From theUnit of Molecular Vascular Medicine, Research School of Medicine,
University of Leeds, Leeds General Infirmary, Leeds, United Kingdom.
Correspondence to Professor Peter J Grant, Unit of Molecular Vascular Medicine, Leeds General Infirmary, Leeds LS1 3EX, UK. E-mail a.j.catto{at}leeds.ac.uk
Methods—Six hundred twelve patients with acute stroke, defined by
World Health Organization criteria and cranial CT, and 436 age-matched
control subjects free of cerebrovascular disease were genotyped
for the factor XIII Val 34 Leu mutation. Venous blood was drawn for the
determination of hemostatic variables and lipids. Factor XIII
genotype was determined through a single-stranded
conformational polymorphism technique and plasminogen
activator inhibitor (PAI)-1 4G/5G promoter
genotype by allele-specific polymerase chain reaction.
Results—The mutation was more frequent in patients with primary
intracerebral hemorrhage (n=62) (54.8%;
P=.05) than in control subjects (41.7%) or in patients
with cerebral infarction (n=529) (46.5%; P=.22). There
was no relationship between PAI-1 levels and the PAI-1 4G/5G
genotype.
Conclusions—There was a slightly higher incidence of factor XIII
Val 34 Leu in patients with PICH. This may be related to impaired
cross-linking of fibrin and/or coagulation proteins.
Factor XIII is activated by thrombin, cleaving the
We have studied a G-to-T point mutation in codon 34 of exon 2 that
codes for a valine-leucine (factor XIII Val 34 Leu) change in the
In view of the apparently protective role of factor XIII Val 34 Leu in
the pathogenesis of MI, we hypothesized that possesion of the mutation
might either be protective against CI or predispose to the development
of PICH through the formation of weaker fibrin structures. The aims of
this study were therefore to investigate (1) the association of the
factor XIII Val 34 Leu genotype and the phenotypes CI
and PICH and (2) the relationships between PAI-1 levels, the PAI-1
4G/5G genotype, and the factor XIII Val 34 Leu mutation in the
pathogenesis of these discrete phenotypes.
Identification of Stroke Phenotype
Analysis of Circulating PAI-1 Activity
Extraction of DNA and Genotype Determinations
Identification of the Factor XIII Val 34 Leu Genotype
Identification of the PAI-1 4G/5G Promoter Genotype
Statistical Methods
Factor XIII Val 34 Leu genotypes were available in all cases
and controls; PAI-1 4G/5G genotypes were available in 558 cases
and 172 controls. PAI-1 activity was measured in the first 312 cases
and in 213 controls. In cases, the median PAI-1 level was 9.8 U/mL
(95% CI, 8.8 to 10.9); in controls, 8.8 U/mL (CI, 7.8 to 10.1)
(P<.0001).
Genotype Distribution in All Cases and Controls
Genotype Frequencies in PICH
There was no difference in distribution of the PAI-1 4G/5G
genotype and factor XIII Val 34 Leu genotypes between
cases of both PICH and CI and no significant relationships between
factor XIII Val 34 Leu and other stroke risk factors.
The precise role for fibrin in the pathogenesis of cerebrovascular
disease has not been established. However, the formation of
cross-linked fibrin from fibrin monomer is pivotal for the development
of a stable thrombus, and abnormalities of fibrin structure and
architecture are associated with premature MI in
men.4 This process involves the action of
thrombin on fibrinogen to produce soluble fibrin and the activation of
factor XIII, which cross-links fibrin, thereby rendering it more
resistant to fibrinolysis. Lysis of fibrin is
dependent on the binding of tissue plasminogen
activator and plasminogen to fibrin with local
plasmin production in an environment protected from the
circulating PAI-1.
In our population, levels of PAI-1 were elevated in PICH (median, 11.4
U/mL) as well as in CI (12.1 U/mL). Unlike in MI, we did not
demonstrate a relationship between the factor XIII Val 34 Leu mutation
and levels of PAI-1 or the 4G/5G genotype, although there was a
trend to higher levels of PAI-1 in subjects with PICH and the factor
XIII Val 34 Leu mutation than in those with PICH and the wild types
(11.8 U/mL and 7.8 U/mL, respectively) (Table 2
The results from this study indicate a slightly higher incidence of the
factor XIII Val 34 Leu mutation and risk of PICH, although the
present study does not provide direct evidence that factor XIII Val
34 Leu results in direct functional alteration in the protein. The
findings of this study have to be viewed in the light of the drawbacks
associated with a case-control study and the relatively small numbers
of PICH subjects available for study in such a cohort. However, while
this finding was not an independent relationship in this population
andthe findings could not be regarded as causal, these observations are
consistent with previous findings in relation to MI, which
indicates that this mutation justifies further study. Attention should
be directed to the heterogeneous nature of PICH, because
the factor XIII Val 34 Leu mutation may be more strongly related to the
different pathological variants of PICH, such as lipohyalinosis or
amyloid angiopathy. Furthermore, the influence of very early mortality
from PICH14 may be acting to dilute the strength
of the association, a possibility that should be considered in future
studies of the factor XIII Val 34 Leu mutation and PICH. This might be
addressed through use of archival DNA methods in subjects who have died
from PICH.
Received November 18, 1997;
revision received January 12, 1998;
accepted January 12, 1998.
2.
Ridker PM, Hennekens CH, Stampfer MJ, Manson JE,
Vaughan DE. Prospective study of endogenous tissue
plasminogen activator and risk of stroke.
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Intern Med. 1992;117:371–375.
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Kohler HP, Stickland MH, Ossei-Gerning N, Carter AM,
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© 1998 American Heart Association, Inc.
Original Contributions
Factor XIII Val 34 Leu
A Novel Association With Primary Intracerebral Hemorrhage
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—A common
G-to-T point mutation (Val 34 Leu) in exon 2 of the 
-subunit of the
factor XIII is strongly negatively associated with the development of
myocardial infarction. This result suggests that factor XIII Val 34 Leu
is interfering with the formation of cross-linked fibrin. The role of
factor XIII Val 34 Leu in the pathogenesis of cerebral infarction and
primary intracerebral hemorrhage is
unknown.
Key Words: factor XIII • fibrin • intracerebral hemorrhage • mutation • risk factors
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The importance of the
hemostatic system in the pathogenesis of atherothrombotic disorders has
been demonstrated in prospective studies. These have identified
increased concentrations of fibrinogen, factor VII, and suppressed
fibrinolysis resulting from elevated PAI-1 in relation
to MI.1 Elevated levels of tissue
plasminogen activator2
and fibrinogen3 are risk factors for CI. In MI,
abnormal fibrin structures have been reported,4
and factor XIII may have a role in this process. -subunit
between Arg37 and Gly38 releasing the N-terminal 37 residues
(activation peptides). The -subunit selectively cross-links fibrin
monomers and other substrates, including -2
antiplasmin.5 Cross-linked fibrin shows increased
resistance to fibrinolysis and enhanced mechanical
strength.6 -subunit, 3 amino acids from the thrombin activation
site,7 in 398 subjects examined for investigation
of coronary artery disease determined by
angiography.8 The prevalence of the mutation was
lower in subjects with MI, indicating that factor XIII Val 34 Leu is
protective against atherothrombotic disease. However, in subjects with
factor XIII Val 34 Leu and MI, higher PAI-1 levels and an increased
frequency of the PAI-1 promoter 4G/4G genotype suggest that
inhibition of fibrinolysis negates the protective
effects of factor XIII Val 34 Leu, which supports a functional role for
this mutation.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Study Population
We recruited 612 consecutive inpatients with acute stroke
defined by World Health Organization Criteria9
(excluding subarachnoid hemorrhage) and 435 healthy
control subjects closely matched for age, sex, and domicile and free of
clinically detectable cerebrovascular disease, as described
previously.10 All subjects gave informed consent
according to a protocol approved by the Research Ethics Committees.
To determine the stroke phenotype (CI or PICH), cranial
CT was performed within 10 days of stroke. Cases with CI were
classified into subtypes according to the Oxfordshire Community Stroke
Project Classification.11
Nonfasting venous blood samples were taken from both cases
(within 10 days of stroke) and controls between 8 and 11 AM
and placed in 0.1 mol/L sodium citrate (9:1, vol/vol) in ice water for
assay of PAI-1 activity, then centrifuged at 2560g
at 4°C for 30 minutes. Samples were stored at -40°C. PAI-1
activity was measured by a chromogenic assay (Spectrolyse,
Biopool).12 The inter- and intra-assay
coefficients of variation for the assay were 5.7% and 3.1%,
respectively. Cholesterol and total
triglyceride levels were measured with the Hitachi 747
automated analyzer (Boehringer Mannheim).
Genomic DNA was extracted from 10 mL venous blood and
anticoagulated with 1.6mg/mL EDTA, with use of a detergent/salt
exchange method described previously.13
A 183-bp fragment of exon 2/intron B of the factor XIII gene was
amplified by PCR, with 5'-ACCCAGAGTGGTGGGGAAG as 5' primer and
5'-GACCTTGTAAAGTCAAAAATGTC as the 3' primer. PCR reaction conditions
were as described previously.8 To detect the
substitution of guanine to thymine (Val 34 Leu), we used a
single-stranded conformational polymorphism technique.
Genotype was classified by two independent observers as wild
type 1/1 (val/val), heterozygote 1/2 (val/leu), or homozygote mutant
2/2 (leu/leu). Confirmation of genotypes was carried out by
sequencing a random selection of samples using dye-labeled terminators
(ABI Prism(TM) Dye Terminator Cycle Sequencing
Ready Reaction Kit, Perkin-Elmer) on an ABI 373A sequencer. There were
no discrepancies between genotypes determined by the two
methods.
The PAI-1 4G/5G promoter polymorphism was determined for
each subject by PCR amplification of genomic DNA with use of
allele-specific primers and PCR conditions, as previously
described. Samples were classified into one of three possible
genotypes (4G/4G, 5G/5G, or heterozygous 4G/5G) and validated
using known genotypes verified by direct sequencing.
Body mass index, cholesterol,
triglycerides and PAI-1 activity were log transformed.
PAI-1 levels in cases and controls were compared using unpaired
t tests. Levels were expressed as geometric means and
antilogged, with 95% CIs. 
2 analysis
was used to compare the genotype distributions. The
determinants of PICH were studied in a logistic regression model, with
the covariates age, sex, current smoking history, past history of
hypertension, diabetes mellitus, ischemic heart disease, and
factor XIII Val 34 Leu genotype. Statistical analysis
was performed with SPSS for Windows, version 6.1 (SPSS Inc).
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Characteristics of the Study Population
The median age of the case patients (n=612) and control subjects
(n=436) was 73.0 years. Conventional vascular risk factors, namely,
ischemic heart disease, MI, diabetes mellitus, hypertension,
and current smoking, were more common in the case patients
(P<.01). Cholesterol levels were lower in cases
than controls (5.1 mmol/L [95% CI, 3.4 to 7.3] and 5.8
mmol/L [CI, 5.6 to 5.9], respectively; P=.003).
The distribution of the factor XIII Val 34 Leu genotype in
cases was G/G, 326 (53.3%); G/T, 240 (39.2%); and T/T,46 (7.5%); in
controls it was G/G, 254 (58.3%); G/T, 157 (36.0%); and T/T, 25
(5.7%). Distribution of the PAI-1 4G/5G genotypes in cases was
4/4, 148 (26.9%); 4/5, 270 (49.1%); and 5/5, 132 (24.0%); in
controls it was 4/4, 60 (33.9%); 4/5, 84 (47.5%); and 5/5, 33
(18.6%). There was no difference in the distribution of the factor
XIII Val 34 Leu (or PAI-1 4G/5G genotypes) between cases and
controls (P=.21 and P=.13, respectively). There
was no age relation with genotype (case patients <60 years
(n=103) compared with age-matched control subjects (n=80);
2=0.16, P=.68), nor was there any
relation in controls when analyzed only by age subdivided by
decades (2 [test for trend]=0.19,
P=.20).
Table 1
demonstrates an excess of
the mutation in patients with PICH (n=62) compared with control
subjects (P=.05). In the logistic regression model,
significant independent variables for PICH were a past history of
ischemic heart disease (P=.006) and diabetes
mellitus (P=.04) but not factor XIII Val 34 Leu
genotype (P=.22). In this model there was no
interaction between ischemic heart disease and factor XIII Val
34 Leu genotype (P>.05).
View this table:
[in a new window]
Table 1. Comparison of Factor XIII Val 34 Leu Combined
Genotypes (Wild Type 1/1 vs. Mutants 1/2 vs. 2/2) in Cases by
Stroke Type (cerebral infarction n=529 and primary
intracerebral hemorrhages n=62) With Controls
(n=436)
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
The results from this study indicate an association between
possession of a G-to-T point mutation coding for factor XIII Val 34 Leu
and PICH. We hypothesized that possession of factor XIII Val 34 Leu
mutation might favor the formation of weaker fibrin structures, thereby
protecting against CI or predisposing to PICH. This study supports our
previous findings that factor XIII Val 34 Leu may play a significant
role in the pathogenesis of vascular disorders. The lack of association
of the mutation with ischemic stroke is interesting when
contrasted with MI. However, this may be accounted for by the
heterogeneous nature of ischemic stroke compared
with that of MI. ).
View this table:
[in a new window]
Table 2. Selected Cardiovascular and
Hemostatic Risk Factors in Patients With PICH (n=72) According to
Factor XIII Val 34 Leu Genotype
Selected Abbreviations and Acronyms
CI
=
confidence interval
IC
=
intracerebral hemorrhage
MI
=
myocardial infarction
PAI
=
plasminogen activator inhibitor
PCR
=
polymerase chain reaction
PICH
=
primary intracerebral hemorrhage
Acknowledgments
This study was supported by the Stroke Association. HPK is
funded by the Royal Society, London, United Kingdom.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
1.
Grant PJ, Prentice CRM, Bloom AL, Forbes CD,
Thomas DP, Tuddenham EGD, eds. Haemostasis and
Thrombosis. 3rd ed. Edinburgh, UK: Churchill Livingstone;
1994;54:1231–1254.2-plasmin
inhibitor to fibrin by fibrin stabilizing factor.
J Clin Invest. 1980;65:290–297.-subunit
of coagulation factor XIII: two novel point mutations demonstrate
different effects on transcript levels. Blood. 1994;84:517–525.
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