Guy L. Reed

Microvascular Thrombosis, Fibrinolysis, Ischemic Injury, and Death After Cerebral Thromboembolism Are Affected by Levels of Circulating α2-Antiplasmin

Objective— Ischemic stroke is primarily attributable to thrombotic vascular occlusion. Elevated &agr;2-antiplasmin (a2AP) levels correlate with increased stroke risk, but whether a2AP contributes to the pathogenesis of stroke is unknown. We examined how a2AP affects thrombosis, ischemic brain injury, and survival after experimental cerebral thromboembolism. Approach and Results— We evaluated the effects of a2AP on stroke outcomes in mice with increased, normal, or no circulating a2AP, as well as in mice given an a2AP-inactivating antibody. Higher a2AP levels were correlated with greater ischemic brain injury (r s=0.88, P<0.001), brain swelling (r s=0.82, P<0.001), and reduced middle cerebral artery thrombus dissolution (r s=−0.93, P<0.001). In contrast, a2AP deficiency enhanced thrombus dissolution, increased cerebral blood flow, reduced brain infarction, and decreased brain swelling. By comparison to tissue plasminogen activator (TPA), a2AP inactivation hours after thromboembolism still reduced brain infarction (P<0.001) and hemorrhage (P<0.05). Microvascular thrombosis, a process that enhances brain ischemia, was markedly reduced in a2AP-deficient or a2AP-inactivated mice compared with TPA-treated mice or mice with increased a2AP levels (all P<0.001). Matrix metalloproteinase-9 expression, which contributes to acute brain injury, was profoundly decreased in a2AP-deficient or a2AP-inactivated mice versus TPA-treated mice or mice with increased a2AP levels (all P<0.001). a2AP inactivation markedly reduced stroke mortality versus TPA (P<0.0001). Conclusions— a2AP has profound, dose-related effects on ischemic brain injury, swelling, hemorrhage, and survival after cerebral thromboembolism. By comparison to TPA, the protective effects of a2AP deficiency or inactivation seem to be mediated through reductions in microvascular thrombosis and matrix metalloproteinase-9 expression.

Bivalirudin Versus Heparin Plus Glycoprotein IIb/IIIa Inhibitors in Patients with Diabetes Mellitus Undergoing Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Controlled Trials.

Diabetes mellitus (DM) is a pro-thrombotic state with enhanced thrombin generation and platelet reactivity. For most patients undergoing percutaneous coronary intervention (PCI), bivalirudin demonstrates efficacy comparable with that of heparin and glycoprotein IIb/IIIa inhibitors (GPIs). Yet, because of their pro-thrombotic condition, we hypothesized that patients with DM may benefit from more aggressive dual antithrombin and antiplatelet therapy. The aim of this paper was to provide a systematic review comparing outcomes of PCI with bivalirudin versus heparin plus GPI in patients with DM using meta-analytical techniques. Eligible studies needed to have reported a subgroup analysis of outcomes among diabetic patients. Six trials comprising 5924 diabetic patients were eligible. At 30 days, bivalirudin was associated with a reduction in net adverse cardiac events [relative risk (RR) 0.81, 95xa0% confidence interval (CI) 0.70–0.93, pxa0=xa00.002] and major bleeds (RR 0.68, 95xa0% CI 0.49–0.95; pxa0=xa00.02), with no difference in composite ischemia (RR 0.92, 95xa0% CI 0.74–1.14; pxa0=xa00.43) or mortality (RR 0.71, 95xa0% CI 0.45–1.13; pxa0=xa00.15). At 1 year, bivalirudin was associated with a significant reduction in all-cause mortality (RR 0.73, 95xa0% CI 0.54–1.00, pxa0=xa00.05) despite similar composite ischemia (RR 1.02, 95xa0% CI 0.56–1.21, pxa0=xa00.811). In conclusion, thrombin inhibition with bivalirudin alone was associated with reduced 30-day major bleeding and 1-year all-cause mortality compared with heparin plus GPI in diabetic patients undergoing PCI.

α2-Antiplasmin: New Insights and Opportunities for Ischemic Stroke.

Thrombotic vascular occlusion is the leading cause of ischemic stroke. High blood levels of α2-antiplasmin (a2AP), an ultrafast, covalent inhibitor of plasmin, have been linked in humans to increased risk of ischemic stroke and failure of tissue plasminogen activator (tPA) therapy. Consistent with these observations, a2AP neutralizes the therapeutic benefit of tPA therapy in experimental stroke. In addition, a2AP has deleterious, dose-related effects on ischemic brain injury in the absence of therapy. Experimental therapeutic inactivation of a2AP markedly reduces microvascular thrombosis, ischemic brain injury, brain swelling, brain hemorrhage, and death after thromboembolic stroke. These data provide new insights into the critical importance of a2AP in the pathogenesis of ischemic brain injury and suggest that transiently inactivating a2AP may have therapeutic value in ischemic stroke.

Reversing the deleterious effects of α2-antiplasmin on tissue plasminogen activator therapy improves outcomes in experimental ischemic stroke

High blood levels of α2-antiplasmin have been associated with failed tissue plasminogen activator (TPA) therapy for ischemic stroke. Yet, other data suggests that α2-antiplasmin may be protective in stroke, because it defends against bleeding and excitotoxicity. To address this paradox, we examined the effects of high α2-antiplasmin levels and α2-antiplasmin inactivation in mice treated with TPA 0.5-2.5h after middle cerebral artery (MCA) thromboembolism. Brain infarction, swelling, hemorrhage, blood brain barrier breakdown and neuronal apoptosis were measured by a blinded observer. Thrombus dissolution was determined by gamma counting. During TPA treatment, high α2-antiplasmin blood levels increased brain infarction (2.2-fold) and swelling (3.7-fold), but decreased MCA thrombus dissolution. Conversely, α2-antiplasmin inactivation during TPA treatment reduced brain infarction, hemorrhage and swelling, but increased MCA thrombus dissolution. Inactivation of α2-antiplasmin during TPA treatment reduced neuronal apoptosis and blood brain barrier breakdown. Inactivation of α2-antiplasmin also reduced short-term mortality. Taken together these data show that α2-antiplasmin opposes the effects of TPA therapy and contributes to enhanced brain injury after experimental thromboembolic stroke. Conversely, α2-antiplasmin inactivation during TPA treatment improves thrombus dissolution and reduces brain infarction, swelling and hemorrhage. Consistent with clinical observations, these data suggest that α2-antiplasmin exerts deleterious effects that reduce the efficacy and safety of TPA therapy for ischemic stroke.

Meta-Analysis of the Relative Efficacy and Safety of Oral P2Y12 Inhibitors in Patients With Acute Coronary Syndrome

A cornerstone of medical therapy for patients with acute coronary syndrome (ACS) is dual antiplatelet therapy, which includes aspirin and a P2Y12 inhibitor. Randomized controlled trials (RCTs) have shown that prasugrel and ticagrelor are superior to clopidogrel, but none directly compared these 3 commonly used oral P2Y12 inhibitors for safety and efficacy. Therefore, we performed a Bayesian network meta-analysis of RCTs to compare the efficacies and safeties of 3 commonly used oral P2Y12 inhibitors in patients with ACS. Scientific databases and websites were searched for relevant RCTs. We included data from 9 RCTs that enrolled 106,288 patients. Clopidogrel decreased the rates of major adverse cardiac event, recurrent myocardial infarction, and all-cause mortality compared with placebo. Both ticagrelor and prasugrel decreased the rates for major adverse cardiac event and recurrent myocardial infarction compared with clopidogrel, but there was no difference between the 2. Both also decreased the stent thrombosis rate compared with clopidogrel, but prasugrel was more effective than ticagrelor. Ticagrelor use was also associated with improved all-cause and CV mortalities compared with clopidogrel. There was no difference in CV mortality or all-cause mortality between clopidogrel and prasugrel. Prasugrel use was also associated with significantly increased risk of major bleeding compared with clopidogrel but showed a nonsignificant trend toward increasing the risk of bleeding compared with ticagrelor. In treatment ranking, ticagrelor was the most efficacious, and prasugrel was the least safe. In conclusion, this meta-analysis shows that in patients with ACS, adding P2Y12 inhibitors to aspirin and other standard treatments reduces ischemic events and all-cause mortality. Among the commonly used oral P2Y12 inhibitors, ticagrelor has the best net efficacy and safety profile.

Physiologic Variations in Blood Plasminogen Levels Affect Outcomes after Acute Cerebral Thromboembolism in Mice: A Pathophysiologic Role for Microvascular Thrombosis

Essentials Physiologic variations in blood plasminogen (Pg) levels may affect ischemic stroke outcomes. We tested Pg effects in a model with translational relevance to human thromboembolic stroke. A dose‐response exists between Pg levels and brain injury, fibrinolysis, barrier breakdown. Higher Pg levels reduce microvascular thrombosis and improve outcomes in ischemic stroke.