The history of the theory of the circulation of the blood.

An obvious candidate for the seminal event in the history of haemorheology is Harvey's presentation of the concept of the circulation of the blood. Prior to this, the ideas concerning the movement of blood were based, in Europe and Middle East, largely on the principles laid down by Galen, and these had been, in effect, dogma for nearly a millennium and a half. These principles were basically that blood is formed in the liver, thence it travels to the bodily organs and is consumed -hence there is one-way flow and no circulation of the blood at all. Harvey's revolutionary idea that blood circulates repeatedly around the cardiovascular system laid the foundation for haemorheology because once that idea was accepted then the fluidity of the blood immediately became potentially of crucial importance - and haemorheology was conceived. In this paper the ideas that preceded Harvey will be presented, i.e. those of Galen, Ibn al-Nafis, Vesalius, Fabricius and Colombo etc. Harvey's awareness of this background, due mainly to time spent in Padua, triggered his many experimental investigations and discoveries. Ultimately, these led to his astonishing insights published in De Mortu Cordis in 1628 which changed the understanding of the cardio-vascular system forever.

RBC aggregation: laboratory data and models.

The reversible aggregation of red blood cells (RBC) into linear and three-dimensional structures continues to be of basic science and clinical interest: RBC aggregation affects low shear blood viscosity and microvascular flow dynamics, and can be markedly enhanced in several clinical states. Until fairly recently, most research efforts were focused on relations between suspending medium composition (i.e., protein levels, polymer type and concentration) and aggregate formation. However, there is now an increasing amount of experimental evidence indicating that RBC cellular properties can markedly affect aggregation, with the term "RBC aggregability" coined to describe the cell's intrinsic tendency to aggregate. Variations of aggregability can be large, with some changes of aggregation substantially greater than those resulting from pathologic states. The present review provides a brief overview of this topic, and includes such areas as donor-to-donor variations, polymer-plasma correlations, effects of RBC age, effects of enzymatic treatment, and current developments related to the mechanisms involved in RBC aggregation.

Influence of cell-specific factors on red blood cell aggregation.

The reversible aggregation of red blood cells (RBC) into linear and three-dimensional structures continues to be of basic science and clinical interest: RBC aggregation affects low shear blood viscosity and microvascular flow dynamics, and can be markedly enhanced in several clinical states. Until fairly recently, most research efforts were focused on relations between suspending medium composition (i.e., protein levels, polymer type and concentration) and aggregate formation. However, there is now an increasing amount of experimental evidence indicating that RBC cellular properties can markedly affect aggregation, with the term "RBC aggregability" coined to describe the cell's intrinsic tendency to aggregate. Variations of aggregability can be large, with some changes of aggregation substantially greater than those resulting from pathologic states. The present review provides a brief overview of this topic, and includes such areas as donor-to-donor variations, polymer-plasma correlations, effects of RBC age, effects of enzymatic treatment, and current developments related to the mechanisms involved in RBC aggregation.

Haemorheological adaptation during pregnancy in a Latin American population.

OBJECTIVE: To investigate haemorheological changes during pregnancy in a Latin American population and compare to previously published data from Caucasian populations. DESIGN: Cross-sectional study. POPULATION: 75 pregnant women at 10-36 wk of gestation and 17 non-pregnant female controls in Lima, Peru. All the women and their ancestors for three generations were born and lived at sea level. METHODS: Viscosity, haematocrit and plasma fibrinogen, albumin and total protein concentrations were determined in blood samples obtained after an overnight period of fasting. RESULTS: At 10 wk of gestation, total protein concentration and plasma viscosity were above non-pregnant levels by about 15% and subsequently decreased linearly with gestation. Fibrinogen concentration was increased in the first trimester; it then decreased to a nadir at about 20 wk and subsequently increased. Albumin concentration decreased linearly with gestation. Haematocrit decreased from pre-pregnancy levels at 10 wk to a nadir at about 26 wk. Blood viscosity increased in the first trimester and then decreased with gestation to a nadir at about 26 wk. CONCLUSION: In the first trimester of pregnancy blood and plasma viscosity are increased and they subsequently fall with advancing gestation. Plasma viscosity reflects the changes in total protein concentration, and blood viscosity is dependent on the interplay of changes in plasma viscosity and haematocrit.

Pilot study of treatment with whole body hypothermia for neonatal encephalopathy.

BACKGROUND: There is extensive experimental evidence to support the investigation of treatment with mild hypothermia after birth asphyxia. However, clinical studies have been delayed by the difficulty in predicting long-term outcome very soon after birth and by concern about adverse effects of hypothermia. OBJECTIVES: The objectives of this study were to determine whether it is feasible to select infants with a bad neurological prognosis and to begin hypothermic therapy within 6 hours of birth, and to observe the effect of this therapy on relevant physiologic variables. METHODS: Sixteen newborn infants with clinical features of birth asphyxia (median cord blood pH: 6.74; range: 6.58-7.08) were assessed by amplitude integrated electroencephalography (aEEG), and mild whole body hypothermia was instituted within 6 hours of birth in the 10 infants with an aEEG prognostic of a bad outcome. Rectal temperature was maintained at 33.2 +/- (standard deviation).6 degrees C for 48 hours. Rectal and tympanic membrane temperature, blood pressure, heart rate, blood gases, blood lactate, full blood count, blood electrolytes, high and low shear rate viscosity, and coagulation studies were monitored during and after cooling. A preliminary assessment of neurological outcome was made by repeated magnetic resonance imaging (MRI) and neurological examination. RESULTS: All infants selected to receive hypothermia developed convulsions and a severe encephalopathy. During 48 hours of hypothermia infants had prolonged metabolic acidosis (median pH: 7.30; base excess: -6.3 mmol x L(-1), a high blood lactate (median lactate: 5.3 mmol x L(-1)) and low blood potassium levels (median value: 3.9 mmol x L(-1)) x Hypothermia was associated with lower heart rate and higher mean blood pressure. However, these changes did not seem to be clinically relevant and no significant complication of hypothermia was encountered. Blood viscosity and coagulation studies were similar during and after cooling. Unusual MRI findings were noted in 3 infants: transverse sinus thrombosis with subsequent small cerebellar infarct; probable thrombosis in the straight sinus; and hemorrhagic cerebral infarction. Six of the 10 cooled infants had minor abnormalities only or normal follow-up neurological examination; 3 infants died and 1 had major abnormalities. None of the 6 infants with a normal aEEG developed severe neonatal encephalopathy or neurological sequel. CONCLUSIONS: After birth asphyxia infants can be objectively selected by aEEG and hypothermia started within 6 hours of birth in infants at high risk of developing severe neonatal encephalopathy. Prolonged mild hypothermia to 33 degrees C to 34 degrees C is associated with minor physiologic abnormalities. Further studies of both the safety and efficacy of mild hypothermia, including further neuroimaging studies, are warranted.

Comparison of haemorrheological parameters and blood pressure in various breeds of dog.

Relationships between blood pressure and haemorrheological factors were examined in three groups of dogs characterised by different levels of blood pressure. The groups used were sight hounds (high pressure), retrievers (low pressure) and a mixed group with intermediate pressure. The three groups had different levels of haematocrit and blood viscosity at both high and low shear rates, with the sight hounds showing the highest and retrievers showing the lowest levels for each of the parameters. The plasma viscosities did not differ significantly between the groups. Blood pressure and blood viscosity or haematocrit were not correlated within dog groups, but when the dog groups were considered together, significant positive correlations existed between pressure and viscosity and pressure and haematocrit.

Haemorheological disturbances in hypertension: the influence of diabetes and smoking.

Patients suffering from diabetes or hypertension commonly exhibit increased blood viscosity compared with healthy controls. This is primarily the result of elevated plasma fibrinogen concentration. Cigarette smokers also exhibit raised blood viscosity but in their case the main cause is a raised haematocrit. In this paper the effects of concurrent hypertension, diabetes and cigarette smoking on blood viscosity is reviewed. Evidence is presented that the haemorheological disturbances associated with each of these modalities are additive when present together in a subject.

Haemorheology and the inflammatory process.

Many forms of tissue injury, whether due to physical or infectious sources, lead to the inflammatory response. During its course a wide variety of events takes place, including alterations in vascular contraction, in vascular permeability, in leucocyte activity and the initiation of the acute phase response. The last results in a leucocytosis and changes in the concentrations of a number of plasma proteins, including fibrinogen. They all cause alterations in haemodynamics, due in part to alteration in geometric resistance, but also to alterations in viscometric resistance as a result of changes in the haemorheological properties of the blood components locally and systemically. While some of these inflammation-induced changes are useful on a local level and assist in the resolution of the damaging factor and in tissue repair, the systemic haemorheological effects may lead to deleterious haemodynamics. Many of the effects are well documented but two new possibilities arise. One is the potential effects of fibrinogen heterogeneity on blood rheology, and the other the possible effects of leucocyte protease release on the aggregability of the red cell.

A comparative study of the haemorheology of various breeds of dog.

Haemorheological parameters in nine breeds of dog were examined. Whole blood viscosity at both high and low shear rates differed significantly between the breeds with a 50% difference between the highest and lowest viscosity at high shear rate and a 140% difference at low shear rate. Athletic breeds (Greyhounds, Deerhounds) had the highest whole blood viscosities. Differences in viscosity correlated well with differences in haematocrit between breeds. When the blood samples were adjusted to a standard haematocrit (45%), there were no significant differences in viscosity. This implied that other rheological factors such as cellular deformability and plasma viscosity did not vary significantly between breeds, and direct measurement showed this to be the case.

Effects of components of meals (carbohydrate, fat, protein) in causing postprandial exertional angina pectoris.

We have shown that unlike fat, protein, xylose, or water, the carbohydrate component of the meal accelerates myocardial ischemia, reduces exercise capacity, and is associated with a more rapid increase in the determinants of myocardial oxygen consumption than exercise in the fasting state. Our results suggest a role for a larger increase in sympathetic nervous activity and/or release of vasoactive gastrointestinal peptides after carbohydrate, but not fat or protein, meals in postprandial angina.

A novel instrument for studying the flow behaviour of erythrocytes through microchannels simulating human blood capillaries.

A novel instrument has been developed to study the microrheology of erythrocytes as they flow through channels of dimensions similar to human blood capillaries. The channels are produced in silicon substrates using microengineering technology. Accurately defined, physiological driving pressures and temperatures are employed whilst precise, real-time image processing allows individual cells to be monitored continuously during their transit. The instrument characterises each cell in a sample of ca. 1000 in terms of its volume and flow velocity profile during its transit through a channel. The unique representation of the data in volume/velocity space provides new insight into the microrheological behaviour of blood. The image processing and subsequent data analysis enable the system to reject anomalous events such as multiple cell transits, thereby ensuring integrity of the resulting data. By employing an array of microfluidic flow channels we can integrate a number of different but precise and highly reproducible channel sizes and geometries within one array, thereby allowing multiple, concurrent isobaric measurements on one sample. As an illustration of the performance of the system, volume/velocity data sets recorded in a microfluidic device incorporating multiple channels of 100 microns length and individual widths ranging between 3.0 and 4.0 microns are presented.

Flash freezing of erythrocyte suspensions.

Freezing whole blood in bulk usually results in severe cellular destruction through the action of ice crystals and osmotic effects in the freezing liquid. The potential of flash freezing blood aerosols onto a liquid nitrogen surface as a means of inhibiting cellular damage was studied in this work. Three commercial spraying devices were employed to spray-freeze either whole blood or concentrated erythrocyte suspensions, using hydroxyethyl starch (HES) as a cryoprotectant. The integrity and viability of the processed cells were assessed by measuring gross rheological properties and the extent of hemolysis. Cells were found to be susceptible to the very high shear stresses imposed by some of the spraying devices. Bulk freezing of blood, even in the presence of cryoprotectant, resulted in complete cellular destruction. Whereas flash freezing was capable of substantially reducing the level of hemolysis to 12.6% and preserving the cellular deformability.

Nicotinamide and pentoxifylline increase human leucocyte filterability: a possible mechanism for reduction of acute hypoxia.

Transient plugging of microcapillaries by leucocytes is a possible reason for the occurrence of acute hypoxia in tumours. We compared the abilities of nicotinamide at 1000 micrograms ml-1 and 150 micrograms ml-1 and pentoxifylline at 300 micrograms ml-1 to increase the filterability of normal and artificially activated human leucocytes through 8 microns pores, as a model for the capillary bed. Using a St George's filtrometer, filterability of treated leucocyte suspensions was compared with control for three to six sequential 60 microliters samples, normalising control values to unity. Pentoxifylline at 300 micrograms ml-1 halved the ratio of treated to control value to 0.47 +/- 0.13 (2 s.e.), P = 0.001 (i.e. an increase in filterability), and nicotinamide at 1000 micrograms ml-1 reduced it to 0.69 +/- 0.22, P = 0.04, but the clinically achievable 150 micrograms ml-1 was ineffective (0.82 +/- 0.25, P = 0.24). Filterability of artificially activated leucocytes was reduced (3.9 +/- 1.20) but was restored to control values of unity by 1000 micrograms ml-1 nicotinamide and 300 micrograms ml-1 pentoxifylline and partially restored by 150 micrograms ml-1 nicotinamide (1.2 mM), which was isoeffective with 100 micrograms ml-1 pentoxifylline (0.37 mM). Pentoxifylline is therefore more effective on a molar basis and was shown to affect both polymorphonuclear leucocytes and lymphocytes, while nicotinamide only affects lymphocytes. The data are consistent with the hypothesis that both agents modify acute hypoxia by increasing leucocyte filterability.

Changes in hemorheology with fetal intravascular transfusion.

OBJECTIVE: Our aim was to determine the changes in fetal hemorheologic parameters caused by fetal intravascular transfusion for alloimmune anemia. STUDY DESIGN: Fetal blood samples were collected before and after 95 fetal transfusions in 31 women. Fetal hematocrit, whole-blood viscosity at a variety of shear rates, plasma viscosity, fetal fibrinogen, and fetal plasma proteins were measured. RESULTS: Fetal whole-blood viscosity increased, sometimes massively, with transfusion. The rise in viscosity was principally dependent on the rise in hematocrit, with a linear rise in hematocrit producing a linear rise in the logarithm of whole-blood viscosity, but was also affected by the amount of adult plasma proteins present in the donor blood. CONCLUSIONS: Rises in fetal whole-blood viscosity during transfusion can be minimized by using donor blood that has been serum depleted to a high hematocrit (> 90%) and by restricting the end hematocrit to 50% to 55%.

The variation with gestational age of the rheological properties of the blood of the new-born.

A study has been made of the variation of blood viscosity and related factors with the gestational age of neonates from 24 weeks to normal term. Viscosity increases significantly over this period by 36% at high shear rate (128.5 s-1) and 250% at low shear (0.277 s-1). The high shear rate changes can be explained largely by the effects of variations in haematocrit and plasma viscosity. At low shear rate the same factors are involved together with changes in the plasma protein composition, in particular the age-related increase in the concentration of the proteins known to induce rouleaux formation. The variation in the degree of sialination of fibrinogen with gestational age may also play a part.

Contrast media-induced effects on blood rheology and their importance in angiography.

Factors which alter blood viscosity may have important consequences during angiography. The differential effects of various concentrations of five different radiocontrast media on the viscosity characteristics of erythrocyte-plasma suspensions were made over a range of applied shear rates. The results showed that, at both high and low shear rates, the rate of change of viscosity with contrast concentration differs markedly between the various types of contrast media. The conventional ionic monomers caused most disturbance to blood viscosity. The monoionic dimer hexabrix was least disturbing to the viscometric characteristics of blood, and the newer non-ionic monomers were intermediate in their effects. Significant effects on blood viscosity may be caused by radiocontrast agents during a number of in vivo angiographic situations, in particular: early after contrast bolus injection into large vessels, in the microcirculation after selective injections, and during angioplasty procedures.

Decrease in erythrocyte glycophorin sialic acid content is associated with increased erythrocyte aggregation in human diabetes.

1. Sialic acid moieties of erythrocyte membrane glycoproteins are the principal determinants of the negative charge on the cell surface. The resultant electrostatic repulsion between the cells reduces erythrocyte aggregation and hence the low shear rate viscosity and yield stress of blood. 2. Using g.c.-m.s., a decrease in sialic acid content has been observed in the major erythrocyte membrane glycoprotein, glycophorin A, obtained from nine diabetic patients compared with that from seven normal control subjects [median (range): 3.30 (0.01-11.90) versus 18.60 (3.20-32.60) micrograms/100 micrograms of protein, P less than 0.02]. 3. Erythrocyte aggregation, measured by viscometry as the ratio of suspension viscosity to supernatant viscosity (LS/S) in fibrinogen solution, was increased in ten diabetic patients compared with ten normal control subjects (mean +/- SEM, 37.6 +/- 1.3 versus 33.8 +/- 0.6, P less than 0.02). 4. In the patients in whom both viscometry and carbohydrate analysis were performed, the decrease in erythrocyte glycophorin sialylation and the increase in erythrocyte aggregation in fibrinogen solution were related statistically (LS/S correlated negatively with glycophorin sialic acid content, r = 0.73, P less than 0.05). 5. Decreased glycophorin sialylation provides an explanation at the molecular level for increased erythrocyte aggregation and it may be important in the pathogenesis of vascular disease in diabetes.