Coagulation Defects and Bleeding in Open-Heart Surgery

Transcription

1 Coagulation Defects and Bleeding in Open-Heart Surgery Enrique E. Signori, M.D., John A. Penner, M.D., and Donald R. Kahn, M.D. H emorrhagic diathesis associated with extracorporeal circulation has been described by a number of investigators, many of whom have emphasized the presence of specific coagulation defects [ 1, 6, 10, 11, Unfortunately, information on the clinical significance of these abnormalities with respect to incidence and their effect on hemostasis has been lacking. With the increasing use of extracorporeal circulation in cardiac surgery, there is a demand for a means of evaluating the adequacy of hemostasis. As a consequence, the interpretation of the results of routine coagulation procedures has agsumed greater importance. The following study was undertaken to provide such information and includes a description of 50 patients, 15 with excessive blood loss and 35 with normal postoperative blood loss. It was presumed correctly that a distinct separation of the two groups of patients could be made on the basis of the coagulation studies. PA TIENT SELECTION Excessive bleeding was observed in 15 patients selected for study. An additional group of 35 patients without excessive bleeding was evaluated. Bleeding was considered significant in adults when observed to continue in excess of 100 ml. per hour in the immediate postoperative period. A lesser but proportional value was considered excessive for children. The Sarns roller-pump oxygenator system was employed in all cases. The pump reservoir required 8 units of fresh heparinized blood, obtained within 24 hours prior to operation. Heparin was administered to the patients in a dosage of 3 mg. per kilogram of body weight. Protamine sulfate, in a similar amount by weight, was used to neutralize circulating heparin immediately after operation. Blood specimens were collected by a two-syringe technique into 3.8% sodium citrate (1:9), ordinarily as soon as the patient arrived in the recovery room. Preoperative specimens were obtained from most of the patients studied. From the Departments of Internal Medicine (Simpson Memorial Institute) and Surgery, University of Michigan Medical Center, Ann Arbor, Mich. Supported by a grant from the Michigan Heart Association. Accepted for publication June 13, Address reprint requests to Dr. Penner, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Mich VOL. 8, NO. 6, DECEMBER,

2 SIGNORI, PENNER, AND KAHN MATERIALS AND METHODS The following coagulation procedures were employed: prothrombin time [ 151; partial thromboplastin time [9];' platelet count, phase microscopy method of Brecher and Cronkite [21; euglobulin lysis time, whole blood t71; fibrinogen agglutination test (Fi test).t A thrombin clotting time was performed on citrated whole blood. Thrombin,$ 3 units in 0.1 ml., was added to blood, 0.4 ml., in a plastic tube at 37 C. The normal thrombin clotting time by this method [121 ranged from 18 to 24 seconds. Values exceeding 180 seconds indicated the presence of heparin activity greater than 0.18 p per milliliter of blood. RESULTS Twenty-four patients with acquired heart disease and 26 with congenital heart disease were included in the study. It should be emphasized that the patients studied were a selected group, and therefore the data do not permit an estimation of the incidence of hemorrhage with a specific form of heart disease or operative procedure. Significant coagulation defects were demonstrated in 13 of 15 patients with documented excessive postoperative bleeding. Data obtained on patients who did not exhibit hemorrhagic complications postoperatively are shown in Table 1. It is interesting to note the rather wide variation in results obtained in nonbleeding patients, both preoperatively and postoperatively. Many of the preoperative abnormalities probably were related to hepatic congestion and did not appear to affect hemostasis during or after operation. Results in the postoperative period often were markedly abnormal, indicating seemingly severe disturbances in coagulation; however, the lack of excessive bleeding in the face of extensive operation demonstrated the adequacy of hemostasis. Not included in the table are 5 patients studied during this period who were treated prophylactically when significantly abnormal postoperative values were obtained. Partial thromboplastin times greater than 3 minutes (control, 80 seconds) and prothrombin times greater than 18 seconds were noted in 3 of these patients. Excessive heparin activity (as indicated by the thrombin time) probably was responsible for the prolonged values in 2, while the third patient had severe liver disease and exhibited a marked prolongation of the prothrombin time (20.7 seconds) in addition to thrombocytopenia (35,000 platelets per cubic millimeter of blood). Excessive fibrinolysin activity was observed in the other 2 patients, as indicated by euglobulin lysis time of less than one hour. Following the administration of appropriate therapy, the postoperative courses were uneventful. The patients exhibiting excessive bleeding during the postoperative period are listed in Table 2. Specific and severe defects were demonstrable in 13 cases and can be grouped in four categories: 1. Excessive heparin activity appeared to be partially or completely responsible for bleeding in 6 instances, as indicated by a prolonged thrombin time of greater than 40 seconds (twice normal value). The abnormal result could be corrected in vitro with protamine sulfate. Administration of this drug (approximately 1.2 mg. per kilogram of body weight) produced a prompt decrease in blood loss. 2. Thrombocytopenia contributed to hemorrhagic tendency in 7 patients. Platelet counts of less than 60,000 per cubic millimeter were observed in this group. Administration of platelet-rich plasma improved hemostasis to the extent 'Cephaloplastin was employed during the earlier part of the study and Activated Cephaloplastin during the latter part. (Dade Laboratories, Miami, Fla.) thyland Laboratories, Los Angeles, Calif. $Thrombin, Topical, Parke, Davis & Co., Detroit, Mich. 522 THE ANNALS OF THORACIC SURGERY

3 < TABLE 1. COAGULATION STUDIES IN NONBLEEDING PATIENTS Platelet Count Prothrombin Partial Thromboplastin Time' (sec.) Euglobulin Thrombin Lvsis Time Values (per mm.3) Time kec.) Activated Nonactivated Time (sec.) (min.) Normal zoo x > 120 Preoperative (33 patients) 0 Mean f SD r 241 f 45 x lo & f f f 1.1 > 120,CO Postoperative z (35 patients) P Mean f SD 141 f 26 x lo f f f ' Q, U M s p "Two patients had complete lysis within one hour and 4 had partial lysis within two hours. Specimens from the remaining 29 were not lysed within two hours.

4 ur cp N TABLE 2. COAGULATION STUDIES IN BLEEDING PATIENTS Patient No. & Age L mo Prothrombin Time Procedure (sec.) Aortic Starr-Edwards Correction of V.S.D.c Correction of A.S.D.d Mitral & aortic Starr-Edwards Aneurysmectomy Mitral valvuloplasty Aortic valvuloplasty Aortic Starr-Edwards Correction of V.S.D. Mitral Starr-Edwards Correction of A.SD.d Correction of A.S.D.d Correction of A.S.D.d Mitral Starr-Edwards Mitidl Starr-Edwards o Partial Thromboplastin Tinic (set.)" >180.0 (80) 78.0 (45) >180.0 (80) (80) 80.6 (80) 53.1 (80) (80) 62.9 (45) 57.6 (45) 34.1 (45) 35.8 (45) 57.9 (45) >180.0 (80) 43.2 (45) 79.9 (80) 87.9 (80) Thrombin Time (sec.) > > > d Fibrinogen Control values are indicated in parentheses. bblood replacement employed as necessary, with whole blood stored for variable periods up to 21 days. Wentricular septal defect. datrial septal defect. Thrombocytopenia developed 24 hours after neutralization of excessive heparin. Epsilon amino caproic acid. Platelet Count (per mm?) 120, , ,000 72, ,000 22,000 56,000 48,000 54,000 56,000 52,000 15, , , ,000 lg4,ooo Euglobulin Lysis Time (min.) 75 min Therapy Protamine sulfate Protaniine sulfate Protamine sulfate Protamine sulfate Protamine sulfate Protamine sulfate E.A.C.A.f E.A.C.A. Surgical correction Surgical correction

5 Coagulation Defects in Open-Heart Szrrgery that blood loss diminished markedly and the patients recoveries proceeded normally. The relationship between the degree of thrombocytopenia and the length of time on the pump oxygenator was examined. An increased incidence of thrombocytopenia (less than 100,000 platelets per cubic millimeter) was associated with pump runs of greater than one hour (10 of 27 cases) as opposed to those of less than one hour (3 of 13 cases). 3. Excessiue fibrinolytic activity, as indicated by the complete lysis of euglobulin clot within one hour, was associated with bleeding in 3 patients. There appeared to be no significant relationship between the period of time on the pump and the appearance of fibrinolytic activity. 4. Plasma factor deficiencies were noted in the bleeding as well as in the nonbleeding patients. Specific deficiencies were not believed to be responsible for excessive blood loss in any of the patients studied, although such deficiencies may have contributed to the hemorrhagic diatheses. COMMENT Coagulation defects developing as a result of extracorporeal circulation have been reported by a number of investigators. A marked increase in fibrinolytic activity and the appearance of a circulating anticoagulant, other than heparin, have been described by von Kaulla and Swan [18]. Other investigators [l, 3, 4, 10, 141 also have implicated the fibrinolytic system as the primary factor in the etiology of hemorrhage. Results of the present study would indicate that fibrinolysin is less frequently responsible for bleeding in the postoperative period and, in contrast to previous reports [18], is observed primarily in patients with congenital rather than acquired heart diseases. A shortening of the euglobulin lysis time was found in 6 of the nonbleeding patients; however, it would appear that fibrinolysin was responsible for bleeding only when sufficient activity was present to shorten the euglobulin lysis time to less than one hour. In these situations, epsilon amino caproic acid (E.A.C.A.) administered intravenously in a dose of 1 to 2 gm. (30 mg. per kilogram of body weight) every two hours effectively controlled hemostasis. It should be noted that the euglobulin lysis test depends upon the presence of an adequate fibrinogen substrate; therefore, hypofibrinogenemia, occurring secondary to intravascular coagulation, could be responsible for the appearance of rapid clot lysis. In such instances, the addition of human fibrinogen or normal human plasma to the test system provides sufficient fibrinogen substrate to assess the fibrinolytic activity. Fibrinogen was judged to be sufficient in all the patients studied, as indicated by a positive Fi agglutination reaction and the initial appearance of a firm euglobulin clot. The latter finding is of particular value because it provides a visual means of estimating the quantity of fibrin present. The Fi test may be affected by split products of fibrin generated by the action of fibrinolysin or thrombin on fibrin. Inadequate neutralization of circulating heparin activity, fre- VOL. 8, NO. 6, DECEMBER,

6 SIGNORI, PENNER, AND KAHN quently seen during the early period of this study, was easily evaluated by means of the thrombin clotting time. The in vitro addition of protamine sulfate, with corresponding correction of the clotting time, fulfilled the criteria for the diagnosis. The effect of heparin also was noted on other clotting-time assays. A decrease in prothrombin time values and partial thromboplastin time could be obtained with neutralization of heparin activity. Administration of protamine sulfate to patients with prolonged thrombin times produced a prompt cessation of bleeding and returned thrombin time values to normal. In several of the clinical situations recorded, heparin activity reappeared and necessitated administration of an additional 50 to 100 mg. of protamine sulfate despite the use of supposedly adequate neutralizing doses. The excess heparin may have appeared as a result of diffusion from extravascular spaces. In the experience of one of the authors, this latter possibility seems to be particularly noticeable in infants and young children exposed to disproportionately large concentrations of heparin. Regarding determination of the neutralizing dose of protamine sulfate, it should be emphasized that administration of an excess of this agent, over and above the amount required to neutralize circulating heparin (greater than 1.2 mg. per kilogram of body weight), can interfere with coagulation and may intensify hemorrhagic problems [5]. Thrombocytopenia was commonly seen postoperatively and was responsible for excessive bleeding in a number of patients. Evidence was obtained to indicate that platelet counts decreased by at least one-third during operation, corresponding to information previously published [5, 8, 11, 13, 161. Longer procedures requiring continuous use of extracorporeal circulation reduced platelet counts to lower levels. In addition to the thrombocytopenia, a qualitative platelet defect has been observed consistently after operation. Poor clot retraction and delayed prothrombin consumption [14] were observed in all patients studied and probably reflect the function of platelets derived from the donor blood used to prime the pump. Other properties of the platelets, agglutination and adhesiveness, probably are affected in a similar manner; but these have not been evaluated. Administration of platelet-rich plasma, or platelet concentrates obtained by plasmaphoresis, has provided effective platelet replacement. Blood loss has been dramatically reduced following the rapid administration of as little as 2 units, although larger quantities of platelet concentrate equivalent to 4 to 6 units of platelet-rich plasma are required for most adults. Plasma-factor deficiencies are common following extracorporeal circulation. Abnormalities in prothrombin time and partial thromboplastin time are frequently seen and apparently are not significant, judging by the range of results seen in the patients who did not develop excessive bleeding. It would appear from the data presented that there 526 THE ANNALS OF THORACIC SURGERY

7 Coagulation Defects in Open-Heart Surgery is an acceptable level of abnormality which does not indicate a need for correctional therapy. This information has been helpful when attempting to evaluate patients who require surgical correction of their bleeding. Results within the range ordinarily seen in the nonbleeding group would indicate that very active bleeding is due to a vascular lesion. In these situations it is not necessary to await a trial of therapy with various hemostatic agents. In several instances, plasma-factor deficiencies have appeared severe enough for therapy to be considered. The patient noted to have severe liver disease with marked prolongation of partial thromboplastin time and prothrombin time, in addition to thrombocytopenia, received platelet-rich plasma prophylactically to correct deficiencies that probably would have led to hemorrhage. It can be concluded that a careful evaluation of patients returning from open-heart surgery is necessary to define coagulation defects. Specific therapy is available and when used is effective. Lacking this information, the only alternative is to proceed with the ineffective administration of large quantities of blood. Such management frequently compounds cardiovascular and hemorrhagic complications and leads eventually to repeated surgical explorations that increase the risk. Interpretation of laboratory values obtained on patients who develop postoperative bleeding may be the responsibility of specialists other than the surgeon. Provided that these specialists are aware of the abnormalities frequently seen following this type of operation, it is possible that rational and effective therapy can be advised on the basis of results obtained from procedures considered to be routine in most hospital laboratories. In this regard it would appear that determination of the platelet count, prothrombin time, partial thromboplastin time, thrombin clotting time, and euglobulin lysis time provides an adequate means of evaluation. Of additional interest is the application of information obtained from this selected group of patients to problems of hemostasis that develop in patients requiring less complex surgical procedures. SUMMARY Hemostasis was evaluated in 50 patients who underwent operations requiring extracorporeal circulation (24 with acquired and 26 with congenital heart disease). Of 15 patients exhibiting excessive bleeding, 13 developed significant coagulation defects, including fibrinolytic activity, excessive heparin activity, and thrombocytopenia. Excessive heparin activity appeared to be primarily responsible for bleeding when the thrombin time exceeded 40 seconds (twice the normal value). Thrombocytopenia was associated with hemorrhage when platelet counts were less than 60,000. Increased fibrinolytic activity was present in 9 patients, 3 of whom developed active bleeding. VOL. 8, NO. 6, DECEMBER,

8 SIGNORI, PENNER, AND KAHN Hemostasis was improved in all the hemorrhagic cases following administration of therapy advised on the basis of data obtained from routine coagulation studies. ACKNOWLEDGMENT The authors gratefully acknowledge the technical assistance of Mrs. Temple M. Lum and the assistance of Dr. Muriel C. Meyers, who reviewed this manuscript. REFERENCES Bloom, A. L. Activation of coagulation and fibrinogen loss after using an extracorporeal circulation. J. Clin. Path. 16:558, Brecher, G., and Cronkite, E. P. Estimation of the Number of Platelets by Phase Microscopy. In L. M. Tocantins and L. A. Kazal (Eds.), Blood Coagulution, Hemorrhage and Thrombosis. New York: Grune & Stratton, Brown, I. W., Jr., and Smith, W. W. Hematological problems associated with the use of extracorporeal circulation for cardiovascular surgery. Ann. Intern. Med. 49: 1035, Gans, H., Lillehei, C. W., and Krivit, W. Problems in hemostasis during open heart surgery: I. On the release of plasminogen activator. Ann. Surc 154: Heinrick, R., and Noe, E. Fibrinolytic changes in the dog in response to protamine sulfate as demonstrated by a new and rapid method (abstract No. 287). Fed. Proc. 15:90, Hoeksema, T. D. D., Mustard, J. R., and Mustard, W. T. A study of some coagulation factor changes occurring in blood during extracorporeal circulation. Trans. Amer. SOC. Artif. Intern. Organs 5:225, Johnson, A. J., Semar, M., and Newman, J. Estimation of Fibrinolytic Activity by Whole-Blood Euglobulin Clot Lysis. In L. M. Tocantins and L. A. Kazal (Eds.), Blood Coagulation, Hemorrhage and Thrombosis. New York: Grune & Stratton, Kendall, A. G., and Lowenstein, L. Alterations in blood coagulation and hemostasis during extracorporeal circulation: Parts I & 11. Canad. Med. Ass. J. 87:786, Langdell, R. D., Wagner, R. H., and Brinkhous, K. M. Determination of Partial Thromboplastin Time (PTT). In L. M. Tocantins and L. A. Kazal (Eds.), Blood Coagulation, Hemorrhage and Thrombosis. New York: Grune & Stratton, Ollendorf, P., Storm, O., Rygg, I., and Arnfred, E. Activation of the thromboplastic and the fibrinolytic systems during extracorporeal circulation. Acta Chir. Scand. 112:217, Penick, A. D., Averette, H. E., Jr., Peters, R. M., and Brinkhous, K. M. Hemorrhagic syndrome complicating extracorporeal shunting of blood. Thromb. Diath. Haemorrh. 2:218, Penner, J. Circulating heparin activity determined by the thrombin clotting time (abstract). Clin. Res. 14:257, Perkins, H. A., Osborn, J. J., and Gerbode, T. Problems in Coagulation. In J. G. Allen (Ed.), Extracorporeal Circulation. Springfield, Ill.: Thomas, Phillips, L. L., Malma, J. R., and Deterling, R. A., Jr. Coagulation defects following extracorporeal circulation. Ann. Surg. 157:317, Hemorrhagic Diseases. Philadelphia: Lea & Febiger, Bleeding after perfusion for open heart Quick, A. J. Rothnie, N. G., and Kinmoth, J. B. 528 THE ANNALS OF THORACIC SURGERY

9 Coagulation Defects in Open-Heart Surgery surgery: Importance of unneutralized heparin and its proper correction. Brit. Med. J. 1:73, Schmidt, P. L. J., Peden, J. C., Jr., Brecher, A., and Beruanowsky, A. Thrombocytopenia and bleeding tendency after extracorporeal circulation, New Eng. J. Med. 265:1181, von Kaulla, K. N., and Swan, H. Clotting deviations in man during cardiac bypass. Fibrinolysis and circulating anticoagulants. J. Thorac. Surg. 36:519, VOL. 8, NO. 6, DECEMBER,