113
faster flow-rates the viscosity in both is about 4-8 cP. The variation of blood viscosity with shear-rate is believed to be due to the flexibility of the red blood-cells and aggregation. When erythrocytes are hardened with acetaldehyde and inflexible, the blood viscosity is higher-approximately 10 cPbut invariant with flow-rate and newtonian.11 With normal flexible cells the viscosity is higher at slow flow-rates owing to the energy utilised in flexing the cells and breaking the weak interactive force forming rouleaux.Fibrinogen is often said to bind the cells together, because more rouleaux are formed with increasing plasma-fibrinogen concentration. Rouleaux do not form, however, with inflexible erythrocytes, even at elevated fibrinogen concentrations. RAMPLING and SIRS 12 have suggested that fibrinogen acts by increasing the flexibility of normal cells. The main factors which affect blood viscosity are flow-rate, the hæmatocrit, plasma protein and fibrinogen concentrations, erythrocyte flexibility, and vessel bore. The vessel-bore effect occurs in tubes of less than 1 mm. diameter, the viscosity steadily falling with decreasing bore-the so-called Fahraeus-Lindquist effect. There are two explanations of this phenomenon. One is that the layer nearest the vessel wall contains fewer cells than are in the bulk of the blood and the lower viscosity of this layer becomes more significant as the vessel diameter decreases. The second, as was stated by Dix and SCOTT-BLAIR 13 for colloidal suspensions, is that the cells in small tubes represent a series of discrete velocity steps, the sigma effect, and the representation of the velocity profile as a continuous curve is no longer valid. Finally, at the capillary level the viscosity is only about 30% greater than that of plasma, with normal flexible erythrocytes in tubes of 4 to 15 um. When the erythrocytes are inflexible, as in sickle-cell blood with lowered Po2, they can no longer be distorted and squeezed through the smaller vessels. Attempts at a theoretical analysis of this situation 14-16 do not accord with the experimental data. 17-19 In particular, the relative viscosity under these conditions is almost independent of the haematocrit up to values of 80%.
controls;
Hæmorheology, Blood-flow, and Venous Thrombosis THE incidence of venous thrombosis is evidently increased by stasis and reduced blood-flow. 1,2 Flowrate is often assumed to be directly determined by the
viscosity of whole blood; but prolonged stasis may under normal conditions without the formation of thrombi,3,4 and viscosity is only one of several elements that influence blood-flow. At present there is no single index of flow for different parts of the circulation. Blood-flow depends primarily on the work done by the heart. This work is converted into fluid motion as kinetic and potential energy (termed inertial flow) and frictional losses (termed viscous flow). In general, inertial factors predominate with flow in large vessels such as the aorta, and viscous factors in small vessels such as capillaries. In large arteries the flow is complicated by its pulsatile nature and the elastic properties of the vessel walls.5 The influence of bends on the nature of blood-flow is still little understood. With a straight vessel, solutes are dispersed across the cross-section by diffusion except in the region adjacent to the vessel wall.6 With curved tubes the conservation of angular momentum shifts the axis of flow towards the outside of the bend and produces rotational secondary flow and some mixing over the cross-section, as in the flow of a river round a bend.7,8 No analysis of this situation fully explains the experimental data.9,10 At bifurcations the situation is even more complicated with additional cross-sectional secondary flows and suboccur
sidiary mixing. Where the viscous term is predominant, the energy loss and pressure drop along the vessel are related to the blood viscosity. With a simple fluid, such as water, the viscosity is independent of the flow-rate (more accurately shear-rate) and is termed newtonian flow. With blood the viscosity depends on the flowrate and is non-newtonian. At very slow flow-rates the blood viscosity is about 100 centipoise in patients with thrombotic disease, and about 10 cP in normal 1.
McLachlin, A. D., McLachlin, J. A., Jory, T. A., Rawling, E. G. Ann. Surg. 1960, 152, 678. 2. Clark, C., Cotton, L. T. Br. J. Surg. 1968, 55, 211. 3. Hewson, W. Experimental Inquiries. London, 1771. 4. Wessler, S. J. clin. Invest. 1952, 31, 1011. 5. McDonald, D. A. Blood Flow in Arteries. London, 1974. 6. Lane, D. A., Sirs, J. A. J. Physiol., Lond. 1974, 241, 689. 7. Caro, C. G., Fitzgerald, J. M., Schroter, R. C. Proc. R. Soc. B, 1971, 177, 109. 8. Leeder, M. R., Bridges, P. H. Nature, 1975, 253, 338. 9. Dean, W. R. Phil. Mag. 1927, 4, 208. 10. McConalogue, D. J., Srivastava, R. S. Proc. R. Soc. A, 1968, 307, 37.
at
Changes of blood viscosity, plasma-fibrinogen concentration, and erythrocyte flexibility have been observed in several diseases.2o-22 Some workers have suggested that viscosity on its own is a prime cause of thrombosis, but decisive evidence is still lacking. Chien, S., Usami, S., Dellenback, E. J., Gregersen, M. I. Science, 1967, 157, 827. 12. Rampling, M., Sirs, J. A. J. Physiol., Lond. 1972, 223, 199. 13. Dix, F. J., Scott-Blair, G. W.J. appl. Phys. 1940, 9, 574. 14. Lighthill, M. J. J. Fluid Mech. 1968, 34, 113. 15. Fitzgerald, J. M. J. appl. Physiol. 1969, 27, 912. 16. Brenner, H., Bungay, P. M. Fedn Proc. 1971, 30, 1565. 17. Prothero, J., Burton, A. C. Biophys. J. 1962, 2, 199. 18. Braasch, D., Jennet, W. Pflügers Arch. ges. Physiol. 1968, 302, 245. 19. Jay, A. W. L., Rowlands, S., Skibo, L. Can. J. Physiol. Pharmac. 1972, 50, 1007. 20. Harris, J. W., Brewster, H. H., Ham, T. H., Castle, W. B. Archs intern. Med. 1956, 97, 145. 21. Swank, R. L. Neurology, Minneap. 1959, 9, 553. 22. Dintenfass, L. Blood Microrheology. London, 1971. 11.
114
viscosity by such agents as dextran are often counter-productive in that, while they lower the haematocrit and reduce aggregation, they make the red blood-cells more inflexible.
Attempts
to
manipulate
blood
Even simple hxmodilution tends to lower the fibrinogen level and reduce erythrocyte flexibility, increasing the resistance to passage through the capillary circulation. Viscosity changes may be observed in normal situations, such as pregnancy, with no untoward effects. Quite pronounced variations are associated with surgical operations. SIRS and MACDONALD 23 studied changes of erythrocyte flexibility during and after operations on healthy rabbits. The flexibility fell initially and then started to rise again after 3-4 hours. After 5-6 hours it was back to normal, and it then rose in the next few hours to become significantly less than the preoperative value. This increased flexibility decayed to its original value over the next 10 days. SiRs and MACDONALD suggest that the are related to plasma-fibrinogen levels. changes These effects have been observed in patients by DUPONT and SIRS,24 who have confirmed a linear relationship of erythrocyte flexibility with fibrinogen concentration. ScHOLZ et al. 25 have observed similar changes in blood viscosity at low shear-rates, and in fibrinogen levels after abdominal operations on patients. They could find no difference, however, in the filtration-rate of 1-5% suspensions, of the red cells in Ringer-albumin solutions through polycarbonate sieves, probably because of the dilution and reduction of fibrinogen concentration. SIRS and MACDONALD found that a low dose of heparin given before the operation can prevent the initial fall and reduce the time which the raised postoperative values take to return to normal. These changes resemble the raised fibrinogen levels found by HAM and CURTIS 26 after injections of bacterial products and are in line with the studies of REEVE et al. 27 on the synthesis and breakdown of mammalian fibrinogen. The results after surgery are consistent with an initial loss of fibrinogen as fibrin clots are formed, a stimulus (probably degradation products) to the liver transiently increasing fibrinogen production, and finally a slow clearance of fibrinogen. The effect of heparin in speeding the clearance suggests that degradation products persist after surgery without heparin, and is indicative of a hypercoagulable postoperative state involving intravascular formation and breakdown of fibrin. In this phase any factor which promotes fibrin formation, such as stasis, high blood viscosity, or excessive platelet stickiness, will balance the odds towards thrombosis. While the changes of viscosity are
detrimental,
these
are
secondary
to
the
plasma-
23. Sirs, J. A. Macdonald, G. J. Thrombosis Res. 1974, 5, 657. 24. Dupont, P., Sirs, J. A. Unpublished. 25. Scholz, P. M., Kinney, J. M., Chien, S. Surgery, St. Louis, 1975,
77, 351. 26. Ham, J. H., Curtis, F. C. Medicine, Baltimore, 1938, 17, 413. 27. Reeve, E. B., Takeda, Y., Atencio, A. C. Prot. biol. Fluid, 1966, 14, 283.
variation. To date there is only limited evidence that degradation products are the stimulus to the liver, and this problem should be further
fibrinogen
investigated. Recurrent Hæmaturia in Children and Young Adults BAEHR’s statement that " ... in contradistinction to
the well-known type of acute haemorrhagic nephritis there occurs a benign form with which most physicians are as yet unacquainted "1 still contains an element of truth. It would now be more accurate to say that both physicians and urological surgeons have been slow to appreciate that a positive diagnosis of this generally benign disease can be made on the characteristic history of recurrent gross haematuria at the height of a febrile illness or following heavy exertion ; occasionally an ache in the loins accompanies the onset of attacks, but usually it is symptomless. Gross haematuria may continue for weeks and be sufficiently heavy to cause ureteric colic; red-cell casts are usually present in the urine; and microscopic haematuria and proteinuria usually persist between attacks. Unlike acute post-streptococcal glomerulonephritis, the period between the onset of an infection and haematuria is short, hypertension and oedema are exceptional, and renal function is generally unimpaired. Evidence of recent streptococcal infection is generally lacking.2-4 An intravenous pyelogram is necessary more to guide the renal biopsy needle than to exclude a renal tumour and, given a classical history, children can be spared renal arteriography and probably cystoscopy too. The syndrome usually starts in childhood, but it is not confined to children. In a unit receiving patients of all ages, HENDLER et al.5 found that only 35 of 57 patients were less than 20 years old. Although recurrent haematuria may punctuate several decades without harm, the disease is not always as benign as BAEHR implied. A spectrum of glomerular disease underlies the syndrome: at worst, a progressive diffuse proliferative glomerulonephritis 5-7 or, rarely, a membranoproliferative glomerulonephritis which provokes a nephrotic syndrome,8 but these are the exception. As a rule, the light microscope reveals a mild segmental nephritis, often focal (sparing some glomeruli altogether) as described by’ VOLHARD and FAHR,9 out sometimes diffuse; neither usually 1. 2. 3. 4. 5. 6.
7. 8. 9.
Baehr, G. J. Am. med. Ass. 1926, 86, 1001. Ayoub, E. M., Vernier, R. L. Am. J. Dis. Child. 1965, 109, 217. McConville, J. M., West, C. D., McAdams, A. J. J. Pediat. 1966, 69, 207. Ferris, T. F., Gorden, P., Kashgarian, M., Epstein, F. H. New Engl. J. Med. 1967, 276, 770. Hendler, E. D., Kashgarian, M., Hayslett, J. P. Lancet, 1972, i, 458. Bodian, M., Black, J. A., Kobayashi, N., Lake, B. D., Shuler, S. E. Q. Jl Med. 1965, 34, 359. Glasgow, E. F., Moncrieff, M. W., White, R. H. R. Br. med. J. 1970, ii, 687. Arneil, G. C., Lam, C. N., McDonald, A. M., McDonald, M. ibid. 1969, ii, 233. Volhard, F., Fahr, T. Die Brightsche Nierenkrankheit, Berlin, 1914.
faster flow-rates the viscosity in both is about 4-8 cP. The variation of blood viscosity with shear-rate is believed to be due to the flexibility of the red blood-cells and aggregation. When erythrocytes are hardened with acetaldehyde and inflexible, the blood viscosity is higher-approximately 10 cPbut invariant with flow-rate and newtonian.11 With normal flexible cells the viscosity is higher at slow flow-rates owing to the energy utilised in flexing the cells and breaking the weak interactive force forming rouleaux.Fibrinogen is often said to bind the cells together, because more rouleaux are formed with increasing plasma-fibrinogen concentration. Rouleaux do not form, however, with inflexible erythrocytes, even at elevated fibrinogen concentrations. RAMPLING and SIRS 12 have suggested that fibrinogen acts by increasing the flexibility of normal cells. The main factors which affect blood viscosity are flow-rate, the hæmatocrit, plasma protein and fibrinogen concentrations, erythrocyte flexibility, and vessel bore. The vessel-bore effect occurs in tubes of less than 1 mm. diameter, the viscosity steadily falling with decreasing bore-the so-called Fahraeus-Lindquist effect. There are two explanations of this phenomenon. One is that the layer nearest the vessel wall contains fewer cells than are in the bulk of the blood and the lower viscosity of this layer becomes more significant as the vessel diameter decreases. The second, as was stated by Dix and SCOTT-BLAIR 13 for colloidal suspensions, is that the cells in small tubes represent a series of discrete velocity steps, the sigma effect, and the representation of the velocity profile as a continuous curve is no longer valid. Finally, at the capillary level the viscosity is only about 30% greater than that of plasma, with normal flexible erythrocytes in tubes of 4 to 15 um. When the erythrocytes are inflexible, as in sickle-cell blood with lowered Po2, they can no longer be distorted and squeezed through the smaller vessels. Attempts at a theoretical analysis of this situation 14-16 do not accord with the experimental data. 17-19 In particular, the relative viscosity under these conditions is almost independent of the haematocrit up to values of 80%.
controls;
Hæmorheology, Blood-flow, and Venous Thrombosis THE incidence of venous thrombosis is evidently increased by stasis and reduced blood-flow. 1,2 Flowrate is often assumed to be directly determined by the
viscosity of whole blood; but prolonged stasis may under normal conditions without the formation of thrombi,3,4 and viscosity is only one of several elements that influence blood-flow. At present there is no single index of flow for different parts of the circulation. Blood-flow depends primarily on the work done by the heart. This work is converted into fluid motion as kinetic and potential energy (termed inertial flow) and frictional losses (termed viscous flow). In general, inertial factors predominate with flow in large vessels such as the aorta, and viscous factors in small vessels such as capillaries. In large arteries the flow is complicated by its pulsatile nature and the elastic properties of the vessel walls.5 The influence of bends on the nature of blood-flow is still little understood. With a straight vessel, solutes are dispersed across the cross-section by diffusion except in the region adjacent to the vessel wall.6 With curved tubes the conservation of angular momentum shifts the axis of flow towards the outside of the bend and produces rotational secondary flow and some mixing over the cross-section, as in the flow of a river round a bend.7,8 No analysis of this situation fully explains the experimental data.9,10 At bifurcations the situation is even more complicated with additional cross-sectional secondary flows and suboccur
sidiary mixing. Where the viscous term is predominant, the energy loss and pressure drop along the vessel are related to the blood viscosity. With a simple fluid, such as water, the viscosity is independent of the flow-rate (more accurately shear-rate) and is termed newtonian flow. With blood the viscosity depends on the flowrate and is non-newtonian. At very slow flow-rates the blood viscosity is about 100 centipoise in patients with thrombotic disease, and about 10 cP in normal 1.
McLachlin, A. D., McLachlin, J. A., Jory, T. A., Rawling, E. G. Ann. Surg. 1960, 152, 678. 2. Clark, C., Cotton, L. T. Br. J. Surg. 1968, 55, 211. 3. Hewson, W. Experimental Inquiries. London, 1771. 4. Wessler, S. J. clin. Invest. 1952, 31, 1011. 5. McDonald, D. A. Blood Flow in Arteries. London, 1974. 6. Lane, D. A., Sirs, J. A. J. Physiol., Lond. 1974, 241, 689. 7. Caro, C. G., Fitzgerald, J. M., Schroter, R. C. Proc. R. Soc. B, 1971, 177, 109. 8. Leeder, M. R., Bridges, P. H. Nature, 1975, 253, 338. 9. Dean, W. R. Phil. Mag. 1927, 4, 208. 10. McConalogue, D. J., Srivastava, R. S. Proc. R. Soc. A, 1968, 307, 37.
at
Changes of blood viscosity, plasma-fibrinogen concentration, and erythrocyte flexibility have been observed in several diseases.2o-22 Some workers have suggested that viscosity on its own is a prime cause of thrombosis, but decisive evidence is still lacking. Chien, S., Usami, S., Dellenback, E. J., Gregersen, M. I. Science, 1967, 157, 827. 12. Rampling, M., Sirs, J. A. J. Physiol., Lond. 1972, 223, 199. 13. Dix, F. J., Scott-Blair, G. W.J. appl. Phys. 1940, 9, 574. 14. Lighthill, M. J. J. Fluid Mech. 1968, 34, 113. 15. Fitzgerald, J. M. J. appl. Physiol. 1969, 27, 912. 16. Brenner, H., Bungay, P. M. Fedn Proc. 1971, 30, 1565. 17. Prothero, J., Burton, A. C. Biophys. J. 1962, 2, 199. 18. Braasch, D., Jennet, W. Pflügers Arch. ges. Physiol. 1968, 302, 245. 19. Jay, A. W. L., Rowlands, S., Skibo, L. Can. J. Physiol. Pharmac. 1972, 50, 1007. 20. Harris, J. W., Brewster, H. H., Ham, T. H., Castle, W. B. Archs intern. Med. 1956, 97, 145. 21. Swank, R. L. Neurology, Minneap. 1959, 9, 553. 22. Dintenfass, L. Blood Microrheology. London, 1971. 11.
114
viscosity by such agents as dextran are often counter-productive in that, while they lower the haematocrit and reduce aggregation, they make the red blood-cells more inflexible.
Attempts
to
manipulate
blood
Even simple hxmodilution tends to lower the fibrinogen level and reduce erythrocyte flexibility, increasing the resistance to passage through the capillary circulation. Viscosity changes may be observed in normal situations, such as pregnancy, with no untoward effects. Quite pronounced variations are associated with surgical operations. SIRS and MACDONALD 23 studied changes of erythrocyte flexibility during and after operations on healthy rabbits. The flexibility fell initially and then started to rise again after 3-4 hours. After 5-6 hours it was back to normal, and it then rose in the next few hours to become significantly less than the preoperative value. This increased flexibility decayed to its original value over the next 10 days. SiRs and MACDONALD suggest that the are related to plasma-fibrinogen levels. changes These effects have been observed in patients by DUPONT and SIRS,24 who have confirmed a linear relationship of erythrocyte flexibility with fibrinogen concentration. ScHOLZ et al. 25 have observed similar changes in blood viscosity at low shear-rates, and in fibrinogen levels after abdominal operations on patients. They could find no difference, however, in the filtration-rate of 1-5% suspensions, of the red cells in Ringer-albumin solutions through polycarbonate sieves, probably because of the dilution and reduction of fibrinogen concentration. SIRS and MACDONALD found that a low dose of heparin given before the operation can prevent the initial fall and reduce the time which the raised postoperative values take to return to normal. These changes resemble the raised fibrinogen levels found by HAM and CURTIS 26 after injections of bacterial products and are in line with the studies of REEVE et al. 27 on the synthesis and breakdown of mammalian fibrinogen. The results after surgery are consistent with an initial loss of fibrinogen as fibrin clots are formed, a stimulus (probably degradation products) to the liver transiently increasing fibrinogen production, and finally a slow clearance of fibrinogen. The effect of heparin in speeding the clearance suggests that degradation products persist after surgery without heparin, and is indicative of a hypercoagulable postoperative state involving intravascular formation and breakdown of fibrin. In this phase any factor which promotes fibrin formation, such as stasis, high blood viscosity, or excessive platelet stickiness, will balance the odds towards thrombosis. While the changes of viscosity are
detrimental,
these
are
secondary
to
the
plasma-
23. Sirs, J. A. Macdonald, G. J. Thrombosis Res. 1974, 5, 657. 24. Dupont, P., Sirs, J. A. Unpublished. 25. Scholz, P. M., Kinney, J. M., Chien, S. Surgery, St. Louis, 1975,
77, 351. 26. Ham, J. H., Curtis, F. C. Medicine, Baltimore, 1938, 17, 413. 27. Reeve, E. B., Takeda, Y., Atencio, A. C. Prot. biol. Fluid, 1966, 14, 283.
variation. To date there is only limited evidence that degradation products are the stimulus to the liver, and this problem should be further
fibrinogen
investigated. Recurrent Hæmaturia in Children and Young Adults BAEHR’s statement that " ... in contradistinction to
the well-known type of acute haemorrhagic nephritis there occurs a benign form with which most physicians are as yet unacquainted "1 still contains an element of truth. It would now be more accurate to say that both physicians and urological surgeons have been slow to appreciate that a positive diagnosis of this generally benign disease can be made on the characteristic history of recurrent gross haematuria at the height of a febrile illness or following heavy exertion ; occasionally an ache in the loins accompanies the onset of attacks, but usually it is symptomless. Gross haematuria may continue for weeks and be sufficiently heavy to cause ureteric colic; red-cell casts are usually present in the urine; and microscopic haematuria and proteinuria usually persist between attacks. Unlike acute post-streptococcal glomerulonephritis, the period between the onset of an infection and haematuria is short, hypertension and oedema are exceptional, and renal function is generally unimpaired. Evidence of recent streptococcal infection is generally lacking.2-4 An intravenous pyelogram is necessary more to guide the renal biopsy needle than to exclude a renal tumour and, given a classical history, children can be spared renal arteriography and probably cystoscopy too. The syndrome usually starts in childhood, but it is not confined to children. In a unit receiving patients of all ages, HENDLER et al.5 found that only 35 of 57 patients were less than 20 years old. Although recurrent haematuria may punctuate several decades without harm, the disease is not always as benign as BAEHR implied. A spectrum of glomerular disease underlies the syndrome: at worst, a progressive diffuse proliferative glomerulonephritis 5-7 or, rarely, a membranoproliferative glomerulonephritis which provokes a nephrotic syndrome,8 but these are the exception. As a rule, the light microscope reveals a mild segmental nephritis, often focal (sparing some glomeruli altogether) as described by’ VOLHARD and FAHR,9 out sometimes diffuse; neither usually 1. 2. 3. 4. 5. 6.
7. 8. 9.
Baehr, G. J. Am. med. Ass. 1926, 86, 1001. Ayoub, E. M., Vernier, R. L. Am. J. Dis. Child. 1965, 109, 217. McConville, J. M., West, C. D., McAdams, A. J. J. Pediat. 1966, 69, 207. Ferris, T. F., Gorden, P., Kashgarian, M., Epstein, F. H. New Engl. J. Med. 1967, 276, 770. Hendler, E. D., Kashgarian, M., Hayslett, J. P. Lancet, 1972, i, 458. Bodian, M., Black, J. A., Kobayashi, N., Lake, B. D., Shuler, S. E. Q. Jl Med. 1965, 34, 359. Glasgow, E. F., Moncrieff, M. W., White, R. H. R. Br. med. J. 1970, ii, 687. Arneil, G. C., Lam, C. N., McDonald, A. M., McDonald, M. ibid. 1969, ii, 233. Volhard, F., Fahr, T. Die Brightsche Nierenkrankheit, Berlin, 1914.
