scholarly journals Computational Modeling and Microfluidics Reveal Characteristic Patterns of Regulation of Clot Structure and Mechanics By Tissue Factor Localization

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1164-1164
Author(s):  
Alexander Y. Mitrophanov ◽  
Vijay Govindarajan ◽  
Shu Zhu ◽  
Scott L. Diamond ◽  
Jaques Reifman
Keyword(s):  
Mechanical Properties ◽  
Blood Flow ◽  
Flow Velocity ◽  
Tissue Factor ◽  
Surface Density ◽  
Viscous Resistance ◽  
Platelet Deposition ◽  
Surface Length ◽  
The U.S ◽  
Thrombin Formation

Abstract The growth of a blood clot is initiated by tissue factor (TF) exposure and is expected to depend on TF localization (i.e., its level and spatial distribution). We sought to understand how the structural and mechanical properties of clots under flow are shaped by simultaneously varying the surface density of TF and its area of exposure. We used a microfluidic device harboring thrombogenic surfaces that differed in length and TF surface density. We perfused human whole blood through this device and continually measured platelet deposition, thrombin formation, and fibrin accumulation by means of fluorescence microscopy. Using our recently developed, detailed mathematical model of spatial clot growth under flow, we performed computational simulations to gain insights into the connection between the structure of a clot and its mechanical properties, such as resistance to blood flow and flow axial velocity. We detected a non-additive, synergistic influence of the thrombogenic surface length and TF surface density on bulk thrombin and fibrin generation. We found that thrombogenic surface length and TF density controlled not only bulk accumulation, but also the occlusivity of the deposited platelet mass, as well as clot resistance to flow. The extent of this control depended on the blood flow velocity. An increase in the TF surface density resulted in condition-dependent differential acceleration of platelet deposition, thrombin formation, and fibrin accumulation. The viscous resistance of the clot was characterized by spatial variations and was higher in the inner clot region. Notably, despite variations in the intraclot structure, variations in the intraclot flow velocity were minor compared to the abrupt decrease in flow velocity at the boundary of the platelet deposition domain. Our analysis revealed characteristic patterns that describe how the shape, size, internal structure, and viscous resistance of a clot depend on the surface density of TF and its area of exposure. Taken together, our results suggest that the structure and mechanics of a growing clot are correlated, but can differ in their regulation by the distinct aspects of TF localization. These findings provide new insights into how initiating signals can temporally and spatially affect thrombus growth under flow. DISCLAIMER: The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army or of the U.S. Department of Defense. This abstract has been approved for public release with unlimited distribution. Disclosures No relevant conflicts of interest to declare.

Recombinant factor VIIa enhances deposition of platelets with congenital or acquired αIIbβ3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor–independent thrombin generation

Blood ◽  
2003 ◽  
Vol 101 (5) ◽  
pp. 1864-1870 ◽  
Author(s):  
Ton Lisman ◽  
Sultana Moschatsis ◽  
Jelle Adelmeijer ◽  
H. Karel Nieuwenhuis ◽  
Philip G. De Groot
Keyword(s):  
Tissue Factor ◽  
Thrombin Generation ◽  
Recombinant Factor Viia ◽  
Factor Viia ◽  
Umbilical Vein ◽  
Novel Approach ◽  
Platelet Deposition ◽  
Platelet Aggregate ◽  
Umbilical Vein Endothelial Cells ◽  
Thrombin Formation

A novel approach to treat bleeding episodes in patients with Glanzmann thrombasthenia (GT) and perhaps also in patients receiving αIIbβ3 inhibitors is the administration of recombinant factor VIIa (rFVIIa). The mechanism of action of rFVIIa in these patients is, however, still unclear. We studied the effect of rFVIIa-mediated thrombin formation on adhesion of αIIbβ3-deficient platelets under flow conditions. Adhesion of αIIbβ3-deficient platelets to the extracellular matrix (ECM) of stimulated human umbilical vein endothelial cells or to collagen type III was studied using a model system with washed platelets and red cells. When αIIbβ3-deficient platelets were perfused over the surface at arterial shear rate for 5 minutes, a low surface coverage was observed (GT platelets, mean ± SEM, 37.5% ± 5.0%; normal platelets preincubated with an RGD-containing peptide, 7.4% ± 2.1%). When rFVIIa, together with factors X and II, was added to the perfusate, platelet deposition significantly increased (GT platelets, mean ± SEM, 67.0% ± 4.3%; normal platelets preincubated with an RGD-containing peptide, 48.2% ± 2.9%). The same effect was observed when normal platelets were pretreated with the commercially available anti-αIIbβ3 drugs abciximab, eptifibatide, or tirofiban. It was shown that tissue factor–independent thrombin generation (presumably induced by binding of rFVIIa to adhered platelets) was responsible for the increase in platelet deposition. In conclusion, defective adhesion of αIIbβ3-deficient platelets to ECM can be restored by tissue factor–independent rFVIIa-mediated thrombin formation. The enhanced generation of platelet procoagulant surface facilitates fibrin formation, so that lack of platelet aggregate formation might be compensated for.

Effects of Radiographic Contrast Agents on Thrombin Formation and Activity

1998 ◽  
Vol 80 (08) ◽  
pp. 266-272 ◽  
Author(s):  
Andrew Parker ◽  
William Fay
Keyword(s):  
Contrast Agents ◽  
Tissue Factor ◽  
Coronary Angioplasty ◽  
Molecular Mechanisms ◽  
Factor Viia ◽  
Minor Effect ◽  
Ionic Contrast ◽  
Radiographic Contrast ◽  
Inhibition Of Thrombin ◽  
Thrombin Formation

SummaryClinical trials suggest that the risk of thrombosis during coronary angioplasty is lower with ionic contrast agents than with nonionic contrast agents. However, the molecular mechanisms underlying this effect are unknown. This study examined the effects of contrast agents on thrombin formation and its interaction with substrates, inhibitors, and ligands to define potential mechanisms by which contrast agents affect thrombus formation. Two ionic agents, diatrizoate and ioxaglate, and one nonionic agent, ioversol, were studied. Ionic agents inhibited factor X activation by the tissue factor-factor VIIa complex more potently than ioversol (53 ± 3.7, 43.0 ± 1.9, and 26.5 ± 2.4% inhibition by diatrizoate, ioxaglate, and ioversol, respectively, at concentrations of 5%). Ionic contrast agents were potent inhibitors of prothrombinase function, inhibiting thrombin formation by >75% at contrast concentrations of 0.6% (p <0.005). Ioversol inhibited prothrombinase to a significantly lesser extent than ionic agents. Clotting assays suggested that ioxaglate was the most potent inhibitor of thrombin generation in plasma despite having the least effect on fibrin polymerization. Contrast agents inhibited binding of thrombin to fibrin, with ionic agents producing a more potent effect than ioversol (p <0.02). However, contrast agents did not inhibit thrombin-mediated platelet activation, had only a minor effect on inhibition of thrombin by antithrombin III, and did not affect thrombin-hirudin interactions. In summary, these studies identify specific mechanisms by which radiographic contrast agents inhibit thrombin formation and function – i.e. inhibition of tissue factor-dependent factor Xa generation, inhibition of the prothrombinase complex, and inhibition of thrombin binding to fibrin. These findings may help to explain the reduced risk of thrombosis during coronary angioplasty associated with ionic contrast agents.

Decrease of blood flow velocity in the middle cerebral artery after stellate ganglion block following aneurysmal subarachnoid hemorrhage: a potential vasospasm treatment?

2020 ◽  
Vol 133 (3) ◽  
pp. 773-779
Author(s):  
Christopher Wendel ◽  
Ricardo Scheibe ◽  
Sören Wagner ◽  
Wiebke Tangemann ◽  
Hans Henkes ◽  
...  
Keyword(s):  
Blood Flow ◽  
Subarachnoid Hemorrhage ◽  
Middle Cerebral Artery ◽  
Flow Velocity ◽  
Neurological Deficit ◽  
Blood Flow Velocity ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Stellate Ganglion ◽  
Stellate Ganglion Block ◽  
Ganglion Block

OBJECTIVECerebral vasospasm (CV) is a delayed, sustained contraction of the cerebral arteries that tends to occur 3–14 days after aneurysmal subarachnoid hemorrhage (aSAH) from a ruptured aneurysm. Vasospasm potentially leads to delayed cerebral ischemia, and despite medical treatment, 1 of 3 patients suffer a persistent neurological deficit. Bedside transcranial Doppler (TCD) ultrasonography is used to indirectly detect CV through recognition of an increase in cerebral blood flow velocity (CBFV). The present study aimed to use TCD ultrasonography to monitor how CBFV changes on both the ipsi- and contralateral sides of the brain in the first 24 hours after patients have received a stellate ganglion block (SGB) to treat CV that persists despite maximum standard therapy.METHODSThe data were culled from records of patients treated between 2013 and 2017. Patients were included if an SGB was administered following aSAH, whose CBFV was ≥ 120 cm/sec and who had either a focal neurological deficit or reduced consciousness despite having received medical treatment and blood pressure management. The SGB was performed on the side where the highest CBFV had been recorded with 8–10 ml ropivacaine 0.2%. The patient’s CBFV was reassessed after 2 and 24 hours.RESULTSThirty-seven patients (male/female ratio 18:19), age 17–70 years (mean age 49.9 ± 11.1), who harbored 13 clipped and 22 coiled aneurysms (1 patient received both a coil and a clip, and 3 patients had 3 untreated aneurysms) had at least one SGB. Patients received up to 4 SGBs, and thus the study comprised a total of 76 SGBs.After the first SGB, CBFV decreased in 80.5% of patients after 2 hours, from a mean of 160.3 ± 28.2 cm/sec to 127.5 ± 34.3 cm/sec (p < 0.001), and it further decreased in 63.4% after 24 hours to 137.2 ± 38.2 cm/sec (p = 0.007). A similar significant effect was found for the subsequent SGB. Adding clonidine showed no significant effect on either the onset or the duration of the SGB. Contralateral middle cerebral artery (MCA) blood flow was not reduced by the SGB.CONCLUSIONSTo the authors’ knowledge, this is the largest study on the effects of administering an SGB to aSAH patients after aneurysm rupture. The data showed a significant reduction in ipsilateral CBFV (MCA 20.5%) after SGB, lasting in about two-thirds of cases for over 24 hours with no major complications resulting from the SGB.

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