Decreased Fibrin Clot Permeability and Susceptibility to Lysis Are Associated with Stroke in Patients with Patent Foramen Ovale.
Authors: Undas Anetta , Podolec Piotr , Pieculewicz Monika , Stepien Ewa , Jedlinski Ireneusz , Duszynska Malgorzata , Hanschke Ewelina , Tracz Wieslawa , Zawilska Krystyna 
Published: October 2019

Abstract
A patent foramen ovale (PFO) has been implicated with embolic stroke. The mechanism underlying this association remains elusive. Since dense fibrin clot structure, resistant to fibrinolysis, has been found to be related to thromboembolic complications of coronary artery disease, we have hypothesized that altered fibrin clot architecture might characterize individuals with stroke associated with PFO. To test this hypothesis, we studied 62 patients (22M, 40F; mean age 40.5 [SD 13.7] years) with documented PFO, who were divided into two groups based on the presence of documented ischemic stroke or not (S+ and S−). Forty-two age- and sex-matched apparently healthy individuals served as controls (n=42). Plasma fibrin clot permeability (expressed as Ks, a measure of the pore size), turbidity (lag phase and maximum absorbancy [max Abs]) and tissue plasminogen activator (tPA)-induced fibrinolysis efficiency (expressed as lysis time in a turbidimetric assay and maximum D-dimer levels, along with their maximum rate of increase in a pressure-driven clot system) were determined. Genotyping for the factor (F)XIII Val34Leu and fibrinogen alpha chain Thr312Ala polymorphisms was performed. Compared to the S- group (n=36), patients with PFO and stroke (n=26) were older (44.8 vs 37.4 years; p=0.03) and had higher creatinine levels (72.7 vs 61.1 umol/L; p=0.01). Other demographic, clinical, and routine laboratory variables were similar. In the S+ group, clot permeability was lower compared with the S− group (median [IQR], Ks, 9.3 [1.4] vs 10.5 [1.3] x 10−9 cm2; p<0.0001), while clot lysis was prolonged (8.45 [3] vs 7.1 [1] min;p<0.0001). Maximum absorbancy was higher and the lag phase shorter in the S+ group than in the S− group (0.865 [0.07] vs 0.7 [0.065]; p<0.0001, and 35.5 [2.6] vs 47 [5] seconds;p<0.0001, respectively). Maximum D-dimer levels, measured at 120 min before the clot collapse in the S+ group, were elevated compared with those in the S− group (3.67 [0.14] vs 3.36 [0.13] mg/L;p<0.0001, respectively). Maximum rate of increase in D-dimer levels were also higher in the former group (0.081[0.008] vs 0.069 [0.0085] mg/L/min;p<0.0001, respectively). Variables describing clot properties in the S− group were similar to those obtained in healthy controls with the exception of decreased rate of D-dimer increase in the former group (p=0.01). Genetic analysis showed no difference in the genotype frequencies among all the groups. After adjustment for fibrinogen levels, Ks, turbidity variables and lysis time remained significantly different between the S+ group and both S− group and healthy controls. Our results suggest that decreased permeability of fibrin clots, composed of thicker fibers, and their relative resistance to fibrinolysis observed in subjects with PFO who experienced stroke, may represent a novel mechanism that might explain why only a small percentage of individuals with PFO suffer from thromboembolic complications.