Wysokiński, Waldemar E.

Objective— Left atrial blood stasis is associated with increased risk for left atrial appendage thrombus (LAAT) and stroke in atrial fibrillation (AF). Von Willebrand factor (VWF) is associated with thromboembolism in AF. VWF thrombogenic activity is proportional to multimer size, which is regulated by VWF-cleaving protease (ADAMTS13). Methods and Results— To assess the association between left atrial blood stasis and VWF-ADAMTS13 system, plasma VWF antigen (VWF:Ag), VWF activity (VWF:Act), and ADAMTS13 activity were measured in 414 consecutive patients with nonvalvular AF (age 63±13 years; 25% women) and in 100 patients (age 64±14 years; 39% women) with normal sinus rhythm. Spontaneous echocardiographic contrast (SEC), left atrial appendage emptying velocity, and LAAT were assessed by transesophageal echocardiography. Presence and intensity of SEC varied directly with VWF:Ag and VWF:Act but not with ADAMTS13 activity. AF patients with LAAT had higher VWF:Ag (200±61 versus 155±52, P =0.0006) and VWF:Act (179±57 versus 141±51 P =0.0026) compared with those without LAAT. VWF:Ag and VWF:Act were independent predictors of LAAT after adjustment for CHADS 2 score ( P =0.0179 and P =0.0497, respectively). Conclusion— The association between VWF and SEC may explain the thrombotic propensity in AF. Elevated VWF:Ag may help identify AF patients at risk for LAAT.

Abstract —Arterial thrombophilia independent of vascular pathology has not been previously defined either experimentally or epidemiologically. To address the existence of an individual propensity to arterial thrombosis, we exploited a previously developed procedure entailing traumatic (crush) injury of paired porcine carotid arteries for generating platelet-rich thrombi. Porcine carotid arteries were injured bilaterally by serial hemostat crushes. Thrombus generation was monitored by local accumulation of autologous 111 In-labeled platelets and Doppler blood flow. Within this cohort of animals of similar age and size, the lowest to the highest responders in thrombus mass spanned a 7-fold range, showing no correlation with shear, platelet or leukocyte count, or plasma concentrations of fibrinogen or von Willebrand factor. However, there was strong intra-individual correlation ( r 2 =0.80; P <0.001) of thrombus deposition between carotid artery pairs. The wide variation in thrombotic response to a standardized stimulus, not accounted for by shear stress or typical hematological variables, appears to be an intrinsic propensity of the individual. The experimental system for thrombus generation is sufficiently quantitative for assessment of variables determining this propensity.

Introduction: To determine the relationship between fibrin D-dimer levels, symptom duration, and thrombus volume, consecutive patients with incident deep venous thrombosis (DVT) were evaluated. Methods: In a cross-sectional study design, patient symptom onset was determined by careful patient questioning. Venous thrombosis was confirmed by compression duplex ultrasonography. Thrombus volume was estimated based on patient’s femur length using a forensic anthropology method. Fibrin D-dimer was measured by latex immunoassay. Results: 72 consecutive patients with confirmed leg DVT agreed to participate. The median symptom duration at the time of diagnosis was 10 days. The median D-dimer concentration was 1050 ng/dL. The median thrombus volume was 12.92 cm 3 . D-Dimer levels correlated with estimated thrombus volume (P < .0006 CI 0.12-0.41; R 2 adjusted = .15) but not symptom duration, patient’s age, or gender. Conclusions: Despite varying symptom duration prior to diagnosis, fibrin D-dimer remains a sensitive measure of venous thrombosis and correlates with thrombus volume.

Objective— Patients with venous thromboembolism (VTE) often require temporary warfarin interruption for an invasive procedure. The incidence of thromboembolism and bleeding related to periprocedural anticoagulation management of such patients is unknown. Methods and Results— In a protocol-driven, inception cohort design study, all VTE patients (n=775) referred for periprocedural anticoagulation management (1997–2007) were followed-up to estimate the 3-month cumulative incidence of thromboembolism and bleeding. Patients were stratified by thrombus acuity (acute, <30 days; subacute, 31–90 days; or chronic ≥91 days). Decisions to provide “bridging” low-molecular-weight heparin were based on estimated thromboembolism and bleeding risk. Low-molecular-weight heparin was more often administered in acute (87%) and subacute (81%) VTE compared to chronic VTE (59%; P <0.001). The 3-month cumulative incidence of thromboembolism (1.8%), major hemorrhage (1.8%), and mortality (1.7%) were low and did not differ by management strategy. Active cancer was the only independent predictor of thrombotic recurrence (HR, 4.86; 95% CI, 1.6–14.5; P =0.005), major hemorrhage (HR, 6.8; 95% CI, 2.1–21.7; P =0.001), and death (HR, 32.7; 95% CI, 4.3–251.2; P =0.0008). Conclusion— Thromboembolism, bleeding, and death among VTE patients in whom anticoagulation is temporarily interrupted for an invasive procedure is low. Cancer patients require particular care given their propensity for both clotting and bleeding.

Objective— To test the hypothesis that statins will acutely inhibit platelet thrombus formation, intravenous lovastatin was assessed in our well-characterized porcine carotid injury model. Methods and Results— The first carotid artery was crush-injured and harvested after 30 minutes. Pigs then received intravenous lovastatin (100 μg/kg bolus+100 μg/kg/h infusion, n=6) or saline (n=11) before injury of the second carotid artery. Thrombus size was quantified by scintillation detection of autologous 111 In-platelets. Sequential carotid injury produced a thrombus more than 50% greater in volume in the second (3149±2053×10 6 /cm 2 ) relative to the first injured artery (2081±1552×10 6 /cm 2 ; P =0.04) in control pigs. This augmentation was inhibited by intravenous lovastatin which acutely reduced platelet deposition (944±246×10 6 /cm 2 ) relative to saline control ( P =0.02). Flow chamber closure times increased on average by 2.45-fold in response to whole blood lovastatin incubation. Lovastatin ( P <0.05) and simvastatin ( P <0.05) reduced platelet dense granule secretion in vitro. Conclusions— Sequential arterial injury augments the thrombotic response suggesting that the propensity for arterial thrombosis is at least partially acquired. This thrombotic augmentation can be acutely attenuated by intravenous lovastatin which may result from a pleiotropic impact on platelet function. These results appear to be a class effect of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors.

Objective— The clinical use of venous stents is increasing dramatically. Although antiplatelet agents are required for arterial stent patency, optimal thrombo-prophylaxis after venous stenting remains undefined. To address this issue, PD0348292, a direct Factor Xa inhibitor, was compared with antiplatelet therapy in a porcine venous stent model. Methods and Results— Four hours before stent deployment, pigs (n=5 to 6 per group) received oral PD0348292 at 0.4, 0.9, 4.3 mg/kg, or 0.4 mg/kg plus aspirin (325 mg). Aspirin, clopidogrel (75 mg), aspirin plus clopidogrel, or vehicle (n=10) were administered daily for 2 days before the procedure. Two hours after stent placement, thrombi were quantified by autologous 111 In-platelet content and weights. Thrombus weight and platelet deposition were significantly reduced by PD0348292 at 0.4 (49±79 mg and 110±145×10 6 /cm 2 ), 0.9 (5±6 mg and 107±128×10 6 /cm 2 ), 4.3 mg/kg (0±0 mg and 87±125×10 6 /cm 2 ), and PD348292 plus aspirin (20±40 mg and 157±70×10 6 /cm 2 ) compared with vehicle (402±226 mg; 584±454×10 6 /cm 2 ). Despite prolonging bleeding times and inhibiting platelet aggregation, neither aspirin (567±683 mg and 533±622×10 6 /cm 2 ), clopidogrel (404±349 mg and 178±101×10 6 /cm 2 ), nor aspirin plus clopidogrel (247±261 mg and 231±266×10 6 /cm 2 ) significantly decreased stent thrombosis. Conclusions— PD0348292 completely inhibited thrombosis after venous stenting. Platelet accretion in these venous thrombi appear to involve pathways distinct from arachidonate metabolism or ADP P 2 Y 12 receptor activation.