Rheological Factors in Circulatory Disorders Tullio Di Perri, M.D., F.I.C.A.



Physiologic Aspects The rheology of circulation concerns the study blood flow in an expansible circulatory system. In every segment of the vascular tree, the pressure-flow relation is determined by the structural and functional characteristics of the cardiac and vascular system and by the flow properties of the blood. From a theoretical point of view, the flow properties of the blood in a tube are, according to the law of Hagen-Poiseuille, determined by the pressure gradient, the length of the tube, the radius of the tube, and the viscosity. This equation was originally developed to describe the flow of a fluid in a glass tube and is not completely applicable to arteries and veins. It must be considered, however, as the basis for an understanding of the regulation of the blood flow. According to this law, the flow of a fluid in a tube can be described by a parabolic velocity profile with a velocity gradient that decreases from the wall, where it reaches the maximal values, to the center, where it is zero. Among other determinant variables, the viscosity of the fluid plays an important role in regulating the flow rate, since the viscosity is dependent on the physicochemical characteristics of the fluid. According to the first definition of Newton, the viscosity of the fluid can be calculated by the ratio between shear stress and shear rate (shear stress = shearing force per unit area; shear rate velocity gradient). In the so-called Newtonian fluid, the viscosity is not dependent on the shear rate changes, whereas in the non-Newtonian fluid every change leads to a change of viscosity. The theoretical evaluation of the viscosity of a fluid is based on the measurement of both shear stress and shear rate: The value of the viscosity is calculated in vitro by the value of the shear stress obtained at a known shear rate in a closed system. Viscosity values obtained in vitro can be applied to the behavior of viscosity of the circulating fluid only when the fluid is Newtonian. The blood is a non-Newtonian fluid and its viscosity appears to be strictly dependent on the shear rate changes. The non-Newtonian nature of the blood is dependent on its physicochemical state, since blood is a suspension of cells in plasma. At rest the cells (mainly erythrocytes) form a continuous structure that breaks under its own weight. The resistance of the blood structure to the forces attempting to deform it is dependent on the viscosity. =

From the Istituto di Semeiotica Medica, School of Medicine,


University of Siena, Siena, Italy

481 The non-Newtonian properties of the blood-the pulsatility of the flow, the complex geometry of the arterial tree, and the distensibility of the wall-do not ensure the reliability of calculating whole blood flow according to Poiseuille’s equation.’ Moreover, the choice of the value of viscosity influences the calculation of the wall shear stress since the cell concentration along the transversal section of the vessel is not uniform-it drops off near the wall. However, the viscosity of the blood measured in vitro may be considered a variable of the flow properties even if it does not permit calculation of the flow equation for every vascular segment. The viscosity of the blood as measured in the conventional viscosimeter must be corrected for plasma viscosity, hematocrit, and temperature. Its value reflects the rheological potential of the blood,2 that is, the rheological potential of the cells suspensed in the plasma under varying flow forces. The blood viscosity is regulated by plasmatic and cellular factors.3-e The plasmatic factors change slowly and have been principally identified with serum and plasma proteins. The number and physicochemical properties of erythrocytes are the most important cellular factors which are considered to change rapidly. The hematocrit value appears to differ greatly in large and small vessels, as well as in the same vessel depending on the changes of the wall permeability. The physicochemical properties of the red blood cell regulate the internal viscosity, which is dependent on many factors. These factors are either metabolic (hemoglobin, ions) or structural (membrane proteins) and influence the flexibility of the membrane. The detection of a high blood viscosity in vitro does not reflect an actual abnormality of the flow: This potential property may become real under conditions of alterated hemodynamic.1I From the physiologic point of view, the viscosity of the blood, when primarily high, can negatively influence the flow in the small vessels. On the other hand an alteration of the peripheral blood flow in a region, leading to a decrease in flow, may produce several changes in the plasmatic and cellular factors of the blood followed by an increase of its viscosity. Such hyperviscosity seems to be principally due to the internal viscosity of erythrocytes, either because of some change in the haemoglobin content or because of an increased transport of calcium inside the cell. Both changes must be understood either as a cause or effect of a peripheral circulatory insufficiency which leads to a decrease of the flow in the small vessels.

Pathologic Aspects According to these considerations the blood hyperviscosity syndrome may be either primary-in which case syndrome is due to a primitive increase of the blood viscosity-or secondary-in which case the syndrome is marked by an increase of the blood viscosity which is not the cause but rather the consequence of the pathologic sequence.


Primary hyperviscosity syndromes are due to a primary alteration of some determinant variable of the blood viscosity: Hyperfibrinogenaemic conditions, macroglobulinic diseases, the polycythemias, and red blood cell diseases such as many hemolytic diseases are characterized by a constant increase of the blood viscosity, which in turn may be plasma-dependent or cell-dependent. The increased blood viscosity impairs flow in the small vessels by decreasing its velocity until the narrow capillaries are blocked. In these syndromes the causes of the blood hyperviscosity and the mechanisms of the peripheral vascular insufficiency appear easily identifiable in terms of cause and effect. The secondary hyperviscosity syndromes are apparently a mixture of clinical situations with a hypothetically common pathophysiologic background. A key to clarifying that the increase of blood viscosity is due to a secondary rather than a primary change of a determinant variable might be the instability and the possible rapid reversibility of the viscosity values. In several clinical situations characterized by either diffuse or regional circulatory insufficiency, the whole blood viscosity is increased over the normal values at all the shear rates tested. The blood viscosity is higher in the subject with acute circulatory impairment than in the subject with a chronic vascular disease. Moreover, in the acute state-cerebral or myocardial infarction-the viscosity of the blood is highest at the onset of the clinical changes, and the improvement of the ischemic disease is accompanied by a decrease in hyperviscosity. A hypothetical correlation between the regional circulatory imhalance and the changes in blood viscosity was then postulated. These changes were related neither to significant modifications of the plasmatic concentration of proteins and fibrinogen, nor to significant changes of hematocrit. The hypothesis arose that the internal viscosity of erythrocytes could play a role in these situations. Moreover, in our laboratory it has been shown that the exercise test leading to positive clinical and electrocardiographic signs in patients with coronary insufficiency, or to the appearance of intermittent claudication in patients with peripheral artery disease was accompanied by a significant increase of the blood viscosity, which returned to the starting values after the end of the circulatory strain.~7 These findings underlined the relationship between the circulatory impairment and the blood viscosity changes. Moreover, the possibility of inducing a increased blood viscosity in vascular patients by a controlled muscular exercise suggests that this exercise-dependent blood hyperviscosity may be a risk factor because of its ischemic fate. The problem of the mechanism leading to the increased blood viscosity in these pathologic conditions appears to be related to the knowledge of the site of production of this change. The presumption of a relationship between the ischemic disease and the hyperviscosity of the blood suggested that the behavior


viscosity of the regional blood should be studied in normal and ischemic subjects. In normal subjects the viscosity of the venous blood is scarcely higher than the viscosity of the arterial blood of the same vascular district. In patients with vascular disease the regional arteriovenous difference of the blood viscosity appears higher than in normal subjects when measured in the affected region.’ of the

Moreover, this difference increases after exercise.

opinion is that the changes of the blood viscosity in circulatory insufficiency might be due to an alteration of the blood flow in the microcirculatory tree. These observations suggested that the increased blood viscosity is generated in the postarterial vessels and probably in the microcirculatory tree. The increase of the viscosity might be due to circulatory alterations at this level: Thus the flow decrease and the secondary metabolic imbalance can be regarded Our

causal factors. The exercise-dependent changes in blood viscosity are more or less reversible since after a short delay after the end of the exercise, the value of the viscosity returns to the starting level. From the analytical point of view, the postexercise increase in viscosity was not correlated in a significant way to the increase in either the protein or the fibrinogen plasmatic concentration, or in the haematocrit. According to these findings the cause of the increased viscosity seems to be some changes in the red blood cells that lead to an increase of aggregability, or to a decrease of deformability. The increase of erythrocyte aggregability may influence the blood flow in the large vessels and thus produce some change in the laminar and radial movement of blood. The decreased deformability will change the blood flow in small vessels and in capillaries with an internal diameter less than the diameter of the erythrocytes. All these findings are rather puzzling, and the exact role of blood viscosity in regulating circulation either in normal or in pathologic conditions is not easy to rationalize in a general view. From a speculative point of view, on the basis of our actual knowledge, a hypothesis in this field can be summarized in the as

following points: 1. In chronic vascular diseases, an increase of the whole blood viscosity can be observed at rest. 2. In chronic vascular diseases the blood viscosity in the vein efferent from the affected vascular region is greater than that of the afferent artery, and this difference is significantly more pronounced than in normal controls.88 3. In chronic vascular diseases, but not in normal controls, physical exercise is followed by a marked increase in blood ViSCOSity.7 4. In acute vascular diseases (myocardial or cerebral infarction) a marked increase of blood viscosity is observed at the onset of the disease. The values of blood viscosity decline following clinical improvement.

484 These considerations suggest that in chronic and acute vascular disease the increase in blood viscosity is directly correlated to the development of regional ischemia. These findings seem to agree with Schmidt-Schbnbein’s theory on the role of blood viscosity, considered as a whole, in regulating blood flow.2 In normal conditions, the peripheral blood flow is mainly regulated by a metabolic mechanism: Ischemia induces the liberation of vasodilator mediators that act on the muscular cells of the distribution vessels by a rapid negative feedback. In organic vascular disease this metabolic pathway is generally insufficient to cancel ischemia, but in that case the persistence of a low flow is followed by an increase in the aggregability and by a decrease in the deformability of the red blood cells, and consequently by an increase in blood viscosity. A positive feedback leads to a progressive decrease in of the blood flow, which induces a progressive and self-maintaining deterioration mechanism of the microcirculation. The blood outflow of the ischemic region is characterized a marked hyperviscosity, which is diluted to lower values when the blood is mixed in bigger vessels. However, as a final point, the blood taken from the general circulation has a viscosity value higher than that of the control mean, but probably lower than that of the blood taken directly from the ischemic area. In conclusion, from the pathophysiologic point of view the increase of blood viscosity in vascular patients must be interpreted as a change due to the progression of ischemia, which is a result of the circulation imbalance. On the other hand it must be remembered that the blood hyperviscosity can be regarded as a determinant variable of a positive feedback which progressively lowers the circulation rate. Thus we can assign a double meaning to blood hyperviscosity in vascular disease. According to the first meaning, it is a sign of the impending ischemic sequence, and therefore it can be considered a &dquo;risk factor.&dquo; However, it does not increase the risk of developing vascular disease but of ischemia, since hyperviscosity is associated with the onset of the ischemic process. The second meaning concerns the role of blood hyperviscosity as a factor of a self-recruiting mechanism of the ischemia.

Pharmacotherapeutic Aspects In this sense the possibility of interfering with the biological processes involved in the development of this change must be considered. According to the pathophysiology of blood hyperviscosity in the ischemic disease, red blood cells seem to be the target of any treatment program, either in terms of aggregability or in terms of membrane deformability. Hematocrit can be lowered by hemodilution brought about by either an isotonic saline infusion or a low molecular weight dextran solution. The ischemia-dependent change of the red blood cell membrane can be theoretically influenced by any metabolic procedure which can in any way antagonize the excessive calcium transport inside the cell. In our laboratory several drugs with


activity on the membrane calcium movement have been tested for their effect on blood viscosity. In many patients with chronic vascular disease and a definite increase in blood viscosity, the activity of cinnarizine has been tested. This drug is known to improve the reduced blood flow both in experimental models and in human vascular disease. In all the vascular patients with a high level of blood viscosity, a single oral dose of 300 mg of cinnarizine was followed, after 6 hours, by a significant reduction of the blood viscosity. Moreover, after a week of treatment with 300 mg of cinnarizine daily, the level of the blood viscosity, which was very high before the treatment, returned to normal.’ The viscosity was lowered without any significant change in hematocrit or protein concentration, and this supported the hypothesis that viscosity is principally due to a modification of cellular deformability. In previous studies the activity of cinnarizine on vascular smooth muscle a


cells has been attributed to an inhibition of calcium channels of the fibrocell membrane itself.10 In our opinion a similar mechanism may be postulated for the drug action on erythrocytes, since an increase of intracellular calcium ions is believed to play a key role in many situations when the erythrocyte membrane loses flexibility and thus induces an increase in the viscosity of whole blood. The activity of cinnarzine to counteract the abnormal accumulation of calcium ions inside the cell can be regarded as the molecular level of its pharmacologic action, leading also to the decrease in blood hyperviscosity. These conclusions are essentially speculative, but they suggest a new approach to the pharmacology of ischemia, which can be antagonized not only by drugs acting on the vessel wall, but also by substances acting on the physicochemical properties of the blood. Tullio Di Perri, M.D., F.I.C.A. Instituto di Semeitica Medica University of Siena

Siena, Italy

R eferen ces 1.McDonald, D. A.: Blood flow in Arteries. Baltimore, Williams & Wilkins, 1974. 2. Schmidt-Schönbein, H.: Microrheology of erythrocytes, blood viscosity and the distribution of blood flow in the microcirculation, in International Review of Physiology. Cardiovascular Physiology II. Vol. 9. Edited by A. C. Guyton, A. W. Cowley. Baltimore, University Park Press, 1976, p. 1. 3. Dormandy, J. A.: Clinical significance of blood viscosity. Ann. R. Coll. Surg. Engl., 47, 211, 1970. 4. Chien, S.: The present study of blood rheology, in Hemodilution: Theoretical Basis

and Clinical Application. Edited by K. MessH. Schmidt-Schönbein. Basel-New mer, York, Karger, 1972. 5. Erhly, A. M.: Rheologically induced impairments of the muscular microcirculation: A new patho-physiological concept of intermittent claudication. Atti di Angiologia. Vol. I, Torino, Minerva Medica, 1974. 6. Dintenfass, L.: Blood Microrheology. Viscosity Factors in Blood Flow, Ischaemia and Thrombosis. London, Butterworths, 1976. 7. Di Perri, T., Forconi, S., Guerrini, M., et al.: Modificazioni della viscosita ematica sistemica in soggetti con vasculopatie croniche

486 distrettuali durante ischemia spontanea e provocata. Boll. Soc. Ital. Cardiol., (in press). 8. Forconi, S., Biasi, G., Guerrini, M., et al.: Arterial and venous blood viscosity in ischemic lower limbs of peripheral obliterative arterial disease patients. J. Cardiovasc. Surg.

(in press). Perri, T., Forconi, S., Guerrini, M.,

et al.: Action of cinnarizine on the hyperviscosity of blood in patients with peripheral obliterative

9. Di



Proc. R. Soc. Med., 70: 25-

28, 1977 (Suppl. 8). 10. Godfraind, T., Sturbois, X.: Inhibition by cinnarizine of heart ionic changes induced by isoprenaline, in Pathophysiology and Morphology of Myocardial Cell Alteration. Edited by A. Fleckenstein, G. Rona. MuenchenBerlin-Wien, Urban & Schwarzenberg, 1975, p. 127.

Rheological factors in circulatory disorders.

Rheological Factors in Circulatory Disorders Tullio Di Perri, M.D., F.I.C.A. SIENA, ITALY Physiologic Aspects The rheology of circulation concerns...
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