Correspondence
Resistance to Activated Protein C
N Engl J Med 1994; 331:129-130July 14, 1994
- Article
To the Editor:
The article by Svensson and Dahlback on resistance to activated protein C (APC) (Feb. 24 issue)1 postulates that there is a genetically determined defect in anticoagulation characterized by resistance to APC. The authors subsequently found the anticoagulant cofactor that corrects inherited APC resistance to be identical to unactivated factor V. I believe that these findings could also be due to hyperhomocysteinemia. It has been demonstrated that hyperhomocysteinemia is an independent risk factor for vascular disease2,3. It was previously demonstrated that homocysteine induced a vascular-endothelial-cell activator that led to the activation of factor V4. I feel that serum homocysteine levels should have been measured by Svensson and Dahlback, and that elevated homocysteine levels may explain their findings.
4 ReferencesWilliam R. Laurence, Jr., M.D., Maj., U.S.A.
Womack Army Medical Center, Fort Bragg, NC 28307-50001
Svensson PJ ,Dahlback B . Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994;330:517-522
Full Text | Web of Science | Medline2
Stampfer MJ ,Malinow MR ,Willett WC , et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268:877-881
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Clarke R ,Daly L ,Robinson K , et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Engl J Med 1991;324:1149-1155
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Rodgers GM ,Kane WH . Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 1986;77:1909-1916
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To the Editor:
Drs. Svensson and Dahlback found a high prevalence of resistance to APC in plasma samples from subjects with venous thromboembolic disease. Some but not all subjects had evidence of a familial basis for the abnormality.
The authors stated that none of the patients they studied, including 72 women, had a lupus anticoagulant -- in our experience, a highly surprising finding in such a population1. The method of testing for lupus anticoagulant is not stated, the only relevant test referred to being automated measurement of the activated partial-thromboplastin time (APTT). It is well recognized that the reliable identification of antiphospholipid antibodies requires a comprehensive approach. In the United Kingdom, the use of a combination of at least two coagulation-based assays sensitive to lupus anticoagulant on carefully collected and prepared plasma, together with solid-phase assays for anticardiolipin antibodies, is recommended2. It is thus likely that subjects with antiphospholipid antibodies were overlooked by Svensson and Dahlback. Antiphospholipid antibodies could be of importance in the interpretation of the results, since we have demonstrated resistance to APC in the plasma of subjects with the antiphospholipid syndrome. Of 16 patients with positive tests for antiphospholipid antibodies but a normal APTT, 5 had APC resistance as assessed by the Chromogenix assay, with a normal range based on assay of samples from 30 healthy subjects. In four of the five subjects the antiphospholipid antibody was demonstrated by the dilute-Russell's-viper-venom assay with platelet neutralization procedure, as well as by an enzyme-linked immunosorbent assay based on the anticardiolipin-antibody method. In the fifth subject a low titer for IgG anticardiolipin antibodies was unaccompanied by detectable lupus anticoagulant.
It is thus apparent that some antiphospholipid-containing plasma samples show APC resistance. This observation complements our earlier ones on interference with the protein C-protein S anticoagulant system by antiphospholipid antibodies3 and clearly could be of pathogenic importance. Finally, it is highly possible that in some of the subjects studied by Svensson and Dahlback, particularly those without evidence of a familial defect, the APC resistance was in fact linked to the presence of antiphospholipid antibodies.
3 ReferencesK.K. Hampton, M.R.C.Path.
F.E. Preston, M.D.
M. Greaves, M.D.
Royal Hallamshire Hospital, Sheffield S102JF, United Kingdom1
Greaves M, Preston FE. Clinical and laboratory aspects of thrombophilia. In: Poller L, ed. Recent advances in blood coagulation. No. 5. Edinburgh, Scotland: Churchill Livingstone, 1991:119-40.
2
Lupus Anticoagulant Working PartyGuidelines on testing for the lupus anticoagulant. J Clin Pathol 1991;44:885-889
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Malia RG ,Kitchen S ,Greaves M ,Preston FE . Inhibition of activated protein C and its cofactor protein S by antiphospholipid antibodies. Br J Haematol 1990;76:101-107
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Author/Editor Response
Dr. Dahlback replies:
To the Editor: Hampton and colleagues are right that it is likely that we may have overlooked occasional patients with antiphospholipid antibodies by using automated measurement of the APTT as the only screening method for lupus anticoagulants. Inherited resistance to APC appears to be highly prevalent in the general population (5 to 10 percent),1 and it is now obvious that APC resistance in a majority of cases is associated with a mutation in the factor V gene2-4. It is of course possible that antiphospholipid antibodies develop in people with this kind of genetic defect and that the combination of APC resistance and the antiphospholipid antibody triggers a thrombotic event. Another possibility is that the antibody itself affects the APC response and contributes to the APC resistance. In the family studies that were presented in our paper1 we found evidence for familial APC resistance in about 67 percent of the cases. This appears to be a minimum, since we are now able to identify relatives with APC resistance in about 90 percent of the cases. The recent identification of a factor V gene mutation that is associated with a majority of cases with APC resistance will help distinguish between APC resistance due to factor V gene mutation and other possible causes of APC resistance. Family studies may in difficult cases be very useful to determine whether the APC resistance is of an inherited nature or not.
In response to Dr. Laurence: we did not measure the serum levels of serum homocysteine, since elevations of homocysteine levels have mainly been associated with arterial thrombosis. Moreover, it is now established that inherited resistance to APC is caused by a mutation in the factor V gene,2-4 which makes it less likely that elevated homocysteine levels are of pathogenic importance.
4 ReferencesBjorn Dahlback, M.D., Ph.D.
University of Lund, S-21401 Malmo, Sweden1
Svensson PJ ,Dahlback B . Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994;330:517-522
Full Text | Web of Science | Medline2
Dahlback B ,Hildebrand B . Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci U S A 1994;91:1396-1400
CrossRef | Web of Science | Medline3
Bertina RM ,Koeleman BPC ,Koster T , et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64-67
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Zoller B, Dahlback B. Inherited resistance to activated protein C, a major basis of venous thrombosis, caused by a factor V gene mutation. Lancet (in press).
- Citing Articles (2)
Citing Articles
1
Juzo MATSUDA, MORITAKA GOTOH, KENGO GOHCHI, KAZUO KAWASUGI, MIYO TSUKAMOTO, NORIKO SAITOH. (1995) Resistance to activated protein C activity of an anti-/ 2 -glycoprotein I antibody in the presence of β-glycoprotein I. British Journal of Haematology 90:1, 204-206
CrossRef2
M. E. Gschwandtner, K. Lechner, I. Pabinger. (1995) Erroneously low APC ratio in patients with lupus anticoagulant. Annals of Hematology 70:3, 169-170
CrossRef
