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INHERITANCE OF CHRONIC GRANULOMATOUS DISEASE
850 If Dr. van Ypersele de Strihou and M. Stragier are seriously concerned about the risk of hepatitis and the burden of transfusion caused by their treatment policy, they should surely try to adopt a policy of non-transfusion rather than pursue their present policy of transfusing their patients to an arbitrarily determined haemoglobin level. The National Kidney Centre, London N.3.
STANLEY SHALDON.
INHERITANCE OF CHRONIC GRANULOMATOUS DISEASE SIR,-Those of us who are attempting to map the Xchromosome, and need first to define conditions dependent upon variant forms of genes which reside there, can hardly remain mere onlookers in the present controversy on the inheritance of chronic granulomatous disease. 1-3 The elegant work of the Minnesota school appeared to have defined a group of children, almost all boys, who suffered from a serious incapacity to kill bacteria; many shared this with their brothers, their mother’s sisters’ sons, and, in one case, their maternal step-brother, but other relatives appeared unaffected. All familial cases were related exclusively through women. One technique showed appearances consistent with those to be expected if the condition were X-linked and one of the two maternal Xchromosomes were fortuitously inactivated (not eliminated), although such a technique, using cells rather than whole test-tubes, involves microscopy and colour perception and would be difficult to quantify. It seemed, from their results, that most of these boys must be afflicted by an X-borne defect, and that the cataloguing of this vast and complicated field of non-resistance to infection was proceeding along the same lines as in the bleeding disorders, where the initial simplicity of one haemophilia is now complicated by other defects, some autosomal, with similar consequences. Some of us had put up another flag on the X, and were awaiting further information on its neighbours. Now we are told to take it down. The laboratory work was insensitive; the model was insecure ; girls could be affected; and, worst of all, the average father differs from the average doctor in antibacterial aggression with the numbered incredulity of statistical significance. We must consider a new model, and, to placate Occam, advance a concept of scholastic complexity, with unobservable postulates, such as unnoticed early fetal deaths of girls, the type of concept with which Occam
originally expressed concern. The argument
was a
little difficult to follow, and involved
comparing the uncited paper of Windhorst et al.4 with the unpublished papers of Thompson and Soothilland of al .6However, now that Windhorst2 has supwhich contains a full bibliography, and added some data, we must consider what type of evidence is necessary before we take down this flag on our most colonised and best mapped chromosome. Soothill’s a priori argument is that, if in this syndrome a cases are autosomally determined and x cases are X-borne, then a or x should be zero. That is, if a is not zero then x ought to be zero. This seems a strange argument, for if we assume that antibacterial aggression is complicated it must involve several enzymes and if, as is a priori fairly likely (n/17 for n Chandra
et
plied the key reference,
1.
Chandra,
R.
K., Cope, W. A., Soothill, J.
F.
Lancet, July 12, 1969,
p. 71.
Windhorst, D. B. Lancet, Sept. 6, 1969, p. 543. Soothill, J. F. ibid. p. 543. Windhorst, D. B., Page, A. R., Holmes, B., Quid, P. D., Good, R. A. J. clin. Invest. 1968, 47, 1026. 5. Thompson, E. N., Soothill, J. F. Unpublished. Cited by Chandra, R. K., Cope, W. A., Soothill, J. F. Lancet, July 12, 1969, p. 71. 6. Chandra, R. K., Cope, W. A., Soothill, J. F. Unpublished. Cited by Thompson et al.5 2. 3. 4.
serially related enzymes since one seventeenth of the female chromosome set is X-borne) that one is X-borne, it is even more likely that at least one other is not. There is no short. age of precedents. A minority of non-clotters, even though involving A.H.G. deficiency, are not hxmophiliacs. A minority of the colour-blind are neither deutan nor protan. Of at least six polysaccharidoses, only one is X-linked. A condition resembling Duchenne’s muscular dystrophy occurs in girls. G-6 P.D. is X-borne; its functional neigh. bour 6-P.G.D. is not. Indeed, we might go so far as to postulate the general rule that X-linked disorders will have autosomal mimics for mendelian disorders in man seem largely restricted to those systems in which there is an amplification due to sequential reactions of great rapidity and, in higher animals, there seems no tendency for functionally related enzymes to be coded by structurally related genes. What is the evidence on which this locus is to be relegated to an unknown chromosome ? First, girls are affected. But are they girls ? About one apparent girl in a thousand has a deficiency of part of an X-chromosome, or has only one X, with or without an accompanying Y. The frequency of the gene determining Windhorst’s condition is certainly less than this. A priori, an apparent girl with a rare X-linked disorder is more likely to be an incomplete girl than a homozygote so that no case is acceptable as a girl with an apparently rare X-linked condition unless sexchromatin from mucosae and polymorphs, and chromosomes from at least one tissue, are examined and a search for more subtle associated peculiarities, or fortuitous total lyonisation in heterozygotes, made by testing for Xga, colour blindness and, where appropriate, G-6 P.D. Since the proportion of affected girls seems a little high to be dismissed in this way an autosomal form of appreciable frequency, say a tenth of the X-linked form, seems more likely. A few cases related to consanguinity, or a consistent failure of maternal lyonization, should confirm this and segregational analysis will allow proportionate estimates of a and x. Some atypical features might also be expected, although, as in haemophilias A and B and von Willebrand’s syndrome, or Hunter’s and Hurler’s syndrome, the consequences may overlap to a confusing extent. The hollow circle in Chandra et aI.,! which is presumably the girl’s, seems somewhat of an outsider. Finally we have the numerical evidence of incredulitythat is, that the fathers differ with high statistical significance from the controls, and show no sign of being in two groups. Here the question is how unlikely, in terms of p values based on a plausible null hypothesis, must we require statistical significance to be before removing our flag and attributing these apparent discoveries to a curious series of coincidences aided and abetted by erroneous expectations. We must first ask: 1. Are the controls satisfactory ? 2. Would we expect the fathers to be
typical in an X-borne condition ? 3. If we are satisfied with the nullity of our hypothesis, are the high values (t=3’3; t=7’û; presumably for six degrees of freedom) for two strangely uncorrelated tests of the same aptitude unequivocal measures of rejection ? Controls are always difficult. On the hypothesis advanced, the father’s brothers are unsuitable. If age is important within the usual limited range of fathers of small boys the environmental factors must be important. Doctors would seem unsatisfactory since they are, on average, underexposed to infection as children and overexposed as adults. Secondly, would we expect average results in fathers if the disorder were X-linked ? I do not think we should, although, as in the autosomal case, the effects are likely to be small. Severe cases are likely to be overrepresented in any series, and where a generalised feebleness to infection
851
is superimposed on a specific X-borne weakness, the disease will be more severe. I would expect that fathers of severe haemophiliacs would have lower clotting powers than fathers of mild haemophiliacs. While this effect may be small, it might well be as great as the effect expected from incomplete recessivity on Soothill’s hypothesis. Thirdly, the level of incredulity is, I find, incredible. The spots in fig. 3 do not seem to overlap much, and t=3’3 is an unlikely t in the statistical sense. In fig. 4 I tried to compute t, measuring the difference between the spots (which is not given) and following the recipe given by Fisherfor data originally analysed by Student. My t came to 1-7 and Fisher’s " long stop " test 8 gave a chance of one sixteenth, so that even ignoring the inflated values likely ,
due
to
difficulty
in
finding controls,
and the
expectation
that, if found, they would differ from relatives, the level of
incredulity does not necessarily reach the arbitrary threshold of conventional surprise and certainly does not seem adequate to wrench this flag from the X-chromosome. This is no necessary criticism of the authors’ arithmetic, for choice of transformations, and even recipes, makes this a rather subjective test, especially when the variances are so clearly different. Whether, in our capacity as purveyors of bad tidings about the unborn, we should hope, as does Soothill, that the locus is autosomal, is another matter which should be irrelevant here, for hopes are not facts. On balance the X seems the best place to carry our misprints. It provides a chance of perhaps 30% or so, and eventually the prospect of certainty on testing, that a sporadic case will stay sporadic. If treatment is successful, the abortion of the daughters of survivors will allow the increase in incidence to be restrained. With autosomal recessives we can neither expect, nor demonstrate, true sporadic cases and we are likely to continue to give consistently distressing prognoses with little hope of reducing future incidence; if therapy succeeds, it will be doomed to plough an ever sandier soil since the product of incidence and lethality will tend to stabilise. Department of Human Genetics, Birmingham Maternity Hospital, J. H. EDWARDS. Birmingham 15.
reported by Windhorst.16 We have also studied 3 male and 1 female patient in whose families no heterozygotes were detectable despite multiple studies. The case very recently reported by Kontras and Bass 17 as the first in which both parents had normal assays is analogous to some of those which we have reported 12,13 and which
patients
Windhorst has also noted." Another of our patients had selective defect for staphylococci, with no heterozygous relatives.14 Neutrophil bactericidal defects have been reported in a patient with Job’s syndrome and her unaffected sister.18 Finally, a reversible bactericidal defect has been observed in a 75-year-old man.14 Apparently, therefore, several different molecular defects may produce abnormal phagocyte function, as suggested by Baehner,2o Windhorst," and ourselves.12-15 Their elucidation awaits the development of more precise biochemical assays of cellular function. STEVEN D. DOUGLAS Section of Hematology Immunology, University of California Medical Center, WILLIAM C. DAVIS H. HUGH FUDENBERG. San Francisco, California. a
a
SIR,-Professor Soothill and his co-workers suggest 9,10 that chronic granulomatous disease (C.G.D.) has a sexmodified autosomal-recessive mode of inheritance. These conclusions are based on the results of quantitative nitroblue tetrazolium and bacterial-killing tests in 8 families. However, there have been serious criticisms of these results, and convincing evidence exists that at least one form of C.G.D. has an X-linked mode of inheritance." Studies in our laboratory have shown several forms of phagocyte dysfunction,12-15 one of which is identical with the X-linked disease first described by Windhorst et aI.16 In 3 families we were able to demonstrate heterozygous mothers; and in one of these there were two affected (maternal) half-brothers, similar to those previously Fisher, R. A. Statistical Methods for Research Workers; p. 123. Edinburgh and London, 1950. 8. Fisher, R. A. ibid. p. 124. 9. Thompson, E. N., Chandra, R. K., Cope, W. A., Soothill, J. F. Lancet, 1969, i, 799. 10. Chandra, R. K., Cope, W. A., Soothill, J. F. ibid. July 12, 1969, 7.
p. 71. Windhorst, D. B. ibid. Sept. 6, 1969, p. 543. Davis, W. C., Douglas, S. D., Fudenberg, H. H. Fedn Proc. 1968, 27, 671. 13. Douglas, S. D., Davis, W. C., Fudenberg, H. H. Am. J. Med. 1969, 46, 901. 14. Davis, W. C., Douglas, S. D., Fudenberg, H. H. Ann. intern Med. 1968, 69, 1237. 15. Douglas, S. D., Fudenberg, H. H. Med. Clins N. Am. 1969, 53, 11. 12.
903.
16.
Windhorst, D. B., Page, A. R., Holmes, B., Quie, R. A. J. clin. Invest. 1968, 47, 1026.
P.
G., Good,
PENTAZOCINE ADDICTION
SIR,-In my letter on this subject (Sept. 27, p. 690) there is one error of consequence. Halfway through the final paragraph is the statement: " Drug addiction, a DSM-II diagnosis, ..." This, of course, should read: " Drug addiction, a DSM-I diagnosis ..." One of the points of the letter was to make physicians aware that we now have a new
terminologv in psvchiatrv-namelv,
Department of Psychiatry, Medical College of South Carolina.
DSM-II.
ROY H. HART.
PLATELET-FUNCTION TESTS SIR,-We are indebted to Mr. Browse and Mr. Hall for their careful study of the effect of dipyridamole on deep vein thrombosis (D.v.T.) (Oct. 4, p. 718). This drug evidently had no beneficial effect on their patients, and this is an important, if negative, finding. I must, however, take issue with them about their apparently unitary concept of platelet stickiness. Dipyridamole treatment evidently altered the results of their test for platelet stickiness, yet the incidence of D.V.T. remained the same. To explain this discrepancy they consider two possibilities; either thrombosis is not primarily platelet-dependent, or the platelets have not been rendered sufficiently abnormal. A third possibility fits the facts perfectly and must also be considered. Their test may measure an attribute of platelets that is not relevant to D.V.T.
A number of different tests have been reported to be abnormal in D.V.T.,21 but there is no general agreement about which test should be used; this perhaps not surprising for the following reason. Despite the pioneer work at Oxford and other centres, we still do not know the precise mechanisms involved in thrombosis; nor do we know exactly what the many and varied platelet-function tests are measuring nor their relevance to in-vivo events. However, it is known that some tests vary independently, and therefore they must measure different parameters of platelet function. 22, 23 There is thus no single perfect stickiness test, and, for all we know, different adhesive forces 17. 18.
Kontras, S., Bass, J. C. Lancet, Sept. 20, 1969, p. 646. Bannatyne, R. M., Skowron, P. N., Weber, J. L. J. Pediatrics, 1969, 75, 236. 19. Douglas, S. D., Lahav, M., Fudenberg, H. H. J. Mt Sinai Hosp. (in the press). 20. Baehner, R. L. New Engl. J. Med. 1969, 280, 1355. 21. O’Brien, J. R. Jl R. Coll. Physns Lond. 1969, 3, 193. 22. O’Brien, J. R. Coagulation, 1969, 1, 311. 23. O’Brien, J. R., Heywood, J. B. Thromb. Diath. Hœm. 1966, 16, 768.
STANLEY SHALDON.
INHERITANCE OF CHRONIC GRANULOMATOUS DISEASE SIR,-Those of us who are attempting to map the Xchromosome, and need first to define conditions dependent upon variant forms of genes which reside there, can hardly remain mere onlookers in the present controversy on the inheritance of chronic granulomatous disease. 1-3 The elegant work of the Minnesota school appeared to have defined a group of children, almost all boys, who suffered from a serious incapacity to kill bacteria; many shared this with their brothers, their mother’s sisters’ sons, and, in one case, their maternal step-brother, but other relatives appeared unaffected. All familial cases were related exclusively through women. One technique showed appearances consistent with those to be expected if the condition were X-linked and one of the two maternal Xchromosomes were fortuitously inactivated (not eliminated), although such a technique, using cells rather than whole test-tubes, involves microscopy and colour perception and would be difficult to quantify. It seemed, from their results, that most of these boys must be afflicted by an X-borne defect, and that the cataloguing of this vast and complicated field of non-resistance to infection was proceeding along the same lines as in the bleeding disorders, where the initial simplicity of one haemophilia is now complicated by other defects, some autosomal, with similar consequences. Some of us had put up another flag on the X, and were awaiting further information on its neighbours. Now we are told to take it down. The laboratory work was insensitive; the model was insecure ; girls could be affected; and, worst of all, the average father differs from the average doctor in antibacterial aggression with the numbered incredulity of statistical significance. We must consider a new model, and, to placate Occam, advance a concept of scholastic complexity, with unobservable postulates, such as unnoticed early fetal deaths of girls, the type of concept with which Occam
originally expressed concern. The argument
was a
little difficult to follow, and involved
comparing the uncited paper of Windhorst et al.4 with the unpublished papers of Thompson and Soothilland of al .6However, now that Windhorst2 has supwhich contains a full bibliography, and added some data, we must consider what type of evidence is necessary before we take down this flag on our most colonised and best mapped chromosome. Soothill’s a priori argument is that, if in this syndrome a cases are autosomally determined and x cases are X-borne, then a or x should be zero. That is, if a is not zero then x ought to be zero. This seems a strange argument, for if we assume that antibacterial aggression is complicated it must involve several enzymes and if, as is a priori fairly likely (n/17 for n Chandra
et
plied the key reference,
1.
Chandra,
R.
K., Cope, W. A., Soothill, J.
F.
Lancet, July 12, 1969,
p. 71.
Windhorst, D. B. Lancet, Sept. 6, 1969, p. 543. Soothill, J. F. ibid. p. 543. Windhorst, D. B., Page, A. R., Holmes, B., Quid, P. D., Good, R. A. J. clin. Invest. 1968, 47, 1026. 5. Thompson, E. N., Soothill, J. F. Unpublished. Cited by Chandra, R. K., Cope, W. A., Soothill, J. F. Lancet, July 12, 1969, p. 71. 6. Chandra, R. K., Cope, W. A., Soothill, J. F. Unpublished. Cited by Thompson et al.5 2. 3. 4.
serially related enzymes since one seventeenth of the female chromosome set is X-borne) that one is X-borne, it is even more likely that at least one other is not. There is no short. age of precedents. A minority of non-clotters, even though involving A.H.G. deficiency, are not hxmophiliacs. A minority of the colour-blind are neither deutan nor protan. Of at least six polysaccharidoses, only one is X-linked. A condition resembling Duchenne’s muscular dystrophy occurs in girls. G-6 P.D. is X-borne; its functional neigh. bour 6-P.G.D. is not. Indeed, we might go so far as to postulate the general rule that X-linked disorders will have autosomal mimics for mendelian disorders in man seem largely restricted to those systems in which there is an amplification due to sequential reactions of great rapidity and, in higher animals, there seems no tendency for functionally related enzymes to be coded by structurally related genes. What is the evidence on which this locus is to be relegated to an unknown chromosome ? First, girls are affected. But are they girls ? About one apparent girl in a thousand has a deficiency of part of an X-chromosome, or has only one X, with or without an accompanying Y. The frequency of the gene determining Windhorst’s condition is certainly less than this. A priori, an apparent girl with a rare X-linked disorder is more likely to be an incomplete girl than a homozygote so that no case is acceptable as a girl with an apparently rare X-linked condition unless sexchromatin from mucosae and polymorphs, and chromosomes from at least one tissue, are examined and a search for more subtle associated peculiarities, or fortuitous total lyonisation in heterozygotes, made by testing for Xga, colour blindness and, where appropriate, G-6 P.D. Since the proportion of affected girls seems a little high to be dismissed in this way an autosomal form of appreciable frequency, say a tenth of the X-linked form, seems more likely. A few cases related to consanguinity, or a consistent failure of maternal lyonization, should confirm this and segregational analysis will allow proportionate estimates of a and x. Some atypical features might also be expected, although, as in haemophilias A and B and von Willebrand’s syndrome, or Hunter’s and Hurler’s syndrome, the consequences may overlap to a confusing extent. The hollow circle in Chandra et aI.,! which is presumably the girl’s, seems somewhat of an outsider. Finally we have the numerical evidence of incredulitythat is, that the fathers differ with high statistical significance from the controls, and show no sign of being in two groups. Here the question is how unlikely, in terms of p values based on a plausible null hypothesis, must we require statistical significance to be before removing our flag and attributing these apparent discoveries to a curious series of coincidences aided and abetted by erroneous expectations. We must first ask: 1. Are the controls satisfactory ? 2. Would we expect the fathers to be
typical in an X-borne condition ? 3. If we are satisfied with the nullity of our hypothesis, are the high values (t=3’3; t=7’û; presumably for six degrees of freedom) for two strangely uncorrelated tests of the same aptitude unequivocal measures of rejection ? Controls are always difficult. On the hypothesis advanced, the father’s brothers are unsuitable. If age is important within the usual limited range of fathers of small boys the environmental factors must be important. Doctors would seem unsatisfactory since they are, on average, underexposed to infection as children and overexposed as adults. Secondly, would we expect average results in fathers if the disorder were X-linked ? I do not think we should, although, as in the autosomal case, the effects are likely to be small. Severe cases are likely to be overrepresented in any series, and where a generalised feebleness to infection
851
is superimposed on a specific X-borne weakness, the disease will be more severe. I would expect that fathers of severe haemophiliacs would have lower clotting powers than fathers of mild haemophiliacs. While this effect may be small, it might well be as great as the effect expected from incomplete recessivity on Soothill’s hypothesis. Thirdly, the level of incredulity is, I find, incredible. The spots in fig. 3 do not seem to overlap much, and t=3’3 is an unlikely t in the statistical sense. In fig. 4 I tried to compute t, measuring the difference between the spots (which is not given) and following the recipe given by Fisherfor data originally analysed by Student. My t came to 1-7 and Fisher’s " long stop " test 8 gave a chance of one sixteenth, so that even ignoring the inflated values likely ,
due
to
difficulty
in
finding controls,
and the
expectation
that, if found, they would differ from relatives, the level of
incredulity does not necessarily reach the arbitrary threshold of conventional surprise and certainly does not seem adequate to wrench this flag from the X-chromosome. This is no necessary criticism of the authors’ arithmetic, for choice of transformations, and even recipes, makes this a rather subjective test, especially when the variances are so clearly different. Whether, in our capacity as purveyors of bad tidings about the unborn, we should hope, as does Soothill, that the locus is autosomal, is another matter which should be irrelevant here, for hopes are not facts. On balance the X seems the best place to carry our misprints. It provides a chance of perhaps 30% or so, and eventually the prospect of certainty on testing, that a sporadic case will stay sporadic. If treatment is successful, the abortion of the daughters of survivors will allow the increase in incidence to be restrained. With autosomal recessives we can neither expect, nor demonstrate, true sporadic cases and we are likely to continue to give consistently distressing prognoses with little hope of reducing future incidence; if therapy succeeds, it will be doomed to plough an ever sandier soil since the product of incidence and lethality will tend to stabilise. Department of Human Genetics, Birmingham Maternity Hospital, J. H. EDWARDS. Birmingham 15.
reported by Windhorst.16 We have also studied 3 male and 1 female patient in whose families no heterozygotes were detectable despite multiple studies. The case very recently reported by Kontras and Bass 17 as the first in which both parents had normal assays is analogous to some of those which we have reported 12,13 and which
patients
Windhorst has also noted." Another of our patients had selective defect for staphylococci, with no heterozygous relatives.14 Neutrophil bactericidal defects have been reported in a patient with Job’s syndrome and her unaffected sister.18 Finally, a reversible bactericidal defect has been observed in a 75-year-old man.14 Apparently, therefore, several different molecular defects may produce abnormal phagocyte function, as suggested by Baehner,2o Windhorst," and ourselves.12-15 Their elucidation awaits the development of more precise biochemical assays of cellular function. STEVEN D. DOUGLAS Section of Hematology Immunology, University of California Medical Center, WILLIAM C. DAVIS H. HUGH FUDENBERG. San Francisco, California. a
a
SIR,-Professor Soothill and his co-workers suggest 9,10 that chronic granulomatous disease (C.G.D.) has a sexmodified autosomal-recessive mode of inheritance. These conclusions are based on the results of quantitative nitroblue tetrazolium and bacterial-killing tests in 8 families. However, there have been serious criticisms of these results, and convincing evidence exists that at least one form of C.G.D. has an X-linked mode of inheritance." Studies in our laboratory have shown several forms of phagocyte dysfunction,12-15 one of which is identical with the X-linked disease first described by Windhorst et aI.16 In 3 families we were able to demonstrate heterozygous mothers; and in one of these there were two affected (maternal) half-brothers, similar to those previously Fisher, R. A. Statistical Methods for Research Workers; p. 123. Edinburgh and London, 1950. 8. Fisher, R. A. ibid. p. 124. 9. Thompson, E. N., Chandra, R. K., Cope, W. A., Soothill, J. F. Lancet, 1969, i, 799. 10. Chandra, R. K., Cope, W. A., Soothill, J. F. ibid. July 12, 1969, 7.
p. 71. Windhorst, D. B. ibid. Sept. 6, 1969, p. 543. Davis, W. C., Douglas, S. D., Fudenberg, H. H. Fedn Proc. 1968, 27, 671. 13. Douglas, S. D., Davis, W. C., Fudenberg, H. H. Am. J. Med. 1969, 46, 901. 14. Davis, W. C., Douglas, S. D., Fudenberg, H. H. Ann. intern Med. 1968, 69, 1237. 15. Douglas, S. D., Fudenberg, H. H. Med. Clins N. Am. 1969, 53, 11. 12.
903.
16.
Windhorst, D. B., Page, A. R., Holmes, B., Quie, R. A. J. clin. Invest. 1968, 47, 1026.
P.
G., Good,
PENTAZOCINE ADDICTION
SIR,-In my letter on this subject (Sept. 27, p. 690) there is one error of consequence. Halfway through the final paragraph is the statement: " Drug addiction, a DSM-II diagnosis, ..." This, of course, should read: " Drug addiction, a DSM-I diagnosis ..." One of the points of the letter was to make physicians aware that we now have a new
terminologv in psvchiatrv-namelv,
Department of Psychiatry, Medical College of South Carolina.
DSM-II.
ROY H. HART.
PLATELET-FUNCTION TESTS SIR,-We are indebted to Mr. Browse and Mr. Hall for their careful study of the effect of dipyridamole on deep vein thrombosis (D.v.T.) (Oct. 4, p. 718). This drug evidently had no beneficial effect on their patients, and this is an important, if negative, finding. I must, however, take issue with them about their apparently unitary concept of platelet stickiness. Dipyridamole treatment evidently altered the results of their test for platelet stickiness, yet the incidence of D.V.T. remained the same. To explain this discrepancy they consider two possibilities; either thrombosis is not primarily platelet-dependent, or the platelets have not been rendered sufficiently abnormal. A third possibility fits the facts perfectly and must also be considered. Their test may measure an attribute of platelets that is not relevant to D.V.T.
A number of different tests have been reported to be abnormal in D.V.T.,21 but there is no general agreement about which test should be used; this perhaps not surprising for the following reason. Despite the pioneer work at Oxford and other centres, we still do not know the precise mechanisms involved in thrombosis; nor do we know exactly what the many and varied platelet-function tests are measuring nor their relevance to in-vivo events. However, it is known that some tests vary independently, and therefore they must measure different parameters of platelet function. 22, 23 There is thus no single perfect stickiness test, and, for all we know, different adhesive forces 17. 18.
Kontras, S., Bass, J. C. Lancet, Sept. 20, 1969, p. 646. Bannatyne, R. M., Skowron, P. N., Weber, J. L. J. Pediatrics, 1969, 75, 236. 19. Douglas, S. D., Lahav, M., Fudenberg, H. H. J. Mt Sinai Hosp. (in the press). 20. Baehner, R. L. New Engl. J. Med. 1969, 280, 1355. 21. O’Brien, J. R. Jl R. Coll. Physns Lond. 1969, 3, 193. 22. O’Brien, J. R. Coagulation, 1969, 1, 311. 23. O’Brien, J. R., Heywood, J. B. Thromb. Diath. Hœm. 1966, 16, 768.