Determination of surface tissue factor thresholds that trigger coagulation at venous and arterial shear rates: amplification of 100 fM circulating tissue factor requires flow

Okorie, Uzoma M.; Denney, William S.; Chatterjee, Manash; Neeves, Keith B.; Diamond, Scott L.

doi:10.1182/blood-2007-08-106229

Cited by 117 publications

(138 citation statements)

References 32 publications

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…Under flow conditions, the generation of thrombin by fibrillar collagen surfaces containing tissue factor has a moderate enhancing effect (approximately 30%) on platelet deposition, but a very large effect on fibrin deposition. 43 Additional donor-specific measurements of receptor levels, fibrinogen and VWF levels, ADP and TXA 2 release, for example, would allow for further tailoring of these parameters for in silico models of blood. Recognizing that k det collagen also coarse grains VWF function, we expect this kinetic parameter to be a function of shear rate above approximately 1500/s.…”

Section: Discussionmentioning

confidence: 99%

Multiscale prediction of patient-specific platelet function under flow

Flamm¹,

Colace²,

Chatterjee³

et al. 2012

Blood

Self Cite

107

121

View full text Add to dashboard Cite

During thrombotic or hemostatic episodes, platelets bind collagen and release ADP and thromboxane A 2 , recruiting additional platelets to a growing deposit that distorts the flow field. Prediction of clotting function under hemodynamic conditions for a patient's platelet phenotype remains a challenge. A platelet signaling phenotype was obtained for 3 healthy donors using pairwise agonist scanning, in which calcium dye-loaded platelets were exposed to pairwise combinations of ADP, U46619, and convulxin to activate the P2Y 1 /P2Y 12 , TP, and GPVI receptors, respectively, with and without the prostacyclin receptor agonist iloprost. A neural network model was trained on each donor's pairwise agonist scanning experiment and then embedded into a multiscale Monte Carlo simulation of donor-specific platelet deposition under flow. The simulations were compared directly with microfluidic experiments of whole blood flowing over collagen at 200 and 1000/s wall shear rate. The simulations predicted the ranked order of drug sensitivity for indomethacin, aspirin, MRS-2179 (a P2Y 1 inhibitor), and iloprost. Consistent with measurement and simulation, one donor displayed larger clots and another presented with indomethacin resistance (revealing a novel heterozygote TP-V241G mutation). In silico representations of a subject's platelet phenotype allowed prediction of blood function under flow, essential for identifying patientspecific risks, drug responses, and novel genotypes. IntroductionDuring a clotting event, platelets respond to combinatorial stimuli, including collagen, adenosine diphosphate (ADP), thromboxane A 2 (TXA 2 ), thrombin, epinephrine, and serotonin, as well as endothelialderived inhibitors such as nitric oxide and prostacyclin (PGI 2 ). Excessive platelet buildup at the site of cardiovascular disease and plaque rupture causes more than 1 million heart attacks and strokes in the United States each year. Excessive thrombus formation after plaque rupture remains difficult to predict and can be linked to hyperactive platelet function. 1,2 Therefore, low-dose aspirin to inhibit platelet cyclooxygenase-1 (COX-1) and clopidogrel to inhibit platelet P2Y 12 signaling are used widely in patients with cardiovascular risks, although patient response to these drugs can vary.Interindividual variations in platelet reactivity, even in the healthy population, have been associated with several factors, including female sex, fibrinogen level, ethnicity, inherited variations, and polymorphisms. 3,4 Similarly, platelet dysfunction or antiplatelet therapy can be associated with bleeding risks. [5][6][7] Furthermore, the function of blood is highly dependent on hemodynamic forces; examples include shear-induced platelet activation at Ͼ 5000/s shear rate, 8,9 requirement of VWF in arterial thrombosis, 10-12 shear effects on VWF structure/function and GPIb-VWF A1 domain-bonding dynamics, 13-17 RBC-dependent platelet migration toward the wall, 18,19 and convection-enhanced mass transfer to and from local zones of clotting or bleeding....

show abstract

Section: Discussionmentioning

confidence: 99%

Multiscale prediction of patient-specific platelet function under flow

Flamm¹,

Colace²,

Chatterjee³

et al. 2012

Blood

Self Cite

107

121

View full text Add to dashboard Cite

show abstract

“…26 Perfusion of blood samples at a shear rate of 1000 s −1 over microspots enriched in collagen (100 ng per microspot) resulted in a rapid formation of platelet thrombi that were rich in fibrin ( Figure 1A-1C). Lowering the collagen content (20 ng per microspot) significantly decreased platelet deposition after 7 minutes of perfusion (area covered, 12.3%±1.4% versus 33.8%±3.0%; P=0.005) and delayed the onset of fibrin formation (3 versus 5 minutes) when compared with the high collagen microspots ( Figure 1A-1C).…”

Section: Collagen-tf Surface Determines the Buildup Of Platelet-fibrimentioning

confidence: 99%

Platelet Control of Fibrin Distribution and Microelasticity in Thrombus Formation Under Flow

Swieringa

Baaten

Verdoold

et al. 2016

ATVB

View full text Add to dashboard Cite

Objective-Platelet-and fibrin-dependent thrombus formation is regulated by blood flow and exposure of collagen and tissue factor. However, interactions between these blood-borne and vascular components are not well understood. Approach and Results-Here, we developed a method to assess whole-blood thrombus formation on microspots with defined amounts of collagen and tissue factor, allowing determination of the mechanical properties and intrathrombus composition. Confining the collagen content resulted in diminished platelet deposition and fibrin formation at high shear flow conditions, but this effect was compensated by a larger thrombus size and increased accumulation of fibrin in the luminal regions of the thrombi at the expense of the base regions. These thrombi were more dependent on tissue factortriggered thrombin generation. Microforce nanoindentation analysis revealed a significantly increased microelasticity of thrombi with luminal-oriented fibrin. At a low shear rate, fibrin fibers tended to luminally cover the thrombi, again resulting in a higher microelasticity. Studies with blood from patients with distinct hemostatic insufficiencies indicated an impairment in the formation of a platelet-fibrin thrombus in the cases of dilutional coagulopathy, thrombocytopenia, Scott syndrome, and hemophilia B. Conclusions-Taken together, our data indicate that (1) thrombin increases the platelet thrombus volume; (2) tissue factor drives the formation of fibrin outside of the platelet thrombus; (3) limitation of platelet adhesion redirects fibrin from bottom to top of the thrombus; (4) a lower shear rate promotes thrombus coverage with fibrin; (5) the fibrin distribution pattern determines thrombus microelasticity; and (6) the thrombus-forming process is reduced in patients with diverse hemostatic defects. Swieringa et al Platelet Control of Fibrin Distribution in Thrombus Formation 693Together, these in vivo findings indicate that the relative availability of platelet-adhesive (like collagen) and coagulation-triggering (like TF) substances determines the buildup of a thrombus and, by implication, the roles of thrombin and fibrin herein. In support of this idea, different patterns of fibrin deposition have been detected in injury models, such as fibrin structures around a thrombus, 16 and thrombin/fibrin-rich areas in the thrombus core region. 17,18 How the platelet and coagulant activities of the thrombogenic surface, for example, the relative abundance of collagen and TF, influence the buildup and composition of a platelet-fibrin thrombus has not been examined so far.Viscoelasticity is considered to be an important hemostatic property of a fibrin-containing thrombus. For instance, in patients with severe factor XI deficiency, a low-density fibrin network is associated with impaired hemostasis. 19,20 However, the conditions that favor high elasticity of a platelet-fibrin thrombus or clot are largely unknown. The limited evidence available suggests that a local, high concentration of thrombin enforces the fibrin net...

show abstract

“…Kastrupet al in 2008 (17) showed that presence of bacteria, such as, Bacillus cereus and Bacillus anthracis can induce coagulation by quorum acting. Recently, a microfluidic system was used to show coagulation of blood in presence of tissue factors (TF) (37)(38)(39)(40)(41)(42). Microcontact printing was used by Okorie et al (40) to generate a surface of collagen and TF to support both platelet aggregation and coagulationin a flow chamber.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a microfluidic system was used to show coagulation of blood in presence of tissue factors (TF) (37)(38)(39)(40)(41)(42). Microcontact printing was used by Okorie et al (40) to generate a surface of collagen and TF to support both platelet aggregation and coagulationin a flow chamber. Ismagilov and colleagues (43) generated arrays of TF patches using photolithographic techniques to study the role of diffusion in coagulation.…”

Section: Discussionmentioning

confidence: 99%