McBane, Robert D.

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.

Background— Effects were compared in patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial of 2 mechanistically different strategies for treatment of hyperglycemia, insulin-sensitizing and insulin-providing strategies, on biomarker profiles reflecting the balance between fibrinolysis and thrombosis and the intensity of inflammation implicated in diabetic vasculopathy. Methods and Results— A total of 2368 patients with type 2 diabetes mellitus and clinically stable, angiographically documented coronary artery disease were randomized to treatment with 1 of the 2 strategies and followed for an average of 5 years. Plasminogen activator inhibitor type 1 antigen and activity, tissue plasminogen activator antigen, fibrinogen, D-dimer, C-reactive protein, insulin, and hemoglobin A 1c were assayed in blood samples acquired at baseline and at 12 regular intervals throughout the follow-up interval. Higher baseline D-dimer, fibrinogen, and C-reactive protein portended a poor prognosis in patients in both groups. In contrast to the insulin-providing strategy, the insulin-sensitizing strategy led to (1) lower plasma insulin; (2) lower plasminogen activator inhibitor type 1 antigen and activity and lower tissue plasminogen activator antigen (known to track with plasminogen activator inhibitor type 1); and (3) lower C-reactive protein and fibrinogen at all intervals after baseline ( P <0.001 for each). Conclusions— The insulin-sensitizing treatment strategy led to changes in biomarker profiles indicative of decreased insulin resistance, an altered balance between thrombosis and fibrinolysis favoring fibrinolysis, and diminished intensity of the systemic inflammatory state, factors that have been associated with cardiovascular risk. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT00006305.

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.

Abstract Immunohistochemical analysis of surgically obtained porcine tissue samples reveals ubiquitous staining for prothrombin in organs rich in smooth muscle content and universal staining of smooth muscle in tissue vasculature. The native character of tissue prothrombin is verified first by chromogenic substrate hydrolysis and hirudin inhibition after incubation of tissue extracts with taipan snake venom and phospholipid. Western analysis of tissue extracts confirms the native zymogen molecular weight. In addition, prothrombin purified in good yield from porcine uterus is activated by Echis carinatus venom which, like taipan venom, is 4-carboxyglutamic acid-sensitive. After correction for blood (gross heme) and interstitial fluid (albumin), excess functional prothrombin is observed in extracts of tissues having abundant smooth muscle. In contrast with factor X, the yield of prothrombin purified from porcine uterus greatly exceeds that attributable to contamination by whole blood. Northern blot analysis from selected bovine tissues extracted for polyadenylated messenger RNA is equivocal for prothrombin mRNA with the exception of liver, which is positive. It is concluded that functionally intact prothrombin is widely distributed among tissues owing to smooth muscle content, although the mechanism of emplacement and physiologic significance of prothrombin in these tissues remains unclear.

Background— Health status is a key outcome for comparing treatments, particularly when mortality does not differ significantly. Methods and Results— Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) randomized 2368 patients with type 2 diabetes mellitus and stable ischemic heart disease to (1) prompt revascularization versus medical therapy and (2) insulin sensitization versus insulin provision. Randomization was stratified by the intended method of revascularization, coronary artery bypass graft surgery or percutaneous coronary intervention. The Duke Activity Status Index and RAND Energy, Health Distress, and Self-Rated Health scales were assessed at study entry and annually thereafter; linear mixed models were used to evaluate the effect of randomized treatment on these measures. Health status improved significantly from baseline to 1 year ( P <0.001) in each randomized treatment group. Compared with medical therapy, prompt revascularization was associated with significantly greater improvements in Duke Activity Status Index (1.32 points; P <0.001), Energy (1.36 points; P =0.02), and Self-rated Health (1.77 points; P =0.007) but not Health Distress (−0.47; P =0.46). These treatment effects were largely maintained over 4 years of follow-up. The effect of revascularization on the Duke Activity Status Index was significantly larger in the subgroup of patients intended for coronary artery bypass graft surgery compared with the subgroup intended for percutaneous coronary intervention. Health status did not differ significantly on any of the 4 measures between the insulin provision and insulin sensitization strategies. Conclusions— Prompt coronary revascularization was associated with small yet statistically significant improvements in health status compared with initial medical therapy among patients with diabetes mellitus and stable ischemic heart disease. Clinical Trial Registration— http://www.clinicaltrials.gov . Unique identifier: NCT00006305.

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.

Background and Purpose— Analyze the relationship between the location and extent of sinus thrombosis and presence and severity of brain lesions. Methods— Retrospective chart and neuroimaging review of patients with documented CVST. A CVST score was devised to quantify the extent of cerebral venous sinus thrombosis. Results— Nineteen of 56 (34%) patients had brain lesions. The extent of sinus thrombus was associated with increased risk of brain lesions (CVST score 1.9 among patients without brain lesions versus 3.1 in those with lesions; P =0.006). Age, sex, and acquired or hereditary thrombophilias were not associated with the risk of parenchymal lesions. Functional outcomes were favorable even in patients with extensive CVST and parenchymal lesions at presentation. Conclusions— The extent of the sinus involvement correlates with the risk of brain lesions in patients with CVST, but additional factors might also contribute to their occurrence.