Blood, 15 January 2003, Vol. 101, No. 2, pp. 782-782
CORRESPONDENCE
To the editor:
A modified Folts model or the original Folts model to evaluate
new antithrombotics?
I read with interest and some misgivings the report by Wu et
al.1 They used a modified Folts model in baboons receiving either a murine antihuman von Willebrand factor (VWF) monoclonal antibody (mAb) 82D6A3 (600µg/kg, n = 2, or 300µg/kg,
n = 3) or a placebo (normal saline, n = 2). Animals receiving
82D6A3 had a 100% decrease in the cyclic flow reductions (CFRs). The
study suggests that a blockade of VWF-collagen interaction by 82D6A3 reduced platelet thrombus formation in the injured and stenosed baboon
femoral arteries. They state that "the VWF-collagen
interaction ... might be a new target for preventing arterial
thrombosis."1(p3623)
The methods and results presented can be accepted without reservations;
however, I would like to make the following comments. First, Wu et al
presented the original Folts model.2 In 1974, John D. Folts developed a canine model of coronary
stenosis.3 A Medline search was performed, and
the first report in the literature was in 1976, not in
1991.4 Wu et al state that the experimental procedure followed was that of the original Folts model except that the
artery was injured with a spring-loaded forceps. It is true that Folts
produced a stenosis in the artery by an externally applied plastic
cylinder.4 However, this was not the only difference between the original Folts model and the "modified Folts model" presented by Wu et al. Folts described CFRs in coronary arteries of
dogs.4 Coronary blood flow showed cyclical
reductions to near zero, with a sudden spontaneous return to near
control levels. In contrast, Wu et al studied baboon femoral
arteries, and when flow was reduced by at least 50%, blood flow was
restored by pushing the spring of the clamp to physically dislodge the
thrombus. However, the Folts model has been evaluated in several animal
species and vascular territories, and mechanically dislodging the
thrombus to restore blood flow has been successfully accomplished by
other groups.5,6
Regarding potential bias, blood pressure monitoring and arterial blood
gases could not be obtained.7 Information
concerning the vaporizer used was lacking (was it periodically
calibrated?) and unfortunately, it was not a blind study. Moreover,
Bertha et al8 studied halothane in Folts model and
reported in 8 of 8 mongrel dogs that CFRs were abolished at a low
concentration of inspired halothane (halothane 0.5%, n = 5;
halothane 0.25%, n = 3).
Finally, as an anesthesiologist, I must remember that lungs are
ventilated, not animals (nor are they intubated; their tracheas are).
Similarly, the correct term is "cuffed tracheal tube," not "cuffed endotracheal tube."1(p3624)
Maurizio Fattorutto
Correspondence: Maurizio Fattorutto, Department of
Anesthesiology, Hopital Erasme, Route de Lennik 808 Brussels 1070, Belgium; e-mail: m.fattorutto{at}swing.be
References
1.
Wu D, Vanhoorelbeke K, Cauwenberghs N, Meiring M, Depraetere H, Kotze HF, et al.
Inhibition of the von Willebrand (VWF)-collagen interaction by an antihuman VWF monoclonal antibody results in abolition of in vivo arterial platelet thrombus formation in baboons.
Blood.
2002;99:3623-3628[Abstract/Free Full Text].
2.
Folts JD.
An in vivo model of experimental arterial stenosis, intimal damage, and periodic thrombosis.
Circulation.
1991;83:IV3-IV14.
3.
Folts JD, Rowe GG.
Cyclical reductions in coronary blood flow in coronary arteries with fixed partial obstruction and their inhibition with aspirin.
Fed Proc.
1974;33:413.
4.
Folts JD, Crowell EB Jr, Rowe GG.
Platelet aggregation in partially obstructed vessels and its elimination with aspirin.
Circulation.
1976;54:365-370[Abstract/Free Full Text].
5.
Mc Ghie AI, McNatt J, Ezov N, et al.
Abolition of cyclic flow variations in stenosed, endothelium-injured coronary arteries in nonhuman primates with a peptide fragment (VCL) derived from human plasma von Willebrand factor-glycoprotein Ib binding domain.
Circulation.
1994;90:2976-2981[Abstract/Free Full Text].
6.
Golino P, Ragni M, Cirillo P, et al.
Antithrombotic effects of recombinant human active site-blocked factor VIIa in a rabbit model of recurrent arterial thrombosis.
Circ Res.
1998;82:39-46[Abstract/Free Full Text].
7.
Oude Egbrink MG, Tangelder GJ, Slaaf DW, Weijmer-van Velzen S, Reneman RS.
Influence of hypercapnia and hypoxia on rabbit platelet aggregation.
Thromb Res.
1990;57:863-875[CrossRef][Medline]
[Order article via Infotrieve].
8.
Bertha BG, Folts JD, Nugent M, Rusy BF.
Halothane, but not isoflurane or enflurane protects against spontaneous and epinephrine-exacerbated acute thrombus formation in stenosed dog coronary arteries.
Anesthesiol.
1989;71:96-105[CrossRef][Medline]
[Order article via Infotrieve].
Response:
A modified Folts model
We would like to express our appreciation to Dr Fattorutto for
going through our paper so thoroughly, and we are happy that his
remarks do not really question the validity or the interpretation of
our findings.
As far as we see, he seems to be concerned mainly with the fact that we
have used a model which is quite different from the original Folts
model, perhaps too different to still call it a "modified Folts
model." It is correct that we did not refer to the first paper on
this model published in 1976,1 but rather to a 1991 review
paper by Folts,2 where he gives a summary of 15 years of
experience with the model, bringing together the improvements
on the model and summarizing the data obtained. We are convinced this
provides more information to the interested reader and, at the same
time, gives a means to readily access the original references.
On the other hand, our model indeed differs considerably from the
original model developed by Folts, and even in more aspects then Dr
Fatturutto puts forward: the animal species used was different, as was
the artery, the anesthesia, systemic and coronary blood pressures, and
ECG measurements; we damaged the vessel, and Folts, in his original
paper, did not; we applied a stenosis not with a cylinder but with a
clamp; we dislodged the thrombus mechanically ... . However, as
correctly stated by Dr Fatturutto, similar and other adaptations have
been described by other groups,3-5 but it seems
that whenever cyclic flow reductions (CFRs) are measured in a
stenosed artery, this is considered a modification of the original
Folts model. Even the injured femoral artery itself has been
used already in pigs, a model that itself was simply referred to as
"the Folts model on femoral arteries."3
Our sole intention was to test whether inhibition of binding of von
Willebrand factor (VWF) to collagen was antithrombotic, for
which we needed a relatively easy (hence the femoral instead of the
coronary artery) high-shear thrombosis model, in a species whose VWF
did crossreact with the antibody. We wanted to give credit to Folts,
and we definitely had no intention to propose our modified model as a
new or better model.
Finally, the study would have been better indeed if blinded; however,
the measurements of blood flow reductions are quite straightforward and
do not leave that much room for interpretation. And as far as the other
remarks are concerned, we believe that we used the proper control
animals to overcome potential artifacts; in addition, the
animals served as their own controls, as we first determined baseline
CFRs before administration of compounds. The study nevertheless
could have been even better; however, perfection is a privilege not
bestowed upon man.
Hans Deckmyn, Karen Vanhoorelbeke, and Harry Kotzé
Correspondence: Hans Deckmyn, Laboratory for Thrombosis
Research, Interdisciplinary Research Centre (IRC), KU Leuven
Campus Kortrijk, E. Sabbelaan 53, B-8500 Kortrijk, Belgium; e-mail:
hans.deckmyn{at}kulak.ac.be
References
1.
Folts JD, Crowell EB Jr, Rowe GG.
Platelet aggregation in partially obstructed vessels and its elimination with aspirin.
Circulation.
1976;54:365-370.
2.
Folts JD.
An in vivo model of experimental arterial stenosis, intimal damage, and periodic thrombosis.
Circulation.
1991;83:IV3-IV14.
3.
Samama CM, Bonnin P, Bonneau M, et al.
Comparative arterial antithrombotic activity of clopidogrel and acetyl salicylic acid in the pig.
Thromb Haemost.
1992;68:500-505[Medline]
[Order article via Infotrieve].
