PubMed Health⌕ Search

Biomedical subjects

D Basmadjian

Publications and source records attributed to D Basmadjian.

14 recordsLinked to original sources
PubMed1997

Coagulation on biomaterials in flowing blood: some theoretical considerations.

Are truly inert biomaterials feasible? Recent mathematical models of coagulation which are reviewed here suggest that such materials are impossible. This conclusion, which is certainly consistent with our collective experimental evidence, arises from the calculation that conversion of Factor XI to XIa never drops to zero even at the highest flow rates and with virtually no Factor XIIa bound to a surface. Residual amounts of XIa are still formed which can in principle kick-off the coagulation cascade. Furthermore, if the flow rates and corresponding mass transfer coefficients are low and in spite of these near-vanishing levels of the initiating coagulants, the surprising result is that substantial amounts of thrombin are produced. On the contrary, under slightly higher flow conditions, there can be more substantial levels of initiating coagulants, yet paradoxically thrombin production is near zero. This article presents a theoretical understanding of the events which take place during the interaction of biomaterials with flowing blood. We follow these events from the time of first contact to the final production of thrombin. The effect of flow and surface activity on the contact phase reactions is examined in detail and the two are found to be intertwined. The common pathway is also examined and here the main feature is the existence of three flow dependent regions which produce either high or very low levels of thrombin, as well as multiple thrombin steady states. In a final analysis we link the two segments of the cascade and consider the events which result. In addition, we note that multiple steady states arise only in the presence of two (thrombin) feedback loops. Single loops or the bare cascade will produce only single steady states. With some imagination one can attribute to the feedback loops the role of providing the cascade with a mechanism to produce high thrombin levels in case of acute need (e.g. bleeding) or to allow levels to subside to 'stand-by' when there is no need for clotting. We present this as a partial answer to the question: Why is the coagulation cascade so complex and what is the importance of the feedback loops?

Biocompatible Materials↗
PubMed1990

The effect of flow and mass transport in thrombogenesis.

The paper presents a mathematical analysis of the contributions of flow and mass transport to a single reactive event at a blood vessel wall. The intent is to prepare the ground for a comprehensive study of the intertwining of these contributions with the reaction network of the coagulation cascade. We show that in all vessels with local mural activity, or in "large" vessels (d greater than 0.1 mm) with global reactivity, events at the tubular wall can be rigorously described by algebraic equations under steady conditions, or by ordinary differential forms (ODEs) during transient conditions. This opens up important ways for analyzing the combined roles of flow, transport, and coagulation reactions in thrombosis, a task hitherto considered to be completely intractable. We report extensively on the dependence of transport coefficient kL and mural coagulant concentration Cw on flow, vessel geometry, and reaction kinetics. It is shown that for protein transport, kL varies only weakly with shear rate gamma in large vessels, and not at all in the smaller tubes (d less than 10(-2) mm). For a typical protein, kL approximately 10(-3) cm s-1 within a factor of 3 in most geometries, irrespective of the mural reaction kinetics. Significant reductions in kL (1/10-1/1,000) leading to high-coagulant accumulation are seen mainly in stagnant zones vicinal to abrupt expansions and in small elliptical tubules. This is in accord with known physical observations. More unexpected are the dramatic increases in accumulation which can come about through the intervention of an autocatalytic reaction step, with Cw rising sharply toward infinity as the ratio of reaction to transport coefficient approaches unity. Such self-catalyzed reactions have the ability to act as powerful amplifiers of an otherwise modest influence of flow and transport on coagulant concentration. The paper considers as well the effect on mass transport of transient conditions occasioned by coagulation initiation or pulsatile flow. During initiation, instantaneous flux varies with diffusivity and bulk concentration, favouring the early adsorption/consumption of proteins with the highest abundance and mobility. This is akin to the 'Vroman effect' seen in narrow, stagnant spaces. The effect of flow pulsatility on kL has the potential, after prolonged cycling, of bringing about segregation or accumulation of proteins, with consequences for the coagulation process.

Biomechanical Phenomena↗
PubMed1989

Embolization: critical thrombus height, shear rates, and pulsatility. Patency of blood vessels.

The present article builds on elementary fluid dynamics and previous analyses by the author to delineate approximate boundaries of mural thrombus height Hp, maximum shear rate gamma Max, and flow pulsatility beyond which thrombi are subject to either very high or very low probabilities of embolization. A thrombus height of approximately 0.1 mm emerges as a critical dividing line: Below it, the maximum embolizing shear stress tau s is independent of thrombus height and varies only linearly with shear rate. Above it, tau s quickly approaches a strong quadratic dependence on both thrombus height and shear rate: tau s approximately (Hp gamma)2, significantly increasing the likelihood of an embolizing event. By contrast, convective-diffusive removal of blood components during the initial stages of thrombus formation varies only weakly with gamma 1/3 in all but the smallest vessels. These maximum embolizing stresses are due principally to fluid drag. Acceleration (pulsatile) forces only begin to make their presence felt at gamma less than 500 s-1 and reach parity with fluid drag at gamma approximately 10 s-1, i.e., at a level where the presence of pulsatility is questionable. The results are used to provide maps of domains with high and low probabilities of an embolytic event and of vessel patency. The maps reveal that relatively modest changes in shear rate and/or vessel lumen can cause shifts from high to low likelihood of vessel patency, opening up possible ways of controlling blockage by manipulation of these variables.

Heart Diseases↗
PubMed1986

The hemodynamic and embolizing forces acting on thrombi--II. The effect of pulsatile blood flow.

A previous analysis (Basmadjian, J. Biomechanics 17, 287-298, 1984) of the embolizing forces acting on thrombi in steady Poiseuille flow has been extended to pulsatile blood flow conditions in the major blood vessels. We show that for incipient and small compact thrombi up to 0.1 mm height, the maximum embolizing stresses can be calculated from the corresponding 'quasi-steady' viscous drag forces and measured maximum wall shear. Their magnitude is from 5 to 30 times (tau w)Max, the maximum wall shear stress during the cardiac cycle in the absence of thrombi. For larger thrombi, inertial and 'history' effects have to be taken into account, leading to embolizing stresses in excess of 100 Pa (1000 dyn cm-2).

Blood Circulation↗
PubMed1984

The hemodynamic forces acting on thrombi, from incipient attachment of single cells to maturity and embolization.

We consider the steady fluid forces acting on a thrombus from the time of first contact of a single cell with a natural or artificial surface, through the attachment process and growth to embolization. For a hemi-spherical or cylindrical attached cell of height less than 1/100-1/20th of the channel width, shear and tensile stresses are solely dependent on viscosity and on the ratio of average fluid velocity to channel width vt/Dt (shear rate). Large values of this ratio reduce adhesion and increase embolization. The average shear stress on such cells is approximately 1-10 Pa (10-100 dyn cm2), the average tensile stress about three times higher. For other shapes and larger protrusions, stress varies with protrusion height as well. Maturing thrombi composed of cell aggregates embedded in a fibrin mesh do not appear to allow significant fluid flow through their porous structure. The interior forces are then due solely to hydrostatic pressure and initially vary directly with vt/Dt and inversely with thrombus height Hp, thus favouring embolization at an early stage and in arterial systems. Rough surfaces are identified as causing an increase in dwell-time and possibly immobilizing an unattached cell due to 'negative lift'.

Blood Viscosity↗
PubMed1983

Relationship between release rate and surface concentration for heparinized materials.

Mathematical models are used to predict surface concentrations that result from the release of heparin into flowing blood and stagnant or well-mixed plasma. Two release rates--4 X 10(-2) and 3 X 10(-5) micrograms/cm2 min--are considered, which describe elution from an ionically heparinized material and from an immobilized heparin-PVA hydrogel, respectively. When heparin is released at the higher rate into blood flowing in cylindrical tubes with dimensions characteristic of the vasculature, or annular tubes representative of catheter experiments, a minimum surface concentration of 0.5 micrograms/mL is attained virtually at the tube inlet. Release at the lower rate requires tube lengths of several thousand meters to attain the same critical value. Similarly, heparin released from a suspension of beads at the higher rate leads to critical surface concentrations of 0.2 micrograms/mL within a fraction of a second in stagnant plasma, or ca. 5 s in a well-mixed environment. At the lower release rate, 45 or 100 min must elapse before the same level is achieved. These results support the validity of 4 X 10(-2) micrograms/cm2 min as a reasonable minimum release rate to produce a heparin microenvironment sufficient to prevent thrombosis. The lower rate is shown to be insufficient to generate a critical concentration, thus supporting the argument that heparin-PVA does not owe its biological activity to a heparin microenvironment. The model equations can be applied to the release of any material to determine surface concentrations.

Blood Coagulation↗
PubMed1980

Flow through brushborders and similar protuberant wall structures.

Longitudinal flow through channels with protuberant wall structures such as brushborders were studied both experimentally and theoretically. The experiments were performed using tubes with synthetic internal brushborders, scaled to resemble the geometry and flow in proximal tubules of the kidney. Fractional flow rates in the brushborder were deduced from transit times of dye traces through the central core and total flow rate. The measured ratios of brushborder to core flow QB/QC were found to be independent of Reynolds number over the range Re = 0.01 - 0.2. They agreed reasonably well with theoretical predictions based on the Kozeny-Carman equation for flow through arrays of parallel cylinders. The predictions can be extended to arbitrary geometries and turbulent flow conditions by appropriate modifications. Extrapolation of the results to the proximal tubule of the kidney indicate that brushborder flowrates there vary from 0.003 to 0.09% of total flow. Any axial transport in these structures would be predominantly diffusive in nature, and would be highly unlikely to affect radial brushborder gradients and transmural flux.

Animals↗
PubMed1979

Computer simulation of flow-dependent absorption in microperfused short Henle's loop of rats.

With computer simulation we examined the extent to which current theories and experimental data explain function of single microperfused superficial Henle's loops in rats. In the model standard phenomenological equations describe transport; two sets of transport parameters labeled rat and rabbit were taken from published experiments; Michaelis-Menten kinetics in the ascending thick limb were adjusted arbitrarily; tubular radius is either constant or depends on luminal pressure with compliance based on experimental observations; the interstitium is an infinite sink with salt and urea concentrations constant in the cortex and exponentially increasing in the outer medulla; concentrations resemble those found in hydropenic or saline diuretic rats. The following predictions were obtained. The model with rabbit parameters does not recirculate urea and will not operate with high medullary urea concentrations; with rat parameters too much urea recirculates an the results of perfusion with equilibrium solution are not reproduced. Using a compromise between rat and rabbit parameters, the model reproduces water absorption, salt reabsorption, and urea recirculation as observed in vivo in rat loops perfused at 5-40 nl/min. It also simulates perfusion with saline, equilibrium solution, saline plus furosemide, and 300 mM mannitol. When the model includes a short early distal segment, effluent salt concentration reaches a minimum at a 15 nl/min perfusion rate as observed in vivo; however, concentration at the macula densa is a monotonically increasing function of flow. When permeation rate is a function of wall surface area and thickness a better fit to experimental results is produced. However, the effect is small: water absorption alters by 4% or less and effluent salt concentration is reduced by up to 10% at low perfusion rates. Comparison of rigid and compliant loops shows no relationship between transit time per se and reabsorption.

Animals↗
PubMed1979

Effects of lumen volume transit time and pressure on loop of Henle function.

Experiments on Henle's loops were designed to demonstrate the relationships of absorption to distal pressure, transit time, and luminal diameter. Loops of superficial nephrons in hydropenic rats, isolated from the rest of the nephron by oil or solid paraffin blocks, were microperfused at 13.6--20 nl/min. Two samples of fluid were collected from the early distal tubule--one with suction in order to lower distal pressure and reduce luminal volume, the other without suction so that the lumen was distended. Transit times were 30 +/- 2 s without and 19 +/- 2 s with suction. Proximal tubule pressure and perfusion rate were not altered by collection with suction. Absolute absorption, however, descreased from 10.6 +/- 0.4 to 8.4 +/- 0.4 nl/min (P less than 0.001). When salt transport was inhibited by 10(-4) M furosemide in the perfusate, water absorption was 7.8 +/- 0.7 nl/min without suction and 6.1 +/- 0.8 nl/min with suction (P less than 0.01). Computer simulation of Henle's loop shows that these observations cannot be explained by changes in transit time, hydrostatic pressure, or unstirred layers. The observations are simulated when radial fluxes depend on wall thickness and surface area in the descending thin limb.

Animals↗
PubMed1978

Examination of transport equations pertaining to permeable elastic tubules such as Henle's loop.

The transport equations applicable to loops of Henle and similar elastic permeable tubules were re-examined to assess the effect of radial transport resistance in the lumen and tubule geometry on solute transport. Active transport at the wall as well as external gradients equivalent to a 2--1,000-fold concentration increase per centimeter of distance were considered. Wall permeabilities and active transport constants were varied up to 2 . 10(-2) cm/s. It is shown that for conditions applicable to the loop of Henle, resistance to radial solute transfer in the lumen is negligible, both for passive and active transmural transport with concomitant water flux, and that axial dispersion further reduces that resistance. These conclusions apply equally to conical and elliptical geometries likely to arise in loop operation. The validity of Poiseuille's equation for these geometries is discussed. Ii is concluded that the one-dimensional transport equations are a valid representation of loop operation.

Biological Transport, Active↗
PubMedDate not supplied

A model of thrombin inactivation in heparinized and nonheparinized tubes with consequences for thrombus formation.

The role of flow and mass transport in determining procoagulant concentration at the wall of synthetic and natural cylindrical blood vessels is analyzed theoretically. The model assumes steady laminar flow and considers, in addition to the fluid dynamic parameters, three rate-determining steps: production of procoagulant (thrombin) and its inactivation at the wall, as well as inactivation in the fluid bulk. The ratio of thrombin wall concentration to production rate Cw/N emerges as a critical parameter in characterizing the behavior of the tube wall. With a wall-inactivation rate typical of heparinized materials, Cw/N = 11.1 s/cm, independent of flow (shear rate) and axial position. This is significantly less than the range of Cw/N (50-500 s/cm) for which the thrombin concentration is high enough to result in significant fibrin formation and thrombosis. Hence little fibrin formation and a high degree of thromboresistance is expected for heparinized materials. Nonheparinized materials have Cw/N values above this range, which are only weakly dependent on shear rate and diameter, suggesting that flow-induced dispersion of thrombin (or other procoagulants) has limited impact on the thrombin wall concentration. These latter results appear to refute the conventional wisdom that attributes the relative patency of large-diameter vessels and differences between venous and arterial thrombi to such flow effects. It is likely that additional factors such as flow pulsatility and wall geometry must be considered to account for these observations.

Blood Coagulation↗
PubMedDate not supplied

A mathematical model of thrombin production in blood coagulation, Part I: The sparsely covered membrane case.

This paper presents the first attempt to model the blood coagulation reactions in flowing blood. The model focuses on the common pathway and includes activation of factor X and prothrombin, including feedback activation of cofactors VIII and V by thrombin, and plasma inhibition of factor Xa and thrombin. In this paper, the first of two, the sparsely covered membrane (SCM) case is presented. This considers the limiting situation where platelet membrane binding sites are in excess, such that no membrane saturation or binding competition occurs. Under these conditions, the model predicts that the two positive feedback loops lead to multiple steady-state behavior in the range of intermediate mass transfer rates. It will be shown that this results in three parameter regions exhibiting very different thrombin production patterns. The model predicts the effect of flow on steady-state and dynamic thrombin production and attempts to explain the difference between venous and arterial thrombi. The reliance of thrombin production on precursor procoagulant protein concentrations is also assessed.

Binding Sites↗
PubMedDate not supplied

An analysis of the contact phase of blood coagulation: effects of shear rate and surface are intertwined.

This work analyzes, for the first time, the combined role of blood flow, protein transport and the reaction network of the contact phase up to the "common pathway" of the blood coagulation cascade. The model is comprised of a set of 20 dominant reactions with 11 components. Systems of ODEs reducible to 4 coupled equations describe rigorously the dynamic behavior, while systems of algebraic equations, reducible to a single polynomial equation, model the steady state concentrations of the coagulants. The analysis showed that there is never more than one stable steady state. This is in contrast to the analysis of common pathway that gives rise to multiple concentration states. It also revealed a general robustness of the system to changes in procoagulant concentrations, inhibition rates and most activation rate constants. The system is largely impervious to the level of activated Factor XII, given that a trace (non-zero) level is present. In contrast, the system displays a dual response to flow and surface activity: A change in either of these factors alone can promote, have no effect on, or (in the case of flow) impede the progress of coagulation, depending on the value of the other factor. Their effects must therefore be examined in unison. These results may help resolve contradictory findings attributed to one or the other factor alone.

Blood Coagulation↗