Coronary angioplasty enhances platelet reactivity through von Willebrand factor release

Gorog, Diana A.; Douglas, Homeyra; Ahmed, Nadia; Lefroy, David; Davies, Geraint

doi:10.1136/heart.89.3.329

Cited by 8 publications

(6 citation statements)

References 4 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: Discussionmentioning

confidence: 89%

“…It is important to note that the effective concentration of ALX-0081 in these ex vivo experiments depended on the VWF concentration in the plasma samples. VWF levels are generally higher in ACS patients, 48,49 explaining the higher effective concentration of ALX-0081 needed to achieve full effect in samples from this patient population (ϳ 0.8 g/mL) compared with healthy individuals (ϳ 0.4 g/mL).Efficacy of ALX-0081 was further investigated in vivo in a baboon Folts model for ACS and stable angina. The ALX-0081 plasma levels needed for full inhibition of CFRs in vivo (0.3-0.5 g/mL) corresponded well to the effective concentration of ALX-0081 in the ex vivo experiments.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs

Ulrichts

Silence

Schoolmeester

et al. 2011

Blood

161

131

View full text Add to dashboard Cite

Neutralizing the interaction of the platelet receptor gpIb with VWF is an attractive strategy to treat and prevent thrombotic complications. ALX-0081 is a bivalent Nanobody which specifically targets the gpIb-binding site of VWF and interacts avidly with VWF. Nanobodies are therapeutic proteins derived from naturally occurring heavy-chain-only Abs and combine a small molecular size with a high inherent stability. ALX-0081 exerts potent IntroductionThe successive adhesion, activation, and aggregation of platelets are key processes in arterial thrombus formation after endothelial damage. 1,2 Both rupture of atherosclerotic plaques as well as surgical interventions to treat atherosclerosis (eg, percutaneous coronary intervention [PCI]) may cause exposure of the subendothelium and subsequent clot formation. Eventually, this can result in the occlusion of arteries, leading to ischemia, myocardial infarcts, or stroke. Given the central role of platelets in thrombosis, a substantial number of currently marketed antithrombotic drugs, such as aspirin, clopidogrel, and abciximab, target different steps involved in platelet activation and aggregation. 1,2 Thanks to their complementary mechanisms of action, the combination of these agents inhibits platelet aggregation to a greater extent than either agent alone. 3 However, the use of these antiplatelet drugs is hampered by an increased bleeding risk 1,2 and the occurrence of treatment resistance in some patients. 4 Moreover, the irreversible nature of their action can complicate the staunching of bleeding. 1,2 Inhibition of the initial adhesion of platelets to subendothelial collagen provides an alternative strategy to prevent unwanted clot formation. The plasma glycoprotein VWF plays a pivotal role in this adhesion via binding to exposed collagen on the one hand, and the interaction of its A1 domain with the gpIb-IX-V receptor complex on the surface of platelets on the other hand. [5][6][7] Interestingly, the VWF A1 domain is only exposed under high-shear conditions, 8,9 so VWF only acts as a bridging molecule between collagen and platelets in small or stenosed arteries. Therefore, it is expected that drugs inhibiting this interaction between VWF and platelets show an improved safety profile with respect to bleeding tendency. Indeed, the antithrombotic effect of several compounds targeting the gpIb-VWF-A1-axis, like aurintricarboxylic acid, 10-12 recombinant VWF fragments, 10,13-16 a recombinant gpIb chimeric protein, 17,18 anti-VWF mAbs, [19][20][21][22][23][24][25][26][27] and an anti-VWF aptamer 28 has been demonstrated in vitro and in vivo, without increasing the bleeding risk. 13,[16][17][18]21,23,25,28,29 Nevertheless, until now only 3 drug candidates have been evaluated in humans, including ALX-0081. [30][31][32][33] We developed ALX-0081, a bivalent humanized Nanobody directed against the A1 domain of VWF. Nanobodies are therapeutic proteins derived from the heavy-chain variable domains (VHH) that occur naturally in heavy-chain-only Igs of Camelidae. 34,35 Here we...

show abstract

Section: Discussionmentioning

confidence: 89%

mentioning

confidence: 99%

Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs

Ulrichts

Silence

Schoolmeester

et al. 2011

Blood

161

131

View full text Add to dashboard Cite

show abstract

“…In vitro perfusion chamber studies, using blood from healthy individuals and PCI patients receiving standard-of-care treatment (aspirin, clopidogrel, and unfractionated heparin), showed the selective inhibition of platelet adhesion on collagen type III by the nanobody under high, arterial shear conditions (shear rates > 1,500 s −1 ), without any effect under low shear conditions. Plasma levels of 0.3 to 0.5 μg/ml were required for total inhibition of cyclic flow reductions (CFRs) by ALX-0081, corresponding to an effective concentration of 0.8 μg/ml in ACS patients and 0.4 μg/ml in healthy individuals in ex vivo experiments (145). The therapeutic window (the difference between the dose required for CFR and the dose resulting in enhanced bleeding rates) of ALX-0081 was found to be superior over abciximab and clopidogrel in baboons.…”

Section: Therapeutics Targeting Shear-dependent Thrombus Formationmentioning

confidence: 99%

Shear-Dependent Platelet Aggregation: Mechanisms and Therapeutic Opportunities

Rana

Westein

Niego

et al. 2019

Front. Cardiovasc. Med.

138

117

View full text Add to dashboard Cite

Cardiovascular diseases (CVD) are the number one cause of morbidity and death worldwide. As estimated by the WHO, the global death rate from CVD is 31% wherein, a staggering 85% results from stroke and myocardial infarction. Platelets, one of the key components of thrombi, have been well-investigated over decades for their pivotal role in thrombus development in healthy as well as diseased blood vessels. In hemostasis, when a vascular injury occurs, circulating platelets are arrested at the site of damage, where they are activated and aggregate to form hemostatic thrombi, thus preventing further bleeding. However, in thrombosis, pathological activation of platelets occurs, leading to uncontrolled growth of a thrombus, which in turn can occlude the blood vessel or embolize, causing downstream ischemic events. The molecular processes causing pathological thrombus development are in large similar to the processes controlling physiological thrombus formation. The biggest challenge of anti-thrombotics and anti-platelet therapeutics has been to decouple the pathological platelet response from the physiological one. Currently, marketed anti-platelet drugs are associated with major bleeding complications for this exact reason; they are not effective in targeting pathological thrombi without interfering with normal hemostasis. Recent studies have emphasized the importance of shear forces generated from blood flow, that primarily drive platelet activation and aggregation in thrombosis. Local shear stresses in obstructed blood vessels can be higher by up to two orders of magnitude as compared to healthy vessels. Leveraging abnormal shear forces in the thrombus microenvironment may allow to differentiate between thrombosis and hemostasis and develop shear-selective anti-platelet therapies. In this review, we discuss the influence of shear forces on thrombosis and the underlying mechanisms of shear-induced platelet activation. Later, we summarize the therapeutic approaches to target shear-sensitive platelet activation and pathological thrombus growth, with a particular focus on the shear-sensitive protein von Willebrand Factor (VWF). Inhibition of shear-specific platelet aggregation and targeted drug delivery may prove to be much safer and efficacious approaches over current state-of-the-art antithrombotic drugs in the treatment of cardiovascular diseases.

show abstract

“…Furthermore, in the poststenotic region at low shear and turbulent flow, small eddies can induce hemolysis (Figure ), and the disrupted red cell membrane fragments also contribute to thrombin generation. The significance of shear‐induced thrombus formation in a stenotic artery is supported by increased platelet reactivity due to vWF release after coronary angioplasty . Because of this key role in arterial thrombogenesis, vWF is regarded as a risk factor, mediator, and pharmacological target in antithrombotic strategy …”

Section: Importance Of High Shear Forcesmentioning

confidence: 99%

Platelet Function Tests: Why They Fail to Guide Personalized Antithrombotic Medication

Gorog

Jeong

2015

JAHA

View full text Add to dashboard Cite

Coronary angioplasty enhances platelet reactivity through von Willebrand factor release

Cited by 8 publications

References 4 publications

Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs

Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs

Shear-Dependent Platelet Aggregation: Mechanisms and Therapeutic Opportunities

Platelet Function Tests: Why They Fail to Guide Personalized Antithrombotic Medication

Contact Info

Product

Resources

About