Microclot array elastometry for integrated measurement of. Identification of platelet function defects by multi. Viii, which is complexed to vwf in plasma, also supports thrombus formation on procoagulant artery sbendothelium. A shear rate of s1 and 50 s1 mimics a venous wall shear rate and shear rate of 1500 s1 represents a shear rate of larger arteries as well as a high shear rate by moderate arterial stenosis 19. One recent study indicated that a platelet function and a mechanism of adhesion and thrombus formation under these shear. Mlevels of intraclot thrombin suggest robust prothrombin penetration into clots.
Fibrin deposition was decreased at all shear rates tested28,31. The role of low endothelial shear stress in the conversion of. At a low shear rate, fibrin fibers tended to luminally cover the thrombi, again resulting in a higher microelasticity. Effects of hematocrit and plasma proteins on human blood rheology at low shear rates. The final common pathway in myocardial infarction and ischemic stroke is occlusion of blood flow from a thrombus forming under high shear rates in arteries.
To evaluate how surface signals collagen, and tissue factor control the growth of a thrombus under controlled flow conditions, we printed microarrays with collagen features containing various concentrations of lipidated tissue factor tf. The wall shear rates generally range from about 10 s 1 in large veins,4 to s 1 in arteries. Highthroughput measurement of human platelet aggregation. Moreover, as mentioned previously, low values of harmonics 0, 1, and 2 of the sr have been correlated with upregulation of nf. Oct 15, 2002 tissue factor tf is an integral membrane protein that is found primarily on the surface of certain cell types that are located outside the vasculature. The range of shear rates covered by the proposed model encompass venous and arterial thrombosis, ranging from low shear rate conditions in abdominal aortic aneurysms and thoracic aortic. Elevated levels of fviii in the clinical setting are associated with an increased risk of dvt,, and recent studies of transgenic mice have revealed that fviii plays a significant role in the development of venous thrombosis. In particular, the effects of increasing concentration of platelets at the vessel wall and activation of platelets at this site increase the growth and stability of the thrombi which may result in a fatal narrowing of the arterial lumen. Under pathologic conditions, such as with a stenosis, shear rates may rise 5000 s 1. Plaque progression rate is determined by the doseresponsive,synergisticeffect ofsystemic hyperlipidemia and local low ess 28.
Determination of a shear rate threshold for thrombus. Targeting thrombogenicity and inflammation in chronic hiv. Functional roles of shear stress in vascular endothelial cells. Impact of tissue factor localization on blood clot. Activation of platelets initiated by adp can occur at a finite distance of separation from a growing thrombus for platelets. Whereas the delivery and removal of soluble coagulation factors to the vessel is. Platelet adhesion signalling and the regulation of thrombus. A highshear thrombus forms rapidly and is distinct from the slow formation of coagulation that occurs in stagnant blood. Blood coagulation is a complex network of biochemical reactions, which is peculiar in that it is time and spacedependent, and has to function in the presence of rapid flow. These thrombi were more dependent on tissue factortriggered thrombin generation.
Equation 3 also shows that wall shear rate increases dramatically as the vessel diameter decreases. Hematopoietic cellderived microparticle tissue factor contributes to fibrin formation during thrombus propagation. A general sheardependent model for thrombus formation. Whole blood based multiparameter assessment of thrombus. Many risk factors have been identified for venous thrombosis that alter blood flow, activate the endothelium, and increase blood coagulation.
B and tissue factor, molecules known to promote inflammatory processes and to stimulate the interaction between platelets and the endothelium. The effects of arterial flow on platelet activation, thrombus growth, and stabilization. The initial interaction of platelets with subendothelial collagens under high shear conditions present in the arterial circulation is indirectly mediated by. Venous thromboembolism vte is a leading cause of morbidity and mortality worldwide. Farris dm, myers dd, im m, wakefield tw, mackman n, fay wp. Pdf determination of a shear rate threshold for thrombus. Tm expression is regulated by shear stress ss via kruppellike factor 2 klf2. Reduced platelet cohe sion was present at low shear rates with low plasma. In addition to flow rate and shear forces, thrombus stability is determined by fibrin characteristics such as density and porosity, plateletdependent clot retraction, and proteins released from. For blood clotting on collagen tissue factor 1 tfmolecule. Anticoagulant agents are widely used for prophylaxis and treatment of venous thrombosis. The model has the advantage of predicting thrombus occlusion time with no significant computational cost using a welltrained model by data extracted from different experiments. However, the mechanisms by which clots are formed in the deep veins have not been determined. Flow effects on coagulation and thrombosis citeseerx.
Reduced model to predict thrombin and fibrin during. Pdf impact of tissue factor localization on blood clot structure. Necrotic core expansion is a key factor of lesion destabilization 14. Vii1dependent thrombus forma tion is pronounced at a wall shear rate of 650s,4 but less so at wall shear rates exceeding 1,300s, at least during the. Factor viii is also critical for tissue factor tfinitiated clot growth. The shear rate has a profound effect on the interactions of the platelets with the surface in the process of arterial thrombus formation. Low circulating levels of 100 fm tissue factor when added to flowing ctitreated whole blood did not substantially left shift the dose response curve for fibrin formation triggered by surface tissue.
Such platelet aggregates are strengthened by fibrinnetwork formation triggered by tissue factor tf. The first step in thrombus formation is for the blood constituents to reach the vessel wall from the central flow. The shear rate and flow rate were calculated at the wall in the center of the model thrombus and the pressure drop was measured across the device. Inhibition by ethanol of shear stressinduced formation of.
The stability of an arterial thrombus, namely its susceptibility to lysis and embolization, is a major determinant of subsequent tissue damage. The model demonstrates that the wall shear rate under these conditions increases until 80% occlusion and then decreases as full channel occlusion is approached. For a typical venous shear rate of 100s, the axial flow velocity at a radial. In contrast, the volume of thrombi formed in the presence of coagulation remained the same at both low and high shear rates. However, several contributing factors are neglected, including mechanisms of thrombus formation in a low shear regime, thrombus mechanics, and embolization. Thrombus growth and embolism on tissue factorbearing. Mar 17, 2011 venous thromboembolism vte is a leading cause of morbidity and mortality worldwide. Stages in the development of a platelet thrombus on collagen exposed at sites of injury. The lowest values of wall shear rates and shear stresses are generally.
Although complex, clotting is stimulated by a simpler concept of shear rate for. To evaluate how surface signals collagen, and tissue factor control the growth of a thrombus under controlled flow conditions, we printed microarrays with collagen features containing various concentrations of lipidated tissue factor tf from 0 to 25 molecules per. Samples of citrateanticoagulated blood may be supplemented with cacl 2 mgcl 2 mixture, and then perfused over a collagen tissue factor surface. Platelets comprise only 1% to 2% of blood volume, and the critical high shear clotting protein, vwf, has a plasma concentration of only 10. Low ess colocalizes with elevated luminal surface low density lipoprotein ldl cholesterol concentration, thereby locally expos. Nonclassical monocytes, which also correlated strongly with highshear rate thrombogenicity in pwh in this study, have been shown to highly express tissue factor in patients infected with hiv, and tissue factor is a highly potent activator. Macrovascular thrombosis is driven by tissue factor derived primarily from the blood. Despite the prevalence of this event, the critical concentration of surface tissue factor required to cause clotting at various hemodynamic conditions remains poorly defined. Determination of surface tissue factor thresholds that. Setting intraclot zymogen concentrations to plasma levels and neglecting cofactor rate limitations allowed the linearization of 7 michaelismenton reactions.
Department of chemical and biomolecular engineering, institute for medicine and engineering. Spatial distribution of factor xa, thrombin, and fibrin. The shear rate dependence of thrombus formation associated with deficiencies of the coagulation factors fvii and fviii was studied on human type iii collagen fibrils. Determination of a shear rate threshold for thrombus formation in intracranial aneurysms. A general sheardependent model for thrombus formation ncbi. A high shear thrombus forms rapidly and is distinct from the slow formation of coagulation that occurs in stagnant blood.
Blood flow velocity effects and role of activation delay time. However, a disadvantage of this procedure is ongoing contact activation in the blood before reaching the tissue factor. Abstract the relative importance of vessel wall tissue factor. Tissue factorinduced coagulation triggers platelet thrombus. This was the case for the vwf deficiency and the vwd subtypes investigated28,29. However, a disadvantage of this procedure is ongoing contact activation in the blood before reaching the tissue. The impact of blood shear rate on arterial thrombus formation ncbi.
Multiscale simulation of thrombus growth and vessel. From a practical point of view, this means that, at small shear rates 0 s1, the lagtime increased slowly with the increase of shear rate from 2. These include tissue factor tf, stimulating the extrinsic coagulation route, and collagen. Polymorphism gpia c807t increased platelet cohesion at high arte. However, this increase became very rapid at higher shear rates, and by 28 s1 the lag time reached 100120 min. Factor viii contributes to plateletfibrin thrombus formation. The transcription factor erg regulates a low shear stress. Impact of tissue factor localization on blood clot structure. The objective of this study was to use systems biology techniques to investigate this regulation and to identify mechanisms. Blood flow controls coagulation onset via the positive. Although thrombin has a key role, other components of the coagulation system, in particular factors. Flow effects on coagulation and thrombosis arteriosclerosis. Determination of a shear rate threshold for thrombus formation in intracranial aneurysms article pdf available in journal of neurointerventional surgery 88 july 2015 with 287 reads.
The shear rate and corresponding shear stress have impacts on arterial thrombus formation. Many experimental studies with genetically modified mice or with blood from patients with haemostatic deficiencies, performed at either arterial high shear rate or venous low shear rate flow conditions, have emphasized that thrombus formation is a complex process encompassing multiple platelet receptors and signalling mechanisms2,3,4. Tissue factor tf is the primary initiator of the coagulation cascade. Microforce nanoindentation analysis revealed a significantly increased microelasticity of thrombi with luminaloriented fibrin. However, little is known about the role of tf in vwfdependent thrombus formation under blood flow conditions. Our results are consistent with this model since we found that platelet derived nitric oxide did not inhibit the rate of thrombus growth at these low, venous levels of shear rate. Plasma fibronectin is also known to have a role in thrombus growth and stability 15.
Suppressive role of tissue factor pathway inhibitor. Department of chemical and biomolecular engineering, institute for. Apr 01, 2008 plaque rupture reveals tissue factor tf to flowing blood, resulting in coronary thrombosis and occlusion with consequent acute myocardial infarction. In addition, the existence, sources, and functional activity of circulating levels of tissue factor are not fully resolved in health or disease. In particular parallelplate microfluidic chambers, using small. Coagulation is believed to be initiated when tissue factor tf.
Factor xii regulates the pathological process of thrombus. Nonclassical monocytes, which also correlated strongly with highshear rate thrombogenicity in pwh in this study, have been shown to highly express tissue factor in patients infected with hiv, and tissue factor is a highly potent activator of blood coagulation and platelet activation. From equation 3, wall shear rate increases with increasing blood. We sought to understand how the growth, structure, and mechanical properties of clots under flow are shaped by the simultaneously varying tf surface density and its exposure. For surface tissue factor ec50 analysis at each shear rate. Multiscale simulation of thrombus growth and vessel occlusion. Inhibition of tissue factor limits the growth of venous thrombus in the rabbit. In the case of atherosclerosis, a reduction in local shear may be achieved by bypass grafting, angioplasty, or stent placements. Recent experimental reports suggest that flow plays a significant role in its regulation. Thrombosis is thought to begin with an event such as plaque rupture, vessel damage, or dysfunctioning endothelium, resulting in the exposure of active tissue factor tf on the vessel wall. Platelet deposition is increased in parallel with the increasing shear rate 15, 2224.
The function of circulating tf in concert with wall. The structure and growth of a blood clot depend on the localization of tissue factor tf, which can trigger clotting during the hemostatic process or promote thrombosis when exposed to blood under pathological conditions. Role of high shear rate in thrombosis sciencedirect. Multiscale simulation of thrombus growth and vessel occlusion triggered by collagen tissue factor using a datadriven model of combinatorial platelet signalling yichen lu, meiyan lee, shu zhu, talid sinno and scott l. Meanwhile, shear stress, which is created due to the friction of the flowing blood on the endothelium of the arterial wall, is critical for vascular homeostasis. Platelets, circulating tissue factor, and fibrin colocalize. Jci new insights into the mechanisms of venous thrombosis. These thrombi were more dependent on tissue factor triggered thrombin generation. Discrimination between plateletmediated and coagulationmediated mechanisms in a model of complex thrombus formation in vivo. Plateletderived no slows thrombus growth on a collagen type. Endothelial cells play remarkable roles in regulating vascular function in health and disease.
Coperfusion of human blood with tissue factor resulted. Venous thrombosis is a leading cause of morbidity and mortality in industrialized countries, especially in the elderly. Platelet control of fibrin distribution and microelasticity. Wagner the cbr institute for biomedical research and department of pathology, harvard medical school, boston, ma, usa to cite this article. Therefore, platelet adhesion at low levels of shear rate can be mediated by a number of different adhesion molecules, some of which do not require platelet activation.
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