The von Willebrand factor (vWF) is a plasma protein that mediates platelet adhesion and leukocyte recruitment to vascular injury sites and carries coagulation factor VIII, a building block of the intrinsic pathway of coagulation. The presence of ultra-large multimers of vWF in the bloodstream is associated with spontaneous thrombosis, whereas its deficiency leads to bleeding. In cardiovascular pathology, the progression of the heart valve disease results in vWF deficiency and cryptogenic gastrointestinal bleeding. The association between higher plasma levels of vWF and thrombotic complications of coronary artery disease was described. Of note, it is not the plasma levels that are crucial for vWF hemostatic activity, but vWF activation, triggered by a rise in shear rates. vWF becomes highly reactive with platelets upon unfolding into a stretched conformation, at shear rates above the critical value (more than 5000 s−1), which might occur at sites of arterial stenosis and injury. The activation of vWF and its counterbalance by ADAMTS-13, the vWF-cleaving protease, might contribute to complications of cardiovascular diseases. In this review, we discuss vWF involvement in complications of cardiovascular diseases and possible diagnostic and treatment approaches.

No abstract

Aim To test a novel method of assessment of platelet adhesion to a fibrinogen‐coated surface in whole blood under flow conditions. Methods We developed a fluidic device that mimics blood flow in vessels. The method of detection of platelet adhesion is based on recording of a scattered laser light signal from a fibrinogen‐covered surface. Testing was performed in platelet‐rich plasma (PRP) and whole blood of healthy volunteers. Control measurements were performed, followed by tests with inhibition of platelet GPIIa/IIIb and GPIb receptors. Then, the same testing sequence was performed in whole blood of persons with autoimmune thrombocytopenia and type 3 von Willebrand disease. Results The change in intensity of scattered light was 2.7 (2.4; 4.1) times higher in whole blood (0.2 ± 0.08V, n = 7) than in PRP (0.05 ± 0.02 V, n = 7), p < 0.01. The blocking of GP IIb/IIIa receptors decreased the intensity of scattered light to 8.5 (6.5;12)%; the blocking of GPIb receptors decreased it to 34 (23;58)%, p < 0.01. In the whole blood of a person with autoimmune thrombocytopenia, the inhibition of GPIb receptors decreased platelet adhesion, but no effect was observed in type 3 von Willebrand disease. Inhibition of platelet GPIIb/IIIa receptors alone or combined inhibition of GPIb and GPIIb/IIIa receptors resulted in almost total suppression of adhesion in both cases. Conclusion Our system effectively registers platelet adhesion to a fibrinogen‐coated surface under controlled‐flow conditions and may successfully be applied to the investigation of platelet adhesion kinetics.

Von Willebrand factor (VWF) is a large multimeric glycoprotein involved in hemostasis. It is essential for platelet adhesion to the subendothelium of the damaged endothelial layer at high shear rates. Such shear rates occur in small-diameter arteries, especially at stenotic sites. Moreover, VWF carries coagulation factor VIII and protects it from proteolysis in the bloodstream. Deficiency or dysfunction of VWF predisposes to bleeding. In contrast, an increase in the concentration of high molecular weight multimers (HMWM) of VWF is closely associated with arterial thrombotic events. Severe aortic stenosis (AS) or hypertrophic obstructive cardiomyopathy (HOCM) can deplete HMWM of VWF and lead to cryptogenic, gastrointestinal, subcutaneous, and mucosal bleeding. Considering that VWF facilitates primary hemostasis and a local inflammatory response at high shear rates, its dysfunction may contribute to the development of coronary artery disease (CAD) and its complications. However, current diagnostic methods do not allow for an in-depth analysis of this contribution. The development of novel diagnostic techniques, primarily microfluidic, is underway. Such methods can provide physiologically relevant assessments of VWF function at high shear rates; however, they have not been introduced into clinical practice. The development and use of agents targeting VWF interaction with the vessel wall and/or platelets may be reasonable in prevention of CAD and its complications, given the prominent role of VWF in arterial thrombosis.

Introduction Von Willebrand factor (vWF) changes conformation from globular to fibrillar in the range of shear rates above 5000 s-1. High shear rates, observed in severe aortic stenosis, create conditions for activation of vWF, which opens up access for platelets and coagulation factors to the previously hidden domains of the molecule. At the same time, vWF undergoes increased degradation by metalloproteinase ADAMTS13. Proteolytic cleavage of vWF leads to deficiency of hemostatically active high molecular weight multimers (HMWM) of vWF, while its mass concentration remains unaltered. This results in the development of acquired von Willebrand disease type 2A (vWD) and concomitant gastrointestinal bleeding. The combination of acquired vWD 2A and gastrointestinal bleeding, developed due to severe aortic stenosis, is called Heyde's syndrome. The correlation of shear stress activation of vWF and gastrointestinal bleeding in patients with Heyde's syndrome remains poorly studied. The aim of the study was to measure vWF-mediated platelet adhesion to fibrinogen-coated surfaces under shear rates higher than 5000 s-1 in whole blood samples of healthy volunteers and patients with Heyde's syndrome. Methods A microfluidic system simulating blood flow in vessels was used to assess platelet adhesion. Platelet adhesion was measured by an increase in the intensity of laser radiation scattered from a fibrinogen-coated surface during a 15 minutes circulation of whole blood samples through a flow chamber under shear rates higher than 5000 s-1. Platelets in whole blood samples were activated with 5 μM ADP prior to measurement. The study included 5 patients with Heyde's syndrome 55–80 years old. The control group included 6 healthy volunteers 25–55 years old. vWF-mediated platelet adhesion was detected by blocking platelet-vWF binding with anti-GPIb monoclonal antibody (mAb). Fibrinogen-mediated platelet adhesion was detected by blocking platelet GPIIb/IIIa receptors with mAb. Result The inhibition of GPIb vWF-receptor reduced platelet adhesion by 7.6±3.5% (p&lt;0.05) in patients with Heyde's syndrome, and by 16.5±3.3% (p&lt;0.05) in healthy volunteers. The inhibition of GPIIb/IIIa fibrinogen receptor reduced platelet adhesion by 96±7% (p&lt;0.05) in patients with Heyde's syndrome, and by 80.2±6.6% (p&lt;0.05) in healthy volunteers. Conclusion Significantly reduced contribution of vWF to platelet adhesion under shear rates higher than 5000 s-1 may indicate a decrease in hemostatically active HMWM of vWF. Shear stress activation of vWF in the range of high shear rates and its subsequent inactivation by ADAMTS13 may lead to functional vWF deficiency and the development of gastrointestinal bleeding in Heyde's syndrome. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): The Russian Science Foundation