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Anticoagulation: A surgical perspective
SURGICAL PHARMACOLOGY
Anticoagulation: A Surgical Perspective Malcolm O. Perry, MD, New York, New York
Commonly used anticoagulants can be divided into two groups: heparin and heparin-like compounds and warfarin derivatives [1]. Although usually used singly, the agents have different mechanisms of action and, on occasion, are employed simultaneously. I chose to discuss 0nly heparin and warfarin. The antiplatelet agents are not really true anticoagulants. In fact, their mode of action continues to be disputed. Although hopes are high for the low-molecular weight heparin fractions, today their role is still under exploration. For the time being, we surgeons must rely on heparin, and on occasion, warfarin for the treatment of thromboembolism. I-Ieparin: Chemical description. Heparin belongs to a group of compounds called linear anionic polyelectrolytes. These are highly negatively charged mucopolysaccharide chains [2]. In man, they are found in the mast cells and in basophilic leukocytes. Four types are distinguished as separated by molecular weights: low-molecular weight heparin (6,000 to 13,000 daltons), macromolecular heparin (up to a million daltons), heparitins, and multisulphated chondroitins. Heparin also varies in the degree of sulfation on any of the three sugars, and in the acetylation of glucosamine. Although the net electrical charge varies, heparin is the most negatively charged natural occurring substance in the body [3]. Heparin is a relatively crude natural product, obtained from either bovine lungs or porcine intestinal mucosa. The heterogeneity of heparin has led to numerous discussions regarding the potency of the two preparations, bovine versus porcine, and raised questions as to whether undesirable side effects are From the Department of Surgery, Division of Vascular Surgery, The New York HospitaI-Cornell Medical Center, New York, New York. Requests for reprints should be addressed to Malcolm O. Perry, MD, Department of Surgery, Division of Vascular Surgery, The New York HospitaI-Cornell Medical Center, 525 East 58th Street, New York, New York, 10021.
268
more common with one preparation than the other. Chemical assays currently accepted for standardization of commercial heparin are performed in vitro on animal plasma, and although hemostatic responses in the dog are different from those in man, this technique has not shown a significant difference between lung- and mucosa-derived heparin. Moreover, there are no scientifically based studies showing differences in potency of the two preparations. In the United States, the sodium salt of hepatin is available and standardized so as to produce a compound which has 156 units/mg (United States Pharmacopea (USP) units). The differences in preparation of heparin may influence its antithrombotic activity in man, but there are no scientific data that justify the selection of one type or brand of heparin in preference to another [1,4]. Pharmacologic properties of heparin. Although heparin is mainly used for its anticoagulant effect, this is only one part of its sphere of activity [2]. In fact, approximately 20 to 30 percent of the commercially prepared heparin can be shown to have an anticoagulation effect as defined by forming a complex with antithrombin III. This complexing appears to be a relatively unusual feature of a few side chains found in commercial heparin, and it may play a minor role in overall heparin activity. The other activities which can be assigned to heparin are anticoagulation (complex with antithrombin III); adherence to vascular endothelium and increased electronegativity; reduction of platelet adhesiveness, increase in plasma lecithinase action; reduction in rigidity of fibrinogen surface layers; blockage of vascular permeability caused by prostaglandin, bradykinin, and histamine; and competitive inhibition of adenosine triphosphatase (decreases endothelial cell construction). Some of these, such as the marked increase in electronegativity of the endothelial surface, may exert a more potent antithrombotic effect in vivo [2].
The American Journal of Surgery
Anticoagulation: A Surgical Perspective
Heparin combines with antithrombin III, a circulating anticoagulant protein produced in the liver. This complex neutralizes the proteolytic activities of several activated clotting factors in the intrinsic and common pathways of the coagulation cascade [3]. All of these clotting factors (XIIIa, XIa, Xa, IXa, and IIa) are serine proteases. The union of heparin to antithrombin III is achieved through a specific antithrombin III-binding site on heparin, and a lysine-containing center on the antithrombin III. This results in a change in the molecular configuration of the antithrombin III molecule which exposes inhibitory binding sites. Heparin also binds with lipolipase, but this binding differs from that of antithrombin III in that it is less avid and nonspecific. The majority of the heparin chains bind with fibrinogen. The effect of the inactivation of the serine proteases in the clotting cascade decreases the overall rate of reaction, but quantitatively, the most imporrant steps are the inhibition of the conversion of factor X to Xa, and the antithrombin effect [4]. The final result is a decrease in the amount of thrombin available for forming fibrin. After the protease and antithrombin III complex has been formed, heparin can be released, and may be available for promoting inhibition of other reactions in the anticoagulation mechanism. Pharmacokinetics. The assessment of the pharmacokinetics of heparin is complicated by the difficulty in standardizing heparin preparations [5]. AIthough a given sample of commercial heparin may assay quite accurately on repeat examination, there is a low level of precision attained when two heparin preparations are compared. The USP assay is not a satisfactory predictor of potency for inhibition, even of clotting of fresh whole blood. The marked variability between samples of commercial heparin is matched by a corresponding variability in the assay potency by in vitro coagulation test systems. Most studies of heparin kinetics are derived from experiments using coagulation tests that do not directly assay the heparin, only its anticoagulant elfect [6]. In vitro, it is not the clotting time but the logarithm that is directly proportional to the amount of added heparin; therefore, there is a narrow range of heparin concentration that gives measurable coagulation time values. Obviously, low doses of heparin have little effect and high doses produce infinitely long clotting times, neither of which give a reliable indication of the actual heparin concentration in the plasma [4]. Heparin is removed rapidly from the blood by adherence to the endothelium, as well as by being taken up by the reticuloendothelial system and by macrophages. A third of the circulating heparin is removed from the blood in a single pass [2]. It has been suggested that adherence to the endothelium
Volume 155, February 1988
is an important feature in its antithrombotic effect, although this has not been proven, but the concentration on the endothelium is 100 times that in the plasma. The uptake by vascular endothelium and the reticuloendothelial system produces unusual peak blood concentrations when heparin is administered subcutaneously or by way of the lungs. After subcutaneous administration of heparin, the peak blood concentrations are 2 percent of the peak values obtained with intravenous injection. Most drugs have a 20 to 40 percent blood concentration. The biologic half-life of heparin increases with increasing doses, since it is cleared in a first-order reaction. In man, the half-life can be shown to be approximately 56 minutes when 100 units/kg are administered, 96 minutes with 200 units/kg, and 152 minutes with 400 units/kg [2]. Furthermore, the rate of heparin clearance from the blood decreases with increasing doses, but the quantity of heparin on the endothelium increases. Despite these variations in kinetics, in the usual dosage employed in man, the half-life of intravenously administered heparin is approximately 90 minutes. One may expect, however, to see disproportionate increases in the plasma heparin concentration as the heparin dose is increased [4]. The metabolic degrading and subsequent elimination of heparin from the body is poorly understood, but after initial clearance from the plasma, heparin is finally eliminated by the liver and the kidneys. The metabolic processes apparently include depolymerization and desulfation. Only small amounts of heparin are excreted unchanged in the urine. It is apparent that the coagulation tests customarily used to assess heparin in the blood represent an in vivo response to the administration of heparin, but these tests do not reflect the concentration in plasma because most of the heparin is in the physiologic depot. It has been demonstrated that regardless of the method of administration, the total amount of heparin required to achieve a desired effect over a given amount of time is about the same [2]. The significant parameter seems to be the concentration of heparin maintained in the plasma [5]. Basis for clinical use. During coagulation, the clotting factors normally react preferentially with their specific substrates rather than with the naturally occurring antithrombin. In the absence of heparin, the reaction between the clotting factors and antithrombin III is slow, but after heparin binds to antithrombin, this reaction becomes virtually instantaneous and coagulation stops. The affinity of the heparin and antithrombin III complex for activated factor X is greater than for factor II (prothrombin); therefore, less heparin is required to neutralize the factor X-to-Xa conversion than is required for antithrombin activity. It is easier to prevent activation of the coagulation cascade than it
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is to halt the mechanism once it is fully engaged. From these observations, two separate modes of heparin therapy have been developed: low-dose heparin for prophylaxis of thromboembolism and heparin therapy for treatment of thromboembolism. Each has a distinct therapeutic objective and they are mutually exclusive [4].
Prophylaxis and treatment of thromboembolism. Numerous clinical studies have demonstrated that low-dose subcutaneous heparin is effective in preventing calf vein thrombosis. In the original studies performed in Europe, the method was to administer 5,000 IU of heparin 2 hours before operation, and then every 8 hours until the patient was fully ambulatory [7-10]. Using the more potent USP preparation, an equivalent unit dose would be approximately 3,700 units. The common regimen employed in the United States today is to administer 5,000 units subcutaneously 2 hours before operation and then repeat the 5,000 units every 12 hours. Although most of these trials have shown some morbidity from an increased incidence of postoperative bleeding in the form of wound hematomas, in the heparin-treated groups there was no evidence that bleeding caused by low-dose heparin has been a direct cause of death [7-9]. The original studies did not show low-dose heparin to be effective in those patients who had the greatest thrombotic tendencies (for example, hip arthroplasty). In a subsequent study, Leyvraz et al [10] treated 79 patients undergoing elective hip surgery. Half of the patients were placed randomly into one group receiving 3,500 IU heparin subcutaneously 2 hours preoperatively and every 8 hours thereafter for 7 to 9 days (fixed dosage). The other group received the same initial dose of heparin, but thereafter the amount of heparin was varied to keep the activated partial thromboplastin time between 31.5 and 36 seconds (adjusted dosage). By venography 16 of 41 patients (39 percent) in the fixed-dose group had recurrence of venous thrombosis, but only 5 of 38 patients (14 percent) in the adjusted-dose group had development of new clots. There were no bleeding episodes in either group. The combination of dihydroergotamine and heparin has been used to prevent venous thrombosis. The venoconstrictive effect of dihydroergotamine is believed to reduce the diameter of systemic veins and thus to increase the velocity of blood fl0w if the volume of blood traversing the veins remains the same. This may reduce venous blood stasis [9,1113].' Although there are only limited data supporting this regimen, the multicenter trial [12], and reports by Comerota and White [13] suggested that in patients at high risk for thrombosis, 0.5 mg of dihydroergotamine and 5,000 units of heparin given every 12 hours may be effective. When dihydroergotamine is given alone or combined with lesser amounts of heparin, little or no benefit was seen. 270
Ergotamine has systemic effects which could be deleterious, especially in patients with multiple injuries, sepsis, hypotension, and vascular diseases. Despite these potential problems, few adverse effects of vasospasm have been detected in the reported trials. Except for the adjusted-dose regimen described by Leyvraz et al [10], low-dose heparin administration protocols do not require serial tests of coagulation. A heparin-activated antiplatelet antibody may occur even with low-dose heparin therapy, although it is seen more frequently in patients receiving conventional doses [3]. Therefore, thrombocytopenia and serious side effects may supervene any time after 3 or 4 days of heparin treatment, and all patients receiving heparin should have a platelet count performed every 3 days while the drug is being administered. The appearance of thrombocytopenia is an absolute indication for discontinuation of heparin therapy. Hirsh and Hull [14] stated that "the evidence that heparin is effective in the treatment of pulmonary embolism comes principally from one controlled study." The study by Barritt and Jordan [15], in 1960, showed that a quarter of the inpatients with pulmonary embolism died if untreated. Subsequent studies have shown a recurrence of pulmonary embolism in only 3 to 8 percent of the patients treated with heparin [3,4,15-17]. The two major problems with heparin therapy for venous thromboembolism are bleeding and recurrent embolism. The national cooperative study revealed an overall incidence of bleeding complications of 27 percent and an incidence of recurrent thromboembolism of 16 percent [8]. These observations increased the controversy over whether heparin should be administered continuously or intermittently by intravenous or subcutaneous routes. No unanimity of opinion has been reached as to which dosages are desirable or which route is best, although heparin clearly is effective in the treatment of thromboembolism. These controversies subsequently led Wilson et al [1] to perform a prospective study of patients with deep vein thrombosis and pulmonary embolism. The 114 patients were randomly assigned to receive either intermittent or continuous heparin therapy. One group was treated with a standard dose, and in a Similar group, the heparin was controlled by attempting to maintain the Lee-White clotting time or activated partial thromboplastin time at a level of 1.5 to 2.5 times normal. In 65 patients assigned to receive heparin controlled by coagulation tests, recurrences happened significantly more often with continuous heparin therapy (28 percent) than with intermittent heparin therapy (3 percent). When the patients at high risk for bleeding were analyzed separately, major bleeding occurred in 42 percent of the group receiving intermittent heparin therapy as The American Journal of Surgery
Anticoagulation: A Surgical Perspective
compared with 7 percent of those who received continuous therapy. This was not statistically significant, however (p -- 0.06). There was no convincing relationship between recurrences and the dose of heparin used, or the effect of monitoring the dose by coagulation tests (Table I). Hull et al [16] studied 115 patients with deep vein thrombosis diagnosed first by clinical methods, then confirmed by noninvasive laboratory techniques and venography. The patients were divided into two groups, one of which was treated with intermittent subcutaneous heparin and the other, with continuous intravenous heparin. The patients treated by subcutaneous injection received 15,000 units of heparin every 12 hours. In the other group, 5,000 units of heparin were given as an intravenous bolus, and then 29,760 units were given as a continuous intravenous infusion. The activated partial thromboplastin time was checked midway between the subcutaneous injections and at the same time of day in the patients receiving intravenous heparin. The activated partial thromboplastin time target was 55 to 75 seconds. Warfarin was begun on the sixth or seventh day, and given for 12 weeks, attempting to keep the prothrombin time at 1.25 to 1.5 times the control value. Recurrent venous thromboembolism occurred in 11 of 57 patients (19.3 percent) receiving subcutaneous heparin, but in only 3 of 58 patients (5.2 percent) treated with continuous intravenous heparin. Bleeding occurred in 5.3 percent of the patients who had subcutaneous heparin and in 6.9 percent of those with intravenous infusion of heparin. In two separate reports, Hirsh and Hull [14,18] noted that there seemed to be less recurrences of venous thromboembolism in patients treated with heparin if the activated partial thromboplastin time was kept near 1.5 times the control prethrombotic values. They found no relationship between the risk of bleeding and the activated partial thromboplastin time in patients receiving continuous or intermittent heparin intravenously. This finding was similar to findings of Wilson et al [17]. Resistance to heparin is seen in patients with extensive thrombosis. Higher doses of heparin may be required, especially during the initial period of treatment [2,4,14]. Hirsh and Hull [14] stated that heparin resistance is usually caused by a rapid clearance of heparin, but they cautioned that the activated partial thromboplastin time may be misleading because of aberrations in the test. Although antithrombin III levels may decrease by as much as 30 percent during the administration of heparin, this apparently has little clinical significance. Congenital deficiencies of antithrombin III occur in approximately 1 of 2,000 persons, but there is no strong evidence that this is a common problem in heparin resistance [3,4,14]. If antithrombin III deficiencies are thought to be an underlying cause of hypercoVolume 155, February 1988
TABLE I
Patients Whose Dose of Intravenous Heparin Was Controlled by a Coagulation Test *t
Heparin
Patients (n)
Intermittent Continuous p value
29 36 ...
Total Bleedin 9 n %
Major Bleedin9 n %
9 10
5 3
31 28 NS
17 8 NS
Recurrence n % 1 3 10 28 <0.02
* Coagulation test refers to Lee-White clotting time or activated partial thromboplastin time, t Reprinted from [17], with permission of the publisher. NS = not significant.
agulability, the blood levels should be measured and specific replacement therapy undertaken. Standard protocol. The regimen used most often in the United States today includes a loading dose of 5,000 to 10,000 units of heparin given intravenously at the initiation of treatment [3,4]. Simultaneously, an intravenous infusion of 10 to 15 units/kg/hour is begun. Usually, an adult patient is given 1,000 to 1,500 units/kg/hour. Heparin is diluted in a solution of 5 percent glucose and water and delivered by a constant infusion pump. Although, as already described herein, tight control with coagulation tests is neither desirable nor feasible. It is generally accepted that 6 to 8 hours after initiation of therapy, some anticoagulation tests should be performed to be certain there is no heparin resistance and to determine that the patient is receiving the drug. Most often, the activated partial thromboplastin time is chosen although the activated thrombin time may be more accurate. It is a more laborious assay, however. The more sophisticated tests are not available in all clinical institutions. The activated partial thromboplastin time continues to be the test most often employed. As seen in Figure 1, there seems to be little difference in the overall accuracy among these tests. Their sensitivity varies, but the slopes of the curves are similar, and any of the tests can be used [5,6]. Coagulation tests are generally performed two or three times until stability has been obtained, and they are repeated whenever the heparin dosage is changed [4]. Tight control within a narrow range is not attempted, but most authorities recommend that the activated partial thromboplastin time be a p p r o x i m a t e l y 1.5 times t h e baseline value [3,14,16,17]. As the thrombotic process recedes, the heparin dosage may need to be reduced. Subsequently, a daily activated partial thromboplastin time is obtained, and every second or third day a hematocrit value and platelet count are also obtained. In the event that bleeding occurs, the heparin dosage may be reduced or eliminated. If thrombocytopenia appears, discontinuation of heparin is necessary. 271
Perry
I Exp. No. 23 6, 24 Yrs. R e l a t i v e Dose 5 7 . 9 u n i t s / k g .
300
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(see) 9
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t~'~WBPTT
]0 I
WBCT(min.) I
I
I
1.0
2,0
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Time A f t e r
Injection
of Heparin (Hrs.)
Patients are most likely to bleed on the third to the fifth day, and elderly women appear to be particularly vulnerable [3]. At that time, endogenous stores of heparin are saturated, the thrombotic process is resolving, and some of the inactive chains become activated while stored in the reticuloendothelial system and are then released into the general circulation [2,4]. There is considerable evidence that the risk of bleeding is directly related to the total daily dose of heparin. Patients most likely to receive high daily doses of heparin are the patients who have relatively insensitive responses as judged by the activated partial thromboplastin time, and thus they receive higher doses [3,14,16,17]. Monitoring the anticoagulatory effect of heparin therapy is apparently more useful to ensure an optimal regim e n t h a n to avoid b l e e d i n g c o m p l i c a t i o n s
[4,14,16,17]. Management of bleeding. In patients who have
only moderate bleeding, heparin can be temporarily stopped and the bleeding can be controlled with local procedures. In patients with severe bleeding, the heparin can be neutralized by the administration of protamine sulfate. This is a strong basic compound which binds ionically to acidic heparin and neutralizes it. It rapidly complexes with heparin. One milligram of protamine sulfate will neutralize approximately 100 units of heparin [2,3]. Be272
(sec.) Figure 1. The half-life of heparin's effect as measured by prothrombin time ( PTr), activated partial thromboplastln time ( APTT), whole blood partial lhromboplastln time ( WBPTT), and whole blood clotting time (WPCT). Reprinted from [5], with permission of the publisher.
cause of the short half-life of intravenous heparin (approximately 90 minutes), it is often best to administer half of the calculated required dose of protamine, then observe its effect before giving a full dose. There are studies suggesting that excessive doses of protam!ne can produce hypotension and even result in paradoxical bleeding [3].
Low-molecular weight heparin: preliminary studies. Commercially produced heparin can be separated into fractions with different mean molecular weights, and studies of these fractions have shown that the anticoagulant activity is highly dependent on molecular weight. Heparin's ability to prolong the clotting time as measured by the activated partial thromboplastin time declines sharply with decreasing molecular weights. Similarly, the ability of heparin to accelerate the inhibition of thrombin by antithrombin also falls off sharply with decreased molecular weights [19]. In 1976, it was found that low-molecular weight heparin fractions (molecular weight near 5,000 daltons) lacked the ability to prolong the clotting time but were capable of potentiating the inhibition of coagulation factor Xa. Previous views had held that the antithrombotic effect of heparin was reflected by its ability to prolong the clotting time or the activated partial thromboplastin time. This new finding challenged that concept, and it subsequently was postulated The American Journal of Surgery
Anticoaflulation: A Surgical Perspective
that the antithrombotic capacity of heparin should be attributed to its antifactor Xa activity [19,20]. The activated partial thromboplastin time activity mainly reflected the undesirable hemorrhage-inducing effect. A number of animal studies further showed that there were heparin fractions with a high affinity for antithrombin and fractions with a low affinity for antithrombin. Fractions with molecular weights of 4,000 to 6,000 daltons (heparin fractions, Fragmin) were found to have a high affinity for antithrombin. Heparin fractions with very low molecular weights (less than 3,000 daltons) were shown to have a limited ability to prevent experimental thrombosis in the rabbit, despite the fact that they exhibited high antifactor Xa activity. Although there are still unanswered questions regarding the mechanism of antithrombotic action of the oligosaccharides, the investigators concluded that heparin fractions of this optimal size possess antithrombotic activities without significantly prolonging the clotting time or the activated partial thromboplastin time [19-21]. In subsequent studies of pharmacokinetics, Bergquist et al [21] found that the plasma levels of antifactor Xa activity recorded after the administration of Fragmin were approximately five times higher than those obtained with conventional unfractionated heparin. Moreover, the duration of the activity of Fragmin was significantly longer than that seen with the usual doses of heparin. These studies suggested that Fragmin may be given in a once-a-day injection subcutaneously rather than giving the several doses required when ordinary unfractionated heparin was employed. These observations led to a number of prospective studies to determine if low-molecular weight heparin is effective in the prevention of thrombotic events, and furthermore, to determine if it was useful in treating established thromboembolism. Prospective studies by Bergquist et al [21] and Kakkar et al [20] showed that a single daily dose of Fragmin (2,500 units) could provide effective prophylaxis against postoperative venous thromboembolism. Although Kakkar et al [20] showed no difference between a dosage regimen employing 2,500 units and 5,000 units, the findings of Bergquist et al [21] revealed that a single injection of 5,000 units reduced the tendency for deep vein thrombosis to the same level as low-dose heparin given twice daily, but there were more bleeding complications. W h e n low-molecular weight heparin was compared with unfractionated heparin in the treatment of deep venous thrombosis, Holmer et al [19] and Lockner et al [22] found that Fragmin was as effective as conventional heparin protocols in preventing the progress of venous thrombosis. Moreover, in treating patients with phlebographically proved deep venous thrombosis, the required therapeutic range was easier to achieve in those who received
Volume 155, February 1988
low-molecular weight heparin as opposed to conventional heparin. Since the activated partial thromboplastin time or the clotting time cannot be depended upon to monitor the administration of low-molecular weight heparin, special assays of antifactor Xa activity are required. However, these more sophisticated and complicated tests are not available in all hospitals. When dose-response relationships of anticoagulant activity in healthy persons were studied after the subcutaneous administration of two low-molecular weight heparins, anticoagulation effects in vivo could not be predicted by the in vitro investigations. This was thought mainly to be due to a higher bioavailability of low-molecular weight heparin as compared with unfractionated heparin. In the study by Hellstern et al [23], the activated partial thromboplastin time was prolonged after administration of Fragmin, although other studies have shown little variation in these tests. Other investigators have also noted that higher activated partial thromboplastin time and antifactor IIa values were seen than would have been predicted by the in vitro studies [20,21]. These findings point out a requirement for pretesting of low-molecular heparin in healthy persons in order to develop appropriate doses for clinical trials. Because of the differences in these reports, it is clear that the desirable dose of low-molecular weight heparin for perioperative thrombosis prophylaxis has yet to be determined. The effectiveness of the drug appears not to be in question, but a safe regimen with reliable and reproducible testing methods awaits further study. Warfarin: Chemical description. All orally administered anticoagulants are derivatives of 4-hydroxycoumarin or indanedione [1]. Warfarin is the most commonly prescribed oral anticoagulant used for the prevention and treatment of thromboembolism. Warfarin interrupts the coagulation cascade by interfering with vitamin K-dependent liver synthesis of prothrombin and factors VII, IX, and X [3,24]. In the presence of warfarin, these biologically active clotting factors become inactive because they lack the carboxyl group which is essential for the binding of calcium. The vitamin K-dependent step in the synthesis of prothrombin, and probably factors IX and X, is the carboxylation of the glutamic acid components of the protein. Ordinarily, during the process of carboxylation, vitamin K is oxidized to vitamin K epoxide. Warfarin prevents the reduction of this epoxide back to vitamin K, and subsequently, there is a depletion of active vitamin K. This leads to the formation of the biologically inactive clotting factors. Pharmacokinetics. Warfarin is rapidly absorbed from the upper gastrointestinal tract, but the rate of absorption varies a great deal from person to person. Peak plasma concentration after administering an oral dose may occur over a period ranging from 2 to
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TABLE II
Drugs That Can Displace Warfarin From Protein-Binding Sltes*t Amiodarone (investigational) Aspirin * Chloral hydrate Ethacrynic acid (Edecrin | Mefenamic acid (Ponstel | Oxyphenbutazone* Sulfinpyrazone * Sulfonamides* Triclofos (Triclos|
* Reprinted from [25], with permission of the publisher. t Interaction with warfarin may occur by other mechanisms.
12 hours. Warfarin is highly protein-bound and this binding is independent of the level of total protein or albumin concentration, but there are marked individual variations in the amount of bound and free fractions of warfarin in the blood. It is the free fraction only that is pharmacologically active. In man, the half-life of warfarin is independent of the dose, but usually falls within the range of 35 to 45 hours. In the body, warfarin is distributed in approximately 8 to 27 percent of the body weight, which is similar to that of albumin (to which it is bound). Because of the high degree of protein binding and a relatively narrow therapeutic index, an increase in the free fraction of warfarin will cause a temporary increase in the pharmacologic effect, as well as lead to an increase in clearance of warfarin from the blood. Therefore, displacement of warfarin from its protein-binding site by other drugs, some of which are listed in Table II, or by uremia will result in transient changes in its effect [24,25]. Warfarin is completely metabolized by the liver and subsequently eliminated by the kidney. Metabolites may appear in the urine for periods of up to 4 weeks after administration of a single dose of the drug.
Prophylaxis and treatment of venous thromboembolism. Because of the danger of bleeding during operation, warfarin has not been used extensively as prophylaxis for deep vein thrombosis. More often, heparin or other agents such as dextran are chosen. Francis et al [26] have suggested a two-step method using warfarin which apparently reduces the risk of bleeding. The drug is started 10 to 14 days before operation, and the prothrombin time is kept at 1.5 to 3 seconds longer than the control values. After operation, the dosage is increased and the prothrombin time is kept near 1.5 times the control value using rabbit brain thromboplastin. In their study, postoperative bleeding occurred in only 4 percent of the patients, and there was a reduction in proximal venous thrombi (iliofemoral) as seen by venography. Despite this study and a few others,
274
low-dose warfarin has not been widely used in prophylaxis against deep vein thrombosis in surgical patients [3,9,27]. Warfarin has been shown to be a valuable agent in the prevention and treatment of venous thromboembolism [1,3,9,24,28]. The mortality rate from recurrent pulmonary embolism is significantly reduced in patients treated with heparin and oral anticoagulants. Thrombosis of the iliac, femoral, and popliteal veins also may be prevented by treatment with warfarin. After initiation of warfarin treatment, complete anticoagulant protection is delayed for several days since it requires time for the elimination of vitamin K stores and the normal clotting factors. They are subsequently replaced by biologically inactive factors. The depletion of factor VII, the clotting factor that has the shortest biologic half-life, results in an initial prolongation of the prothrombin time, but because this factor is of minor importance in the pathogenesis of venous thrombi, the full antithrombotic activity of warfarin will not be achieved until active prothrombin and factors IX and X have been depleted. This process may take up to 4 days. Therefore, when intravenous heparin is to be replaced by oral warfarin, there must be an overlap of 4 to 5 days before the heparin is discontinued, regardless of the change in prothrombin time. This period of overlap may be associated with an increased risk of thrombosis because the half-life of protein C, a vitamin K-dependent protein produced by the liver, is 4 to 6 hours, which is similar to that of factor VII. With the early decrease in protein C levels, there may be some increase in coagulability. Heparin is needed until levels of factor II, IX, and X decrease [14]. There is little convincing evidence that loading doses of I0 to 15 mg accelerate achieving full anticoagulant protection, and there are data which suggest that such loading doses are associated with an increased incidence of bleeding and perhaps other complications such as skin necrosis [3,25]. It is usually best to begin patients on a daily dose of 5 mg orally and continue this until complete protection is obtained. As already noted herein, there is considerable variation among patients in the response to warfarin anticoagulation [24,25]. Drugs that can displace warfarin for protein-binding sites are listed in Table II. Other drugs may increase the speed of warfarin metabolism or interfere with its activity. Some of these drugs are barbiturates, carbamazepine (Tegretol| ethanol (chronic abuse), ethchlorvynol (Placidyl| glutethimide, griseofulvin, and rifampin [25]. Moreover, there are other drugs and chemicals that may increase the potency of warfarin and perhaps, can lead to bleeding. These agents are allopurinol, amiodarone (investigational), cimetidine
The American Journal of Surgery
Anticoagulation: A
(Tagamet| disulfiram, ethanol (acute intoxication), metronidazole, oxyphenylbutazone, phenylbutazone, phenytoin (Dilantin| and sulfonamides (trimethoprim and sulfamethoxazole) [25]. During the establishment of warfarin anticoagulation, the possibility of these drug interactions must be considered if the regimen is to be effective and safe. Monitoring therapy. Following the anticoagulant effect of warfarin by performing weekly prothrombin time determinations is relatively easily done. It has been found that the incidence of recurrence of thromboembolism is lower in patients receiving more intense therapy than in patients who have less anticoagulant activity [24]. Prothrombin activity of 20 to 30 percent, as measured by the saline solution of normal plasma, corresponds to a prothrombin time of approximately twice the normal value. The therapeutic goal widely used is to maintain the prothrombin time at 2 to 2.5 times the normal values
[3,24,28]. Bleeding. Warfarin is rapidly and completely absorbed and has a long half-life and a very prolonged effect. Therefore, the use of large initial doses may be especially hazardous in regard to bleeding complications. The annual significant bleeding complication rate for warfarin anticoagulation has been reported to be as high as 8 percent [3]. More recent experiences suggest that it is unnecessary in the usual clinical setting to administer these larger doses of warfarin. It appears that prolongation of the prothrombin time to i and 1.5 times the baseline provides adequate protection against new clots without as much risk of bleeding [3,24,25]. Hemorrhage may occur at any level of anticoagulant control because of the Variability just described and operations, trauma, or other drug interactions may increase this tendency. The most frequent sites of bleeding include the gastrointestinal tract, the urinary tract, and the skin. More serious episodes occur when bleeding is present in the central nervous system. Minor hemorrhagic complications from excessive prolongation of prothrombin time usually can be managed by adjusting the dose or administering oral vitamin K1. These episodes are frequently transient and can be controlled. More serious hemorrhagic complications, particularly bleeding in the central nervous system, require stopping warfarin therapy and perhaps giving vitamin K1. A response will usually occur within 3 to 4 hours after parenteral administration of vitamin K1, but the maximal effect occurs within 8 hours. A more rapid response cannot be achieved by using doses larger than 25 mg [24,25]. The other adverse effects of warfarin can include skin necrosis [3]. This is most likely to occur in the fleshy area of women 3 to 5 days after the initiation of warfarin therapy. Although it usually is only a local phenomenon, on occasion, it can be lethal. It is
Volume 155, February 1988
Surgical
Perspective
thought to be most likely to occur in its severe form in patients who have protein C deficiency. During the initiation of warfarin therapy, a rapid increase in the prothrombin time may be an ominous finding. If this complication is suspected, anticoagulation should promptly be discontinued. Other therapeutic uses. The value of oral anticoagulants in the treatment of transient attacks of cerebral ischemia has not been substantiated in several trials [1,3,24,25,28]. There is no convincing evidence that anticoagulant therapy either reduces the incidence of stroke or increases the survival rate of patients who are having transient attacks of ischemia. In fact, data from several randomized trials show greater mortality and morbidity rates in treatment groups than in control groups [3]. Patients with cardiomyopathy, rheumatic valve disease, and chronic atrial fibrillation, and patients with prosthetic heart valves may be at high risk for recurrent arterial embolization [28]. There are data supporting the use of anticoagulant therapy in rheumatic heart disease and in patients with arrhythmias and prosthetic valves. The risk of recurrent arterial embolization in these conditions is persistent, and long-term anticoagulant treatment with warfarin is recommended. Thromboembolism may occur in patients despite adequate anticoagulant control. This suggests to some clinicians that there may be a possible role for combined treatment with antiplatelet agents. Since salicylates may cause gastric mucosal irritation, which could lead to gastrointestinal hemorrhage, they are generally not employed. O t h e r agents such as i b u p r o f e n are preferred. All of these drugs should be used with caution, however, since the likelihood of significant complications are increased because of drug interactions.
Summary Heparin combines with antithrombin III, and the resulting complex inactivates several clotting factors (all are serine proteases) in the coagulation cascade, but the most important steps are inhibition of the conversion of factor X to Xa and the antithrombin effect. Heparin pharmacokinetics are poorly understood, but when the usual doses are given intravenously, heparin is rapidly removed from the blood and has a half-life of approximately 90 minutes. Warfarin is not a true anticoagulant but is readily absorbed after oral administration. It interrupts the coagulation mechanism by interfering with the vitamin K-dependent synthesis of prothrombin and factors VII, IX, and X. This process takes 4 to 5 days. The drug has a long half-life, and its activity is enhanced or blunted by many chemicals. The effective treatment of thromboembolism with heparin, followed by warfarin, requires a basic understanding of the complex pharmacologic aspects and drug interactions.
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References 1. Coon WW. Use of anticoagulant drugs. Am Soc Pharmacol Exper Ther 1979; 13: 1-6. 2. Jaques LB. Heparins: anionic polyelectrolyte drugs. Pharm Review 1980; 31: 99-166. 3. Ansell JE. Handbook of hemostasis and thrombosis. Boston: Little, Brown and Co., 1986:73-117. 4. Bjornsson TD, Greenberg C. Heparinization in the surgical patient. Infect Surg 1985: 87-97. 5. Estes JW. Heparin'therapy. Int Med Dig 1971: 33-42. 6. Perry MO, Horton J. Kinetics of heparin administration. Arch Surg 1976; 111: 403-9. 7. Prevention of fatal postoperative pulmonary embolism by low doses of heparin. An international multicenter trial. Lancet 1975; 2: 45-56. 8. Consensus Conference. Prevention of venous thrombosis and pulmonary embolism. JAMA 1986; 256: 744-9. 9. Hull RD, Raskob G, Hirsh J. Prophylaxis of venous thromboembolism: an overview. Chest 1986; 89: 3745-835. 10. Leyvraz PF, Richer T, Bachman F, et al. Adjusted versus fixeddose subcutaneous heparin in the prevention of deep vein thrombosis. N Eng! J Med 1983; 309: 954-8. 11. Kakkar VV, Stamatkis JD, Bentley PG, et al. Prophylaxis for post-operative deep vein thrombosis; synergistic effect of heparin and dihydroergotamine. JAM,&, 1979; 241: 39-42. 12. Multicenter-Trial Committee. Dihydroergotamine heparin prophylaxis of post-operative deep vein thrombosis. JAMA 1984; 251: 2960-6. 13. Comerota AJ, White JV. The use of dihydroergotamine and heparin in the prophylaxis of deep vein thrombosis. Chest 1986; 89: 389-400. 14. Hirsh J, Hull RD. Treatment of venous thromboembolism. Chest 1986; 89:426-37 15. Barritt DW, Jordan SC. Anticoagulant drugs in the treatment of pulmonary embolism. Lancet 1960; 1: 1309-12. 16. Hull RD, Raskob G, Hirsh J, et al. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis. N Engl J
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Med 1986; 315: 1109-14. 17. Wilson JE, Bynum LJ, Parkey RW. Heparin therapy in venous thromboembolism. Am J Med 1981; 70: 808-16. 18. Hul! RD, Delmore T, Carter C, et al. Adjusted subcutaneous heparin versus warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med 1982; 30: 189-93. 19. Holmer E, Soderberg K, Bergquist D, Lindalh U. Heparin and its low molecular weight derivatives: anticoagulant and antithrombotic properties. Haemostasis 1986; 16(suppl 2): 17. 20. Kakkar VV, Kakkar S, Sanderson RM, Peers CE. Efficacy and safety of two regimens of low molecular weight heparin fragments (Fragmin) in preventing postoperative venous thromboembolism. Haemostasis 1986; 16(suppl 2): 19-24. 21. Bergquist D, Burmack US, Frisell J, et al. Prospective doubleblind comparison between Fragmin and conventional lowdose heparin: thromboprophylactic effect and bleeding complications. Haemostasis 1986; 16(suppl 2): 11-8. 22. Lockner D, Bratt G, Tomebohm E, ,&`bergS. Intravenous and subcutaneous administration of Fragmin in deep venous thrombosis. Haemostasis 1986; 16(suppl 2): 25-9. 23. Hellstern P, Kiehl R, von Blohn G, Kohler M, Meierherrick U, Wenzel E. Dose response relationships of anticoagulant activities after subcutaneous administration of two low molecular weight heparins in healthy individuals. Thromb Haemost 1986; 56: 225-8. 24. Palmer JD. Clinical uses of warfarin. Drug Ther 1981: 49-60. 25. Platt DR, Nightingale CH. Warfarin drug interactions. Infect Surg 1986; 91-8. 26. Francis CW, Marder VJ, Evart M, Yaukoolbodi S. Two-step warfarin therapy: prevention of post-operative venous thrombosis without excessive bleeding. JAMA 1983; 249: 374-8. 27. Taberner DA, Poller L, Burslem RW, Jones JB. Oral anticoagulants controlled by the British comparative thromboplastin versus low-dose heparin in prophylaxis of deep vein thrombosis. Br Med J 1978; 1: 272-4. 28. Wessler S, Gitel SN. Coagulation for cardiologists. Am Heart J 1978; 96:811-23.
/
The American Journal of Surgery
Anticoagulation: A Surgical Perspective Malcolm O. Perry, MD, New York, New York
Commonly used anticoagulants can be divided into two groups: heparin and heparin-like compounds and warfarin derivatives [1]. Although usually used singly, the agents have different mechanisms of action and, on occasion, are employed simultaneously. I chose to discuss 0nly heparin and warfarin. The antiplatelet agents are not really true anticoagulants. In fact, their mode of action continues to be disputed. Although hopes are high for the low-molecular weight heparin fractions, today their role is still under exploration. For the time being, we surgeons must rely on heparin, and on occasion, warfarin for the treatment of thromboembolism. I-Ieparin: Chemical description. Heparin belongs to a group of compounds called linear anionic polyelectrolytes. These are highly negatively charged mucopolysaccharide chains [2]. In man, they are found in the mast cells and in basophilic leukocytes. Four types are distinguished as separated by molecular weights: low-molecular weight heparin (6,000 to 13,000 daltons), macromolecular heparin (up to a million daltons), heparitins, and multisulphated chondroitins. Heparin also varies in the degree of sulfation on any of the three sugars, and in the acetylation of glucosamine. Although the net electrical charge varies, heparin is the most negatively charged natural occurring substance in the body [3]. Heparin is a relatively crude natural product, obtained from either bovine lungs or porcine intestinal mucosa. The heterogeneity of heparin has led to numerous discussions regarding the potency of the two preparations, bovine versus porcine, and raised questions as to whether undesirable side effects are From the Department of Surgery, Division of Vascular Surgery, The New York HospitaI-Cornell Medical Center, New York, New York. Requests for reprints should be addressed to Malcolm O. Perry, MD, Department of Surgery, Division of Vascular Surgery, The New York HospitaI-Cornell Medical Center, 525 East 58th Street, New York, New York, 10021.
268
more common with one preparation than the other. Chemical assays currently accepted for standardization of commercial heparin are performed in vitro on animal plasma, and although hemostatic responses in the dog are different from those in man, this technique has not shown a significant difference between lung- and mucosa-derived heparin. Moreover, there are no scientifically based studies showing differences in potency of the two preparations. In the United States, the sodium salt of hepatin is available and standardized so as to produce a compound which has 156 units/mg (United States Pharmacopea (USP) units). The differences in preparation of heparin may influence its antithrombotic activity in man, but there are no scientific data that justify the selection of one type or brand of heparin in preference to another [1,4]. Pharmacologic properties of heparin. Although heparin is mainly used for its anticoagulant effect, this is only one part of its sphere of activity [2]. In fact, approximately 20 to 30 percent of the commercially prepared heparin can be shown to have an anticoagulation effect as defined by forming a complex with antithrombin III. This complexing appears to be a relatively unusual feature of a few side chains found in commercial heparin, and it may play a minor role in overall heparin activity. The other activities which can be assigned to heparin are anticoagulation (complex with antithrombin III); adherence to vascular endothelium and increased electronegativity; reduction of platelet adhesiveness, increase in plasma lecithinase action; reduction in rigidity of fibrinogen surface layers; blockage of vascular permeability caused by prostaglandin, bradykinin, and histamine; and competitive inhibition of adenosine triphosphatase (decreases endothelial cell construction). Some of these, such as the marked increase in electronegativity of the endothelial surface, may exert a more potent antithrombotic effect in vivo [2].
The American Journal of Surgery
Anticoagulation: A Surgical Perspective
Heparin combines with antithrombin III, a circulating anticoagulant protein produced in the liver. This complex neutralizes the proteolytic activities of several activated clotting factors in the intrinsic and common pathways of the coagulation cascade [3]. All of these clotting factors (XIIIa, XIa, Xa, IXa, and IIa) are serine proteases. The union of heparin to antithrombin III is achieved through a specific antithrombin III-binding site on heparin, and a lysine-containing center on the antithrombin III. This results in a change in the molecular configuration of the antithrombin III molecule which exposes inhibitory binding sites. Heparin also binds with lipolipase, but this binding differs from that of antithrombin III in that it is less avid and nonspecific. The majority of the heparin chains bind with fibrinogen. The effect of the inactivation of the serine proteases in the clotting cascade decreases the overall rate of reaction, but quantitatively, the most imporrant steps are the inhibition of the conversion of factor X to Xa, and the antithrombin effect [4]. The final result is a decrease in the amount of thrombin available for forming fibrin. After the protease and antithrombin III complex has been formed, heparin can be released, and may be available for promoting inhibition of other reactions in the anticoagulation mechanism. Pharmacokinetics. The assessment of the pharmacokinetics of heparin is complicated by the difficulty in standardizing heparin preparations [5]. AIthough a given sample of commercial heparin may assay quite accurately on repeat examination, there is a low level of precision attained when two heparin preparations are compared. The USP assay is not a satisfactory predictor of potency for inhibition, even of clotting of fresh whole blood. The marked variability between samples of commercial heparin is matched by a corresponding variability in the assay potency by in vitro coagulation test systems. Most studies of heparin kinetics are derived from experiments using coagulation tests that do not directly assay the heparin, only its anticoagulant elfect [6]. In vitro, it is not the clotting time but the logarithm that is directly proportional to the amount of added heparin; therefore, there is a narrow range of heparin concentration that gives measurable coagulation time values. Obviously, low doses of heparin have little effect and high doses produce infinitely long clotting times, neither of which give a reliable indication of the actual heparin concentration in the plasma [4]. Heparin is removed rapidly from the blood by adherence to the endothelium, as well as by being taken up by the reticuloendothelial system and by macrophages. A third of the circulating heparin is removed from the blood in a single pass [2]. It has been suggested that adherence to the endothelium
Volume 155, February 1988
is an important feature in its antithrombotic effect, although this has not been proven, but the concentration on the endothelium is 100 times that in the plasma. The uptake by vascular endothelium and the reticuloendothelial system produces unusual peak blood concentrations when heparin is administered subcutaneously or by way of the lungs. After subcutaneous administration of heparin, the peak blood concentrations are 2 percent of the peak values obtained with intravenous injection. Most drugs have a 20 to 40 percent blood concentration. The biologic half-life of heparin increases with increasing doses, since it is cleared in a first-order reaction. In man, the half-life can be shown to be approximately 56 minutes when 100 units/kg are administered, 96 minutes with 200 units/kg, and 152 minutes with 400 units/kg [2]. Furthermore, the rate of heparin clearance from the blood decreases with increasing doses, but the quantity of heparin on the endothelium increases. Despite these variations in kinetics, in the usual dosage employed in man, the half-life of intravenously administered heparin is approximately 90 minutes. One may expect, however, to see disproportionate increases in the plasma heparin concentration as the heparin dose is increased [4]. The metabolic degrading and subsequent elimination of heparin from the body is poorly understood, but after initial clearance from the plasma, heparin is finally eliminated by the liver and the kidneys. The metabolic processes apparently include depolymerization and desulfation. Only small amounts of heparin are excreted unchanged in the urine. It is apparent that the coagulation tests customarily used to assess heparin in the blood represent an in vivo response to the administration of heparin, but these tests do not reflect the concentration in plasma because most of the heparin is in the physiologic depot. It has been demonstrated that regardless of the method of administration, the total amount of heparin required to achieve a desired effect over a given amount of time is about the same [2]. The significant parameter seems to be the concentration of heparin maintained in the plasma [5]. Basis for clinical use. During coagulation, the clotting factors normally react preferentially with their specific substrates rather than with the naturally occurring antithrombin. In the absence of heparin, the reaction between the clotting factors and antithrombin III is slow, but after heparin binds to antithrombin, this reaction becomes virtually instantaneous and coagulation stops. The affinity of the heparin and antithrombin III complex for activated factor X is greater than for factor II (prothrombin); therefore, less heparin is required to neutralize the factor X-to-Xa conversion than is required for antithrombin activity. It is easier to prevent activation of the coagulation cascade than it
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is to halt the mechanism once it is fully engaged. From these observations, two separate modes of heparin therapy have been developed: low-dose heparin for prophylaxis of thromboembolism and heparin therapy for treatment of thromboembolism. Each has a distinct therapeutic objective and they are mutually exclusive [4].
Prophylaxis and treatment of thromboembolism. Numerous clinical studies have demonstrated that low-dose subcutaneous heparin is effective in preventing calf vein thrombosis. In the original studies performed in Europe, the method was to administer 5,000 IU of heparin 2 hours before operation, and then every 8 hours until the patient was fully ambulatory [7-10]. Using the more potent USP preparation, an equivalent unit dose would be approximately 3,700 units. The common regimen employed in the United States today is to administer 5,000 units subcutaneously 2 hours before operation and then repeat the 5,000 units every 12 hours. Although most of these trials have shown some morbidity from an increased incidence of postoperative bleeding in the form of wound hematomas, in the heparin-treated groups there was no evidence that bleeding caused by low-dose heparin has been a direct cause of death [7-9]. The original studies did not show low-dose heparin to be effective in those patients who had the greatest thrombotic tendencies (for example, hip arthroplasty). In a subsequent study, Leyvraz et al [10] treated 79 patients undergoing elective hip surgery. Half of the patients were placed randomly into one group receiving 3,500 IU heparin subcutaneously 2 hours preoperatively and every 8 hours thereafter for 7 to 9 days (fixed dosage). The other group received the same initial dose of heparin, but thereafter the amount of heparin was varied to keep the activated partial thromboplastin time between 31.5 and 36 seconds (adjusted dosage). By venography 16 of 41 patients (39 percent) in the fixed-dose group had recurrence of venous thrombosis, but only 5 of 38 patients (14 percent) in the adjusted-dose group had development of new clots. There were no bleeding episodes in either group. The combination of dihydroergotamine and heparin has been used to prevent venous thrombosis. The venoconstrictive effect of dihydroergotamine is believed to reduce the diameter of systemic veins and thus to increase the velocity of blood fl0w if the volume of blood traversing the veins remains the same. This may reduce venous blood stasis [9,1113].' Although there are only limited data supporting this regimen, the multicenter trial [12], and reports by Comerota and White [13] suggested that in patients at high risk for thrombosis, 0.5 mg of dihydroergotamine and 5,000 units of heparin given every 12 hours may be effective. When dihydroergotamine is given alone or combined with lesser amounts of heparin, little or no benefit was seen. 270
Ergotamine has systemic effects which could be deleterious, especially in patients with multiple injuries, sepsis, hypotension, and vascular diseases. Despite these potential problems, few adverse effects of vasospasm have been detected in the reported trials. Except for the adjusted-dose regimen described by Leyvraz et al [10], low-dose heparin administration protocols do not require serial tests of coagulation. A heparin-activated antiplatelet antibody may occur even with low-dose heparin therapy, although it is seen more frequently in patients receiving conventional doses [3]. Therefore, thrombocytopenia and serious side effects may supervene any time after 3 or 4 days of heparin treatment, and all patients receiving heparin should have a platelet count performed every 3 days while the drug is being administered. The appearance of thrombocytopenia is an absolute indication for discontinuation of heparin therapy. Hirsh and Hull [14] stated that "the evidence that heparin is effective in the treatment of pulmonary embolism comes principally from one controlled study." The study by Barritt and Jordan [15], in 1960, showed that a quarter of the inpatients with pulmonary embolism died if untreated. Subsequent studies have shown a recurrence of pulmonary embolism in only 3 to 8 percent of the patients treated with heparin [3,4,15-17]. The two major problems with heparin therapy for venous thromboembolism are bleeding and recurrent embolism. The national cooperative study revealed an overall incidence of bleeding complications of 27 percent and an incidence of recurrent thromboembolism of 16 percent [8]. These observations increased the controversy over whether heparin should be administered continuously or intermittently by intravenous or subcutaneous routes. No unanimity of opinion has been reached as to which dosages are desirable or which route is best, although heparin clearly is effective in the treatment of thromboembolism. These controversies subsequently led Wilson et al [1] to perform a prospective study of patients with deep vein thrombosis and pulmonary embolism. The 114 patients were randomly assigned to receive either intermittent or continuous heparin therapy. One group was treated with a standard dose, and in a Similar group, the heparin was controlled by attempting to maintain the Lee-White clotting time or activated partial thromboplastin time at a level of 1.5 to 2.5 times normal. In 65 patients assigned to receive heparin controlled by coagulation tests, recurrences happened significantly more often with continuous heparin therapy (28 percent) than with intermittent heparin therapy (3 percent). When the patients at high risk for bleeding were analyzed separately, major bleeding occurred in 42 percent of the group receiving intermittent heparin therapy as The American Journal of Surgery
Anticoagulation: A Surgical Perspective
compared with 7 percent of those who received continuous therapy. This was not statistically significant, however (p -- 0.06). There was no convincing relationship between recurrences and the dose of heparin used, or the effect of monitoring the dose by coagulation tests (Table I). Hull et al [16] studied 115 patients with deep vein thrombosis diagnosed first by clinical methods, then confirmed by noninvasive laboratory techniques and venography. The patients were divided into two groups, one of which was treated with intermittent subcutaneous heparin and the other, with continuous intravenous heparin. The patients treated by subcutaneous injection received 15,000 units of heparin every 12 hours. In the other group, 5,000 units of heparin were given as an intravenous bolus, and then 29,760 units were given as a continuous intravenous infusion. The activated partial thromboplastin time was checked midway between the subcutaneous injections and at the same time of day in the patients receiving intravenous heparin. The activated partial thromboplastin time target was 55 to 75 seconds. Warfarin was begun on the sixth or seventh day, and given for 12 weeks, attempting to keep the prothrombin time at 1.25 to 1.5 times the control value. Recurrent venous thromboembolism occurred in 11 of 57 patients (19.3 percent) receiving subcutaneous heparin, but in only 3 of 58 patients (5.2 percent) treated with continuous intravenous heparin. Bleeding occurred in 5.3 percent of the patients who had subcutaneous heparin and in 6.9 percent of those with intravenous infusion of heparin. In two separate reports, Hirsh and Hull [14,18] noted that there seemed to be less recurrences of venous thromboembolism in patients treated with heparin if the activated partial thromboplastin time was kept near 1.5 times the control prethrombotic values. They found no relationship between the risk of bleeding and the activated partial thromboplastin time in patients receiving continuous or intermittent heparin intravenously. This finding was similar to findings of Wilson et al [17]. Resistance to heparin is seen in patients with extensive thrombosis. Higher doses of heparin may be required, especially during the initial period of treatment [2,4,14]. Hirsh and Hull [14] stated that heparin resistance is usually caused by a rapid clearance of heparin, but they cautioned that the activated partial thromboplastin time may be misleading because of aberrations in the test. Although antithrombin III levels may decrease by as much as 30 percent during the administration of heparin, this apparently has little clinical significance. Congenital deficiencies of antithrombin III occur in approximately 1 of 2,000 persons, but there is no strong evidence that this is a common problem in heparin resistance [3,4,14]. If antithrombin III deficiencies are thought to be an underlying cause of hypercoVolume 155, February 1988
TABLE I
Patients Whose Dose of Intravenous Heparin Was Controlled by a Coagulation Test *t
Heparin
Patients (n)
Intermittent Continuous p value
29 36 ...
Total Bleedin 9 n %
Major Bleedin9 n %
9 10
5 3
31 28 NS
17 8 NS
Recurrence n % 1 3 10 28 <0.02
* Coagulation test refers to Lee-White clotting time or activated partial thromboplastin time, t Reprinted from [17], with permission of the publisher. NS = not significant.
agulability, the blood levels should be measured and specific replacement therapy undertaken. Standard protocol. The regimen used most often in the United States today includes a loading dose of 5,000 to 10,000 units of heparin given intravenously at the initiation of treatment [3,4]. Simultaneously, an intravenous infusion of 10 to 15 units/kg/hour is begun. Usually, an adult patient is given 1,000 to 1,500 units/kg/hour. Heparin is diluted in a solution of 5 percent glucose and water and delivered by a constant infusion pump. Although, as already described herein, tight control with coagulation tests is neither desirable nor feasible. It is generally accepted that 6 to 8 hours after initiation of therapy, some anticoagulation tests should be performed to be certain there is no heparin resistance and to determine that the patient is receiving the drug. Most often, the activated partial thromboplastin time is chosen although the activated thrombin time may be more accurate. It is a more laborious assay, however. The more sophisticated tests are not available in all clinical institutions. The activated partial thromboplastin time continues to be the test most often employed. As seen in Figure 1, there seems to be little difference in the overall accuracy among these tests. Their sensitivity varies, but the slopes of the curves are similar, and any of the tests can be used [5,6]. Coagulation tests are generally performed two or three times until stability has been obtained, and they are repeated whenever the heparin dosage is changed [4]. Tight control within a narrow range is not attempted, but most authorities recommend that the activated partial thromboplastin time be a p p r o x i m a t e l y 1.5 times t h e baseline value [3,14,16,17]. As the thrombotic process recedes, the heparin dosage may need to be reduced. Subsequently, a daily activated partial thromboplastin time is obtained, and every second or third day a hematocrit value and platelet count are also obtained. In the event that bleeding occurs, the heparin dosage may be reduced or eliminated. If thrombocytopenia appears, discontinuation of heparin is necessary. 271
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I Exp. No. 23 6, 24 Yrs. R e l a t i v e Dose 5 7 . 9 u n i t s / k g .
300
2OO zoo PTT
.~
(see) 9
4~ 0
30[
t~'~WBPTT
]0 I
WBCT(min.) I
I
I
1.0
2,0
3.0
Time A f t e r
Injection
of Heparin (Hrs.)
Patients are most likely to bleed on the third to the fifth day, and elderly women appear to be particularly vulnerable [3]. At that time, endogenous stores of heparin are saturated, the thrombotic process is resolving, and some of the inactive chains become activated while stored in the reticuloendothelial system and are then released into the general circulation [2,4]. There is considerable evidence that the risk of bleeding is directly related to the total daily dose of heparin. Patients most likely to receive high daily doses of heparin are the patients who have relatively insensitive responses as judged by the activated partial thromboplastin time, and thus they receive higher doses [3,14,16,17]. Monitoring the anticoagulatory effect of heparin therapy is apparently more useful to ensure an optimal regim e n t h a n to avoid b l e e d i n g c o m p l i c a t i o n s
[4,14,16,17]. Management of bleeding. In patients who have
only moderate bleeding, heparin can be temporarily stopped and the bleeding can be controlled with local procedures. In patients with severe bleeding, the heparin can be neutralized by the administration of protamine sulfate. This is a strong basic compound which binds ionically to acidic heparin and neutralizes it. It rapidly complexes with heparin. One milligram of protamine sulfate will neutralize approximately 100 units of heparin [2,3]. Be272
(sec.) Figure 1. The half-life of heparin's effect as measured by prothrombin time ( PTr), activated partial thromboplastln time ( APTT), whole blood partial lhromboplastln time ( WBPTT), and whole blood clotting time (WPCT). Reprinted from [5], with permission of the publisher.
cause of the short half-life of intravenous heparin (approximately 90 minutes), it is often best to administer half of the calculated required dose of protamine, then observe its effect before giving a full dose. There are studies suggesting that excessive doses of protam!ne can produce hypotension and even result in paradoxical bleeding [3].
Low-molecular weight heparin: preliminary studies. Commercially produced heparin can be separated into fractions with different mean molecular weights, and studies of these fractions have shown that the anticoagulant activity is highly dependent on molecular weight. Heparin's ability to prolong the clotting time as measured by the activated partial thromboplastin time declines sharply with decreasing molecular weights. Similarly, the ability of heparin to accelerate the inhibition of thrombin by antithrombin also falls off sharply with decreased molecular weights [19]. In 1976, it was found that low-molecular weight heparin fractions (molecular weight near 5,000 daltons) lacked the ability to prolong the clotting time but were capable of potentiating the inhibition of coagulation factor Xa. Previous views had held that the antithrombotic effect of heparin was reflected by its ability to prolong the clotting time or the activated partial thromboplastin time. This new finding challenged that concept, and it subsequently was postulated The American Journal of Surgery
Anticoaflulation: A Surgical Perspective
that the antithrombotic capacity of heparin should be attributed to its antifactor Xa activity [19,20]. The activated partial thromboplastin time activity mainly reflected the undesirable hemorrhage-inducing effect. A number of animal studies further showed that there were heparin fractions with a high affinity for antithrombin and fractions with a low affinity for antithrombin. Fractions with molecular weights of 4,000 to 6,000 daltons (heparin fractions, Fragmin) were found to have a high affinity for antithrombin. Heparin fractions with very low molecular weights (less than 3,000 daltons) were shown to have a limited ability to prevent experimental thrombosis in the rabbit, despite the fact that they exhibited high antifactor Xa activity. Although there are still unanswered questions regarding the mechanism of antithrombotic action of the oligosaccharides, the investigators concluded that heparin fractions of this optimal size possess antithrombotic activities without significantly prolonging the clotting time or the activated partial thromboplastin time [19-21]. In subsequent studies of pharmacokinetics, Bergquist et al [21] found that the plasma levels of antifactor Xa activity recorded after the administration of Fragmin were approximately five times higher than those obtained with conventional unfractionated heparin. Moreover, the duration of the activity of Fragmin was significantly longer than that seen with the usual doses of heparin. These studies suggested that Fragmin may be given in a once-a-day injection subcutaneously rather than giving the several doses required when ordinary unfractionated heparin was employed. These observations led to a number of prospective studies to determine if low-molecular weight heparin is effective in the prevention of thrombotic events, and furthermore, to determine if it was useful in treating established thromboembolism. Prospective studies by Bergquist et al [21] and Kakkar et al [20] showed that a single daily dose of Fragmin (2,500 units) could provide effective prophylaxis against postoperative venous thromboembolism. Although Kakkar et al [20] showed no difference between a dosage regimen employing 2,500 units and 5,000 units, the findings of Bergquist et al [21] revealed that a single injection of 5,000 units reduced the tendency for deep vein thrombosis to the same level as low-dose heparin given twice daily, but there were more bleeding complications. W h e n low-molecular weight heparin was compared with unfractionated heparin in the treatment of deep venous thrombosis, Holmer et al [19] and Lockner et al [22] found that Fragmin was as effective as conventional heparin protocols in preventing the progress of venous thrombosis. Moreover, in treating patients with phlebographically proved deep venous thrombosis, the required therapeutic range was easier to achieve in those who received
Volume 155, February 1988
low-molecular weight heparin as opposed to conventional heparin. Since the activated partial thromboplastin time or the clotting time cannot be depended upon to monitor the administration of low-molecular weight heparin, special assays of antifactor Xa activity are required. However, these more sophisticated and complicated tests are not available in all hospitals. When dose-response relationships of anticoagulant activity in healthy persons were studied after the subcutaneous administration of two low-molecular weight heparins, anticoagulation effects in vivo could not be predicted by the in vitro investigations. This was thought mainly to be due to a higher bioavailability of low-molecular weight heparin as compared with unfractionated heparin. In the study by Hellstern et al [23], the activated partial thromboplastin time was prolonged after administration of Fragmin, although other studies have shown little variation in these tests. Other investigators have also noted that higher activated partial thromboplastin time and antifactor IIa values were seen than would have been predicted by the in vitro studies [20,21]. These findings point out a requirement for pretesting of low-molecular heparin in healthy persons in order to develop appropriate doses for clinical trials. Because of the differences in these reports, it is clear that the desirable dose of low-molecular weight heparin for perioperative thrombosis prophylaxis has yet to be determined. The effectiveness of the drug appears not to be in question, but a safe regimen with reliable and reproducible testing methods awaits further study. Warfarin: Chemical description. All orally administered anticoagulants are derivatives of 4-hydroxycoumarin or indanedione [1]. Warfarin is the most commonly prescribed oral anticoagulant used for the prevention and treatment of thromboembolism. Warfarin interrupts the coagulation cascade by interfering with vitamin K-dependent liver synthesis of prothrombin and factors VII, IX, and X [3,24]. In the presence of warfarin, these biologically active clotting factors become inactive because they lack the carboxyl group which is essential for the binding of calcium. The vitamin K-dependent step in the synthesis of prothrombin, and probably factors IX and X, is the carboxylation of the glutamic acid components of the protein. Ordinarily, during the process of carboxylation, vitamin K is oxidized to vitamin K epoxide. Warfarin prevents the reduction of this epoxide back to vitamin K, and subsequently, there is a depletion of active vitamin K. This leads to the formation of the biologically inactive clotting factors. Pharmacokinetics. Warfarin is rapidly absorbed from the upper gastrointestinal tract, but the rate of absorption varies a great deal from person to person. Peak plasma concentration after administering an oral dose may occur over a period ranging from 2 to
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TABLE II
Drugs That Can Displace Warfarin From Protein-Binding Sltes*t Amiodarone (investigational) Aspirin * Chloral hydrate Ethacrynic acid (Edecrin | Mefenamic acid (Ponstel | Oxyphenbutazone* Sulfinpyrazone * Sulfonamides* Triclofos (Triclos|
* Reprinted from [25], with permission of the publisher. t Interaction with warfarin may occur by other mechanisms.
12 hours. Warfarin is highly protein-bound and this binding is independent of the level of total protein or albumin concentration, but there are marked individual variations in the amount of bound and free fractions of warfarin in the blood. It is the free fraction only that is pharmacologically active. In man, the half-life of warfarin is independent of the dose, but usually falls within the range of 35 to 45 hours. In the body, warfarin is distributed in approximately 8 to 27 percent of the body weight, which is similar to that of albumin (to which it is bound). Because of the high degree of protein binding and a relatively narrow therapeutic index, an increase in the free fraction of warfarin will cause a temporary increase in the pharmacologic effect, as well as lead to an increase in clearance of warfarin from the blood. Therefore, displacement of warfarin from its protein-binding site by other drugs, some of which are listed in Table II, or by uremia will result in transient changes in its effect [24,25]. Warfarin is completely metabolized by the liver and subsequently eliminated by the kidney. Metabolites may appear in the urine for periods of up to 4 weeks after administration of a single dose of the drug.
Prophylaxis and treatment of venous thromboembolism. Because of the danger of bleeding during operation, warfarin has not been used extensively as prophylaxis for deep vein thrombosis. More often, heparin or other agents such as dextran are chosen. Francis et al [26] have suggested a two-step method using warfarin which apparently reduces the risk of bleeding. The drug is started 10 to 14 days before operation, and the prothrombin time is kept at 1.5 to 3 seconds longer than the control values. After operation, the dosage is increased and the prothrombin time is kept near 1.5 times the control value using rabbit brain thromboplastin. In their study, postoperative bleeding occurred in only 4 percent of the patients, and there was a reduction in proximal venous thrombi (iliofemoral) as seen by venography. Despite this study and a few others,
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low-dose warfarin has not been widely used in prophylaxis against deep vein thrombosis in surgical patients [3,9,27]. Warfarin has been shown to be a valuable agent in the prevention and treatment of venous thromboembolism [1,3,9,24,28]. The mortality rate from recurrent pulmonary embolism is significantly reduced in patients treated with heparin and oral anticoagulants. Thrombosis of the iliac, femoral, and popliteal veins also may be prevented by treatment with warfarin. After initiation of warfarin treatment, complete anticoagulant protection is delayed for several days since it requires time for the elimination of vitamin K stores and the normal clotting factors. They are subsequently replaced by biologically inactive factors. The depletion of factor VII, the clotting factor that has the shortest biologic half-life, results in an initial prolongation of the prothrombin time, but because this factor is of minor importance in the pathogenesis of venous thrombi, the full antithrombotic activity of warfarin will not be achieved until active prothrombin and factors IX and X have been depleted. This process may take up to 4 days. Therefore, when intravenous heparin is to be replaced by oral warfarin, there must be an overlap of 4 to 5 days before the heparin is discontinued, regardless of the change in prothrombin time. This period of overlap may be associated with an increased risk of thrombosis because the half-life of protein C, a vitamin K-dependent protein produced by the liver, is 4 to 6 hours, which is similar to that of factor VII. With the early decrease in protein C levels, there may be some increase in coagulability. Heparin is needed until levels of factor II, IX, and X decrease [14]. There is little convincing evidence that loading doses of I0 to 15 mg accelerate achieving full anticoagulant protection, and there are data which suggest that such loading doses are associated with an increased incidence of bleeding and perhaps other complications such as skin necrosis [3,25]. It is usually best to begin patients on a daily dose of 5 mg orally and continue this until complete protection is obtained. As already noted herein, there is considerable variation among patients in the response to warfarin anticoagulation [24,25]. Drugs that can displace warfarin for protein-binding sites are listed in Table II. Other drugs may increase the speed of warfarin metabolism or interfere with its activity. Some of these drugs are barbiturates, carbamazepine (Tegretol| ethanol (chronic abuse), ethchlorvynol (Placidyl| glutethimide, griseofulvin, and rifampin [25]. Moreover, there are other drugs and chemicals that may increase the potency of warfarin and perhaps, can lead to bleeding. These agents are allopurinol, amiodarone (investigational), cimetidine
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(Tagamet| disulfiram, ethanol (acute intoxication), metronidazole, oxyphenylbutazone, phenylbutazone, phenytoin (Dilantin| and sulfonamides (trimethoprim and sulfamethoxazole) [25]. During the establishment of warfarin anticoagulation, the possibility of these drug interactions must be considered if the regimen is to be effective and safe. Monitoring therapy. Following the anticoagulant effect of warfarin by performing weekly prothrombin time determinations is relatively easily done. It has been found that the incidence of recurrence of thromboembolism is lower in patients receiving more intense therapy than in patients who have less anticoagulant activity [24]. Prothrombin activity of 20 to 30 percent, as measured by the saline solution of normal plasma, corresponds to a prothrombin time of approximately twice the normal value. The therapeutic goal widely used is to maintain the prothrombin time at 2 to 2.5 times the normal values
[3,24,28]. Bleeding. Warfarin is rapidly and completely absorbed and has a long half-life and a very prolonged effect. Therefore, the use of large initial doses may be especially hazardous in regard to bleeding complications. The annual significant bleeding complication rate for warfarin anticoagulation has been reported to be as high as 8 percent [3]. More recent experiences suggest that it is unnecessary in the usual clinical setting to administer these larger doses of warfarin. It appears that prolongation of the prothrombin time to i and 1.5 times the baseline provides adequate protection against new clots without as much risk of bleeding [3,24,25]. Hemorrhage may occur at any level of anticoagulant control because of the Variability just described and operations, trauma, or other drug interactions may increase this tendency. The most frequent sites of bleeding include the gastrointestinal tract, the urinary tract, and the skin. More serious episodes occur when bleeding is present in the central nervous system. Minor hemorrhagic complications from excessive prolongation of prothrombin time usually can be managed by adjusting the dose or administering oral vitamin K1. These episodes are frequently transient and can be controlled. More serious hemorrhagic complications, particularly bleeding in the central nervous system, require stopping warfarin therapy and perhaps giving vitamin K1. A response will usually occur within 3 to 4 hours after parenteral administration of vitamin K1, but the maximal effect occurs within 8 hours. A more rapid response cannot be achieved by using doses larger than 25 mg [24,25]. The other adverse effects of warfarin can include skin necrosis [3]. This is most likely to occur in the fleshy area of women 3 to 5 days after the initiation of warfarin therapy. Although it usually is only a local phenomenon, on occasion, it can be lethal. It is
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thought to be most likely to occur in its severe form in patients who have protein C deficiency. During the initiation of warfarin therapy, a rapid increase in the prothrombin time may be an ominous finding. If this complication is suspected, anticoagulation should promptly be discontinued. Other therapeutic uses. The value of oral anticoagulants in the treatment of transient attacks of cerebral ischemia has not been substantiated in several trials [1,3,24,25,28]. There is no convincing evidence that anticoagulant therapy either reduces the incidence of stroke or increases the survival rate of patients who are having transient attacks of ischemia. In fact, data from several randomized trials show greater mortality and morbidity rates in treatment groups than in control groups [3]. Patients with cardiomyopathy, rheumatic valve disease, and chronic atrial fibrillation, and patients with prosthetic heart valves may be at high risk for recurrent arterial embolization [28]. There are data supporting the use of anticoagulant therapy in rheumatic heart disease and in patients with arrhythmias and prosthetic valves. The risk of recurrent arterial embolization in these conditions is persistent, and long-term anticoagulant treatment with warfarin is recommended. Thromboembolism may occur in patients despite adequate anticoagulant control. This suggests to some clinicians that there may be a possible role for combined treatment with antiplatelet agents. Since salicylates may cause gastric mucosal irritation, which could lead to gastrointestinal hemorrhage, they are generally not employed. O t h e r agents such as i b u p r o f e n are preferred. All of these drugs should be used with caution, however, since the likelihood of significant complications are increased because of drug interactions.
Summary Heparin combines with antithrombin III, and the resulting complex inactivates several clotting factors (all are serine proteases) in the coagulation cascade, but the most important steps are inhibition of the conversion of factor X to Xa and the antithrombin effect. Heparin pharmacokinetics are poorly understood, but when the usual doses are given intravenously, heparin is rapidly removed from the blood and has a half-life of approximately 90 minutes. Warfarin is not a true anticoagulant but is readily absorbed after oral administration. It interrupts the coagulation mechanism by interfering with the vitamin K-dependent synthesis of prothrombin and factors VII, IX, and X. This process takes 4 to 5 days. The drug has a long half-life, and its activity is enhanced or blunted by many chemicals. The effective treatment of thromboembolism with heparin, followed by warfarin, requires a basic understanding of the complex pharmacologic aspects and drug interactions.
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