855
by hepatocellular disease by oral-anticoagulant treatment, when clotting activities fall below the safety level. On the debit side, there is always the danger that these clotting
combined defects caused or
Clinical Concentrates of
Clotting-factor
IX
FRACTIONATION increases the usefulness of blood for transfusion. Anaemic patients require red cells but usually not plasma. Plasma is valuable for restoring blood-volume, but whole plasma need seldom be given. Plasma-protein fraction, which is exerts roughly the same colloid osmotic pressure as reconstituted, freeze-dried plasma, but can be heat sterilised; its manufacture also allows gamma-globulin (for instance) to be separately concentrated. Similarly, various concentrates of coagulation factors can be prepared: the National Health Service needs greatly increased supplies of factor VIII to treat haemophiliacs. Defective synthesis of factor VIII, in both hmmophilia and von Willebrand’s disease, is the commonest of the life-long clotting disorders; the component next most often affected is factor IX, in Christmas disease. In the present state of the art, clinical concentrates of factor IX cannot be freed from factors II (prothrombin) and X; and some, in addition, contain factor VII, although for technical reasons the British fractionation laboratories find it more satisfactory to make concentrates without VII; the Oxford material is called DE(1)1 and the Edinburgh product, which is similar, is called DEFIX.2There are advantages and disadvantages in having several factors in the same preparation. On the credit side, the material mainly provided for treatment of Christmas disease can conveniently also be used in the rarer isolated congenital defects of factors II or X (or VII). There is also the interesting possibility of using the fractions to treat the much commoner
mainly albumin,
factors will have become activated in the course of preparation. Activated factor X is thought to be thrombogenic; and prothrombin is activated to thrombin which clots fibrinogen. As with any blood fraction which is made from pooled plasma and which, unlike plasma-protein fraction, cannot be sterilised, there is also a greater risk of transmitting hepatitis than when single donations are given, although the risk is progressively falling as screening of donations improves. There is also the danger of haemolysis from blood-group alloantibodies. In addition, fractionation is generally associated with loss of recovery. For these reasons, some workers still prefer whole plasma for the treatment of minor bleeding episodes in haemophilia and Christmas disease,3although the incidence of reactions is probably higher than with cryoprecipitate or dried fractions. However, it is not usually possible to administer sufficient activity as whole plasma to cover major surgery or trauma. As with factor-VIII concentrates in haemophilia, the replacement of factor IX in Christmas disease has been managed very satisfactorily with concentrates, for over ten years.4Lately, reports have been accumulating of thromboembolic or clotting complications after use of some preparations in Christmas disease,6-9 factor-X deficiency, 10 and liver disease.’The British concentrates have a clean record in Christmas disease so far. A report from Oxford12 analyses the use, without evidence of thromboembolism, of 2436 bottles from 143 batches in 72 patients, 11 of whom were covered for major surgery; special laboratory studies in 14 of these patients revealed no evidence of disseminated intravascular coagulation. In the whole country over 300 patients have now been treated, with only 1 thromboembolic complication reported-a deep-vein thrombosis about twenty days after total hip replacement (Charnley prosthesis).13 In liver disease, where the mechanisms for neutralising14 or removing15 activated factors may be impaired, the danger of triggering intravascular clotting is greater. The DE(1) 3. Lurie, A., Oberwaldner, B., Shapiro, M. S. Afr. med. J. 1975, 49, 931. 4. Larrieu, M-J., Caen, J., Soulier, J. P., Bernard, J. Path. Biol. 1959, 7, 2507. 5. Biggs, R., Bidwell, E., Handley, D. A., Macfarlane, R. G., Trueta, J., ElliottSmith, A., Dike, G. W. R., Ash, B. J. Br. J. Hæmat. 1961, 7, 349. 6. Kasper, C. K. New Engl. J. Med. 1973, 289, 160. 7. Edson, J. R. ibid. 1974, 290, 403. 8. Marchesi, S. L., Burney, R. ibid. p. 40. 9. Kasper, C. K. ibid. p. 404. 10. Blatt, P. M., Lundblad, R. L., Kingdon, H. S., McLean, G., Roberts, H. R. Ann. intern. Med. 1974, 81, 766. 11. Gazzard, B. G., Lewis, M. L., Ash, G., Rizza, C. R., Bidwell, E., Williams, R. Gut, 1974, 15, 993. 12. Lane, J. L., Rizza, C. R., Snape, T. J. Br. J. Hæmat. 1975, 30, 435. 13. Bidwell, E., Rizza, C. R., Dike, G. W. R., Snape, T. J. Abstracts of XIV Congress of the International Society of Blood Transfusion and X Congress of the World Federation of Hemophilia, Helsinki, July 27-Aug. 1,
1975, p. 60. 1 Dike, G. W. R., Bidwell, E., Rizza, C. R. Br. J. Hæmat. 1972, 22, 469. 2 Middleton, S. H., Bennett, I. H., Smith, J. K. Vox Sang. 1973, 24, 441.
14. Dioguardi, 15. Deykin, D.
N., Mannucci, P. M. Lancet, July 26, 1975, p. 188. J. clin. Invest. 1966, 45, 256.
856
material has been implicatedll here, although some protection was afforded by heparinising the patients during treatment."All batches of DE(1) used in the Christmas disease and hepatitis studies had passed a screening test 16 designed to eliminate activated materials. Tests for potential thrombogenicity are being refined.17 18 An older British concentrate (type C19), containing also factor VII, has been found useful in liver disease, and has not given evidence of intravascular clotting or thromboembolism;2o 21 separate commercial concentrates of factors II, IX, and X and of factor VII, used in association, have also been promising.14 However, it is not really clear that the presence of VII materially affects the safety of the product. In judging the therapeutic effect,20it is to be expected, and that the prothrombinthese reports confirm,14 time will not become normal if a deficiency of factor VII is not made good; but other experience suggests that haemostatic competence may be improved by raising the levels of II, IX, and X alone. The value and safety of concentrates in liver disease needs further investigation.22 The II, IX, and X concentrates are relatively inexpensive and economical of plasma resources, and have a good safety record, and it is encouraging that a Medical Research Council working-party is organising trials in both liver disease and anticoagulant reversal. The British fractionation laboratories make different four-factor products (containing factor VII) in small amounts, but would require good evidence that a factor-VII preparation was really necessary before they would divert further resources to preparing it. There may also be a place for factor-IX concentrates in haemophilia complicated by anti-factorVIII antibody. Good results have been claimed with "activated" preparations,23—25 tried in the hope that they might bypass the clotting step dependent on factor-VIII activity. The danger of injecting activated material cannot be overlooked, and benefit with unactivated material has already been reported.24 The three-factor concentrates, which have proved so safe in factor-IX deficiency, should also be tried here, but that is another story.
16.
Bidwell, E., Dike, G. W. R. in Treatment of Hæmophilia and other Coagulation Disorders (edited by R. Biggs and R. G. Macfarlane); p. 66. Oxford,
17.
Sas, G., Owens, R. E., Smith, J. K., Middleton, S., Cash, J. D. Br. J. Hæmat. 1975, 31, 25. Kingdon, H. S., Lundblad, R. L., Veltkamp, J. J., Aronson, D. L. Thromb. Diath. hæmorrh. 1975, 33, 617. Bidwell, E., Booth, J. M., Dike, G. W. R., Denson, K. W. E. Br. J. Hæmat. 1967, 13, 568. Green, G., Poller, L., Dymock, I. W., Thomson, J. M. Lancet, 1975, i. 1311. Green, G., Poller, L., Dymock, I. W., Thomson, J. M. ibid. Aug. 16, 1975, p. 328. Preston, F. E., Winfield, D. A. ibid. Fekete, I. F., Hoist, S. L., Peetoom, F., De Veber, L. L. Abstracts of XIV International Congress of Hematology, São Paulo, July 16-21, 1972, no.
1966.
18. 19. 20. 21. 22. 23.
295. 24 25.
Kurczynski, E. M., Penner, J. A. New Engl. J. Med. 1974, 291, 164. Abildgaard, C. F., Harrison, J., Abstracts of XIV Congress of the International Society of Blood Transfusion and X Congress of the World Federation of Hemophilia, Helsinki, July-Aug. 1, 1975, p. 100.
Dangerous Offenders THE Butler Committee has outlined with dispiriting clarity the difficulties encountered by doctors and others trying to operate existing provisions for the humane and safe management of mentally abnormal offenders. Three themes underlie the 140 final recommendations: criminal responsibility in the presence of mental disorder; the management of dangerousness; and the nature and relevance of treatment in personality disorder. In all
these areas the precise thought and language of the report highlight uncomfortable dilemmas, some of which are the concern of doctors, others the concern of every responsible adult. Finding the M’Naghten Rules unsatisfactory for the determination of criminal responsibility, the committee recommends the introduction of a "special verdict" which shall apply when two points have been established-firstly, did the plaintiff know what he was doing? and, secondly, was he suffering from severe mental illness or severe subnormality? (If he did not know what he was doing, the special, verdict applies on this alone. If he did know, but was mentally severely ill or subnormal, the verdict equally applies.) The committee defines severe mental illness in terms limited strictly to mental phenomena which can be demonstrated and recorded as abnormal on examination. It specifies that factual tests of these phenomena will have to be spelt out and examining doctors will be required to depose to them. Every psychiatrist whose practice includes the writing of court reports must read and ponder paragraph 18.35 where this definition is laid out. Since many think that an undue emphasis on phenomenology is the death-knell of therapeutic understanding in psychiatric practice, the definition is bound to cause controversy. Nevertheless, something must be done about the impasse wherein the court asks the doctor "Is this man mentally ill?" and the doctor answers "He is not psychotic but he suffers a severe personality disorder"-leaving both sides spitting with rage and frustration because the court has asked a meaningless question and the doctor has given an unusable answer. The justification for this definition lies in two facts not usually made plain to the examining doctor: firstly, that "Degrees of responsibility are legal, not medical concepts" so that the doctor’s function is to provide facts upon which the jury can decide the degree of responsibility; secondly, that the doctor’s first duty, in providing a court report, is to the court (and to the public represented by the court), not as in all other medical situations to the therapeutic needs of his patient. This order of priorities is a difficult one for doctors to swallow-especially since, in the existing structure of forensic psychiatric outpatient services, the examining doctor is 1.
of the Committee on Mentally Abnormal Offenders Butler). Command 6244. H.M. Stationery Office. £3.95
Report
(chairman, Lord
by hepatocellular disease by oral-anticoagulant treatment, when clotting activities fall below the safety level. On the debit side, there is always the danger that these clotting
combined defects caused or
Clinical Concentrates of
Clotting-factor
IX
FRACTIONATION increases the usefulness of blood for transfusion. Anaemic patients require red cells but usually not plasma. Plasma is valuable for restoring blood-volume, but whole plasma need seldom be given. Plasma-protein fraction, which is exerts roughly the same colloid osmotic pressure as reconstituted, freeze-dried plasma, but can be heat sterilised; its manufacture also allows gamma-globulin (for instance) to be separately concentrated. Similarly, various concentrates of coagulation factors can be prepared: the National Health Service needs greatly increased supplies of factor VIII to treat haemophiliacs. Defective synthesis of factor VIII, in both hmmophilia and von Willebrand’s disease, is the commonest of the life-long clotting disorders; the component next most often affected is factor IX, in Christmas disease. In the present state of the art, clinical concentrates of factor IX cannot be freed from factors II (prothrombin) and X; and some, in addition, contain factor VII, although for technical reasons the British fractionation laboratories find it more satisfactory to make concentrates without VII; the Oxford material is called DE(1)1 and the Edinburgh product, which is similar, is called DEFIX.2There are advantages and disadvantages in having several factors in the same preparation. On the credit side, the material mainly provided for treatment of Christmas disease can conveniently also be used in the rarer isolated congenital defects of factors II or X (or VII). There is also the interesting possibility of using the fractions to treat the much commoner
mainly albumin,
factors will have become activated in the course of preparation. Activated factor X is thought to be thrombogenic; and prothrombin is activated to thrombin which clots fibrinogen. As with any blood fraction which is made from pooled plasma and which, unlike plasma-protein fraction, cannot be sterilised, there is also a greater risk of transmitting hepatitis than when single donations are given, although the risk is progressively falling as screening of donations improves. There is also the danger of haemolysis from blood-group alloantibodies. In addition, fractionation is generally associated with loss of recovery. For these reasons, some workers still prefer whole plasma for the treatment of minor bleeding episodes in haemophilia and Christmas disease,3although the incidence of reactions is probably higher than with cryoprecipitate or dried fractions. However, it is not usually possible to administer sufficient activity as whole plasma to cover major surgery or trauma. As with factor-VIII concentrates in haemophilia, the replacement of factor IX in Christmas disease has been managed very satisfactorily with concentrates, for over ten years.4Lately, reports have been accumulating of thromboembolic or clotting complications after use of some preparations in Christmas disease,6-9 factor-X deficiency, 10 and liver disease.’The British concentrates have a clean record in Christmas disease so far. A report from Oxford12 analyses the use, without evidence of thromboembolism, of 2436 bottles from 143 batches in 72 patients, 11 of whom were covered for major surgery; special laboratory studies in 14 of these patients revealed no evidence of disseminated intravascular coagulation. In the whole country over 300 patients have now been treated, with only 1 thromboembolic complication reported-a deep-vein thrombosis about twenty days after total hip replacement (Charnley prosthesis).13 In liver disease, where the mechanisms for neutralising14 or removing15 activated factors may be impaired, the danger of triggering intravascular clotting is greater. The DE(1) 3. Lurie, A., Oberwaldner, B., Shapiro, M. S. Afr. med. J. 1975, 49, 931. 4. Larrieu, M-J., Caen, J., Soulier, J. P., Bernard, J. Path. Biol. 1959, 7, 2507. 5. Biggs, R., Bidwell, E., Handley, D. A., Macfarlane, R. G., Trueta, J., ElliottSmith, A., Dike, G. W. R., Ash, B. J. Br. J. Hæmat. 1961, 7, 349. 6. Kasper, C. K. New Engl. J. Med. 1973, 289, 160. 7. Edson, J. R. ibid. 1974, 290, 403. 8. Marchesi, S. L., Burney, R. ibid. p. 40. 9. Kasper, C. K. ibid. p. 404. 10. Blatt, P. M., Lundblad, R. L., Kingdon, H. S., McLean, G., Roberts, H. R. Ann. intern. Med. 1974, 81, 766. 11. Gazzard, B. G., Lewis, M. L., Ash, G., Rizza, C. R., Bidwell, E., Williams, R. Gut, 1974, 15, 993. 12. Lane, J. L., Rizza, C. R., Snape, T. J. Br. J. Hæmat. 1975, 30, 435. 13. Bidwell, E., Rizza, C. R., Dike, G. W. R., Snape, T. J. Abstracts of XIV Congress of the International Society of Blood Transfusion and X Congress of the World Federation of Hemophilia, Helsinki, July 27-Aug. 1,
1975, p. 60. 1 Dike, G. W. R., Bidwell, E., Rizza, C. R. Br. J. Hæmat. 1972, 22, 469. 2 Middleton, S. H., Bennett, I. H., Smith, J. K. Vox Sang. 1973, 24, 441.
14. Dioguardi, 15. Deykin, D.
N., Mannucci, P. M. Lancet, July 26, 1975, p. 188. J. clin. Invest. 1966, 45, 256.
856
material has been implicatedll here, although some protection was afforded by heparinising the patients during treatment."All batches of DE(1) used in the Christmas disease and hepatitis studies had passed a screening test 16 designed to eliminate activated materials. Tests for potential thrombogenicity are being refined.17 18 An older British concentrate (type C19), containing also factor VII, has been found useful in liver disease, and has not given evidence of intravascular clotting or thromboembolism;2o 21 separate commercial concentrates of factors II, IX, and X and of factor VII, used in association, have also been promising.14 However, it is not really clear that the presence of VII materially affects the safety of the product. In judging the therapeutic effect,20it is to be expected, and that the prothrombinthese reports confirm,14 time will not become normal if a deficiency of factor VII is not made good; but other experience suggests that haemostatic competence may be improved by raising the levels of II, IX, and X alone. The value and safety of concentrates in liver disease needs further investigation.22 The II, IX, and X concentrates are relatively inexpensive and economical of plasma resources, and have a good safety record, and it is encouraging that a Medical Research Council working-party is organising trials in both liver disease and anticoagulant reversal. The British fractionation laboratories make different four-factor products (containing factor VII) in small amounts, but would require good evidence that a factor-VII preparation was really necessary before they would divert further resources to preparing it. There may also be a place for factor-IX concentrates in haemophilia complicated by anti-factorVIII antibody. Good results have been claimed with "activated" preparations,23—25 tried in the hope that they might bypass the clotting step dependent on factor-VIII activity. The danger of injecting activated material cannot be overlooked, and benefit with unactivated material has already been reported.24 The three-factor concentrates, which have proved so safe in factor-IX deficiency, should also be tried here, but that is another story.
16.
Bidwell, E., Dike, G. W. R. in Treatment of Hæmophilia and other Coagulation Disorders (edited by R. Biggs and R. G. Macfarlane); p. 66. Oxford,
17.
Sas, G., Owens, R. E., Smith, J. K., Middleton, S., Cash, J. D. Br. J. Hæmat. 1975, 31, 25. Kingdon, H. S., Lundblad, R. L., Veltkamp, J. J., Aronson, D. L. Thromb. Diath. hæmorrh. 1975, 33, 617. Bidwell, E., Booth, J. M., Dike, G. W. R., Denson, K. W. E. Br. J. Hæmat. 1967, 13, 568. Green, G., Poller, L., Dymock, I. W., Thomson, J. M. Lancet, 1975, i. 1311. Green, G., Poller, L., Dymock, I. W., Thomson, J. M. ibid. Aug. 16, 1975, p. 328. Preston, F. E., Winfield, D. A. ibid. Fekete, I. F., Hoist, S. L., Peetoom, F., De Veber, L. L. Abstracts of XIV International Congress of Hematology, São Paulo, July 16-21, 1972, no.
1966.
18. 19. 20. 21. 22. 23.
295. 24 25.
Kurczynski, E. M., Penner, J. A. New Engl. J. Med. 1974, 291, 164. Abildgaard, C. F., Harrison, J., Abstracts of XIV Congress of the International Society of Blood Transfusion and X Congress of the World Federation of Hemophilia, Helsinki, July-Aug. 1, 1975, p. 100.
Dangerous Offenders THE Butler Committee has outlined with dispiriting clarity the difficulties encountered by doctors and others trying to operate existing provisions for the humane and safe management of mentally abnormal offenders. Three themes underlie the 140 final recommendations: criminal responsibility in the presence of mental disorder; the management of dangerousness; and the nature and relevance of treatment in personality disorder. In all
these areas the precise thought and language of the report highlight uncomfortable dilemmas, some of which are the concern of doctors, others the concern of every responsible adult. Finding the M’Naghten Rules unsatisfactory for the determination of criminal responsibility, the committee recommends the introduction of a "special verdict" which shall apply when two points have been established-firstly, did the plaintiff know what he was doing? and, secondly, was he suffering from severe mental illness or severe subnormality? (If he did not know what he was doing, the special, verdict applies on this alone. If he did know, but was mentally severely ill or subnormal, the verdict equally applies.) The committee defines severe mental illness in terms limited strictly to mental phenomena which can be demonstrated and recorded as abnormal on examination. It specifies that factual tests of these phenomena will have to be spelt out and examining doctors will be required to depose to them. Every psychiatrist whose practice includes the writing of court reports must read and ponder paragraph 18.35 where this definition is laid out. Since many think that an undue emphasis on phenomenology is the death-knell of therapeutic understanding in psychiatric practice, the definition is bound to cause controversy. Nevertheless, something must be done about the impasse wherein the court asks the doctor "Is this man mentally ill?" and the doctor answers "He is not psychotic but he suffers a severe personality disorder"-leaving both sides spitting with rage and frustration because the court has asked a meaningless question and the doctor has given an unusable answer. The justification for this definition lies in two facts not usually made plain to the examining doctor: firstly, that "Degrees of responsibility are legal, not medical concepts" so that the doctor’s function is to provide facts upon which the jury can decide the degree of responsibility; secondly, that the doctor’s first duty, in providing a court report, is to the court (and to the public represented by the court), not as in all other medical situations to the therapeutic needs of his patient. This order of priorities is a difficult one for doctors to swallow-especially since, in the existing structure of forensic psychiatric outpatient services, the examining doctor is 1.
of the Committee on Mentally Abnormal Offenders Butler). Command 6244. H.M. Stationery Office. £3.95
Report
(chairman, Lord
