic events represent frequent and life-threat ening complications in homocystinuric patients and are responsible for their early deaths. Reduced levels of antithrombin III activity in homocystinuric patients have recently been reported. So, high plasma L-homocysteine concentration could play a role in the low anti thrombin III activity level. In the present study, we have studied the relationship between total plasma homocysteine and inhibitors of blood coagulation levels in 16 patients with malignancies who received bone marrow grafts. There were no correlations between homo cysteine values and inhibitors of blood coagulation levels. So, while the defect in amino acid transsulfuration that is responsible for homocystinuria can directly affect the synthesis or activity of some clotting factors, homocysteine concentration is not responsible for this effect.
Bienvenu/Chadefaux/Ankri/Leblond/Coude/Salehian/Binet/Kamoun
66
Patients
Diagnosis
Day after graft
1 REN. 2 LEN. 3 DEL.
Myeloma AML AML
4 REZ. 5 KOU. 6 DOR.
Myeloma Myeloma ALL
7 SAN.
CML
8 PAS. 9 DER.
CML CML
0 0 6 39 50 56 68 20 21 22 77 89 22 29 39 50 68 94 135 106 210 117 270 300 180 200 426 438 450 510 540 497 540 570 750
10 JOL.
CML
11 KAR.
AML
12 GRE.
AML
13 FOR.
CML
14 JAQ.
CML/AML
15 VAU.
CML
16 LEG.
CML
Antithrombin III/homocysteine Protein C/homocysteine Protein S/homocysteine
ND
Hey pmol/1 6.8 6.2 49.2 17.8 22.3 16.7 11.9 11.9 87.7 37.1 22.5 30.4 31.9 25.9 97.3 161.9 13.4 18.3 10.8 5.2 9.8 6.3 8.1 6.2 9.0 7.8 16.9 19.7 16.1 12.8 18.6 8.9 7.2 7.2 8.6
ATI 11 %
Prot. C %
Prot. S %
88 90 109 114 150 131 121 89 121 101 160 115 150 150 ND 114 163 116 130 113 86 123 100 95 116 140 134 112 110 124 126 101 106 111 105
86 85 78 104 180 154 123 69 74 79 180 175 80 83 ND 95 135 136 166 90 92 86 62 85 158 150 144 165 91 99 101 107 110 108 119
110 91 105 100 120 140 110 110 145 91 160 120 100 110 ND 85 120 145 120 100 160 110 110 150 150 160 140 130 98 110 200 70 80 82 110
r = 0.075 r = -0.154 r = -0.114
NS NS NS
y = 0.052x+116.9 y = -0 .1 7 8 x + 120.5 y - -0.1 lOx+121.3
ALL = Acute lymphoblastic leukemia; AML = acute myeloid leukemia; CML = chronic myeloid leukemia; = not done; NS = not significant.
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Table 1. Plasma total L-homocysteine concentration, protein C and antithrombin III activity and protein S antigen in 16 patients with malignancies who received allogeneic or autologous grafts at different times after transplantation, and correlation and linear regression equation between total homocysteine and inhibitors of coagulation plasma concentrations
Antithrombin III Activity and Homocysteinemia
References 1 Mudd, S.H.; Skovby, F.; Levy, H.L.; Pettigrew, K.D.; Wilcken, B.; Pyeritz, R.E.; Andria, G.; Boers, G.H.J.; Bromberg, I.L.; Cerone, R.; Fowler, B.; Grobe, H.; Schmidt, H.; Schweitzer, L.: The natural history of homocystinuria due to cysta thionine B-synthase deficiency. Am. J. hum. Ge net. 37: 1-31 (1985). 2 Palaretti, G.; Coccheri, S.: Lowered antithrombin III activity and other clothing changes in homo cystinuria: effects of a pyridoxine folate regimen. Haemostasis 19: suppl. 1, pp. 24-28 (1989). 3 Milligan, D.W.; Quick, A.; Barnard, D.L.: Vita min Bi 2 absorption after allogeneic bone marrow transplantation. J. clin. Pathol. 40: 1472-1474 (1987). 4 Link, H.; Blaurock, M.; Wernet, P.; Niethammer, D.; Wilms, K.; Ostendorf, P.: Acute folic acid defi ciency after bone marrow transplantation. Klin. Wschr. 64: 423-432 (1986). 5 Storb, R.; Deeg, H.J.; Whitehead, J.; Appelbaum, F. ; Beatty, P.; Bensinger, W.; Buckner, D.; Clift, R.; Doney, K.; Farewell, V.; Hansen, J.; Hill, R.; Lum, L.; Martin, P.; Me Guffin, R.; Sanders, J.; Stewart, P.; Sullivan, K.; Witherspoon, R.; Yee, G. ; Donnall Thomas, E.: Methotrexate and cyclo sporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. New Engl. J. Med. 314: 729-735 (1986). 6 Chadefaux, B.; Coude, M.; Hamet, M.; Bienvenu, T.; Fraigne, P.; Aupetit, J.; Kamoun, P.: Dosage radioisotopique de la ¿-homocystéine totale dans le plasma et l’urine: application à des dosages en séries. Annls Biol. Clin. 48: 33-36 (1990). Received: July 20, 1990 Accepted: August 29, 1990 by Prof. Tobelem T. Bienvenu Laboratoire de Biochimie Génétique Hôpital Necker-Enfants-Malades F-75743 Paris (France)
Downloaded by: Nagoya University 133.6.82.173 - 1/15/2019 1:04:01 AM
The age of the recipients ranged from 24 to 59 years (median 37.5 years). CCNU, VP 16, melphalan and total body irradiation (TBI) was given to 6 patients with acute myeloid leukemia or acute lymphoblastic leukemia, CCNU, VP 16, cyclophosphamide, mel phalan and TBI to 3 with myeloma, and cyclophosphamide and TBI to 7 patients with chronic myeloid leukemia. To prevent acute graft-versus-host disease, all patients received ciclosporin from day 1 before BMT to day 180 after BMT and a short course of methotrexate [5], Total plasma ¿-homocys teine concentrations were determined by a radioisotopic assay [6]. Antithrombin III and protein C plasma concentrations were determined by a chromogenic assay with an automatic device (Chromotimer, Behring) using commercial reagents (Behring). Pro tein S antigen was determined by electroim munodiffusion using a commercial reagent (Assera-plate protein S. Diagnostica Stago). Results of the natural anticoagulants were expressed as a percentage of a mixed adult normal serum pool. The following normal ranges were estab lished for these assays: protein C (70-120%), protein S (70-120%), antithrombin III (70120%). The results are reported in table 1. There was no correlation between ¿-ho mocysteine concentrations and inhibitors of blood coagulation levels. So, if the defect in amino acid transsulfuration that is responsi ble for homocystinuria can directly affect the synthesis or activity of some clotting factors, homocysteine concentration is not responsi ble for this effect.
67
