Accumulating clinical data indicate that the administration of thrombolytic agents for the treatment of coronary artery thrombosis, deep venous thrombosis, pulmonary embolism, and peripheral arterial occlusion may reduce the morbidity and mortality associated with these clinical conditions. When anti-coagulants or antiplatelet-aggregating agents are used sequentially or concomitantly as adjunctives to thrombolytic therapy, they appear to enhance its efficacy but may also exacerbate the hemorrhagic complications of this therapeutic approach. An appreciation of the pharmacologic mechanisms of these drugs will provide the rationale for developing the safest and most effective therapeutic regimens.
ASPIRIN
Aspirin (acetylsalicylic acid) specifically inhibits the platelet-initiated aspect of hemostasis. When the normally nonthrombogenic vascular endothelial cells are damaged or denuded, components of the subendothelial matrix are exposed to the circulating platelets and plasma coagulation proteins. The process of platelet adhesion to the areas of damaged endothelium is mediated by the laminar flow characteristics of whole blood, which increase the likelihood of platelet interactions with the vascular surface, and by the presence of specific glycoproteins on the cell membrane of platelets. Glycoprotein Ib is the high-shear-rate specific platelet receptor site for von Willebrand factor protein, which is bound to the exposed fibrillar collagen contained in the subendothelial matrix. The von Willebrand factor thus functions as an "adhesive" bridge between the platelet and the blood vessel. The largest of the high-molecular-weight multimers of von Willebrand factor preferentially bind to collagen type I; they bind less to collagen types III, IV, and V. Interestingly, fibrillar collagen type I is particularly abundant in ruptured atherosclerotic plaques, whereas collagen types III, IV, and V predominate in the normal subendothelium. [1,2] The glycoprotein Ia/IIa complex recently has been identified as a direct collagen-binding receptor site on the platelet surface and may also be important in the process of platelet adhesion. [3,4] Thus, the usual mechanisms for initiating platelet adhesion and the subsequent formation of platelet aggregates at site of damaged vasculature are probably responsible also for the development of platelet thrombi at sites of atherosclerotic plaques. Platelets interacting with disrupted plaques in coronary arteries may precipitate the onset of unstable angina and myocardial infarction [5] (Fig 1).
The interaction of platelets with collagen promotes platelet activation with the subsequent release of substances from their cytoplasmic dense bodies and alpha granules. Serotonin from the dense granules and thromboxane [A.sub.2], generated from arachidonic acid released from the platelet membrane, are potent mediators of local vasoconstriction and platelet aggregation and recruitment. Vasoconstriction is also enhanced and prolonged by endothelin, which is synthesized in and released from endothelial cells in response to thrombin and adrenergic substances. [6] The release of adenosine diphosphate (ADP) and divalent calcium cations from the dense granules also promotes platelet aggregation and recruitment. This process is accompanied by the simultaneous release of adhesive integrin proteins from the alpha granules, which mediate platelet-platelet interactions during the formation of the platelet plug. These integrin proteins include von Willebrand factor, fibrinogen, vitronectin, and fibronectin, which bind to the platelet membrane glycoprotein complex IIb/IIIa via arginine-glycine-aspartate sequences, and thrombospondin, which complexes with glycoprotein IV. These platelet glycoproteins become expressed following platelet stimulation and shape change induced by thrombin, collagen, ADP, epinephrine, serotonin, arachidonic acid, ionophore, and thromboxane [A.sub.2]. The platelet aggregation phenomenon becomes irreversible with the continued generation of thromboxane [A.sub.2] and the release of endogenous ADP from recruited platelets (Fig 2).
Thromboxane [A.sub.2] is the body's most potent vasoconstrictor and platelet-aggregating substance. It is synthesized from the arachidonic acid released from a phospholipase complex on the cell membrane of the stimulated platelet. The arachidonic acid undergoes a series of reactions initiated by the enzyme cyclo-oxygenase, which generates thromboxane [A.sub.2] and several other cyclic prostaglandin endoperoxides with much less capacity to promote platelet aggregation (Fig 3).
The cyclo-oxygenase pathway for arachidonic acid metabolism is also present in the vascular endothelial cell; however, the predominant end-product synthetase enzyme is different, so that prostacyclin rather than thromboxane [A.sub.2] is the major metabolite. Prostacyclin, by increasing intraplatelet levels of cyclic adenosine monophosphate (cAMP), is the body's most potent anti-platelet-aggregating substance and is capable of inhibiting platelet adhesion to the subendothelium, particularly at high shear rates (Fig 3). Prostacyclin is also a very potent vasodilator.
Aspirin irreversibly acetylates the cyclo-oxygenase enzyme involved in arachidonic acid metabolism. Thus, the generation of prostaglandin peroxides and thromboxane [A.sub.2] is blocked, and the platelet aggregation and release responses to various agonists are prevented for the 9- to 10-day life span of the platelet. Aspirin inhibition of platelet aggregation can be overcome by the presence of high concentrations of thrombin. [7] Platelet adhesion and shape change are not affected by aspirin. The cyclo-oxygenase enzyme in platelets is considerably more sensitive to the inhibitory effects of aspirin than is the endothelial cyclo-oxygenase. This differentiated response is probably due to the ongoing synthesis of cyclo-oxygenase in the endothelial cell despite aspirin versus the metabolically inert state of the platelet, in which the cyclo-oxygenase is not replenished after depletion. Theoretically, small doses of aspirin (as little as 80 mg daily) would inhibit platelet aggregation without interfering with endothelial production of prostacyclin. On the other hand, much larger doses of aspirin (2 to 3 g daily) may inhibit the cyclo-oxygenase in both platelets and endothelial cells and produce a paradoxical hypercoagulable state due to the absence of prostacyclin. Although this situation has been reported in an experimental rabbit model, it has not been observed in humans.
The bleeding time is the most sensitive indicator of in vivo aspirin effects and may be prolonged for at least 1 week following the ingestion of a dose. Concomitant ingestion of ethanol may exaggerate the prolongation of bleeding times due to aspirin. The accuracy of the bleeding time is technician- and technique-dependent, but results correlate well with the degree of clinical bleeding and bruising. Platelet aggregation responses to ADP, epinephrine, and collagen are characteristically abnormal following aspirin use and may remain abnormal for up to 7 days. Collagen-induced aggregation appears to be the most sensitive to the inhibitory effects of aspirin. Ristocetin-induced platelet aggregation may be normal, since this assay measures platelet agglutination rather than platelet aggregation and release. Platelet aggregation responses in von Willebrand's disease are normal with ADP, epinephrine, and collagen, but are abnormal with ristocetin. In Glanzmann's thrombasthenia (hereditary absence of platelet glycoprotein IIb/IIIa) and platelet storage pool disease, ristocetin response is unaffected, while aggregation to the other agonists is absent.
Typically, normal platelet aggregation consists of two visible response curves when ADP and epinephrine are used as agonists in platelet-rich plasma. The first, or primary, wave represents a response to the exogenously added agonist and is reversible. The second curve results from the irreversible aggregation response to endogenously derived ADP and serotonin and does not occur with aspirinated platelets. Collagen aggregation is characterized by a single response curve following a 1- to 3-min lag period after addition of collagen to the platelet-rich plasma. Aspirinated platelets do not respond to collagen. Arachidonic acid normally induces a 2-wave platelet aggregation response; however, its conversion to thromboxane is cyclo-oxygenase-dependent, and in the presence of aspirin arachidonic acid response is absent (Fig 4). Infusions of 1-desamino-8-d-arginine vasopressin (DDAVP) (0.3 [microgram]/kg over 20 min) have successfully reversed aspirin-induced prolongations of bleeding times and platelet-aggregation abnormalities [8] and should be considered for preoperative prophylaxis or for the treatment of aspirin-treated patients who might otherwise experience significant intraoperative or postoperative bleeding complications. Alternatively, the transfusion of adequate amounts of platelets to correct the bleeding time (usually 30% of the total platelet count) can be employed, although the risk of non-A, non-B hepatitis is inherent in this treatment approach.
Choline and sodium salicylate do not acetylate cyclo-oxygenase and, in addition to acetaminophen, can be administered without prolonging the bleeding time or interfering with platelet function. Nonsteroidal antiinflammatory agents (eg, ibuprofen, sulfinpyrazone, and indomethacin) inhibit platelet cyclo-oxygenase in a reversible manner so that the duration of antiplatelet effects reflects the circulating half-lives of each drug (usually less than 24 to 48 h).
Aspirin effects appear to be potentiated clinically by adding dipyridamole, which raises cAMP levels in platelets by inhibiting phosphodiesterase. Dipyridamole provides little to no antithrombotic benefit when administered alone and does not prolong the bleeding time. This drug may affect platelet adhesion to damaged subendothelial components.
The clinical complications of aspirin use are well known to all physicians who administer this drug, which is contained in over 300 commercial and prescription preparations in the United States. The side effects of aspirin appear to be dose-related; clinical studies are attempting to determine the lowest dose that will convey maximum effectiveness and safety. Although aspirin use in normally hemostatic individuals usually produces minimal or no apparent bleeding problems, it is associated with increased blood loss following numerous surgical procedures and constitutes the most common iatrogenic coagulopathy. [9-12] The prolongation of the bleeding time and the severity of hemorrhagic episodes are exacerbated when aspirin is administered to individuals with underlying qualitative or quantitative platelet disorders or inherited or acquired coagulopathies, such as uremia, hemophilia, von Willebrand's disease, and autoimmune thrombocytopenic purpura. Small doses of aspirin (325 mg or less) have precipitated massive bleeding from previously occult lesions (malignant and benign) and have been associated with a slightly increased incidence of hemorrhagic stroke in otherwise healthy individuals. [13,14] Gastrointestinal intolerance of aspirin is notorious, with signs and symptoms ranging from nonspecific abdominal pains and discomfort to occult or massive blood loss. Ingestion of 3 g of aspirin daily for 3 to 6 days results in an average fecal blood loss of about 5 ml/day. [15] Multiple discrete ulcers and hemorrhagic gastritis, but not duodenal ulcers, are produced by aspirin, probably by modification of the protective integrity of the gastric mucous barrier. Many of these side effects can be minimized or eliminated by dose reduction (to less than 325 mg daily), concomitant use of antacids or [H.sub.2-blockers,] or use of enteric-coated aspirin preparations, which may produce ileal lesions rather than gastric mucosal ulcerations. Reversal of the antiplatelet effects of aspirin can be accomplished with intravenous DDAVP infusions or platelet transfusions. [16] The uricosuric effects, alterations in acid-base balance associated with respiratory alkalosis, and hypoprothrombinemia usually occur following the administration of aspirin doses much larger than those currently recommended as adjunctive antithrombotic therapy.
By virtue of the fact that platelet aggregation, recruitment, and plug formation are inhibited by aspirin, the formation of arterial rather than venous thrombi would be expected to be prevented by aspirin. This concept has generally been supported by the results derived from a number of randomized studies that evaluated the effectiveness of aspirin in the prevention of deep venous thrombosis in patients undergoing total hip replacement surgery. [17] Aspirin produced no significant reduction in the incidence of deep venous thrombosis. In contrast, in several other studies of patients undergoing total hip replacement surgery, significantly fewer cases of deep venous thrombosis were found in patients being treated with aspirin, [18-20] with the antithrombotic benefits of aspirin appreciated only in male patients. [20]
Predominant male benefit from aspirin has also been reported in the treatment of arterial diseases. [21, 22] Larger aspirin doses appeared to protect patients from recurrent myocardial infarction and death [21] and from recurrent transient ischemic attacks (TIAs), post-TIA related cerebrovascular accidents, and stroke-related death. [22] The basis of this male antithrombotic advantage with aspirin remains unclear but is provocative enough to merit longitudinal, prospective, controlled studies to confirm the validity of the observation.
The most convincing evidence generated thus far to support the usefulness of aspirin as an effective antithrombotic agent is derived from clinical studies of acute coronary artery ischemic syndromes, including unstable angina, primary and recurrent myocardial infarction, and postthrombolytic reocclusion. Each of these events appears to be initiated by the formation of platelet thrombi at sites of ruptured atherosclerotic plaques. [23] The progression or lability of these thrombi and the persistence of the stimulus for local platelet activation and aggregation will determine ultimately the duration and severity of intracoronary stenosis and/or ischemia. Initially, platelets that are transiently activated by ruptured plaques in coronary arteries aggregate and release serotonin and thromboxane [A.sub.2]. The subsequent localized vasoconstriction and platelet recruitment (aggregability) result in superimposition of a platelet thrombus on the disrupted plaque with varying degrees of severity of circulatory compromise and poststenotic ischemia. If the platelet plug is eventually replaced by a fixed fibrin thrombus, irreversible ischemia and Q-wave infarction may occur. [23] This sequence of events is substantiated indirectly by numerous in vivo and in vitro observations. In an experimental model in which endothelial injury is produced in an isolated, stenosed coronary artery, aspirin, but not heparin, has been effective in preventing the development of platelet aggregates and coronary thrombosis. [24,25] Human studies have documented the generation of significantly increased urinary and plasma levels of thromboxane and fibrinopeptide A during episodes of unstable angina and chest pain, [26,27] indicating that activation of both platelets and the coagulation system (thrombin production) occurs in this clinical setting. Large randomized, placebo-controlled trials have also confirmed the anti-thrombotic effectiveness of aspirin in significantly reducing the incidence of vascular death and acute myocardial infarction in patients with a history of unstable angina. [28,29] Lower-dose aspirin regimes (325 mg daily) appeared as beneficial as higher-dose regimens.
A decreased risk of primary myocardial infarction has been associated with low-dose aspirin regimens in several large retrospective [30] and prospective [14] randomized studies of otherwise healthy adults. Another smaller trial did not confirm the antithrombotic advantage of prophylactic aspirin but did reveal an increase in the incidence of hemorrhagic stroke. [13] The increased number of strokes recorded in these studies [13,14] was not statistically significant but highlights a potential concern for those using aspirin as prophylactic antithrombotic therapy.
Reocclusion rates following thrombolytic therapy of coronary artery thrombosis range between 5% and 29%. [31] The occurrence of this phenomenon may be dependent on both the choice of thrombolytic agent administered and the basic coronary artery disorder at the site of thrombus formation. The Second International Study of Infarct Survival Collaborative Group suggested that aspirin therapy (160 mg/day) initiated within 24 h of myocardial infarction significantly reduced cardiac mortality, presumably because of reduction of reocclusion rates. [32] The reduction in mortality associated with aspirin was similar to that produced by streptokinase alone; the combination of streptokinase and aspirin improved post-myocardial infarction survival in an additive manner. [32]
There is evidence of platelet activation and generation of thrombin in myocardial infarction patients prior to and after administration of streptokinase or recombinant tissue plasminogen activator (rt-PA) [33,34] for coronary thrombolysis. The antiplatelet-aggregating effects of aspirin may be somewhat compromised in the postinfarction and postthrombolytic therapy periods since thrombin-induced platelet aggregation is not completely inhibited by aspirin [7]; however, the synergism of streptokinase thrombolysis and aspirin in preventing reocclusion may be due to the production of fibrin/fibrinogen degradation products (FDPs), which may potentiate the antiplatelet aggregatory effects of aspirin and which may interfere with fibrinogen binding to platelets and fibrin polymerization. Contradictory data recently have indicated that significantly higher coronary patency rates are associated with concomitant systemic heparinization (71% to 82%) compared with aspirin administration (43% to 52%) when either is used as adjunctive therapy with rt-PA for coronary lysis in myocardial infarction. [35,36] Perhaps the increased fibrin specificity of rt-PA (which produces lower titers of FDPs to interfere with platelet function when compared to other less fibrin-specific thrombolytic agents) explains why the antithrombotic advantages of aspirin were less apparent than those of heparin. Heparin, on the other hand, may have been more effective because of its capacity to inhibit thrombin generation.
An innovative approach to the inhibition of platelet activation and aggregation has been achieved with the availability of monoclonal antibodies directed against the platelet membrane glycoprotein IIb/IIIa complex, which is critical for platelet-platelet interactions during the aggregation process. [37] Encouraging preliminary results have been described from studies of postthrombolysis coronary reocclusion in experimental animals. In these trials, monoclonal platelet antibodies have been administered simultaneously with rt-PA or with rt-PA given concomitantly with single-chain urokinase plasminogen activator. [38-40] Adequate human studies remain to be conducted.
HEPARIN
Evolution of the primary platelet plug to include a fibrin thrombus is dependent on the formation of thrombin through the activation of the coagulation system. The coagulation system is divided into the intrinsic and extrinsic pathways (Fig 5). Both pathways consist of zymogen proteins, which are activated in sequence by a preceding activated clotting protein, producing in essence an amplification cascade. The intrinsic system receives its designation by virtue of the fact that components intrinsic to the blood vessel are critical for initiating the cascade. Factor XII (Hageman factor) binds to the highly negatively charged surfaces of the collagen fibrils contained in the endothelial cells. Once bound, factor XII becomes activated (factor XIIa) by undergoing a conformational alteration that makes it susceptible to proteolytic cleavage by kallikrein, plasmin, factor XIIa, and other serine proteases. Factor XIIa can then activate the factor XI zymogen by limited proteolysis, and the amplification process continues until all coagulation zymogens are activated, ultimately forming thrombin. Because the initial sequence of events occurs on a negatively charged surface, it has been labeled the contact phase of coagulation. It is modulated by the presence of kallikrein, which directly activates factor XII, and by high-molecular-weight kininogen, which functions as a surface cofactor by complexing with prekallikrein (the precursor of kallikrein) and with factor XI and assembling them on the vessel surface adjacent to factor XIIa. Collagen-bound factor XII can also be activated by substances released from damaged endothelial cells and by circulating immune complexes. This same process of intrinsic pathway activation can proceed on the surface of ruptured atherosclerotic plaques, which contain an abundance of collagen.
In vitro, the negatively charged surface for contact-phase assembly and activation of the intrinsic pathway can be provided by glass (eg, nonsiliconized test-tube surfaces, kaolin, ellagic acid, and cephalin). Kaolin and cephalin are the most commonly used activators for the activated partial thromboplastin time (APTT), the laboratory coagulation assay routinely employed to screen for intrinsic pathway activity.
The extrinsic pathway of coagulation is activated by tissue factor or tissue thromboplastin, a lipoprotein apparently located extrinsic to the blood vessel and introduced to the circulating coagulation proteins following vascular injury. Tissue factor is particularly abundant in lung, placenta, and brain and is most likely contained in atherosclerotic plaque. Factor VII can be activated through proteolytic cleavage by thrombin, factor Xa, factor XIIa, and factor IXa. Factor VIIa complexes with tissue factor and in the presence of calcium activates factor Xa, which completes a feedback loop of events modulated by extrinsic pathway inhibitor. Factor VIIa may also activate factor IX. The activity of the extrinsic pathway is monitored by the prothrombin time determination, in which calcium and tissue thromboplastin (rabbit or human brain origin) are added to the citrated plasma specimen.
Numerous natural circulating inhibitors exist in plasma to modulate the activity of the procoagulants. Antithrombin III inhibits the activated serine proteases IIa (thrombin), IXa, Xa, XIa, and plasmin. Modulatory effects of antithrombin III are mediated by the conformational changes produced by interacting with heparin (Fig 6). In the nonheparinized individual, the heparan sulfate located on the endothelial surface serves as the heparin equivalent. When all of the antithrombin III has been consumed by the presence of excessive thrombin in the plasma, heparin cofactor II becomes available for thrombin inactivation. The physiologic importance of [[alpha].sub.2-macroglobulin] and [[alpha].sub.1-antitrypsin] for modulation of coagulation is probably minimal.
Another approach to the regulation of procoagulant activity involves the two hepatically synthesized vitamin-K-dependent proteins C and S. [41-44] Protein C is activated by thrombin cleavage and complexes to protein S, which functions as a cofactor. The protein C-protein S complex then proteolyzes and inactivates factors Va and VIIa, thus limiting further thrombin production. These reactions occur predominantly on the surface membranes of platelets and endothelial cells; protein C activation is greatly enhanced when thrombin is bound to its specific receptor thrombomodulin, located on the endothelial cell membrane. Interestingly, when thrombin is bound to thrombomodulin, it is unable to cleave fibrinogen to form fibrin, activate platelets, or activate factor V. [43]
The protein C-protein S complex also has a role in the regulation of fibrinolysis by inactivating the primary inhibitor of t-PA (designated PAI-1), leading to enhanced fibrinolytic activity in the area of perturbed or injured endothelial cells. [45] The physiologic importance of the regulatory functions of proteins C and S in coagulation and fibrinolysis is very apparent in vivo since a congenital or acquired deficiency in either may be associated with hypercoagulability. [46,47]
Pharmacologic control of the coagulation pathway for the prophylaxis of hypercoagulability or for the treatment of acute thrombotic events is rapidly achieved with the parenteral administration of heparin. Heparin is an anionic, highly sulfated glycosaminoglycan mucopolysaccharide, which has been isolated from porcine intestinal mucosa or bovine lung for therapeutic use. By virtue of its strong negative charges, heparin binding to antithrombin III induces a conformational alteration, which greatly enhances the inhibition of activated serine protease procoagulants. Because factor Xa is most sensitive to inhibition by the antithrombin III-heparin complex and because it is strategically located at the merging point of the intrinsic and extrinsic pathways (common pathway), considerably smaller amounts of heparin would be required to prevent thrombin formation than would be necessary to inhibit the activity of intrinsically generated thrombin for therapeutic anticoagulation. This observation forms the basis for prophylactic antithrombotic regimens employing subcutaneous administration of minidoses of heparin.
The APTT and the thrombin time, which measures the ability of thrombin to cleave fibrinogen to form fibrin, are the most sensitive laboratory screening assays for heparin activity. The prothrombin time is also prolonged in the presence of high plasma concentrations of heparin.
There is evidence that the lower-molecular-weight heparin molecules contained in commercial preparations have greater anti-Xa activity than the higher-molecular-weight molecules. The high-molecular-weight fractions may spontaneously induce platelet aggregation [48] and may contribute to the development of so-called heparin-induced thrombocytopenia. The frequency of this condition has been reported to range up to 24% in patients receiving beef-lung heparin preparations, but it is much less commonly associated (7%) with the use of porcine-derived heparin. [49] Recent evidence also suggests that this problem may be specific as to heparin lot, so that clusters of cases may be detected. Heparin-induced thrombocytopenia may be clinically insignificant or may produce severe hemorrhagic complications dependent on the degree of thrombocytopenia. In addition, a paradoxical hypercoagulable state may occur, leading to serious and extensive venous or arterial thromboembolic events, perhaps precipitated by spontaneous platelet aggregation in vivo. There may also be a contributory immune component, such as a heparin antibody.
Heparin-induced thrombocytopenia is usually encountered 5 to 9 days after initiation of heparin therapy and resolves over time if heparin is discontinued. It may recur if the patient is reexposed to heparin on future occasions. The diagnosis can be established easily by detecting the spontaneous aggregation of platelet-rich plasma in an aggregometer after addition of heparin. Alternatively, if the patient's platelet count is too low to allow harvesting of an adequate number of platelets in the platelet-rich plasma, spontaneous platelet aggregation can be elicited in heparin-induced thrombocytopenia when the patient's platelet-poor plasma or heat-treated serum is added to normal platelet-rich plasma in the presence of heparin. The sensitivity of this diagnostic procedure can be increased by using normal serotonin [14] C-loaded platelets; lets; however, this assay is cumbersome and is not readily available or practical for most clinical laboratories. Heparin-induced thrombocytopenia may be produced by as little heparin as that contained in heparin flushes of indwelling access lines. Therefore, in the absence of laboratory confirmation of heparin as the cause of thrombocytopenia, heparin should be discontinued along with any other concurrent medications known to affect platelet counts. If bovine heparin is implicated, an in vitro and/or in vivo trial of porcine heparin may be considered. For individuals requiring anticoagulation after discontinuation of heparin, therapeutic options include immediate initiation of Coumadin therapy, administration of arvin (a debribrinating enzyme not currently licensed in the United States) or prostacyclin, or the use of low-molecular-weight heparin.
Conventional heparins consist of a mixture of molecules ranging in molecular weight from 4,000 to 40,000 daltons. These forms of heparin convey anti-Xa activity via their lower-molecular-weight molecules and platelet aggregatory properties with their higher-molecular-weight components. Low-molecular-weight (2,500 to 15,000 daltons) heparins have been produced by multiple fractionation steps and/or depolymerization of conventional porcine heparin. As expected, they have increased anti-Xa activity and decreased platelet activation effects. Clinical trials with several low-molecular-weight preparations are currently under way in the United States, and approval of such by the Food and Drug Administration is anticipated in the near future. The data suggest that low-molecular-weight heparins may have a larger margin of safety with respect to bleeding complications than standard heparin preparations because their anti-Xa activity is present without prolonging the APTT.
Heparin therapy in prophylactic antithrombotic regimens, such as those used following surgery or prolonged bed rest, is usually administered subcutaneously at a dosage of 5,000 units every 12 h. No or minimal effects on the APTT should be seen. The acute treatment of thrombotic events, such as pulmonary embolus or deep venous thrombosis, is managed with a bolus dose of 70 to 75 units/kg of body weight followed by the continuous intravenous infusion of heparin (1,000 units/h). The heparin dose is titrated to achieve and maintain an APTT between 1.5 and 2.0 times normal. This regimen is easier to monitor, uses less heparin, and is associated with fewer bleeding complications than the previously popular intermittent intravenous bolus-dose heparin therapy. For chronic heparin therapy, such as might be used for prevention of recurrence of pulmonary embolism or propagation of deep venous thrombosis, a moderate dosing scheme proposed by Hull et al, [50] which maintains the APTT at 1.5 to 2.0 times baseline measured 6 h after each dose of heparin (about 10,000 to 15,000 units) administered subcutaneously every 12 h, can be used. Treatment for 3 to 6 months is considered adequate unless the patient experiences recurrent events. Recurrent thrombotic episodes should prompt a hypercoagulability workup.
Bleeding is the most frequent complication of heparin use, occurring acutely in up to 25% of patients and in 2% to 4% of patients per year with chronic therapy. The frequency of bleeding can be minimized by using lower-dose regimens and by obtaining laboratory assays that provide adequate surveillance of anticoagulant effects. If heparin effects require rapid reversal, fresh-frozen plasma or protamine sulfate can be administered. Excess protamine sulfate can also have anticoagulant effects. Patients allergic to protamine may respond to the heparin-neutralizing properties of toluidine blue or methylene blue. Osteoporosis, alopecia, and hyperkalemia are very rare complications associated with extended use of heparin.
Heparin has received increased attention recently as an effective adjunctive therapy with thrombolytic agents in the maintenance of coronary artery patency following myocardial infarction. In a large Italian trial, [51] heparinized patients with acute myocardial infarction experienced decreased mortality rates compared with those who received no heparin. An intermittent subcutaneous heparin regimen (after a small initial bolus) was used in this study, as it was in the International t-PA/SK GISSI-2 Mortality Trial, in which mortality benefits were equivalent in heparinized patients randomized to receive rt-PA or streptokinase following myocardial infarction. In the Heparin-Aspirin Reperfusion Trial, [36] initial coronary patency was increased significantly in the patients given continuous intravenous heparin versus aspirin as adjunctive therapy for rt-PA lysis of myocardial infarction (82% in the rt-PA and heparin group vs 52% in the rt-PA and aspirin group). It is likely that coronary artery patency is influenced less by the choice of a specific thrombolytic agent administered to achieve it than by the different adjunctive regimens employed to sustain it. For example, the peaks and valleys of plasma heparin concentration that accompany the subcutaneous intermittent bolus approach may be suboptimal to prevent the thrombin generation [27,52] and platelet activation [26,27,34] associated with acute myocardial infarction and ischemic heart disease before or after thrombolytic therapy. Continuous infusion regimens may produce constant levels of heparin adequate to quench clotting and platelet activity. Others have speculated that the rate of reocclusion is inversely related to the degree of systemic lytic effects induced by the thrombolytic agent and the attendant antiplatelet effects of the generated FDPs. [31] There is evidence that the future availability of specific thrombin inhibitors, such as hirudin, may be more important than the use of heparin in preventing thrombus formation on disrupted atherosclerotic plaques [53] or in inhibiting postthrombolysis reocclusion. [54]
Less controversial are the benefits of heparin anticoagulation in the setting of acute myocardial infarction to prevent the development of deep venous thrombosis during prolonged bed rest and to prevent thromboembolic phenomena from mural thrombosis, atrial fibrillation, and congestive heart failure.
COUMARIN
The vitamin K-dependent coagulation proteins, factors II, VII, IX, and X, as well as proteins C and S, undergo a vitamin K-mediated postribosomal modification in the hepatocyte, which consists of carboxylation of their [gamma]-glutamyl regions. The [gamma]-carboxyglutamic acid residues enable these proteins to interact with phospholipid surfaces (on activated platelets or endothelial cells) in the presence of calcium cations. Coumarin interferes with the conversion of the functionally inactive oxidized form of vitamin [K.sub.1], vitamin [K.sub.1] epoxide, to its functionally active reduced form, which participates in the modification of coagulation proteins (Fig 7). Thus, coumarinized patients are not vitamin K-deficient but have a relative deficiency of functional vitamin [K.sub.1] and as a result produce decarboxylated coagulation proteins designated PIVKAS (proteins induced in vitamin K absence), which are essentially nonfunctional. The anticoagulant effects of coumarin are realized as the activities of the vitamin K-dependent procoagulants are decreased, according to their respective half-lives. Factor VII, with a half-life of approximately 6 h, is the first to decrease, which leads to prolongation of the prothrombin time, which is utilized to monitor the extrinsic pathway of coagulation. Prolongation of the prothrombin time, however, is not equivalent to antithrombotic effect since the other vitamin K-dependent clotting factors possess longer half-lives (up to 60 h for factor II). By that time, prolongation of the APTT is also present. In addition, protein C anticoagulant activity is also depressed by coumarin therapy as rapidly as factor VII is depleted, potentially producing a paradoxically hypercoagulable state. Decreased protein C activity may contribute to the development of skin necrosis associated with coumarin anticoagulation.
As with heparin, bleeding is the most common complication of coumarin administration. Use of lower doses to maintain the prothrombin time at 1.3 to 1.5 times normal appears to minimize this problem without sacrificing antithrombotic benefits. Anticoagulation with coumarin is a balance between the dosage administered and the vitamin K ingested in the diet. Changes in diet and intercurrent illnesses may disrupt this balance. Large loading doses to initiate anticoagulation should be avoided to prevent excessive prolongation of the prothrombin time and to reduce rapid depression of the protein C level, which may be associated with coumarin necrosis. Bleeding complications are more common when other medications known to potentiate the anticoagulant effects of coumarin are administered concomitantly. Such drugs include cephalosporins with the N-methyl-thiotetrazole side chain (eg, cefamandole and moxalactam), sulfonamides, sulfonylurea hypoglycemic agents, quinidine, and cholestyramine. Other medications, such as phenobarbital, rifampin, and cimetidine, inhibit the anticoagulant effects of coumarin.
Less common side effects of coumarin include alopecia, the purple toe syndrome, and dermatitis. Coumarin use during pregnancy, particularly during the first trimester, produces characteristic fetopathic teratology and probably increases the risk of spontaneous abortion. Heparin is used during this time. Controversy surrounds the use of coumarin during the remainder of pregnancy until delivery; current studies suggest that coumarin can be used in the second and third trimesters without increasing teratogenicity and fetal hemorrhage. Coumarin can be detected in breast milk, but the levels are negligible; therefore, perinatologists and obstetricians who specialize in high-risk pregnancies permit women receiving coumarin to breast-feed.
Coumarin effects can be reversed with fresh-frozen plasma or small doses (2.5 to 5.0 mg) of vitamin [K.sub.1] given subcutaneously or intravenously. Large doses may make future coumarin anticoagulation more difficult to achieve. The use of prothrombin complex concentrates in emergency situations for rapid reversal is often complicated by transmission of non-A, non-B hepatitis and in some cases by hypercoagulability.
By virtue of the long lag time to achieve an antithrombotic state, coumarin use has been reserved primarily for chronic treatment of thromboembolic disease rather than for acute management. Coumarin therapy should be initiated while heparin is being infused acutely, and an overlap of the two agents should be
maintained for approximately 5 days. This will minimize the incidence of coumarin necrosis, will provide sufficient anticoagulation if heparin-induced thrombocytopenia develops, and may reduce the total hospital stay necessary to achieve therapeutic anticoagulation in a patient requiring chronic coumarin use.
In cardiovascular disease, long-term use of coumarin has not been generally recommended as beneficial except when atrial fibrillation or the risk of mural thrombus formation with embolization is present. In one uncontrolled study, [55] researchers found a long-term benefit for coumarin in decreasing the incidence of reinfarction and postinfarction mortality. These findings were recently confirmed by a well-designed randomized controlled trial. [56] Two other studies pooled data from previously published randomized trials and reached similar conclusions, but their statistical methods have been criticized. [57,58] Postinfarction patients restricted to bed rest for a prolonged period would also be expected to benefit from coumarin.
THROMBOLYTIC THERAPY
Once thrombin has been generated within the coagulation cascade, it is available to act on numerous substrates, including fibrinogen, platelets, protein C, factor VIII, factor V, and factor XIII. The majority of these interactions amplify additional thrombin generation and fibrin formation. Activation of protein C and the inactivation of previously activated factors VIIIa and Va are examples of the anticoagulant modulation of the coagulation cascade initiated by thrombin.
When fibrinogen is the thrombin substrate, the sequential release of fibrinopeptides A and B occurs from the central arginyl-glycine bonds on the amino terminal regions of the alpha and beta chains, respectively. Fibrinopeptide A cleavage promotes end-to-end interactions of fibrin molecules while fibrinopeptide B proteolysis allows for lateral interactions. This produces a tensile, unstabilized, polymerized fibrin clot, which is subsequently stabilized by factor XIIIa-mediated cross-linking of the glutamyl-lysine regions of adjacent fibrin gamma chains in the presence of calcium cations. Cross-linking renders fibrin clots more resistant to thrombolysis, and the susceptibility of such clots to successful pharmacologic thrombolytic therapy may be inversely proportional to the degree of cross-linking (eg, the older, more cross-linked thrombus may be more resistant to lysis). Fibrin clot formation may occur superimposed on a disrupted atheromatous plaque.
Fibrinolysis is achieved by the proteolytic serine protease plasmin, generated from its hepatically synthesized zymogen plasminogen. Conversion of plasminogen to plasmin is physiologically mediated through the plasminogen activator effects of factor XIIa from the intrinsic pathway. The importance of this mechanism is debated, although some individuals with inherited factor XII deficiency may manifest hypercoagulability. [58] More significant are the other endogenous plasminogen activators found in vivo, specifically, urokinaselike activators and t-PA, which is synthesized, stored, and released from endothelial cells. The t-PA activity is modulated by the activated protein C-protein S complex, which inactivates PAI-1, the primary inhibitor of t-PA. Therefore, individuals with acquired or inherited deficiencies of protein C or protein S would be expected to have defective plasmin generation and to manifest hypercoagulability, which in reality is occasionally observed (Fig 8).
Pharmacologic plasminogen conversion can be achieved by streptokinase, urokinase, t-PA, lys-plasminogen streptokinase complex (anistreplase), and recombinant single-chain urokinase plasminogen activator (Fig 9). Streptokinase is not a plasminogen activator by itself, but when complexed with plasminogen it expresses plasminogen activator activity. Uncomplexed residual plasminogen can then be proteolyzed to plasmin. This is an inefficient process since in the presence of a large thrombus burden, inadequate residual plasminogen may be available for sufficient plasmin formation to result in significant clot dissolution. Thus, paradoxical plasminogen deficiency and hypercoagulability may be observed during SK administration.
Urokinase is a more efficient plasminogen activator because it directly cleaves plasminogen to form plasmin. Recombinant t-PA and recombinant single-chain urokinase plasminogen activator activate plasminogen by a mechanism similar to that of urokinase. Anistreplase is an in vitro-manufactured plasminogen activator complex of human lys-plasminogen and streptokinase, modified chemically to preserve the fibrin-binding sites of the plasminogen moiety and inactivated by an anisoyl group placed at the catalytic site for plasminogen activation. This molecule theoretically should allow for increased fibrin specificity, decreased plasminogen consumption, and decreased fibrinogenolysis systemically. In practice, however, these advantages have not been completely realized.
Tissue plasminogen activator is a natural substance synthesized, stored, and released from normal endothelial cells. Recent interest in its use as a therapeutic drug was enhanced after it was isolated and purified from human uterine tissue and malignant melanoma cell lines. Identification and cloning of the gene responsible for t-PA in bacterial cell lines (rt-PA) have ensured that the protein will be available in quantities adequate to be a clinically useful addition to the armamentarium of thrombolytic agents.
Recombinant t-PA is a genetically engineered serine protease capable of directly cleaving the arginyl-valyl bonds of plasminogen to form plasmin, similar to the mechanism of fibrinolytic activation by the other fibrinolytic agents. The structural homology that exists between rt-PA and the fibrin-binding sites of plasminogen (kringles) conveys the relatively fibrin-specific properties of rt-PA as a thrombolytic drug. Because the increased binding specificity of rt-PA to fibrin is not absolute, a mild to moderate degreee of fibrinogenolysis usually can be detected in clincial situations. Nevertheless, the close proximity of rt-PA and plasminogen-binding sites within the fibrin matrix and the preferentially high affinity of these molecules of fibrin over fibrinogen promote the local generation of plasmin and result in the most fibrin-specific thrombolytic therapy obtainable with any of the currently available agents.
Plasmin is rapidly inactivated by a specific inhibitor, [alpha.sub.2]-antiplasmin. This can be achieved within the cross-linked polymerized fibrin clot meshwork to which plasminogen has bound. Plasminogen activators or circulating plasmin can then percolate into the clot and generate plasmin for localized thrombolysis. The specificity and efficiency of fibrinolysis can be increased significantly if the plasminogen activator has a high binding affinity for fibrin, thus minimizing systemic plasminogen activation and fibrinogenolysis. It must be remembered that fibrinogen and fibrin are not specific substrates for plasmin. Factor VIII, von Willebrand factor, components of the complement pathway, and platelet membrane glycoproteins are also susceptible to plasmin digestion and may contribute to the hemorrhagic complications and coagulopathy associated with thrombolytic therapy.
Fibrinolytic activity can be monitored easily in any coagulation laboratory by watching for decreases in the plasma fibrinogen concentration. The thrombin time, which is prolonged during thrombolytic therapy because of reduced fibrinogen levels and the presence of increased FDPs, is another sensitive assay. Distinguishing between FDPs and heparin as the cause of increased thrombin times can be difficult; however, the thrombin time obtained with either ancrod or reptilase is normal in the presence of heparin but is prolonged by the presence of FDPs. Protomine sulfate or toluidine blue added to the plasma will also neutralize contaminating heparin.
Plasmin proteolysis of fibrinogen or fibrin produces soluble fragments that can interfere with platelet function and/or the coagulation processes. These initial fragments are designated X and Y, and are subsequently degraded further to fragments D and E. fibrin fragments are characterized by forming D-dimers, reflecting the proteolysis of the cross-linked gamma chains. Commercially available latex agglutination assays, using tanned erythrocytes or latex beads, are useful techniques for measuring FDPs. The ability to quantitate fragments of the B-beta chain are a specific, although laborious, laboratory assay for detecting fibrinogenolysis (B-beta 1-42) or fibrinolysis (B-beta 15-42). The euglobulin clot lysis time, which is shortened during fibrinolysis, can also be accelerated nonspecifically by exercise, febrile illnesses, and medications, and is very sensitive to drops in fibrinogen levels. The euglobulin lysis time measures the time required for the euglobulin precipitate of patient plasma (which contains plasminogen activators) to lyse normal fibrin clots.
Reversal of systemic thrombolytic effects is reserved for the treatment of severe hemorrhagic complications. The synthetic lysine analogues, [epsilon]-aminocaproic acid (Amicar; Lederle Laboratories, Wayne, NJ) and tranexamic acid (Cyklokapron; KabiVitrum, Franklin, Ohio), block fibrinolysis and fibrinogenolysis by competing with plasminogen for lysine-binding sites. Both agents may induce hypercoagulability. Tranexamic acid possesses a longer plasma half-life (about 120 min) and longer duration of activity (about 7 h) than [epsilon]-aminocaproic acid (70 min and 2 h, respectively). [epsilon]-aminocaproic acid is usually administered intravenously at a dosage of 0.5 mg to 1.0 g/h after a loading bolus dose of 100 mg/kg. Tranexamic acid is infused at a dosage of 10 mg/kg every 2 to 6 h following a loading dose of 10 mg/kg.
Despite the availability, for over a decade, of thrombolytic agents for the treatment of pulmonary embolism and deep venous thrombosis, their use has remained limited, perhaps because of the adverse effects associated with their administration. Allergic hypersensitivity reactions and high fever have been reported most commonly with the use of streptokinase therapy and are most likely related to the bacterial origin of streptokinase. Temperatures of over 104[degrees]F occur in approximately 3% to 4% of patients who are treated with streptokinase [60]; the percentage is less with anistreplase, or anisoylated plasminogen streptokinase activator complex (APSAC). [61] High fevers are less commonly seen with urokinase [62] and are rarely seen with rt-PA. [62,63] Allergic reactions (eg, nausea, urticaria, and headache) occur much more commonly with streptokinase (in up to 45% of patients) [60,61,64,65] and APSAC [61] than with urokinase [62,63,65] or rt-PA. [62,63] Acute hypotensive episodes occur in 2% to 3% of patients receiving streptokinase and APSAC [60,66] and may confuse the clinical situation when one is trying to distinguish whether streptokinase induced the hypotension or whether it resulted from recurrent
[TABULAR DATA OMITTED]
pulmonary embolism or extension of a myocardial infarction. [32] These side effects may force premature discontinuation of thrombolytic therapy [62,67] and thus adversely affect therapeutic efficacy. The antigenicity of streptokinase and APSAC result in elevated titers of antistreptococcal antibodies, which prevent repeat use for at least 6 months. Urokinase and rt-PA are nonantigenic.
A comparison of the pharmacologic characteristics of each of the thrombolytic agents is provided in Table 1. The increased half-life of APSAC renders it a useful bolus therapy; however, current clinical studies are examining the efficacy of urokinase and rt-Pa in bolus administration regimens. The increased figrin specificity of rt-PA probably explains its ability to lyse intracoronary thrombi and pulmonary emboli more rapidly than the other agents. [62,63] In addition, increased fibrin specificity will help determine the degree of systemic fibrinolytic and fibrinogenolytic effects and antihemostatic activity.
The titers of FDPs generated by rt-PA are less than those generated by urokinase, streptokinase, or APSAC. These degradation products, which may interfere with platelet aggregation and fibrin polymerization, may influence the early patency and reocclusion rates and the incidence of hemorrhagic complications associated with the various thrombolytic agents. This may be paricularly critical in view of the evidence that thrombin generation persists depsite thrombolysis and that platelet activation can be stimulated by the thrombolytic agents themselves. Thus, the concomitant use of heparin or aspirin with the more fibrin-specific thrombolytic agents, such as rt-PA, may help to prevent rethrombosis, whereas with the less fibrin-specific agents, such as APSAC and streptokinase, early administration of heparin or anti-platelet aggregation agents may induce excessive and potentially detrimental anticoagulant effects.
During thrombolytic therapy of deep venous thrombosis or pulmonary emboli, initiation of heparin anti-coagulation as a continuous infusiion without a loading bolus is usually delayed until the postthrombolytic thrombin times have decreased to 2 to 3 times the normal value, indicating dissipation of FDPs. For intracoronary disease, heparin rather than aspirin enhances the patency rates associated with rt-PA therapy, [36] which suggests that inhibiting thrombin generation in this clinical setting is more important to preserving patency than preventing platelet activation.
Future studies will determine whether the efficacy and safety of thrombolytic agents can be improved by using specific thrombin inhibitors, such as recombinant hirudin. Administration of monoclonal antibodies against the platelet membrane glycoproteins that participate in platelet-platelet or platelet-subendothelial matrix interactions or concomitant infusions of combinations of thrombolytic agents that can induce an immediate and rapid thrombolysis and sustain a prolonged systemic fibrinolytic or fibrinogenolytic effect may be additional options. Therefore, an understanding of the pharmacologic features of the various thrombolytic agents, anticoagulants, and antiplatelet agents can provide a basis for devising new regimens that can improve the safety and efficacy of thrombolytic therapy in cardiopulmonary disease.
REFERENCES
[1] Mayne R. Collagenous proteins of blood vessels. Arteriosclerosis 1986;6:585-93
[2] Madri JA, Dreyer B, Pitlick FA, Furthmayr H. The collagenous components of the subendothelium: correlation of structure and function. Lab Invest 1980;43:303-15.
[3] Niewenhis HK, Sakariassen KS, Houdijk WPM, et al. Deficiency of platelet membrane glycoprotein Ia associated with decreased platelet adhesion to subendothelium: a defect in platelet spreading. Blood 1986;68:692-95
[4] Kunichi TJ, Nugent DJ, Staats SJ, et al. The human fibroblast class II extracellular matrix receptor mediates platelet adhesion to collagen and is identical to the platelet glycoprotein Ia-Ila complex. J Biol Chem 1988; 263:4516-19
[5] Fuster V, Chesebro JH. Mechanisms of unstable angina. N Engl J Med 1986; 315:1023-25
[6] Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332:411-14
[7] O'Brien JR. Effect of salicylates on human platelets. Lancet 1968; 1:779-83
[8] Kobrinsky NL, Gerrard JM, Watson CM, et al. Shortening of bleeding time by 1-deamino-8-D-arginine vasopressin in various leeding disorders. Lancet 1984; 1:1145-48
[9] Kitchen L, Erichson RB, Sideropoulous H. Effect of drug induced platelet dysfunction on surgical bleeding. Am J Surg 1982; 143:215-17
[10] Weksler BB, Pett SB, Richter RC, et al. Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med 1983; 308:800-5
[11] Kennedy BM. Aspirin and surgery: a review. Ir Med J 1984; 77:363-70
[12] Ferraris VA, Ferraris S, Lough FC, Berry WR. Preoperative aspirin injection increases operative blood loss after coronary artery bypass grafting. Ann Thorac Surg 1988; 45:71-74
[13] Peto R, Gray R, Collins R, Wheatley K, Hennekens C, et al. A randomized trial of the effects of prophylactic daily aspirin among male British doctors. Br Med J 1988; 296:313-16
[14] Steering Committee fo the Physicians' Health Study Research Group. N Engl J Med 1988; 318:262-64
[15] Woodbury DM. Analgesic-antipyretics, anti-inflammatory agents, and inhibitors of uric acid synthesis. In: Goodman LS, Gilman A, eds. The pharmacological basis of therapeutics. New York: Macmillan, 1970; 314-20
[16] Chard RB, Kam CA, Nunn GR, Johnson DC, Maldrum-Hanna W. Use of desmopressin in the management of aspirin-related and intractable hemorrhage after cardiopulmonary bypass. Aust N Z J Surg 1990; 60:125-28
[17] Hirsh J, Levine M. Prevention of venous thrombosis in patients undergoing major orthopedic surgical procedures. Br J Clin Pract 1989; 43(suppl):2-8
[18] Hume M, Bierbau B, Kuriakose TX, Suprenant J. Prevention of postoperative thrombosis by aspirin. Am J Surg 1977; 133:420-22
[19] Hume M, Donaldson WR, Suprenant J. Sex, aspirin, and venous thrombosis. Orthop Clin North Am 1978; 9:761-67
[20] Harris WH, Salzman EW, Athanasoulis CA, Waltman AC, DeSanctis RW. Aspirin prophylaxis of venous thromboembolism after total hip replacement. N Engl J Med 1977; 297:1246-48
[21] Elwood PC, Sweetnam PM. Aspirin and secondary mortality after myocardial infarction. Lancet 1979; 2:1313-15
[22] Canadian Cooperative Study Group: A randomized trial of aspirin and sulphinpyrazone in threatened stroke. N Engl J Med 1978; 299:53-59
[23] Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J. Insights into the pathogenesis of acute ischemic syndromes. Circulation 1988; 77:1213-20
[24] Folts JD, Crowell EB, Rowe GG. Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation 1979; 54:365-70
[25] Bolli R, Ware A, Brandon TA, Wielbaecher DG, Mace ML. Platelet mediated thrombosis in stenosed canine coronary arteries: inhibition by nicergoline, a platelet active alpha-adrenergic antagonist. J Am Coll Cardiol 1984; 3:1417-26
[26] Fitzgerald DJ, Roy L, Catella F, Fitzgerald GA. Platelet activation in unstable coronary disease. N Engl J Med 1986; 315:983-89
[27] Theroux P, Latour JG, Leger-Gauthier C, DeLara J. Fibrinopeptide A and platelet factor levels in unstable angina pectoris. Circulation 1987; 75:156-62
[28] Lewis HD, Davis JW, Archibald DG, Steinke WE, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: results of a Veterans Administration Cooperative Study. N Engl J Med 1983; 309:396-403
[29] Cairns JA, Gent M, Singer J, et al. Aspirin, sulfinpyrazone or both in unstable angina: results of a Canadian multicenter trial. N Engl J Med 1985; 313:1369-75
[30] Boston Collaborative Drug Surveillance Group. Regular aspirin intake and myocardial infarction. Br Med J 1974; 1:440-43
[31] Scheidt S, Kloner RA, Guerci A, Verstraete M, Ross A. Thrombolytic therapy: medical panel discussion. Cardiovasc Rev Rep 1990; 11:1-14
[32] Second International Study of Infarct Survival Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 2:349-55
[33] Eisenberg PR, Sherman L, Rich M, Schwartz D, et al. Importance of continued activation of thrombin reflected by fibrinopeptide A to the efficacy of thrombolysis. J Am Coll Cardiol 1986; 7:1255-62
[34] Fitzgerald DJ, Catella F, Roy L, Fitzgerald GA. Marked platelet activation in vivo after intravenous streptokinase in patients with acute myocardial infarction. Circulation 1988; 77:142-50
[35] Bleich SD, Nichols T, Schumacher R, Cooke D, et al. The role of heparin following coronary thrombolysis with tissue plasminogen activator (abstract). Circulation 1989; 80(suppl 2):455a
[36] Hsia J, Hamilton WP, Kleiman N, et al. A comparison between heparin and low-dose aspirin as adjunctive therapy with tissue plasminogen activator for acute myocardial infarction. N Engl J Med 1990; 323:1433-38
[37] Coller BS. A new murine monoclonal antibody prevents an activation dependent change in the conformation and/or micro-environment of the platelet GP IIb-IIIa complex. J Clin Invest 1985; 76:101-08
[38] Gold HK, Coller BS, Yasuda T, Saito T, Fallon JT, et al. Rapid and sustained coronary artery recanalization with a combined bolus injection of recombinant tissue-type plasminogen activator and monoclonal antiplatelet GP IIb-IIIa antibody in a canine preparation. Circulation 1988; 77:670-77
[39] Hanson SR, Pareti FI, Ruggeri ZM, Marzec UM, Kunicki TS, et al. Effects of monoclonal antibodies against the platelet glycoprotein IIb/IIIa complex on thrombosis and hemostasis in the baboon. J Clin Invest 1988; 81:149-58
[40] Yasuda T, Gold HK, Fallon JT, Leinbach RC, et al. Monoclonal antibody against the platelet glycoprotein IIb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue-type plasminogen activation in dogs. J Clin Invest 1988; 81:1284-91
[41] Walker FJ, Sexton PW, Esmon CT. The inhibition of blood coagulation by activated protein C through the selective inactivation of activated factor V. Biochin Biophys Acta 1979; 571:333-42
[42] Marlar RA, Kleiss AJ, Griffin JH. Mechanism of action of human activated protein C, a thrombin dependent anti-coagulant enzyme. Blood 1982; 59:1067-72
[43] Esmon CT, Esmon NL, Harris KW. Complex formation between thrombin and thrombomodulin inhibits both thrombin catalyzed fibrin formation and factor V activation. J Biol Chem 1982; 257:7944-47
[44] Stern D, Brett J, Harris K, Nawroth P. Participation of endothelial cells in the protein C-protein S anticoagulant pathway: the synthesis and release of protein S. J Cell Biol 1986; 102:1971-78
[45] de Fouw NJ, van Hinsbergh VW, de Jong YF, et al. The interaction of activated protein C and thrombin with the plasminogen activator inhibitor released from human endothelial cells. Thromb Haemost 1987; 57:176-82
[46] Griffin JH, Evatt B, Zimmermann TS, et al. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68:1370-73
[47] Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med 1984; 311:1525-28
[48] Salzman EW, Rosenberg RD, Smith MH, Lindon JN, Favreau L. Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest 1980; 65:64-73
[49] Bell WR, Royall RM. Heparin-associated thrombocytopenia: a comparison of three heparin preparations. N Engl J Med 1980; 303:902-7
[50] Hull R, 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; 306:189-94
[51] Studio sulla Calciparina nell'Angina e nella Trombosi Ventricolare nell' Infarto Group. Randomized controlled trial of subcutaneous calcium heparin in acute myocardial infarction. Lancet 1989; 2:182-86
[52] Gallino A, Haeberli A, Baur HR, Straub PW. Fibrin formation and platelet aggregation in patients with severe coronary disease: relationship with the degree of myocardial ischemia. Circulation 1985; 72:27-30
[53] Heras M, Chesebro JH, Penny WJ, Bailey KR, et al. Effects of thrombin inhibition on the development of acute platelet-thrombus deposition during angioplasty in pigs: heparin versus recombinant hirudin, a specific thrombin inhibitor. Circulation 1989; 79:657-65
[54] Fitzgerald DJ, Fitzgerald GA. Role of thrombin and thromboxane [A.sub.2] in reocclusion following coronary thrombolysis with tissue-type plasminogen activator. Proc Natl Acad Sci U S A 1989; 86:7585-89
[55] de Vries WA, Tijssen JGP, de Jonge H, Loeliger EA, Ross J. Het effect van het staken van langdurige antistallingbehandeling wegens myocardinfarct bej ouderen: een dubbelblind onderzaek. Ned Tijdschr Geneeskd 1979; 123:1211-12
[56] Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med 1990; 323:147-52
[57] Chalmers TC, Matta RJ, Smith H, et al. Evidence favoring the use of anticoagulants in the hospital phase of acute myocardial infarction. N Engl J Med 1977; 297:1091-96
[58] Mitchell JRA. Anticoagulants in coronary heart disease: retrospect and prospect. Lancet 1981; 3:1014-17
[59] Ratnoff OD, Busse RJ, Sheon RP. The demise of John Hageman. N Engl J Med 1968; 279:760-61
[60] Rutkowski DM, Burkle WS. Advances in thrombolytic therapy. Drug Intell Clin Pharm 1983; 16:115-21
[61] Rothbard RL, Anderson JL, Fitzpatrick PG, Hakworthy RA, Sorensen SG, Marder VJ. Tolerance and complications in a multicenter trial of intravenous APSAC and intracoronary streptokinase in acute myocardial infarction. Clin Cardiol 1990; 13:11-14
[62] Goldhaber SZ, Kessler CM, Heit J, Sharma GVRK, et al. Randomized controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 1988; 2:293-98
[63] Sobel BE. Safety and efficacy of tissue-type plasminogen activator produced by recombinant DNA techonology. J Am Coll Cardiol 1987; 10(suppl B):40-44
[64] Urokinase-Streptokinase Embolism Trial. Phase 2 results. JAMA 1974; 229:1606-13
[65] Zimmerman R, Epping J, Raschi H, et al. Urokinase and streptokinase treatment of deep vein thrombosis: results of a randomized study (abstract). Haemostasis 1986; 16(suppl 5):9
[66] Nazari J, Davison R, Kaplan K, et al. Adverse reactions to thrombolytic agents: implications for coronary reperfusion following myocardial infarction. Med Toxicol 1987; 2:274-86
[67] Thayer CF. Results of postmarketing surveillance program on streptokinaase. Curr Ther Res 1981; 30:129-40
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