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FACTOR VIII
803 of the
lymphocyte-transformation
average again. In our Au-antigen carrier
cases
reached
tests
the
P.H.A.
response
the was
present in the culture. We suppose that a blocking factor in the patient’s plasma was responsible for the diminished response. The simultaneous use of autologous plasma in the cultures creates conditions similar to those in vivo, so this is a more informative way of testing the immune response in special circumstances.
diminished only when autologous plasma
Blood Transfusion Centre, University Medical School, P.O. Box 464, Szeged,
Hungary.
was
ILDIKÓ B. PETRI ELIZABETH J. MÉSZÁROS.
HIGH SERUM-ACID-PHOSPHATASE LEVELS
SIR,-In the following case, the serum-acid-phosphate were extremely high.
levels
74-year-old man with prostatism was admitted under the J. Burke at this hospital in 1971. On rectal examination a hard, nodular prostate was palpable. Skeletal survey demonstrated osteoblastic metastases. Total serum-acid-phosphatase was 82 King-Armstrong units per 100 ml. (normal less than 3), the tartrate labile fraction being71 K.A. units per 100 ml. (normal less than 0-7) using phenylphosphate substrate. Adenocarcinoma of the prostate was confirmed histologically after transurethral resection. The patient was treated with oral stilboestrol (10 mg. three times daily). A
care
of Mr
In 1973 the osteoblastic metastases had increased, total acidwas 2500 K.A. units per 100 ml. (tartrate labile estimation of enzyme activities at this level the standard method was adapted by (a) reducing the 60-minute incubation period to 1 minute and (b) preliminary dilution of the serum, both procedures giving essentially similar values. This very high result was confirmed at the Department of Chemical Pathology, St. Paul’s Hospital, London WC2, where the previously highest recorded acid phosphatase level was 356.2 Survey of the literature showed previously recorded levels of up to 1300 K.A. units per 100 ml." Bilateral subcapsular orchidectomy failed to control the condition and acid-phosphatase levels have now reached 5360 K.A. units per 100 ml.
phosphatase 2335). For
St. James’ Hospital, Sarsfeld Road, London SW12 8HW.
behaviour between F.-viu activity and F.-vm-like antigen in transfused vWd subjects indicating that newly synthesised F. vin activity does not precipitate with the antibody produced in rabbits against human F. VIII. Dr Bloom and his colleagues (March 24, p. 661) could even separate a fraction from post-transfusion vWd plasma containing such F. vui activity. The numerous observations that purified F. VIII consists of subunits and might even be an aggregate of oligomers of F. vui and a molecule from another species 6 are not to be disputed, but do not imply that this complexed molecule is the only one to exert F. vui activity. - The aggregation might be a completely passive phenomenon and not related to the pathway of synthesis. In our opinion F. vui synthesis is induced by vWF as indicated by the presence of c.R.M.-negative F. vui activity after transfusion in vWd patients and the existence of considerable de-novo synthesis of F. viu activity in homozygous vWd patients. The problem of " dominance " of the vWd gene mentioned by Dr Boulton (June 23, p. 1446) must then be explained by a regulator gene mutation-i.e., a mutation of the gene that produces the repressor substance for the vWd locus.’ The abnormal repressor (super-repressor) can exert its activity on both the alleles in cis and trans position and dependent on its affinity for the operon of the vWd locus induce a more or less severe defect in vWF synthesis."8 The defective vWF synthesis will subsequently affect F. vui synthesis. The great variability found in heterozygotes carrying the same mutant gene remains unsolved, but we should realise that when we look at the effects of a mutant gene the farther away from the primary gene product the more possibilities exist for modification of the final result-that is, the phenotype. Hæmostasis and Thrombosis Research Unit,
University Hospital, Leiden, Netherlands.
JAN J. VELTKAMP.
ROYAL MEDICAL BENEVOLENT FUND CHRISTMAS APPEAL
M. P. OSBORNE F. M. SANDERSON.
SIR,-Iam asking once again that you will be kind to give space to the Royal Medical Benevolent
enough FACTOR VIII
SIR,-Dr Graham and Dr Barrow’s hypothesis (Aug. 18, 388) that factor vm (F. VIII) is a multimeric protein, which is an extension of their earlier combining subunit theory,‘’ could explain the sometimes dominant effect of the von Willebrand’s disease (vWd) gene and the crossreactive-material (c.R.M.)-negative phenotype in vWd patients. The hypothesis is supported by the earlier observation that homozygous vWd patients respond very poorly to transfusion as compared with heterozygotes. Our own 2 homozygous vWd patients, however, react extremely well to transfusion; when transfused with cryoprecipitate continuously for several days they show F.-vm activity levels that are 6 times higher than expected in a case of sex-linked hemophilia A. Furthermore the multimeric-protein hypothesis does not account for F.-VIII activity in the absence of C.R.M. p.
since the presence of one A" subunit in a F.-vm multimeric molecule would destroy both coagulational and
Fund’s annual Christmas Appeal. Most of us are fortunate enough to look forward to a traditional Christmas spent amongst our families and close friends and to enjoy the giving and receiving of gifts and the other good things we associate with this season of the year.
I
ask you
to
remember those colleagues and their
will not be able to afford the sort of Christmas which most of us will enjoy. I am therefore inviting all members of the profession to give generous support to this appeal. Contributions may be passed direct to the treasurers or medical representatives of the local Guilds of the Royal Medical Benevolent Fund or sent, marked " Christmas Appeal ", to the Director, Royal Medical Benevolent Fund, 24 King’s Road, Wimbledon, London SW19 8QN.
antigenic activity. Bennett and othersdemonstrated
now
dependants who are not so fortunate: the elderly, many of whom are living alone, widows with young families, those who have been stricken by illness or other misfortune and all of whom have one thing in common-namely, that they
T. HOLMES a
difference
in
SELLORS,
President, Royal Medical Benevolent Fund.
King, E. J., Jegatheeson, K. A. J. clin. Path. 1959, 12, 85. Rose, G. A. Personal communication, 1973. Sullivan, T. J., Gutman, E. B., Gutman, A. B. J. Urol. 1942, 48, 426. 4. Barrow, E. S., Heindel, C. C., Roberts, H. R., Graham, J. B. Proc. Soc. exp. Biol. Med. 1965, 118, 684. 5. Bennett, B., Ratnoff, O. D., Levin, J. J. clin. Invest. 1972, 51, 2597. 1. 2. 3.
van Mourik, J. A., Bouma, B. N., Labriuyère, W. T., et al. (in the press). 7. Holmberg, L., Nillson, I. M. Br. med. J. 1972, iii, 317. 8. Dreyfus, J.-C. Progress in Medical Genetics; vol. VI, chap. 5. New York, 1969. 6.
lymphocyte-transformation
average again. In our Au-antigen carrier
cases
reached
tests
the
P.H.A.
response
the was
present in the culture. We suppose that a blocking factor in the patient’s plasma was responsible for the diminished response. The simultaneous use of autologous plasma in the cultures creates conditions similar to those in vivo, so this is a more informative way of testing the immune response in special circumstances.
diminished only when autologous plasma
Blood Transfusion Centre, University Medical School, P.O. Box 464, Szeged,
Hungary.
was
ILDIKÓ B. PETRI ELIZABETH J. MÉSZÁROS.
HIGH SERUM-ACID-PHOSPHATASE LEVELS
SIR,-In the following case, the serum-acid-phosphate were extremely high.
levels
74-year-old man with prostatism was admitted under the J. Burke at this hospital in 1971. On rectal examination a hard, nodular prostate was palpable. Skeletal survey demonstrated osteoblastic metastases. Total serum-acid-phosphatase was 82 King-Armstrong units per 100 ml. (normal less than 3), the tartrate labile fraction being71 K.A. units per 100 ml. (normal less than 0-7) using phenylphosphate substrate. Adenocarcinoma of the prostate was confirmed histologically after transurethral resection. The patient was treated with oral stilboestrol (10 mg. three times daily). A
care
of Mr
In 1973 the osteoblastic metastases had increased, total acidwas 2500 K.A. units per 100 ml. (tartrate labile estimation of enzyme activities at this level the standard method was adapted by (a) reducing the 60-minute incubation period to 1 minute and (b) preliminary dilution of the serum, both procedures giving essentially similar values. This very high result was confirmed at the Department of Chemical Pathology, St. Paul’s Hospital, London WC2, where the previously highest recorded acid phosphatase level was 356.2 Survey of the literature showed previously recorded levels of up to 1300 K.A. units per 100 ml." Bilateral subcapsular orchidectomy failed to control the condition and acid-phosphatase levels have now reached 5360 K.A. units per 100 ml.
phosphatase 2335). For
St. James’ Hospital, Sarsfeld Road, London SW12 8HW.
behaviour between F.-viu activity and F.-vm-like antigen in transfused vWd subjects indicating that newly synthesised F. vin activity does not precipitate with the antibody produced in rabbits against human F. VIII. Dr Bloom and his colleagues (March 24, p. 661) could even separate a fraction from post-transfusion vWd plasma containing such F. vui activity. The numerous observations that purified F. VIII consists of subunits and might even be an aggregate of oligomers of F. vui and a molecule from another species 6 are not to be disputed, but do not imply that this complexed molecule is the only one to exert F. vui activity. - The aggregation might be a completely passive phenomenon and not related to the pathway of synthesis. In our opinion F. vui synthesis is induced by vWF as indicated by the presence of c.R.M.-negative F. vui activity after transfusion in vWd patients and the existence of considerable de-novo synthesis of F. viu activity in homozygous vWd patients. The problem of " dominance " of the vWd gene mentioned by Dr Boulton (June 23, p. 1446) must then be explained by a regulator gene mutation-i.e., a mutation of the gene that produces the repressor substance for the vWd locus.’ The abnormal repressor (super-repressor) can exert its activity on both the alleles in cis and trans position and dependent on its affinity for the operon of the vWd locus induce a more or less severe defect in vWF synthesis."8 The defective vWF synthesis will subsequently affect F. vui synthesis. The great variability found in heterozygotes carrying the same mutant gene remains unsolved, but we should realise that when we look at the effects of a mutant gene the farther away from the primary gene product the more possibilities exist for modification of the final result-that is, the phenotype. Hæmostasis and Thrombosis Research Unit,
University Hospital, Leiden, Netherlands.
JAN J. VELTKAMP.
ROYAL MEDICAL BENEVOLENT FUND CHRISTMAS APPEAL
M. P. OSBORNE F. M. SANDERSON.
SIR,-Iam asking once again that you will be kind to give space to the Royal Medical Benevolent
enough FACTOR VIII
SIR,-Dr Graham and Dr Barrow’s hypothesis (Aug. 18, 388) that factor vm (F. VIII) is a multimeric protein, which is an extension of their earlier combining subunit theory,‘’ could explain the sometimes dominant effect of the von Willebrand’s disease (vWd) gene and the crossreactive-material (c.R.M.)-negative phenotype in vWd patients. The hypothesis is supported by the earlier observation that homozygous vWd patients respond very poorly to transfusion as compared with heterozygotes. Our own 2 homozygous vWd patients, however, react extremely well to transfusion; when transfused with cryoprecipitate continuously for several days they show F.-vm activity levels that are 6 times higher than expected in a case of sex-linked hemophilia A. Furthermore the multimeric-protein hypothesis does not account for F.-VIII activity in the absence of C.R.M. p.
since the presence of one A" subunit in a F.-vm multimeric molecule would destroy both coagulational and
Fund’s annual Christmas Appeal. Most of us are fortunate enough to look forward to a traditional Christmas spent amongst our families and close friends and to enjoy the giving and receiving of gifts and the other good things we associate with this season of the year.
I
ask you
to
remember those colleagues and their
will not be able to afford the sort of Christmas which most of us will enjoy. I am therefore inviting all members of the profession to give generous support to this appeal. Contributions may be passed direct to the treasurers or medical representatives of the local Guilds of the Royal Medical Benevolent Fund or sent, marked " Christmas Appeal ", to the Director, Royal Medical Benevolent Fund, 24 King’s Road, Wimbledon, London SW19 8QN.
antigenic activity. Bennett and othersdemonstrated
now
dependants who are not so fortunate: the elderly, many of whom are living alone, widows with young families, those who have been stricken by illness or other misfortune and all of whom have one thing in common-namely, that they
T. HOLMES a
difference
in
SELLORS,
President, Royal Medical Benevolent Fund.
King, E. J., Jegatheeson, K. A. J. clin. Path. 1959, 12, 85. Rose, G. A. Personal communication, 1973. Sullivan, T. J., Gutman, E. B., Gutman, A. B. J. Urol. 1942, 48, 426. 4. Barrow, E. S., Heindel, C. C., Roberts, H. R., Graham, J. B. Proc. Soc. exp. Biol. Med. 1965, 118, 684. 5. Bennett, B., Ratnoff, O. D., Levin, J. J. clin. Invest. 1972, 51, 2597. 1. 2. 3.
van Mourik, J. A., Bouma, B. N., Labriuyère, W. T., et al. (in the press). 7. Holmberg, L., Nillson, I. M. Br. med. J. 1972, iii, 317. 8. Dreyfus, J.-C. Progress in Medical Genetics; vol. VI, chap. 5. New York, 1969. 6.