508
BRITISH MEDICAL JOURNAL
25 FEBRUARY 1978
recurrent DVT and have grade IV post-phlebitic Dr Williams suggests that the summer peak in legs. One son has, in addition, also had an inferior emergency admission for renal stones and colic SIR,-The impressive family study of anti- vena cava thrombosis (age 8) and mesenteric may merely reflect increased availability of surgical thrombosis (age 30). The father, a maternal aunt, beds during the summer. He writes that "during thrombin III (ATIII) deficiency in the west of and the fourth son and his son are asymptomatic the winter months, especially in the less wellScotland by Dr M Mackie and his colleagues and all have AT III levels above 80 %. resourced regions, surgical beds have to be 'bor(21 January, p 136) will stimulate the search rowed' to cater for the increased demand from The typical clinical presentations are patients for further examples. The incidence reported suffering from serious acute medical by them of clinical thrombotic disease in the demonstrated by this small family, but the conditions such as pneumonia." However, our inferior vena cava thrombosis developing at data show that the variation in winter and summer deficient patients (7 out of 12) and its severity follow the patterns to be found in the literature the age of 8 years in one member illustrates admission rates is similar in extent in all regions, cited. It is reasonable to assume that another that symptoms may not be confined only to irrespective of the numbers of beds. We think his is unlikely to be true. thrombogenic factor may be present to adulthood. Mendelsohn3 has reported multiple suggestion Dr McCarthy states that regional variations in account for those affected clinically. It is less thrombotic events in an 8-month-old infant appendicitis admissions are similar to those for likely that the ATIII-deficient persons who with an AT III deficiency. Furthermore, renal stones. This is incorrect. The statement is are unaffected have special protection. The familial AT III deficiency may not be as rare based on admission rates for appendicitis quoted in recent study' in our laboratory of a smaller but as is currently thought. Since we have started the reports of the Hospital Inpatient Enquiry similar family showed not only a lower rate of screening patients with strong family histories (HIPE). The correlation coefficient between thromboses in the deficient (2 out of 9) but also of venous thrombosis we have uncovered appendicitis admissions in the most recent report, an indication that hypertriglyceridaemia may several subjects with low AT III levels and that for 1973, and the emergency admission rates their families are now under investigation. It is for renal stones and colic cited in our paper is only have been the additional factor. 0-24. This falls to 0 08 if the analysis is restricted Deficiency of ATIII should provide a our policy to recommend self-administered to admission rates for acute appendicitis-that is, sensitive human model for the evaluation of low dose subcutaneous heparin for all con- patients coded as acute appendicitis who were thrombotic risk factors. Clearly these may not firmed cases. admitted as emergencies and operated upon H A DE HAAS (unpublished data). This points to the need for be the same in different families or even M F SCULLY detailed analyses of HIPE data when making individuals, but it is logical to plan a compreS E CLARK inferences about incidence rather than basing hensive survey in any future study. Such V V KAKKAR conclusions on the summarised data presented in knowledge will be of use in assessing the need published tables. Thrombosis Research Unit, for prophylaxis, which, as the authors state, is King's Hospital Medical School, Confirmation of our conclusion that there usually anticoagulation with warfarin. How- LondonCollege SE5 is a higher incidence of renal stones in southern ever, we are less certain about their suggested M F, and Kakkar, V V, Clinica Chimica Acta, England can come only from a special survey. use of subcutaneous heparin in pregnancy. The l Scully, 1977, 79, 595. decreased levels of ATIII found by Marciniak 2 Fagerhol, M H, and Abilgaard, U, Scandinavian We agree with Mr R Scott and Dr S Ljunghall 3'ournal of Haematology, 1970, 7, 10. (18 February, p 439) that a survey is necessary and Gockerman2 in patients receiving full 3Mendelsohn, G, Gomperts, E D, and Gurwitz, D, and feasible. Two such surveys, into Paget's doses of heparin for at least three days were Thrombosis and Haemostasis, 1976, 36, 495. disease of bone' and Perthes's disease of the also found in our patient who rethrombosed hip,2 have recently been completed in this shortly after being taken off heparin.3 Subsedepartment. For both diseases HIPE data quently we have measured a fall in ATIII Regional variations in incidence of would be predicted to be inappropriate as levels of between 12 and 41 % in seven patients urinary stones indicators of incidence or prevalence. Yet the receiving minidose subcutaneous heparin for five days after myocardial infarction. This may SIR,-The letters from Dr B T Williams (28 findings of the surveys confirmed for each not be important when the levels do not fall January, p 233) and Dr M J McCarthy disease the suggestion from HIPE analyses far below the normal range, but where the (p 234) commenting on our paper (14 January, of a higher frequency in the north-west of resting level is already 50 0 below normal the p 67) again raise the question of the extent to England than the south. To dismiss hospital admission rates as results may not be desirable and may account which regional differences in provision of for the reported failures of heparin therapy in hospital beds nullify the use of hospital indicators of geographical differences in this condition. It is true that if, in addition to admission rates as comparative indicators of disease incidence within Britain is to take too heparin, the necessary volume of plasma can disease incidence. The degree to which admis- superficial a view. Although, as we stated in be given sufficiently often to raise the level of sion rates reflect incidence varies from one our paper, biases such as those produced by ATIII this potential danger will not arise. The disease to another. At one extreme patients regional differences in hospital admission possibility of producing a plasma concentrate4 with perforated peptic ulcers will be admitted practice cannot be eliminated, we nevertheless may prove to be the answer in this high-risk to hospital irrespective of the number of think that detailed analyses of HIPE data group. available beds, and hospital admission rates are a useful preliminary in geographical O H B GYDE will therefore be a measure of incidence. At studies of disease incidence. D J P BARKER W A LITTLER the other extreme regional admission rates for S P B DONNAN D E STABLEFORTH non-infective skin disease show a high correlaDepartment of Department of Haematology, tion with total numbers of dermatological beds University Community Medicine, East Birmingham Hospital, available and the admission rates cannot be Southampton General Hospital, Birmingham taken as indicators of incidence. Dr Williams Southampton I Gyde, 0 H B, et al, British Medical _ournal. In press. speculates that emergency admission for Barker, D J P, et al, British Medical journal, 1977, 1, 2 Marciniak, E, and Gockerman, J P, Lancet, 1977, 2, 1181. renal stones and renal colic may correspond to 581. D J P, Paper read to meeting of Society for 2Barker, Fisken, R A, et al, Lancet, 1977, 2, 1231. the latter. He thereby implies that many of 4 Wickerhauser, M, personal communication. Social Medicine, Birmingham, September 1977. the patients admitted as emergencies to hospitals in southern England would, had they SIR,-The recent report by Dr M Mackie lived in the north of England, be looked after Duration of immunity conferred by and others (21 January, p 136) of a Scottish at home by their general practitioners. rubella vaccines Dr Williams's suggestion arises from the correlafamily with familial antithrombin III (AT III) tion numbers of (coefficient= 0.44) between deficiency prompts us to report the first EngSIR,-The short reply in your Any Questions lish family with the same condition. A mother surgical and urological beds per 100 000 population column (3 December, p 1466) on the duration and emergency admission rates for renal stones and three of her four sons, living on the south and colic. However, numbers of beds are a poor of immunity provided by rubella vaccines coast, are affected. indicator of actual availability of beds for emergency implies that it is only a matter of time before The mother's AT III level measured by func- admissions because bed availability is critically studies confirm that vaccination confers lifetional assay' is 51 % and by immunological assay2 influenced by patients' average duration of stay in long protection. Your expert also wrongly 54 %. She is reported to have had deep vein hospital. Moreover, the low correlation coefficient implies that all vaccine strains are equivalent thrombosis (DVT) after every pregnancy and has of 0-44 implies that at most only 20 % of the varia- or that the strains of vaccine principally used recently developed a spontaneous axillary vein tion in admission rates is explained by variation in in vaccination programmes in the United thrombosis. Three sons have AT III levels of 48 %, numbers of beds. (Likewise the correlation co55%, and 56% (functional) and 50%, 55%, and efficient of 0 49 between total surgical beds and all States and Great Britain are the same. Many 37 % (immunological), respectively, while levels of admissions for appendicitis, which Dr Williams studies have shown that the immediate ocl-antitrypsin and OC2-macroglobulin were found to cites, shows that at most only 25 % of the variation antibody responses elicited by vaccination be within normal ranges. These sons have all had in appendicitis is explained in this way.) differ with strains'-4 and others5-"3 indicate
Familial antithrombin III deficiency
BRITISH MEDICAL JOURNAL
25 FEBRUARY 1978
recurrent DVT and have grade IV post-phlebitic Dr Williams suggests that the summer peak in legs. One son has, in addition, also had an inferior emergency admission for renal stones and colic SIR,-The impressive family study of anti- vena cava thrombosis (age 8) and mesenteric may merely reflect increased availability of surgical thrombosis (age 30). The father, a maternal aunt, beds during the summer. He writes that "during thrombin III (ATIII) deficiency in the west of and the fourth son and his son are asymptomatic the winter months, especially in the less wellScotland by Dr M Mackie and his colleagues and all have AT III levels above 80 %. resourced regions, surgical beds have to be 'bor(21 January, p 136) will stimulate the search rowed' to cater for the increased demand from The typical clinical presentations are patients for further examples. The incidence reported suffering from serious acute medical by them of clinical thrombotic disease in the demonstrated by this small family, but the conditions such as pneumonia." However, our inferior vena cava thrombosis developing at data show that the variation in winter and summer deficient patients (7 out of 12) and its severity follow the patterns to be found in the literature the age of 8 years in one member illustrates admission rates is similar in extent in all regions, cited. It is reasonable to assume that another that symptoms may not be confined only to irrespective of the numbers of beds. We think his is unlikely to be true. thrombogenic factor may be present to adulthood. Mendelsohn3 has reported multiple suggestion Dr McCarthy states that regional variations in account for those affected clinically. It is less thrombotic events in an 8-month-old infant appendicitis admissions are similar to those for likely that the ATIII-deficient persons who with an AT III deficiency. Furthermore, renal stones. This is incorrect. The statement is are unaffected have special protection. The familial AT III deficiency may not be as rare based on admission rates for appendicitis quoted in recent study' in our laboratory of a smaller but as is currently thought. Since we have started the reports of the Hospital Inpatient Enquiry similar family showed not only a lower rate of screening patients with strong family histories (HIPE). The correlation coefficient between thromboses in the deficient (2 out of 9) but also of venous thrombosis we have uncovered appendicitis admissions in the most recent report, an indication that hypertriglyceridaemia may several subjects with low AT III levels and that for 1973, and the emergency admission rates their families are now under investigation. It is for renal stones and colic cited in our paper is only have been the additional factor. 0-24. This falls to 0 08 if the analysis is restricted Deficiency of ATIII should provide a our policy to recommend self-administered to admission rates for acute appendicitis-that is, sensitive human model for the evaluation of low dose subcutaneous heparin for all con- patients coded as acute appendicitis who were thrombotic risk factors. Clearly these may not firmed cases. admitted as emergencies and operated upon H A DE HAAS (unpublished data). This points to the need for be the same in different families or even M F SCULLY detailed analyses of HIPE data when making individuals, but it is logical to plan a compreS E CLARK inferences about incidence rather than basing hensive survey in any future study. Such V V KAKKAR conclusions on the summarised data presented in knowledge will be of use in assessing the need published tables. Thrombosis Research Unit, for prophylaxis, which, as the authors state, is King's Hospital Medical School, Confirmation of our conclusion that there usually anticoagulation with warfarin. How- LondonCollege SE5 is a higher incidence of renal stones in southern ever, we are less certain about their suggested M F, and Kakkar, V V, Clinica Chimica Acta, England can come only from a special survey. use of subcutaneous heparin in pregnancy. The l Scully, 1977, 79, 595. decreased levels of ATIII found by Marciniak 2 Fagerhol, M H, and Abilgaard, U, Scandinavian We agree with Mr R Scott and Dr S Ljunghall 3'ournal of Haematology, 1970, 7, 10. (18 February, p 439) that a survey is necessary and Gockerman2 in patients receiving full 3Mendelsohn, G, Gomperts, E D, and Gurwitz, D, and feasible. Two such surveys, into Paget's doses of heparin for at least three days were Thrombosis and Haemostasis, 1976, 36, 495. disease of bone' and Perthes's disease of the also found in our patient who rethrombosed hip,2 have recently been completed in this shortly after being taken off heparin.3 Subsedepartment. For both diseases HIPE data quently we have measured a fall in ATIII Regional variations in incidence of would be predicted to be inappropriate as levels of between 12 and 41 % in seven patients urinary stones indicators of incidence or prevalence. Yet the receiving minidose subcutaneous heparin for five days after myocardial infarction. This may SIR,-The letters from Dr B T Williams (28 findings of the surveys confirmed for each not be important when the levels do not fall January, p 233) and Dr M J McCarthy disease the suggestion from HIPE analyses far below the normal range, but where the (p 234) commenting on our paper (14 January, of a higher frequency in the north-west of resting level is already 50 0 below normal the p 67) again raise the question of the extent to England than the south. To dismiss hospital admission rates as results may not be desirable and may account which regional differences in provision of for the reported failures of heparin therapy in hospital beds nullify the use of hospital indicators of geographical differences in this condition. It is true that if, in addition to admission rates as comparative indicators of disease incidence within Britain is to take too heparin, the necessary volume of plasma can disease incidence. The degree to which admis- superficial a view. Although, as we stated in be given sufficiently often to raise the level of sion rates reflect incidence varies from one our paper, biases such as those produced by ATIII this potential danger will not arise. The disease to another. At one extreme patients regional differences in hospital admission possibility of producing a plasma concentrate4 with perforated peptic ulcers will be admitted practice cannot be eliminated, we nevertheless may prove to be the answer in this high-risk to hospital irrespective of the number of think that detailed analyses of HIPE data group. available beds, and hospital admission rates are a useful preliminary in geographical O H B GYDE will therefore be a measure of incidence. At studies of disease incidence. D J P BARKER W A LITTLER the other extreme regional admission rates for S P B DONNAN D E STABLEFORTH non-infective skin disease show a high correlaDepartment of Department of Haematology, tion with total numbers of dermatological beds University Community Medicine, East Birmingham Hospital, available and the admission rates cannot be Southampton General Hospital, Birmingham taken as indicators of incidence. Dr Williams Southampton I Gyde, 0 H B, et al, British Medical _ournal. In press. speculates that emergency admission for Barker, D J P, et al, British Medical journal, 1977, 1, 2 Marciniak, E, and Gockerman, J P, Lancet, 1977, 2, 1181. renal stones and renal colic may correspond to 581. D J P, Paper read to meeting of Society for 2Barker, Fisken, R A, et al, Lancet, 1977, 2, 1231. the latter. He thereby implies that many of 4 Wickerhauser, M, personal communication. Social Medicine, Birmingham, September 1977. the patients admitted as emergencies to hospitals in southern England would, had they SIR,-The recent report by Dr M Mackie lived in the north of England, be looked after Duration of immunity conferred by and others (21 January, p 136) of a Scottish at home by their general practitioners. rubella vaccines Dr Williams's suggestion arises from the correlafamily with familial antithrombin III (AT III) tion numbers of (coefficient= 0.44) between deficiency prompts us to report the first EngSIR,-The short reply in your Any Questions lish family with the same condition. A mother surgical and urological beds per 100 000 population column (3 December, p 1466) on the duration and emergency admission rates for renal stones and three of her four sons, living on the south and colic. However, numbers of beds are a poor of immunity provided by rubella vaccines coast, are affected. indicator of actual availability of beds for emergency implies that it is only a matter of time before The mother's AT III level measured by func- admissions because bed availability is critically studies confirm that vaccination confers lifetional assay' is 51 % and by immunological assay2 influenced by patients' average duration of stay in long protection. Your expert also wrongly 54 %. She is reported to have had deep vein hospital. Moreover, the low correlation coefficient implies that all vaccine strains are equivalent thrombosis (DVT) after every pregnancy and has of 0-44 implies that at most only 20 % of the varia- or that the strains of vaccine principally used recently developed a spontaneous axillary vein tion in admission rates is explained by variation in in vaccination programmes in the United thrombosis. Three sons have AT III levels of 48 %, numbers of beds. (Likewise the correlation co55%, and 56% (functional) and 50%, 55%, and efficient of 0 49 between total surgical beds and all States and Great Britain are the same. Many 37 % (immunological), respectively, while levels of admissions for appendicitis, which Dr Williams studies have shown that the immediate ocl-antitrypsin and OC2-macroglobulin were found to cites, shows that at most only 25 % of the variation antibody responses elicited by vaccination be within normal ranges. These sons have all had in appendicitis is explained in this way.) differ with strains'-4 and others5-"3 indicate
Familial antithrombin III deficiency
