Aprotinin improves hemostasis after cardiopulmonary bypass better than single-donor platelet concentrate

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Sunny Dzik, Marion E. Reid, and John J. Freedman, Abstract Editors

A Comparison of Conservative and Aggressive Transfusion Regimens in the Perioperative Management of Sickle Cell Disease. VichinskyEP, Haberkern CM, NeumayrL, eta/. N Engl J Med 333:206-213, 1995. Patients with sickle cell disease are commonly "prepared" for major surgery by deliberate transfusions. The usual goal of this approach is to reduce the percentage of hemoglobin S to 30% or lower. The intention of this treatment is to reduce the risk of intraoperative or postoperative complications, such as sickle crisis, acute chest syndrome, or vaso-occlusion with organ infarction. This study compared two different regimens of preoperative transfusion: one "aggressive" regimen, the goal of which was to attain at least 70% hemoglobin A in the patient before surgery, and one "conservative" regimen with the goal of simply raising the total hemoglobin to greater than 10 g/dL. Patients in the conservative regimen required fewer transfusions and entered surgery with an average total hemoglobin of 11 g/dL containing 59% hemoglobin S. Patients in the aggressive regimen entered surgery with an average 10.6 g/dL and only 31% hemoglobin S. The procedures consisted of cholecysteetomy; ear, nose, and throat procedures, orthopedic procedures, splenectomy, and others. The results run counter to existing dogma because the patients randomized to receive aggressive preoperative transfusion fared no better in terms of the incidence of perioperative complications attributed to sickling. Specifically, acute chest syndrome occurred in 10 of 301 patients in the conservative transfusion group and l 1 of 303 patients in the aggressive transfusion group. The incidence of fever/infection, painful crisis, and other miscellaneous events was no different in the two groups. The incidence of major neurological events, renal complications, and death was too low in both groups to measure accurately. Not surprisingly, the patients who were more aggressively transfused had a higher incidence of transfusion-related complications. For example, immediate hemolytic reactions were observed in 3 of 303 patients in the aggressively transfused group but none in the other group. Delayed hemolytic reactions occurred in 16 of 303 individuals in the aggressive transfusion group but only 4 of 301 in the conservative group. New alloimmunizafion was also more frequent in those given more transfusions. The results in both groups highlight the previous observation that sickle cell patients experience perioperative complications at a much higher rate than patients without sickle cell disease. This randomized controlled trial suggests that hypertransfusion to achieve a goal of at least 70% hemoglobin A is no more effective than a conservative transfusion policy aimed at increasing the overall hemoglobin to at least l0 g/dL and that hypertransfusion increases the frequency of transfusionrelated complications.

Risk of Recurrent Stroke in Patients With Sickle Cell Disease Treated With Erythrocyte Transfusions. Transfusion Medicine Reviews, Vol X, No 1 (January), 1996: pp 71-76

Pegelow CH, Adams RJ, McKie V, et aL J Pediatr 126:896-899, 1995. Stroke is reported to occur in 5% to 10% of children with sickle ceil anemia; most are due to cerebral infarction rather than hemorhage. The risk of recurrent stroke in these children has been estimated to be 47% to 93%. Several investigators have reported that recurrent strokes can be prevented by long-term transfusion therapy designed to maintain hemoglobin S levels below 30% to 40%. These authors reviewed the clinical experience with transfusion therapy in 60 subjects whose initial stroke occurred after January 1988; the subjects were followed for 191,7 patient-years at eight different centers. Eight of the 60 had a single recurrent stroke--two intracranial hemorrhages and six infarctions (ie, a prevalence of 13.3% or one recurrence for each 24 patient-years of observation). Thirteen patients had 15 transient neurological events; two of these had subsequent strokes. Hemoglobin S levels were above the desired 30% at the time of 44% of the transient neurological events and in 83% of the infarctions; they were below 30% in the two cases of cerebral hemorrhage. The stroke recurrence rate was significantly less than that reported for children who did not receive transfusion therapy. This experience, although retrospective and compared with historical controls without transfusion, corroborates the success of long-term transfusion therapy and yields information about recurrence risk. The adjustment for the length of observation is useful as longer periods would be expected to yield more events; determination of incidence allows a more meaningful comparison of rates. Although the data support the use of transfusion therapy in children with sickle cell anemia in preventing recurrent infarction, it does not prevent transient neurologic events; these events, although common, do not appear to be related to recurrent stroke. The optimal intensity and duration of this therapy remain to be determined.

Aprotinin Improves Hemostasis After Cardiopulmonary Bypass Better Than Single-Donor Platelet Concentrate. Shinfeld A, Zippel D, Levee J, et el. Ann Thorac Surg 59:872-876, 1995. Impaired hemostasis after cardiac surgery is primarily due to acquired platelet dysfunction and decrease in platelet count. The protease inhibitor, aprotinin, improves hemostasis by its effect on platelet adhesiveness and aggregation. Platelet transfusions are also used to improve postoperative hemostasis, and fresh single-donor plateletpheresis concentrates (SDPC) have been employed because they reduce allogeneic exposure and provide relatively large amounts of platelets. The authors compared these two methods of improving postoperative hemostasis in 40 randomized patients undergoing various open heart procedures. Group A included 20 subjects who received ABO-compatible SDPC immediately after bypass; group B consisted of 20 patients who received high dose aprotinin (6 X 106 kallikrein-

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72 inhibiting unit) before and during cardiopulmonary bypass. The patients in each group were similar in sex distribution and age, in time on bypass, aortic cross-clamp time, and in body temperature. Platelet counts were, as expected, higher in those who received SDPC (157 _+ 36 X 109/1 v 118 + 42 • 109/1; P < .05). Platelet aggregation on an extracellular matrix, as assessed by scanning electron microscope, however, was better in group B patients (3.4 _+ 0.7 v 2.8 _+ 0.9; P < 0.05). Despite the fact that there were more reoperative open heart procedures in group B, 24-hour blood loss was significantly less in the aprotinin-treated group (396 • 125 v 617 • 233 mL; P < 0.01). Ten (50%) of the patients in the aprotinin-treated group were never exposed to allogeneic transfusion, whereas all patients in group A were exposed; overall, patients in group B received a mean of 1.1 • 1.6 units of red cells versus 5.4 • 3.4 in group A patients. Hence, this study supports those of others on the efficacy of high-dose aprotinin in improving clinical hemostasis in open heart surgery and indicated that it was superior to administration of SDPC. It indicates that preservation of platelet function is more important than increasing the platelet count by transfusion. Aprotinin may also have beneficial effects on fibrinolysis and platelet stimulation by thrombin and plasmin. In these times of concern about transfusion-transmitted infections, aprotinin merits consideration, and further studies with longer follow-up should be pursued.

Retransfusion of Suctioned Blood During Cardiopulmonary Bypass Impairs Hemostasis. de Haan J, Boonstra PW, Monnink SHJ, et al. Ann Thorac Surg 59:901-907, 1995. Among approaches to reduce exposure to allogeneic transfusion is retransfusion of blood suctioned from the thoracic cavity during cardiopulmonary bypass. In a prospective clinical study on 40 patients, the authors investigated the effect of retransfusing blood suctioned during coronary artery bypass grafting on systemic blood activation and on postoperative hemostasis. In those patients who had suctioned blood retransfusion, there was an immediate and significant increase in circulating concentrations of thrombin-antithrombin III complexes, tissue-type plasminogen activator, fibrin degradation products, and free plasma hemoglobin. Thus, there was evidence of renewed systemic clotting and fibrinolysis as a direct result of the retransfusion of suctioned blood. There was greater postoperative blood loss in patients receiving suctioned blood than in those who did not (mean 822 mL v 611 mL; P < .05) as well as a slight, but not statistically significant, lower perioperative consumption of blood products in those not receiving suctioned blood transfusions (414 v 513 mL red cells and 150 v 384 mL single-donor plasma). This study emphasizes the need for continuing assessment of new approaches and cautions that, despite its laudatory intention, retransfusion of blood suctioned during cardiopulmonary bypass may not be as salutary as believed.

Protease-Modified Erythrocytes: CD55 and CD59 Deficient PNH-Like Cells. Yuan FF, Bryant JA, Fletcher A. Immunol Cell Bio173:66-72, 1995. The increased susceptibility to homologous complement in paroxysmal nocturnal hemoglobinuria (PNH) is associated with deficiency of the membrane complement inhibitors CD59 and CD55. In studies on the relationship between the content of

CURRENT LITERATURE CD59 and CD55 in complement susceptibility, these authors used various proteases to modify human red cells. The differential resistance of the enzyme-treated cells to complementmediated injury was measured by acidified complementmediated lysis. In addition, the effects of monoclonal antibodies to CD55 and CD59 on red cell complement susceptibility were measured in reactive lysis assays. Surface expression of CD55 and CD59 were assessed by flow cytometry, and immunoblotting was employed to examine sensitivity of CD55 and CD59 on red cells to protease cleavage. Pronase-treated erythrocytes lacked both CD55 and CD59, and were susceptible to complement-mediated lysis. Papain reduced red cell CD55 content, but did not affect CD59 and induced little susceptibility to complement-mediated lysis. Trypsin destroyed 80% of CD59 but had little effect of CD55, and trypsin-treated cells had only slightly increased susctibility to lysis. Thus, partial CD55 and CD59 activity was sufficient to protect cells from complementmediated lysis. Anti-CD55, and particularly anti-CD59, induced hemolysis, and lysis was increased when cells were incubated with both antibodies simultaneously. The findings are consistent with other observations on the importance of CD59 (eg, in individuals with the Inab phenotype, red cells lack CD55 completely but have essentially normal sensitivity to acidified serum lysis. In addition to providing further elucidation of the relative importance of CD59 in the pathophysiology of hemolysis in PNH, this report provides relatively simple methods of preparing PNH-like red cells, which may be useful in routine transfusion laboratories.

Re-Evaluation of the Storage Conditions for Blood Samples Which Are Used for Determination of Complement Activation. Stove S, Klos A, Bauthsch W, Kohl J. J Immunol Meth 182:1-5, 1995. Complement activation correlates with disease activity and with clinical outcome. However, difficult sample processing, long assay times, and requirement for storage conditions at - 7 0 ~ often prevent routine measurement of complement anaphylotoxin values in clinical laboratories. These authors employed a convenient recently described method for determining C3a/C3a-des-Arg or C5a/C5a-des-Arg plasma levels within 25 minutes (Hartmann H, Lubbers B, Casaretto M, et al. Rapid quantification of C3a and C5a using a combination of chromatographic and immunoassay procedures. J Immunol Methods 166:35, 1993). The method allows on-line measurement of these proinflammatory mediators, allowing them to be used readily as diagnostic parameters. The current investigations examined EDTA blood samples from normal subjects and from septic patients, assessing in vitro complement activation during the first 48 hours after phlebotomy in samples stored at 4~ and 20~ Within the septic patient group, no complement activation was detectable throughout the observation period of 48 hours. In contrast, if blood from healthy subjects was stored longer than 6 hours at 20~ complement activation occurred, and this was progressive with time with a fourfold increase at 48 hours. Within the first 6 hours, however, there was no increase in complement activation products. The data thus suggest that often-employed maneuvers of immediate cooling of ethylenediaminetetra-acetic (EDTA) blood to 4~ and the immediate separation of plasma, are not necessary for determination of plasma anaphylotoxin values. Storage of EDTA blood samples for up to 6 hours without the need to perform centrifugation