Cerebral Venous Thrombosis and Activated Protein C Resistance
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.
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 Dahlbäck 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.
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.
CVT in patients with APC-R has been mentioned by Dahlbäck 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
|APC(-R)||=||activated protein C (resistance)|
|APTT||=||activated partial thromboplastin time|
|CVT||=||cerebral venous thrombosis|
|ELISA||=||enzyme-linked immunosorbent assay|
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.
- Copyright © 1996 by American Heart Association
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