342
bladder within 15 minutes after injection. Similar results were obtained in all four patients and a normal
Preliminary Communications
control.
Discussion The capability of imaging thrombi, fresh and old, with a radioactive tagged material is the goal of several laboratories.2 5-8 The technique would predictably be atraumatic and of low morbidity, be applicable to old and fresh clots, and be available at most medium-sized community hospitals. Millar2 reported success with Tc-99m-labelled urokinase utilising a relatively easy tagging method which has been employed to label other proteins. This approach would represent a quick and easy solution to the problem and we attempted duplication of Millar’s work. Tc-99m pertechnetate and urokinase in the amounts used have been demonstrated to be safe in man. Our goal was display of thrombi. Direct evaluation of the end-result without extensive preliminary evaluation was believed justified and was pursued. Marginal encouragement was obtained from two of the studies but after four attempts it was apparent that satisfactory images were not being obtained. The rapid disappearance of radioactivity from the blood is consistent with the previous estimates of urokinase half-life of less than 15 minutes.7 The rapid disappearance of injected radioactivity, the low activity thighcounts, and the scintiscan appearance with very low activity are indications that the problem is not excess background activity. It does not seem useful to wait longer before imaging. Blood background has substantially disappeared within the time of our study. The problem is an inability to get sufficient activity to the clot rather than failure of clearing background. The great majority of injected activity (see table) is present in the liver and a large amount is in the bladder. The liver-counts probably represent a Tc/urokinase complex, possibly with !X2-macroglobulin.8 Studies are currently underway to document the nature of the liver and bladder activity. Our goal was to duplicate Millar’s2 successful thrombus imaging. We have gone directly to the endpoint of the process-production of a satisfactory diagnostic image-and have been unsuccessful. Evaluation of the chemical and physiological processes involved in labelling urokinase and in the lysis of thrombi by urokinase may in the future allow successful use of the system.
This work was supported by National Institutes of Health, N01-HB-42977 N.H.L.I.
EFFECT OF LOW-DOSE SUBCUTANEOUS HEPARIN ON WHOLE-BLOOD VISCOSITY A. ERDI* D. P. THOMAS
Thrombosis Research Unit, Department of Surgery, King’s College Hospital Medical School, Denmark Hill, London SE5 8RX
J. A. DORMANDY Clinical Research Laboratories, St. George’s Hospital Medical School, Blackshaw Road, London SW 17 0QT The change in blood-viscosity at low shear-rates (0·77 s-1 and 2·62 s-1 was measured in eighteen normal subjects and postoperatively in sixteen patients after administration of 5000 I.U. of subcutaneous heparin. In both groups there was a significant decrease in the mean blood-viscosity 4 to 6 hours after the injection of heparin. This fall in blood-viscosity may be involved in the prophylactic effect of low-dose subcutaneous heparin in preventing venous thrombosis.
Summary
INTRODUCTION
lipoprotein lipase from the tissues, blood-triglyceride concentrations and increases free fatty acid concentrations.3In four healthy subjects 10 000 i.u. of intravenous heparin altered the triglyceride concentration and the wholeblood viscosity in alimentary hyperlipaemia .4 Low-dose subcutaneous heparin is effective in preventing postoperative venous thromboembolism.5-1 Although heparin is known to have many actions, itis generally assumed that its effectiveness in preventing deep-vein thrombosis (D.V.T.) is primarily due to an effect on blood coagulation. However, if subcutaneous heparin also decreases blood-viscosity, then its prophylactic effect HEPARIN
may in part be due to
REFERENCES
Rhodes, B. A., Bell, W. R., Som, P. in International Symposium on Radiopharmaceuticals (edited by G. Subramanian, B. A. Rhodes, J. F. Cooper and V. J. Sodd). New York, 1975. 2 Millar, W. T., Smyth, J. F. B. Lancet, 1974, ii, 695. 3. Kempi, J., Van der Linden, W., Von Scheele, C. Br. med. J. 1974, iv, 748. 4. Johnson, A. J., Semar, M., Newman, J. in Blood Coagulation, Hemorrhage, and Thrombosis (edited by L. M. Tocantins and L. A. Kazal); p. 465. New York, 1964. 5. Coates, G., De Nardo, S. J., De Nardo, G. L., Troy, F. A. J. nucl. Med. 1975, 16, 136. 6. Sigel, M. E., Malmud, L. S., Rhodes, B. A., Bell, W. S., Wagner, H. N., Jr. Radiology, 1972, 103, 695. 7. Woodard, W. T. Jr., Day, E. D., Silver, D. Surgery, St. Louis, 1970, 68, 692. R.
J., Douglas, A.
an
indirect action
on
blood-flow, In
study, we measured the effect of subcutaneous heparin on blood-viscosity in eighteen normal volunteers and in sixteen surgical patients.
this
METHODS
1.
73.
a
contract
Requests for reprints should be addressed to G. J. W., Department of Nuclear Medicine, Marshfield Clinic, 1000 North Oak Avenue, Marshfield, Wisconsin 54449, U.S.A.
Ogston, D., Bennett, B., Herbert,
releases
1which reduces
no.
8.
V. V. KAKKAR D. A. LANE
S. Clin. Sci.
1973, 44,
of heparin was given by subcutaneous injection to normal volunteers and blood-viscosity was measured eighteen before and 2, 4, 6, and 8 hours after injection. Blood-viscosity was also determined in five normal subjects at similar intervals, but without injection of heparin. Sixteen surgical patients were given 5000 LU. of heparir subcutaneously before operation and at 8-hourly intervals for 10 days thereafter. Baseline viscosity measurements were ma. before operation, and again on the 4th postoperative da before and 5 hours after an injection of heparin. The 4th postoperative day was chosen because at this time fibrinogen concentration which increases postoperativelv has usually stabilised,9 and blood-viscosity and plasma-fibrinoge 5000
l.u.
*Present address: Department of Surgery, Weil Emil cal School, 29 Uzsoki Street, Budapest, Hungary.
Hospital, Medi
343
concentration are
directly related, especially
rates.10 Comparable blood-viscosity
at lower shearmeasurements were carried who did not receive
postoperatively in six patients arophylactic heparin. Ithole-blood viscosity was measured on 10 ml of venous blood anticoagulated with 125 I.U of solid lithium heparin. This amount of heparin, added in vitro, has been repeatedly shown to have no effect on blood-viscosity 11 12 and lipid cut
oètabo!ism.13 Blood
measurements were carried out at two shear-rates—0.77 and 2.62 s-1—by means of a Contraves lowshear viscometer. To eliminate the effect of alterations in hæmatocrit on viscosity, all measurements were corrected to a packed-cell volume of 45% using a haematocrit-viscosity relasion previously described.14 The fibrinogen and triglyceride ;mccntrations were determined in each sample by a thrombinclotting method" and a fluorometric method,16 respectively.
RESULTS
In normal
volunteers, no changes were observed in blood-viscosity 2 hours after the injection of heparin. However, blood-viscosity was significantly decreased 4 and 6 hours afterwards (P< 0.001). The mean decrease in viscosity was 13’7% when measured at a shear-rate of 0.77 s’ and 107%
shear-rate of 2.62 s.’ Bloodinitial levels 8 hours after injection (fig. 1). There were no fluctuations in the blood-viscosity of the control subjects who did not receive heparin. In the patients, there was the expected postoperative increase in blood-viscosity, due to the increase in plasmafibrinogen. By the 4th postoperative day the mean increase in blood-viscosity was 27% at 0.77 s-1 and 14% at 2.62 S,-1 when measured immediately before a heparin injection. Simultaneously, the mean increase in plasmafibrinogen was 736%. 5 hours after the injection of heparin the viscosity decreased by 9-8% at 0.77s-1 and 4.8% at 2.62 g4 (P
bladder within 15 minutes after injection. Similar results were obtained in all four patients and a normal
Preliminary Communications
control.
Discussion The capability of imaging thrombi, fresh and old, with a radioactive tagged material is the goal of several laboratories.2 5-8 The technique would predictably be atraumatic and of low morbidity, be applicable to old and fresh clots, and be available at most medium-sized community hospitals. Millar2 reported success with Tc-99m-labelled urokinase utilising a relatively easy tagging method which has been employed to label other proteins. This approach would represent a quick and easy solution to the problem and we attempted duplication of Millar’s work. Tc-99m pertechnetate and urokinase in the amounts used have been demonstrated to be safe in man. Our goal was display of thrombi. Direct evaluation of the end-result without extensive preliminary evaluation was believed justified and was pursued. Marginal encouragement was obtained from two of the studies but after four attempts it was apparent that satisfactory images were not being obtained. The rapid disappearance of radioactivity from the blood is consistent with the previous estimates of urokinase half-life of less than 15 minutes.7 The rapid disappearance of injected radioactivity, the low activity thighcounts, and the scintiscan appearance with very low activity are indications that the problem is not excess background activity. It does not seem useful to wait longer before imaging. Blood background has substantially disappeared within the time of our study. The problem is an inability to get sufficient activity to the clot rather than failure of clearing background. The great majority of injected activity (see table) is present in the liver and a large amount is in the bladder. The liver-counts probably represent a Tc/urokinase complex, possibly with !X2-macroglobulin.8 Studies are currently underway to document the nature of the liver and bladder activity. Our goal was to duplicate Millar’s2 successful thrombus imaging. We have gone directly to the endpoint of the process-production of a satisfactory diagnostic image-and have been unsuccessful. Evaluation of the chemical and physiological processes involved in labelling urokinase and in the lysis of thrombi by urokinase may in the future allow successful use of the system.
This work was supported by National Institutes of Health, N01-HB-42977 N.H.L.I.
EFFECT OF LOW-DOSE SUBCUTANEOUS HEPARIN ON WHOLE-BLOOD VISCOSITY A. ERDI* D. P. THOMAS
Thrombosis Research Unit, Department of Surgery, King’s College Hospital Medical School, Denmark Hill, London SE5 8RX
J. A. DORMANDY Clinical Research Laboratories, St. George’s Hospital Medical School, Blackshaw Road, London SW 17 0QT The change in blood-viscosity at low shear-rates (0·77 s-1 and 2·62 s-1 was measured in eighteen normal subjects and postoperatively in sixteen patients after administration of 5000 I.U. of subcutaneous heparin. In both groups there was a significant decrease in the mean blood-viscosity 4 to 6 hours after the injection of heparin. This fall in blood-viscosity may be involved in the prophylactic effect of low-dose subcutaneous heparin in preventing venous thrombosis.
Summary
INTRODUCTION
lipoprotein lipase from the tissues, blood-triglyceride concentrations and increases free fatty acid concentrations.3In four healthy subjects 10 000 i.u. of intravenous heparin altered the triglyceride concentration and the wholeblood viscosity in alimentary hyperlipaemia .4 Low-dose subcutaneous heparin is effective in preventing postoperative venous thromboembolism.5-1 Although heparin is known to have many actions, itis generally assumed that its effectiveness in preventing deep-vein thrombosis (D.V.T.) is primarily due to an effect on blood coagulation. However, if subcutaneous heparin also decreases blood-viscosity, then its prophylactic effect HEPARIN
may in part be due to
REFERENCES
Rhodes, B. A., Bell, W. R., Som, P. in International Symposium on Radiopharmaceuticals (edited by G. Subramanian, B. A. Rhodes, J. F. Cooper and V. J. Sodd). New York, 1975. 2 Millar, W. T., Smyth, J. F. B. Lancet, 1974, ii, 695. 3. Kempi, J., Van der Linden, W., Von Scheele, C. Br. med. J. 1974, iv, 748. 4. Johnson, A. J., Semar, M., Newman, J. in Blood Coagulation, Hemorrhage, and Thrombosis (edited by L. M. Tocantins and L. A. Kazal); p. 465. New York, 1964. 5. Coates, G., De Nardo, S. J., De Nardo, G. L., Troy, F. A. J. nucl. Med. 1975, 16, 136. 6. Sigel, M. E., Malmud, L. S., Rhodes, B. A., Bell, W. S., Wagner, H. N., Jr. Radiology, 1972, 103, 695. 7. Woodard, W. T. Jr., Day, E. D., Silver, D. Surgery, St. Louis, 1970, 68, 692. R.
J., Douglas, A.
an
indirect action
on
blood-flow, In
study, we measured the effect of subcutaneous heparin on blood-viscosity in eighteen normal volunteers and in sixteen surgical patients.
this
METHODS
1.
73.
a
contract
Requests for reprints should be addressed to G. J. W., Department of Nuclear Medicine, Marshfield Clinic, 1000 North Oak Avenue, Marshfield, Wisconsin 54449, U.S.A.
Ogston, D., Bennett, B., Herbert,
releases
1which reduces
no.
8.
V. V. KAKKAR D. A. LANE
S. Clin. Sci.
1973, 44,
of heparin was given by subcutaneous injection to normal volunteers and blood-viscosity was measured eighteen before and 2, 4, 6, and 8 hours after injection. Blood-viscosity was also determined in five normal subjects at similar intervals, but without injection of heparin. Sixteen surgical patients were given 5000 LU. of heparir subcutaneously before operation and at 8-hourly intervals for 10 days thereafter. Baseline viscosity measurements were ma. before operation, and again on the 4th postoperative da before and 5 hours after an injection of heparin. The 4th postoperative day was chosen because at this time fibrinogen concentration which increases postoperativelv has usually stabilised,9 and blood-viscosity and plasma-fibrinoge 5000
l.u.
*Present address: Department of Surgery, Weil Emil cal School, 29 Uzsoki Street, Budapest, Hungary.
Hospital, Medi
343
concentration are
directly related, especially
rates.10 Comparable blood-viscosity
at lower shearmeasurements were carried who did not receive
postoperatively in six patients arophylactic heparin. Ithole-blood viscosity was measured on 10 ml of venous blood anticoagulated with 125 I.U of solid lithium heparin. This amount of heparin, added in vitro, has been repeatedly shown to have no effect on blood-viscosity 11 12 and lipid cut
oètabo!ism.13 Blood
measurements were carried out at two shear-rates—0.77 and 2.62 s-1—by means of a Contraves lowshear viscometer. To eliminate the effect of alterations in hæmatocrit on viscosity, all measurements were corrected to a packed-cell volume of 45% using a haematocrit-viscosity relasion previously described.14 The fibrinogen and triglyceride ;mccntrations were determined in each sample by a thrombinclotting method" and a fluorometric method,16 respectively.
RESULTS
In normal
volunteers, no changes were observed in blood-viscosity 2 hours after the injection of heparin. However, blood-viscosity was significantly decreased 4 and 6 hours afterwards (P< 0.001). The mean decrease in viscosity was 13’7% when measured at a shear-rate of 0.77 s’ and 107%
shear-rate of 2.62 s.’ Bloodinitial levels 8 hours after injection (fig. 1). There were no fluctuations in the blood-viscosity of the control subjects who did not receive heparin. In the patients, there was the expected postoperative increase in blood-viscosity, due to the increase in plasmafibrinogen. By the 4th postoperative day the mean increase in blood-viscosity was 27% at 0.77 s-1 and 14% at 2.62 S,-1 when measured immediately before a heparin injection. Simultaneously, the mean increase in plasmafibrinogen was 736%. 5 hours after the injection of heparin the viscosity decreased by 9-8% at 0.77s-1 and 4.8% at 2.62 g4 (P
