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The influence of plasma exchange on whole blood viscosity
31
Plasma Ther Ttansfus Technol1987; 8:31-35
The Influence of Plasma Exchange on Whole Blood Viscosity J. c. C. Borleffs, Mq PhD J. H. A. Heuvelmans H. Goslinga, MD, PhD J. W. Imhof, MD, PhD
Plasma exchange (PEl has been widely used in the treatmentof several diseases. One of the most importantindicationsfor therapeuticPE is the hyperviscosity syndrome caused by macroglobulinemia, multiple myeloma, and other diseases. t Furthermore,PE has proved its value in removing certain plasma constituents such as thyroid hormones in thyrotoxic crisis and toxic substances in poisoning. PE also appears to be a useful adjunct to the treatment of myasthenia gravis, maternalalloimmunizationto Rhesus (01 antigen, systemic lupus erythematosus, and Raynaud's syndrome. 2.3 In the hyperviscosity syndrome. the elevated levels of blood constituents lead to an increase in plasma viscosity. However. there are also other diseases in which rheologic changes play an important role.such as anginapectoris, intermittent claudication,and transientischemic attacks. Among patients suffering from one of these ischemic disorders, a significantly increased whole-blood viscosity was found when compared with controls.v? Interestingly, the viscosity only appearedto be increasedwhen measured
From the Hospital De Lichtenberg, Department of Inter nal Medicine ,Amersfoort, The Netherlands; and Sint Lucas Hospital!Departmentof Anaesthesiology, Amsterdam, The Nether ands. Reprint requests to Dr. Borleffs, Univers ity Hospital, Department of Internal Medicinel Catharijnesingel 101, 3511 GV Utrecht, The Netherlanas. Received 6/85; Accepted 1/86.
at lower shear rates, comparable to the physiologic flow rate in venules, at other shear rates, a normal viscosity was found;s and in those patients a striking improvement in the circulationcould be achieved by hemodilution using dextrans.v The clinical applicationof norrnovolemic hemodilution, however, is limited by the patient's cardiac condition and by the fact that histologic damage to the liver comparable to that of shock can be induced by this procedure.to It could be speculated that PEmight be an attractive and relatively harmless alternative form of treatment in patients with ischemic diseases. It thereforeseemed of interest to investigate whether one PE in normal volunteers would produce a reduction in the viscosity of whole blood, especially when measuredat lower shear rates, and subsequently, to determine how long such an effect would last. MATERIAL AND METHODS Five healthy volunteers (3 men, 2 women, aged 28 to 32 years)participated(with informed consent) in this study. They all had normal liver, kidney, and cardiac functions. PE was performedwith an IBM 2997 continuous-flow blood cell separator. Anticoagulation was achieved with acid citrate dextrose formula B (ratio blood:anticoagulant = 13:11. In order to avoid possible hypocalcemia, a prophylactic dose of 10 mL of 10% calcium
32 Plasma Therapy Vol. 8, No. 1
gluconate was given intravenously after each liter of exchanged plasma. The plasma that was removed was replacedby the same volume of a 5% solution of human placentalalbumin[Merieux].The volume of plasma removed (corrected for the anticoagulant mixtureI was 2 liters. Blood samples were collected before and immediately after PEl and 11 417/ 141 and 21 days thereafter. Laboratory parametersthat were determined included whole blood and plasma viscosity, hemoglobin, hematocrit, erythrocyte sedimentationrate (ESRI I level of plasma fibrinogen, and the concentrationof serum albumin, at globulin, a 2 globulin} ~ globulin, and 'Y globulin. The whole blood viscosity was measured at both a low shear rate (0.04 sec - 11 and a high shear rate (69.5 sec -11 at 37°C using a Contraves Low-Shear 30 viscometer. 11.12 Plasma viscosity, which is not influencedby shear rate, was alsomeasuredusing a Contraves Low-Shear 30 viscometer.
RESULTS The effect of one PEon whole blood viscosity is shown in Figure 1. The solid lines representthe viscosity measuredat a low shear rate, and the dotted lines represent viscosity measured at a high shearrate. The data show that PE has an influenceon viscosity at low shearrates. In all volunteers} a reductionof viscosity of 50% to 75% was achieved. Twenty-four hours after PEl normal values of viscosity were measured in four of five volunteers. In volunteer M I viscosity returned to normal on the fourth day after exchange. None of the volunteers showed a significant reductionin viscosity at a high shear rate. Figure 2 illustrates the influence of one PEon plasma viscosity. In all volunteers, a slight but clear reductionin plasma viscosity was observed, but this effect had disappeared within 24 hours. With respect to the other laboratory I
100
low shear rate high shear rate
p.., u
....>: ~
C/)
0
v
.;;
B S
u C/)
M
50
R
1
+ plasma exchange
4
7
Figure 1. Influenceof one plasmaexchange on whole blood viscosity
days
PE and Whole BloodViscosity 33
1.5
p...
V R M B
o
~
.~ en
0 en
u
S
'>
1.0
1
4
7
14
21
days
'"
plasma exchange Figure 2. Influence of one plasma exchange on plasma viscosity
parameters,Table 1 shows that decreased levels of plasma fibrinogen and ai, au {3, and 'Y globulins were found immediately after PEi these values returnedto normal within four to seven days. Neither the level of albumin nor the hematologic parameters were influenced by PE. DISCUSSION
The data presented clearly demonstrate that PE leads to asignificantreductionin
whole blood viscosity but only at a low shearrate, which represents the rheologic condition in venules. However,the viscosity at high shear rate-the rheologic condition in large arteries andarteriolesdid not change. At lower shearrates, blood viscosity is determined mainly by red cell aggregation. Since aggregation iscaused by cell protein interactionowing to the presence of fibrinogenand globulin, a reductionof these blood constituents will lead to a
'Thble1. Influenceof One PlasmaExchangeon Hemoglobin, Hematocrit, Erythrocyte Sedimentation Rate, Fibrinogen,Albumin, all au {3, and 'Y Globulinin HealthyVolunteers (median value). Plasma Exchange Days After Plasma Exchange Before After 1 4 14 21 7 Hemoglobin' 9.5 9.1 9.7 9.2 9.0 8.9 9.4 Hematocrits 45.0 43.0 44.0 42.0 40.0 44.0 43.0 ESRc 4.0 1.0 1.0 3.0 4.0 2.0 2.0 Fibrinogens 2.1 1.1 1.5 2.0 2.4 1.9 2.4 Albumins 49.1 47.8 53.8 47.1 48.9 49.9 50.5 a 1 globulin2.3 1.3 1.6 2.1 2.8 2.4 2.3 a 2 globulin4.8 2.8 3.3 3.6 5.0 5.1 5.0 {3 globulins 7.4 8.4 9.2 4.4 5.9 6.9 6.9 'Y globulins 8.1 8.4 9.4 5.0 5.3 8.0 6.0 a mmollL -1; b %; c after one hour; d g/L-l
34 Plasma Therapy Vol. 8, No. 1
reduced red cell aggregationand therefore decreased blood viscosity. 13 At high shear rates, however, red cell aggregation contributes little to the blood viscosity; at these shearrates viscosity is determined mainly by solid blood components, i.e., blood cells, of which the numberand concentrationare not affected by PE.12 This explains the differences in the effect of PE on whole blood viscosity at low and high shear rates. As far as plasma viscosity is concerned, only a slight reduction was observed after one PE. This is in agreement with reports of other investigators who observed a modest influenceof PE on viscosity in patients sufferingfrom disorders in which normalviscosity is found, such as primary Raynaud's disease. 14 Surprisingly, this pilot study shows a recovery of both whole blood and plasma viscosity before the levels of plasma fibrinogen, a 1, au {3, and 'Y globulins have returned to normal. Clearly, viscosity is determined by other factors as well. Proteins suchas immunoglobulins,antitrypsin, a 2 macroglobulin, transferrin,'a nd complement components, as well as red cell deformability, contribute to the viscosity.1S.1S These parameters were not measuredin this study, however. This appears to contradictthe findings of others, who reported a reductionin viscosity and symptomatic improvement after PEin patients with Raynaud's syndrome, which persisted for longer thanthe reductionin fibrinogen.re-v In those patients, however, PE had been performed at least four times, which makes a comparison with our results, obtained after one exchange, difficult. The viscosity before PE in volunteer M (Figure 11 was lower than that of the othervolunteers. This could beexplained by her having donated 500 mL of blood a few days before the experiment. With respect to the viscosity in patients with ischemic diseases, it appears that their blood flow is preferentially compromised in venules. Chmiel reported a doubling of blood viscosity at a low shearrate on the second day after admis-
sion to the hospital among patients with myocardial infarction.» The same was described earlierby Eisenbergin patients with cerebral infarction.w In the latter group of patients, a strikingimprovement in circulation could be achieved by hemodilution using dextrans, whereas vasodilating agents hardly affected the blood flow at the venular level. 9 Although hemodilution with dextrans is of certain clinical value in patients with ischemic disorders, this procedurehas not become anestablished mode of treatment because it involves several risks.10 This pilot study shows that the same beneficial influence on whole blood viscosity at lower shear rates achieved with hemodilution can also be reached with plasma exchange. Furthermore, PE is not only a relatively harmless clinical procedure, but it also has no adverse effects on hemoglobin or hematocrit. The oxygen transportcapacity of the blood is thereforenot decreased, anessential consideration in patients with this type of disorder.
Acknowledgments We would like to thank Merieux (Lyon,France) for financial support, Professor Kater forcritical reading of the manuscript,and E. Meyer and R. Reuvekamp fortechnical assistance.
REFERENCES 1. Schwab P], Fakey]C:Treatmentof Waldenstrom's macroglobulinemia by plasmapheresis. N Eng]JMed 1960;263:574-579. 2. ShumakKH, Rock GA: Therapeuticplasma exchanges. N Eng] J Med 1984; 310:762-771. 3. Talpos G, Horrocks M, White ]M, Cotton L1': Plasmapheresisin Raynaud's disease. Lancet 1978; 1:416-417. 4. Nicolaides AN, Bowers R, Horboume T, Kinder PH,BestermanEM: Blood viscosity, red-cell flexibility, hematocrit and plasma-fibrinogenin patients with angina. Lancet 1977; 2:943-945. 5. Dormandy ]A: Clinical significance of blood viscosity. Ann R Coll Sutg Eng] 1980; 47:211-218.
PE and Whole Blood Viscosity 35
6. Jan KM,ChienS: Effect ofhematocritvariations on coronary hemodynamics and oxygen utilization. Am J Physiol 1977; 233:106-113. 7. Thomas DJ,MarshallJ, Ross Russell RW; Wetherley-Mein G, DuBoulayGH, Pearson Te, Symon L, Zilkka E: Effect of hematocriton cerebralblood-flow in man. Lancet 1977; 2:941-943. 8. DintenfassLD: Blood rheology and rheology of blood coagulation as diagnostic tools in study of malignanttumors, cardiovasculardiseases and hematologicaldisorders. Biorheology 1972; 9:149-150. 9. Gottstein U, Held K, Sedlmeyer I:Cerebral andperipheralblood flow as affected by induced hemodilution, in Messmer K, Schrnid-SchonbeinH (eds): Hemodilution,
Theoretical Basis and Clinical Application. Basel, Karger, 1971, pp 247-258. 10. BiernatS, Kulig A, Lepast R, Orlowski T. Pathomorphologic and histochemical changesin the liver duringhemodilution. Am J Sutg 1974; 128:24. 11. Dormandy JA: Measurement of whole blood viscosity, in Cowe GDO, Barbenel JD, Forbes CD (eds): Clinical Aspects 0/
Blood Viscosity and Cell Defotmability. Berlin, Springer, 1981, pp 67-79. 12. Goslinga H:The viscosity of blood. An experimental study into the effects of alterations in blood viscosity during shock. Thesis, Utrecht, 1982.
13. Brown MM, Marshall J: Effect ofplasma exchangeon blood viscosity and cerebral blood flow. Br Med J1982; 284:1733-1736. 14. Jacobs MJHM:Capillary microscopy and haemorheology in vasospastic and occlusive vasculardiseases. Thesis, Maastricht, 1985. 15. Cornelissen H, Golterman AFL, KerckhaertJAM, Wiel A van de, Imhof JW: Fixed IgM reductionin plasmaexchange: A standardized method for calculating the volume to be removed per session. Plas-
ma Ther Trans/us Technol 1984; 51:365-370. 16. Dodds AJ; O'Reilly MJG, Yates CJP, Cotton L~ Flute P~ Dormandy JA: Haemorheological response to plasma exchangein Raynaud'ssyndrome. Br Med J 1979; 2:1186-1187. 17. O'Reilly MJG, Talpos G, Roberts VC, White JM, Cotton LT. Controlled trial of plasma exchange in treatment of Raynaud's syndrome. Br Med J 1979; 1:1113-1115. 18. Eisenberg S: Blood viscosity and fibrinogen concentrationfollowing cerebral infarction.-Circulation1966; 33/34, suppl. 2, 2:10. 19. Chmiel H, Efferts S, Mathey D: Rheologische veranderungen des Blutes beim akuten Herzinfarkt und dessen Risikofactoren. Dtsch Med Wochenschr 1973; 98:1641.
Plasma Ther Ttansfus Technol1987; 8:31-35
The Influence of Plasma Exchange on Whole Blood Viscosity J. c. C. Borleffs, Mq PhD J. H. A. Heuvelmans H. Goslinga, MD, PhD J. W. Imhof, MD, PhD
Plasma exchange (PEl has been widely used in the treatmentof several diseases. One of the most importantindicationsfor therapeuticPE is the hyperviscosity syndrome caused by macroglobulinemia, multiple myeloma, and other diseases. t Furthermore,PE has proved its value in removing certain plasma constituents such as thyroid hormones in thyrotoxic crisis and toxic substances in poisoning. PE also appears to be a useful adjunct to the treatment of myasthenia gravis, maternalalloimmunizationto Rhesus (01 antigen, systemic lupus erythematosus, and Raynaud's syndrome. 2.3 In the hyperviscosity syndrome. the elevated levels of blood constituents lead to an increase in plasma viscosity. However. there are also other diseases in which rheologic changes play an important role.such as anginapectoris, intermittent claudication,and transientischemic attacks. Among patients suffering from one of these ischemic disorders, a significantly increased whole-blood viscosity was found when compared with controls.v? Interestingly, the viscosity only appearedto be increasedwhen measured
From the Hospital De Lichtenberg, Department of Inter nal Medicine ,Amersfoort, The Netherlands; and Sint Lucas Hospital!Departmentof Anaesthesiology, Amsterdam, The Nether ands. Reprint requests to Dr. Borleffs, Univers ity Hospital, Department of Internal Medicinel Catharijnesingel 101, 3511 GV Utrecht, The Netherlanas. Received 6/85; Accepted 1/86.
at lower shear rates, comparable to the physiologic flow rate in venules, at other shear rates, a normal viscosity was found;s and in those patients a striking improvement in the circulationcould be achieved by hemodilution using dextrans.v The clinical applicationof norrnovolemic hemodilution, however, is limited by the patient's cardiac condition and by the fact that histologic damage to the liver comparable to that of shock can be induced by this procedure.to It could be speculated that PEmight be an attractive and relatively harmless alternative form of treatment in patients with ischemic diseases. It thereforeseemed of interest to investigate whether one PE in normal volunteers would produce a reduction in the viscosity of whole blood, especially when measuredat lower shear rates, and subsequently, to determine how long such an effect would last. MATERIAL AND METHODS Five healthy volunteers (3 men, 2 women, aged 28 to 32 years)participated(with informed consent) in this study. They all had normal liver, kidney, and cardiac functions. PE was performedwith an IBM 2997 continuous-flow blood cell separator. Anticoagulation was achieved with acid citrate dextrose formula B (ratio blood:anticoagulant = 13:11. In order to avoid possible hypocalcemia, a prophylactic dose of 10 mL of 10% calcium
32 Plasma Therapy Vol. 8, No. 1
gluconate was given intravenously after each liter of exchanged plasma. The plasma that was removed was replacedby the same volume of a 5% solution of human placentalalbumin[Merieux].The volume of plasma removed (corrected for the anticoagulant mixtureI was 2 liters. Blood samples were collected before and immediately after PEl and 11 417/ 141 and 21 days thereafter. Laboratory parametersthat were determined included whole blood and plasma viscosity, hemoglobin, hematocrit, erythrocyte sedimentationrate (ESRI I level of plasma fibrinogen, and the concentrationof serum albumin, at globulin, a 2 globulin} ~ globulin, and 'Y globulin. The whole blood viscosity was measured at both a low shear rate (0.04 sec - 11 and a high shear rate (69.5 sec -11 at 37°C using a Contraves Low-Shear 30 viscometer. 11.12 Plasma viscosity, which is not influencedby shear rate, was alsomeasuredusing a Contraves Low-Shear 30 viscometer.
RESULTS The effect of one PEon whole blood viscosity is shown in Figure 1. The solid lines representthe viscosity measuredat a low shear rate, and the dotted lines represent viscosity measured at a high shearrate. The data show that PE has an influenceon viscosity at low shearrates. In all volunteers} a reductionof viscosity of 50% to 75% was achieved. Twenty-four hours after PEl normal values of viscosity were measured in four of five volunteers. In volunteer M I viscosity returned to normal on the fourth day after exchange. None of the volunteers showed a significant reductionin viscosity at a high shear rate. Figure 2 illustrates the influence of one PEon plasma viscosity. In all volunteers, a slight but clear reductionin plasma viscosity was observed, but this effect had disappeared within 24 hours. With respect to the other laboratory I
100
low shear rate high shear rate
p.., u
....>: ~
C/)
0
v
.;;
B S
u C/)
M
50
R
1
+ plasma exchange
4
7
Figure 1. Influenceof one plasmaexchange on whole blood viscosity
days
PE and Whole BloodViscosity 33
1.5
p...
V R M B
o
~
.~ en
0 en
u
S
'>
1.0
1
4
7
14
21
days
'"
plasma exchange Figure 2. Influence of one plasma exchange on plasma viscosity
parameters,Table 1 shows that decreased levels of plasma fibrinogen and ai, au {3, and 'Y globulins were found immediately after PEi these values returnedto normal within four to seven days. Neither the level of albumin nor the hematologic parameters were influenced by PE. DISCUSSION
The data presented clearly demonstrate that PE leads to asignificantreductionin
whole blood viscosity but only at a low shearrate, which represents the rheologic condition in venules. However,the viscosity at high shear rate-the rheologic condition in large arteries andarteriolesdid not change. At lower shearrates, blood viscosity is determined mainly by red cell aggregation. Since aggregation iscaused by cell protein interactionowing to the presence of fibrinogenand globulin, a reductionof these blood constituents will lead to a
'Thble1. Influenceof One PlasmaExchangeon Hemoglobin, Hematocrit, Erythrocyte Sedimentation Rate, Fibrinogen,Albumin, all au {3, and 'Y Globulinin HealthyVolunteers (median value). Plasma Exchange Days After Plasma Exchange Before After 1 4 14 21 7 Hemoglobin' 9.5 9.1 9.7 9.2 9.0 8.9 9.4 Hematocrits 45.0 43.0 44.0 42.0 40.0 44.0 43.0 ESRc 4.0 1.0 1.0 3.0 4.0 2.0 2.0 Fibrinogens 2.1 1.1 1.5 2.0 2.4 1.9 2.4 Albumins 49.1 47.8 53.8 47.1 48.9 49.9 50.5 a 1 globulin2.3 1.3 1.6 2.1 2.8 2.4 2.3 a 2 globulin4.8 2.8 3.3 3.6 5.0 5.1 5.0 {3 globulins 7.4 8.4 9.2 4.4 5.9 6.9 6.9 'Y globulins 8.1 8.4 9.4 5.0 5.3 8.0 6.0 a mmollL -1; b %; c after one hour; d g/L-l
34 Plasma Therapy Vol. 8, No. 1
reduced red cell aggregationand therefore decreased blood viscosity. 13 At high shear rates, however, red cell aggregation contributes little to the blood viscosity; at these shearrates viscosity is determined mainly by solid blood components, i.e., blood cells, of which the numberand concentrationare not affected by PE.12 This explains the differences in the effect of PE on whole blood viscosity at low and high shear rates. As far as plasma viscosity is concerned, only a slight reduction was observed after one PE. This is in agreement with reports of other investigators who observed a modest influenceof PE on viscosity in patients sufferingfrom disorders in which normalviscosity is found, such as primary Raynaud's disease. 14 Surprisingly, this pilot study shows a recovery of both whole blood and plasma viscosity before the levels of plasma fibrinogen, a 1, au {3, and 'Y globulins have returned to normal. Clearly, viscosity is determined by other factors as well. Proteins suchas immunoglobulins,antitrypsin, a 2 macroglobulin, transferrin,'a nd complement components, as well as red cell deformability, contribute to the viscosity.1S.1S These parameters were not measuredin this study, however. This appears to contradictthe findings of others, who reported a reductionin viscosity and symptomatic improvement after PEin patients with Raynaud's syndrome, which persisted for longer thanthe reductionin fibrinogen.re-v In those patients, however, PE had been performed at least four times, which makes a comparison with our results, obtained after one exchange, difficult. The viscosity before PE in volunteer M (Figure 11 was lower than that of the othervolunteers. This could beexplained by her having donated 500 mL of blood a few days before the experiment. With respect to the viscosity in patients with ischemic diseases, it appears that their blood flow is preferentially compromised in venules. Chmiel reported a doubling of blood viscosity at a low shearrate on the second day after admis-
sion to the hospital among patients with myocardial infarction.» The same was described earlierby Eisenbergin patients with cerebral infarction.w In the latter group of patients, a strikingimprovement in circulation could be achieved by hemodilution using dextrans, whereas vasodilating agents hardly affected the blood flow at the venular level. 9 Although hemodilution with dextrans is of certain clinical value in patients with ischemic disorders, this procedurehas not become anestablished mode of treatment because it involves several risks.10 This pilot study shows that the same beneficial influence on whole blood viscosity at lower shear rates achieved with hemodilution can also be reached with plasma exchange. Furthermore, PE is not only a relatively harmless clinical procedure, but it also has no adverse effects on hemoglobin or hematocrit. The oxygen transportcapacity of the blood is thereforenot decreased, anessential consideration in patients with this type of disorder.
Acknowledgments We would like to thank Merieux (Lyon,France) for financial support, Professor Kater forcritical reading of the manuscript,and E. Meyer and R. Reuvekamp fortechnical assistance.
REFERENCES 1. Schwab P], Fakey]C:Treatmentof Waldenstrom's macroglobulinemia by plasmapheresis. N Eng]JMed 1960;263:574-579. 2. ShumakKH, Rock GA: Therapeuticplasma exchanges. N Eng] J Med 1984; 310:762-771. 3. Talpos G, Horrocks M, White ]M, Cotton L1': Plasmapheresisin Raynaud's disease. Lancet 1978; 1:416-417. 4. Nicolaides AN, Bowers R, Horboume T, Kinder PH,BestermanEM: Blood viscosity, red-cell flexibility, hematocrit and plasma-fibrinogenin patients with angina. Lancet 1977; 2:943-945. 5. Dormandy ]A: Clinical significance of blood viscosity. Ann R Coll Sutg Eng] 1980; 47:211-218.
PE and Whole Blood Viscosity 35
6. Jan KM,ChienS: Effect ofhematocritvariations on coronary hemodynamics and oxygen utilization. Am J Physiol 1977; 233:106-113. 7. Thomas DJ,MarshallJ, Ross Russell RW; Wetherley-Mein G, DuBoulayGH, Pearson Te, Symon L, Zilkka E: Effect of hematocriton cerebralblood-flow in man. Lancet 1977; 2:941-943. 8. DintenfassLD: Blood rheology and rheology of blood coagulation as diagnostic tools in study of malignanttumors, cardiovasculardiseases and hematologicaldisorders. Biorheology 1972; 9:149-150. 9. Gottstein U, Held K, Sedlmeyer I:Cerebral andperipheralblood flow as affected by induced hemodilution, in Messmer K, Schrnid-SchonbeinH (eds): Hemodilution,
Theoretical Basis and Clinical Application. Basel, Karger, 1971, pp 247-258. 10. BiernatS, Kulig A, Lepast R, Orlowski T. Pathomorphologic and histochemical changesin the liver duringhemodilution. Am J Sutg 1974; 128:24. 11. Dormandy JA: Measurement of whole blood viscosity, in Cowe GDO, Barbenel JD, Forbes CD (eds): Clinical Aspects 0/
Blood Viscosity and Cell Defotmability. Berlin, Springer, 1981, pp 67-79. 12. Goslinga H:The viscosity of blood. An experimental study into the effects of alterations in blood viscosity during shock. Thesis, Utrecht, 1982.
13. Brown MM, Marshall J: Effect ofplasma exchangeon blood viscosity and cerebral blood flow. Br Med J1982; 284:1733-1736. 14. Jacobs MJHM:Capillary microscopy and haemorheology in vasospastic and occlusive vasculardiseases. Thesis, Maastricht, 1985. 15. Cornelissen H, Golterman AFL, KerckhaertJAM, Wiel A van de, Imhof JW: Fixed IgM reductionin plasmaexchange: A standardized method for calculating the volume to be removed per session. Plas-
ma Ther Trans/us Technol 1984; 51:365-370. 16. Dodds AJ; O'Reilly MJG, Yates CJP, Cotton L~ Flute P~ Dormandy JA: Haemorheological response to plasma exchangein Raynaud'ssyndrome. Br Med J 1979; 2:1186-1187. 17. O'Reilly MJG, Talpos G, Roberts VC, White JM, Cotton LT. Controlled trial of plasma exchange in treatment of Raynaud's syndrome. Br Med J 1979; 1:1113-1115. 18. Eisenberg S: Blood viscosity and fibrinogen concentrationfollowing cerebral infarction.-Circulation1966; 33/34, suppl. 2, 2:10. 19. Chmiel H, Efferts S, Mathey D: Rheologische veranderungen des Blutes beim akuten Herzinfarkt und dessen Risikofactoren. Dtsch Med Wochenschr 1973; 98:1641.