Emicizumab improves thrombus formation of type 2A von willebrand disease under high shear condition

Haemophilia ◽  
2021 ◽  
Author(s):  
Hiroaki Yaoi ◽  
Yasuaki Shida ◽  
Takehisa Kitazawa ◽  
Midori Shima ◽  
Keiji Nogami
Keyword(s):  
Thrombus Formation ◽  
Von Willebrand Disease ◽  
High Shear ◽  
Von Willebrand ◽  
Shear Condition

Reduced Effect of Aspirin on Thrombus Formation at High Shear and Disturbed Laminar Blood Flow

1996 ◽  
Vol 75 (05) ◽  
pp. 827-832 ◽  
Author(s):  
R Marius Barstad ◽  
Una Ørvim ◽  
Maria J A.G Hamers ◽  
Geir E Tjønnfjord ◽  
Frank R Brosstad ◽  
...  
Keyword(s):  
Blood Flow ◽  
Thrombus Formation ◽  
Secondary Prophylaxis ◽  
Significant Inhibition ◽  
Von Willebrand Disease ◽  
Shear Stresses ◽  
High Shear ◽  
Cross Sectional ◽  
Wall Shear ◽  
Von Willebrand

SummaryAspirin is the most commonly used antithrombotic drug in primary and secondary prophylaxis against cardio- and cerebrovascular disease. In previous studies from our laboratory it was demonstrated that the effect of aspirin on collagen-induced thrombus formation in a parallelplate perfusion device with laminar blood flow is shear rate dependent. Although aspirin did not affect collagen-induced thrombus formation at 650 s-1 (medium sized arteries), a significant inhibition of thrombus formation by approximately 38% at 2,600 s-1 (moderately stenoses in medium sized arteries) was observed. At present we have extended these studies to thrombus formation at the apex of eccentric stenoses in a parallel-plate perfusion chamber device. The stenoses reduced the cross-sectional area of the blood flow channel of the perfusion chambers by 60 or 80%, introducing disturbed laminar flow and apex wall shear rates of 2,600 and 10,500 s-1, respectively. The corresponding wall shear stresses were 80 and 315 dynes/cm2, respectively.Aspirin reduced the platelet thrombus volume at the 60% stenosis by 45% (p <0.03), and the fibrin deposition by 70% (p <0.004). However, none of these parameters were affected by aspirin at the 80% stenosis. These observations may at least partly explain why aspirin has a limited clinical effect in preventing arterial thrombus formation in atherosclerotic vessels at high shear and disturbed blood flow. In contrast, thrombus formation in blood from one patient with Glanzmann’s thrombasthenia and two patients with von Willebrand disease subtype 2M was almost abolished at this blood flow condition. Thus, blocking the function of either von Willebrand factor or glycoprotein IIb/IIIa may represent better antithrombotic approaches for such critical events than blocking the prostaglandin metabolism by aspirin. The lack of effect of aspirin on thrombus formation at the 80% stenosis may reflect shear-induced platelet activation at the stenosis inlet region, since shear-induced platelet aggregation in rotational viscometers is not affected by aspirin at shear stresses exceeding 100 dynes/cm2.

Monitoring of coagulation factor therapy in patients with von Willebrand disease type 3 using a microchip flow chamber system

2017 ◽  
Vol 117 (01) ◽  
pp. 75-85 ◽  
Author(s):  
Margareta Holmström ◽  
David E. Schmidt ◽  
Kazuya Hosokawa ◽  
Margareta Blombäck ◽  
Paul Hjemdahl ◽  
...  
Keyword(s):  
Whole Blood ◽  
Thrombus Formation ◽  
Flow Chamber ◽  
Von Willebrand Disease ◽  
High Shear ◽  
Fviii Activity ◽  
Concentrate Treatment ◽  
Type 3 ◽  
Von Willebrand ◽  
Low Shear

SummaryPatients with type 3 von Willebrand disease (VWD-3) have no measurable levels of VW factor (VWF) and usually require treatment with VWF-FVIII concentrate to prevent and/or stop bleeding. Even though the patients are treated prophylactically, they may experience bleeding symptoms. The aim of this study was to evaluate the effect of VWF-FVIII concentrate treatment in VWD-3 patients with the Total Thrombus Analysis System (T-TAS®), which measures thrombus formation under flow conditions. Coagulation profiles of 10 VWD-3 patients were analysed using T-TAS before and 30 minutes after VWF-FVIII concentrate (Haemate®) injection. Results were compared to VWF- and FVIII activity in plasma, and results with thromboelastometry and ris-tocetin-activated platelet impedance aggregometry (Multiplate®) in whole blood. For comparison, 10 healthy controls were also analysed with T-TAS. A median dose of 27 (range 15–35) IU/kg of VWF-FVIII concentrate increased VWF- and FVIII activity as expected. T-TAS thrombus formation was enhanced when a tissue factor/collagen-coated flow chamber was used at low shear, but treatment effects at high shear using a collagen-coated flow chamber were minimal. Whole blood coagulation assessed by thromboelastometry was normal and did not change (p > 0.05) but ristocetin-induced platelet aggregation improved (p < 0.001). In conclusion, T-TAS detects effects of VWF-FVIII concentrate treatment on coagulation-dependent thrombus formation at low shear, but minor effects are observed on platelet-dependent thrombus formation at high shear. The poor prediction of bleeding by conventional laboratory monitoring in VWD-3 patients might be related to insufficient restoration of platelet-dependent thrombus formation.

Activation of pp125FAK by type 2B recombinant von Willebrand factor binding to platelet GPIb at a high shear rate occurs independently of αIIbβ3 engagement

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4363-4371 ◽  
Author(s):  
Médina Mekrache ◽  
Christilla Bachelot-Loza ◽  
Nadine Ajzenberg ◽  
Abdelhafid Saci ◽  
Paulette Legendre ◽  
...  
Keyword(s):  
Shear Rate ◽  
Von Willebrand Factor ◽  
Thrombus Formation ◽  
High Shear Rate ◽  
Von Willebrand Disease ◽  
High Shear ◽  
High Level ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Shear-induced platelet aggregation (SIPA) involves the sequential interaction of von Willebrand factor (VWF) with both glycoprotein Ib (GPIb) and αIIbβ3 receptors. Type 2B recombinant VWF (2B-rVWF), characterized by an increased affinity for GPIb, induces strong SIPA at a high shear rate (4000 s–1). Despite the increased affinity of 2B-rVWF for GPIb, patients with type 2B von Willebrand disease have a paradoxical bleeding disorder, which is not well understood. The purpose of this study was to determine if SIPA induced by 2B-rVWF was associated with αIIbβ3-dependent platelet activation. To this end, we have addressed the influence of 2B-rVWF (Val553Met substitution) on SIPA-dependent variations of tyrosine protein phosphorylation (P-Tyr) and the effect of αIIbβ3 blockers. At a high shear rate, 2B-rVWF induced a strong SIPA, as shown by a 92.7% ± 0.4% disappearance of single platelets (DSP) after 4.5 minutes. In these conditions, increased P-Tyr of proteins migrating at positions 64 kd, 72 kd, and 125 kd were observed. The band at 125 kd was identified as pp125FAK using anti–phospho-FAK antibody. This effect, which required a high level of SIPA (&gt; 70% DSP), was observed at 4000 s–1 but not at 200 s–1. Monoclonal antibodies (MoAbs) 6D1 (anti-GPIb) and 328 (anti-VWF A1 domain), completely abolished SIPA and p125FAK phosphorylation mediated by 2B-rVWF. In contrast, neither RGDS peptide nor MoAb 7E3, both known to block αIIbβ3 engagement, had any effect on SIPA and pp125FAK. The size of aggregates formed at a high shear rate in the presence of 2B-rVWF was decreased by genistein, demonstrating the biologic relevance of pp125FAK. These findings provide a unique mechanism whereby the enhanced interaction of 2B-rVWF with GPIb, without engagement of αIIbβ3, is sufficient to induce SIPA but does not lead to stable thrombus formation.

scholarly journals Platelet von Willebrand factor: evidence for its involvement in platelet adhesion to collagen

Blood ◽  
1987 ◽  
Vol 70 (4) ◽  
pp. 1214-1217
Author(s):  
E Fressinaud ◽  
D Baruch ◽  
C Rothschild ◽  
HR Baumgartner ◽  
D Meyer
Keyword(s):  
Shear Rate ◽  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Von Willebrand Disease ◽  
High Shear ◽  
Shear Rates ◽  
High Shear Rates ◽  
Von Willebrand ◽  
Willebrand Factor

Although it is well established that plasma von Willebrand Factor (vWF) is essential to platelet adhesion to subendothelium at high shear rates, the role of platelet vWF is less clear. We studied the respective role of both plasma and platelet vWF in mediating platelet adhesion to fibrillar collagen in a parallel-plate perfusion chamber. Reconstituted blood containing RBCs, various mixtures of labeled washed platelets and plasma from controls or five patients with severe von Willebrand disease (vWD), was perfused through the chamber for five minutes at a shear rate of 1,600 s-1. Platelet-collagen interactions were estimated by counting the radioactivity in deposited platelets and by quantitative morphometry. When the perfusate consisted of normal platelets suspended in normal plasma, platelet deposition on the collagen was 24.7 +/- 3.6 X 10(6)/cm2 (mean +/- SEM, n = 6). Significantly less deposition (16 +/- 2.3) was observed when vWD platelets were substituted for normal platelets. In mixtures containing vWD plasma, significantly greater deposition (9 +/- 2.2) was obtained with normal than with vWD platelets (1 +/- 0.4) demonstrating a role for platelet vWF in mediating the deposition of platelets on collagen. Morphometric analysis confirmed these data. Our findings indicate that platelet, as well as plasma, vWF mediates platelet-collagen interactions at a high shear rate.

Effect of recombinant von Willebrand factor reproducing type 2B or type 2M mutations on shear-induced platelet aggregation

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3796-3803 ◽  
Author(s):  
Nadine Ajzenberg ◽  
Anne-Sophie Ribba ◽  
Ghassem Rastegar-Lari ◽  
Dominique Meyer ◽  
Dominique Baruch
Keyword(s):  
Platelet Aggregation ◽  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
High Shear ◽  
Shear Rates ◽  
High Shear Rates ◽  
Consistent Increase ◽  
A1 Domain ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract The aim was to better understand the function of von Willebrand factor (vWF) A1 domain in shear-induced platelet aggregation (SIPA), at low (200) and high shear rate (4000 seconds-1) generated by a Couette viscometer. We report on 9 fully multimerized recombinant vWFs (rvWFs) expressing type 2M or type 2B von Willebrand disease (vWD) mutations, characterized respectively by a decreased or increased binding of vWF to GPIb in the presence of ristocetin. We expressed 4 type 2M (-G561A, -E596K, -R611H, and -I662F) and 5 type 2B (rvWF-M540MM, -V551F, -V553M, -R578Q, and -L697V). SIPA was strongly impaired in all type 2M rvWFs at 200 and 4000 seconds-1. Decreased aggregation was correlated with ristocetin binding to platelets. In contrast, a distinct effect of botrocetin was observed, since type 2M rvWFs (-G561A, -E596K, and -I662F) were able to bind to platelets to the same extent as wild type rvWF (rvWF-WT). Interestingly, SIPA at 200 and 4000 seconds-1 confirmed the gain-of-function phenotype of the 5 type 2B rvWFs. Our data indicated a consistent increase of SIPA at both low and high shear rates, reaching 95% of total platelets, whereas SIPA did not exceed 40% in the presence of rvWF-WT. Aggregation was completely inhibited by monoclonal antibody 6D1 directed to GPIb, underlining the importance of vWF-GPIb interaction in type 2B rvWF. Impaired SIPA of type 2M rvWF could account for the hemorrhagic syndrome observed in type 2M vWD. Increased SIPA of type 2B rvWF could be responsible for unstable aggregates and explain the fluctuant thrombocytopenia of type 2B vWD.

The role of platelet von Willebrand factor in platelet adhesion and thrombus formation: a study of 34 patients with various subtypes of type I von Willebrand disease

1994 ◽  
Vol 86 (2) ◽  
pp. 327-332 ◽  
Author(s):  
Edith Fressinaud ◽  
Augusto B. Federici ◽  
Giancarlo Castaman ◽  
Chantal Rothschild ◽  
Francesco Rodeghiero ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Von Willebrand Disease ◽  
Type I ◽  
Von Willebrand ◽  
Willebrand Factor

scholarly journals Screening for von Willebrand Disease With a New Analyzer Using High Shear Stress: A Study of 60 Cases

Blood ◽  
1998 ◽  
Vol 91 (4) ◽  
pp. 1325-1331 ◽  
Author(s):  
Edith Fressinaud ◽  
Agnès Veyradier ◽  
Florence Truchaud ◽  
Isabelle Martin ◽  
Catherine Boyer-Neumann ◽  
...  
Keyword(s):  
Shear Stress ◽  
High Sensitivity ◽  
Adenosine Diphosphate ◽  
Normal Subjects ◽  
Von Willebrand Disease ◽  
High Shear ◽  
High Shear Stress ◽  
Platelet Disorder ◽  
Von Willebrand

AbstractWe have evaluated the performance of a new analyzer using high shear stress, the PFA-100 (Platelet Function Analyzer, Dade International, Massy, France), for screening of patients with von Willebrand disease (vWD). Whole citrated blood is aspirated through a capillary to the central aperture of a membrane coated with collagen and with a platelet agonist (either epinephrine or adenosine diphosphate [ADP]). The time required to obtain occlusion of the aperture by a platelet plug is defined as the closure time (CT). We studied 60 patients with different types of vWD and 96 normal subjects. Fourteen subjects with hemophilia and 15 patients with a platelet disorder were also analyzed. When omitting results from two patients with type 2N, the 58 other patients with type 1, type 2A, type 2B, type 3, or acquired vWD all exhibited an abnormal occlusion with collagen-ADP (sensitivity, 100%) and 56 of 58 had an abnormal CT with collagen-epinephrine (sensitivity, 96.5%). Only two patients with mild type 1 were not detected with collagen-epinephrine. In comparison, the bleeding time (BT) was normal in 20 patients: 17 with type 1, two with type 2A, and one with acquired vWD (sensitivity, 65.5%). The specificity of the PFA-100 was over 95% with both types of cartridges. Thus, the analyzer is well adapted to routine testing, as it has the advantages of simplicity and ease of execution, and demonstrates a high sensitivity, clearly superior to that of BT, for the screening of patients with vWD.

Usefulness of the Total Thrombus-Formation Analysis System (T-TAS) in the diagnosis and characterization of von Willebrand disease

Haemophilia ◽  
2016 ◽  
Vol 22 (6) ◽  
pp. 949-956 ◽  
Author(s):  
V. Daidone ◽  
G. Barbon ◽  
M. G. Cattini ◽  
E. Pontara ◽  
C. Romualdi ◽  
...  
Keyword(s):  
Thrombus Formation ◽  
Von Willebrand Disease ◽  
Analysis System ◽  
Von Willebrand

Von Willebrand disease in patients with intracardiac high shear conditions: a PFA-100 analysis

2007 ◽  
Vol 24 (Supplement 41) ◽  
pp. 15
Author(s):  
F. Pappalardo ◽  
G. Landoni ◽  
M. Costantini ◽  
A. Franco ◽  
A. Zangrillo
Keyword(s):  
Von Willebrand Disease ◽  
High Shear ◽  
Von Willebrand
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