Serial Coagulation Studies in Patients Undergoing Mustard Procedure

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1 Serial Coagulation Studies in Patients Undergoing Mustard Procedure Anne L. Wedemeyer, M.D., Aldo R. Castaiieda, M.D., J. Roger Edson, M.D., and William Krivit, M.D. ABSTRACT Following the Mustard procedure for operative correction of transposition of the great arteries, the incidence of serious hemorrhage in our original series was nearly %. Coagulation studies were performed serially in the next 4 patients undergoing the operation in an attempt to elucidate the etiology. Preexisting coagulation defects were present in all, but none had evidence of intravascular coagulation. Multiple clotting factors and platelets were decreased in the immediate postoperative period with gradual improvement in two weeks. n a patient with thrombocytopenia or deficient coagulation factors, preoperative phlebotomies may elevate these values to normal levels. When complete correction of the coagulation system has been achieved by this maneuver, a normal amount of postoperative bleeding has occurred in our patients. T he Mustard procedure [ 141 for operative correction of transposition of the great arteries (TGA) has been associated with a high incidence of serious hemorrhage. Excessive bleeding, defined as more than 5 ml. per kilogram of body weight per hour, occurred in nearly y0 of our original series [ 191. Certainly the coagulation aberrations noted preoperatively in patients with TGA may predispose a patient to hemorrhage. However, one or more factors may be involved in the catastrophic bleeding that occurs postoperatively [ 191. n order to understand these variables, it was deemed advisable to study several patients with TGA in serial fashion through the operation. This paper delineates the preoperative hemostatic status of 4 patients with TGA. Serial variations following the Mustard procedure are also noted. Finally, multiple phlebotomies are assessed as a rational therapeutic regimen for the prevention and control of excessive postoperative hemorrhage. Patients and Methods n 4 consecutive patients the following studies were performed preoperatively and at selected times postoperatively: hematocrit, platelet From the Departments of Pediatrics, Surgery, and Laboratory Medicine, University of Minnesota Hospitals, Minneapolis, Minn. Supported in part by research grants from the Minnesota Heart Association, The Paul S. and Faith S. Dwan Cardiac Fund, Cardiovascular Clinical Research Training Grant HE 0522-B, and U.S. Public Health Service Grants CA and CA Accepted for publication Aug. 1, Address reprint requests to Dr. Wedemeyer, Children s Hospital of Pittsburgh, 125 DeSoto St., Pittsburgh, Pa THE ANNALS OF THORACC SURGERY

2 Coagulation Studies During Mustard Procedure count, fibrinogen and plasminogen concentrations, euglobulin clot lysis time, fibrin degradation products (FDP), one-stage prothrombin time, and assays of factors 11, V, V, X, and X. Blood was collected through a 19-gauge needle into plastic syringes and transferred to tubes containing buffered citrate in a ratio of nine parts of blood to one part of anticoagulant (based on a normal hematocrit of y0). The amount of anticoagulant was decreased proportional to the decreased plasma volume if the patient was polycythemic. Platelet enumeration was done by phase microscopy. Prothrombin time, kaolin partial thromboplastin time, plasma thrombin time, fibrinogen level, and factor assays were determined by modification of standard methods [l, 2, 7, 15, 161. Preexisting Defects The preoperative hematocrits in the 4 patients with TGA were 57, 68, 70, and 70y0. The results of the coagulation studies before operation are shown in Table 1. Patient S. G. had abnormally elevated levels of factor V and V and a slightly low factor X. Patient M. L. presented with a mild hypofibrinogenemia and a slightly short euglobulin clot lysis time. Patient S. M. had an elevated factor V level, a markedly shortened euglobulin clot lysis time, and 1 yo FDP, which is interpreted as slightly positive. Patient C. S. had thrombocytopenia and an elevated factor V level. n summary, a wide spectrum of coagulation abnormalities was noted in the preoperative period in this small group of patients. There was no evidence of disseminated intravascular coagulation. Similar changes were noted in our larger group of 15 patients with TGA [18], who were studied only preoperatively, and in patients reported by other authors [3-6,8-13, 171. nduced Defects (Postoperative) mmediately after operation, Patient S. G. had a decrease in platelet count and in factors 11, V, V, and X. Factor X, which was low before operation, was decreased even further. Plasminogen was slightly elevated and FDP was mildly positive, but the fibrinogen concentration remained in the normal range. These defects persisted the following day. n fact, the platelet count dropped to 45,000 per cubic millimeter, but no excessive bleeding occurred from the chest tubes. By the eighth postoperative day the levels of the coagulation factors were either normal or slightly elevated but the FDP was still positive. This test was normal when the patient was restudied on the twentieth day. No serious medical complications occurred following operation (see Table 1). Patient M. L. had a decrease in the platelet count and factor V, and FDP was positive following operation. Two days later the platelet count and factor V were even lower, but no excessive bleeding occurred. Nine days after operation the coagulation studies revealed a slightly low factor V, very VOL. 15, NO. 2, FEBRUARY,

3 WEDEMEYER ET AL. TABLE 1. SERAL COAGULATON STUDES N Patient & Time of Study Normal S. G. Preoperative PAR 1 day postop. 8 days postop. 20 days postop. M. L. Preoperative PAR 2 days postop. 9 days postop. 22 days postop. c. s. Preoperative PAR 2 days postop. 9 days postop. S..M. Preoperative 1 day postop. 3 days postop. 9 days postop. 16 days postop. Hct. (%> Plat. (1,000/ mm.3) Fib. hg./ PT 100 ml.) (sec.) PTT (sec.) TT (sec.) Hct. = hematocrit; Plat. = platelets; Fib. = fibrinogen; ECL = euglobulin clot lysis; Plas. r plasminogen; FDP = fibrin degradation products; PT = prothrombin time; PTT = partial thromboplastin time; TT = thrombin time; PAR = postanesthesia recovery room;... = not tested. high factor V, and positive FDP. A low plasminogen level was recorded on the twenty-second day after operation. Significant complications were prolonged respiratory insufficiency and tracheostomy. Patient C. S. had a platelet count of 82,000 per cubic millimeter preoperatively which fell to 30,000 following operation. Three days later, because of persistent bleeding and severe thrombocytopenia, a bone marrow study was performed; this revealed decreased megakaryocytes on the smear and concentrate. This child was given six platelet infusions during the early postoperative period. Five days after operation the bleeding abated. Coagulation factors X and X were decreased.two days after operation but had returned to normal at nine days. The platelet count spontaneously and gradually increased beginning on the twelfth day and was 225,000 per cubic millimeter on the twentieth postoperative day (Figure). Coagulation studies following operation in S. M. revealed a decrease in platelets, fibrinogen, and factors 11, V, X, and X. By the third day the platelet count had dropped to,000 per cubic millimeter, but he did not 122 THE ANNALS OF THORACC SURGERY

4 Coagulation Studies During Mustard Procedure PATENTS UNDERGONG THE MUSTARD PROCEDURE Plas. Blood Factors (yo) ECL Casein FDP 1 V V X X 0.lml.) (% >2 2-4 < > 2% >2% >2% > 2% > % >2% >2% > > > 2% >2% >2% >2% >2% > 2% manifest excessive hemorrhage from the chest tubes. Gradual recovery of the levels of the clotting factors occurred during the next week. By the sixteenth day all studies were essentially normal except for a positive FDP. Medical complications included prolonged respiratory insufficiency and a tracheostomy. Comment The quantitative definition of excessive bleeding postoperatively in the pediatric patient with cyanotic congenital heart disease has been assessed on occasion [4, 191. n our series of cyanotic patients with TGA and severe tetralogy of Fallot, bleeding occurred at a rate of 2.8 to 23 ml. per kilogram of body weight per hour during the first 4 postoperative hours. n terms of square meters of body surface area, these values are 225 to 2,500 ml. per square meter for the total 4-hour period. The report by Ekert and his associates [4] on 8 patients who underwent the Mustard procedure revealed

5 WEDEMEYER ET AL. TABLE 2. DATA ON 6 PATENTS WTH CYANOTC CONGENTAL Laboratory Data, Operation, & No. 1, 2 yr., TB No. 2, 3 yr., TGA Postop. Bleeding Normal Preop. Postop. Preop. Postop. Hct. (%) Platelets (l,ow/mm.3) PT (%> PTT (sec.) TT (sec. 2 control) k Fibrinogen (mg./l00 ml.) Factors (yo) V V + x V X Operation Open Open Postop. bleeding (ml. / kg. / hr.)" "Blood loss through thoracotomy tubes during first 4 hours after operation. Hct. = hematocrit; PT = plasma prothrombin time; PTT = partial thromboplastin time; TT plasma thrombin time; TB = TaussigBing anomaly; TGA = transposition of great arteries; TOF =tetralogy of Fallot. a blood loss of 60 to 1,3 ml. per square meter of body surface area in the first 4 hours after operation. After several years of clinical observation of cyanotic patients undergoing open-heart operation, we have found it useful to define excessive bleeding in children as greater than 5 ml. per kilogram of body weight per hour during the first 4 postoperative hours. The length of pump oxygenation in patients undergoing an open-heart operation was directly related to the decrease in platelets, fibrinogen, and prothrombin content [6]. This was assumed to be the result of intravascular clotting or direct damage to the cellular elements during cardiac bypass SUROERY t. C.S. W S.G ML Oa SM PRE msr OF c DAYS Serial platelet counts in patients undergoing the Mustard procedure. C. S., the only patient with thrombocytopenia prior to operation, required platelet infusions (P) for profuse hemorrhage for 4 days. 124 THE ANNALS OF THORACC SURGERY

6 Coagulation Studies During Mustard Procedure HEART DSEASE BEFORE AND AFTER PHLEBOTOMY Patient No., Age, & Diagnosis No. 3, 1 yr., TGA No. 4, 1 yr., TGA No. 5, 5 yr., TOF No. 6, 3 yr., TB Preop. Postop. Preop. Postop. Preop. Postop. Preop. Postop Open Open Open Open ncreased fibrinolytic activity ensued. Similar abnormalities may be found as a result of impaired liver function following use of the pump oxygenator. Severe thrombocytopenia following an open-heart procedure was corrected by Woods and colleagues [ZO] by removing platelets from fresh blood and transfusing these undamaged platelets into the patient immediately after operation. When this maneuver successfully increased the circulating platelet count, the patients bled less than those who were perfused with whole blood. The administration of platelets in cyanotic patients in their series appeared to effect a 50% reduction in postoperative blood loss. A relationship between preoperative hemostatic defect and severity of postoperative hemorrhage in cyanotic patients was reported by Ekert and colleagues [4]. These investigators did not report serial studies following operation, and they planned postoperative replacement therapy on the basis of the preoperative hemostatic defect. These authors recommended appropriate coagulation assays preoperatively so that prevention or prompt treatment of postoperative hemorrhage could be realized. f coagulation deficits exist in the patient before operation, routine plans should be made for medical support (phlebotomy, whole-blood transfusions, fresh-frozen plasma, platelet infusions). Preoperative phlebotomy should be considered in a patient with thrombocytopenia or deficient coagulation factors. We have demonstrated that deficient coagulation factors VOL. 15, NO. 2, FEBRUARY,

7 WEDEMEYER ET AL. may return to normal in patients with marked polycythemia who have undergone multiple phlebotomies with replacement using normal saline solution [19]. Many years ago, Hartmann [9j and Jackson [lo] demonstrated that a transient rise in the platelet count could be achieved in approximately 10 days by multiple phlebotomies, which correlates well with the time of spontaneous increase in platelets following the Mustard procedure. We have now studied 6 patients with thrombocytopenia secondary to cyanotic heart disease; following multiple phlebotomies (100 ml. per square meter of body surface area per phlebotomy for about 8 days) a significant increase in the platelet count has been achieved without ill effect (Table 2). mmediately following operation, several of these patients were given a prophylactic infusion of platelet concentrate. None required platelet infusions for hemorrhage or severe thrombocytopenia (less than 80,000 platelets per cubic millimeter) or both, and the platelet count has gradually increased to normal levels within two weeks. Multiple phlebotomies in patients with thrombocytopenia secondary to cyanotic heart disease may be postulated to stimulate the bone marrow. This would result in an earlier release of platelets with concomitant elevation of that cell in the peripheral blood shortly after operation. This conceivably could reduce the incidence of hemorrhage. As phlebotomies were not performed in many of the patients recorded in the literature, serious hemorrhage frequently ensued. Platelet production and survival have not been studied in patients with polycythemia secondary to cyanotic heart disease. These should prove valuable in the elucidation of the mechanism of thrombocytopenia. Some investigators have found normal megakaryocyte morphology in cyanotic patients, irrespective of the peripheral platelet count. Defective platelet adhesion to collagen has been found in 2 of 4 patients investigated for this abnormality, but neither of the 2 manifested a bleeding tendency. n order to provide the best service, a detailed analysis of coagulation in all cyanotic patients with a hematocrit exceeding 60% ought to be considered. Preoperative phlebotomy may be indicated in those patients with preexisting coagulation defects in order to lower the hematocrit and blood viscosity simultaneously while elevating deficient clotting factor levels or the platelet count or both. f complete correction is achieved by this maneuver, a normal amount of postoperative bleeding can be predicted. f less than complete correction is achieved, some increase in bleeding following operation may occur, and replacement therapy can be planned on the basis of the preoperative hemostatic defect. Kirklin s method [20] of harvesting and administering platelets during operation may be valuable in the prevention of early postoperative hemorrhage. 126 THE ANNALS OF THORACC SURGERY

8 Coagulation Studies During Mustard Procedure References 1. Backman, F., Duckert, F., and Koller, F. The Stuart-Prower factor and its clinical significance. Thromb. Diath. Haemorrh. 2:24, Biggs, R., and MacFarlane, R. G. Human Blood Coagulation and ts Disorders (3d ed.). Philadelphia: Davis, P Dennis, L. H., Stewart, J. L., and Conrad, M. E. A consumption coagulation defect in congenital cyanotic heart disease and its treatment with heparin. J. Pediatr. 71:7, Ekert, H., Gilchrist, G. S., Stanton, R., and Hammond, D. Hemostasis in cyanotic congenital heart disease. J. Pediatr. 76:221, Gans, H., and Krivit, W. Hemostatic defects in patients undergoing cardiac bypass. Surg. Forum 12:202, Gans, H., and Krivit, W. Problems in hemostasis during and after openheart surgery: V. Over-all changes in blood coagulation mechanism. J.A.M.A. 179:145, Gaston, L. W., Mack, B. F., and Beck, W. W. Hemophilia A and concurrent factor V deficiency. N. Engl. J. Med. 264: 1078, Gross, S., Keefer, V., and Liebman, J. The platelets in cyanotic congenital heart disease. Pediatrics 42:651, Hartmann, R. C. A hemorrhagic disorder occurring in patients with cyanotic congenital heart disease. Bull. Johns Hofikins Hosfi. 91:49, Jackson, D. P. Hemorrhagic diathesis in patients with cyanotic congenital heart disease: Pre-operative management. Ann. N.Y. Acad. Sci. 115:235, Komp, D. M., and Sparrow, A. W. Fibrinolysis in cyanotic heart disease. J. Pediatr. 77:679, Komp, D. M., and Sparrow, A. W. Polycythemia in cyanotic heart disease-a study of altered' coagulation.,j. Pediatr. 76:231, Kontras, S. B., Bodenbender, J. G., Craemen, J., and Hosier, D. M. Hyperviscosity in congenital heart disease. J. Pediatr. 76:214, Mustard, W. T. Successful two-stage correction of transposition of the great vessels. Surgery 55:469, Proctor, R. R., and Rapaport, S.. The partial thromboplastin time with kaolin. Am. J. Clin. Pathol. 36:212, Ratnoff, 0. D., and Menzie, C. A new method for the determination of fibrinogen in small samples of plasma. J. Lab. Clin. Med. 37:316, Somerville, J,, McDonald, L., and Edgill, M. Post-operative hemorrhage and related abnormalities of blood coagulation in cyanotic congenital heart disease. Br. Heart J. 27:4, Wedemeyer, A. L., Edson, J. R., and Krivit, W. Coagulation factor alterations in cyanotic congenital heart disease. Am. J. Dis. Child. 124:656, Wedemeyer, A. L., and Lewis, J. H. Response to phlebotomy in cyanotic cardiac patient. J. Pediatr. n press. 20. Woods, J. E., Taswell, H. F., Kirklin, J. W., and Owen, C. A., Jr. The transfusion of platelet concentrates in patients undergoing heart surgery. Mayo Clin. Proc. 42:318, VOL. 15, NO. 2, FEBRUARY,