A quantitative determination of perfusion fibrinolysis James A. O'Neill, Jr., M.D.,* Norman Ende, M.D., Isabella S. Collins, M.D., and Harold A. Collins, M.D., Nashville, Tenn. J—/xcessive bleeding following surgical pro- cedures involving cardiopulmonary bypass is a frequent phenomenon. It has been the opinion of some observers that trauma to blood is probably the causative factor and numerous modifications in pump, oxygena- tor, and suction equipment have been made on this account. 9 ' li The administration of massive quantities of blood has also been considered to be deleterious to normal clot- ting systems. 10 Efforts have been made to pin point the specific clotting defects which are responsi- ble for increased bleeding following extra- corporeal circulation in order that specific therapy might be effectively utilized. Plate- let, prothrombin, factor V, fibrinogen, and other deficiencies have occasionally been found to be contributory to postoperative bleeding. 4 - '• *• "• 1S Bleeding due to fibrinolysis is a well- recognized clinical entity, 2 but very little information is available concerning the ex- tent to which this phenomenon is involved in postperfusion bleeding. This investiga- tion was undertaken to obtain information From the Departments of Surgery and Pathology, Vander- bilt University Medical Center, and Veterans Adminis- tration Hospital, Nashville, Tenn. Supported in part by U. S. Public Health Service Grants HE-08195, HE-6567, and FR-95. Received for publication Dec. 20, 1965. •Present address: U. S. Army Surgical Research Unit, Brooke Army Medical Center, Fort Sam Houston, Texas. concerning the latter point and also to evaluate a new method of determining fibrinolytic activity. Methods Fifty consecutive patients who underwent cardiopulmonary bypass for various types of congenital and acquired heart disease were studied in a standard manner. Pre- operative hematologic studies included he- moglobin, hematocrit, white blood cell, dif- ferential, and platelet counts, and determi- nations of bleeding time, prothrombin, and partial thromboplastin generation times. Studies to determine the presence of fibrinolytic activity included determinations of whole blood clot lysis, euglobulin clot lysis time, and, also, Ende's adaptation of the Ratnoff and Menzie quantitative fibrino- gen assay for determining fibrinolysis. 10 The details of this have been described previ- ously/'- '- Blood was drawn, immediately placed in ice, and determinations were made within 4 hours. Samples were drawn from the primed pump and the patient prior to perfusion, from the patient at intervals dur- ing bypass, and from the patient after termination of bypass. Plasma hemoglobin determinations were made on samples of pump and patient blood at identical time intervals in order to compare the degree of fibrinolytic activity with the amount of hemolysis which occurred. Plasma hemo- globins were determined by Ham's modi- 777
A quantitative determination of perfusion fibrinolysis
Feb 12, 2023
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
A quantitative determination of perfusion fibrinolysisA quantitative determination of perfusion fibrinolysis James A. O'Neill, Jr., M.D.,* Norman Ende, M.D., Isabella S. Collins, M.D.,
and Harold A. Collins, M.D., Nashville, Tenn.
J—/xcessive bleeding following surgical pro- cedures involving cardiopulmonary bypass is a frequent phenomenon. It has been the opinion of some observers that trauma to blood is probably the causative factor and numerous modifications in pump, oxygena- tor, and suction equipment have been made on this account.9 ' l i The administration of massive quantities of blood has also been considered to be deleterious to normal clot- ting systems.10
Efforts have been made to pin point the specific clotting defects which are responsi- ble for increased bleeding following extra- corporeal circulation in order that specific therapy might be effectively utilized. Plate- let, prothrombin, factor V, fibrinogen, and other deficiencies have occasionally been found to be contributory to postoperative bleeding.4- '• *• "•1S
Bleeding due to fibrinolysis is a well- recognized clinical entity,2 but very little information is available concerning the ex- tent to which this phenomenon is involved in postperfusion bleeding. This investiga- tion was undertaken to obtain information
From the Departments of Surgery and Pathology, Vander- bilt University Medical Center, and Veterans Adminis- tration Hospital, Nashville, Tenn.
Supported in part by U. S. Public Health Service Grants HE-08195, HE-6567, and FR-95.
Received for publication Dec. 20, 1965. •Present address: U. S. Army Surgical Research Unit,
Brooke Army Medical Center, Fort Sam Houston, Texas.
concerning the latter point and also to evaluate a new method of determining fibrinolytic activity.
Methods
Fifty consecutive patients who underwent cardiopulmonary bypass for various types of congenital and acquired heart disease were studied in a standard manner. Pre- operative hematologic studies included he- moglobin, hematocrit, white blood cell, dif- ferential, and platelet counts, and determi- nations of bleeding time, prothrombin, and partial thromboplastin generation times.
Studies to determine the presence of fibrinolytic activity included determinations of whole blood clot lysis, euglobulin clot lysis time, and, also, Ende's adaptation of the Ratnoff and Menzie quantitative fibrino- gen assay for determining fibrinolysis.10 The details of this have been described previ- ously/'- '- Blood was drawn, immediately placed in ice, and determinations were made within 4 hours. Samples were drawn from the primed pump and the patient prior to perfusion, from the patient at intervals dur- ing bypass, and from the patient after termination of bypass. Plasma hemoglobin determinations were made on samples of pump and patient blood at identical time intervals in order to compare the degree of fibrinolytic activity with the amount of hemolysis which occurred. Plasma hemo- globins were determined by Ham's modi-
7 7 7
Thoracic and Cardiovascular Surgery
fication of Bing and Baker's method, as described by Crosby and Dameshek.^
The above data were compared with the amount of bleeding noted after heparin was neutralized with protamine, and also with the amount of hourly chest tube drainage and the amount of blood administration necessary in the postoperative period. Bleed- ing was considered significant if there was excessive oozing during closure, if 100 ml. of blood or more drained per hour during the first 6 hours postoperatively, or if ad- ministration of more than 1,000 ml. of blood was required during the same period.
A Kay-Cross rotating disc oxygenator and roller pump were utilized and standard techniques and flow rates were employed. Hypothermia of 30° to 33° C. was used in virtually every case. One thousand milli- liters of 10 per cent low molecular weight dextran in 0.9 per cent saline (Rheomac- rodex) were added to the perfusate in 40 of the 50 cases.
Results
Forty-eight of the 50 patients had pre- operative hematologic studies within the
range of normal. The 2 with abnormalities had excessive postoperative bleeding with evidence of fibrinolytic activity. Both of the latter patients had long-standing aortic ste- nosis with insufficiency. One of the 2 had a background of alcoholism, Bromsulpha- lein retention of 18 per cent in 45 minutes, and a prothrombin time of 16 seconds which did not respond to the administration of vitamin KL oxide. The other patient also had a prolonged prothrombin time of 16 seconds initially, but responded to vitamin K therapy before operation was undertaken.
Thirty-two of the 50 patients had exces- sive bleeding postoperatively. Three of these did not have evidence of fibrinolytic ac- tivity. Two of the latter 3 were re-explored and bleeding sites were found. The third patient required additional protamine which promptly controlled the oozing. One addi- tional patient who bled excessively required additional protamine and also had evidence of fibrinolysis.
Forty-nine of the 50 patients had some degree of plasma clot lysis on the quantita- tive assay, even though minimal in several instances (Fig. 1). It is of interest that the
% LYSIS
S O -
S O - -
5 0
4 0 - -
2 0 - -
BB B B B BB BB B B B B B BB
R BE
BB B
H0- R nri| nn n\ 10 20 30 40 50
PATIENTS
Fig. I. Relationship of excessive postoperative bleeding to degree of fibrinolysis.
Volume 51 Number 6 June, 1966
Perfusion fibrinolysis 7 7 9
1 patient who did not have any evidence of fibrinolytic activity and who did not bleed excessively had a IVi hour period of cardiopulmonary bypass. The highest plasma hemoglobin level in this patient was 97.5 mg. per 100 ml.
Whenever the quantitative assay for fibrinolytic activity was 50 per cent or higher, excessive bleeding occurred, and this was the case in 29 patients. Likewise, bleeding due to fibrinolysis was not a prob- lem when the quantitative assay of plasma clot lysis was less than 50 per cent. Minimal lysis was occasionally detected in pump and patient blood prior to perfusion. Fibrino- genolysis was possibly a problem in only 1 patient. Whole blood clot lysis was com- plete in the 29 patients with greater than 50 per cent plasma clot lysis and also in 2 others who did not bleed excessively and
who had negligible plasma clot lysis. Eu- globulin clot lysis time was 180 minutes or less and usually less than 60 minutes in all the 29 patients with greater than 50 per cent plasma clot lysis and also in 6 others who did not bleed and who had less than 50 per cent plasma clot lysis.
No consistent correlation could be made between plasma hemoglobin levels, the amount of coronary suction used, and sig- nificant degrees of fibrinolytic activity (over 50 per cent lysis) as measured by the quantitative assay. The 32 patients with excessive bleeding had plasma hemoglobin levels ranging from 52 to 990 mg. per 100 ml. The 18 nonbleeders had plasma hemo- globins ranging from 6 to 222 mg. per 100 ml. Those patients with plasma hemoglobin levels higher than 300 mg. per 100 ml. had excessive bleeding and significant quantita-
3 5 0 - -
3 0 0 - -
2 5 0 - -
Mg. % PLASMA z0°"
B B O j O B
D B. B B B
O o o o
PATIENTS
Fig. 2. Postoperative bleeding in relation to highest level of plasma hemoglobin.
7 8 0 O'Neill et al. Journal of
Thoracic and Cardiovascular
Bleeding related to fibrinolysis
Fig. 3. Postoperative bleeding and significant fibrinolysis in relation to perfusion time.
tive fibrinolytic activity (Fig. 2) . After eight of the fifty pump procedures,
large amounts of fibrin were noted on the filter screen of the oxygen ator. Seven of the 8 patients had excessive bleeding and evidence of significant fibrinolytic activity.
The longer the period of cardiopulmo- nary bypass, the greater the incidence of excessive bleeding. Thirty-one patients re- quired bypass for 55 minutes or more and 23 of these had excessive bleeding. Two of the latter number were re-explored and bleeding sites found. Nineteen patients had bypass for 35 minutes or less and 9 had excessive oozing. One of the latter 9 pa- tients required additional protamine ad- ministration and another had evidence of significant fibrinolytic activity as well as a need for additional protamine (Fig. 3) .
Bleeding was not excessive and only in- significant amounts of fibrinolytic activity were detected in 8 of the 10 patients who did not have low molecular weight dextran added to the perfusate. On the other hand, 27 of 40 patients who had dextran added to the perfusate had significant fibrinolysis.
None of the 50 patients died because of bleeding. In the 32 patients with excessive oozing, the oozing either stopped in time, or they were re-explored and a bleeding
site controlled, or they responded to the administration of additional protamine, fresh blood and/or epsilon amino caproic acid.
Comment
Activation of fibrinolytic systems has oc- casionally been implicated as the cause of uncontrollable bleeding during and follow- ing various types of operative proce- dures.2, 18 It would appear from these stud- ies that some degree of lysis occurs in al- most every patient either during or follow- ing cardiopulmonary bypass; however, this is not always significant (see Fig. 1). Simi- lar findings have been noted by Kevy and co-workers11 with the use of different meth- ods.
It is not possible from the available data to predict which patients will be liable to develop plasminogen activation except to say that the incidence is higher in those perfused for an hour or longer (see Fig. 3).
It has generally been held that trauma to blood is the main cause of bleeding di- atheses following extracorporeal circula- tion.9' " Activation of fibrinolytic systems is probably related in part to trauma, but not necessarily to red cell hemolysis. In this group of patients there was no correlation
Volume 51
Number 6
June, 1966
Perfusion fibrinolysis 7 8 1
between the level of plasma hemoglobin and fibrinolytic activity until the plasma hemoglobin was 300 mg. per 100 ml. or higher (see Fig. 2). Plasma hemoglobin levels are difficult to evaluate, however, be- cause of individual variations in clearance of hemoglobin by the kidneys and the re- ticuloendothelial system. There was also no correlation between lysis and the amount of coronary suction used. On the other hand, those who were perfused 55 minutes or longer had a higher incidence of lysis.
Certainly multiple clotting defects may occur during and following cardiopulmo- nary bypass,1- 7- ls but activation of fibrino- lytic systems would oppear to be the main defect. The so-called "heparin rebound" phenomenon occurred in 2 patients who re- quired additional protamine.17 This may simply represent mobilization of unneutral- ized heparin from the tissues and brings up the practicality of protamine titrations as part of a test battery on patients in whom there appears to be excessive oozing."
Several methods of determining the pres- ence of plasminogen activation are avail- able.1 • :i '' " Ui Whole blood clot lysis will usually indicate the presence of fibrinolysis, but it is not quantitative and difficult to cor- relate clinically. Also, it is not specific for it reflects the presence of other clotting de- fects, such as fibrinogenolysis, as well. The euglobulin test measures fibrinolysis after the inhibitors have been removed, and in this group of patients some "false positives" occurred, for the euglobulin lysis time was occasionally quite shortened when the quan- titative assay did not indicate the presence of significant amounts of fibrinolytic activity and clinically there was no evidence of ex- cessive bleeding. The quantitative assay of fibrinolytic activity was the only one of the three tests which correlated well with the amount of clinical bleeding. It is a sensitive method of determining even minute amounts of fibrinolytic activity. The test is not difficult to perform, and it is capable of providing information within 45 minutes, particularly when there is massive fibrinoly- sis. Although the administration of epsilon
amino caproic acid, which inhibits plasmin- ogen activation, is theoretically safe, diffi- culties from widespread thromboses have occurred with apparent overdosage." On this account, some objective indication that fibrinolysis is actually present is probably warranted prior to administration of this agent.
Although the figures are not statistically significant, there appeared to be a higher incidence of significant degrees of lysis when low molecular weight dextran was utilized in the perfusate for either short or long periods of bypass. Of related interest is the fact that in a study of 48 patients, Hell- strom and Bjork10 noted an increase in postoperative bleeding when low molecular weight dextran was used for hemodilution perfusion when the duration of perfusion was 90 minutes or more.
Summary
Fifty consecutive patients undergoing car- diopulmonary bypass procedures were evalu- ated from the standpoint of postoperative bleeding and its possible relationship to plasminogen activation. With the use of quantitative assay of fibrinolytic activity, it was found that some degree of activity is present in almost every patient undergoing bypass. This was found to be significant and related to excessive oozing in 29 of the 50 patients. The practical application of this assay is discussed.
REFERENCES
1 Adleson, E., and Roeder, W. H.: Studies of Fibrinolysis Using a Clinically Practical Method of Quantitative Determination, J. Clin. Path. 11: 82, 1958.
2 Astrup, T.: Fibrinolysis in the Organism, Blood 11: 781, 1956.
3 Astrup, T., and Mullertz, S.: The Fibrin Plate Method for Estimating Fibrinolytic Activity, Arch. Biochem. 40: 346, 1952.
4 Blomback, M., Noren, I., and Senning, A.: Coagulation Disturbance During Extracor- poreal Circulation and the Postoperative Period, Acta chir. scand. 127: 433, 1964.
5 Crosby, W. H., and Dameshek, W.: The Significance of Hemoglobinuria and Associated Hemosiderinuria With Particular Reference to
7 8 2 O'Neill et al.
Various Types of Hemolytic Anemia, J. Lab. &Cl in . Med. 38: 829, 1951.
6 Ende, N., and Auditore, J. V.: Activation of Fibrinolytic System in a Dog With Mast Cell Tumor, Am. J. Physiol. 206: 562, 1964.
7 Gans, H., and Krivit, W.: Problems in Hemostasis During Open-heart Surgery. IV. On the Changes in the Blood Clotting Mech- anism During Cardiopulmonary Bypass Pro- cedures, Ann. Surg. 155: 353, 1962.
8 Gans, H., Lillehei, C. W., and Krivit, W.: Problems in Hemostasis During Open-heart Surgery. I. On the Release of Plasminogen Activator, Ann. Surg. 154: 915, 1961.
9 Gibbon, J. H., Jr., and Camishion, R. C : Problems in Hemostasis With Extracorporeal Apparatus, Ann. New York Acad. Sc. 115: 195, 1964.
10 Hellstrom, G., and Bjork, V. O.: Hemodilu- tion With Rheomacrodex During Total Body Perfusion, J. THORACIC & CARDIOVAS. SURG. 45: 395, 1963.
11 Kevy, S. V., Glickman, R. M., Bernhard, W. F., Gross, R. E., and Diamond, L. K.: Quan- titative Assay of the Fibrinolytic System in Open Heart Surgery, S. Forum 15: 282, 1964.
12 Lankford, P. G.: A Quantitative Method for Measuring Fibrinolytic Activity in Humans, Am. J. Med. Tech. 33: 225, 1965.
13 Nilsson, I. M , and Olow, B.: Determination
Journal of
of Fibrinogen and Fibrinogenolytic Activity, Thromb. Diath. Haemorrh. 8: 297, 1962.
14 Osborn, J. J., Mackenzie, R., Shaw, A., Perkins, H., Hurt, R., and Gerbode, F.: Cause and Prevention of Hemorrhage Following Extracorporeal Circulation, S. Forum 6: 96, 1955.
15 Perkins, H. A., and Rolfs, M. R.: Quantita- tive Assay of Fibrinogen and Fibrinolytic Activity, Blood 22: 485, 1963.
16 Ratnoff, O. D., and Menzie, C : A New Method for the Determination of Fibrinogen in Small Samples of Plasma, J. Lab. & Clin. Med. 37: 316, 1951.
17 Salisbury, P. F., Miller, J. H., Morgenstern, L., Hyman, M. M., Shore, J. M., and State D.: Physiologic Factors in the Use of Pump Oxygenator, Tr. Am. Soc. Artif. Intern. Organs 1: 68, 1955.
18 Von Kaulla, K. N., and Swan, H.: Clotting Deviations in Man During Cardiac Bypass: Fibrinolysis and Circulating Anticoagulant, J. THORACIC SURG. 36: 519, 1958.
and Harold A. Collins, M.D., Nashville, Tenn.
J—/xcessive bleeding following surgical pro- cedures involving cardiopulmonary bypass is a frequent phenomenon. It has been the opinion of some observers that trauma to blood is probably the causative factor and numerous modifications in pump, oxygena- tor, and suction equipment have been made on this account.9 ' l i The administration of massive quantities of blood has also been considered to be deleterious to normal clot- ting systems.10
Efforts have been made to pin point the specific clotting defects which are responsi- ble for increased bleeding following extra- corporeal circulation in order that specific therapy might be effectively utilized. Plate- let, prothrombin, factor V, fibrinogen, and other deficiencies have occasionally been found to be contributory to postoperative bleeding.4- '• *• "•1S
Bleeding due to fibrinolysis is a well- recognized clinical entity,2 but very little information is available concerning the ex- tent to which this phenomenon is involved in postperfusion bleeding. This investiga- tion was undertaken to obtain information
From the Departments of Surgery and Pathology, Vander- bilt University Medical Center, and Veterans Adminis- tration Hospital, Nashville, Tenn.
Supported in part by U. S. Public Health Service Grants HE-08195, HE-6567, and FR-95.
Received for publication Dec. 20, 1965. •Present address: U. S. Army Surgical Research Unit,
Brooke Army Medical Center, Fort Sam Houston, Texas.
concerning the latter point and also to evaluate a new method of determining fibrinolytic activity.
Methods
Fifty consecutive patients who underwent cardiopulmonary bypass for various types of congenital and acquired heart disease were studied in a standard manner. Pre- operative hematologic studies included he- moglobin, hematocrit, white blood cell, dif- ferential, and platelet counts, and determi- nations of bleeding time, prothrombin, and partial thromboplastin generation times.
Studies to determine the presence of fibrinolytic activity included determinations of whole blood clot lysis, euglobulin clot lysis time, and, also, Ende's adaptation of the Ratnoff and Menzie quantitative fibrino- gen assay for determining fibrinolysis.10 The details of this have been described previ- ously/'- '- Blood was drawn, immediately placed in ice, and determinations were made within 4 hours. Samples were drawn from the primed pump and the patient prior to perfusion, from the patient at intervals dur- ing bypass, and from the patient after termination of bypass. Plasma hemoglobin determinations were made on samples of pump and patient blood at identical time intervals in order to compare the degree of fibrinolytic activity with the amount of hemolysis which occurred. Plasma hemo- globins were determined by Ham's modi-
7 7 7
Thoracic and Cardiovascular Surgery
fication of Bing and Baker's method, as described by Crosby and Dameshek.^
The above data were compared with the amount of bleeding noted after heparin was neutralized with protamine, and also with the amount of hourly chest tube drainage and the amount of blood administration necessary in the postoperative period. Bleed- ing was considered significant if there was excessive oozing during closure, if 100 ml. of blood or more drained per hour during the first 6 hours postoperatively, or if ad- ministration of more than 1,000 ml. of blood was required during the same period.
A Kay-Cross rotating disc oxygenator and roller pump were utilized and standard techniques and flow rates were employed. Hypothermia of 30° to 33° C. was used in virtually every case. One thousand milli- liters of 10 per cent low molecular weight dextran in 0.9 per cent saline (Rheomac- rodex) were added to the perfusate in 40 of the 50 cases.
Results
Forty-eight of the 50 patients had pre- operative hematologic studies within the
range of normal. The 2 with abnormalities had excessive postoperative bleeding with evidence of fibrinolytic activity. Both of the latter patients had long-standing aortic ste- nosis with insufficiency. One of the 2 had a background of alcoholism, Bromsulpha- lein retention of 18 per cent in 45 minutes, and a prothrombin time of 16 seconds which did not respond to the administration of vitamin KL oxide. The other patient also had a prolonged prothrombin time of 16 seconds initially, but responded to vitamin K therapy before operation was undertaken.
Thirty-two of the 50 patients had exces- sive bleeding postoperatively. Three of these did not have evidence of fibrinolytic ac- tivity. Two of the latter 3 were re-explored and bleeding sites were found. The third patient required additional protamine which promptly controlled the oozing. One addi- tional patient who bled excessively required additional protamine and also had evidence of fibrinolysis.
Forty-nine of the 50 patients had some degree of plasma clot lysis on the quantita- tive assay, even though minimal in several instances (Fig. 1). It is of interest that the
% LYSIS
S O -
S O - -
5 0
4 0 - -
2 0 - -
BB B B B BB BB B B B B B BB
R BE
BB B
H0- R nri| nn n\ 10 20 30 40 50
PATIENTS
Fig. I. Relationship of excessive postoperative bleeding to degree of fibrinolysis.
Volume 51 Number 6 June, 1966
Perfusion fibrinolysis 7 7 9
1 patient who did not have any evidence of fibrinolytic activity and who did not bleed excessively had a IVi hour period of cardiopulmonary bypass. The highest plasma hemoglobin level in this patient was 97.5 mg. per 100 ml.
Whenever the quantitative assay for fibrinolytic activity was 50 per cent or higher, excessive bleeding occurred, and this was the case in 29 patients. Likewise, bleeding due to fibrinolysis was not a prob- lem when the quantitative assay of plasma clot lysis was less than 50 per cent. Minimal lysis was occasionally detected in pump and patient blood prior to perfusion. Fibrino- genolysis was possibly a problem in only 1 patient. Whole blood clot lysis was com- plete in the 29 patients with greater than 50 per cent plasma clot lysis and also in 2 others who did not bleed excessively and
who had negligible plasma clot lysis. Eu- globulin clot lysis time was 180 minutes or less and usually less than 60 minutes in all the 29 patients with greater than 50 per cent plasma clot lysis and also in 6 others who did not bleed and who had less than 50 per cent plasma clot lysis.
No consistent correlation could be made between plasma hemoglobin levels, the amount of coronary suction used, and sig- nificant degrees of fibrinolytic activity (over 50 per cent lysis) as measured by the quantitative assay. The 32 patients with excessive bleeding had plasma hemoglobin levels ranging from 52 to 990 mg. per 100 ml. The 18 nonbleeders had plasma hemo- globins ranging from 6 to 222 mg. per 100 ml. Those patients with plasma hemoglobin levels higher than 300 mg. per 100 ml. had excessive bleeding and significant quantita-
3 5 0 - -
3 0 0 - -
2 5 0 - -
Mg. % PLASMA z0°"
B B O j O B
D B. B B B
O o o o
PATIENTS
Fig. 2. Postoperative bleeding in relation to highest level of plasma hemoglobin.
7 8 0 O'Neill et al. Journal of
Thoracic and Cardiovascular
Bleeding related to fibrinolysis
Fig. 3. Postoperative bleeding and significant fibrinolysis in relation to perfusion time.
tive fibrinolytic activity (Fig. 2) . After eight of the fifty pump procedures,
large amounts of fibrin were noted on the filter screen of the oxygen ator. Seven of the 8 patients had excessive bleeding and evidence of significant fibrinolytic activity.
The longer the period of cardiopulmo- nary bypass, the greater the incidence of excessive bleeding. Thirty-one patients re- quired bypass for 55 minutes or more and 23 of these had excessive bleeding. Two of the latter number were re-explored and bleeding sites found. Nineteen patients had bypass for 35 minutes or less and 9 had excessive oozing. One of the latter 9 pa- tients required additional protamine ad- ministration and another had evidence of significant fibrinolytic activity as well as a need for additional protamine (Fig. 3) .
Bleeding was not excessive and only in- significant amounts of fibrinolytic activity were detected in 8 of the 10 patients who did not have low molecular weight dextran added to the perfusate. On the other hand, 27 of 40 patients who had dextran added to the perfusate had significant fibrinolysis.
None of the 50 patients died because of bleeding. In the 32 patients with excessive oozing, the oozing either stopped in time, or they were re-explored and a bleeding
site controlled, or they responded to the administration of additional protamine, fresh blood and/or epsilon amino caproic acid.
Comment
Activation of fibrinolytic systems has oc- casionally been implicated as the cause of uncontrollable bleeding during and follow- ing various types of operative proce- dures.2, 18 It would appear from these stud- ies that some degree of lysis occurs in al- most every patient either during or follow- ing cardiopulmonary bypass; however, this is not always significant (see Fig. 1). Simi- lar findings have been noted by Kevy and co-workers11 with the use of different meth- ods.
It is not possible from the available data to predict which patients will be liable to develop plasminogen activation except to say that the incidence is higher in those perfused for an hour or longer (see Fig. 3).
It has generally been held that trauma to blood is the main cause of bleeding di- atheses following extracorporeal circula- tion.9' " Activation of fibrinolytic systems is probably related in part to trauma, but not necessarily to red cell hemolysis. In this group of patients there was no correlation
Volume 51
Number 6
June, 1966
Perfusion fibrinolysis 7 8 1
between the level of plasma hemoglobin and fibrinolytic activity until the plasma hemoglobin was 300 mg. per 100 ml. or higher (see Fig. 2). Plasma hemoglobin levels are difficult to evaluate, however, be- cause of individual variations in clearance of hemoglobin by the kidneys and the re- ticuloendothelial system. There was also no correlation between lysis and the amount of coronary suction used. On the other hand, those who were perfused 55 minutes or longer had a higher incidence of lysis.
Certainly multiple clotting defects may occur during and following cardiopulmo- nary bypass,1- 7- ls but activation of fibrino- lytic systems would oppear to be the main defect. The so-called "heparin rebound" phenomenon occurred in 2 patients who re- quired additional protamine.17 This may simply represent mobilization of unneutral- ized heparin from the tissues and brings up the practicality of protamine titrations as part of a test battery on patients in whom there appears to be excessive oozing."
Several methods of determining the pres- ence of plasminogen activation are avail- able.1 • :i '' " Ui Whole blood clot lysis will usually indicate the presence of fibrinolysis, but it is not quantitative and difficult to cor- relate clinically. Also, it is not specific for it reflects the presence of other clotting de- fects, such as fibrinogenolysis, as well. The euglobulin test measures fibrinolysis after the inhibitors have been removed, and in this group of patients some "false positives" occurred, for the euglobulin lysis time was occasionally quite shortened when the quan- titative assay did not indicate the presence of significant amounts of fibrinolytic activity and clinically there was no evidence of ex- cessive bleeding. The quantitative assay of fibrinolytic activity was the only one of the three tests which correlated well with the amount of clinical bleeding. It is a sensitive method of determining even minute amounts of fibrinolytic activity. The test is not difficult to perform, and it is capable of providing information within 45 minutes, particularly when there is massive fibrinoly- sis. Although the administration of epsilon
amino caproic acid, which inhibits plasmin- ogen activation, is theoretically safe, diffi- culties from widespread thromboses have occurred with apparent overdosage." On this account, some objective indication that fibrinolysis is actually present is probably warranted prior to administration of this agent.
Although the figures are not statistically significant, there appeared to be a higher incidence of significant degrees of lysis when low molecular weight dextran was utilized in the perfusate for either short or long periods of bypass. Of related interest is the fact that in a study of 48 patients, Hell- strom and Bjork10 noted an increase in postoperative bleeding when low molecular weight dextran was used for hemodilution perfusion when the duration of perfusion was 90 minutes or more.
Summary
Fifty consecutive patients undergoing car- diopulmonary bypass procedures were evalu- ated from the standpoint of postoperative bleeding and its possible relationship to plasminogen activation. With the use of quantitative assay of fibrinolytic activity, it was found that some degree of activity is present in almost every patient undergoing bypass. This was found to be significant and related to excessive oozing in 29 of the 50 patients. The practical application of this assay is discussed.
REFERENCES
1 Adleson, E., and Roeder, W. H.: Studies of Fibrinolysis Using a Clinically Practical Method of Quantitative Determination, J. Clin. Path. 11: 82, 1958.
2 Astrup, T.: Fibrinolysis in the Organism, Blood 11: 781, 1956.
3 Astrup, T., and Mullertz, S.: The Fibrin Plate Method for Estimating Fibrinolytic Activity, Arch. Biochem. 40: 346, 1952.
4 Blomback, M., Noren, I., and Senning, A.: Coagulation Disturbance During Extracor- poreal Circulation and the Postoperative Period, Acta chir. scand. 127: 433, 1964.
5 Crosby, W. H., and Dameshek, W.: The Significance of Hemoglobinuria and Associated Hemosiderinuria With Particular Reference to
7 8 2 O'Neill et al.
Various Types of Hemolytic Anemia, J. Lab. &Cl in . Med. 38: 829, 1951.
6 Ende, N., and Auditore, J. V.: Activation of Fibrinolytic System in a Dog With Mast Cell Tumor, Am. J. Physiol. 206: 562, 1964.
7 Gans, H., and Krivit, W.: Problems in Hemostasis During Open-heart Surgery. IV. On the Changes in the Blood Clotting Mech- anism During Cardiopulmonary Bypass Pro- cedures, Ann. Surg. 155: 353, 1962.
8 Gans, H., Lillehei, C. W., and Krivit, W.: Problems in Hemostasis During Open-heart Surgery. I. On the Release of Plasminogen Activator, Ann. Surg. 154: 915, 1961.
9 Gibbon, J. H., Jr., and Camishion, R. C : Problems in Hemostasis With Extracorporeal Apparatus, Ann. New York Acad. Sc. 115: 195, 1964.
10 Hellstrom, G., and Bjork, V. O.: Hemodilu- tion With Rheomacrodex During Total Body Perfusion, J. THORACIC & CARDIOVAS. SURG. 45: 395, 1963.
11 Kevy, S. V., Glickman, R. M., Bernhard, W. F., Gross, R. E., and Diamond, L. K.: Quan- titative Assay of the Fibrinolytic System in Open Heart Surgery, S. Forum 15: 282, 1964.
12 Lankford, P. G.: A Quantitative Method for Measuring Fibrinolytic Activity in Humans, Am. J. Med. Tech. 33: 225, 1965.
13 Nilsson, I. M , and Olow, B.: Determination
Journal of
of Fibrinogen and Fibrinogenolytic Activity, Thromb. Diath. Haemorrh. 8: 297, 1962.
14 Osborn, J. J., Mackenzie, R., Shaw, A., Perkins, H., Hurt, R., and Gerbode, F.: Cause and Prevention of Hemorrhage Following Extracorporeal Circulation, S. Forum 6: 96, 1955.
15 Perkins, H. A., and Rolfs, M. R.: Quantita- tive Assay of Fibrinogen and Fibrinolytic Activity, Blood 22: 485, 1963.
16 Ratnoff, O. D., and Menzie, C : A New Method for the Determination of Fibrinogen in Small Samples of Plasma, J. Lab. & Clin. Med. 37: 316, 1951.
17 Salisbury, P. F., Miller, J. H., Morgenstern, L., Hyman, M. M., Shore, J. M., and State D.: Physiologic Factors in the Use of Pump Oxygenator, Tr. Am. Soc. Artif. Intern. Organs 1: 68, 1955.
18 Von Kaulla, K. N., and Swan, H.: Clotting Deviations in Man During Cardiac Bypass: Fibrinolysis and Circulating Anticoagulant, J. THORACIC SURG. 36: 519, 1958.
Related Documents
