188 suffered no side-effects. Haemolysis has also been described with intermediate-purity 4,5 and high-purity concentrate,6 and appears to be due to the accumulation in vivo of the infused-blood-group allo-agglutinins. In all cases reported the haemolysis was moderate, and regressed spontaneously when treatment with A.H.F. was stopped. The risk of a high allo-agglutinin titre or the presence of hasmolysins in cryoprecipitate or concentrate could be avoided by screening the individual donations of plasma or, in the instance of concentrate, possibly by preparing it from pools of plasma selected in proportion to the normal distribution of the ABO groups or by neutralising alloagglutinins with A and B blood-group substances. This problem is being examined at the Blood Products Laboratory, where the factor-vm concentrate given to the above patient was prepared. Hæmophilia Centre, Royal Free Hospital, G. P. TAMAGNINI Pond Street, KATHARINE M. DORMANDY. London NW3 2QG.
probably a very effective prosthesis, but somewhat embarrassing if it should burst while walking through the pigeons in the churchyard! Regional Cancer Registry, Queen Elizabeth Medical Centre, Birmingham B15 2TH.
JUNE MARCHANT.
FACTOR-VIII CONCENTRATE IN HÆMOPHILIA
SIR,-Cecilia Cronin (June 7, p. 1303) draws attention to the possible need to consider the ABO blood-group of the patient when large quantities of factor vm either as cryoprecipitate or concentrate have to be given, because of the allo-agglutinins that these preparations may contain. The following case is of interest in this context: A 34-year-old man with severe haemophilia (factor vm less than 1%) underwent arthrodesis of the left shoulder under cover of intermediate-potency facior-viu concentrate. Haemostasis was satisfactory during surgery, and to maintain the level of factor vm above 30% he required eight-hourly infusions of 1000 units of A.H.F. for twelve days. The wound healed rapidly and the stitches were removed on the fourteenth day under cover of cryoprecipitate. While he was receiving A.H.F. hmmoglobin dropped steadily from
Blood Products Laboratory, Lister Institute of Preventive
Medicine, Elstree, Hertfordshire.
concentrate, the patient’s 12-5 to 7-6 g. per dl., the
D. ELLIS W. D’A. MAYCOCK.
PROTHROMBIN-COMPLEX CONCENTRATES IN LIVER DISEASE SIR,-Reports from the United States have warned us of the hazards of thromboembolism associated with commercial prothrombin-complex concentrates.7,8 Although such complications have not been reported with the products used in Europe, one is happy to accept the encouraging conclusions of Dr Green and his colleagues (June 14, p. 1311) that factor-vn-rich concentrates can be safely used in high-risk patients with liver failure. We should like to report our experience with other preparations, providing additional laboratory evidence that their use is not accompanied by signs of activation of the coagulation system.
’Prothromplex’ (Immuno AG, Vienna), a freeze-dried containing 25 units per ml. of factors n, ix, and x, has been used by us since 1973 in patients with liver disease who needed biopsy, laparoscopy, or portacaval shunts and had prolonged prothrombin-time (r.T.) (patientplasma/normal-plasma ratio > 1.3) and/or prolonged partial thromboplastin-time (P.T.T.) (ratio > 1 ’2). Although there was no instance of abnormal bleeding, complete correction of coagulation tests was usually not achieved at a dosage of 25 units per kg. Therefore, a factor-vn concentrate recently made available by the same manufacturers has been given (25 units per ml.) to patients in whom administration of prothromplex was not followed by complete correction of the abnormal coagulation screening-tests. The results obtained in four patients with chronic liver disease submitted to biopsy or laparoscopy are shown in the accompanying table. The abnormality of P.T., P.T.T., and ’Normotest ’ (N.T.) usually persisted after the infusion of prothromplex. The subsequent administration of factorvn concentrate achieved a complete correction of P.T. and concentrate
Laboratory findings during treatment with A.H.F. concentrate rose to 16%, and the peripheral blood film showed increasing rouleaux formation, spherocytosis, and polychromasia (see accompanying figure). The osmotic fragility was greatly increased and the total bilirubin rose to 1-8 mg. per 100 ml. with a conjugated bilirubin of 0-3 mg. per 100 ml. The direct
reticulocyte-count
antiglobulin
test
(D.A.T.)
was
positive owing
to
complement
on
the surface of the red cells. The patient’s blood-group was A rhesus-positive, the titre of anti-B agglutinins was 32; no anti-A and no hsemolysins were detected. The titres of saline allo-agglutinins anti-A and anti-B in several batches of dissolved A.H.F. concentrate used in this patient were 32 and 16 respectively. No IgG antibodies were. detected. His haemoglobin rose spontaneously after infusions of A.H.F. concentrate were stopped. .
During the early trials of treatment with Cohn fraction I degree of hsemolysis was a constant feature in patients of blood-groups A and B,1-3 while patients of blood-group 0 a
McMillan, C. W., Diamond, L. K., Surgenor, D. M. New Engl. J. Med. 1961, 265, 224. 2. Newcombe, T. F., Walston, M. E. J. Am. med. Ass. 1963, 185, 628. 3. Maider, M. J., Shulman, N. R. Am. J. Med. 1966, 41, 56. 1.
After the infusion of each concentrate, there was no of platelet-count, plasma-fibrinogen, factors v and VIII, and serum F.D.P. P.T.T., however,
N.T.
significant change 4.
5. 6. 7. 8.
Schorr, J. H., Ballard, M. S., Radel, E., Yu, M. Transfusion, 1966, 6, 522. Johnson, A. H., Karpatkin, M. H., Newman, J. Br. J. Hœmat. 1971, 21, 21. Rosati, L. A., Barnes, B., Oberman, H. A. Transfusion, 1970, 10, 139. Kasper, C. K. New Engl. J. Med. 1973, 289, 160. Blatt, P. M., Lundblad, R. L., Kingdon, H. S., MacLean, G., Roberts, H. R. Ann. intern. Med. 1974, 81, 766.
189 FINDINGS IN FOUR PATIENTS WITH LIVER DISEASE WHO RECEIVED PROTHROMPLEX AND FACTOR-VII CONCENTRATE I
= before treatment. b = 15 min. after treatment with Normal value 13-17 sec. t Normal value 40-50 sec. t Normal value 18-24 sec.
a
prothromplex.
*
remained abnormal or showed a further prolongation. These findings are probably related to lack of factor v in both the concentrates, and to the presence of small amounts of heparin in factor-vii concentrate. We have also measured the low-molecular-weight 0(2globulin inhibitor9 variously known as antithrombin III and xa inhibitor (anti-Xa) using both an immunochemical " and biological assay. 11The basal values were often reduced; there was no change after prothromplex, whereas administration of factor-vn concentrate was followed by an increase of the inhibitor-measured by biological assay (presumably due to small amounts of heparin in the concentrate the inhibitor). Activation of factor x is considered to play a key role in the coagulation sequence and in the occurrence of intravascular thrombosis.I2Reduction of the naturally occurring inhibitor in liver disease may increase thromboembolic hazard if the rate of xa formation exceeds its neutralisation by the inhibitor. It is reassuring, therefore, to know that administration of concentrates which might contain activated clotting factor was not accompanied by decrease of the inhibitor.
potentiating
..
c = 15 min. after treatment with factor-vn concentrate. § Normal value 70-130 sec. Tf Normal value 75-125%. II Normal value 75-130%.
rich in factor vn,
as illustrated by Penner and Kelly. 1 , Despite this, D.i.c. and/or thrombosis have been seen following their use-especially in patients with liver disease.11-22 It is our belief that the induction of i).i.c. (or conversely the lack of it) in patients with liver disease is related to the presence or absence of the activated clotting factors in various preparations of prothrombin-complex
concentrate 18,17,23 and not related to the content of factor vil. We would, therefore, be curious to know whether the to assay for activated Oxford fraction has been
subjected clotting factors and how many different lots of material were used in the 13 patients. We would expect that if this material lacks activated clotting factors and can be reproducibly manufactured, it should indeed be safe in patients with liver disease. Until these data are available, and a broader experience is gained with its use, we feel that caution needs to be exerted before this material is broadly used in patients with liver disease. Departments of Medicine and Pathology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27514, U.S.A.
PHILIP M. BLATT HAROLD R. ROBERTS.
3rd Institute of Clinical Medicine, Hæmophilia and Thrombosis Centre,
University of Milan, Via Pace 15, 20122 Milan,
Italy.
N. DIOGUARDI P. M. MANNUCCI.
SiR,—Green et al.I3 are to be commended for their report of 13 successful liver biopsies performed in patients with active liver disease under cover of a new prothrombin complex-concentrate rich in factor vn. We would question, however, whether sufficient data are presented to allow the authors to conclude that the " Oxford factor-vn-rich concentrate seems to be the preparation of choice in patients with liver disease requiring temporary correction of their coagulation defect". The authors observed that the Oxford preparation, which is rich in factor vn, was not associated with the induction of disseminated intravascular coagulation (D.i.c.). They go on to comment that other current prothrombin complex concentrates contain little or no factor vii but have been associated with the induction of D.l.C. Green et al. thus clearly imply that factor vii somehow prevents this D.I.C. induction. In the U.S.A., prothrombin complex concentrates are Yin, E. T., Wessler, S., Stell, P. J. biol. Chem. 1971, 246, 3712. Fagerhol, M. K., Abildgaard, U. Scand. J. Hœmat. 1970, 7, 10. Biggs, R., Denson, K. W. E., Akman, N., Bonett, R., Hadden, M. Br. J. Hœmat. 1970, 19, 283. 12. Wessler, S., Yin, E. T. Circulation, 1973, 47, 671. 13. Green, G., Poller, L., Dymock, I. M., Thompson, J. M. Lancet, 1975, i, 1311. 9. 10. 11.
FOLATE-RESPONSIVE SCHIZOPHRENIA SIR,-Some of your readers may be misled by your editorial (June 7, p. 1283) if they have not read the case-report of 5,10-methylenetetrahydrofolate-reductase deficiency by Freeman et al.,24 on which it is based. You do not indicate that during the course of the patient’s mental illness her i.Q. fell from normal to 30-35, and she was drowsy and incontinent, with extensor plantar responses and a diffusely slow E.E.G. In short, this patient had a metabolic encephalopathy with psychotic features (organic psychosis) and it is doubtful whether any British psychiatrist would have diagnosed schizophrenia.
14. Penner, J. A., Kelly, P. E. Sem. Thromb. Hemostas. 1975, 1, 386. 15. Cederbaum, A. I., Roberts, H. R. Clin. Res. 1973, 21, 92. 16. Cederbaum, A. I., Blatt, P. M., Roberts, H. R. Unpublished. 17. Blatt, P. M., Lundblad, R. L., Kingdon, H. S., McLean, G. W., Roberts, H. R.: Ann. intern. Med. 1974, 81, 766. 18. Kasper, C. K. New Engl. J. Med. 1973, 289, 160. 19. Kasper, C. K. Unpublished. 20. Edson, J. R. New Engl. J. Med. 1974, 290, 403. 21. Marchesi, S. L., Burney, R. ibid. 22. Steinberg, M. H., Dreiling, B. J. ibid. 1973, 289, 592. 23. Kingdon, H. S., Lundblad, R. L., Veltkamp, J. J., Aronson, D. L.
Unpublished. 24. Freeman, J. M., Finkelstein, J. D., 1975, 292, 491.
Mudd, S. H. New Engl. J. Med.
probably a very effective prosthesis, but somewhat embarrassing if it should burst while walking through the pigeons in the churchyard! Regional Cancer Registry, Queen Elizabeth Medical Centre, Birmingham B15 2TH.
JUNE MARCHANT.
FACTOR-VIII CONCENTRATE IN HÆMOPHILIA
SIR,-Cecilia Cronin (June 7, p. 1303) draws attention to the possible need to consider the ABO blood-group of the patient when large quantities of factor vm either as cryoprecipitate or concentrate have to be given, because of the allo-agglutinins that these preparations may contain. The following case is of interest in this context: A 34-year-old man with severe haemophilia (factor vm less than 1%) underwent arthrodesis of the left shoulder under cover of intermediate-potency facior-viu concentrate. Haemostasis was satisfactory during surgery, and to maintain the level of factor vm above 30% he required eight-hourly infusions of 1000 units of A.H.F. for twelve days. The wound healed rapidly and the stitches were removed on the fourteenth day under cover of cryoprecipitate. While he was receiving A.H.F. hmmoglobin dropped steadily from
Blood Products Laboratory, Lister Institute of Preventive
Medicine, Elstree, Hertfordshire.
concentrate, the patient’s 12-5 to 7-6 g. per dl., the
D. ELLIS W. D’A. MAYCOCK.
PROTHROMBIN-COMPLEX CONCENTRATES IN LIVER DISEASE SIR,-Reports from the United States have warned us of the hazards of thromboembolism associated with commercial prothrombin-complex concentrates.7,8 Although such complications have not been reported with the products used in Europe, one is happy to accept the encouraging conclusions of Dr Green and his colleagues (June 14, p. 1311) that factor-vn-rich concentrates can be safely used in high-risk patients with liver failure. We should like to report our experience with other preparations, providing additional laboratory evidence that their use is not accompanied by signs of activation of the coagulation system.
’Prothromplex’ (Immuno AG, Vienna), a freeze-dried containing 25 units per ml. of factors n, ix, and x, has been used by us since 1973 in patients with liver disease who needed biopsy, laparoscopy, or portacaval shunts and had prolonged prothrombin-time (r.T.) (patientplasma/normal-plasma ratio > 1.3) and/or prolonged partial thromboplastin-time (P.T.T.) (ratio > 1 ’2). Although there was no instance of abnormal bleeding, complete correction of coagulation tests was usually not achieved at a dosage of 25 units per kg. Therefore, a factor-vn concentrate recently made available by the same manufacturers has been given (25 units per ml.) to patients in whom administration of prothromplex was not followed by complete correction of the abnormal coagulation screening-tests. The results obtained in four patients with chronic liver disease submitted to biopsy or laparoscopy are shown in the accompanying table. The abnormality of P.T., P.T.T., and ’Normotest ’ (N.T.) usually persisted after the infusion of prothromplex. The subsequent administration of factorvn concentrate achieved a complete correction of P.T. and concentrate
Laboratory findings during treatment with A.H.F. concentrate rose to 16%, and the peripheral blood film showed increasing rouleaux formation, spherocytosis, and polychromasia (see accompanying figure). The osmotic fragility was greatly increased and the total bilirubin rose to 1-8 mg. per 100 ml. with a conjugated bilirubin of 0-3 mg. per 100 ml. The direct
reticulocyte-count
antiglobulin
test
(D.A.T.)
was
positive owing
to
complement
on
the surface of the red cells. The patient’s blood-group was A rhesus-positive, the titre of anti-B agglutinins was 32; no anti-A and no hsemolysins were detected. The titres of saline allo-agglutinins anti-A and anti-B in several batches of dissolved A.H.F. concentrate used in this patient were 32 and 16 respectively. No IgG antibodies were. detected. His haemoglobin rose spontaneously after infusions of A.H.F. concentrate were stopped. .
During the early trials of treatment with Cohn fraction I degree of hsemolysis was a constant feature in patients of blood-groups A and B,1-3 while patients of blood-group 0 a
McMillan, C. W., Diamond, L. K., Surgenor, D. M. New Engl. J. Med. 1961, 265, 224. 2. Newcombe, T. F., Walston, M. E. J. Am. med. Ass. 1963, 185, 628. 3. Maider, M. J., Shulman, N. R. Am. J. Med. 1966, 41, 56. 1.
After the infusion of each concentrate, there was no of platelet-count, plasma-fibrinogen, factors v and VIII, and serum F.D.P. P.T.T., however,
N.T.
significant change 4.
5. 6. 7. 8.
Schorr, J. H., Ballard, M. S., Radel, E., Yu, M. Transfusion, 1966, 6, 522. Johnson, A. H., Karpatkin, M. H., Newman, J. Br. J. Hœmat. 1971, 21, 21. Rosati, L. A., Barnes, B., Oberman, H. A. Transfusion, 1970, 10, 139. Kasper, C. K. New Engl. J. Med. 1973, 289, 160. Blatt, P. M., Lundblad, R. L., Kingdon, H. S., MacLean, G., Roberts, H. R. Ann. intern. Med. 1974, 81, 766.
189 FINDINGS IN FOUR PATIENTS WITH LIVER DISEASE WHO RECEIVED PROTHROMPLEX AND FACTOR-VII CONCENTRATE I
= before treatment. b = 15 min. after treatment with Normal value 13-17 sec. t Normal value 40-50 sec. t Normal value 18-24 sec.
a
prothromplex.
*
remained abnormal or showed a further prolongation. These findings are probably related to lack of factor v in both the concentrates, and to the presence of small amounts of heparin in factor-vii concentrate. We have also measured the low-molecular-weight 0(2globulin inhibitor9 variously known as antithrombin III and xa inhibitor (anti-Xa) using both an immunochemical " and biological assay. 11The basal values were often reduced; there was no change after prothromplex, whereas administration of factor-vn concentrate was followed by an increase of the inhibitor-measured by biological assay (presumably due to small amounts of heparin in the concentrate the inhibitor). Activation of factor x is considered to play a key role in the coagulation sequence and in the occurrence of intravascular thrombosis.I2Reduction of the naturally occurring inhibitor in liver disease may increase thromboembolic hazard if the rate of xa formation exceeds its neutralisation by the inhibitor. It is reassuring, therefore, to know that administration of concentrates which might contain activated clotting factor was not accompanied by decrease of the inhibitor.
potentiating
..
c = 15 min. after treatment with factor-vn concentrate. § Normal value 70-130 sec. Tf Normal value 75-125%. II Normal value 75-130%.
rich in factor vn,
as illustrated by Penner and Kelly. 1 , Despite this, D.i.c. and/or thrombosis have been seen following their use-especially in patients with liver disease.11-22 It is our belief that the induction of i).i.c. (or conversely the lack of it) in patients with liver disease is related to the presence or absence of the activated clotting factors in various preparations of prothrombin-complex
concentrate 18,17,23 and not related to the content of factor vil. We would, therefore, be curious to know whether the to assay for activated Oxford fraction has been
subjected clotting factors and how many different lots of material were used in the 13 patients. We would expect that if this material lacks activated clotting factors and can be reproducibly manufactured, it should indeed be safe in patients with liver disease. Until these data are available, and a broader experience is gained with its use, we feel that caution needs to be exerted before this material is broadly used in patients with liver disease. Departments of Medicine and Pathology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27514, U.S.A.
PHILIP M. BLATT HAROLD R. ROBERTS.
3rd Institute of Clinical Medicine, Hæmophilia and Thrombosis Centre,
University of Milan, Via Pace 15, 20122 Milan,
Italy.
N. DIOGUARDI P. M. MANNUCCI.
SiR,—Green et al.I3 are to be commended for their report of 13 successful liver biopsies performed in patients with active liver disease under cover of a new prothrombin complex-concentrate rich in factor vn. We would question, however, whether sufficient data are presented to allow the authors to conclude that the " Oxford factor-vn-rich concentrate seems to be the preparation of choice in patients with liver disease requiring temporary correction of their coagulation defect". The authors observed that the Oxford preparation, which is rich in factor vn, was not associated with the induction of disseminated intravascular coagulation (D.i.c.). They go on to comment that other current prothrombin complex concentrates contain little or no factor vii but have been associated with the induction of D.l.C. Green et al. thus clearly imply that factor vii somehow prevents this D.I.C. induction. In the U.S.A., prothrombin complex concentrates are Yin, E. T., Wessler, S., Stell, P. J. biol. Chem. 1971, 246, 3712. Fagerhol, M. K., Abildgaard, U. Scand. J. Hœmat. 1970, 7, 10. Biggs, R., Denson, K. W. E., Akman, N., Bonett, R., Hadden, M. Br. J. Hœmat. 1970, 19, 283. 12. Wessler, S., Yin, E. T. Circulation, 1973, 47, 671. 13. Green, G., Poller, L., Dymock, I. M., Thompson, J. M. Lancet, 1975, i, 1311. 9. 10. 11.
FOLATE-RESPONSIVE SCHIZOPHRENIA SIR,-Some of your readers may be misled by your editorial (June 7, p. 1283) if they have not read the case-report of 5,10-methylenetetrahydrofolate-reductase deficiency by Freeman et al.,24 on which it is based. You do not indicate that during the course of the patient’s mental illness her i.Q. fell from normal to 30-35, and she was drowsy and incontinent, with extensor plantar responses and a diffusely slow E.E.G. In short, this patient had a metabolic encephalopathy with psychotic features (organic psychosis) and it is doubtful whether any British psychiatrist would have diagnosed schizophrenia.
14. Penner, J. A., Kelly, P. E. Sem. Thromb. Hemostas. 1975, 1, 386. 15. Cederbaum, A. I., Roberts, H. R. Clin. Res. 1973, 21, 92. 16. Cederbaum, A. I., Blatt, P. M., Roberts, H. R. Unpublished. 17. Blatt, P. M., Lundblad, R. L., Kingdon, H. S., McLean, G. W., Roberts, H. R.: Ann. intern. Med. 1974, 81, 766. 18. Kasper, C. K. New Engl. J. Med. 1973, 289, 160. 19. Kasper, C. K. Unpublished. 20. Edson, J. R. New Engl. J. Med. 1974, 290, 403. 21. Marchesi, S. L., Burney, R. ibid. 22. Steinberg, M. H., Dreiling, B. J. ibid. 1973, 289, 592. 23. Kingdon, H. S., Lundblad, R. L., Veltkamp, J. J., Aronson, D. L.
Unpublished. 24. Freeman, J. M., Finkelstein, J. D., 1975, 292, 491.
Mudd, S. H. New Engl. J. Med.
