Progress Report: T h e Activated Coagulation. T i m e of Whole Blood (ACT)

Transcription

1 Progress Report: T h e Activated Coagulation T i m e of Whole Blood (ACT) PAUL G. HATTERSLEY, M.D. Department of Internal Medicine and Pathology, University of Calif ornia at Davis School of Medicine, Sacramento Medical Center, Sacramento, California ABSTRACT Hattersley, Paul G.: Progress report: The activated coagulation time of whole blood (ACT). Am J Clin Pathol 66: , The activated coagulation time of whole blood (ACT) has, in the nearly ten years since its first description in the literature, proven itself one of the best laboratory tests for the control of heparin therapy, both for patients undergoing treatment for thromboembolic disease and for those on extracorporeal circulation. It is simple, largely free from subjective variation, precise, and quick. Prolongation of the ACT in the heparinized individual is directly proportional to the concentration of heparin in the blood, and the test accurately reflects the semilogarithmic disappearance of the anticoagulant effect in most patients. In addition, the test serves well as a bedside screening test for deficiencies of the intrinsic coagulation mechanism. The author summarizes the studies that have been carried out on this technic since its original description, and briefly presents three protocols for heparinization of patients who have thromboembolic disease. (Key words: Activation with silicious earth; Intrinsic coagulation mechanism; Monitoring heparin therapy; Thromboembolic disease.) IN 1966, the author, appalled at the lack of sensitivity and precision of the widely used Lee-White coagulation time test, 13 and its excessive time demands in the control of heparin therapy, devised and reported 9 a new test with the aim of obviating these shortcomings. The determination of the activated coagulation time of whole blood (ACT) consisted of drawing 2 ml of venous blood into a warmed tube containing 12 mg of diatomaceous earth, inverting the tube a few times to mix, allowing it to stand for 60 seconds at 37 C, and Received December 9, 1975; received revised manuscript January 22, 1976; accepted for publication January 22, Address reprint requests to Dr. Hattersley: Division of Pathology, Sacramento Medical Center, 2315 Stockton Boulevard, Sacramento, California then tilting it at 5-second intervals, looking for the first definite clot.* The ACT, when performed exactly according to directions, proved to be quick, sensitive and reproducible. The test gave a bell-shaped curve of normal distribution among specimens from 5,000 presurgical patients, with a mean clotting time of approximately 1% minutes (Fig. 1). It proved very nearly as sensitive to defects in the intrinsic coagulation mechanism as the activated partial thromboplastin time (APTT) test, and its precision was likewise comparable, with a coefficient of variation of 4.1% of replicate determinations. * Becton-Dickinson Co., Rutherford. N. ).. distributes a tube containing 12 mg silicious earth, evacuated to draw 2 ml blood. It is their stock item No

2 900 HATTERSLEY A J. C.P. Vol. 66 FIG. 1. Activated coagulation times determined in 5,000 consecutive routine presurgical determinations. (From Hattersley, 9 reproduced with permission.) cs'rj fin *» -^ >o in'.. i i i, i i,-^i TIME-Minutes ond Seconds I i I CN i! cs 'o r> We suggested it as a routine presurgical screening test, 9,10 and as a means of monitoring cryoprecipitate therapy of hemophiliac patients. 9,11 We also suggested that it might prove the test of choice in monitoring heparin therapy. As a matter of fact, the ACT has found its widest use in monitoring heparin therapy of patients receiving treatment for thromboembolic disease, 1,2>15 in hemodialysis, 2-6,14 on extracorporeal circulation for cardiac surgery, 3-5 or on the Bramson membrane oxygenator. 12 Brittin 2 discussed the test at some length. In addition to the characteristics described in the initial paper, he pointed out that the test reflects the known semilogarithmic disappearance of heparin's anticoagulant effect. He further listed as practical advantages the simplicity of the test, which allows apprentice technologists to master it quickly; its freedom from significant subjective variation, as shown by identical normal ranges in different laboratories, when performed according to instructions; the convenience of a single reagent; and the availability of the results at the bedside within a very few minutes after the blood has been drawn. Perry and colleagues 14 used the ACT to determine heparin half-lives with normal and impaired renal function. They injected 0.3 or 0.6 units heparin/ml whole blood into a series of normal volunteers, and into 13 patients who had chronic renal failure. In the normal-renal-function group the mean anticoagulant half-lives were 36.8 minutes for the 0.6 U/ml dose, and 22.7 min for the 0.3 U/ml dose, thus contradicting the findings of Estes, 7 who had reported that the half-life of heparin does not vary with the dose, and is about 1 l A hrs. Perry found that patients who had chronic renal failure had significantly longer heparin half-lives than did healthy volunteers. By use of the equations of first-order pharmacokinetics, they derived a heparin dosage schedule through which anticoagulation of patients can proceed by means of constant infusion of the drug. The schedule is applicable to patients who have normal renal function as well as to patients in renal failure. Wallace and associates, 17 concerned about the high incidence of arterial embolic disease following angiography, instituted general heparinization of such patients. Of 525 patients undergoing angiography by this technic, only two had signs of embolus. They followed the coagulation status of their patients by drawing frequent blood specimens on which they performed the ACT test as well as plasma APTT and prothrombin time (PT) tests.

3 November 1976 ACTIVATED COAGULATION TIME (ACT) 901 The ACT gave the promptest evaluation of the patient's heparin level. Hill and associates, 12 working with patients receiving long-term extracorporeal circulation on the Bramson membrane oxygenator for acute respiratory insufficiency, compared the accuracy of the ACT test with that of the Lee-White test in evaluating heparinization. They reported that the ACT gave rapid, reproducible and reliable results, making it possible to maintain a relatively stable state with heparin adjustments, even when requirements were changing rapidly. In 11 patients whose therapy was being monitored with the ACT at the time of publication, they had encountered neither clotting in the extracorporeal circuit, nor severe hemorrhage in the patient. Perhaps the most sophisticated use of the ACT has been by Bull and colleagues. 3-5 In investigating various protocols of heparin therapy used during extracorporeal circulation for open-heart surgery, they demonstrated that many protocols in use for this purpose endanger the patient, by inadequate heparinization, excessive heparinization, or inadequate neutralization of heparin by protamine at the end of the procedure. They pointed out that the amount of heparin required to produce an arbitrary prolongation in the ACT may vary threefold from patient to patient, and that the rapidity with which administered heparin disappears from the blood may vary fourfold. They felt that an ACT of less than 300 seconds indicated insufficient heparin during a surgical procedure, and that an ACT of more than 600 seconds indicated overheparinization. An elevated ACT after protamine indicated inadequate heparin neutralization. In setting up a presumably safer protocol than any they had encountered, they chose doses of heparin and of protamine on the basis of a dose-response curve determined for each patient. They suggested the following procedure: (1) Determine the baseline ACT. (2) Infuse a routine 200 units of heparin per kilogram of body weight, and after 5 minutes determine a second ACT. (3) By extrapolation from the two ACT's, determine the amount of add - tional heparin necessary to prolong the ACT to 480 seconds. Infuse that amount. (4) Repeat the ACT at hourly intervals, infusing additional heparin as needed to return the ACT to 480 seconds. (5) Shortly before the conclusion of the bypass, determine another ACT. From this value, determine the amount of heparin still circulating in milligrams per kilogram. (6) Calculate and infuse the appropriate dose of protamine to neutralize the heparin. In 50 patients handled on this protocol, maintenance of ACT's within the desired range was essentially 100%, and the ACT's after protamine injection were normal in all. These authors point out that with such a program, the diagnosis of postoperative bleeding disorders becomes relatively simple, since heparin and protamine excess can both be excluded. Bull and colleagues 5 compared the practicality of the ACT with that of a quantitative protamine titration (QPT) in ten patients. They point out that the QPT is so time-consuming as to be impractical when prompt results are needed, as in openheart surgery. Also, unlike tests of the clotting time, the QPT cannot be interpreted without a quantitative determination of plasma volume, which varies sharply among patients. In their evaluation, any method of monitoring heparin that is based on protamine titration is less practical than a test of the coagulation mechanism. Of the many technics available for the latter, they prefer the ACT because of its simplicity and the promptness of obtaining results. Estes, 8 while largely confining his extensive studies of control of heparin therapy to the Lee-White clotting time, the wholeblood APTT, the plasma APTT, and the plasma PTT, lists in a table and discusses briefly a number of additional technics,

4 902 HATTERSLEY A.J.C.P. Vol. 66 W H 200 <i -j- LIFE= 73 MINUTES ISO < <-> > < «^ CO 70 Q, 1- Z O 50 -^ o <-> ^W 40 S3 t </) C3 O < 20 _l O O ct Q. U >w _ \ s * ELAPSED TIME SINCE INFUSION, MINUTES FIG. 2. Characteristic logarithmic clearance of heparin anticoagulant effect after infusion of 3 units heparin sodium/ml plasma volume (as determined by 125 I) o 5^ > <-> K "* 400 -V u < LL) [/) 300 u. S \ P 200 _ V z z <-> o o "J ^J» h- r- o < <. -J 100 z => o o j < 70 o o * 50 \ _ \ ELAPSED 1st slope- -jlife = 10 min 2nd slope- ylife=l33min I i i i i TIME SINCE INFUSION, MINUTES FIG. 3. Atypical biphasic clearance of heparin anticoagulant effect after infusion of 3 units heparin sodium/ml plasma volume. including the ACT test. Of the four tests he studied in detail, he preferred the whole-blood APTT, because it is quick and can be done at the bedside. He states, however: "The activated clotting time (ACT, or Celite test) will probably provide equally good precision and economy of heparin assay." \ Regarding any partial thromboplastin time technic that is to be used to control heparin therapy, Estes 8 points out that any laboratory should "always use the same product," because each gives a different dose-effect curve with increasing doses of heparin, as pointed out by Soloway and associates. 16 (Incidentally, neither Estes nor Soloway gives any proof that various batches of partial thromboplastin from a given company may not likewise show wide variation.) Since first reporting the ACT, my colleagues and I have used it routinely in many ways, and have done much unpublished research with the technic. We have confirmed the fact that the decay of the anticoagulant effect of heparin in most individuals is on a logarithmic basis, as previously reported (Fig. 2). Sometimes, however, when specimens from certain individuals are collected at 10- minute intervals from the moment of heparin injection, the curve is biphasic (Fig. 3), with a very steep drop in the first 10 or 20 minutes, changing to a much more gradual slope at 30 to 40 minutes. The explanation for this sharp difference among individuals in the first few minutes remains unclear, but its occurrence probably explains the large differences observed by Bull and colleagues, and many others, in amounts of heparin needed to produce ACT-seconds O O Heparin Infusion 29u/min%%^36u/mini%^%%^%X^ Heparin 2000 u i l i i HOURS FIG. 4. Activated coagulation times from renal dialysis unit at one-hour intervals after initiation of dialysis.

5 November 1976 ACTIVATED COAGULATION TIME (ACT) 903 FIG. 5. Characteristic graph of patient receiving heparin therapy for pulmonary embolus (Protocol II). the same prolongation of clotting times in different individuals. Patients undergoing systemic heparinization in our renal dialysis unit receive a push infusion of 50 to 100 units of heparin per kilogram of body weight, followed by controlled flow of heparin at a concentration of 3.3 mg/ml physiologic saline solution. We obtain specimens at 60- minute intervals for the ACT test, and adjust the pump to keep the clotting times between 150 and 180 seconds. For regional heparinization, we add protamine to the blood returning to the patient, controlling the flows of both heparin and protamine by pump. We take blood specimens from both sides of the unit at 30-minute intervals, attempting to keep the blood in the coil showing an ACT of 150 to 180 seconds, while in the patient it is in or close to the normal range. Times are short enough to permit close control of the infusion rate of heparin and protamine. The ACT has been accepted eagerly by the staff of the renal dialysis unit because of the time saved, compared with the Lee-White technic formerly used (see Fig. 4 for a typical example.) We have used the ACT test as the laboratory test of choice in controlling heparin dosages for patients with thromboembolic disorders. Acting on our conviction that patients receiving heparin should receive doses related in some way to body weight, we have set up three protocols. Protocol I involves continuous intravenous administration of heparin by infusion pump, starting with a push infusion of 50 units per kilogram as a priming dose, and continuing with 25 units per kilogram per hour, subsequently adjusting the dose to an ACT of 150 to 210 seconds. Protocol II uses intermittent intravenous push infusions at four-hour intervals, starting at 100 units per kilogram, and adjusting to a 3 '/2-hour post-infusion ACT of 150 to 210 seconds (Fig. 5). Protocol III uses subcutaneous administration of heparin, giving 200 units per kilogram each eight hours, or 150 units each six hours, and adjusting the dose to a preinjection ACT of 150 to 210 seconds. Since the initial dose of heparin is weight-related, one must weigh the patient, or record an estimated weight, before heparinizing. Likewise, it is well to determine the blood urea nitrogen or creatinine, as well as the ACT and the platelet count. As pointed out by Perry, 14 poor renal function causes slow clearance of heparin from the plasma, necessitating smaller doses. Severe thrombocytopenia likewise increases the likelihood of troublesome bleeding. These protocols have been used for many hundreds of patients in more than

6 904 HATTERSLEY A.J.C.P. Vol. 66 five years. We offer no statistical evidence of their superiority over other methods of controlling heparin therapy. Our experience, however, indicates that in acute thromboembolic disease, such treatment programs provide anticoagulation adequate to prevent ongoing thrombus formation or repeated embolization, with minimal risk of hemorrhage. We have also used the ACT in the bedside control of heparin therapy of patients with disseminated intravascular coagulation (DIC). The deficiencies of factors V and VIII and fibrinogen that characterize DIC make any coagulation test a poor measure of heparin function. Likewise, the thrombocytopenia of DIC increases the danger of bleeding during heparin administration. We have therefore often corrected the factor VIII and fibrinogen deficiencies with large infusions of cryoprecipitates immediately after heparinization, and have given large infusions of platelets. Subsequently, the ACT reflects heparin level as in treatment of thromboembolic disease, and bleeding due to thrombocytopenia is usually avoided. In summary, then, nearly ten years after its first description in the literature, one may say of the ACT: (1) It has thoroughly proven itself a satifactory test for the control of heparin therapy. (2) Although as a screening test for coagulopathies it has very largely been replaced by the plasma APTT test, as a quick bedside screening test, available in the emergency room or in surgery, it is of great potential value. (3) It remains an excellent monitor of responses to specific therapies of patients who have deficiencies of factors VIII, IX and XI. References 1. Allison S, Clark S, Brown F: The activated clotting time in the control of heparin therapy. Bull Geisinger Med Center 21: , Brittin G: "Fibrinolysis." American Society of Clinical Pathologists, Committee on Continuing Education, Chicago, Bull B, Korpman R, Huse W, et al: Heparin therapy during extracorporeal circulation: I. Problems inherent in existing heparin protocols. J Thorac Cardiovasc Surg 69: , Bull B, Huse W, Brauer F, et al: Heparin therapy during extracorporeal circulation: II, The use of a dose-response curve to individualize heparin and protamine dosage. J Thorac Cardiovasc Surg 69: , Bull M, Huse W, and Bull B: Evaluation of tests used to monitor heparin therapy during extracorporeal circulation. Anesthesiology 43: , Congdon J, Kardinal C, Wallin J: Monitoring heparin therapy in hemodialysis. JAMA 226: , Estes J: Kinetics of the anticoagulant effect of heparin. JAMA , Estes J: The laboratory control of heparin therapy. Curr Ther Res 18:58-65, Hattersley P: Activated coagulation time of whole blood. JAMA 196: , Hattersley, P: The activated coagulation time of whole blood as a routine pre-operative screening test. Calif Med 114:15-18, Hattersley P: The treatment of classical hemophilia with cryoprecipitates. JAMA 198: , Hill J, Dontigny L, de Leval M, et al: A simple method of heparin management during prolonged extracorporeal circulation. Ann Thorac Surg 17: , Lee R, White P: A clinical study of the coagulation time of blood. Am J Med Sci 145: , Perry P, Herron G, King J: Heparin halflife in normal and impaired renal function. Clin Pharmacol Ther 16: , Raich P, Hahn M, Korst D: Heparin therapy. Am Fam Physician 10: , Soloway H, Cornett B, Grayson J Jr: Comparison of various activated thromboplastin reagents in the laboratory control of heparin therapy. Am J Clin Pathol 59: , Wallace S, Medellin H, de Johngh D, et al: Systematic heparinization for angiography. Am J Roentgenol Radium Ther Nucl Med 116: , 1972