Abstract WP97: The Aptamer BT200 Blocks Von Willebrand Factor and Platelet Function in Blood of Stroke Patients

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Katarina Kovacevic ◽  
Stefan Greisenegger ◽  
Nina Buchtele ◽  
Georg Gelbenegger ◽  
Agnes Langer ◽  
...  
Keyword(s):  
Shear Stress ◽  
Acute Stroke ◽  
Platelet Function ◽  
Stroke Prevention ◽  
Large Artery ◽  
Secondary Stroke Prevention ◽  
High Shear ◽  
High Shear Stress ◽  
Stroke Patients ◽  
Blood Samples

Background: The effect of conventional anti-platelet agents is limited in secondary stroke prevention, and their effects are further blunted under conditions of high shear stress in the presence of increased levels of circulating VWF. VWF mediates platelet adhesion to collagen under high shear stress and is thereby critically involved in thrombus formation at sites of stenotic extracranial intracranial arteries (reviewed by Buchtele et al. 2018). We have created a novel anti-VWF aptamer (BT200) which could be useful for secondary stroke prevention, because the anti-VWF aptamer ARC1779 effectively reduced cerebral embolization after carotid endarterectomy (Markus et al. 2011). Aims: To characterize the effects of BT200 in blood of patients with large artery atherosclerosis stroke. Methods: Blood samples were obtained from 30 patients with acute stroke Inhibition of VWF activity by BT200 was quantified by REAADS ELISA and VWF ristocetin cofactor activity (VWF:RCo), platelet function under high shear rates with the PFA-100, and ristocetin-induced platelet aggregation in whole blood. Results: The majority of stroke patients had elevated VWF:RCo levels (mean: 198%; range 55-330%). Of 15 patients receiving clopidogrel with or without aspirin, only two had a prolonged collagen adenosine diphosphate closure time (CADP-CT) >123s, and only one patient had a ristocetin induced aggregation of <20U. BT200 concentration dependently inhibited VWF activity to <3% and VWF dependent platelet function (p<0.001): BT200 invariably prolonged CADP-CT to target levels of >300s, and decreased aggregation to <20U in blood samples from all patients. Conclusions: BT200 effectively inhibits VWF activity and VWF-dependent platelet function in blood from patients with acute stroke. Results from this study proved useful for planning of the ongoing phase I and planned phase II trial.

scholarly journals The aptamer BT200 blocks von Willebrand factor and platelet function in blood of stroke patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Katarina D. Kovacevic ◽  
Stefan Greisenegger ◽  
Agnes Langer ◽  
Georg Gelbenegger ◽  
Nina Buchtele ◽  
...  
Keyword(s):  
Platelet Function ◽  
Von Willebrand Factor ◽  
Stroke Prevention ◽  
Adenosine Diphosphate ◽  
Target Range ◽  
Large Artery ◽  
Dependent Manner ◽  
Secondary Stroke Prevention ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractThe effect of conventional anti-platelet agents is limited in secondary stroke prevention, and their effects are blunted under high shear stress in the presence of increased levels of circulating von Willebrand factor (VWF). VWF is critically involved in thrombus formation at sites of stenotic extracranial/intracranial arteries. A third generation anti-VWF aptamer (BT200) has been generated which could be useful for secondary stroke prevention. To characterize the effects of BT200 in blood of patients with large artery atherosclerosis stroke (LAA). Blood samples were obtained from 33 patients with acute stroke or transient ischemic attack to measure inhibition of VWF activity and VWF-dependent platelet function. Patients who received clopidogrel or dual antiplatelet therapy did not differ in VWF dependent platelet function tests from aspirin treated patients. Of 18 patients receiving clopidogrel with or without aspirin, only 3 had a prolonged collagen adenosine diphosphate closure time, and none of the patients had ristocetin induced aggregation in the target range. BT200 concentration-dependently reduced median VWF activity from 178 to < 3%, ristocetin induced platelet aggregation from 40U to < 10U and prolonged collagen adenosine diphosphate closure times from 93 s to > 300 s. Baseline VWF activity correlated (r = 0.86, p < 0.001) with concentrations needed to reduce VWF activity to < 20% of normal, indicating that BT200 acts in a target concentration-dependent manner. Together with a long half-life supporting once weekly administration, the safety and tolerability observed in an ongoing phase I trial, and the existence of a reversal agent, BT200 is an interesting drug candidate.

Investigating the effect of operation points on crystal quality in reactive crystallization using continuous flow with high shear stress

2021 ◽  
Vol 176 ◽  
pp. 116-122
Author(s):  
Shuntaro Amari ◽  
Chinami Sugawara ◽  
Ryo Harada ◽  
Shoji Kudo ◽  
Hiroshi Takiyama
Keyword(s):  
Shear Stress ◽  
Continuous Flow ◽  
Crystal Quality ◽  
High Shear ◽  
High Shear Stress ◽  
Reactive Crystallization

Abstract P252: Discharge Antithrombotic Therapy for Ischemic Stroke Patients With Prior Aspirin Failure

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Ying Xian ◽  
Haolin Xu ◽  
Deepak L Bhatt ◽  
Gregg C Fonarow ◽  
Eric E Smith ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Stroke Prevention ◽  
Antithrombotic Therapy ◽  
Recurrent Stroke ◽  
Oral Anticoagulants ◽  
The United States ◽  
Future Research ◽  
Large Artery ◽  
Secondary Stroke Prevention ◽  
Stroke Registry

Introduction: Aspirin is one of the most commonly used medications for cardiovascular disease and stroke prevention. Many older patients who present with a first or recurrent stroke are already on aspirin monotherapy, yet little evidence is available to guide antithrombotic strategies for these patients. Method: Using data from the American Heart Association Get With The Guidelines-Stroke Registry, we described discharge antithrombotic treatment pattern among Medicare beneficiaries without atrial fibrillation who were discharged alive for acute ischemic stroke from 1734 hospitals in the United States between October 2012 and December 2017. Results: Of 261,634 ischemic stroke survivors, 100,016 (38.2%) were on prior aspirin monotherapy (median age 78 years; 53% women; 79.4% initial stroke and 20.6% recurrent stroke). The most common discharge antithrombotics (Figure) were 81 mg aspirin monotherapy (20.9%), 325 mg aspirin monotherapy (18.2%), clopidogrel monotherapy (17.8%), and dual antiplatelet therapy (DAPT) of 81 mg aspirin and clopidogrel (17.1%). Combined, aspirin monotherapy, clopidogrel monotherapy, and DAPT accounted for 86.8% of discharge antithrombotics. The rest of 13.2% were discharged on either aspirin/dipyridamole, warfarin or non-vitamin K antagonist oral anticoagulants with or without antiplatelet, or no antithrombotics at all. Among patients with documented stroke etiology (TOAST criteria), 81 mg aspirin monotherapy (21.2-24.0%) was the most commonly prescribed antithrombotic for secondary stroke prevention. The only exception was those with large-artery atherosclerosis, in which, 25.3% received DAPT of 81 mg aspirin and clopidogrel at discharge. Conclusion: Substantial variations exist in discharge antithrombotic therapy for secondary stroke prevention in ischemic stroke with prior aspirin failure. Future research is needed to identify best management strategies to care for this complex but common clinical scenario.

scholarly journals 5065Platelet desialylation induced by high shear-stress mechanical circulatory support

2018 ◽  
Vol 39 (suppl_1) ◽  
Author(s):  
H Spillemaeker ◽  
A Dupont ◽  
A Kauskot ◽  
A Rauch ◽  
F Vincent ◽  
...  
Keyword(s):  
Shear Stress ◽  
Mechanical Circulatory Support ◽  
Circulatory Support ◽  
High Shear ◽  
High Shear Stress

scholarly journals Nitric Oxide–Dependent and Nitric Oxide–Independent Transcriptional Responses to High Shear Stress in Endothelial Cells

Hypertension ◽  
2005 ◽  
Vol 45 (4) ◽  
pp. 672-680 ◽  
Author(s):  
Branko Braam ◽  
Remmert de Roos ◽  
Hans Bluyssen ◽  
Patrick Kemmeren ◽  
Frank Holstege ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Shear Stress ◽  
High Shear ◽  
High Shear Stress ◽  
Transcriptional Responses

DIFFUSION LIMITED AGGREGATION FROM SHEAR STRESS AS A SIMPLE MODEL OF VASCULOGENESIS

Fractals ◽  
1999 ◽  
Vol 07 (01) ◽  
pp. 33-39 ◽  
Author(s):  
VINCENT FLEURY ◽  
LAURENT SCHWARTZ
Keyword(s):  
Shear Stress ◽  
Dendritic Growth ◽  
High Shear ◽  
Vascular Pattern ◽  
Laplacian Growth ◽  
High Shear Stress ◽  
Diffusion Limited Aggregation ◽  
Diffusion Limited ◽  
Capillary Bed ◽  
Arteries And Veins

A model is proposed by which the formation of the vascular network in animals proceeds via progressive penetration of the vessel ramification into a capillary mesh, by means of a laplacian growth mechanism of hydrodynamical origin. In this model, the growth of both arteries and veins follows the directions of high shear stress provoked by the blood flow on the endothelial wall of a pre-existing capillary mesh. This process is shown to be identical to the phenomenon of dendritic growth, which is responsible for the formation of such well-known patterns as dendritic crystals, lightning sparks or branching aggregates of bacteria. A number of straightforward consequences of potentially important medical and physiological interests are deduced. These include the natural and spontaneous organization of the arterial and venal trees, the spontaneous and unavoidable tropism of arteries towards veins and vice-versa, the hierarchical character of the vessels and the possibility of computerized prediction of the vascular pattern from the shape of the capillary bed.

scholarly journals Antithrombotic Effects of Paeoniflorin from Paeonia suffruticosa by Selective Inhibition on Shear Stress-Induced Platelet Aggregation

2019 ◽  
Vol 20 (20) ◽  
pp. 5040 ◽  
Author(s):  
Thien Ngo ◽  
Keunyoung Kim ◽  
Yiying Bian ◽  
Hakjun Noh ◽  
Kyung-Min Lim ◽  
...  
Keyword(s):  
Shear Stress ◽  
Platelet Aggregation ◽  
Ex Vivo ◽  
Antiplatelet Agents ◽  
Human Platelets ◽  
Platelet Glycoprotein ◽  
High Shear ◽  
High Shear Stress ◽  
Paeonia Suffruticosa ◽  
Induced Aggregation

Antiplatelet agents are important in the pharmacotherapeutic regime for many cardiovascular diseases, including thrombotic disorders. However, bleeding, the most serious adverse effect associated with current antiplatelet therapy, has led to many efforts to discover novel anti-platelet drugs without bleeding issues. Of note, shear stress-induced platelet aggregation (SIPA) is a promising target to overcome bleeding since SIPA happens only in pathological conditions. Accordingly, this study was carried out to discover antiplatelet agents selectively targeting SIPA. By screening various herbal extracts, Paeonia suffruticosa and its major bioactive constituent, paeoniflorin, were identified to have significant inhibitory effects against shear-induced aggregation in human platelets. The effects of paeoniflorin on intraplatelet calcium levels, platelet degranulation, and integrin activation in high shear stress conditions were evaluated by a range of in vitro experiments using human platelets. The inhibitory effect of paeoniflorin was determined to be highly selective against SIPA, through modulating von Willebrand Factor (vWF)-platelet glycoprotein Ib (GP Ib) interaction. The effects of paeoniflorin on platelet functions under high shear stress were confirmed in the ex vivo SIPA models in rats, showing the good accordance with the anti-SIPA effects on human platelets. Treatment with paeoniflorin significantly prevented arterial thrombosis in vivo from the dose of 10 mg/kg without prolonging bleeding time or blood clotting time in rats. Collectively, our results demonstrated that paeoniflorin can be a novel anti-platelet agent selectively targeting SIPA with an improved safety profile.

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