Target finding for atherothrombosis in a population of patients diagnosed with peripheral obstructive arterial disease.

Atherosclerosis is and will remain a major health care problem for at least the
next decade, and will likely cause many atherothrombotic complications,
inducing mortality, morbidity and associated increased health care expenses. In
order to optimize care, treatment and prevention, more research should be
directed at this serious and yet common problem.

Identification of patients at the highest risk of atherothrombotic
complications might help to better target treatment and at the same time
provide the opportunity to further characterize the underlying processes
contributing to this enhanced risk profile. Until now it remains unclear why
atherothrombotic complications occur in some patients, and never occur in other
patients diagnosed with PAD.

In a previous study on the role of hypercoagulation in the onset and
propagation of PAD, we found limited evidence for a hypercoagulable state in
patients with PAD as assessed by Thrombin Generation test (TG; ThrombogramTM).
The study showed contra intuitive results of reduced peak height and prolonged
lag time; both of these findings are usually associated with reduced
coagulability rather than increased coagulability. This finding is however in
line with publications of inverse relationships for TG in similar patient
populations that showed prolonged lag time associated with recurrent events,
and low peak height with decreased time to event free survival. The regulated
network of pro- and anti-coagulation driven actions of thrombin makes it
imaginable that both low and high thrombin concentrations can be relevant in
the pathophysiology of arterial vascular disease and atherothrombosis. Low
amounts of thrombin would theoretically provide insufficient drive for protein
C activation, to protect against clotting and inflammation. Relatively high
thrombin concentrations could overcome locally protective effects of activated
protein C to drive protease activated receptor (PAR) mediated cell signalling
functions. Another important factor that may influence thrombosis risk, and
which is not present in TG testing is platelet reactivity. Therefore further
research should include platelet rich plasma or whole blood.

Primary objective:
To compare the biochemical and functional differences in coagulation and
inflammation status in PAD patients with (recurrent) atherothrombotic events
and those without events within 1 year of inclusion into the study

Objective 2:
To validate a (newly developed) functional assay by discriminating patients
with (recurrent) events from those without events within 1 year of inclusion
into the study*

Objective 3:
To correlate platelet reactivity by VerifyNow testing or VASP-testing in
patients with Clopidogrel, with (recurrent) atherothrombotic events within 1
year of inclusion into the study

Objective 4:
To correlate a compliance tool (ARMS) to laboratory assessment of treatment
efficacy as well as to (recurrent) atherothrombotic events within 1 year of
inclusion into the study.

*For patients who undergo a new atherothrombotic event, or in case of
laboratory findings that require further investigation, repeated sampling will
be necessary (with a maximum of 3 times) to adjust the assay cascade according
to the findings and to get sufficient material for further analysis (e.g. blood
cells or immune cells).

This is a prospective observational cohort study including consecutive adult
patients objectively diagnosed with peripheral artery disease. Eligible
patients are those with ABI <= 0.9 and Fontaine-classification II or III at the
time of diagnosis.

Patients with mild as well as more severe forms of PAD (but without ulcers)
will be included. Patients can be newly diagnosed, but may also be patients
with established PAD that are currently followed at the vascular surgery
outpatient clinic of the MUMC+.

The follow-up duration will be one year.

The study can only be performed in PAD patients, as the study of the nature of
the underlying pathophysiology of PAD is the central issue of this
investigation. There is limited risk associated with participation in the
study, patients will be asked to undergo at least one, and in some instances up
to three, venapuncture(s). Other procedures are performed in the context of
usual patient care. Study visits will be combined with normal follow up visits
at the outpatient clinic. Patients will be asked to fill out a compliance
questionnaire once. There is no direct benefit of participation in the study.
It is not anticipated that participation in the study will cause physical or
physiological discomfort.