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Validation of a bedside method of activated partial thromboplastin time measurement with clinical range guidelines
Validation of a Bedside Method of Activated Partial Thromboplastin Time Measurement with Clinical Range Guidelines James L. Vacek, MD, Kazuhira Hibiya, MD, Thomas L. Rosamond, MD, Paul H. Kramer, MD, and Gary D. Beauchamp, MD apid measurement of an anticoagulant effect due to heparin is desirablein a variety of settings. Patients with cardiovascular diseasesundergo heparinization for many reasonsincluding management of unstable angina, in conjunction with thrombolytic therapy for myocardial infarction, percutaneoustransluminal coronary angioplasty,extracorporealbypass,atria1 fibrillation with perceivedembolic risk, prosthetic heart valves and several variants of cerebral vascular disease.1-9 Standard clinical laboratory measurementsof partial thromboplastin time (PTT) are cumbersomeand slow, and prone to multiple potential sources of error.2-4s10-13 To provide a rapid, simple, accuratebedside means of PTT measurement, the Hemochron system was used to assessa means of automated immediate analysis. We assessedthe utility of this system in the cardiac catheterization laboratory by comparing PTT measurementsderived from this techniquewith activated
R
clotting times (ACT) in patients undergoing cardiac catheterization and angioplastyboth before and after the procedure. The study group consisted of 176 patients undergoing cardiac catheterization or coronary angioplasty. Baseline (0 heparin) PTT and ACT measurements were obtained immediately after vascular access of the femoral artery and placement of an 8Fr catheter introducer sheath. Blood samples were obtained after 5-ml backjlush of blood. Of the patients undergoing cardiac catheterization, 51 received 2,000 I/ of heparin intravenously after vascular access was achieved at the discretion of the catheterizing physi-
TABLE I Measured Laboratory Values for Heparin Groups Heparin (U)
No.of pts. PTT (set) ACTkec)
From The Mid-America Heart Institute, St. Luke’s Hospital, Kansas City, Missouri 64111.Dr. Vacek’s addressis: Mid-America Cardiology Associates, 4321 Washington, Suite 4000, Kansas City, Missouri 64111. Manuscript received January 23, 1991; revised manuscript received and acceptedApril 22,199l.
xxiemll8iM
25.00 FIGURE 1. Distribution
68.75 of activated
2,000
10,000
176 67 + 14 119 f 21
51 153 2 74 184k 64
65 480 IT 150 460 + 141
Values are means 2 1 standarcl deviation. ACT = activated clotting time: PTT = activated
I
112.50
0
partial thromboplastin
time.
8.75
156.25
clotting times in 0 heparin group (follows normal diitribution). BRIEF REPORTS 557
cian. All the patients who underwent coronary angioplasty received 10,000 U after vascular access. In the patients who received heparin, repeat ACT and PTT measurements were obtained at the conclusion of the procedure to address the effects of heparin on anticoagulant parameters. Cardiac catheterization and angioplasty were performed via standard femoral technique using 8Fr diagnostic and guide configurations and a variety of over-the-wire balloon angioplasty
rntmmal
systems. Dextran was not used in any patient, nor was any patient receiving heparin or coumadin before the study. Most patients undergoing diagnostic catheterization and all undergoing angioplasty were receiving aspirin, 325 mg/day. The heparin administered throughout the duration of the study was porcine heparin (LyphoMed, Inc., Melrose Park, Illinois). ACTS and activated PTTs were measured in the catheterization laboratory, us-
l ixm I
5.00
8
25.00
75.00
50.00
FIGURE 2. Distribution
of partial thromboplaetin
times in 0 hqwin
100.00 group (follows
125.00
normal distribution).
PTT
800 600
0
600
400
200
800
ACT -..FlGURE 3. Plot of partial thrambeplaetin 558
n
n
time (PlT) verslls activated
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68
292 clotting time (ACT) for all vabes (linear correlatien).
AUGUST 15, 1991
ing the materials of the Hemochron system (International Technidyne Inc., Edison, New Jersey). The Hemochron 800 assay device was used in conjunction with Al01 test tubes for PTT measurement. The tubes contain pre-prepared lyophilized sodium citrate, diatomaceous earth activator, platelet factor substitute, stabilizers and buffers and are combined with I .Oml of calcium chloride (0.032 M). This method utilizes fresh whole blood and has been demonstrated to result in PTT measurements that are reproducible and correlate well with standard clinical laboratory methods. However, the values obtained with this method are higher than those obtained through standard clinical laboratory techniques. Mean PTT in a normal population is 70 seconds(standard deviation 7.3, range 55 to 85, noted in the product literature). ACTS were also measured using the Hemochron 800 instrument, with FTCA.510 tubes that are celite-activated (I 2 mg Johns Manville celite diatomaceous earth). This method has been shown to be a reliable and reproducible means of measuring activated coagulation times in a variety of settings.2,5,7,9314-17 Both ACT and PTT results are routinely available within 5 to 10 minutes of blood drawing. Statistical analysis included calculations of mean f 1 standard deviation, Pearsonproduct moment correlation, best curvefit analysis, and standard calculation of sensitivity, specificity, accuracy and predictive values. Table I lists the number of data points reflecting the effects of 0, 2000, or 10,000 U of heparin with accompanying descriptive statistics. The ACT and PTT values obtained showing 0 heparin effect follow normal distributions (Figures I and 2). Overall correlation between PTT and ACT was excellent (r = 0.902 by linear correlation [PTT = (1.066 X ACT) -45.9361 and r = 0.925 by power function (InPTT = [I .333 X InACT] - 2.094). Figure 3 plots the relation betweenPTT and ACT by linear analysis. Becauseas the postheparin measurements were obtained over variable intervals after drug administration, they provide a range of data representing a broad spectrum of anticoagulant effect. In our laboratory, normal ACT measurements are 129 f 9 seconds (range of 110 to). Therapeutic ACT is believed to be 2200 seconds during standard anticoagulation.2~5~7~9~14-17 For protection during angioplasty we prefer an ACT 2300 seconds to achieve supratherapeutic anticoagulant effect.‘y9,t7 By sequential testing, a PTT measurement 2120 seconds was believed to yield optimal sensitivity and specificity for diagnosis of therapeutic standard anticoagulant effect when compared with ACT values. A PTT 2120 seconds, when correlated with an ACT 2200
seconds,resulted in a sensitivity of 99%, a specificity of 93%, an accuracy of 93%, a positive predictive value of 85% and a negative predictive value of 99%. To assess supratherapeutic effect for adequate anticoagulation during angioplasty, a PTT 2300 seconds correlated with an ACT 1300 secondswith sensitivity of 90%, specificity of 97%, positive predictive value 89%, negativepredictive value 97%, and accuracy 96%. The Hemochron system for PTT measurementappears to fulfill many of the requirements for a rapid, simple and reproducible technique. However, to our knowledge,this method has not beenvalidated in a large number of patients undergoing cardiac catheterization. Our study demonstratesthe utility of this technique and provides guidelines for its use, including the assessment of a therapeutic anticoagulant effect of heparin used during coronary angioplasty, when “supratherapeutic” levels of anticoagulation are desired.
1. Kapsch DN, Kasulke RJ, Silver D. Anticoagulant therapy. VascDiagn Thempy 1981;2:19-27. 2. Hattersley PG. Heparin anticoagulation. In: Koepke JA, cd. Laboratory Hematology. New York: Churchill Livingstone, 1984:789-818. 3. de Takats G. Special communication: Monitoring hemostasis in the perioperative period. Vast Diag Therapy 1983;4:17-19. 4. Gambino R. Monitoring heparin therapy. Lab Report for Physicians 1982; 417-20. 5. Schriever HG, Epstein SE, Mintz MD. Statistical correlation and heparin sensitivity of activated partial thromboplastin time, whole blood coagulation time, and an automated coagulation time. Am J C/in Pathol 1973;60:323-329. 6. Kazmier FJ. Monitoring of heparin therapy. In: Lundblad RL, Brown WV, Mann KG, Roberts HR, eds. Chemistry and Biology of Heparin. North Holland, New York: Elsevier, 1981:615-624. 7. Hill JD, Dontigny L, de Leval M, Mielke CH Jr. A simple method of heparin management during prolonged extracorporeal circulation. Ann Thorac Surg 1974;17:129-134. 6. Vacek JL, Bellinger RL, Phelix J. Heparin bolus therapy during cardiac catheterization. Am J Cardiol 1988;62:1314-1317. 9. Jobes DR, Schwartz AJ, Ellison N, Andrew R, Ruffini BS, Ruflini JJ. Monitoring heparin anticoagulation and its neutralization. Ann Thorac Surg 1981;31:161-166, 10. Shapiro GA, Huntzinger SW, Wilson JE. Variation among commercial activated partial thromboplastin time reagents in response to heparin. Am J Chin Path 1977;67:477-480. 11. Triplett DA, Harms CS, Koepke JA. The effect of heparin on the activated partial thromboplastin time. Am J Clin Path 1978;70:556-559. 12. Koepke JA, Triplett DA, Banez G. The partial thromboplastin time for monitoring heparin therapy. In: Lundhlad R, Brown WV, Mann KG, Roberts HR, eds. Chemistry and Biology of Heparin. North Holland, New York: Elsevier, 1981:625. 13. Basu D, Gallers A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972;281:324-327. 14. Esposito RA, Culliford AT, Calvin SB, Thomas SJ, Lackner H, Spencer FC. Heparin resistance during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;85:346-353. 15. Doty DB, Knott HW, Hoyt JL, Koepke JA. Heparin dose for accurate anticoagulation in cardiac surgery. J Cardiowc Surg 1979;20:597-604. 16. Lindsay RM. Practical use of anticoagulants. In: Druker W, Parsons FM, Maher JF, eds. Replacement of Renal Function by Dialysis. Norwell, Mass: Martinus Nijhoff, 1983:201-222. 17. Lefemine AA, Lewis M. Activated clotting time for control of anticoagulation during surgery. Am Surg 1985;51:274-278.
BRIEF REPORTS 559
R
clotting times (ACT) in patients undergoing cardiac catheterization and angioplastyboth before and after the procedure. The study group consisted of 176 patients undergoing cardiac catheterization or coronary angioplasty. Baseline (0 heparin) PTT and ACT measurements were obtained immediately after vascular access of the femoral artery and placement of an 8Fr catheter introducer sheath. Blood samples were obtained after 5-ml backjlush of blood. Of the patients undergoing cardiac catheterization, 51 received 2,000 I/ of heparin intravenously after vascular access was achieved at the discretion of the catheterizing physi-
TABLE I Measured Laboratory Values for Heparin Groups Heparin (U)
No.of pts. PTT (set) ACTkec)
From The Mid-America Heart Institute, St. Luke’s Hospital, Kansas City, Missouri 64111.Dr. Vacek’s addressis: Mid-America Cardiology Associates, 4321 Washington, Suite 4000, Kansas City, Missouri 64111. Manuscript received January 23, 1991; revised manuscript received and acceptedApril 22,199l.
xxiemll8iM
25.00 FIGURE 1. Distribution
68.75 of activated
2,000
10,000
176 67 + 14 119 f 21
51 153 2 74 184k 64
65 480 IT 150 460 + 141
Values are means 2 1 standarcl deviation. ACT = activated clotting time: PTT = activated
I
112.50
0
partial thromboplastin
time.
8.75
156.25
clotting times in 0 heparin group (follows normal diitribution). BRIEF REPORTS 557
cian. All the patients who underwent coronary angioplasty received 10,000 U after vascular access. In the patients who received heparin, repeat ACT and PTT measurements were obtained at the conclusion of the procedure to address the effects of heparin on anticoagulant parameters. Cardiac catheterization and angioplasty were performed via standard femoral technique using 8Fr diagnostic and guide configurations and a variety of over-the-wire balloon angioplasty
rntmmal
systems. Dextran was not used in any patient, nor was any patient receiving heparin or coumadin before the study. Most patients undergoing diagnostic catheterization and all undergoing angioplasty were receiving aspirin, 325 mg/day. The heparin administered throughout the duration of the study was porcine heparin (LyphoMed, Inc., Melrose Park, Illinois). ACTS and activated PTTs were measured in the catheterization laboratory, us-
l ixm I
5.00
8
25.00
75.00
50.00
FIGURE 2. Distribution
of partial thromboplaetin
times in 0 hqwin
100.00 group (follows
125.00
normal distribution).
PTT
800 600
0
600
400
200
800
ACT -..FlGURE 3. Plot of partial thrambeplaetin 558
n
n
time (PlT) verslls activated
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68
292 clotting time (ACT) for all vabes (linear correlatien).
AUGUST 15, 1991
ing the materials of the Hemochron system (International Technidyne Inc., Edison, New Jersey). The Hemochron 800 assay device was used in conjunction with Al01 test tubes for PTT measurement. The tubes contain pre-prepared lyophilized sodium citrate, diatomaceous earth activator, platelet factor substitute, stabilizers and buffers and are combined with I .Oml of calcium chloride (0.032 M). This method utilizes fresh whole blood and has been demonstrated to result in PTT measurements that are reproducible and correlate well with standard clinical laboratory methods. However, the values obtained with this method are higher than those obtained through standard clinical laboratory techniques. Mean PTT in a normal population is 70 seconds(standard deviation 7.3, range 55 to 85, noted in the product literature). ACTS were also measured using the Hemochron 800 instrument, with FTCA.510 tubes that are celite-activated (I 2 mg Johns Manville celite diatomaceous earth). This method has been shown to be a reliable and reproducible means of measuring activated coagulation times in a variety of settings.2,5,7,9314-17 Both ACT and PTT results are routinely available within 5 to 10 minutes of blood drawing. Statistical analysis included calculations of mean f 1 standard deviation, Pearsonproduct moment correlation, best curvefit analysis, and standard calculation of sensitivity, specificity, accuracy and predictive values. Table I lists the number of data points reflecting the effects of 0, 2000, or 10,000 U of heparin with accompanying descriptive statistics. The ACT and PTT values obtained showing 0 heparin effect follow normal distributions (Figures I and 2). Overall correlation between PTT and ACT was excellent (r = 0.902 by linear correlation [PTT = (1.066 X ACT) -45.9361 and r = 0.925 by power function (InPTT = [I .333 X InACT] - 2.094). Figure 3 plots the relation betweenPTT and ACT by linear analysis. Becauseas the postheparin measurements were obtained over variable intervals after drug administration, they provide a range of data representing a broad spectrum of anticoagulant effect. In our laboratory, normal ACT measurements are 129 f 9 seconds (range of 110 to). Therapeutic ACT is believed to be 2200 seconds during standard anticoagulation.2~5~7~9~14-17 For protection during angioplasty we prefer an ACT 2300 seconds to achieve supratherapeutic anticoagulant effect.‘y9,t7 By sequential testing, a PTT measurement 2120 seconds was believed to yield optimal sensitivity and specificity for diagnosis of therapeutic standard anticoagulant effect when compared with ACT values. A PTT 2120 seconds, when correlated with an ACT 2200
seconds,resulted in a sensitivity of 99%, a specificity of 93%, an accuracy of 93%, a positive predictive value of 85% and a negative predictive value of 99%. To assess supratherapeutic effect for adequate anticoagulation during angioplasty, a PTT 2300 seconds correlated with an ACT 1300 secondswith sensitivity of 90%, specificity of 97%, positive predictive value 89%, negativepredictive value 97%, and accuracy 96%. The Hemochron system for PTT measurementappears to fulfill many of the requirements for a rapid, simple and reproducible technique. However, to our knowledge,this method has not beenvalidated in a large number of patients undergoing cardiac catheterization. Our study demonstratesthe utility of this technique and provides guidelines for its use, including the assessment of a therapeutic anticoagulant effect of heparin used during coronary angioplasty, when “supratherapeutic” levels of anticoagulation are desired.
1. Kapsch DN, Kasulke RJ, Silver D. Anticoagulant therapy. VascDiagn Thempy 1981;2:19-27. 2. Hattersley PG. Heparin anticoagulation. In: Koepke JA, cd. Laboratory Hematology. New York: Churchill Livingstone, 1984:789-818. 3. de Takats G. Special communication: Monitoring hemostasis in the perioperative period. Vast Diag Therapy 1983;4:17-19. 4. Gambino R. Monitoring heparin therapy. Lab Report for Physicians 1982; 417-20. 5. Schriever HG, Epstein SE, Mintz MD. Statistical correlation and heparin sensitivity of activated partial thromboplastin time, whole blood coagulation time, and an automated coagulation time. Am J C/in Pathol 1973;60:323-329. 6. Kazmier FJ. Monitoring of heparin therapy. In: Lundblad RL, Brown WV, Mann KG, Roberts HR, eds. Chemistry and Biology of Heparin. North Holland, New York: Elsevier, 1981:615-624. 7. Hill JD, Dontigny L, de Leval M, Mielke CH Jr. A simple method of heparin management during prolonged extracorporeal circulation. Ann Thorac Surg 1974;17:129-134. 6. Vacek JL, Bellinger RL, Phelix J. Heparin bolus therapy during cardiac catheterization. Am J Cardiol 1988;62:1314-1317. 9. Jobes DR, Schwartz AJ, Ellison N, Andrew R, Ruffini BS, Ruflini JJ. Monitoring heparin anticoagulation and its neutralization. Ann Thorac Surg 1981;31:161-166, 10. Shapiro GA, Huntzinger SW, Wilson JE. Variation among commercial activated partial thromboplastin time reagents in response to heparin. Am J Chin Path 1977;67:477-480. 11. Triplett DA, Harms CS, Koepke JA. The effect of heparin on the activated partial thromboplastin time. Am J Clin Path 1978;70:556-559. 12. Koepke JA, Triplett DA, Banez G. The partial thromboplastin time for monitoring heparin therapy. In: Lundhlad R, Brown WV, Mann KG, Roberts HR, eds. Chemistry and Biology of Heparin. North Holland, New York: Elsevier, 1981:625. 13. Basu D, Gallers A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time. N Engl J Med 1972;281:324-327. 14. Esposito RA, Culliford AT, Calvin SB, Thomas SJ, Lackner H, Spencer FC. Heparin resistance during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;85:346-353. 15. Doty DB, Knott HW, Hoyt JL, Koepke JA. Heparin dose for accurate anticoagulation in cardiac surgery. J Cardiowc Surg 1979;20:597-604. 16. Lindsay RM. Practical use of anticoagulants. In: Druker W, Parsons FM, Maher JF, eds. Replacement of Renal Function by Dialysis. Norwell, Mass: Martinus Nijhoff, 1983:201-222. 17. Lefemine AA, Lewis M. Activated clotting time for control of anticoagulation during surgery. Am Surg 1985;51:274-278.
BRIEF REPORTS 559