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Clinical Concentrates of

Clotting-factor IXFRACTIONATION increases the usefulness of blood

for transfusion. Anaemic patients require red cellsbut usually not plasma. Plasma is valuable for re-storing blood-volume, but whole plasma need sel-dom be given. Plasma-protein fraction, which is

mainly albumin, exerts roughly the same colloidosmotic pressure as reconstituted, freeze-driedplasma, but can be heat sterilised; its manufacturealso allows gamma-globulin (for instance) to be

separately concentrated. Similarly, various concen-trates of coagulation factors can be prepared: theNational Health Service needs greatly increasedsupplies of factor VIII to treat haemophiliacs.Defective synthesis of factor VIII, in both hmmo-philia and von Willebrand’s disease, is the com-monest of the life-long clotting disorders; the com-ponent next most often affected is factor IX, inChristmas disease.

In the present state of the art, clinical concen-trates of factor IX cannot be freed from factors II(prothrombin) and X; and some, in addition, con-tain factor VII, although for technical reasons theBritish fractionation laboratories find it more satis-factory to make concentrates without VII; the Ox-ford material is called DE(1)1 and the Edinburghproduct, which is similar, is called DEFIX.2 Thereare advantages and disadvantages in having severalfactors in the same preparation. On the credit side,the material mainly provided for treatment ofChristmas disease can conveniently also be used inthe rarer isolated congenital defects of factors II orX (or VII). There is also the interesting possibilityof using the fractions to treat the much commoner

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.

combined defects caused by hepatocellular diseaseor by oral-anticoagulant treatment, when clottingactivities fall below the safety level. On the debitside, there is always the danger that these clottingfactors will have become activated in the course ofpreparation. Activated factor X is thought to bethrombogenic; and prothrombin is activated to

thrombin which clots fibrinogen. As with any bloodfraction which is made from pooled plasma andwhich, unlike plasma-protein fraction, cannot besterilised, there is also a greater risk of transmittinghepatitis than when single donations are given,although the risk is progressively falling as screen-ing of donations improves. There is also the dangerof haemolysis from blood-group alloantibodies. Inaddition, fractionation is generally associated withloss of recovery. For these reasons, some workersstill prefer whole plasma for the treatment of minorbleeding episodes in haemophilia and Christmas dis-ease,3 although the incidence of reactions is prob-ably higher than with cryoprecipitate or dried frac-tions. However, it is not usually possible to

administer sufficient activity as whole plasma tocover major surgery or trauma. As with factor-VIIIconcentrates in haemophilia, the replacement offactor IX in Christmas disease has been managedvery satisfactorily with concentrates, for over tenyears.4 Lately, reports have been accumulatingof thromboembolic or clotting complications afteruse of some preparations in Christmas disease,6-9factor-X deficiency, 10 and liver disease.’ The Bri-tish concentrates have a clean record in Christmasdisease so far. A report from Oxford12 analyses theuse, without evidence of thromboembolism, of2436 bottles from 143 batches in 72 patients, 11 ofwhom were covered for major surgery; speciallaboratory studies in 14 of these patients revealedno evidence of disseminated intravascular coagula-tion. In the whole country over 300 patients havenow been treated, with only 1 thromboembolic

complication reported-a deep-vein thrombosisabout twenty days after total hip replacement(Charnley prosthesis).13 In liver disease, where themechanisms for neutralising14 or removing15 acti-vated factors may be impaired, the danger of trig-gering 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., Elliott-

Smith, 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 Con-gress of the World Federation of Hemophilia, Helsinki, July 27-Aug. 1,1975, p. 60.

14. Dioguardi, N., Mannucci, P. M. Lancet, July 26, 1975, p. 188.15. Deykin, D. J. clin. Invest. 1966, 45, 256.

856

material has been implicatedll here, although someprotection was afforded by heparinising the pa-tients during treatment." All batches of DE(1)used in the Christmas disease and hepatitis studieshad passed a screening test 16 designed to eliminateactivated materials. Tests for potential thrombo-genicity are being refined.17 18 An older Britishconcentrate (type C19), containing also factor VII,has been found useful in liver disease, and has notgiven evidence of intravascular clotting or throm-boembolism;2o 21 separate commercial concentratesof factors II, IX, and X and of factor VII, used inassociation, have also been promising.14 However,it is not really clear that the presence of VII

materially affects the safety of the product. In judg-ing the therapeutic effect, it is to be expected, andthese reports confirm,14 20 that the prothrombin-time will not become normal if a deficiency of fac-tor VII is not made good; but other experience sug-gests that haemostatic competence may be improvedby raising the levels of II, IX, and X alone. Thevalue and safety of concentrates in liver diseaseneeds further investigation.22 The II, IX, and Xconcentrates are relatively inexpensive and eco-

nomical of plasma resources, and have a goodsafety record, and it is encouraging that a MedicalResearch Council working-party is organisingtrials in both liver disease and anticoagulant rever-sal. The British fractionation laboratories makedifferent four-factor products (containing factor

VII) in small amounts, but would require good evi-dence that a factor-VII preparation was reallynecessary before they would divert furtherresources to preparing it.There may also be a place for factor-IX concen-

trates in haemophilia complicated by anti-factor-VIII antibody. Good results have been claimed with"activated" preparations,23—25 tried in the hopethat they might bypass the clotting step dependenton factor-VIII activity. The danger of injectingactivated material cannot be overlooked, and ben-efit with unactivated material has already beenreported.24 The three-factor concentrates, whichhave proved so safe in factor-IX deficiency, shouldalso be tried here, but that is another story.

16. Bidwell, E., Dike, G. W. R. in Treatment of Hæmophilia and other Coagula-tion Disorders (edited by R. Biggs and R. G. Macfarlane); p. 66. Oxford,1966.

17. Sas, G., Owens, R. E., Smith, J. K., Middleton, S., Cash, J. D. Br. J.Hæmat. 1975, 31, 25.

18. Kingdon, H. S., Lundblad, R. L., Veltkamp, J. J., Aronson, D. L. Thromb.Diath. hæmorrh. 1975, 33, 617.

19. Bidwell, E., Booth, J. M., Dike, G. W. R., Denson, K. W. E. Br. J. Hæmat.1967, 13, 568.

20. Green, G., Poller, L., Dymock, I. W., Thomson, J. M. Lancet, 1975, i. 1311.21. Green, G., Poller, L., Dymock, I. W., Thomson, J. M. ibid. Aug. 16, 1975,

p. 328.22. Preston, F. E., Winfield, D. A. ibid.23. 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.295.

24 Kurczynski, E. M., Penner, J. A. New Engl. J. Med. 1974, 291, 164.25. Abildgaard, C. F., Harrison, J., Abstracts of XIV Congress of the Interna-

tional Society of Blood Transfusion and X Congress of the World Federa-tion of Hemophilia, Helsinki, July-Aug. 1, 1975, p. 100.

Dangerous OffendersTHE Butler Committee has outlined with dis-

piriting clarity the difficulties encountered by doc-tors and others trying to operate existing provisionsfor the humane and safe management of mentallyabnormal offenders. Three themes underlie the140 final recommendations: criminal responsibilityin the presence of mental disorder; the manage-ment of dangerousness; and the nature and rele-vance of treatment in personality disorder. In allthese areas the precise thought and language of thereport highlight uncomfortable dilemmas, some ofwhich are the concern of doctors, others the con-cern of every responsible adult. Finding the

M’Naghten Rules unsatisfactory for the determina-tion of criminal responsibility, the committeerecommends the introduction of a "special verdict"which shall apply when two points have been estab-lished-firstly, did the plaintiff know what he wasdoing? and, secondly, was he suffering from severemental illness or severe subnormality? (If he didnot know what he was doing, the special, verdictapplies on this alone. If he did know, but was men-tally severely ill or subnormal, the verdict equallyapplies.) The committee defines severe mental ill-ness in terms limited strictly to mental phenomenawhich can be demonstrated and recorded as abnor-mal on examination. It specifies that factual tests ofthese phenomena will have to be spelt out and exa-mining doctors will be required to depose to them.Every psychiatrist whose practice includes the writ-ing of court reports must read and ponder para-graph 18.35 where this definition is laid out. Sincemany think that an undue emphasis on pheno-menology is the death-knell of therapeutic under-standing in psychiatric practice, the definition isbound to cause controversy. Nevertheless, some-thing must be done about the impasse wherein thecourt asks the doctor "Is this man mentally ill?"and the doctor answers "He is not psychotic but hesuffers a severe personality disorder"-leavingboth sides spitting with rage and frustrationbecause the court has asked a meaningless questionand the doctor has given an unusable answer. Thejustification for this definition lies in two facts notusually made plain to the examining doctor: firstly,that "Degrees of responsibility are legal, not medi-cal concepts" so that the doctor’s function is to pro-vide facts upon which the jury can decide the

degree of responsibility; secondly, that the doctor’sfirst duty, in providing a court report, is to thecourt (and to the public represented by the court),not as in all other medical situations to the thera-

peutic needs of his patient. This order of prioritiesis a difficult one for doctors to swallow-especiallysince, in the existing structure of forensic psychiat-ric outpatient services, the examining doctor is

1. Report of the Committee on Mentally Abnormal Offenders (chairman, LordButler). Command 6244. H.M. Stationery Office. £3.95