|
Paul J Burns*
Damien A Mosquera
Andrew W Bradbury*
*University Department of Vascular Surgery,
and Department of Vascular Surgery
Birmingham Heartlands Hospital
Bordesley Green East
Birmingham B9 5SS
In addition to
well-established risk factors such as smoking, diabetes, hypercholesterolaemia
and hypertension, an increasing number of novel humoral and endothelial factors
have recently been implicated in the aetiology and progression of vascular
disease. Thrombophilia may be defined as a propensity to thrombosis secondary to
abnormalities in haemostasis.(1) Thrombophilia has long been recognised as
contributing to venous thrombosis, but is increasingly associated with arterial
disease. It is important because screening may identify patients at high risk of
thrombosis who may then be offered prophylaxis. This review will focus on the
prevalence and significance of thrombophilic states associated with peripheral
arterial occlusive disease (PAOD) and discuss possible strategies for screening
and treatment.
Back to the top
If thrombophilia is
important in PAOD then there should be evidence of activation of coagulation in
affected patients. Thrombin and fibrinogen, and products of their metabolism,
including thrombin-antithrombin (TAT) complexes, prothrombin fragments (PF) 1+2
and fibrin degradation products (FDPs) can be used to measure coagulation
activation. Cross-sectional(2-5) and longitudinal(6) epidemiological studies
have demonstrated an association between activation of coagulation and PAOD.
Furthermore, in 1988, Boneu showed that PAOD was associated with inhibition of
fibrinolysis.(7) In young patients (<51 years old) undergoing lower limb
revascularisation, as many as 76% may have a hypercoagulable state (increased
platelet aggregation or coagulation abnormality).(8)
A mild elevation of
homocysteine levels (hyperhomocysteinaemia) affects 5% or more of the population
and is increasingly recognised as an independent risk factor for atherosclerosis
and thrombosis.(9) Hyperhomocysteinaemia can cause increased Factor V activity,
possibly via a decrease in thrombomodulin cell surface activity and a
corresponding decrease in activated protein C (Figure 1).(10-13) The prevalence
of hyperhomocysteinaemia in PAOD may be between 50 and 60%(14-16) and many
cross-sectional studies have demonstrated a clear association between plasma
homocysteine levels and PAOD.(17)
Anti-thrombin III (AT III)
is an endogenous anti-coagulant, produced by the liver, which inactivates
thrombin and factor Xa. Deficiency of AT III is inherited in an autosomal
dominant fashion. In a population-based study of 7983 subjects over 55 years old
3.1% had deficiency of AT III, defined as <75% activity.(18)
Fibrinogen is the substrate
on which the end-product of the coagulation cascade, thrombin, acts to produce
fibrin, and ultimately, a blood clot. Its effects are diverse and include
increases in blood viscosity, red cell aggregation, platelet aggregation and
activation.(19) Fibrinogen deposited in the arterial intima may also lead to
smooth muscle cell proliferation and leukocyte migration.(20-23)
Hyperfibrinogenaemia has long been associated with cardiovascular disease and is
present in more than 50% of patients with PAOD.(24-26)
Antiphospholipid antibodies (aPL) are a group of auto
antibodies originally thought to be targeted towards negatively charged
phospholipid, although recent work suggests that they are directed against β2-glycoprotein
I.(27) aPLs are of two types, detected by different laboratory methods: the
anticardiolipin antibody (aCL) enzyme linked immunoassay and the lupus
anticoagulant (LAC) coagulation assay. Although the lupus assay relies on the
in-vitro effect of aPL to prolong coagulation assays, the in-vivo
effect is procoagulant, the mechanism for which is uncertain. Antiphospholipid
antibodies may inhibit protein C and protein S, and have prothrombotic effects
via enhanced platelet reactivity or endothelial cell surface molecules such as
heparan sulphate and tissue factor.(27)
Cross-sectional studies
have shown that the prevalence of aPL amongst patients with PAOD requiring
intervention varies between 26% and 45%.(28-30) This mostly comprises patients
with aCL who constitute 84%-94% the total. A small proportion of patients with
aPL have both LAC and aCL (2%-3%).(28,30,31) No studies have yet compared the
prevalence of aPL in PAOD with the prevalence in the general population, and no
large cross-sectional studies have been performed to give a population
prevalence of aPL.
Protein C is a vitamin K
dependent protein which, when activated by the thrombin-thrombomodulin complex,
inactivates factors Va and VIIIa (Figure 1). Protein C deficiency is established
as a risk factor for venous thrombosis, but its role in arterial pathology is
less clear. Few studies have investigated the prevalence of protein C deficiency
in PAOD. In a recent study of 116 claudicants, deficiency of protein C was found
in 2 (1.7%).(31) Other studies have shown the prevalence of protein C deficiency
to be between 2.5 and 15% in PAOD patients, but no comparisons were made with
control groups.(8,32-34)
Activated protein C (APC)
resistance is the most common inherited risk factor for thrombosis. The
prevalence varies in different ethnic populations; in UK it is 3.5-4.9%,
Africans 0% and in Cyprus 13%.(35,36) The most common cause of APC resistance is
a mutation in the factor V gene leading to the replacement of Arginine 506 with
Glutamine, (factor V Leiden, fVL) which renders it more resistant to degradation
by protein C. This is responsible for 90-95% of APC resistance, the remainder of
which is made up of acquired conditions such as aPL, pregnancy and the oral
contraceptive pill.(37-40) APC resistance is measured using a plasma assay and
exogenous activated protein C, and is indicated by a lowering of the APC ratio
(normal range 2.2 to 2.6). This will identify the majority, but not all of
patients with fVL. fVL may also be identified directly using genomic analysis,
but not all mutations lead to lowering of the APC ratio. fVL is thought to
underlie 18%-30% of venous thromboses, but its importance in arterial disease is
less well defined.
Both APC resistance and fVL
have been demonstrated to be more common in patients with PAOD compared with the
general population. Sampram found the prevalence of fVL and APC resistance
(defined as ratio <2.6) to be higher (26.4%) in 359 patients with PAOD than in
278 controls (12.2%).(41) A smaller study by Foley in patients who had undergone
lower limb arterial bypass surgery reported a 17.8% prevalence of fVL, compared
with a local population prevalence of 3.5%.(35) Evans only reported one positive
APC resistant patient in 116 claudicants(31). Variations in these reported
figures may be explained by the preferential use of DNA analysis or APC ratio to
define fVL; variations in the lower end of the normal range for defining the
normal APC ratio and the severity of the presenting PAOD.
Protein S is a vitamin K
dependent plasma protein and an essential co-factor for the anticoagulant and
profibrinolytic effect of activated protein C.(42) Protein S deficiency has been
identified as a cause of venous thrombosis, and more recently has been proposed
as a factor in arterial disease. The prevalence of protein S deficiency in the
general population is thought to be around 0.7%.(43) There are only a few small
studies investigating the prevalence of protein S deficiency in PAOD. Allart in
1990 showed protein S deficiency to be present in 3 out of 45 patients (8%) less
than 45 years old who required surgical treatment for PAOD.(42). A study of 33
patients undergoing arterial surgery, and 10 controls found a prevalence of
protein S deficiency in PAOD patients of 15%. Although no statistical difference
was shown between patients and healthy controls, all five subjects with protein
S levels less than normal were PAOD patients.(44)
A G to A transition at
position 20210A of the prothrombin gene is associated with an increased risk of
venous thrombosis, although the underlying mechanism is not clear. The
prevalence of this mutation is 1.2% to 4.3% in patients with venous thrombosis,
5.7% in patients with PAOD, and 0.7% in controls.(45,46) However, no specific
studies have been performed investigating the association between prothrombin
20210A and arterial disease.
Despite studies screening
for different states, using a variety of methods, in patients with a range of
disease severity, it is clear that there is an increased prevalence of
thrombophilic states in PAOD, perhaps as high as 60%. Although common, the
clinical relevance of thrombophilia in PAOD is a more important issue, which
will now be discussed.
Back to the top
There is a correlation
between the level of coagulation activation and the severity of PAOD as
determined by walking distance(4), ankle-brachial pressure index (ABPI)(47,48),
duplex ultrasonography, angiography(49) and clinical symptoms(25). For example,
Ray reported the prevalence of thrombophilia (protein C deficiency, protein S
deficiency, antithrombin III deficiency, lupus anticoagulant) to be 11% in
controls, 27% in claudicants and 40% in patients who had received a
revascularisation.(34)
The importance of a
hypercoagulable state in PAOD has also been revealed through the association
between coagulation abnormalities and the progression of PAOD. In the Edinburgh
Artery Study, whole blood viscosity, plasma viscosity and fibrinogen levels were
predictive of the requirement for vascular intervention,(50) or fall in ABPI,(6)
over a six year follow-up period. Furthermore, whole blood viscosity, and
fibrinogen levels have been shown to be predictive for the progression of PAOD
as determined by walking distance.(51)
Thrombophilic states may
also important causes of failure of arterial interventions. In 1994, Ray studied
124 patients undergoing arterial reconstruction and reported 75 graft occlusions
after a mean follow up of 44 months.(34) Almost half (49%) of these were
subsequently identified as having a thrombophilia, compared with 27% of patent
reconstructions. Abnormalities identified in the graft occlusion group were:
protein C deficiency (21% of occlusions), protein S deficiency (17%), lupus
anticoagulant (25%) and multiple abnormalities (12%). A subsequent prospective
study, investigated the presence of a thrombophilia prior to arterial
reconstruction in 60 patients with one-year follow up. (52) A pre-operative
thrombophilia was identified in 65% of patients whose graft subsequently
occluded within one year, compared with 20% of those with a patent graft (P <
.05). The presence of thrombophilia was particularly significant in early graft
failures, where 11 of the 12 occlusions within one month had a pre-operative
hypercoagulable abnormality. A prospective study of 137 patients undergoing a
mixture of arterial reconstructions identified 14 patients (10%) with a
hypercoagulable state.(33). Three of these patients (27%) suffered a graft
thrombosis within 30 days, compared with two of 123 patients with a normal
thrombophilia screen (1.6%). Eldrup Jorgensen studied 20 young (<51years old)
patients undergoing aorto-iliac (7) or infra-inguinal (13) vascular surgery.(8)
Four patients suffered an early (<30 days) post-operative thrombosis, all of who
had thrombophilia identified pre-operatively. Patients with multiple coagulation
abnormalities appear to be at special risk. Thus, of 124 patients undergoing
revascularisation studied by Ray, 11 had multiple thrombophilias, all of whom
had had a previous revascularisation. Nine of these patients had a further
occlusion during the follow-up period.(34)
Hyperhomocysteinaemic
patients have an increased rate of vein graft stenosis and increased failure of
bypass grafts and angioplasty. (16,53) Patients undergoing peripheral arterial
bypass surgery with elevated homocysteine have evidence of pre-existing intimal
hyperplasia in saphenous vein biopsies.(15) A prospective study investigating
hyperhomocysteinaemia and progression of PAOD, with mean follow-up of 37 months
found a trend towards an association, but this was not statistically
significant.(54) This may, however, represent a type II error as only a
relatively small number of patients (22) were judged to have progression of PAOD
during follow-up.
Fibrinogen levels correlate
with the severity of PAOD, higher levels being associated with more severe
disease, as determined by claudication distance,(25) angiography,(55,56) and
ABPI.(47,49,57) Hyperfibrinogenaemia has been shown to be predictive for the
progression of PAOD, as measured by change in claudication distance,(51) or the
requirement for intervention.(50)
Given that
hyperfibrinogenaemia is associated with the development and progression of PAOD,
it is unsurprising that high levels of fibrinogen are predictive of failure of
interventions for PAOD. Prospective studies have shown that hyperfibrinogenaemia
is associated with failure of vein and prosthetic femoral popliteal bypass
grafts.{Hamer, Ashton, et al. 1973 ID: 93}{Woodburn, Rumley, et al. 1996 ID:
43}(59,62) In addition, associations have been demonstrated between raised
fibrinogen levels and graft stenosis, implying that it is not simply an
increased thrombotic tendency underlying the failure of such
interventions.{Hicks, Ellis, et al. 1995 ID: 96}{Cheshire, Wolfe, et al. 1996
ID: 63} Data regarding fibrinogen and patency following percutaneous angioplasty
are conflicting. Two prospective studies have shown that hyperfibrinogenaemia is
associated with poorer patency rates, while another prospective study showed
that high fibrinogen levels measured prior to angioplasty were associated with
improved patency rates.(63-65)
At present there are no
selective treatments available to lower fibrinogen and consequently no reported
trials confirming benefit in treating hyperfibrinogenaemia. While there is a
great deal of evidence associating fibrinogen levels and PAOD, it is difficult
to conclude that this relationship is causal until such trials are available.
Fibrinogen is an acute phase protein, and its increased levels in arterial
disease may merely be representative of an underlying low-grade inflammatory
process.
No studies to date have
demonstrated an association between the prevalence of aPL and the progression of
PAOD. However, aPL and the antiphospholipid syndrome are associated with an
increased risk of thrombotic complications of vascular surgery, although the
majority of these studies are retrospective.(28,66-68) Ahn retrospectively
identified seven patients with aPL who underwent a total of 18 vascular
procedures.(69) Three of these patients, none of whom were anticoagulated
developed multiple post-operative thrombotic complications and all eventually
required amputation. The remaining four vascular patients in this study were
taking steroids, anticoagulants, or vitamin K at the time of the initial
operation. A similar study found that 16 of 19 patients with aPL undergoing a
vascular procedure suffered a thrombosis, 12 of who died.(70) In a retrospective
report of 234 patients undergoing vascular surgery, aPLs were associated with a
shorter bypass patency period (17 v 58 weeks) and a risk of occlusion that was
5.6 times greater than patients without aPLs.(28)
The only prospective study
to investigate the association between aPL and the outcome of vascular
intervention, showed a trend towards the presence of aPL and failure of arterial
bypass surgery, but this did not reach statistical significance.(30) This result
is unfortunately confounded by the fact that, significantly more of the aPL
group were anticoagulated post-operatively thus diminishing any likely
difference between the groups.
Ouriel prospectively
monitored 76 patients who underwent lower limb revascularisation for a mean of
47 months. 60% of those with APC resistance (defined as APC ratio <2.0) had an
occlusion of their graft, while only 24% of those without APC resistance
suffered a graft failure (P < .02).(71) A similar finding was seen in Samprams
study in which 32% of those with fVL and 49% of those with APC resistance
suffered a graft occlusion (both P < .001).(41) A study from Foley et al
reported no association between fVL and graft occlusion, but excluded patients
whose graft occluded within six weeks of surgery, a time that others have
reported as important in graft occlusion associated with thrombophilia(35).
Although the prevalence of
protein S deficiency is higher in patients with PAOD, its significance is
unknown. Allart investigated the families of young (<45 years old) PAOD patients
who were found to be heterozygotes for protein S deficiency, but no association
was found between likelihood of protein S deficiency, and arterial
thrombosis.(42) This finding corroborated a previous study, which showed that
relatives of protein S deficient individuals did not have an increased incidence
of arterial thrombosis.(72)
Deficiency of protein S was
identified in 4 of 20 patients (20%) whose arterial reconstruction failed
compared with 6 of 40 (15%) of those with a successful reconstruction at 30 days
post surgery, although this difference did not reach statistical
significance.(42)
In Van der Boms population
study, examination of 7983 subjects revealed a complex relationship between
level of AT III and ABPI.(18) In men, mild PAOD was associated with a high level
of ATIII, while severe PAOD was associated with lower levels of ATIII. Whilst in
women, there was in an inverse relationship between ABPI and ATIII level. The
authors suggest that levels of ATIII rise in the presence of cardiovascular
disease as a protective mechanism, but as vascular disease progresses, ATIII
becomes consumed, leading to lower levels. The reason for the difference between
the sexes is not clear.
The poor results of
intervention in patients with thrombophilias, in terms of intervention failure
and mortality, reinforce the clinical importance of these states in patients
with PAOD. The presence of two or more co-existent thrombophilias, seems to have
an additive effect, and be particularly dangerous clinically. However, many
thrombophilic states may be asymptomatic for many years and the two-hit
hypothesis suggests that thrombophilic states only become apparent when a
subject is exposed to some other thrombogenic trigger such as surgery,
oestrogen-containing medication, dehydration or systemic upset.
Back to the top
The British Committee for
Standards in Haematology (BCSH) identified 10 groups of patients who should be
screened for thrombophilia (Table 1).{British Society for Haematology. 1990 ID:
112} The treatment of thrombophilic abnormalities is complex, and the decision
for treatment, which may be lifelong anticoagulation, should only be made after
careful consideration of the patient, the individual thrombophilia and any
triggering factors that may have precipitated a previous thrombosis. It is our
recommendation that such patients are referred to a haematologist.
Patients with PAOD who do
not fall into one of the groups in table 1, thrombophilia screening is still
likely to reveal an abnormality in approximately 30 - 60% of patients. In those
who are not undergoing a vascular intervention, there is no evidence to suggest
that treatment of the thrombophilia will alter the progression of arterial
disease. There is evidence however, that patients with a thrombophilia
undergoing a vascular intervention have a poor prognosis, with increased risk of
graft occlusion, limb loss and death, and this can be partially offset by
treatment. It is therefore recommended that all patients undergoing a vascular
intervention should be screened for a thrombophilic tendency.
Testing for thrombophilia
should depend on the individual abnormality. Antiphospholipid antibodies,
activated protein C resistance, and hyperhomocysteinaemia are the commonest
abnormalities, and should form the basis of a thrombophilia screen. Screening
for protein C and S deficiency, prothrombin 20210A, and antithrombin III
deficiency may be useful, but likely to yield less positive results, although no
less significant.
Assays for homocysteine
have previously been difficult to perform, due to the requirement for immediate
cooling of the sample and separation within 1 hour. New techniques are being
developed to improve the stability of blood samples for homocysteine analysis,
increasing the ease by which homocysteine assays can be performed.{Hill & Kenney
2000 ID: 175}{Al-Khafaji, Bowron, et al. 1998 ID: 174}
The cost of thrombophilia
screening is used as an argument against its use. However, if screening were
targeted to high-risk groups, such as those in Table 1, or those undergoing
intervention, the cost of screening would be offset against the reduced risk of
failure of vascular intervention. The treatment of intervention failure may
include prolonged hospital stay, repeated intervention, or amputation, all with
significant costs. A more detailed cost-benefit analysis is beyond the scope of
this article, and would be difficult to perform given that the lack of trials in
this area means the true benefit of screening and/or treatment cannot be
quantified.
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Although numerous different
treatments are available for thrombophilias, they have not been formally studied
in patients with PAOD to determine whether improved outcomes can be attained.
Hyperhomocysteinaemia. Patients with
hyperhomocysteinaemia, who are undergoing a vascular intervention, should be
treated with homocysteine lowering therapy prior to surgery if there is
sufficient time. If the surgery is urgent, consideration should be given to
formally anticoagulating these patients until the level of homocysteine can be
reduced. Hyperhomocysteinaemia may be corrected simply with folic acid, and
vitamins B12 and/or B6, although it has yet to be
demonstrated whether such treatment will lead to a reduction in cardiovascular
risk or improvement in patency rates. Trials are presently being undertaken to
determine whether lowering homocysteine levels is beneficial in terms of outcome
for vascular patients both in PAOD and in cardiac and cerebrovascular disease.
It seems sensible in the absence of current evidence however, to lower
homocysteine levels in PAOD patients undergoing intervention.
Anti-coagulation. Anticoagulation in non-thrombophilic
patients is of benefit in femoro-popliteal bypass grafts when compared with no
treatment, but when compared to aspirin, the data are conflicting. {Jackson &
Clagett 2001 ID: 168}. The largest study was a multicentre, randomised
controlled trial investigating the effectiveness of oral anticoagulation (to
maintain an INR 4.0-4.5) against aspirin (80mg daily) in 2690 patients
undergoing infrainguinal bypass surgery,{Dutch Bypass Oral Anticoagulants or
Aspirin (BOA) Study Group 2000 ID: 170} which showed no overall benefit of
either treatment in preventing graft occlusion. Patients with antiphospholipid
antibodies who are anticoagulated (with heparin and subsequently warfarin) when
they underwent vascular surgery were noticed to suffer fewer complications(69).
No studies to date have prospectively investigated the use of anticoagulation in
PAOD patients with a thrombophilia. However, Khamashita et al retrospectively
studied the effectiveness of anticoagulation in patients with antiphospholipid
syndrome.(74) They showed that anticoagulation with warfarin to an international
normalised ratio (INR) of >3 was significantly more effective in preventing
recurrent thrombosis than anticoagulating to an INR < 3, or aspirin. This study
was not confined to patients with PAOD, but is significant in demonstrating a
benefit of aggressive anticoagulation in thrombophilia.
Steroids. Whilst the thrombophilias discussed previously
are not thought to be associated with a vasculitis, patients with the lupus
anticoagulant who are taking steroids seem to have a reduced thrombotic
risk.(69) The protective effect of steroids in conjunction with aspirin has been
demonstrated previously in obstetric patients, and leads to a decrease in lupus
anticoagulant levels.(75) There are no data on the use of steroids for PAOD
patients with thrombophilia.
Anti-platelet agents. Aspirin is beneficial in obstetric
patients with the lupus anticoagulant.(76) The use of aspirin has not been
investigated in PAOD with a thrombophilia, but it is suggested that it be used
in patients with aPL, with no history of thrombosis. Patients with aPL
undergoing surgery, or with a history of thrombosis should be formally
anticoagulated, as these patients are at high risk of thrombosis.
Factor replacement. An alternative treatment for patients with protein C or S deficiency undergoing
surgery is the use of peri-operative fresh frozen plasma or protein C
concentrate. In the case of peripheral vascular surgery, patients will usually
require formal anticoagulation to ensure the patency of the graft.
Nucleic acid therapy. Recently, oligonucleotides have
been shown to have in-vitro anticoagulant effects through specific protein
binding.(77) It remains to be seen whether this will translate into improved
outcomes in thrombophilias.
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The evidence to date
supports an association between certain thrombophilias and peripheral vascular
disease. Hyperhomocysteinaemia, hyperfibrinogenaemia, APCR and aPL syndrome are
more common in PAOD, but there is no clear evidence for the other
thrombophilias.
Thrombophilic states in
general are associated with an increased failure rate of vascular
reconstruction. This is particularly marked when considering patients with
multiple thrombophilias, and early intervention failures. No conclusive evidence
yet exists to show that treatment of these thrombophilic states can lead to an
improvement in the course of PAOD, or the results of intervention. While it may
be appropriate to anticoagulate patients identified with a thrombophilia who are
undergoing a vascular intervention, it cannot yet be justified to recommend
screening of all patients with PAOD for thrombophilia. There is a pressing need
for well-designed trials of therapeutic intervention in patients with
thrombophilia to determine whether outcomes are genuinely improved.
|
1 |
Venous
thromboembolism before the age of 40-45 years |
|
2 |
Recurrent
venous thrombosis or thrombophlebitis |
|
3 |
Thrombosis in
an unusual site, eg mesenteric vein, cerebral vein etc |
|
4 |
Unexplained
neonatal thrombosis |
|
5 |
Skin
necrosis, particularly if on coumarins |
|
6 |
Arterial
thrombosis before the age 30 years |
|
7 |
Relatives of
patients with thrombophilic abnormality |
|
8 |
Patients with
clear family history of venous thrombosis |
|
9 |
Unexplained
prolonged activated partial thromboplastin time |
|
10 |
Patients with
recurrent foetal loss, idiopathic thrombocytopaenia or SLE |
Table 1. Patients to be investigated for
thrombophilia.
Back to the top
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