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Heparin prophylaxis: Room for improvement
EDITORIAL
Heparin Prophylaxis: Room for Improvement
Geza de Takats, MD, FACS, Chicago,
Illinois
Ever since the 19409, reports have appeared on the great variation in patients’ responses to heparin [I] and the ability of the human body to store and release an anticoagulant under stress [2]. The fact, however, that the reticuloendothelial system and particularly the vascular endothelium contains and releases a heparinoid was only recently documented from the laboratory of Hiebert and Jaques [3]. The assumption that prolongation of clotting time or other markers of increased anticoagulant activity are directly related to blood levels of injected heparin thus needs reexamination. Commercial heparin seems to mobilize heparinoids in the vascular endothelium, one of which, heparan sulfate, has been synthesized and is available as a commercial product widely used in Germany [4]. (The analogue also lengthens prothrombin time, which heparin does not [5].) This concept strengthens the idea, put forth and clinically applied 30 years ago, that heparin prophylaxis should begin at least 3 days before a scheduled operation and stop the night before surgery [S]. Preloading the patient with heparin will take care of his needs after surgery. Regretfully, there are no unicentric, multicentric, international, randomized, or double-blind studies to demonstrate the efficacy and safety of such a regimen. It is truly anecdotal, originally started on the vascular surgical service at old St. Luke’s Hospital. Only two other investigators have reported favorably on this regimen [7,8]. It is a simple, costeffective procedure that obviously cannot be used in the case of emergency operations or after trauma. However, it has been employed in the presence of acute thromboembolism after 2 days of massive doses of 60,000 to 120,000 units of heparin. Just like operative trauma, a massive iliofemoral thrombus or a pulmonary embolus induces not only heparinoid release but fibrinolytic activity. That is the time when the patient becomes sensitive to heparin and is most apt to bleed [9]. There is no From the Abraham Lincoln School of Medicine, University of Illinois. and Rush-Presbyterian Medical Center, Chicago, Illinois. Author’s address: 1 Calvin Circle #C-205, Evanston, Illinois 60201. No reprints available.
Vufume 143, June 1962
doubt that many surgeons, although well aware of the incidence of thromboembolic complications in the endangered group, shy away from minidose heparin prophylaxis, which is still associated with a considerable incidence of major hemorrhage and even fatal outcome, especially when stress is added to anticoagulation [IO] . Ultralow dose intravenous heparin reduces postoperative bleeding considerably and may also mobilize endothelial anticoagulant [ I1 1. It seems ideal for patients who are receiving continuous intravenous drip infusion or are on a pump, but it would be more difficult to administer to patients with early ambulation. Suggested Routine Patients who are obviously at greater risk of postoperative thromboembolism have been defined as the endangered group. They are over 40 years of age, have a history of thromboembolism, are obese, carcinomatous, have a high hematocrit, high blood viscosity, and are to undergo major surgery, such as an orthopedic procedure. They show little or no clotting time response to the 10 mg (1,000 units) test dose of heparin after 10 minutes. Five thousand units of heparin are given subcutaneously twice a day for 3 days, the last injection being given the night before the operation. No heparin is administered during or after the operative procedure except in cardiac or arterial repair, because the patient’s response to establish a hemostatic equilibrium by mobilizing heparinoids and fibrinolysin may lead to hemorrhage. When the dose of 5,000 units of subcutaneous heparin is reduced to 2,500 units twice a day and is reinforced with dihydroergotamine, the velocity of venous flow in the limbs is increased and the incidence of bleeding is decreased [12]. Since the drug is an alpha-receptor blocking agent and yet produces smooth muscle contraction, it may well have untoward side effects in peri- or postoperative stages. Should one really want to increase venous flow in the limbs-and also promote fibrinolysis-the use of intermittent venous constriction produced by rhythmic compression boots seems far more reasonable (131. Thus, one should not allow the curse of Kelvin, which Feinstein (141 tried to exorcise over 10 years ago, to dominate the field of anticoagulant prophylaxis. Lord Kelvin’s basic theme, expressed 100 years ago, was that “when you
711
de Takats
cannot express it in numbers, your knowledge is meager and unsatisfactory.” The countless clinical studies supported by impeccable statistical analyses have one obvious fault: they are testing a minidose regimen which, based on physiologic considerations and clinical observations, does not seem to be the optimal choice. Since blood clots are most apt to form during and shortly after surgical trauma, a minidose of 5,000 units of heparin given for the first time 2 hours before surgery cannot possibly be sufficiently preventive. Preloading the patient’s vascular endothelium with small doses of heparin should and does produce a heparinoid reserve ready to act on antithrombin iii [14]. Since both the heparinoid and the fibrinolytic potential of the patient become active around the third day, postoperative injections of minidoses may now and then produce hemorrhage [8]. Thus, our empirical regimen is being supported-although it is not yet statistically confirmed-by recent biochemical information.
Summary In spite of the widespread use of heparin for the prevention of thromboembolism, two important points are frequently neglected. First, each individual has his own response to heparin and this should be tested before the prophylactic or therapeutic administration of the drug. Second, heparin should be given at least 3 days before elective surgery so that the body can store it and release it when subjected to operative stress. Since the body responds normally to an operation with fibrinolysis, postoperative doses of heparin, even in minidoses, carry a risk of hemorrhage, which can be prevented by stopping the drug the night before surgery.
712
References
5. 6. 7.
6.
9. 10. 11.
12. 13.
14.
15.
de Takats G. Heparin tolerance. A test for the clotting mechanism. Surg Gynecol Obstet 1943;77:31-9. de Takats G, Marshall MH. The response of the clotting equilibrium to postoperative stress. Surgery 1952;31:13-27. Hiebert LM, Jaques LB. The observation of heparin on endothelium after injection. Thromb Res 1976;6:195-204. Kakkar VV, Lawrence D, Bentley PG,Haas HA, Ward VP, Scully MF. A comparative study of heparin and a heparin analogue on the prevention of postoperative deep venous thrombosis. Thromb Res 1976; 13:11l-2. Kakkar VV. Letter to the editor. Lancet 1961;1:1167. de Takats G. Anticoagulant therapy. Surgery 1953;34:9651004. Morris GK, Henry APY, Preston BY. Prevention of deep venous thrombosis by low dose heparin in patients undergoing hip replacement. Lancet 1974:2:797-g. Shamoff JG, Rosen RL, Sadler AH, Ibarra-lsunzaGC. Prevention of fatal pulmonary embolism by heparin prophylaxis after surgery for hip fractures. J Bone Joint Surg 1976;58:9136. Walker AM, Jick H. Prediction of bleeding during heparin therapy. JAMA 1980;244: 1209- 12. Jaques LB. Heparins-anionic polyelectrotyte drugs. marmecol Rev 1960;31:99-166. Negus D, Freedgood A, Wells BW. Ultra-low dose intravenous heparin in the prevention of postoperative deep venous thrombosis. Lancet 1960; 1:69 l-4. Kakkar VV, Stamatakis JD, Bentley PG. Synergistic effect of heparin and dihydroergotamine. JAMA 1979;241:39-42. Sabri S, Roberts VL, Cotton LC. Prevention of early postoperative deep venous thrombosis by intermittent compression of the leg during surgery. Br Med J 1971;3:503-6. Feinstein AR. Clinical biostatistics. 12. Dn exorcising the ghost of Gauss and the curse of Kelvin. Clin Pharmacol Ther 1971;12:1003-16. Wessler S, Gitel SN. Heparin: new concepts relevant to clinical use. Blood 1979;53:525-44.
The Amwlcan Journal ol Surgery
Heparin Prophylaxis: Room for Improvement
Geza de Takats, MD, FACS, Chicago,
Illinois
Ever since the 19409, reports have appeared on the great variation in patients’ responses to heparin [I] and the ability of the human body to store and release an anticoagulant under stress [2]. The fact, however, that the reticuloendothelial system and particularly the vascular endothelium contains and releases a heparinoid was only recently documented from the laboratory of Hiebert and Jaques [3]. The assumption that prolongation of clotting time or other markers of increased anticoagulant activity are directly related to blood levels of injected heparin thus needs reexamination. Commercial heparin seems to mobilize heparinoids in the vascular endothelium, one of which, heparan sulfate, has been synthesized and is available as a commercial product widely used in Germany [4]. (The analogue also lengthens prothrombin time, which heparin does not [5].) This concept strengthens the idea, put forth and clinically applied 30 years ago, that heparin prophylaxis should begin at least 3 days before a scheduled operation and stop the night before surgery [S]. Preloading the patient with heparin will take care of his needs after surgery. Regretfully, there are no unicentric, multicentric, international, randomized, or double-blind studies to demonstrate the efficacy and safety of such a regimen. It is truly anecdotal, originally started on the vascular surgical service at old St. Luke’s Hospital. Only two other investigators have reported favorably on this regimen [7,8]. It is a simple, costeffective procedure that obviously cannot be used in the case of emergency operations or after trauma. However, it has been employed in the presence of acute thromboembolism after 2 days of massive doses of 60,000 to 120,000 units of heparin. Just like operative trauma, a massive iliofemoral thrombus or a pulmonary embolus induces not only heparinoid release but fibrinolytic activity. That is the time when the patient becomes sensitive to heparin and is most apt to bleed [9]. There is no From the Abraham Lincoln School of Medicine, University of Illinois. and Rush-Presbyterian Medical Center, Chicago, Illinois. Author’s address: 1 Calvin Circle #C-205, Evanston, Illinois 60201. No reprints available.
Vufume 143, June 1962
doubt that many surgeons, although well aware of the incidence of thromboembolic complications in the endangered group, shy away from minidose heparin prophylaxis, which is still associated with a considerable incidence of major hemorrhage and even fatal outcome, especially when stress is added to anticoagulation [IO] . Ultralow dose intravenous heparin reduces postoperative bleeding considerably and may also mobilize endothelial anticoagulant [ I1 1. It seems ideal for patients who are receiving continuous intravenous drip infusion or are on a pump, but it would be more difficult to administer to patients with early ambulation. Suggested Routine Patients who are obviously at greater risk of postoperative thromboembolism have been defined as the endangered group. They are over 40 years of age, have a history of thromboembolism, are obese, carcinomatous, have a high hematocrit, high blood viscosity, and are to undergo major surgery, such as an orthopedic procedure. They show little or no clotting time response to the 10 mg (1,000 units) test dose of heparin after 10 minutes. Five thousand units of heparin are given subcutaneously twice a day for 3 days, the last injection being given the night before the operation. No heparin is administered during or after the operative procedure except in cardiac or arterial repair, because the patient’s response to establish a hemostatic equilibrium by mobilizing heparinoids and fibrinolysin may lead to hemorrhage. When the dose of 5,000 units of subcutaneous heparin is reduced to 2,500 units twice a day and is reinforced with dihydroergotamine, the velocity of venous flow in the limbs is increased and the incidence of bleeding is decreased [12]. Since the drug is an alpha-receptor blocking agent and yet produces smooth muscle contraction, it may well have untoward side effects in peri- or postoperative stages. Should one really want to increase venous flow in the limbs-and also promote fibrinolysis-the use of intermittent venous constriction produced by rhythmic compression boots seems far more reasonable (131. Thus, one should not allow the curse of Kelvin, which Feinstein (141 tried to exorcise over 10 years ago, to dominate the field of anticoagulant prophylaxis. Lord Kelvin’s basic theme, expressed 100 years ago, was that “when you
711
de Takats
cannot express it in numbers, your knowledge is meager and unsatisfactory.” The countless clinical studies supported by impeccable statistical analyses have one obvious fault: they are testing a minidose regimen which, based on physiologic considerations and clinical observations, does not seem to be the optimal choice. Since blood clots are most apt to form during and shortly after surgical trauma, a minidose of 5,000 units of heparin given for the first time 2 hours before surgery cannot possibly be sufficiently preventive. Preloading the patient’s vascular endothelium with small doses of heparin should and does produce a heparinoid reserve ready to act on antithrombin iii [14]. Since both the heparinoid and the fibrinolytic potential of the patient become active around the third day, postoperative injections of minidoses may now and then produce hemorrhage [8]. Thus, our empirical regimen is being supported-although it is not yet statistically confirmed-by recent biochemical information.
Summary In spite of the widespread use of heparin for the prevention of thromboembolism, two important points are frequently neglected. First, each individual has his own response to heparin and this should be tested before the prophylactic or therapeutic administration of the drug. Second, heparin should be given at least 3 days before elective surgery so that the body can store it and release it when subjected to operative stress. Since the body responds normally to an operation with fibrinolysis, postoperative doses of heparin, even in minidoses, carry a risk of hemorrhage, which can be prevented by stopping the drug the night before surgery.
712
References
5. 6. 7.
6.
9. 10. 11.
12. 13.
14.
15.
de Takats G. Heparin tolerance. A test for the clotting mechanism. Surg Gynecol Obstet 1943;77:31-9. de Takats G, Marshall MH. The response of the clotting equilibrium to postoperative stress. Surgery 1952;31:13-27. Hiebert LM, Jaques LB. The observation of heparin on endothelium after injection. Thromb Res 1976;6:195-204. Kakkar VV, Lawrence D, Bentley PG,Haas HA, Ward VP, Scully MF. A comparative study of heparin and a heparin analogue on the prevention of postoperative deep venous thrombosis. Thromb Res 1976; 13:11l-2. Kakkar VV. Letter to the editor. Lancet 1961;1:1167. de Takats G. Anticoagulant therapy. Surgery 1953;34:9651004. Morris GK, Henry APY, Preston BY. Prevention of deep venous thrombosis by low dose heparin in patients undergoing hip replacement. Lancet 1974:2:797-g. Shamoff JG, Rosen RL, Sadler AH, Ibarra-lsunzaGC. Prevention of fatal pulmonary embolism by heparin prophylaxis after surgery for hip fractures. J Bone Joint Surg 1976;58:9136. Walker AM, Jick H. Prediction of bleeding during heparin therapy. JAMA 1980;244: 1209- 12. Jaques LB. Heparins-anionic polyelectrotyte drugs. marmecol Rev 1960;31:99-166. Negus D, Freedgood A, Wells BW. Ultra-low dose intravenous heparin in the prevention of postoperative deep venous thrombosis. Lancet 1960; 1:69 l-4. Kakkar VV, Stamatakis JD, Bentley PG. Synergistic effect of heparin and dihydroergotamine. JAMA 1979;241:39-42. Sabri S, Roberts VL, Cotton LC. Prevention of early postoperative deep venous thrombosis by intermittent compression of the leg during surgery. Br Med J 1971;3:503-6. Feinstein AR. Clinical biostatistics. 12. Dn exorcising the ghost of Gauss and the curse of Kelvin. Clin Pharmacol Ther 1971;12:1003-16. Wessler S, Gitel SN. Heparin: new concepts relevant to clinical use. Blood 1979;53:525-44.
The Amwlcan Journal ol Surgery