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Oral contraceptives, venous thromboembolic disease, and ABO blood type
664
THE LANCET, SEPTEMBER
jaundice. Bileduct obstruction was suspected, and the patient was operated on. The surgeon reported obstructive jaundice due to scarring of the common duct, thought to be the result of chronic unspecific inflammation. There were no gallstones. A T-drain was inserted and the icterus gradually subsided. In December, 1968, however, the patient again noticed pruritus, malaise, and icterus. r-tube cholangiography revealed narrowing of the proximal part of the common duct. The T-tube was therefore changed, in January, 1969. At that time the diagnosis of primary sclerosing cholangitis was made. The patient did well until the summer of 1970. In July, 1970, the bilirubin level increased to 9·7 mg. per 100 ml, Progressive stenosis of the common duct, proximal to the T-tube, was demonstrated by X-rays. The patient was started on corticosteroids and azathioprine (150 mg. a day), in addition to antibiotics according to the antibiogram, There was no dramatic response. The bilirubin level remained at 10-12 mg. per 100 ml., but the patient did fairly well. In April, 1971, while on treatment with 100 mg. azathioprine and 8 mg. dexamethasone his condition deteriorated. The serum-bilirubin rose to 19'1 mg. per 100 ml. and the creatinine to 8'7 mg. per 100 ml, He died in coma and renal failure. At necropsy, in addition to primary sclerosing cholangitis, numerous small liver abscesses were found scattered all over the liver. The inhibition of bile-flow due to primary sclerosing cholangitis as well as the permanent T-tube were undoubtedly important factors in the development of this complication. However, the immunosuppressive properties of azathioprine and the corticosteroids may well have contributed to the fatal outcome in this case. Invenellstrasse 63, 85 Nurnberg, We,t Germany.
A.
WAGNER.
ORAL CONTRACEPTIVES, VENOUS THROMBOEMBOLIC DISEASE, AND ABO BLOOD TYPE SIR,-Mourant et a1,1 made a plea for more data about the blood-type distribution in women who have had a thromboembolic episode while on oral contraceptives. ELOOO-GROUP DISTRIBUTION IN WOMEN WHO DEVELOPED DEEP VENOUS THROMllOSIS ON ORAL CONTRACEPTIVES-AND IN HOSPITAL PATIENTS WITHOUT KNOWN PREDISPOSING DlSBASE (% IN PARllNTHHSES)
Thrombosle after Otalcontraceptive,
Previous data (Sweden) I New data Totals
A
Control group (female:blooddonors)
---
AB
0
10(17)·
All groups
65 (60)
8 (14) 7 (14) 15 (14)
5 (8) 4 (8) 9 (8)
10 (20)t 20 (18)·
59 (100) 50 (100) 109 (100)
20 (61)
6 (18)
3 (9)
4 (12)t
.33 (100)
36 (61) 29 (58)
Posidve phlebogram (new data)
B
7108 (45) 1759 (11) 887 (6) 6048 (38) 15,802 (100)
I
x· analysis. t 0'01 < p < 0,05. During the period 1969-70 another 50 cases have been added to the Swedish series presented in the paper by lick et a1. 2 These women were all admitted to hospital because of deep venous thromboembolism without any known predisposing disease, and were reported to have • P
< 0'001 by
1. Mourant, A. E., Kopec, A., Domaniewska-Sobczak, 1<. Lan.", 1971, i,223. 2. lick, H., Slone, D., Westerholm, B., Inman, W. H. W•• Vessey, M. P., Shapiro, S., Lewis, G. P., Worcester, J. ibid. 1969, I, 539.
18, 1971
used oral contraceptives during the month before they were taken ill. The total number of Swedish women with venous thromboembolism in whom the blood type is known now amounts to 109. In 33 the diagnosis was verified by phlebogram. The accompanying table shows that the deficit of blood type 0 is still significant both in the new series (p < 0'05) and in the combined data (p < 0,001) as compared with female controls. The controls were blood-donors in all age groups. Depllrtrnent of Drugs, Swedish National Board of Health and Welfare, S 104 01 Stockholm. Sabbatsberg's Hospital, S Il.3 82 Stockholm. Institute of Statistics, University of Stockholm, P.O. Box 6701. S 11385 Stockholm 23, Sweden.
B.
WBSTERHOLM.
B. WmCHBL.
G. EKLUND.
ANTITHROMBIN-ill CONCENTRATION AND ABO BLOOD-GROUPS Sm,-Several investigations,reviewed by Mourant et al.,l have suggested an association between blood-group A and an increased risk of thromboembolic disease. During blood coagulation antithrombin-In (At-In) is partly consumed, and the At-In level is higher in plasma than in serum. We have found that pulmonary embolism, diffuse intravascular coagulationj'' and use of oral contraceptives.s-" are associated with lowered levels of At-In. Normalisation of the At-III level in response to anticoagulant therapy suggests that the low levels in thromboembolic disease may be due to increased consumption of At-III by complex formation with thrombin 3 and activated factor x.5 If individuals of blood-group A more often have thrombosis caused by activation of larger amounts of coagulation factors (and/or higher frequency of such events) than those of type 0, this might be reflected in lowerlevelsof At-III. As shown in the table, such a correlation with ABO groups has been found. We investigated 1747 individuals who donated blood during a 3-week period. The variation of the At-In level with age, sex, and use of oral contraceptives in this sample has already been reported. s However, 125 persons in the original sample were excludedowing to lack of information on the hemoglobin concentration, Rh genotypes, &c., necessary for use of a special computer program. The At-III concentrations in serum were estimated by an immunechemical method,' without knowledge of the blood-groups of the subjects. The mean At-III concentration in blood-group A l donors is significantly lower (Student's r-test) than in bloodgroups As (p < 0'Q01) and 0 (p < 0'001), and also lower than in the total series (p < 0,001). Even if blood-groups Al and A~ are pooled, the mean value is lower than that in group 0 (0'005 < P < 0,001). The last comparison was done because association between thromboembolic disease and bloodgroup A was observed in some series without A1/Az subgrouping, We think the most likely explanation of our findings is that the lower At-III level in group-A, individuals is due to increased consumption of this protein. The basis for this may be increased levels of beta-lipoproteins 0 and 1. Mourant, A. E., Kopec, A., Domaniewska-Sobczak, K. Lancet, 1971, I, 223. 2. Abildgaard, U., Fagerhol, M. K., Egeberg, O. Scand, J. C1l'II. Lab. Inuett, 1970, 26, 349. 3. Fagerhol, M. K., Abildgaard, U. Scand.J. Heemas. 1970,7,10. 4. Fagerhol, M. K., Ablldgaard, U., Berg.jll, P., Jacobsen, J. H. Lancet, 1970, i, 1175. 5. Billll8,R., Denson, 1<. W. E., Akman, N., Berrett, R., Hadden, M. Br.1. Heemat. 1970, 19,283. 6. Ledvina, M., Kellen, J. Folia Heemat, 1962,79,382.
THE LANCET, SEPTEMBER
jaundice. Bileduct obstruction was suspected, and the patient was operated on. The surgeon reported obstructive jaundice due to scarring of the common duct, thought to be the result of chronic unspecific inflammation. There were no gallstones. A T-drain was inserted and the icterus gradually subsided. In December, 1968, however, the patient again noticed pruritus, malaise, and icterus. r-tube cholangiography revealed narrowing of the proximal part of the common duct. The T-tube was therefore changed, in January, 1969. At that time the diagnosis of primary sclerosing cholangitis was made. The patient did well until the summer of 1970. In July, 1970, the bilirubin level increased to 9·7 mg. per 100 ml, Progressive stenosis of the common duct, proximal to the T-tube, was demonstrated by X-rays. The patient was started on corticosteroids and azathioprine (150 mg. a day), in addition to antibiotics according to the antibiogram, There was no dramatic response. The bilirubin level remained at 10-12 mg. per 100 ml., but the patient did fairly well. In April, 1971, while on treatment with 100 mg. azathioprine and 8 mg. dexamethasone his condition deteriorated. The serum-bilirubin rose to 19'1 mg. per 100 ml. and the creatinine to 8'7 mg. per 100 ml, He died in coma and renal failure. At necropsy, in addition to primary sclerosing cholangitis, numerous small liver abscesses were found scattered all over the liver. The inhibition of bile-flow due to primary sclerosing cholangitis as well as the permanent T-tube were undoubtedly important factors in the development of this complication. However, the immunosuppressive properties of azathioprine and the corticosteroids may well have contributed to the fatal outcome in this case. Invenellstrasse 63, 85 Nurnberg, We,t Germany.
A.
WAGNER.
ORAL CONTRACEPTIVES, VENOUS THROMBOEMBOLIC DISEASE, AND ABO BLOOD TYPE SIR,-Mourant et a1,1 made a plea for more data about the blood-type distribution in women who have had a thromboembolic episode while on oral contraceptives. ELOOO-GROUP DISTRIBUTION IN WOMEN WHO DEVELOPED DEEP VENOUS THROMllOSIS ON ORAL CONTRACEPTIVES-AND IN HOSPITAL PATIENTS WITHOUT KNOWN PREDISPOSING DlSBASE (% IN PARllNTHHSES)
Thrombosle after Otalcontraceptive,
Previous data (Sweden) I New data Totals
A
Control group (female:blooddonors)
---
AB
0
10(17)·
All groups
65 (60)
8 (14) 7 (14) 15 (14)
5 (8) 4 (8) 9 (8)
10 (20)t 20 (18)·
59 (100) 50 (100) 109 (100)
20 (61)
6 (18)
3 (9)
4 (12)t
.33 (100)
36 (61) 29 (58)
Posidve phlebogram (new data)
B
7108 (45) 1759 (11) 887 (6) 6048 (38) 15,802 (100)
I
x· analysis. t 0'01 < p < 0,05. During the period 1969-70 another 50 cases have been added to the Swedish series presented in the paper by lick et a1. 2 These women were all admitted to hospital because of deep venous thromboembolism without any known predisposing disease, and were reported to have • P
< 0'001 by
1. Mourant, A. E., Kopec, A., Domaniewska-Sobczak, 1<. Lan.", 1971, i,223. 2. lick, H., Slone, D., Westerholm, B., Inman, W. H. W•• Vessey, M. P., Shapiro, S., Lewis, G. P., Worcester, J. ibid. 1969, I, 539.
18, 1971
used oral contraceptives during the month before they were taken ill. The total number of Swedish women with venous thromboembolism in whom the blood type is known now amounts to 109. In 33 the diagnosis was verified by phlebogram. The accompanying table shows that the deficit of blood type 0 is still significant both in the new series (p < 0'05) and in the combined data (p < 0,001) as compared with female controls. The controls were blood-donors in all age groups. Depllrtrnent of Drugs, Swedish National Board of Health and Welfare, S 104 01 Stockholm. Sabbatsberg's Hospital, S Il.3 82 Stockholm. Institute of Statistics, University of Stockholm, P.O. Box 6701. S 11385 Stockholm 23, Sweden.
B.
WBSTERHOLM.
B. WmCHBL.
G. EKLUND.
ANTITHROMBIN-ill CONCENTRATION AND ABO BLOOD-GROUPS Sm,-Several investigations,reviewed by Mourant et al.,l have suggested an association between blood-group A and an increased risk of thromboembolic disease. During blood coagulation antithrombin-In (At-In) is partly consumed, and the At-In level is higher in plasma than in serum. We have found that pulmonary embolism, diffuse intravascular coagulationj'' and use of oral contraceptives.s-" are associated with lowered levels of At-In. Normalisation of the At-III level in response to anticoagulant therapy suggests that the low levels in thromboembolic disease may be due to increased consumption of At-III by complex formation with thrombin 3 and activated factor x.5 If individuals of blood-group A more often have thrombosis caused by activation of larger amounts of coagulation factors (and/or higher frequency of such events) than those of type 0, this might be reflected in lowerlevelsof At-III. As shown in the table, such a correlation with ABO groups has been found. We investigated 1747 individuals who donated blood during a 3-week period. The variation of the At-In level with age, sex, and use of oral contraceptives in this sample has already been reported. s However, 125 persons in the original sample were excludedowing to lack of information on the hemoglobin concentration, Rh genotypes, &c., necessary for use of a special computer program. The At-III concentrations in serum were estimated by an immunechemical method,' without knowledge of the blood-groups of the subjects. The mean At-III concentration in blood-group A l donors is significantly lower (Student's r-test) than in bloodgroups As (p < 0'Q01) and 0 (p < 0'001), and also lower than in the total series (p < 0,001). Even if blood-groups Al and A~ are pooled, the mean value is lower than that in group 0 (0'005 < P < 0,001). The last comparison was done because association between thromboembolic disease and bloodgroup A was observed in some series without A1/Az subgrouping, We think the most likely explanation of our findings is that the lower At-III level in group-A, individuals is due to increased consumption of this protein. The basis for this may be increased levels of beta-lipoproteins 0 and 1. Mourant, A. E., Kopec, A., Domaniewska-Sobczak, K. Lancet, 1971, I, 223. 2. Abildgaard, U., Fagerhol, M. K., Egeberg, O. Scand, J. C1l'II. Lab. Inuett, 1970, 26, 349. 3. Fagerhol, M. K., Abildgaard, U. Scand.J. Heemas. 1970,7,10. 4. Fagerhol, M. K., Ablldgaard, U., Berg.jll, P., Jacobsen, J. H. Lancet, 1970, i, 1175. 5. Billll8,R., Denson, 1<. W. E., Akman, N., Berrett, R., Hadden, M. Br.1. Heemat. 1970, 19,283. 6. Ledvina, M., Kellen, J. Folia Heemat, 1962,79,382.