GpIbα-VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice

Béhot, Audrey Le; Gauberti, Maxime; Lizarrondo, Sara Martínez de; Montagne, Axel; Lemarchand, Eloïse; Repesse, Yohann; Guillou, Sylvain; Denis, Cécile V.; Maubert, Eric; Orset, Cyrille; Vivien, Denis

doi:10.1182/blood-2013-12-543074

Cited by 65 publications

(61 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A combination of both strategies could even further improve thrombolytic success. 38 A promising aspect of this approach, at least in experimental models, is the absence of bleeding, in contrast to t-PA. 34,38,39 We did not observe any bleeding complications when treating mice with rhADAMTS13, which is in line with previous studies on the safe use of ADAMTS13 in stroke experiments. 21 ADAMTS13 even reduced bleeding complications associated with t-PA in another murine stroke model.…”

Section: Discussionsupporting

confidence: 89%

See 1 more Smart Citation

ADAMTS13-mediated thrombolysis of t-PA–resistant occlusions in ischemic stroke in mice

Denorme

Langhauser²,

Desender

et al. 2016

Blood

149

172

View full text Add to dashboard Cite

Key Points• ADAMTS13 dissolves t-PAresistant cerebral occlusions in a mouse model of stroke.• The thrombolytic activity of ADAMTS13 could become useful for more efficient and safer thrombolytic treatment of acute ischemic stroke.Rapid vascular recanalization forms the basis for successful treatment of cerebral ischemia. Currently, tissue plasminogen activator (t-PA) is the only approved thrombolytic drug for ischemic stroke. However, t-PA does not always result in efficient thrombus dissolution and subsequent blood vessel recanalization. To better understand thrombus composition, we analyzed thrombi retrieved from ischemic stroke patients and found a distinct presence of von Willebrand factor (VWF) in various samples. Thrombi contained on average 20.3% 6 10.1% VWF, and this was inversely correlated with thrombus red blood cell content. We hypothesized that ADAMTS13 can exert a thrombolytic effect in VWF-containing thrombi in the setting of stroke. To test this, we generated occlusive VWF-rich thrombi in the middle cerebral artery (MCA) of mice. Infusion of t-PA did not dissolve these MCA occlusions. Interestingly, administration of ADAMTS13 5 minutes after occlusion dose-dependently dissolved these t-PA-resistant thrombi resulting in fast restoration of MCA patency and consequently reduced cerebral infarct sizes (P < .005). Delayed ADAMTS13 administration 60 minutes after occlusion was still effective but to a lesser extent (P < .05). These data show for the first time a potent thrombolytic activity of ADAMTS13 in the setting of stroke, which might become useful in treatment of acute ischemic stroke.

show abstract

Section: Discussionsupporting

confidence: 89%

“…38,39 Thus, targeting VWF either via direct cleavage by ADAMTS13 or by inhibition of VWF-platelet binding might become an interesting alternative strategy in thrombolytic therapy. A combination of both strategies could even further improve thrombolytic success.…”

Section: Discussionmentioning

confidence: 99%

ADAMTS13-mediated thrombolysis of t-PA–resistant occlusions in ischemic stroke in mice

Denorme

Langhauser²,

Desender

et al. 2016

Blood

149

172

View full text Add to dashboard Cite

show abstract

“…This absence of restoration of Wistar rat vessel patency is consistent with a hierarchical process of occlusive thrombosis in which platelet-platelet cross-linking in the inner core mainly involves GPIIb/IIIa, whereas once the thrombus has occluded 50% of the artery, platelet cross-linking in the external layer occurs in a GPIbα-vWF-dependent manner. 32,33 Although it is now increasingly recognized that multiple concomitant mechanisms regulate the formation and stability of arterial thrombi, our study further points to the attractiveness of this GPIbα-vWF axis as a potential therapeutic target for occlusive thrombosis in the context of hypertension. Whether coadministration of an inhibitor of GPIbα-vWF interactions and a specific inhibitor of integrin α v β 3 to target thrombin generation on the surface of SMCs may lead to the development of more efficient therapeutic strategies remains to be investigated.…”

Section: Discussionmentioning

confidence: 70%

“…Recent data have highlighted the role of GPIbα-vWF interactions during vessel lumen closure and revealed that disruption of these interactions restores vessel patency after occlusive thrombosis but with a limited therapeutic window. 32 Whereas fully occlusive thrombi in SHR were efficiently disaggregated by GPIbα-vWF inhibitors, nonocclusive thrombi in Wistar rats were resistant. This absence of restoration of Wistar rat vessel patency is consistent with a hierarchical process of occlusive thrombosis in which platelet-platelet cross-linking in the inner core mainly involves GPIIb/IIIa, whereas once the thrombus has occluded 50% of the artery, platelet cross-linking in the external layer occurs in a GPIbα-vWF-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Vascular Smooth Muscle Cells Are Responsible for a Prothrombotic Phenotype of Spontaneously Hypertensive Rat Arteries

Ait‐Aissa

Lagrange

Mohamadi

et al. 2015

ATVB

View full text Add to dashboard Cite

Objective-The hypothesis that hypertension induces a hypercoagulable state arises from the complications associated with hypertension: stroke and myocardial infarction. Here, we determine whether hypertension causes changes in the thrombin-generating capacity of the vascular wall. Approach and Results-We used spontaneously hypertensive rats (SHR) compared with Wistar rats. The addition of thoracic aortic rings of SHR to a Wistar or SHR plasma pool resulted in a greater increase in thrombin generation compared with equivalent rings from Wistar. This increase occurred in 12-but not 5-week-old rats and was prevented by an angiotensin II-converting enzyme inhibitor, indicating that established hypertension is required to induce increased thrombin generation within the vessel wall. Whereas no difference was observed for endothelial cells, thrombin formation was higher on aortic smooth muscle cells (SMCs) from SHR than on those from Wistar. Exposure of negatively charged phospholipids was higher on SHR than on Wistar rings, as well as on cultured SMCs. Tissue factor activity was higher in SHR SMCs. Twelve-week-old SHR exhibited accelerated FeCl 3 -induced thrombus formation in carotid arteries, and the resulting occlusive thrombi were disaggregated by blockade of glycoprotein Ibα-von Willebrand factor interactions. SHR SMCs were more sensitive to thrombin-induced proliferation than Wistar SMCs. This effect was totally abolished by a protease-activated receptor 1 inhibitor. Conclusions-The prothrombotic phenotype of the SHR vessel wall was due to the ability of SMCs to support greater thrombin generation and resulted in accelerated occlusive thrombus formation after arterial injury, which was sensitive to glycoprotein Ibα-von Willebrand factor inhibitors. Ait Aissa et al Thrombin Generation in SHR Arteries 931One concern is that the function of the complex thrombin generation process is difficult to assess from estimates of its separate contributing elements. It would be preferable to estimate the overall activity of the hemostatic and thrombotic system and its relation with vascular function. This can be attempted by using a global in vitro test, such as the calibrated automated thrombogram, designed to explore the thrombin generation process under conditions as close as possible to those in vivo. This test has been shown to indicate a thrombotic tendency in several clinical settings, 11-14 which seems to be an independent predictor of acute ischemic stroke. 15The present study tests, in SHR, the hypothesis that changes in coagulation proteins and membrane phospholipid organization cause an increased thrombin-generating capacity within the vascular wall because SMC phenotypic modulation is a hallmark of hypertension. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results Hypertension-Associated Changes in Circulating Endothelial MarkersThe weight of SHR rats was significantly lower compared with the age-matched Wistar rats (94±5 versus 141±2 g at 5 weeks of age and 335±5...

show abstract

“…Previously, it has been shown that NAC promotes disaggregation of arterial thrombi by interfering with the platelet/VWF interactions and interfering with disulfide bonds inside multimeric VWF 8,9 . To investigate if NAC had a similar effect during the formation of stagnation point thrombi, the assay was repeated with a high dose of NAC.…”

Section: Resultsmentioning

confidence: 99%

Thrombi Produced in Stagnation Point Flows Have a Core–Shell Structure

Herbig

Diamond

2017

Cel. Mol. Bioeng.

View full text Add to dashboard Cite

Introduction In regions of flow separation/reattachment within diseased arteries, the local hemodynamics can result in stagnation point flow that provides an atypical environment in atherosclerosis. Impinging flows occur with recirculation eddies distal of coronary stenosis or diseased carotid bifurcations. Methods By perfusing whole blood directly perpendicular to a fibrillar collagen thrombotic surface, a microfluidic device produced a stagnation point flow. Side view visualization of thrombosis in this assay allowed for observation of clot structure and composition at various flow rates and blood biochemistry conditions. Results For clotting over collagen/tissue factor surfaces, platelet thrombi formed in this device displayed a core-shell architecture with a fibrin-rich, platelet P-selectin-positive core and an outer platelet P-selectin-negative shell. VWF was detected in clots at low and high shear, but when N-acetylcysteine was added to the whole blood, both platelet and VWF deposition were markedly decreased at either low or high flow. To further examine the source of clot stability, 1 mM GPRP was added to prevent fibrin formation while allowing the PAR1/4-cleaving activity of thrombin to progress. The inhibition of fibrin polymerization did not change the overall structure of the clots, demonstrating the stability of these clots without fibrin. Conclusion Impinging flow microfluidics generate thrombi with a core-shell structure.

show abstract

GpIbα-VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice

Cited by 65 publications

References 38 publications

ADAMTS13-mediated thrombolysis of t-PA–resistant occlusions in ischemic stroke in mice

ADAMTS13-mediated thrombolysis of t-PA–resistant occlusions in ischemic stroke in mice

Vascular Smooth Muscle Cells Are Responsible for a Prothrombotic Phenotype of Spontaneously Hypertensive Rat Arteries

Thrombi Produced in Stagnation Point Flows Have a Core–Shell Structure

Contact Info

Product

Resources

About