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CONTROL OF ANTICOAGULANT TREATMENT

ANTICOAGULANT treatment depends for success and

safety on good laboratory control. Work is in hand on anational and an international basis to improve control bythe provision of laboratory standards. Most hospitals inBritain and elsewhere use some modification of Quick’sprothrombin-time technique. 1 In this simple test therecalcification time of plasma is accelerated by theaddition of a powerful tissue extract (thromboplastin).The depressions produced by anticoagulants in the levelsof three of the four coumarin clotting factors (prothrombin,factor vii, and factor x) are measured. The test isinsensitive to changes in factor ix (Christmas factor).But the universal use of the Quick method has done littleto bring uniformity to anticoagulant treatment. Thereare innumerable variations in technique and in themethod of expressing results. Even if all the variableswere standardised, the simple substitution of differenttissue-extract thromboplastins in the test produces widevariations in results on the same patient’s blood.2-5 Theclotting factors have species specificity in their reactionwith tissue extracts, and human clotting factors react lesswell with animal tissues. Some commercial preparations,which are necessarily animal extracts, are also grosslyinsensitive to one of the important factors reduced byanticoagulants-factor vn. In some hospitals, therefore, thecustomary therapeutic range of 15-30% prothrombinactivity, or 2-3 times prothrombin ratio, is homceopathic,whereas in other centres the same range indicates a

dangerous overdose.In Britain a national scheme has been gradually evolved

to overcome these difficulties. 6 Routine supplies of asensitive tissue thromboplastin are distributed from onecentre and a laboratory technique is recommended. Theroutine service covers most of the hospitals serving apopulation of 15 million. Other hospitals throughout thecountry receive a small sample of the same reagent atregular intervals to match against successive batches oftheir home-made or commercial extracts. The equivalenttherapeutic range, whether expressed as prothrombinactivity, ratio, or index, may be determined by parallelobservation on patients having anticoagulant treatment.A method for determining the "equivalent" prothrom-

bin ratio of an unknown thromboplastin reagent has beendescribed by Biggs and Denson 5, using the same principleof parallel observation of two thromboplastin reagents.This technique may be a useful way of screening outinferior preparations.Another approach has come from the United States,

where the situation is rather different, since commercialtissue extracts are used, human brain extracts beingunavailable or unacceptable. These animal preparationsare relatively or grossly insensitive to the three humanfactors reduced by oral anticoagulants, and none is suitableas a reference preparation. Miale and La Fond’s pre-liminary study 7, using freeze-dried plasma of knowncomposition as standards in a large survey, and a latersurvey in Britain by Poller and Thomson have shown thedifficulties of using lyophilised plasma standards. Much1. Quick, A. J., Stanley-Brown, M., Bancroft, F. W. Am. J. med. Sci.

1935, 190, 501.2. Poller, L. Theory and Practice of Anticoagulant Treatment; p. 61.

Bristol, 1962.3. Poller, L. Br. med. J. 1964, ii, 565.4. Hougie, C. Fundamentals of Blood Coagulation; p. 166. New York,

1963.5. Biggs, R., Denson, K. W. E. Br. med. J. 1967, i, 84.6. Poller, L. Lancet, 1967, i, 491.7. Miale, J. B., La Fond, D. J. Am. J. clin. Path. 1967, 4, 740.

more work remains to be done before they can be con-sidered as a substitute for a thromboplastin standard.A meeting of the International Committee for Haemostasisin Washington last November decided on further inter-national collaborative studies on plasma standards; andthe merits of four specific thromboplastin extracts as

international reference preparations will be examined.In the absence of an international standard, what can

doctors and manufacturers best do ? Two of the recom-mended thromboplastin preparations have been widelyused in clinical practice. The Manchester ComparativeReagent is freely available to Health Service hospitals inBritain, and the therapeutic levels equivalent to its 15-30%prothrombin activity (1-8-3-0 times ratio) can readily bedetermined by parallel observation. Abroad the positionis less satisfactory. Owren’s thrombotest preparation 8 ismanufactured and distributed commercially and, althoughit is not quite as simple to use as a reference preparationnor is it strictly reproducible between batches, the rangeequivalent to 6-10% activity gives a reasonably safe levelof anticoagulation.

A CARCINOGEN IN JUTE PROCESSING

CARBONACEOUS material in the earth’s crust oftencontains carcinogens; and medical recognition of thisfact has had an important influence on the development ofexperimental cancer research. Moreover, public-healthauthorities must be perpetually vigilant when a newindustrial use is proposed for mineral oils. In the 19th

century the jute fibre was rendered more pliable-andtherefore amenable to spinning-by treatment with oils ofanimal origin. But the amount of animal oils has been

progressively reduced in the past few decades, mainlyby the substitution of mineral oil for whale oil. The

experimental study by Roe and his colleagues 9 is thereforetimely. They found that the periodic application of thismineral oil in small doses (0-25 ml.) to the skin of micewas followed by the appearance of malignant skin tumours.When the oil was applied after pretreatment of the skinwith dimethylbenzanthracene in a dose insufficient initself to give rise to many tumours, the subsequentyield of malignant tumours was greatly increased. This

finding certainly suggests that the situation in the juteindustry should be carefully watched. But it may wellbe that, as in the modern cotton industry, skin cancer isnot the hazard it used to be.From the industrial-health aspect, the convincing

demonstration that the suspected oil contained a car-

cinogen seems enough to justify these experiments. Lessobvious issues, however, are also dealt with. Did the oilact as a

" complete carcinogen " or as a "

promoter " ? Inother words, did the oil act carcinogenically in the sameway as the familiar polycyclic compound which had beenadded or did it act, at least in part, as a co-carcinogen?Certainly, at the dosage employed and using relatively fewlaboratory mice, the polycyclic compound by itselfseemed to be only slightly carcinogenic. On the other

hand, a small quantity of it added to the mineral oilincreased its carcinogenicity very considerably. The

hydrocarbon is obviously adjuvant to the carcinogenicityof the mineral oil, but on present evidence the precisemode of its carcinogenic action is hard to define.8. Owren, P. A. Lancet, 1959, ii, 754.9. Roe, F. J. C., Carter, R. L., Taylor, W. Br. J. Cancer, 1967, 31, 694.