scholarly journals Effects of red blood cell concentration on hemostasis and thrombus formation in a primate model

Blood ◽  
1990 ◽  
Vol 75 (11) ◽  
pp. 2185-2193
Author(s):  
Y Cadroy ◽  
SR Hanson
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Thrombus Formation ◽  
Low Flow ◽  
Flow Conditions ◽  
Primate Model ◽  
Shunt System ◽  
Local Flow ◽  
Shear Rates ◽  
Venous Shunt

Because the effects of red blood cell (RBC) concentration on hemostasis and thrombus formation have not been studied experimentally under conditions of whole blood flow without anti-coagulation, normal baboons were bled or transfused to obtain three different groups: a low hematocrit (Ht) group (20% less than Ht less than 25%), a normal Ht group (35% less than Ht less than 40%), and a high Ht group (50% less than Ht less than 55%). Measurements of platelet count, bleeding time, platelet aggregation, fibrinogen level, and coagulation time (APTT) were equivalent to normal values in each group. Thrombus formation was induced using a device composed of collagen-coated tubing followed by two sequentially placed expansion chambers designed to exhibit flow recirculation and stasis. The device was exposed for up to 40 minutes in an arterio-venous shunt system. Wall shear rates in the tubular collagen segment were 100 seconds-1 and 500 to 750 seconds-1. The accumulation of 111In-platelets and 125I-fibrinogen/fibrin was measured radioisotopically; RBC incorporation was determined from measurements of total thrombus hemoglobin. Thrombus that formed on the collagen substrate was rich in platelets and poor in fibrin and RBCs. Under high flow conditions, thrombus composition showed no dependence on Ht. Surprisingly, under low flow conditions, platelet thrombus volume was negatively correlated with Ht (r = -.73, P = .005), and was increased by greater than twofold in the low Ht group as compared with the high Ht group. Thrombus that formed in the disturbed flow regions contained relatively few platelets but was rich in fibrin and RBCs. The predominant finding was a positive correlation between RBC incorporation and Ht at both high and low shear rates (r = .90, P = .00003; and r = .77, P = .002, respectively), with thrombus volume increasing three- to sixfold between the low and high Ht groups. Thus, in vivo variations in Ht ranging between 20% and 55% did not affect hemostasis, but were found either to promote or inhibit the net accumulation of thrombus, depending on local flow conditions.

scholarly journals Effects of red blood cell concentration on hemostasis and thrombus formation in a primate model

Blood ◽  
1990 ◽  
Vol 75 (11) ◽  
pp. 2185-2193 ◽  
Author(s):  
Y Cadroy ◽  
SR Hanson
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Thrombus Formation ◽  
Low Flow ◽  
Flow Conditions ◽  
Primate Model ◽  
Shunt System ◽  
Local Flow ◽  
Shear Rates ◽  
Venous Shunt

Abstract Because the effects of red blood cell (RBC) concentration on hemostasis and thrombus formation have not been studied experimentally under conditions of whole blood flow without anti-coagulation, normal baboons were bled or transfused to obtain three different groups: a low hematocrit (Ht) group (20% less than Ht less than 25%), a normal Ht group (35% less than Ht less than 40%), and a high Ht group (50% less than Ht less than 55%). Measurements of platelet count, bleeding time, platelet aggregation, fibrinogen level, and coagulation time (APTT) were equivalent to normal values in each group. Thrombus formation was induced using a device composed of collagen-coated tubing followed by two sequentially placed expansion chambers designed to exhibit flow recirculation and stasis. The device was exposed for up to 40 minutes in an arterio-venous shunt system. Wall shear rates in the tubular collagen segment were 100 seconds-1 and 500 to 750 seconds-1. The accumulation of 111In-platelets and 125I-fibrinogen/fibrin was measured radioisotopically; RBC incorporation was determined from measurements of total thrombus hemoglobin. Thrombus that formed on the collagen substrate was rich in platelets and poor in fibrin and RBCs. Under high flow conditions, thrombus composition showed no dependence on Ht. Surprisingly, under low flow conditions, platelet thrombus volume was negatively correlated with Ht (r = -.73, P = .005), and was increased by greater than twofold in the low Ht group as compared with the high Ht group. Thrombus that formed in the disturbed flow regions contained relatively few platelets but was rich in fibrin and RBCs. The predominant finding was a positive correlation between RBC incorporation and Ht at both high and low shear rates (r = .90, P = .00003; and r = .77, P = .002, respectively), with thrombus volume increasing three- to sixfold between the low and high Ht groups. Thus, in vivo variations in Ht ranging between 20% and 55% did not affect hemostasis, but were found either to promote or inhibit the net accumulation of thrombus, depending on local flow conditions.

Revised Model for Platelet Adhesion to Collagen.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2999-2999
Author(s):  
Lucia Stefanini ◽  
Moritz Stolla ◽  
Sean F Maloney ◽  
Timothy Daniel Ouellette ◽  
Claire Roden ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Mapk Signaling ◽  
Low Flow ◽  
Flow Conditions ◽  
Integrin Activation ◽  
Shear Rates ◽  
Slow Kinetics ◽  
Rap1 Activation

Abstract Abstract 2999 Poster Board II-968 The Gi-coupled ADP receptor, P2Y12, is the target of clopidogrel bisulfate (Plavix), currently the most successful anti-platelet strategy used in the clinic. In a recent study, we have shown that the Ca2+-sensing nucleotide exchange factor, CalDAG-GEFI, and P2Y12 represent the major signaling pathways leading to Rap1 and integrin activation in platelets (Cifuni et al., 2008, Blood). In the present study, we have further evaluated the importance of CalDAG-GEFI signaling and Rap1 activation for various aspects of platelet activation, and we have compared thrombus formation of CalDAG-GEFI−/− and WT/clopidogrel platelets under static and flow conditions in vitro. Our studies establish a revised model for platelet activation by collagen. In platelets activated with threshold concentrations of GPVI agonists, CalDAG-GEFI serves as a highly sensitive response element to Ca2+ that allows for the rapid activation of Rap1. CalDAG-GEFI-mediated Rap1 activation triggers a first wave of integrin activation and ERK (MAPK) signaling, followed by TxA2 release. TxA2 provides crucial feedback for the activation of PKC and granule/ADP release. ADP in turn triggers the second, P2Y12-dependent wave of Rap1-mediated signaling events, leading to the sustained activation of integrins and further release of TxA2. Higher concentrations of GPVI agonists lead to the concomitant activation of CalDAG-GEFI and PKC, facilitating platelet aggregation independent of feedback by endogenous TxA2. Under physiological flow conditions, CalDAG-GEFI-dependent platelet activation (clopidogrel-treated WT platelets) allowed for the formation of small but unstable thrombi, which rapidly disintegrated at high shear rates. In contrast, CalDAG-GEFI−/− platelets (P2Y12-dependent platelet activation) in anticoagulated blood firmly adhered to the thrombogenic surface but failed to form thrombi, even at high concentrations of collagen. Addition of exogenous TxA2 to anticoagulated CalDAG-GEFI−/− blood did not restore thrombus formation under flow. However, small thrombi were observed with non-anticoagulated CalDAG-GEFI−/− blood perfused at venous but not arterial shear rates, suggesting that a) locally generated thrombin facilitates the recruitment of free flowing CalDAG-GEFI−/− platelets to already adherent platelets, and b) the slow kinetics of P2Y12-dependent Rap1 activation only supports thrombin-induced platelet-platelet cohesion at low shear conditions. In conclusion, our studies demonstrate that CalDAG-GEFI/Rap1 signaling plays a critical role for the first wave of integrin activation and TxA2 generation important for platelet adhesion to a thrombogenic surface. Signaling by P2Y12/Rap1 is essential for sustained platelet activation/thrombus stabilization and partially compensates for CalDAG-GEFI/Rap1-mediated platelet adhesion under low flow conditions. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Calibration of hydrological models for ecologically relevant streamflow predictions: a trade-off between fitting well to data and estimating consistent parameter sets?

2020 ◽  
Vol 24 (3) ◽  
pp. 1031-1054 ◽  
Author(s):  
Thibault Hallouin ◽  
Michael Bruen ◽  
Fiachra E. O'Loughlin
Keyword(s):  
Flow Regime ◽  
River Flow ◽  
Freshwater Ecosystems ◽  
Living Environment ◽  
Rate Of Change ◽  
Low Flow ◽  
Hydrological Models ◽  
Flow Conditions ◽  
Local Flow ◽  
Trade Off

Abstract. The ecological integrity of freshwater ecosystems is intimately linked to natural fluctuations in the river flow regime. In catchments with little human-induced alterations of the flow regime (e.g. abstractions and regulations), existing hydrological models can be used to predict changes in the local flow regime to assess any changes in its rivers' living environment for endemic species. However, hydrological models are traditionally calibrated to give a good general fit to observed hydrographs, e.g. using criteria such as the Nash–Sutcliffe efficiency (NSE) or the Kling–Gupta efficiency (KGE). Much ecological research has shown that aquatic species respond to a range of specific characteristics of the hydrograph, including magnitude, frequency, duration, timing, and the rate of change of flow events. This study investigates the performance of specially developed and tailored criteria formed from combinations of those specific streamflow characteristics (SFCs) found to be ecologically relevant in previous ecohydrological studies. These are compared with the more traditional Kling–Gupta criterion for 33 Irish catchments. A split-sample test with a rolling window is applied to reduce the influence on the conclusions of differences between the calibration and evaluation periods. These tailored criteria are shown to be marginally better suited to predicting the targeted streamflow characteristics; however, traditional criteria are more robust and produce more consistent behavioural parameter sets, suggesting a trade-off between model performance and model parameter consistency when predicting specific streamflow characteristics. Analysis of the fitting to each of 165 streamflow characteristics revealed a general lack of versatility for criteria with a strong focus on low-flow conditions, especially in predicting high-flow conditions. On the other hand, the Kling–Gupta efficiency applied to the square root of flow values performs as well as two sets of tailored criteria across the 165 streamflow characteristics. These findings suggest that traditional composite criteria such as the Kling–Gupta efficiency may still be preferable over tailored criteria for the prediction of streamflow characteristics, when robustness and consistency are important.

CRGT Peptide In Cytoplasm Regulates Thrombus Formation Via Dissociating c-Src-β3 Interaction

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3501-3501
Author(s):  
Jiansong Huang ◽  
Xiaofeng Shi ◽  
Wenda Xi ◽  
Ping Liu ◽  
Xiaodong Xi
Keyword(s):  
Molecular Mechanisms ◽  
Platelet Adhesion ◽  
Thrombus Formation ◽  
Human Platelets ◽  
Flow Conditions ◽  
Cho Cell ◽  
Integrin Αiibβ3 ◽  
Shear Rates ◽  
Platelet Adhesion And Aggregation

Abstract The RGT sequences of the integrin β3 tail directly and constitutively bind the inactive c-Src, regulating integrin αIIbβ3 signaling and platelet function. Previous work has shown that disrupting the interaction of c-Src with β3 via myristoylated RGT peptide or deletion of the RGT sequences in β3 selectively inhibits integrin αIIbβ3 outside-in signaling in platelets. However, the precise molecular mechanisms by which the Src-β3 association regulates integrin αIIbβ3 signaling need to be clarified. We found that active c-Src phosphoylated the Y747 and Y759 residues of β3 directly at the in vitro protein/protein level or in CHO cell models bearing Tac-β3 chimeras, which were devoid of the intact β3 signal transduction. Furthermore, data from mass spectrometry, [γ-32P] ATP incorporation assays and CHO cell/Tac-β3 chimeras demonstrated that the direct phosphorylation of Y747 and Y759 by active c-Src did not depend on the binding of c-Src to the RGT sequences of the β3 tail. To further investigate the biological functions of Src-β3 association in signal transduction we employed a cell-permeable and reduction-sensitive peptide (myr-AC∼CRGT), which disrupted the Src-β3 association in platelets independent of membrane-anchorage, and found that when platelets were stimulated by thrombin the c-Src activation and the phosphorylation of the tyrosine residues of the β3 tail were substantially inhibited by the presence of the peptide. These results suggest that one of the crucial biological functions of Src-β3 association is to serve as a “bridge” linking integrin signaling with the c-Src full activation and phosphorylation of the tyrosines of the β3 tail. To answer whether the RGT peptide binding to Src is able to alter the enzymatic activity of c-Src, we examined the Src-Csk association, the phosphorylation status of Y416 and Y527 of c-Src and the c-Src kinase catalytic activity. Results showed that myr-AC∼CRGT did not dissociate Csk from c-Src in resting platelets and the phosphorylation level of Y416 and Y527 of c-Src remained unaltered. Consistent data were also obtained from in vitro analysis of the c-Src kinase catalytic activity in the presence of CRGT peptide. These results suggest that myr-AC∼CRGT peptide per se does not fully activate c-Src. Myr-AC∼CRGT was also found to inhibit integrin αIIbβ3 outside-in signaling in human platelets. To examine the effect of the myr-AC∼CRGT on platelet adhesion and aggregation under flow conditions, we measured the platelet thrombus formation under different shear rates. Myr-AC∼CRGT did not affect the platelet adhesion at a wall shear rate of 125 s-1. The inability of myr-AC∼CRGT to affect platelet adhesion and aggregation remained at 500 s-1 shear rates. At 1,500 s-1, or 5,000 s-1 rates, myr-AC∼CRGT partially inhibited platelet adhesion and aggregation. These observations indicate that the Src-regulated outside-in signaling plays a pivotal role in the stable thrombus formation and the thrombus growth under flow conditions. The present study reveals novel insights into the molecular mechanisms by which c-Src regulates integrin αIIbβ3 signaling, particularly the phorsphorylation of the β3 cytoplasmic tyrosines, and provides first evidence in human platelets that the RGT peptide or derivatives regulate thrombus formation through dissociating the Src-β3 interaction. The data of this work allow us to anticipate that intracellular delivery of the RGT peptide or its analogues may have potential in the development of a new antithrombotic strategy where only the Src-β3 interaction is specifically interrupted so as to provide an effective inhibition on thrombosis together with a decent hemostasis. Disclosures: No relevant conflicts of interest to declare.

Analysis of mechanisms for platelet near-wall excess under arterial blood flow conditions

2011 ◽  
Vol 676 ◽  
pp. 348-375 ◽  
Author(s):  
L. CROWL ◽  
A. L. FOGELSON
Keyword(s):  
Blood Cell ◽  
Red Blood Cells ◽  
Red Blood Cell ◽  
Blood Cells ◽  
Vessel Wall ◽  
Arterial Blood Flow ◽  
Free Layer ◽  
Flow Conditions ◽  
Cell Free Layer ◽  
Near Wall

The concentration of platelets near the blood vessel wall is important because platelets survey the condition of the vessel wall and respond to injuries to it. Under arterial flow conditions, platelets are non-uniformly distributed across the vessel lumen and have a high concentration within a few microns of the vessel wall. This is believed to be a consequence of the complex motion of red blood cells which constitute a large fraction of the blood's volume. We use a novel lattice Boltzmann-immersed boundary method to simulate, in two dimensions, the motion of dense red blood cell suspensions and their effect on platelet-sized particles. We track the development of a red blood cell-free layer near the wall and the later development of the platelet near-wall excess. We find that the latter develops more quickly at high wall shear rates and that the magnitude of the excess and its proximity to the wall are dependent on haematocrit. Treating the simulation data as if it were generated by a drift–diffusion process, we find that the effective lateral platelet diffusivity depends strongly on lateral position; it has a magnitude of order of 10−6 cm2 s−1 over much of the lumen but drops to almost zero close to the wall. This large effective diffusivity over the core of the lumen combined with reduced space for platelets in this region because of the inward migration of red blood cells largely but not completely accounts for the observed platelet-concentration profiles. We present evidence for a highly localized red blood cell-induced platelet drift at the edge of the red cell-free layer and suggest a physical mechanism that may generate it.

Platelet Deposition Induced by Severely Damaged Vessel Wall Is Inhibited by a Boroarginine Synthetic Peptide with Antithrombin Activity

1994 ◽  
Vol 71 (04) ◽  
pp. 511-516 ◽  
Author(s):  
J J Badimon ◽  
D Weng ◽  
J H Chesebro ◽  
V Fuster ◽  
L Badimon
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Synthetic Peptide ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Blood Platelet ◽  
Flow Conditions ◽  
Local Flow ◽  
Platelet Deposition ◽  
Damaged Vessel

SummaryThrombin plays a key role in platelet activation and thrombosis. Specific inhibition of thrombin appears to be one of the best approaches to prevent thrombus formation. We have studied the effects of a synthetic a-aminoboronic acid derivative - [Ac, (D) Phe-Pro-Boro-Arg-Hydrocloric acid] - on platelet deposition on severely damaged arterial wall. Platelet deposition was evaluated under well characterized rheological conditions in an original perfusion chamber and detected by autologous mIn-labeled platelets. The study was performed “in vivo” in a porcine model of arterial thrombosis triggered by severely damaged vessel wall at blood flow conditions mimicking mild stenosis (1690 s−1) and patent (212 s−1) vessels. In addition, ex-vivo platelet aggregation activity was evaluated by whole blood impedance aggregometry using collagen, ADP and thrombin as agonists. The synthetic a-aminoboronic peptide was intravenously administered as a bolus followed by continuous infusion. Ex vivo thrombin-induced whole blood platelet aggregation was totally abolished, while ADP- and Collagen-induced whole blood platelet aggregation was not modified. The effects of the synthetic antithrombin on platelet deposition were evaluated in native blood (non-anticoagulated) conditions and in combination with heparin. Under both experimental conditions, the synthetic peptide significantly inhibited platelet deposition at local flow conditions of both high (1690 s−1) and low (212s−1) shear rates. Our results suggest that specific inhibition of locally generated thrombin might be a good strategy to prevent platelet dependent arterial thrombus formation independently of the local flow shear rate of the area at risk.

scholarly journals Red blood cell (RBC) aggregation and its influence on non-Newtonian nature of blood in microvasculature

2017 ◽  
Vol 1 (1) ◽  
Author(s):  
Chitra Murali ◽  
Perumal Nithiarasu
Keyword(s):  
Blood Flow ◽  
Blood Cell ◽  
Red Blood Cell ◽  
Cell Aggregation ◽  
Time Dependent ◽  
Shear Rates ◽  
Red Blood Cell Aggregation ◽  
Significant Difference ◽  
Rbc Aggregation ◽  
Rouleaux Formation

AbstractA robust computational model is proposed to investigate the non-Newtonian nature of blood flow due to rouleaux formation in microvasculature. The model consists of appropriate forces responsible for red blood cell (RBC) aggregation in the microvasculature, tracking of RBCs, and coupling between plasma flow and RBCs. The RBC aggregation results have been compared against the available data. The importance of different hydrodynamic forces on red blood cell aggregation has been delineated by comparing the time dependent path of the RBCs. The rheological changes to the blood flow have been investigated under different shear rates and hematocrit values and quantified with and without RBC aggregation. The results obtained in terms of wall shear stress (WSS) and blood viscosity indicate a significant difference between Newtonian and powerlaw fluid assumptions.

A simple model to understand the effect of membrane shear elasticity and stress-free shape on the motion of red blood cells in shear flow

Soft Matter ◽  
2015 ◽  
Vol 11 (42) ◽  
pp. 8372-8382 ◽  
Author(s):  
Jules Dupire ◽  
Manouk Abkarian ◽  
Annie Viallat
Keyword(s):  
Simple Model ◽  
Shear Flow ◽  
Blood Cell ◽  
Red Blood Cells ◽  
Red Blood Cell ◽  
Time Variation ◽  
Blood Cells ◽  
Shear Rates ◽  
Shear Elasticity

Time variation of the inclination (θ) and the membrane rotation (ω) of a red blood cell tumbling in a shear flow for three shear rates.

Contributions of collision rate and collision efficiency to erythrocyte aggregation in postcapillary venules at low flow rates

2007 ◽  
Vol 293 (3) ◽  
pp. H1947-H1954 ◽  
Author(s):  
Sangho Kim ◽  
Janet Zhen ◽  
Aleksander S. Popel ◽  
Marcos Intaglietta ◽  
Paul C. Johnson
Keyword(s):  
Blood Cell ◽  
Red Blood Cells ◽  
Red Blood Cell ◽  
Blood Cells ◽  
Collision Frequency ◽  
Low Flow ◽  
Aggregate Formation ◽  
Middle Region ◽  
Collision Efficiency ◽  
Flow Rates

Red blood cell aggregation at low flow rates increases venous vascular resistance, but the process of aggregate formation in these vessels is not well understood. We previously reported that aggregate formation in postcapillary venules of the rat spinotrapezius muscle mainly occurs in a middle region between 15 and 30 μm downstream from the entrance. In light of the findings in that study, the main purpose of this study was to test two hypotheses by measuring collision frequency along the length of the venules during low flow. We tested the hypothesis that aggregation rarely occurs in the initial 15-μm region of the venule because collision frequency is very low. We found that collision frequency was lower than in other regions, but collision efficiency (the ratio of aggregate formation to collisions) was almost nil in this region, most likely because of entrance effects and time required for aggregation. Radial migration of red blood cells and Dextran 500 had no effect on collision frequency. We also tested the hypothesis that aggregation was reduced in the distal venule region because of the low aggregability of remaining nonaggregated cells. Our findings support this hypothesis, since a simple model based on the ratio of aggregatable to nonaggregatable red blood cells predicts the time course of collision efficiency in this region. Collision efficiency averaged 18% overall but varied from 0 to 52% and was highest in the middle region. We conclude that while collision frequency influences red blood cell aggregate formation in postcapillary venules, collision efficiency is more important.

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