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(Stroke. 1996;27:44-48.)
© 1996 American Heart Association, Inc.

Articles

Ischemic Stroke in the Elderly

Role of the Common Factor V Mutation Causing Resistance to ActivatedProtein C

Richard D. Press, MD, PhD; Xiao-Yuan Liu, MD; Nancy Beamer, MS Bruce M. Coull, MD

From the Departments of Pathology (R.D.P., X.-Y.L.) and Neurology (N.B., B.M.C.), Oregon Health Sciences University, and the Veteran's Affairs Medical Center (N.B., B.M.C.), Portland, Ore.

Correspondence to Oregon Health Sciences University, Department of Pathology, Mail Code L113, 3181 SW Sam Jackson Park Rd, Portland, OR 97201-3098. E-mail pressr@ohsu.edu.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose A common missense mutation in coagulation factor V (Arg 506 Gln) creates phenotypic resistance to the anticoagulant effects of activated protein C and predisposes carriers to venous thrombosis. To assess a correlation between this common hypercoagulable state and ischemic cerebrovascular disease, we have compared the prevalence of this mutation in a group of stroke patients with that in several control patient groups.

Methods The presence of the factor V Arg 506 Gln mutation was determined by a direct polymerase chain reaction–based assay on peripheral blood leukocytes from 161 elderly patients with acute ischemic stroke, 116 elderly patients with stroke risk factors but without acute stroke, 54 healthy elderly control subjects, and 287 younger control individuals (197 blood donors and 90 neonates).

Results The prevalence of the heterozygous Arg 506 Gln factor V mutation was not significantly different in the elderly stroke patients (2.5%) compared with either of the age-matched control groups (2% to 4%). The prevalence of this mutation was significantly higher in each of two younger control groups (8%) than in the elderly stroke patients (2.5%).

Conclusions The common factor V Arg 506 Gln mutation predisposing to venous thrombosis is not a significant genetic risk factor for ischemic stroke in the elderly.

Key Words: blood coagulation • cerebrovascular disorders • mutation • risk factors • thrombosis

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The prothrombotic conditions promoting cerebrovascular thrombosis are normally counterbalanced by the actions of anticoagulant factors such as protein C, protein S, and antithrombin III. The common disease syndromes with inappropriate coagulation (stroke, myocardial infarction, pulmonary embolism, etc) are thus often the result of an imbalance in the usual prothrombotic-antithrombotic equilibrium. Patients with an acquired or inherited deficiency of an anticoagulant factor are thus prone not only to venous thrombosis but to arterial thrombosis as well.¹ Although up to half of all cases of venous thrombosis are associated with specific exogenous procoagulant risk factors (surgery, trauma, prolonged immobility, or estrogen excess), genetic factors contribute to the remaining half of these cases. Protein C, protein S, or antithrombin III mutations, however, account for only about 5% to 10% of thrombosis-prone families.² In comparison, approximately half of these thrombosis-prone families have recently been found to have an inherited functional resistance to the anticoagulant effects of activated protein C (APC),^{3 4} the antithrombotic protein that normally cleaves and inactivates coagulation factors Va and VIIIa. The addition of APC to the plasma of these hypercoagulable individuals then fails to adequately prolong the in vitro clotting time.⁵ The genetic basis for this common hypercoagulable syndrome has recently been defined as a common point mutation in the gene for coagulation factor V at the exact site (Arg 506) where APC normally cleaves and inactivates the Va procoagulant.⁶ The persistence of this degradation-resistant factor Va is responsible for the increased thrombotic risk in individuals both heterozygous and homozygous for this common allele. Heterozygotes thus carry a 3- to 10-fold increased risk of venous thrombosis.^{3 7 8} The thrombotic risk in homozygotes⁹ or those with other concomitant thrombotic risks (pregnancy, oral contraceptive use, or protein C deficiency) is then significantly higher.^{10 11}

The association between the prevalent Arg 506 Gln factor V mutation and the common arterial thrombotic syndromes (strokes and myocardial infarctions) is a matter of continued debate. Some studies have thus shown a significantly increased prevalence of this hypercoagulable syndrome in stroke¹² or coronary artery disease patients,¹³ whereas other studies have failed to find any significant difference.^{7 14 15 16 17 18 19} In this study, we have therefore determined the prevalence of the Arg 506 Gln factor V allele in a group of elderly patients with ischemic stroke compared with its prevalence in several control patient groups. We found no significant increase in the prevalence of the mutant factor V allele in the stroke patients compared with the control subjects, implying that this mutation does not predispose to the development of ischemic stroke in the elderly.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects
Stroke, Risk, and Elderly Control Patients
Three groups of elderly subjects were prospectively recruited from the wards and outpatient clinics at the Portland Veterans Affairs Medical Center and Oregon Health Sciences University. These three groups comprised individuals with acute stroke, those with risk factors for stroke, and healthy elderly persons. All procedures involving human subjects were in accordance with institutional guidelines and were approved by an institutional review committee. All subjects gave written informed consent to participate and undergo phlebotomy. Eligibility for the acute stroke group was limited to patients who had experienced an ischemic stroke within 7 days of enrollment (regardless of the stroke mechanism). Subjects with subarachnoid or intracerebral hemorrhage were excluded, as were subjects with cerebral venous thrombosis. The probable stroke mechanism was assigned on the basis of the criteria of the Stroke Data Bank.²⁰ Subjects were entered into the stroke risk group if they had two or more known habits or cardiovascular diseases that are recognized stroke risk factors, such as a prior history of stroke or transient ischemic attack, hypertension, diabetes mellitus, tobacco use, atrial fibrillation, ischemic or valvular heart disease, or peripheral vascular disease. Subjects entered into the healthy elderly control group denied the presence of stroke risk factors, were currently nonsmoking, were not receiving prescription drugs, and were enrolled only if results of their complete blood count and routine serum chemistry panel were normal. At enrollment, all subjects were interviewed for a history of stroke and heart disease in immediate family members.

Younger Control Patients
The prevalence of the Arg 506 Gln factor V mutation in our normal reference population (predominantly white) was determined by genotyping blood specimens obtained from 197 healthy Portland, Ore, Red Cross blood donors (courtesy of Dr Jay Mead) who voluntarily scheduled themselves for blood donation and from whom blood was collected during the course of a single day. The subjects in this group were 50% men and ranged from 19 to 77 years old (average age, 46±14 years). We obtained 90 additional control specimens from healthy neonates randomly collected in 1 month through a neonatal screening program in Quebec, Canada.²¹ These neonatal samples had been archived since 1993 and were kindly provided as Chelex-prepared DNA by Dr Marcus Grompe, Oregon Health Sciences University Department of Molecular and Medical Genetics.

Factor V Genotyping by Polymerase Chain Reaction
Peripheral leukocyte genomic DNA was extracted from either freshly drawn peripheral blood or peripheral blood cell pellets that had been frozen in 16% glycerol. DNA was prepared by one of two different standard methods: a rapid boiling method using Chelex resin for most of the specimens or a silica-resin affinity chromatography method for the rare problematic specimen. For the Chelex method, we followed the whole blood procedure of Walsh et al²² with some minor modifications.²³ For the silica column method, we used the reagents and protocols provided in a commercially available DNA preparation kit (QIAamp blood kit from Qiagen).

The region surrounding the factor V Arg 506 Gln mutation site was polymerase chain reaction (PCR) amplified using a modification of the original mutation detection procedure⁶ as previously described.²³ The presence or absence of the 1691 G-to-A substitution was then determined by digestion of the factor V PCR product with the restriction enzyme Mnl I, agarose gel electrophoresis, and ethidium bromide staining (also as previously described).²³ Each factor V genotype assay included the analysis of a known Arg 506 Gln homozygote, a known Arg 506 Gln heterozygote, a wild-type individual, and a "no DNA" contamination control. As an additional control for complete Mnl I digestion, an uncut 267-bp factor V amplicon was electrophoresed in each gel. A schematic representation of this direct detection assay for the factor V Arg 506 Gln mutation is shown in the Figure.

View larger version (43K): [in this window] [in a new window]   Figure 1. Schematic diagram shows direct detection of the factor V Arg 506 Gln mutation by a polymerase chain reaction (PCR)–based assay. Peripheral blood DNA from 6 representative stroke patients (lanes 5 through 10) was PCR-amplified with factor V specific primers, digested with Mnl I, and separated by agarose gel electrophoresis. As the codon 506 mutation destroys one of the two Mnl I sites in this amplicon, the genotype can be determined by the pattern of 200-bp and 163-bp fragments. Lanes 1 through 4 show control specimens with a homozygous mutation (lane 1), no mutation (lane 2), without Mnl I digestion (the uncut PCR product; lane 3), and no DNA (water control; lane 4). Of the stroke patients shown on this gel, 3 are heterozygous for the mutation (lanes 5 through 7) and 3 are without the mutation (lanes 8 through 10). APC indicates activated protein C.

Statistics
Fisher's exact test was used to compare the prevalence rates of the factor V mutation in the various patient groups. Two-tailed probability values were then calculated using the INSTAT software package (GraphPad Software) on a Macintosh computer.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The clinical characteristics of the five groups of subjects that were genotyped for the factor V mutation are shown in Table 1. The acute stroke, stroke risk, and healthy elderly groups were composed predominantly of elderly men (average age, 66 years) (Table 1). As the prevalence of stroke risk factors was not significantly different between the acute stroke and stroke risk groups (Table 1), any allele frequency difference between these groups might define a phenotype associated with this mutation. Since the blood donor and neonate control groups were composed of much younger individuals, the prevalence of the Arg 506 Gln mutation in these subjects should reflect that of the general white population.

View this table: [in this window] [in a new window]   Table 1. Clinical Characteristics of the Study Group Patients

As the Arg 506 Gln factor V mutation destroys a restriction enzyme recognition site, electrophoretic analysis of restriction enzyme–digested, PCR-amplified genomic DNA allowed a definitive diagnosis of the presence of this mutation in either or both alleles. A representative factor V genotype determination is shown in the Figure. In this assay, the mutated factor V allele yields a 200-bp DNA fragment in comparison to the shorter 163-bp fragment from the wild-type allele. The simultaneous presence of both fragments indicates a factor V Arg 506 Gln heterozygote.

Of the 161 patients in the acute stroke group, 4 (2.5%) were found to be heterozygous for the Arg 506 Gln mutation (Table 2). In comparison, heterozygous mutations were found in 2 of 116 (1.7%) individuals from the stroke risk group and 2 of 54 (3.7%) individuals from the healthy elderly group. There were no clinical features that distinguished the 8 elderly subjects heterozygous for the factor V mutation from others within the three cohorts of elderly subjects. When compared with others within their groups, neither the factor V heterozygotes nor their immediate family members appeared to have a significantly increased frequency of previous arterial or venous thrombotic events.

View this table: [in this window] [in a new window]   Table 2. Prevalence of the Factor V Arg 506 Gln Mutation

There was no statistically significant difference in the prevalence of the factor V Arg 506 Gln mutation in the acute stroke patients (2.5%) compared with its prevalence in either of the age-matched control groups (1.7% and 3.7%; P>.6 for both comparisons). Both the acute stroke group and the stroke risk group (but not the elderly control group), however, contained individuals with a prior history of symptomatic cerebrovascular disease (28% of the acute stroke group, 38% of the risk group; Table 1). We therefore reevaluated the data by combining the stroke risk group patients with a prior history of stroke (44 individuals) together with the acute stroke patients to create a composite group of 205 individuals with histories of stroke (Table 2). This alternate evaluation also failed to find any statistically significant difference in the prevalence of the Arg 506 Gln mutation in those with any history of stroke (4 of 205, 2.0%) versus either those in the risk group with no history of stroke (2 of 72, 2.8%) or those in the elderly control group (2 of 54, 3.7%) (P>.6 for both comparisons). A heterozygous factor V Arg 506 Gln mutation then is not a significant genetic risk factor for thrombotic stroke in the elderly.

The higher prevalence of the Arg 506 Gln mutation (8% to 9%) in the two young control groups (blood donors and normal neonates) compared with the stroke group (2.5%) further supports the lack of an association between this allele and ischemic stroke (Table 2). The mutation prevalence in our young control individuals (8% overall) was in fact significantly greater than the prevalence in both the acute stroke group (2.5%; P<.025) and the risk group (1.7%; P<.025). The mutation prevalence rate did not significantly differ, however, between the healthy young control subjects (8%) (either group or both combined together) and the healthy elderly control subjects (4%) (P>.3). The prevalence of the factor V Arg 506 Gln mutation may then be higher in healthy young individuals than in elderly individuals with either cerebrovascular disease or its risk factors (but no different than in healthy elderly individuals).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We have found no increase in the prevalence of the factor V Arg 506 Gln mutation in elderly patients with stroke compared with several control groups. We conclude that the factor V Arg 506 Gln mutation, which is a common predisposing risk factor for the development of venous thrombosis, is not a significant risk factor for the development of ischemic stroke in the elderly. In agreement with this report, two recent studies also have failed to find a correlation between the factor V Arg 506 Gln mutation and stroke.^{7 19} In contrast to our study, the control and stroke groups in each of these prior studies were not carefully matched for clinical characteristics such as age and atherosclerosis risk factors. The similar Arg 506 Gln factor V allele frequencies in the stroke and control groups in these two prior reports then might not be related directly to stroke but rather to some other clinical difference(s) among the patient groups.

In the only published study suggesting a significant correlation between the Arg 506 Gln factor V mutation and cerebrovascular disease,¹² conclusions were based not on DNA analysis but on a functional clotting time test for APC resistance, which often fails to properly classify those with or without the causative genetic mutation.^{23 24} Furthermore, as only 30 stroke patients were evaluated in that study, the increased frequency of APC resistance might have related to the small sample size.

To assess whether the factor V Arg 506 Gln mutation might be a risk factor for noncerebrovascular arterial thromboembolism, five recent studies have failed to find any correlation between this mutation and myocardial infarction.^{7 16 17 18 25} The only study to the contrary¹³ reported a marginally significant (P=.032) increase in the prevalence of the Arg 506 Gln factor V mutation in patients with coronary artery disease (not necessarily myocardial infarction) compared with control subjects. Even this study, however, failed to find a significant difference in the prevalence of this mutation in coronary artery disease patients either with or without a history of myocardial infarction. The presence of a degradation-resistant factor Va procoagulant thus does not contribute to an increased risk of symptomatic atherothrombotic occlusions within either the cerebral or coronary arterial vasculatures.

The advanced age of our stroke group suggests that our conclusion that there is no increased risk of stroke in heterozygous carriers of the factor V mutation should perhaps be limited to elderly individuals with atherothrombotic stroke. Although the relationship between the prevalence of this mutation and age has not been reported, a recent study of the effects of APC resistance on pregnancy-associated thromboembolism found an unusually high rate of APC resistance among normal young women (10%).²⁶ If the factor V Arg 506 Gln mutation did in fact predispose affected younger individuals to fatal cerebrovascular disease, an analysis of elderly individuals might then fail to detect this association by including only survivors. In dispute of this hypothesis, however, two recent studies of somewhat younger stroke victims have also failed to find an increased prevalence of functional APC resistance.^{14 15} Nevertheless, sporadic case reports have shown that young individuals with the factor V Arg 506 Gln mutation can develop arterial as well as venous thrombosis.^{12 25 27} This association may be particularly relevant for juvenile stroke, since familial hypercoagulable syndromes have been reported in these individuals.^{28 29}

Contrary to initial expectations, our data suggest that the frequency of the factor V mutation in elderly individuals with either stroke or at risk of stroke (2%) may actually be lower than in healthy young individuals (8%). In contrast, the prevalence of this mutation in our healthy elderly control subjects (4%) was not significantly different from that in our healthy young controls (8%) (P>.3). Similar population-based allele frequencies have been reported elsewhere.^{6 7 18 30} Since our healthy elderly control patients were free of the atherosclerosis-related risk factors present in the stroke and stroke risk group patients (Table 1), these data might then suggest that individuals with both atherothrombotic risk and resistance to APC may not survive to old age. This proposed increase in mortality could perhaps be the result of an increased incidence of fatal venous thrombosis (pulmonary embolism). Alternatively, since we do not have accurate histories of venous thrombosis in our patients, we cannot rule out the possibility that the selection criteria for our stroke and risk groups were somehow biased toward individuals without a propensity for venous disease.

The lack of an association between the common factor V mutation and the development of ischemic stroke suggests that there is no need to screen the typical elderly stroke patient for this prevalent allele. In contrast, a complete hypercoagulability workup (including a factor V mutation analysis) may be clinically justified in younger stroke patients, in those without significant atherosclerosis, or in those with significant family histories of venous thrombosis. Because the factor V Arg 506 Gln mutation is by far the most common genetic alteration predisposing to thrombosis, a functional or DNA-based assay for this mutation could identify those patients at highest risk for future thrombotic events who might benefit most from prophylactic or therapeutic anticoagulants.

	Acknowledgments

 
This work was supported by developmental funds provided by the Oregon Health Sciences University Department of Pathology (Dr Press), by a grant from the Oregon Affiliate of the American Heart Association (Dr Press), and by National Institutes of Health grant NS-17493 (Dr Coull).

Received August 15, 1995; revision received October 10, 1995; accepted October 10, 1995.

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