Case Reports
British Journal of Haematology, 1992, 82 ever, despite all efforts, the disease progressed rapidly, the patient’s condition steadily deteriorated and he died in December 1989. Ph chromosome has been found occasionally in tumours with a B lymphocytic differentiation (Juliusson et al, 1985; Martiat et al, 1990: Mitani et al, 1990) and rarely in lymphomas of T cell origin (Terjanian et al, 1989). Few BCR gene studies have been performed in lymphomas (Terjanian et al, 1989: Mitani eta!. 1990; Sanchez et al, 1990; Tesch et al, 1990).Recently, contradictory results have been obtained in patients with lymphomas: BCR rearrangement, as is usually observed in chronic myelocytic leukaemia (CML), has been found in some cases (Sanchezet al, 1990)whereas other authors have not detected rearrangement of this gene (Tesch et aJ. 1990). Moreover, in a Ph-positive B-cell type nonHodgkin’s lymphoma case, similar molecular events to those found in some Ph-positive acute lymphocytic leukaemias (ALL) were observed (Mitani et al, 1990). Although our patient was Ph-positive. no BCR rearrangement could be demonstrated by conventional DNA study. However, PCR evidenced that BCR gene was involved in the same way as it is usual in CML: a fused mRNA joining BCR exon 3 to C-ABL exon 2. As far as we know, it is the first time that this molecular abnormality has been described in a lymphoma. To our knowledge, a similar molecular event has only been reported in a CML Ph-positive patient, who lacked M-BCR rearrangement by Southern blotting, but mRNA studied by PCR revealed an amplificationproduct consistent with the b2 a2 junction characteristic of many cases of Ph-positive CML. These findings could be explained by a genomic breakpoint downstream of the BCR gene, associated with a long-range splicing that excluded most or all of the 3’BCR exons (Ling Min et al, 1989). Although few lymphomas with BCR gene molecular studies have been reported, current knowledge suggests the existence in this lymphoproliferative disease of a similar molecular heterogeneity to that found in ALL and CML and emphasizes the usefulness of molecular research in lymphomas.
ACKNOWLEDGMENTS We are grateful to Dr G. Morgan, London, for PCR analysis. We would also like to thank Dr M. Greaves, London (CDA2 and 3A1), Dr D. Catovsky, London (MY9 and anti Tdt) and Dr
627
J. Vives, Barcelona (Cris-I, 100-1A5,93-1B3 and Cris-4) for the generous gift of their respective monoclonal antibodies.
Departments of Molecular Biology, Immunology and Clinical Haematology, lnstituto de Hematolgia e Inmunologia. La Habana, Cuba
A. HERNANDEZ L. CORRAL A. MURIZ C. ALAEZ c. CRUZ G. VECA E. DORTICOS G. MART~NEZ P. HERNANDEZ
REFERENCES Juliusson, G., Friberg. K. & Gahrton. G. (1985) Ph-chromosome and B-cell malignancy-associated chromosomal aberrations in nonleukaemic immunoblastic B-cell lymphoma. Acta Haematologica. 74. 171-174. Ling Min, G., Martiat. P., Su Cai, B. & Goldman. J. (1989) Molecular studies in CML patients lacking rearrangement of M-bcr: the BCR gene is still involved in Ph-positive but not in Ph-negative cases. (Abstract). Blood. 7 4 (Suppl. I), 88a. Martiat, P., Mecucci. C., Nizet, Y., Stul, M.. Philippe, M.. Cassiman. J.J., Michaux, J.L., Van den Berghe, H. & Sokal, G. (1990) P190 BCR/ABL transcript in a case of Philadelphia positive multiple myeloma. Leukemia. 4, 751-754. Mitani. K.. Sato. Y., Tojo. A., Ishikawa, F.. Kobayashi. Y.. Miura. Y.. Miyazono, K., Urabe, A. & Takaku. F. (1990) Philadelphia chromosome positive B-cell type malignant lymphoma expressing an aberrant 190 kDa bcr-abl protein. British Journal oJ Haematology, 76, 221-225. Morgan, C.J., Hernandez, A.. Chan. L.C.. Hughes, T., Martiat. P. & Weiedemann, L.M. ( 1 990) The role of alternative splicing patterns of BCR/ABL transcripts in the generation of the blast crisis of chronic myeloid leukaemia. British Journal oftiaematology, 7 6 , 3 338. Sanchez. I., Martin-Seisdedos, C., Corral, J., Fernandez. F.J.. Moraleda, J.M. & Gonzalez-Sarmiento.R. (1990) Estudio de la region Mbcr en linfomas. (Resumen). Sangre. 35 (Suppl. 2). 72. Terjanian, T., Blick, M.B., Shtabrid, M., Manning, J.T., Trujillo.J.M. & Cabanillas, F. (1989) Philadelphia chromosome without break point cluster region rearrangement in a case of Lennert’s lymphoma of suppressor phenotype. Hematological Oncology, 7, 1 89194. Tesch. H.. May, P., Krueger, G.R.F., Fischer. R. & Diehl. V. (1990) Analysis of immunoglobulin, T cell receptor and bcr rearrangements in human malignant lymphoma and Hodgkin’s diseases. Oncology. 47, 215-223.
TREATMENT OF HEPARIN-INDUCED THROMBOCYTOPENIA BY USE OF ARGATROBAN, A SYNTHETIC THROMBIN INHIBITOR We used argatroban as substitute anticoagulant for unfractionated porcine heparin (UFH) in a haemodialysis patient with heparin-induced thrombocytopenia (HIT). The rechallenge of UFH could be achieved in subsequent haemodialysis sessions after the use of argatroban. A 78-year-old woman (height 142 cm, weight 45 kg) had suffered from non-insulin dependent diabetes for about 30
years before she was admitted for the treatment of azotaemia by haemodialysis. Haemodialysis was carried out using a hollow fibre dialyser (FB-90MGA Nipro, Japan) UFH (Mitsui Co., Japan) was used as the anticoagulant (initial dose 500 U; maintenance dose 500 U/h). Fibrin formation in the air chambers and residual blood in the dialyser were noted during the sixth haemodialysis session at 16 d after the
628
Case Reports
initiation of dialysis, although the APTT value was 1.5-2.0 times the pretreatment baseline value. Similar clot formation occurred during the subsequent three sessions despite an additional bolus of UFH ( 1000 [I). During the tenth session the platelet count decreased from 308 x 109/1before haemodialysis to 1 7 8 x 1O’/l at 1 8 0 min when clots formed in the circuit. Platelet aggregation was tested according to Chong’s method (Chong et a/, 1983) using UFH at three final concentrations (0.1. 1.0 and 10 Uiml). Aggregation occurred with 1.0 U/ml of UFH. A low molecular weight heparin (LMWH, Fragmin. Kabi) was substituted for UFH in the eleventh session, after confirming that no aggregation was induced by three concentrations of this heparin (Vitroux et al. 1986). LMWH was administered at an initial dose of 1000 U and a maintenance dose of 500 U/h (mean APTT during haemodialysis 1.4 times the baseline). However. haemodialysis had to be discontinued at 1 5 0 min after starting, because of clot formation in the circuit and a decrease of the platelet count to 1 3 0 x lOy/1. Argatroban (Kikumoto et a/. 1984)is a synthetic thrombin inhibitor ( 2 R . 4R)-4-methyI- I -[N’-((3-methyl-l.2.3.4-tetrahydro-8-quinolinyl) sulfonyl)-~-arginyl]-2-piperidinecarboxylicacid. This agent was used for the twelfth and thirteenth haemodialysis sessions. Continuous infusion of argatroban ( 2 0 mg/h) was carried out to keep its plasma level about 2.0 pg/ml. a concentration that suppressed the increase in plateletbinding IgG (PBIgG) in vitro (Fig 1 ). The prolongation of APTT was about 2.5 times the baseline value with this dose of argatroban (Matsuo 6; Nakao. 19871. No clotting or thrombocytopenia occurred during haemodialysis with argatroban. Since the platelet aggregation and following heparin binding studies both became negative. rechallenge of the same batch of lJFH was subsequently attempted. No HIT was noted after rechallenge with the same batch of UFH. and haemodialysis could be uneventfully performed twice a week for the following 7 weeks. Then. haemodialysis was discontinued because of improvement of the patient’s uraemia. The PBIgG level was determined by EIJSA. Data were expressed as ELISA units (k:.C.:l E.U. = 1 SD of the mean 1 SD of the absorbances of 10 samples obtained from healthy volunteers). On 3/11 occasions, PBIgG exceeded the normal rangeof2E.L. fortheuseofUFH. being2.7E.Ii.. 5.1 E.C:.and 4.2 E.U. during HIT episodes. Following in vitro UFH addition (Matsuo rt a!, 1988). PBIgG was determined after incubating serum from this patient and five other HIT patients with three concentrations of UFH (0.1, 1.0 and 10 U/rnl). The E.L. values of each sample were divided by those obtained without the addition of UFH. The maximum and minimum increases in PRIgC of the five HIT patients after addition of 1 .0 U / m l of I,’FH ranged from -3.2 to 8.0-fold. The PKIgG of this patient showed a 1h. I -fold increase after addition of 1.0 U/ml of IJFH. Serum incubated with argatroban at a final concentration of 2.0 pg/ml showed no increase of PBIgG (Fig 1 ). Although the platelet aggregation test was negative with LVWH. an &fold increase of PBIgG was obtained after LMWH addition. The increase in PBIgG following the addition of I:FH or LMWH was inhibited in serum obtained after subsiding HIT with argatroban. In some HIT patients.
British Journal of Haematology, 1992, 82 5.0 1 4.0 .
.-c
I
3
.2
-80 m
3.0 . 2.0 .
a
1.0 .
+
1.0 U/me UHF
t’ig 1 . It1 vitro reduction of the increase in PBIgC produced by heparin d t e r addition of argatroban to HIT serum. No response was observed ). Serum ivith serum after treatment with argatroban ( x-x hefore argatroban therapy (0-0). Age and sex matched non-HTT kiaemodialysis patients ( 0 . ’ . O ) .
LMWH has been reported as a n effective alternative to UFH (Gouault-Heilmann et al, 1987). We initially used LMWH to replace IJFH. but could not prevent the development of HIT. Heparin-induced platelet aggregation is inhibited in a dosedependent manner when HIT serum is preincubated with various concentrations of argatroban (Matsuo et al, 1990). suggesting that this synthetic thrombin inhibitor has a favourable effect via the platelet thrombin-reactive domain. ‘The precise mechanism needs further clarification. ,lCKNOWLEDGMENTS ‘This study was supported in part by Grants-in-Aid from the Foundation for the Development of the Community (Tochigi, Japan)and Japanese Medical Association (Hyogo, Japan). ilepnrtr?ient of lnternal Medicine trnd Central Laboratory. Xyogo Prefectural Awuji Hospital, : ~ ~ o n o t Hyogo. o, japan
TAKEFUMI MATSUO KAZ~JOMIKAKIO YO SHIM^ CHIKAHIRA KAZUKIYONAKAO YAMADA TSUTOMU
REFERENCES (’hong. R.H.. Pitney. W.R. & Castaldi. P.A. (1 98 3 ) Heparin induced thrombocytopenia: association of thrombotic complications with heparin dependent IgG antibody that induces thromboxane synthesis and platelet aggregation. Lancet. ii. 1246- 1148. (;ouauIt-Heilmann, M.. Huet. Y.. Adnot. A,. Contant, C.. Bonnet, I:. RIntractor. I.. ( 1 9 8 i ) Low molecular weight heparin fraction as an alternative therapy in heparin-induced thrombocytopenia. Hrrerr~ostnsis.17. 1 34-1 40. Kikunioto. R.. Tamao. Y.. Temka. T.. Tonomura. S.. Hara. H.. Ninomiya. K.. Hijikata. A. R- Okamoto. S. ( 1 9 8 4 ) Selective ( inhibition of thrombin by (2R.4R)-4-methyl-1 - [ N ~ - ( 3-methyl-
Case Reports
British Journal of Haematology, 1992, 82 1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl)-~-ar~iny1]-2-piperidinecarboxylic acid. Biochemistry, 23, 85-90. Matsuo, T., Chikahira, Y.. Yamada. T.. Nakao, K.. Ueshirna. S. & Matsuo. 0. ( 1 988) Effect of synthetic thrombin inhibitor (MD805) as an alternative drug in heparin-induced thrombocytopenia during hernodialysis Thrombosis Research, 52, 165-1 71. Matsuo, T. & Nakao, K. (1987) Plasma antithrombin activity of MD805 determined by chromogenic substrate during hemodialysis. Blood and Vessel (lapanese), 18, 378-380.
629
Matsuo, T., Yamada, T . . Yamanashi. T. & Ryo, R. ( 1 990). AnticoagoIant therapy with MD805 of a hernodialysis patients with heparininduced thrombocytopenia. Thrombosis Research. 58, 663-666. Vitroux. J.F.. Mathieu, J.F., Roncato. M., Fiessinger, J.N. & Ajach. M. (1986) Heparin-associated thrombocytopenia, treatment with low molecular weight heparin. Thrombosis and Huemostas, 5 5 , 3739.
British Journal of Haematology, 1992, 82 ever, despite all efforts, the disease progressed rapidly, the patient’s condition steadily deteriorated and he died in December 1989. Ph chromosome has been found occasionally in tumours with a B lymphocytic differentiation (Juliusson et al, 1985; Martiat et al, 1990: Mitani et al, 1990) and rarely in lymphomas of T cell origin (Terjanian et al, 1989). Few BCR gene studies have been performed in lymphomas (Terjanian et al, 1989: Mitani eta!. 1990; Sanchez et al, 1990; Tesch et al, 1990).Recently, contradictory results have been obtained in patients with lymphomas: BCR rearrangement, as is usually observed in chronic myelocytic leukaemia (CML), has been found in some cases (Sanchezet al, 1990)whereas other authors have not detected rearrangement of this gene (Tesch et aJ. 1990). Moreover, in a Ph-positive B-cell type nonHodgkin’s lymphoma case, similar molecular events to those found in some Ph-positive acute lymphocytic leukaemias (ALL) were observed (Mitani et al, 1990). Although our patient was Ph-positive. no BCR rearrangement could be demonstrated by conventional DNA study. However, PCR evidenced that BCR gene was involved in the same way as it is usual in CML: a fused mRNA joining BCR exon 3 to C-ABL exon 2. As far as we know, it is the first time that this molecular abnormality has been described in a lymphoma. To our knowledge, a similar molecular event has only been reported in a CML Ph-positive patient, who lacked M-BCR rearrangement by Southern blotting, but mRNA studied by PCR revealed an amplificationproduct consistent with the b2 a2 junction characteristic of many cases of Ph-positive CML. These findings could be explained by a genomic breakpoint downstream of the BCR gene, associated with a long-range splicing that excluded most or all of the 3’BCR exons (Ling Min et al, 1989). Although few lymphomas with BCR gene molecular studies have been reported, current knowledge suggests the existence in this lymphoproliferative disease of a similar molecular heterogeneity to that found in ALL and CML and emphasizes the usefulness of molecular research in lymphomas.
ACKNOWLEDGMENTS We are grateful to Dr G. Morgan, London, for PCR analysis. We would also like to thank Dr M. Greaves, London (CDA2 and 3A1), Dr D. Catovsky, London (MY9 and anti Tdt) and Dr
627
J. Vives, Barcelona (Cris-I, 100-1A5,93-1B3 and Cris-4) for the generous gift of their respective monoclonal antibodies.
Departments of Molecular Biology, Immunology and Clinical Haematology, lnstituto de Hematolgia e Inmunologia. La Habana, Cuba
A. HERNANDEZ L. CORRAL A. MURIZ C. ALAEZ c. CRUZ G. VECA E. DORTICOS G. MART~NEZ P. HERNANDEZ
REFERENCES Juliusson, G., Friberg. K. & Gahrton. G. (1985) Ph-chromosome and B-cell malignancy-associated chromosomal aberrations in nonleukaemic immunoblastic B-cell lymphoma. Acta Haematologica. 74. 171-174. Ling Min, G., Martiat. P., Su Cai, B. & Goldman. J. (1989) Molecular studies in CML patients lacking rearrangement of M-bcr: the BCR gene is still involved in Ph-positive but not in Ph-negative cases. (Abstract). Blood. 7 4 (Suppl. I), 88a. Martiat, P., Mecucci. C., Nizet, Y., Stul, M.. Philippe, M.. Cassiman. J.J., Michaux, J.L., Van den Berghe, H. & Sokal, G. (1990) P190 BCR/ABL transcript in a case of Philadelphia positive multiple myeloma. Leukemia. 4, 751-754. Mitani. K.. Sato. Y., Tojo. A., Ishikawa, F.. Kobayashi. Y.. Miura. Y.. Miyazono, K., Urabe, A. & Takaku. F. (1990) Philadelphia chromosome positive B-cell type malignant lymphoma expressing an aberrant 190 kDa bcr-abl protein. British Journal oJ Haematology, 76, 221-225. Morgan, C.J., Hernandez, A.. Chan. L.C.. Hughes, T., Martiat. P. & Weiedemann, L.M. ( 1 990) The role of alternative splicing patterns of BCR/ABL transcripts in the generation of the blast crisis of chronic myeloid leukaemia. British Journal oftiaematology, 7 6 , 3 338. Sanchez. I., Martin-Seisdedos, C., Corral, J., Fernandez. F.J.. Moraleda, J.M. & Gonzalez-Sarmiento.R. (1990) Estudio de la region Mbcr en linfomas. (Resumen). Sangre. 35 (Suppl. 2). 72. Terjanian, T., Blick, M.B., Shtabrid, M., Manning, J.T., Trujillo.J.M. & Cabanillas, F. (1989) Philadelphia chromosome without break point cluster region rearrangement in a case of Lennert’s lymphoma of suppressor phenotype. Hematological Oncology, 7, 1 89194. Tesch. H.. May, P., Krueger, G.R.F., Fischer. R. & Diehl. V. (1990) Analysis of immunoglobulin, T cell receptor and bcr rearrangements in human malignant lymphoma and Hodgkin’s diseases. Oncology. 47, 215-223.
TREATMENT OF HEPARIN-INDUCED THROMBOCYTOPENIA BY USE OF ARGATROBAN, A SYNTHETIC THROMBIN INHIBITOR We used argatroban as substitute anticoagulant for unfractionated porcine heparin (UFH) in a haemodialysis patient with heparin-induced thrombocytopenia (HIT). The rechallenge of UFH could be achieved in subsequent haemodialysis sessions after the use of argatroban. A 78-year-old woman (height 142 cm, weight 45 kg) had suffered from non-insulin dependent diabetes for about 30
years before she was admitted for the treatment of azotaemia by haemodialysis. Haemodialysis was carried out using a hollow fibre dialyser (FB-90MGA Nipro, Japan) UFH (Mitsui Co., Japan) was used as the anticoagulant (initial dose 500 U; maintenance dose 500 U/h). Fibrin formation in the air chambers and residual blood in the dialyser were noted during the sixth haemodialysis session at 16 d after the
628
Case Reports
initiation of dialysis, although the APTT value was 1.5-2.0 times the pretreatment baseline value. Similar clot formation occurred during the subsequent three sessions despite an additional bolus of UFH ( 1000 [I). During the tenth session the platelet count decreased from 308 x 109/1before haemodialysis to 1 7 8 x 1O’/l at 1 8 0 min when clots formed in the circuit. Platelet aggregation was tested according to Chong’s method (Chong et a/, 1983) using UFH at three final concentrations (0.1. 1.0 and 10 Uiml). Aggregation occurred with 1.0 U/ml of UFH. A low molecular weight heparin (LMWH, Fragmin. Kabi) was substituted for UFH in the eleventh session, after confirming that no aggregation was induced by three concentrations of this heparin (Vitroux et al. 1986). LMWH was administered at an initial dose of 1000 U and a maintenance dose of 500 U/h (mean APTT during haemodialysis 1.4 times the baseline). However. haemodialysis had to be discontinued at 1 5 0 min after starting, because of clot formation in the circuit and a decrease of the platelet count to 1 3 0 x lOy/1. Argatroban (Kikumoto et a/. 1984)is a synthetic thrombin inhibitor ( 2 R . 4R)-4-methyI- I -[N’-((3-methyl-l.2.3.4-tetrahydro-8-quinolinyl) sulfonyl)-~-arginyl]-2-piperidinecarboxylicacid. This agent was used for the twelfth and thirteenth haemodialysis sessions. Continuous infusion of argatroban ( 2 0 mg/h) was carried out to keep its plasma level about 2.0 pg/ml. a concentration that suppressed the increase in plateletbinding IgG (PBIgG) in vitro (Fig 1 ). The prolongation of APTT was about 2.5 times the baseline value with this dose of argatroban (Matsuo 6; Nakao. 19871. No clotting or thrombocytopenia occurred during haemodialysis with argatroban. Since the platelet aggregation and following heparin binding studies both became negative. rechallenge of the same batch of lJFH was subsequently attempted. No HIT was noted after rechallenge with the same batch of UFH. and haemodialysis could be uneventfully performed twice a week for the following 7 weeks. Then. haemodialysis was discontinued because of improvement of the patient’s uraemia. The PBIgG level was determined by EIJSA. Data were expressed as ELISA units (k:.C.:l E.U. = 1 SD of the mean 1 SD of the absorbances of 10 samples obtained from healthy volunteers). On 3/11 occasions, PBIgG exceeded the normal rangeof2E.L. fortheuseofUFH. being2.7E.Ii.. 5.1 E.C:.and 4.2 E.U. during HIT episodes. Following in vitro UFH addition (Matsuo rt a!, 1988). PBIgG was determined after incubating serum from this patient and five other HIT patients with three concentrations of UFH (0.1, 1.0 and 10 U/rnl). The E.L. values of each sample were divided by those obtained without the addition of UFH. The maximum and minimum increases in PRIgC of the five HIT patients after addition of 1 .0 U / m l of I,’FH ranged from -3.2 to 8.0-fold. The PKIgG of this patient showed a 1h. I -fold increase after addition of 1.0 U/ml of IJFH. Serum incubated with argatroban at a final concentration of 2.0 pg/ml showed no increase of PBIgG (Fig 1 ). Although the platelet aggregation test was negative with LVWH. an &fold increase of PBIgG was obtained after LMWH addition. The increase in PBIgG following the addition of I:FH or LMWH was inhibited in serum obtained after subsiding HIT with argatroban. In some HIT patients.
British Journal of Haematology, 1992, 82 5.0 1 4.0 .
.-c
I
3
.2
-80 m
3.0 . 2.0 .
a
1.0 .
+
1.0 U/me UHF
t’ig 1 . It1 vitro reduction of the increase in PBIgC produced by heparin d t e r addition of argatroban to HIT serum. No response was observed ). Serum ivith serum after treatment with argatroban ( x-x hefore argatroban therapy (0-0). Age and sex matched non-HTT kiaemodialysis patients ( 0 . ’ . O ) .
LMWH has been reported as a n effective alternative to UFH (Gouault-Heilmann et al, 1987). We initially used LMWH to replace IJFH. but could not prevent the development of HIT. Heparin-induced platelet aggregation is inhibited in a dosedependent manner when HIT serum is preincubated with various concentrations of argatroban (Matsuo et al, 1990). suggesting that this synthetic thrombin inhibitor has a favourable effect via the platelet thrombin-reactive domain. ‘The precise mechanism needs further clarification. ,lCKNOWLEDGMENTS ‘This study was supported in part by Grants-in-Aid from the Foundation for the Development of the Community (Tochigi, Japan)and Japanese Medical Association (Hyogo, Japan). ilepnrtr?ient of lnternal Medicine trnd Central Laboratory. Xyogo Prefectural Awuji Hospital, : ~ ~ o n o t Hyogo. o, japan
TAKEFUMI MATSUO KAZ~JOMIKAKIO YO SHIM^ CHIKAHIRA KAZUKIYONAKAO YAMADA TSUTOMU
REFERENCES (’hong. R.H.. Pitney. W.R. & Castaldi. P.A. (1 98 3 ) Heparin induced thrombocytopenia: association of thrombotic complications with heparin dependent IgG antibody that induces thromboxane synthesis and platelet aggregation. Lancet. ii. 1246- 1148. (;ouauIt-Heilmann, M.. Huet. Y.. Adnot. A,. Contant, C.. Bonnet, I:. RIntractor. I.. ( 1 9 8 i ) Low molecular weight heparin fraction as an alternative therapy in heparin-induced thrombocytopenia. Hrrerr~ostnsis.17. 1 34-1 40. Kikunioto. R.. Tamao. Y.. Temka. T.. Tonomura. S.. Hara. H.. Ninomiya. K.. Hijikata. A. R- Okamoto. S. ( 1 9 8 4 ) Selective ( inhibition of thrombin by (2R.4R)-4-methyl-1 - [ N ~ - ( 3-methyl-
Case Reports
British Journal of Haematology, 1992, 82 1,2,3,4-tetrahydro-8-quinolinyl)sulfonyl)-~-ar~iny1]-2-piperidinecarboxylic acid. Biochemistry, 23, 85-90. Matsuo, T., Chikahira, Y.. Yamada. T.. Nakao, K.. Ueshirna. S. & Matsuo. 0. ( 1 988) Effect of synthetic thrombin inhibitor (MD805) as an alternative drug in heparin-induced thrombocytopenia during hernodialysis Thrombosis Research, 52, 165-1 71. Matsuo, T. & Nakao, K. (1987) Plasma antithrombin activity of MD805 determined by chromogenic substrate during hemodialysis. Blood and Vessel (lapanese), 18, 378-380.
629
Matsuo, T., Yamada, T . . Yamanashi. T. & Ryo, R. ( 1 990). AnticoagoIant therapy with MD805 of a hernodialysis patients with heparininduced thrombocytopenia. Thrombosis Research. 58, 663-666. Vitroux. J.F.. Mathieu, J.F., Roncato. M., Fiessinger, J.N. & Ajach. M. (1986) Heparin-associated thrombocytopenia, treatment with low molecular weight heparin. Thrombosis and Huemostas, 5 5 , 3739.
