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A multiscale model of venous thrombus formation with surface-mediated control of blood coagulation cascade.

ABSTRACT: A combination of the extended multiscale model, new image processing algorithms, and biological experiments is used for studying the role of Factor VII (FVII) in venous thrombus formation. A detailed submodel of the tissue factor pathway of blood coagulation is introduced within the framework of the multiscale model to provide a detailed description of coagulation cascade. Surface reactions of the extrinsic coagulation pathway on membranes of platelets are studied under different flow conditions. It is shown that low levels of FVII in blood result in a significant delay in thrombin production, demonstrating that FVII plays an active role in promoting thrombus development at an early stage.

SUBMITTER: Xu Z

PROVIDER: S-EPMC2862154 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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A multiscale model of venous thrombus formation with surface-mediated control of blood coagulation cascade.

Xu Zhiliang Z Lioi Joshua J Mu Jian J Kamocka Malgorzata M MM Liu Xiaomin X Chen Danny Z DZ Rosen Elliot D ED Alber Mark M

Biophysical journal 20100501 9

A combination of the extended multiscale model, new image processing algorithms, and biological experiments is used for studying the role of Factor VII (FVII) in venous thrombus formation. A detailed submodel of the tissue factor pathway of blood coagulation is introduced within the framework of the multiscale model to provide a detailed description of coagulation cascade. Surface reactions of the extrinsic coagulation pathway on membranes of platelets are studied under different flow conditions ...[more]

PMID: 20441735

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Project description:BackgroundEarly recanalization of an occluded vessel is associated with a better clinical outcome in acute ischemic stroke. Intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) is only available in a minority of patients and often fails to reopen the occluded vessel. Mechanical recanalization is more effective in this matter but only available for selected patients when a thrombectomy centre can be reached. Therefore, sonothrombolysis might represent an alternative or complementary approach. Here, we tested microbubble-mediated sonothrombolysis (mmSTL) in a thromboembolic stroke model for middle cerebral artery occlusion (MCAO) in rats.MethodsSixty-seven male Wistar rats underwent MCAO using an autologous full blood thrombus and were randomly assigned to four groups receiving rt-PA, mmSTL, a combination of both, or a placebo. Diagnostic workup included neurological examination, assessment of infarct size, and presence of intracerebral haemorrhage by magnetic resonance imaging (MRI) and presence of microbleedings in histological staining.ResultsNeurological examination revealed no differences between the treatment groups. In all treatment groups, there was a reduction in infarct size 24 hours after MCAO as compared to the placebo (P≤0.05), but there were no differences between the active treatment groups (P>0.05) (placebo 0.75±0.10 cm3; mmSTL 0.43±0.07 cm3; rt-PA 0.4±0.07 cm3; mmSTL + rt-PA 0.27±0.08 cm3). Histological staining displayed intracerebral microbleedings in all animals. The frequency of gross bleeding detected by MRI did not differ between the groups (placebo 3; mmSTL 4; rt-PA 2; mmSTL + rt-PA 2; P>0.05) and was not associated with worse performance in clinical testing (P>0.05). There were no statistical differences in the mortality between the groups (P>0.05).ConclusionsOur study showed the efficacy and safety of mmSTL with or without rt-PA in an embolic rat stroke model using a continuous full blood thrombus. Sonothrombolysis might be useful for patients who need to be transported to a thrombectomy centre or for those with distal vessel occlusion.

Project description:BACKGROUND AND PURPOSE:The residual blood flow artifact is a critical confounder for MR black-blood thrombus imaging of cerebral venous sinus thrombosis. This study aimed to conduct a validation of a new MR black-blood thrombus imaging technique with enhanced blood signal suppression. MATERIALS AND METHODS:Twenty-six participants (13 volunteers and 13 patients) underwent conventional imaging methods followed by 2 randomized black-blood thrombus imaging scans, with a preoptimized delay alternating with nutation for tailored excitation (DANTE) preparation switched on and off, respectively. The signal intensity of residual blood, thrombus, brain parenchyma, normal lumen, and noise on black-blood thrombus images were measured. The thrombus volume, SNR of residual blood, and contrast-to-noise ratio for residual blood versus normal lumen, thrombus versus residual blood, and brain parenchyma versus normal lumen were compared between the 2 black-blood thrombus imaging techniques. Segmental diagnosis of venous sinus thrombosis was evaluated for each black-blood thrombus imaging technique using a combination of conventional imaging techniques as a reference. RESULTS:In the volunteer group, the SNR of residual blood (11.3 ± 2.9 versus 54.0 ± 23.4, P < .001) and residual blood-to-normal lumen contrast-to-noise ratio (7.5 ± 3.4 versus 49.2 ± 23.3, P < .001) were significantly reduced using the DANTE preparation. In the patient group, the SNR of residual blood (16.4 ± 8.0 versus 75.0 ± 35.1, P = .002) and residual blood-to-normal lumen contrast-to-noise ratio (12.4 ± 7.8 versus 68.8 ± 35.4, P = .002) were also significantly lower on DANTE-prepared black-blood thrombus imaging. The new black-blood thrombus imaging technique provided higher thrombus-to-residual blood contrast-to-noise ratio, significantly lower thrombus volume, and substantially improved diagnostic specificity and agreement with conventional imaging methods. CONCLUSIONS:DANTE-prepared black-blood thrombus imaging is a reliable MR imaging technique for diagnosing cerebral venous sinus thrombosis.

Project description:A comprehensive understanding of thrombus formation as a physicochemical process that has evolved to protect the integrity of the human vasculature is critical to our ability to predict and control pathological states caused by a malfunctioning blood coagulation system. Despite numerous investigations, the spatial and temporal details of thrombus growth as a multicomponent process are not fully understood. Here, we used computational modeling to investigate the temporal changes in the spatial distributions of the key enzymatic (i.e., thrombin) and structural (i.e., platelets and fibrin) components within a growing thrombus. Moreover, we investigated the interplay between clot structure and its mechanical properties, such as hydraulic resistance to flow. Our model relied on the coupling of computational fluid dynamics and biochemical kinetics, and was validated using flow-chamber data from a previous experimental study. The model allowed us to identify the distinct patterns characterizing the spatial distributions of thrombin, platelets, and fibrin accumulating within a thrombus. Our modeling results suggested that under the simulated conditions, thrombin kinetics was determined predominantly by prothrombinase. Furthermore, our simulations showed that thrombus resistance imparted by fibrin was ∼30-fold higher than that imparted by platelets. Yet, thrombus-mediated bloodflow occlusion was driven primarily by the platelet deposition process, because the height of the platelet accumulation domain was approximately twice that of the fibrin accumulation domain. Fibrinogen supplementation in normal blood resulted in a nonlinear increase in thrombus resistance, and for a supplemented fibrinogen level of 48%, the thrombus resistance increased by ∼2.7-fold. Finally, our model predicted that restoring the normal levels of clotting factors II, IX, and X while simultaneously restoring fibrinogen (to 88% of its normal level) in diluted blood can restore fibrin generation to ∼78% of its normal level and hence improve clot formation under dilution.

Dataset Information

A multiscale model of venous thrombus formation with surface-mediated control of blood coagulation cascade.

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A multiscale model of venous thrombus formation with surface-mediated control of blood coagulation cascade.

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