Total-Thrombus-Formation Analysis System Using a Microchip Flow Chamber Reflects Bleeding Severity of Patients with Type 1 Von Willebrand Disease.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2237-2237 ◽  
Author(s):  
Kenichi Ogiwara ◽  
Keiji Nogami ◽  
Tomoko Matsumoto ◽  
Shoko Furukawa ◽  
Hiroaki Minami ◽  
...  
Keyword(s):  
Clinical Phenotype ◽  
Thrombus Formation ◽  
Flow Chamber ◽  
Von Willebrand Disease ◽  
Clinical Severity ◽  
Pressure Curve ◽  
Constant Flow Rate ◽  
Analysis System ◽  
Von Willebrand

Abstract Abstract 2237 Introduction: von Willebrand disease (VWD) has clinically heterogeneous phenotype. Routine measurements of von Willebrand factor (VWF) antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo) and FVIII activity (FVIII:C) do not always reflect clinical severity, especially in type 1 VWD. These assays evaluate VWF function under non-physiological static condition - lacking blood flow. We had reported that a new microchip flow chamber system, total-thrombus-formation analysis system (T-TAS®, Fujimori Kogyo, Tokyo) would be a clinically useful flow assay for VWD (ASH 2011). In this study, we extended this study for application to evaluation and hemostatic monitoring for type 1 VWD. Methods: Citrated or hirudin-added blood from 15 patients with type 1 VWD was utilized. Re-calcified citrated blood added corn trypsin inhibitor was injected to a microchip in T-TAS at a constant flow rate (240 s−1), which flow surface was coated by collagen and tissue factor (AR chip). Hirudin-added blood was injected to a microchip in T-TAS at higher shear rate (1,000 s−1) which surface was coated by collagen (PL chip). Flow pressure curve was visualized and time until reach to 10 kPa (T10) was evaluated. AR chip promoted thrombus formation by both platelet aggregation and fibrin generation, whilst PL chip promoted thrombus formation by platelet alone. Standard laboratory tests for VWD were also performed. Clinical severities of VWD patients were evaluated by using a quantitative bleeding score (BS, from −3 without any symptoms to +45 with all major symptoms) previously reported by Tosetto (JTH, 2006). Results: Fifteen patients with type 1 VWD showed low levels of VWF:Ag [median 14% (range 1.3–51%)], VWF:RCo [8% (1.6–32%)], and FVIII:C [31% (3.0–68%)]. T10 in AR chip or PL chip was 17.7 min (11->30) or 7.1 min (3.3->10) [normal control (n=20); 12.2 min (8.6–16.6) or 3.5 min (2.4–6.6), respectively], showing delayed thrombus formation in type 1 VWD. Correlations between VWF:Ag and VWF:RCo (r2=0.80, p<0.01) or VWF:Ag and FVIII:C (r2=0.74, p<0.01) were significant in Spearman's correlation test. Correlation of BS [5 (0–11)] to VWF:RCo was not significant (r2=0.27, p=0.05), whilst, that of BS to T10 in PL chip of T-TAS showed more significant (r2=0.62, p<0.01) but not T10 in AR chip (r2=0.04, p=0.4). Interestingly, when focused on the patients whose VWF:RCo were less than 20% [n=10, 5.8% (1.6–13%)], correlation of VWF:RCo to BS was worse (r2=0.02). However, T10 in PL chip showed greater correlation to BS (r2=0.62, p<0.01; Figure 1). Patients who were treated with desmopressin infusion or replacement therapy showed the improvement of T-TAS parameters within normal range. Conclusion: Traditional standard assays did not always reflect the clinical phenotype of patients with VWD. In contrast, T-TAS parameters in PL chip showed good correlations to BS, indicating its usefulness for distinguishing clinical phenotype and for monitoring of treatment for patients with type 1 VWD. Disclosures: Hosokawa: Fujimori Kogyo: Employment.

scholarly journals Assessing the clinical severity of type 1 von Willebrand disease patients with a microchip flow-chamber system

2016 ◽  
Vol 14 (4) ◽  
pp. 667-674 ◽  
Author(s):  
K. Nogami ◽  
K. Ogiwara ◽  
K. Yada ◽  
Y. Shida ◽  
M. Takeyama ◽  
...  
Keyword(s):  
Flow Chamber ◽  
Von Willebrand Disease ◽  
Clinical Severity ◽  
Chamber System ◽  
Von Willebrand

Evaluation of Comprehensive Hemostatic Function of Patients with Von Willebrand Disease (VWD) Under Flow Using a New Microchip Flow Chamber System

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2283-2283 ◽  
Author(s):  
Kenichi Ogiwara ◽  
Kazuya Hosokawa ◽  
Keiji Nogami ◽  
Tomoko Matsumoto ◽  
Midori Shima
Keyword(s):  
Ex Vivo ◽  
Thrombus Formation ◽  
Flow Chamber ◽  
Pressure Curve ◽  
Defect Type ◽  
Clinical Phenotypes ◽  
Wide Range ◽  
Plasma Factor ◽  
Von Willebrand

Abstract Abstract 2283 Introduction: von Willebrand factor (VWF) acts as bridging molecule between platelets and vessel wall or as a career for plasma factor VIII (FVIII). Earlier reports using flow chamber had revealed that VWF acts as an “initiator” through its interactionwith glycoprotein (GP) Ib, whereas fibrinogen, via its binding to GP IIb-IIIa, acts as a “stabilizer” against high shear. VWD is categorized as partial or complete quantitative defect (type 1 or 3) or qualitative defect (type 2) of VWF based on laboratory tests, such as VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), and FVIII activity (FVIII:C). However, the diagnosis of VWD remains difficult because the clinical and laboratory phenotype has wide-spectrum. An assay reflecting clinical phenotypes of VWD and effect of the treatment would be helpful for clinicians. Methods: We evaluated a thrombus formation with a new applicative microchip flow chamber instrument, total-thrombus-formation analysis system (T-TAS®). Citrated or hirudin-added blood from healthy volunteers (n=5) or 3 patients with VWD [symptomatic type 1 (S-1), asymptomatic type 1 (AS-1), and symptomatic type 3 (S-3)] were utilized. Normal blood was mixed with inhibitor for GP Ib (OS-1), GP IIb-IIIa (abciximab) and monoclonal antibody against for VWF (mAb-VWF). Patients' blood was infused with FVIII/VWF concentrates in (ex) vivo. Re-calcified citrated blood (450 μl) added corn trypsin inhibitor (30 μg/ml) was infused to AR chip of T-TAS at constant flow rate (240–600 s−1), which surface was coated by collagen and tissue factor. Hirudin-added blood (350 μl) was infused to PL chip of T-TAS at higher shear (1,000–2,000 s−1) which surface was coated by collagen. Flow pressure curve was plotted and time to 10 kPa (T10) was evaluated. Furthermore, flow images were recorded with a micro camera. AR chip promoted white thrombus formation (WTF) which reflected both platelet aggregation and fibrin generation, whilst PL chip did only platelet thrombus formation (PTF). Rotational thromboerastometry (ROTEM) were simultaneously investigated. Results: Both abciximab (0.5–2.0 μg/ml) and OS-1 (100–400 nM) inhibited WTF in AR chip dose-dependently. OS-1 (200 nM) inhibited WTF partially at 240 s−1 (T10 15.4±1.6 min, control 8.9±0.4 min), but completely at 600 s−1 (T10 >30 min, control 7.5±0.2 min). In PL chip, both agents inhibited PTF at much lower dose than those in AR chip. ROTEM parameters showed little change in both agents. Using mAb-VWF, similar results to OS-1 were obtained. These data showed that GP Ib-VWF interaction was shear-dependent, consistent with earlier reports. In in (ex) vivo assays, S-1 and AS-1 had comparable VWF levels (VWF:Ag/VWF:RCo 20%/6.4% and 5.8%/3.2%, respectively) in spite of clear difference of clinical phenotype. ROTEM parameters of S-1 were rather better than those of AS-1 likely reflecting FVIII:C (60% and 7.2%). Interestingly, however, PTF in PL chip (at 1,000 s−1) showed significant delay of T10 in S-1 (9.0 min, control 4.1±0.5 min) compared to AS-1 (5.2 min) and after in vivo infusion of FVIII/VWF concentrates, T10 in S-1 was improved (5.0 min). In S-3, ROTEM parameters declined reflecting low FVIII:C (1.2%), and prolonged T10 (>30 min) in AR chip likely reflected complete defect of VWF:Ag (<1.0%) and VWF:RCo (<1.6%). Ex vivo infusion of FVIII concentrates improved ROTEM parameters but not T-TAS parameters, whilst infusion of FVIII/VWF concentrates improved both parameters. Interestingly, scanned images with micro camera in OS-1, mAb-VWF, S-1 and S-3 was quite similar, whilst the image of AS-1 was similar to normal control. S-3 showed the normal images after infusions of FVIII/VWF concentrates (Figure). Conclusion: T-TAS has potentials for diagnosis of VWD reflecting clinical phenotypes and for monitoring the drug effects. Further, AR chip of T-TAS might have a possibility of being a potent tool for categorizing wide-range bleeding disorders “at a glance”. Disclosures: Hosokawa: Fujimori Kogyo: Employment. Nogami:Bayer Award 2009: Research Funding.

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

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.

Whole blood ristocetin‐induced platelet impedance aggregometry does not reflect clinical severity in patients with type 1 von Willebrand disease

Haemophilia ◽  
2019 ◽  
Vol 25 (3) ◽  
Author(s):  
Yuto Nakajima ◽  
Keiji Nogami ◽  
Koji Yada ◽  
Kenichi Ogiwara ◽  
Shoko Furukawa ◽  
...  
Keyword(s):  
Whole Blood ◽  
Von Willebrand Disease ◽  
Clinical Severity ◽  
Impedance Aggregometry ◽  
Von Willebrand

scholarly journals The Intriguing Relationships of von Willebrand Factor, ADAMTS13 and Cardiac Disease

2021 ◽  
Vol 8 (9) ◽  
pp. 115
Author(s):  
Benjamin Reardon ◽  
Leonardo Pasalic ◽  
Emmanuel J. Favaloro
Keyword(s):  
Von Willebrand Factor ◽  
Cardiac Disease ◽  
Thrombus Formation ◽  
Von Willebrand Disease ◽  
Primary Hemostasis ◽  
A Disintegrin And Metalloproteinase ◽  
Von Willebrand ◽  
Relationship Of ◽  
Willebrand Factor

von Willebrand factor (VWF) is an adhesive protein involved in primary hemostasis and facilitates platelet adhesion to sites of vascular injury, thereby promoting thrombus formation. VWF exists in plasma as multimers of increasing size, with the largest (high molecular weight; HMW) expressing the greatest functional activity. A deficiency of VWF is associated with a bleeding disorder called von Willebrand disease (VWD), whereas an excess of VWF, in particular the HMW forms, is associated with thrombosis. ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif-13), also known as VWF-cleaving protease, functions to moderate the activity of VWF by cleaving multimers of VWF and limiting the expression of the largest multimers of VWF. A deficiency of ADAMTS13 is therefore associated with an excess of (HMW forms of) VWF, and thus thrombosis. Indeed, any disturbance of the VWF/ADAMTS13 ratio or ‘axis’ may be associated with pathophysiological processes, including prothrombotic tendency. However, both thrombosis or bleeding may be associated with such disturbances, depending on the presenting events. This review evaluates the relationship of VWF and ADAMTS13 with cardiac disease, including cardiac failure, and associated pathophysiology.

scholarly journals Assessment of Platelet Thrombus Formation under Flow Conditions in Adult Patients with COVID-19: An Observational Study

2021 ◽  
Author(s):  
Andrea Artoni ◽  
Mauro Panigada ◽  
Stefano Ghirardello ◽  
Anna Lecchi ◽  
Stefano Aliberti ◽  
...  
Keyword(s):  
Thrombus Formation ◽  
Flow Chamber ◽  
Illness Severity ◽  
Pressure Curve ◽  
Start Time ◽  
Occlusion Time ◽  
Group A ◽  
Platelet Thrombus ◽  
Analysis System ◽  
Group B

Abstract Background Coronavirus disease 2019 (COVID-19) is associated with systemic inflammation, which may dysregulate platelet function. Total Thrombus-Formation Analysis System (T-TAS) is a flow-chamber device that analyses platelet-mediated thrombus formation in capillary channels through the following parameters: (1) the area under the flow-pressure curve (AUC), (2) occlusion start time (OST), time needed to reach OST, and (3) occlusion time (OT), time needed to reach the occlusion pressure. Methods and Findings Sixty-one COVID-19 patients admitted to intensive, subintensive, and low intensive care were prospectively enrolled according to the time of admission: group A (up to 8 days) (n = 18); group B (from 9 to 21 days) (n = 19), and group C ( > 21 days) (n = 24). T-TAS measurements were performed at enrolment and after 7 days. Median OST was similar among groups. AUC was lower in group A compared to B (p = 0.001) and C (p = 0.033). OT was longer in group A compared to B (p = 0.001) and C (p = 0.028). Platelet count (PC) was higher in group B compared to A (p = 0.024). The linear regression showed that OT and AUC were independent from PC in group A (OT: 0.149 [95% confidence interval [CI]: –0.326 to 0.624], p = 0.513 and AUC: 0.005 [95% CI: –0.008 to 0.017], p = 0,447). In contrast, in group B, PC was associated with OT (–0.019 [–0.028 to 0.008], p = 0.023) and AUC (0.749 [0.358–1.139], p = 0,015), similarly to group C. Conversely, patients with different illness severity had similar T-TAS parameters. Conclusion COVID-19 patients display an impaired platelet thrombus formation in the early phase of the disease compared to later stages and controls, independently from illness severity.

scholarly journals The Use of Total Thrombus Formation Analysis System as a Tool to Assess Platelet Function in Bleeding and Thrombosis Risk—A Systematic Review

2021 ◽  
Vol 22 (16) ◽  
pp. 8605
Author(s):  
Joanna Sikora ◽  
Aleksandra Karczmarska-Wódzka ◽  
Joanna Bugieda ◽  
Przemysław Sobczak
Keyword(s):  
Platelet Function ◽  
Thrombus Formation ◽  
Blood Platelets ◽  
Basic Research ◽  
Flow Chamber ◽  
Clot Formation ◽  
Bleeding Events ◽  
Thrombosis Risk ◽  
Analysis System ◽  
Von Willebrand

Background. Today there are many devices that can be used to study blood clotting disorders by identifying abnormalities in blood platelets. The Total Thrombus Formation Analysis System is an automated microchip flow chamber system that is used for the quantitative analysis of clot formation under blood flow conditions. For several years, researchers have been using a tool to analyse various clinical situations of patients to identify the properties and biochemical processes occurring within platelets and their microenvironment. Methods. An investigation of recent published literature was conducted based on PRISMA. This review includes 52 science papers directly related to the use of the Total Clot Formation Analysis System in relation to bleeding, surgery, platelet function assessment, anticoagulation monitoring, von Willebrand factor and others. Conclusion. Most available studies indicate that The Total Thrombus Formation Analysis System may be useful in diagnostic issues, with devices used to monitor therapy or as a significant tool for predicting bleeding events. However, T-TAS not that has the potential for diagnostic indications, but allows the direct observation of the flow and the interactions between blood cells, including the intensity and dynamics of clot formation. The device is expected to be of significant value for basic research to observe the interactions and changes within platelets and their microenvironment.

Evaluation of clinical severity in patients with type 2N von Willebrand disease using microchip-based flow-chamber system

2019 ◽  
Vol 111 (3) ◽  
pp. 369-377
Author(s):  
Yuto Nakajima ◽  
Keiji Nogami ◽  
Koji Yada ◽  
Takeshi Kawamura ◽  
Kenichi Ogiwara ◽  
...  
Keyword(s):  
Flow Chamber ◽  
Von Willebrand Disease ◽  
Clinical Severity ◽  
Chamber System ◽  
Von Willebrand
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