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.
190 The significance of the case-report is that it adds to the growing evidence that disturbed folate metabolism, especially if severe and prolonged, may lead to neurological disease, including mental symptoms. This evidence has emerged from studies of epileptic,25-27 psychiatric,2a.29 and neurological 30 patients, as well as other inborn errors of metabolism associated with mental retardation from Japan. 311 The type of mental change is variable (as also occurs with vitamin-B12 deficiency) and includes organic psychoses, but probably ultimately the deficiency leads to dementia. In 1968 I discussed 32 the possible relationship between disturbances in folate metabolism and biochemical aspects of schizophrenia because anticonvulsant folate deficiency can sometimes precipitate schizophrenia-like psychoses in epileptic patients, and, as Freeman et al.,24 Baldessarini,33 and Levi and Waxman 34 again imply, there is some common ground between folate metabolism and the abnormal methylation hypothesis of schizophrenia. However, I pointed out then that one difficulty in postulating a disturbance in folate metabolism in schizophrenia is that ultimately the disturbed metabolism would lead to dementia, which is not a feature of schizophrenia. Nevertheless, the fact that folate disturbances may lead to mental symptoms is of considerable interest in relation to biochemical aspects of psychiatric illness, and deserves further investigation, especially as folate deficiency is not uncommon amongst psychiatric patients, 28,29 and there is selective concentration of the vitamin in the nervous system, where its functions are largely unknown.26.35 In addition to possible functions which may be extrapolated from hsematological studies (i.e., nucleoprotein synthesis, methionine synthesis, &c.) there is already evidence that folic acid and its derivatives have potent excitatory properties.26 In relation to a possible influence on monoamine metabolism it is of interest that an inverse relationship between cerebrospinal fluid (c.s.F.) folate and bothC.S.F. 5-hydroxyindoleacetic acid (5-H.I.A.A.) and C.s.F. homovanillic acid (H.v.A.) has recently been observed in drug-treated epileptic patients. 35
folate
reported
University Department of Neurology and Institute of Psychiatry, King’s College Hospital, London SE5 8AF.
E. H. REYNOLDS.
REVERSIBLE RENAL CONCENTRATING DEFECT IN SHOCK SIR,-Professor Whang and Professor Brandfonbrener (Feb. 15, p. 372) do not give credit where it is due in formulating their hypothesis concerning the mechanism of the reversible renal concentrating defect seen in shock. Leaf et al.,36 in an experiment performed 21 years ago on dogs, showed that the osmolality of urine formed by the affected kidney rose and then fell as the renal artery supplying the same kidney was progressively constricted. Levin25. Reynolds, E. H., Chanarin, I., Milner, G., Matthews, D. M. Epilepsia, 1966, 7, 261. 26. Reynolds, E. H. ibid. 1975, 16, 319. 27. Melamed, E., Reches, A., Hershko, C. J. neurol. Sci. 1975, 25, 93. 28. Carney, M. W. P. Br. med. J. 1967, iv, 512. 29. Reynolds, E. H., Preece, J., Johnson, A. L. J. Neurol. Neurosurg. Psychiat. 1971, 34, 726. 30. Reynolds, E. H., Rothfeld, P., Pincus, J. H. Br. med. J. 1973, ii, 398. 31. Arakawa, T. Am. J. Med. 1970, 48, 594. 32. Reynolds, E. H. Lancet, 1968, i, 398. 33. Baldessarini, R. J. New Engl. J. Med. 1975, 292, 527. 34. Levi, R. N., Waxman, S. Lancet, 1975, ii, 11. 35. Reynolds, E. H., Chadwick, D., Jenner, P., Chanarin, I. J. neurol. Sci. (in the press). 36. Leaf, A., Kerr, W. S., Jr., Wrong, O., Chatillon, J. Y. Am. J.
Physiol. 1954, 179,
191.
sky et al. 37 obtained similar results and further demonstrated that urea and mannitol prevented the fall in urine osmolality of the hypoperfused kidney. These authors concluded that failure of sodium and urea delivery to the renal medulla underlay the concentrating defect associated with hypoperfusion. In addition, they directly measured the medullary urea and sodium concentrations of the affected kidney and found them reduced. With respect to reversal of the concentrating defect after restoration of renal perfusion, Whang and Brandfonbrener state in their summary that restoring superficial cortical nephron perfusion " decreased juxtamedullary perfusion and in this manner eliminated medullary washout". Do the authors wish to imply that medullary perfusion actually decreases on reversal of haemorrhagic shock? University Hospital, ROY M. MALETZ Ann Arbor, Michigan 48104, U.S.A.
FRIEDRICH K. PART.
**
We showed this letter to Professor Whang and Professor Brandfonbrener, whose reply follows.-ED. L. to thank Dr Maletz and Dr Port for The works cited demonstrate that with progressive, severe renal hypoperfusion due to renal-artery constriction the ischasmic kidney eventually elaborated a less concentrated urine than its non-constricted counterpart. We did not cite these elegant observations because in neither protocol were the dogs subjected to hasmorrhagic shock. While both hæmorrhagic shock and renal-artery constriction lead to renal hypoperfusion, in our opinion the condition of the studies cited by Dr Maletz and Dr Port and our own observations are as dissimilar as a patient in shock from an exsanguinating peptic ulcer is from a patient with unilateral renal-artery stenosis. We view hxmorrhagic shock as a multifactorial problem, as contrasted with the relatively pristine perturbation of unilateral renal-artery constriction. If the reading of the summary led to the misinterpretation that restoration of blood-volume diminishes medullary perfusion, then it was evidently not lucidly written. What was intended was that, with restoration of blood-volume, regeneration of the hypertonic renal interstitium occurred by permitting more Na and Cl to present at the ascending" limb " pump " as well as to decrease medullary’" washout by diminishing the inappropriately high juxtamedullary perfusion during shock.
SIR,-We wish
their
comments.
Veterans Administration
Hospital, Indianapolis, Indiana 46202, U.S.A.
ROBERT WHANG MARTIN BRANDFONBRENER.
AN ERROR IN RECOMMENDED DOSE OF GENTAMICIN
SIR,-We request use of your columns to warn of a dangerous drug dosage error in the article on infective endocarditis by one of us (P. B. B.) in the new (14th) edition of the Textbook of Medicine (W. B. Saunders). The error is in the 6th paragraph, lst column, p. 315, where the recommended dose of gentamicin is given as 50-100 mg. per kg. body-weight. The correct figure should be 1.0-1.5 mg. per kg. body-weight, intramuscularly or intravenously, every eight hours. The error was discovered after several thousand copies of the book had been distributed in May and June of this year. All copies released by the publishers in July and 37.
Levinsky, N. G., Davidson, D. G., Berliner, R. W. J. clin. Invest. 1959, 38, 730.
= 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.
190 The significance of the case-report is that it adds to the growing evidence that disturbed folate metabolism, especially if severe and prolonged, may lead to neurological disease, including mental symptoms. This evidence has emerged from studies of epileptic,25-27 psychiatric,2a.29 and neurological 30 patients, as well as other inborn errors of metabolism associated with mental retardation from Japan. 311 The type of mental change is variable (as also occurs with vitamin-B12 deficiency) and includes organic psychoses, but probably ultimately the deficiency leads to dementia. In 1968 I discussed 32 the possible relationship between disturbances in folate metabolism and biochemical aspects of schizophrenia because anticonvulsant folate deficiency can sometimes precipitate schizophrenia-like psychoses in epileptic patients, and, as Freeman et al.,24 Baldessarini,33 and Levi and Waxman 34 again imply, there is some common ground between folate metabolism and the abnormal methylation hypothesis of schizophrenia. However, I pointed out then that one difficulty in postulating a disturbance in folate metabolism in schizophrenia is that ultimately the disturbed metabolism would lead to dementia, which is not a feature of schizophrenia. Nevertheless, the fact that folate disturbances may lead to mental symptoms is of considerable interest in relation to biochemical aspects of psychiatric illness, and deserves further investigation, especially as folate deficiency is not uncommon amongst psychiatric patients, 28,29 and there is selective concentration of the vitamin in the nervous system, where its functions are largely unknown.26.35 In addition to possible functions which may be extrapolated from hsematological studies (i.e., nucleoprotein synthesis, methionine synthesis, &c.) there is already evidence that folic acid and its derivatives have potent excitatory properties.26 In relation to a possible influence on monoamine metabolism it is of interest that an inverse relationship between cerebrospinal fluid (c.s.F.) folate and bothC.S.F. 5-hydroxyindoleacetic acid (5-H.I.A.A.) and C.s.F. homovanillic acid (H.v.A.) has recently been observed in drug-treated epileptic patients. 35
folate
reported
University Department of Neurology and Institute of Psychiatry, King’s College Hospital, London SE5 8AF.
E. H. REYNOLDS.
REVERSIBLE RENAL CONCENTRATING DEFECT IN SHOCK SIR,-Professor Whang and Professor Brandfonbrener (Feb. 15, p. 372) do not give credit where it is due in formulating their hypothesis concerning the mechanism of the reversible renal concentrating defect seen in shock. Leaf et al.,36 in an experiment performed 21 years ago on dogs, showed that the osmolality of urine formed by the affected kidney rose and then fell as the renal artery supplying the same kidney was progressively constricted. Levin25. Reynolds, E. H., Chanarin, I., Milner, G., Matthews, D. M. Epilepsia, 1966, 7, 261. 26. Reynolds, E. H. ibid. 1975, 16, 319. 27. Melamed, E., Reches, A., Hershko, C. J. neurol. Sci. 1975, 25, 93. 28. Carney, M. W. P. Br. med. J. 1967, iv, 512. 29. Reynolds, E. H., Preece, J., Johnson, A. L. J. Neurol. Neurosurg. Psychiat. 1971, 34, 726. 30. Reynolds, E. H., Rothfeld, P., Pincus, J. H. Br. med. J. 1973, ii, 398. 31. Arakawa, T. Am. J. Med. 1970, 48, 594. 32. Reynolds, E. H. Lancet, 1968, i, 398. 33. Baldessarini, R. J. New Engl. J. Med. 1975, 292, 527. 34. Levi, R. N., Waxman, S. Lancet, 1975, ii, 11. 35. Reynolds, E. H., Chadwick, D., Jenner, P., Chanarin, I. J. neurol. Sci. (in the press). 36. Leaf, A., Kerr, W. S., Jr., Wrong, O., Chatillon, J. Y. Am. J.
Physiol. 1954, 179,
191.
sky et al. 37 obtained similar results and further demonstrated that urea and mannitol prevented the fall in urine osmolality of the hypoperfused kidney. These authors concluded that failure of sodium and urea delivery to the renal medulla underlay the concentrating defect associated with hypoperfusion. In addition, they directly measured the medullary urea and sodium concentrations of the affected kidney and found them reduced. With respect to reversal of the concentrating defect after restoration of renal perfusion, Whang and Brandfonbrener state in their summary that restoring superficial cortical nephron perfusion " decreased juxtamedullary perfusion and in this manner eliminated medullary washout". Do the authors wish to imply that medullary perfusion actually decreases on reversal of haemorrhagic shock? University Hospital, ROY M. MALETZ Ann Arbor, Michigan 48104, U.S.A.
FRIEDRICH K. PART.
**
We showed this letter to Professor Whang and Professor Brandfonbrener, whose reply follows.-ED. L. to thank Dr Maletz and Dr Port for The works cited demonstrate that with progressive, severe renal hypoperfusion due to renal-artery constriction the ischasmic kidney eventually elaborated a less concentrated urine than its non-constricted counterpart. We did not cite these elegant observations because in neither protocol were the dogs subjected to hasmorrhagic shock. While both hæmorrhagic shock and renal-artery constriction lead to renal hypoperfusion, in our opinion the condition of the studies cited by Dr Maletz and Dr Port and our own observations are as dissimilar as a patient in shock from an exsanguinating peptic ulcer is from a patient with unilateral renal-artery stenosis. We view hxmorrhagic shock as a multifactorial problem, as contrasted with the relatively pristine perturbation of unilateral renal-artery constriction. If the reading of the summary led to the misinterpretation that restoration of blood-volume diminishes medullary perfusion, then it was evidently not lucidly written. What was intended was that, with restoration of blood-volume, regeneration of the hypertonic renal interstitium occurred by permitting more Na and Cl to present at the ascending" limb " pump " as well as to decrease medullary’" washout by diminishing the inappropriately high juxtamedullary perfusion during shock.
SIR,-We wish
their
comments.
Veterans Administration
Hospital, Indianapolis, Indiana 46202, U.S.A.
ROBERT WHANG MARTIN BRANDFONBRENER.
AN ERROR IN RECOMMENDED DOSE OF GENTAMICIN
SIR,-We request use of your columns to warn of a dangerous drug dosage error in the article on infective endocarditis by one of us (P. B. B.) in the new (14th) edition of the Textbook of Medicine (W. B. Saunders). The error is in the 6th paragraph, lst column, p. 315, where the recommended dose of gentamicin is given as 50-100 mg. per kg. body-weight. The correct figure should be 1.0-1.5 mg. per kg. body-weight, intramuscularly or intravenously, every eight hours. The error was discovered after several thousand copies of the book had been distributed in May and June of this year. All copies released by the publishers in July and 37.
Levinsky, N. G., Davidson, D. G., Berliner, R. W. J. clin. Invest. 1959, 38, 730.
