Marked increase of fibrin gel permeability with very low dose ASA treatment.
BACKGROUND
Previous data from our group show that acetylsalicylic acid (ASA), especially at low dose, alters the network structure of fibrin, rendering it more porous. The present study was performed to extend the dose-response curve for effects of ASA on fibrinogen clotting properties and to examine the variability of these effects during a 24-h dose interval.


METHODS
Fifteen healthy volunteers received ASA 37.5 mg daily (low dose) for 10 days and, after an interval of 2 weeks, 320 mg daily (medium dose) for 7 days, followed by a single bolus dose of 640 mg (high dose). The plasma fibrinogen concentrations were determined and the permeability of fibrin gels (Ks) was assayed with a recently modified flow measurement technique. Three-dimensional (3D) structure of the fibrin network was studied by confocal microscopy.


RESULTS
ASA therapy did not influence fibrinogen concentrations. Compared to baseline, Ks levels were increased by 21% and 31% in samples during medium and high dose ASA treatment (p<0.01) and, even more markedly, by 44% (p<0.0001) with very low dose ASA treatment (p<0.01, compared to the higher doses). The effects of ASA on fibrin gel permeability were stable over a 24-h dose interval. During ASA treatment, thicker fibrin fibers and larger network pores with irregular structure were observed by confocal microscopy.


CONCLUSIONS
Acetylation of lysine residues in the fibrinogen molecule may explain the alterations in its clotting property, resulting in altered fibrin gel permeability. The mechanism(s) behind the greater increase in fibrin gel permeability and alterations in 3D structure of the fibrin network observed, and why this phenomenon is more pronounced at low compared to intermediate or high ASA doses, deserve further investigations.
Antovic
Aleksandra
A
Dept. of Surgical Sciences, Coagulation Research Division, Karolinska University Hospital, Sweden. saskaant@yahoo.com
Perneby
Christina
C
Ekman
Gunilla Jacobsson
GJ
Wallen
Håkan N
HN
Hjemdahl
Paul
P
Blombäck
Margareta
M
He
Shu
S
D000328:Adult; D001241:Aspirin / Q000008:administration & dosage* / Q000494:pharmacology; D001780:Blood Coagulation Tests; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005337:Fibrin / Q000187:drug effects / Q000378:metabolism*; D005340:Fibrinogen / Q000032:analysis / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D005782:Gels; D006801:Humans; D021621:Imaging, Three-Dimensional; D008297:Male; D018613:Microscopy, Confocal; D010539:Permeability / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D016062:Porosity; D013997:Time Factors
D005343:Fibrinolytic Agents; D005782:Gels; D010975:Platelet Aggregation Inhibitors; D005337:Fibrin; D005340:Fibrinogen; D001241:Aspirin