(Stroke. 1996;27:1731-1733.)
© 1996 American Heart Association, Inc.
Articles |
Cerebral Venous Thrombosis and Activated Protein C Resistance
the Departments of Neurology (D.A.D., C.C.L., H.S.S.) and Medicine (E.C.W.), University of Wisconsin-Madison Medical School.
Correspondence to Henry S. Schutta, Department of Neurology, University of Wisconsin Medical School, 600 Highland Ave, Madison, WI 53792. E-mail schutta@neurology.wisc.edu.
 |
Abstract |
|---|
 Top Abstract IntroductionCase ReportsDiscussionReferences |
|---|
Background Activated protein C resistance (APC-R) due to factor V Leiden has recently been established as an important risk factor for cerebral venous thrombosis (CVT). The clinical significance of abnormal or borderline functional APC-R in the absence of factor V Leiden is uncertain. Our observations suggest that APC-R due to mechanisms other than factor V Leiden may also contribute to the development of CVT.
Case Descriptions We describe three women who had superior sagittal and lateral sinus thrombosis while taking oral contraceptives and had a number of additional risk factors for CVT. Each had APC-R for different reasons.
Conclusions Inherited thrombophilia, including APC-R, should be looked for in all patients with CVT. Functional APC-R is a highly prevalent coagulopathy, but the reasons for this abnormality are diverse; abnormal and borderline functional APC-R results should be supplemented by DNA analysis for the presence of factor V Leiden.
Key Words: cerebral embolism and thrombosis • contraceptives, oral • protein C • protein S deficiency • sinus thrombosis
|
Introduction |
|---|
|
TopAbstractIntroductionCase ReportsDiscussionReferences |
|---|
One or more risk factors for thrombosis were seen in over 80% of 1100 patients with CVT reported in the last 10 years. Although this is an improvement over previous decades, when 25% to 50% of CVT was labeled as "idiopathic," in some 20% of patients with CVT the risk factors for CVT still go undetected. In addition to acquired risk factors for thrombosis, 10% to 15% of patients with CVT may also have a congenital form of thrombophilia.1 2 APC-R has recently been added to the list of the inherited thrombophilias.3 The molecular basis for the thrombophilia in many, but by no means all, patients with APC-R is the presence of a modified factor V (factor V Leiden) that is resistant to cleavage by protein C.3 4 5 The evidence that persons with APC-R who do not have the factor V Leiden mutation also have a degree of thrombophilia is compelling, but the mechanism of the APC-R is unknown.4 We describe three consecutive patients who developed CVT while taking oral contraceptives who were tested for the presence of APC-R.
The methods used for the detection of functional APC-R and of factor V Leiden have been previously described.6 The test for functional APC-R is a modification of the original method of Dahlback and Svensson.5 It is less influenced by the presence of anticoagulants and is more sensitive and specific. Functional APC-R is expressed as the ratio of APTT in the presence of APC to APTT in the absence of APC (Chromogenic Pharmacia Hepar, product No. 822908). Protein C and protein S antigen levels were measured before anticoagulants with ELISA and are expressed as a percentage of the value found in pooled normal plasma.
|
Case Reports |
|---|
|
TopAbstractIntroductionCase ReportsDiscussionReferences |
|---|
The symptomatology and risk factors in three patients are summarized in Table 1
. Antithrombin III levels were normal; tests for lupus anticoagulant and anticardiolipin antibodies were negative in all patients. All patients were treated with intravenous heparin followed by warfarin anticoagulation. All functional tests for APC-R were obtained while the patients were anticoagulated with warfarin. Patient 1 also received antibiotics to treat her ethmoid sinusitis, and patient 2 became euthyroid with radioactive iodine treatment. The result of repeated APC-R testing in the thyrotoxic patient (patient 2) 12 months after discharge, when the patient was euthyroid, was 2.0 (abnormal, <2.1). APC-R in patient 3 remained borderline at 2.3 (borderline, 2.1 to 2.5) 18 months after hospitalization when the patient was asymptomatic. All patients made a prompt recovery and were discharged from the hospital within 13 days. Warfarin was continued in two patients (patients 1 and 2) because of continued oral contraceptive use (patient 1) and morbid obesity (patient 2). Warfarin was discontinued for patient 3 during bouts of depression. Complete recanalization of all sinuses was shown by MRA in patient 1 at 1 month and in patient 2 at 12 months after discharge. Patient 3 showed no significant recanalization at 5 and 10 months.
|
|
Discussion |
|---|
|
TopAbstractIntroductionCase ReportsDiscussionReferences |
|---|
CVT in patients with APC-R has been mentioned by Dahlback and Svensson,5 and a fatal case of CVT in a patient with APC-R taking oral contraceptives has been reported.8 Since then, three systematic studies of patients with CVT comprising 84 patients have reported an incidence of the factor V Leiden of 10% to 21%.9 10 11 Estimates of the prevalence of the heterozygous state of factor V Leiden range from 3% to 10% in populations of European descent. The incidence of APC-R in the presence of venous thrombosis in this population ranges from 21% to 64%.12 In patients who use oral contraceptives, the risk of thrombosis increases 30- to 50-fold in the presence of APC-R.13 This defect constitutes not only the most common inherited thrombophilic condition in the European gene pool but appears to be the most prevalent genetic defect associated with any disease process in that population.3
Although it is now well established that APC-R associated with factor V Leiden is an important risk factor for CVT, the clinical significance of functional APC-R, and particularly borderline APC-R, in the absence of factor V Leiden is not clear. In a family study of 50 Swedish families with thrombophilia and inherited APC-R, the factor V Leiden was lacking in three families and was absent in some members of families that had the factor V Leiden gene mutation.4 Patients with borderline abnormal functional APC-R results (2.1 to 2.5) appear to be common among patients with CVT. In a recent study, 12 of 40 patients had APC-R results in that range. Factor V Leiden was demonstrated in only one of those patients.10
In our cases, patient 1 had an unequivocally abnormal functional APC-R (1.5) and factor V polymorphism. Patient 2 had APC-R results in the high abnormal range (1.9 and 2.0) without factor V Leiden. Because the patient was euthyroid at the time that APC-R was demonstrated, thyrotoxicosis cannot account for this abnormality, and in this case the mechanism of APC-R remains unknown. Patient 3 with borderline APC-R (2.3 and 2.4), who was Chinese, did not carry the factor V Leiden mutation but had protein S deficiency. Intact factor V is synergistic with protein S as cofactor to APC.14 The possibility that thrombophilia in patients who have protein S deficiency may be the result of factor V mutations other than Arg506 substitution has been suggested.4
Table 2 lists the acquired risk factors in CVT patients with APC-R or borderline APC-R published to date. All but two patients with factor V Leiden and all but one patient with borderline APC-R without factor V Leiden had one or more acquired risk factors for thrombosis, including thyrotoxicosis.15 This suggests that, as is the case in other types of inherited thrombophilia, additional risk factors are required in most cases to precipitate CVT in patients with APC-R. APC-R with or without factor V Leiden appears to augment the risk for CVT from oral contraceptives, and patients should be counseled accordingly. Our cases again demonstrate that in patients with abnormal and borderline results the functional APC resistance test should be supplemented by DNA analysis for factor V Leiden and that other types of inherited thrombophilia must be looked for.6
|
All patients were treated with intravenous heparin followed by warfarin anticoagulation, which resulted in prompt recovery without complications, demonstrating again that hemorrhage resulting from CVT is no contraindication to anticoagulation.1 On the other hand, the decision to provide anticoagulation for patients with APC-R and a single thrombotic event indefinitely must be made on a case-by-case basis. This decision would be influenced by the ability to remove other risk factors for thrombosis.16
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
The authors wish to thank Rosemary Croft, Sue Hoffman, Donna Lawler, Randi Matthews, and Carolyn Senty of the Special Coagulation Laboratory of the University of Wisconsin Hospital for providing the results of the coagulation tests.
Received May 2, 1996; revision received August 2, 1996; accepted August 7, 1996.
|
References |
|---|
|
TopAbstractIntroductionCase ReportsDiscussionReferences |
|---|
1. Bousser MG, Barnett HJM. Cerebral venous thrombosis. In: Barnett HJM, Mohr JP, Stein BM, Yatsu FM, eds. Stroke: Pathophysiology, Diagnosis, and Management. 2nd ed. New York, NY: Churchill Livingstone Inc; 1992.
2. Schutta HS. Cerebral venous thrombosis. In: Joynt RJ, Ed. Clinical Neurology. Philadelphia, Pa: JB Lippincott; 1991.
3. Dahlback B. New molecular insights into the genetics of thrombophilia: Resistance to activated protein C caused by Arg (506) to Gln Mutation in factor V as a pathogenic risk factor for venous thrombosis. Thromb Haemost. 1995;74:139-148.[Medline] [Order article via Infotrieve]
4. Zoller B, Svensson PJ, He X, Dahlback B. Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest. 1994;6:2521-2524.
5.
Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med. 1994;330:517-522.
6. Voelkerding KV, Wu L, Williams EC, Hoffman SM, Sabatini LM, Borcherding WR, Huber S. Factor V R506Q gene mutation analysis by PCR-RLF: optimization, comparison with functional testing for resistance to activated protein C, and establishment of cell line controls. J Clin Pathol. 1996;106:100-106.
7. Trossaertt M, Conard J, Horellou MH, Samama MM, Ireland H, Bayston TA, Lane DA. Modified APC resistance assay for patients on oral anticoagulants. Lancet. 1994,344:1709.
8. Bridey F, Wolf M, Laissy JP, Morin V, Lefebvre M, de Prost S. Fatal cerebral venous thrombosis associated with the factor V Leiden mutation and the use of oral contraceptives. Thromb Haemost. 1995;74:1379. Letter.[Medline] [Order article via Infotrieve]
9. Martinelli I, Landi G, Merati G, Cella E, Tosetto A, Mannucci PM. Factor V gene mutation is a risk factor for cerebral venous thrombosis. Thromb Haemost. 1996;75:393-394.[Medline] [Order article via Infotrieve]
10.
Deschiens MA, Conard J, Horellou MH, Ameri A, Preter M, Chedru F, Samama MM, Bousser M-G. Coagulation studies, factor V Leiden, and anticardiolipin antibodies in 40 cases of cerebral venous thrombosis. Stroke. 1996;27:1724-1730.
11.
Zuber M, Toulon P, Marnet L, Mas J-L. Factor V Leiden mutation in cerebral venous thrombosis. Stroke. 1996;27:1721-1723.
12. Koster FR, Rosendaal FR, de Ronde H, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet. 1993;342:1507-1506.[Medline] [Order article via Infotrieve]
13. Vandenbroucke JP, Koster T, Briet E, Reitsma PH, Bertina RM, Rosendaal FR. Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden. Lancet. 1994;344:1453-1457.[Medline] [Order article via Infotrieve]
14.
Shen L, Dahlback B. Factor V and protein S as synergistic cofactors to activated protein C in degradation of factor VIIIa. J Biol Chem. 1994;269:18735-18738.
15.
Siegert CEH, Smelt AHM, de Bruin TWA. Superior sagittal sinus thrombosis and thyrotoxicosis: possible association in two cases. Stroke. 1995;26:496-497.
16.
De Stefano V, Finazzi G, Mannuci PM. Inherited thrombophilia: pathogenesis, clinical syndromes and management. Blood. 1996;87:3531-3544.
This article has been cited by other articles:
 |
|
 |
|
  E. M. Wysokinska, W. E. Wysokinski, R. D. Brown, K. Karnicki, I. Gosk-Beirska, D. Grill, and R. D. McBane II Thrombophilia differences in cerebral venous sinus and lower extremity deep venous thrombosis Neurology, February 19, 2008; 70(8): 627 - 633. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Squizzato, V.E.A. Gerdes, D.P.M. Brandjes, H.R. Buller, and J. Stam Thyroid Diseases and Cerebrovascular Disease Stroke, October 1, 2005; 36(10): 2302 - 2310. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. S. Donahue Factor V Leiden and Perioperative Risk Anesth. Analg., June 1, 2004; 98(6): 1623 - 1634. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Heller, A. Heinecke, R. Junker, R. Knofler, A. Kosch, K. Kurnik, R. Schobess, A. von Eckardstein, R. Strater, B. Zieger, et al. Cerebral Venous Thrombosis in Children: A Multifactorial Origin Circulation, September 16, 2003; 108(11): 1362 - 1367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Wenderoth and C. C. Phatouros Incidental Discovery of a Dural Arteriovenous Fistula in a Patient with Activated Protein C Resistance AJNR Am. J. Neuroradiol., August 1, 2003; 24(7): 1369 - 1371. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Ludemann, D. G. Nabavi, R. Junker, E. Wolff, K. Papke, H. Buchner, G. Assmann, and E. B. Ringelstein Factor V Leiden Mutation Is a Risk Factor for Cerebral Venous Thrombosis : A Case-Control Study of 55 Patients Stroke, December 1, 1998; 29(12): 2507 - 2510. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M W KELLETT, P J MARTIN, T P ENEVOLDSON, C BRAMMER, and C M TOH Cerebral venous sinus thrombosis associated with 20210A mutation of the prothrombin gene J. Neurol. Neurosurg. Psychiatry, October 1, 1998; 65(4): 611 - 612. [Full Text]
|
|
|
|
 |
|
 I. Martinelli, E. Sacchi, G. Landi, E. Taioli, F. Duca, and P. M. Mannucci High Risk of Cerebral-Vein Thrombosis in Carriers of a Prothrombin-Gene Mutation and in Users of Oral Contraceptives N. Engl. J. Med., June 18, 1998; 338(25): 1793 - 1797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. T. Longstreth Jr, F. R. Rosendaal, D. S. Siscovick, H. L. Vos, S. M. Schwartz, B. M. Psaty, T. E. Raghunathan, T. D. Koepsell, and P. H. Reitsma Risk of Stroke in Young Women and Two Prothrombotic Mutations: Factor V Leiden and Prothrombin Gene Variant (G20210A) Stroke, March 1, 1998; 29(3): 577 - 580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. R. Carhuapoma, P. Mitsias, and S. R. Levine Cerebral Venous Thrombosis and Anticardiolipin Antibodies Stroke, December 1, 1997; 28(12): 2363 - 2369. [Abstract] [Full Text]
|
|
|
|
|
|
R. L. Brey and B. M. Coull Cerebral Venous Thrombosis: Role of Activated Protein C Resistance and Factor V Gene Mutation Stroke, October 1, 1996; 27(10): 1719 - 1720. [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||