Antithrombotic and Thrombolytic Therapy



Antithrombin

Antithrombin inhibits thrombin, factor Xa, and other activated clotting factors, but in the absence of heparin, these reactions occur slowly. Heparin addition will increase the rate of inhibition of these reactions by 1,000-fold (22). Small amounts of the proteoglycan heparan sulfate located on the luminal surface may maintain intact endothelium in a nonthrombogenic state (23).


Fibrinolytic Degradation of Fibrin

This system is designed to remove intravascular fibrin and restore normal blood circulation. Fibrinolysis is initiated by plasminogen activators that convert plasminogen to plasmin, a trypsinlike protease. Plasmin degrades fibrin into soluble fibrin degradation products (24).


D-Dimers. D-Dimers are a specific fibrin degradation product formed only by plasmin degradation of fibrin and not by plasmin degradation of intact fibrinogen (Fig. 145.3). Thus, its presence indicates that fibrin has been formed. d-Dimer has been validated as a diagnostic tool to help in the exclusion of venous thrombosis and pulmonary embolism and is widely used in the emergency room setting for this purpose (25–27). Elevated d-dimer levels have been reported as a marker of risk for both multiple organ failure and death in critically ill patients (28).


ANTIPLATELET AGENTS


Platelet aggregation leading to a disruption of blood flow can have devastating outcomes, often causing permanent disability or death. The understanding of normal platelet function has led to the rational basis for the development of antiplatelet agents.


Aspirin

The efficacy of aspirin in acute coronary syndrome (ACS) has been established in numerous clinical trials. For example, the International Study of Infarct Survival (ISIS)-2 demonstrated that for acute MI, aspirin alone reduced mortality to a similar extent as did streptokinase alone, with an additive benefit when both agents were used (29). A recent meta-analysis by the Antiplatelet Trialists’ Collaboration found that aspirin reduced the risk of MI, stroke, or death from 13.3% to 8.0% in patients with unstable angina (30). The meta-analysis also found that the greatest risk reduction occurred with a dose of 75 to 150 mg per day; higher doses such as 325 mg per day did not appear to confer any added benefit. In a subsequent investigation, the CURRENT/OASIS-7 (Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs—Organization to Assess Strategies in Ischemic Syndromes) trial compared the effectiveness of double-dose clopidogrel versus a standard dose for 30 days coupled to an open label randomization to high (300 to 325 mg/day) versus a low dose (75 to 100 mg/day) of aspirin in 25,086 patients with ACSs undergoing invasive therapy. This study found no significant difference between either regimen with respect to the primary outcome of cardiovascular death, infarction, or stroke. It did however note a small increase in the incidence of major gastrointestinal bleeding among patients receiving the higher-dose aspirin regimen as compared to the lower dosage (47 patients [0.4%] vs. 29 patients [0.2%]; p = 0.04) (31). Aspirin therapy has, thus, become the standard for the secondary prevention of cardiovascular events in high-risk patients. The role of aspirin alone, versus other antithrombotic agents, in atrial fibrillation has been addressed in many studies, the results suggesting that the risk reduction of ischemic strokes associated with oral vitamin K–inhibiting anticoagulant therapy is greater than that provided by aspirin (32,33).



FIGURE 145.1 Model for venous thrombosis. Coagulation in veins is initiated by the tissue factor-VIIa complex which then activates factors IX and X. Factor II, prothrombin; factor IIa, thrombin; PSGL-1, p-selectin glycoprotein ligand-1.


Aspirin Resistance

The efficacy of aspirin in the inhibition of platelet function differs between patients. Cardiovascular events occur preferentially in patients with low responses to aspirin therapy (34), referred to as aspirin resistance. The prevalence is reported to vary between 5% and 60%, depending on the laboratory studies used (35). Gum et al. (36), in a prospective study, followed 325 patients with stable coronary artery disease for 2 years, finding aspirin resistance in 5.5% of patients using optical platelet aggregability, and in 9.5% by using the Platelet Function Analyzer 100 (PFA-100). Aspirin-resistant patients were noted to have a 24% risk of death, MI, or stroke, as compared with a 10% risk for patients who were aspirin sensitive.


There are two aspects of resistance: biochemical and clinical. Biochemical resistance refers to the inability of aspirin to initiate platelet inhibition, whereas clinical resistance indicates an increased risk of cardiovascular events in patients receiving treatment with aspirin (37). Platelet receptor polymorphism is thought to be responsible for aspirin resistance (38).


The risk of hemorrhage, especially from the gastrointestinal tract, is a major concern when doses higher than 325 mg per day are used. The local effect of aspirin on the gastric mucosa is more prevalent with the higher doses, but patients with vascular malformations or mucosal lesions may bleed at lower doses. There is also a risk of cerebral hemorrhage in patients with prior stroke or with uncontrolled hypertension. In the event of hemorrhage, aspirin should be discontinued and the patient observed but, if needed, the patient may be treated with fresh platelet transfusion. For elective surgical procedures, aspirin should be stopped 5 days before the intervention (39). Aspirin is not recommended for venous thromboembolic prophylaxis (40); other forms of standard venous thromboembolism prophylaxis—for example, subcutaneous heparin and pneumatic compression devices—are preferred.



FIGURE 145.2 Arterial thrombi begin with a dysfunctional endothelium, resulting in monocyte infiltration and subsequent macrophage differentiation, foam cell lipid accumulation, and smooth muscle cell proliferation. Normally, there is a balance between blood fibrinolysis and coagulation. When plaques rupture, the balance between fibrinolysis and coagulation is shifted (greater thrombosis), and an occlusive thrombus may form. CAM, cellular adhesion molecule; SMC, smooth muscle cell; vW factor, von Willebrand factor.


P2Y12 Receptor Antagonists

Adenosine diphosphate (ADP) interacts with two different receptors on platelets, known as P2Y1 and P2Y12. Interaction with P2Y1 receptors initiates the platelet response while interaction with P2Y12 receptors promotes the response. Blockade of the effects of ADP at either of these receptors results in a marked reduction in the overall effect of ADP on platelet function. The initial response to ADP is a change in the shape of the platelet; the disc-shaped cells will convert into a spherical form from which pseudopodia emerge. This change, mediated by the P2Y1 receptor, involves Ca2+ influx, intracellular Ca2+ mobilization, and actin polymerization. Interaction of ADP with the P2Y12 receptor results in inhibition of adenylate cyclase, which is accompanied by platelet aggregation (41,42). P2Y12 inhibition is recommended for patients undergoing antiplatelet therapy for the prevention of ischemic events.


The thienopyridine (ticlopidine, clopidogrel, and prasugrel) and nonthienopyridine (cangrelor and ticagrelor) class of antiplatelet agents have been approved for clinical use. These medications achieve their antiplatelet effect by irreversibly blocking the binding of ADP to the specific platelet receptor P2Y12, thus inhibiting adenyl cyclase and platelet aggregation (Fig. 145.4).


Clopidogrel

Clopidogrel, a member of the thienopyridine family, is a potent platelet inhibitor, working by irreversibly binding to low-affinity ADP receptors. It is rapidly absorbed and metabolized by the hepatic cytochrome P450 enzyme system to an active metabolite that selectively and irreversibly inhibits ADP-induced platelet aggregation. This metabolite also impairs the activation of glycoprotein (GP) IIb/IIIa complex and prevents fibrinogen binding to the platelets. Platelets exposed to this drug are affected for the remainder of their life span. Dose-dependent platelet inhibition can be seen within 2 hours after a single oral dose. For maximum effect, patients may be given a loading dose of 300 to 600 mg, followed by 75 mg per day. With repeated doses of 75 mg per day, maximum platelet inhibition can be achieved within 3 to 7 days (43).


When steady state is achieved, platelet aggregation is inhibited by 40% to 60% (44). Prolongation of bleeding time is independent of age, renal impairment, or gender. Platelet aggregation and bleeding time generally return to baseline about 5 days after discontinuation of clopidogrel. The CAPRIE trial was among the first to establish that clopidogrel is more effective than aspirin in reducing atherosclerotic events—including peripheral vascular disease, MI, and stroke—by 8.7% (45). The efficacy and safety of clopidogrel have been evaluated in ACS patients in the CURE trial, showing a 20% relative risk reduction in composite triple end points: nonfatal MI, death, or stroke (46). Clopidogrel, like ticlopidine, prolongs the bleeding time. While there was an incidence of neutropenia reported at 0.1% in the CAPRIE trial, there have been rare case reports of clopidogrel-associated thrombotic thrombocytopenic purpura. The incidence of gastrointestinal bleeding is less when compared to aspirin, but the incidence of bleeding is higher among patients requiring urgent surgical procedures who take clopidogrel (47). However, the clopidogrel effect can be reversed by transfusion of fresh platelets.



FIGURE 145.3 Fibrin clot formation and degradation. This figure shows the simplified conversion of fibrinogen into fibrin monomers called fibrinopeptides A and B. These monomers either polymerize to form fibrin clot or degrade into fibrinogen degradation products (without d-dimer formation). Fibrinolysis of a fibrin clot leads to formation of fibrin degradation products and d-dimers. Positive d-dimer assays are indicative of fibrin clot formation, followed by degradation by plasmin.


Ticlopidine

Ticlopidine, an older thienopyridine compound, inhibits platelet aggregation irreversibly and interferes with ADP-induced binding of fibrinogen to platelet receptors. It has fallen out of favor because of two major side effects: neutropenia and thrombotic thrombocytopenic purpura. Rare case reports of severe bone marrow toxicity limit ticlopidine use to patients who are intolerant or unresponsive to aspirin.


Prasugrel

Prasugrel, a third-generation thienopyridine, is an orally administered irreversible platelet P2Y12 receptor antagonist. It is a prodrug and requires metabolism via a cytochrome P450–dependent pathway into its active metabolite. Compared to clopidogrel, it has a more rapid onset of action after oral administration, it achieves and renders a more consistent and predictable platelet inhibition in individual patients (48). This occurs because the metabolism of prasugrel is different than clopidogrel and there are greater and more predictable amounts of active metabolite produced. This leads to longer recovery of platelet function (7 days for a 75% return to baseline platelet function as opposed to 5 days for clopidogrel). Surgical bleeding may be more problematic as a result (49).



FIGURE 145.4 The coagulation cascade. The extrinsic pathway of coagulation is initiated by the factor VIIa/tissue factor complex, whereas the intrinsic pathway is initiated when factor XII contacts a foreign surface. Both pathways lead to factor IX and X activation. Activated factor IXa propagates coagulation by activating factor X in a reaction using activated factor VIIIa as a cofactor. Activated factor Xa combining with activated factor Va acts as a cofactor and converts prothrombin (factor II) to thrombin (factor IIa). Thrombin then converts fibrinogen to fibrin.


In patients with ACSs undergoing percutaneous coronary intervention (PCI), prasugrel offers more effective antithrombotic therapy when compared to clopidogrel as shown in the TRITON-TIMI 38 study (trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in MI 38) (48). This was a double-blinded, randomized controlled trial directly comparing prasugrel (60-mg loading dose followed by a 10-mg maintenance dose) and standard clopidogrel (300-mg loading dose followed by a 75-mg maintenance dose). The primary efficacy end point (cardiovascular death, nonfatal MI, or nonfatal stroke) occurred significantly less often in patients treated with prasugrel (9.9 vs. 12.1%; p < 0.001). The rate of probable stent thrombosis was significantly decreased in the prasugrel group (1.1 vs. 2.4%; p < 0.001). There was, however, a significant increased risk of bleeding associated with prasugrel in comparison to clopidogrel (2.4 vs. 1.8%; p = 0.03), most notable in patients with a prior history of stroke, age >75 years, and those with a body weight of <60 kg. Prasugrel effects are not modulated by aspirin dose or cytochrome interfering drugs including proton pump inhibitors. A washout period of 7 days is indicated for prasugrel-treated patients requiring surgery.


Ticagrelor

Ticagrelor is an orally administered cyclopentyltriazolopyrimidine, a new compound class very different from both clopidogrel and prasugrel, ticagrelor interacts with P2Y12 receptors on platelets, disabling their ability to interact with ADP. Although this compound is metabolized to an active agent, it is chemically very similar to the parent compound and metabolic conversion is not required for receptor interaction. It directly binds to the platelet receptor and allows for a faster onset of action, more intense, and consistent platelet inhibition than does clopidogrel (50). The reversible binding effects and the plasma half-life of 8 to 12 hours necessitate twice daily dosing (51). The ONSET/OFFSET study demonstrated ticagrelor exhibited greater platelet inhibition than clopidogrel. It looked at 123 patients with stable coronary artery disease on aspirin therapy and compared the addition of clopidogrel (600 mg load followed by 75 mg/day maintenance) or ticagrelor (180 mg load followed by 90 mg twice daily) or placebo. Analysis performed 2 hours after the loading doses demonstrated 90% of patients receiving ticagrelor achieved greater than 70% platelet inhibition as compared to 16% in the clopidogrel group. This effect was sustained at 6 weeks with patients taking ticagrelor (51).


Additionally, the PLATO trial (Platelet Inhibition and Patient Outcomes) examined the clinical benefit of ticagrelor (180-mg loading dose followed by 90 mg twice daily) compared to clopidogrel (300- to 600-mg loading dose followed by 75 mg daily) in 18,624 patients with ACSs randomized to receive either medication as soon as possible after hospital admission. The PLATO trial demonstrated that ticagrelor significantly reduced the rate of the primary end point (death from vascular causes, nonfatal myocardial infarct, or nonfatal stroke) at 12 months (9.8% vs. 11.7%; Hazard Ratio 0.84, p = 0.0001). There were no significant differences in the rate of major bleeding between either medication (11.6% vs. 11.2%, respectively), but ticagrelor was associated with a significantly higher rate of major bleeding not related to coronary artery bypass grafting (4.5% vs. 3.8%) (52).


Ticagrelor has been approved for clinical use and is indicated for the prevention of atherothrombotic events in patients with ACSs, including patients managed medically and invasively. In addition to being contraindicated in patients at high risk for bleeding, ticagrelor is contraindicated in patients with prior hemorrhagic stroke and severe hepatic dysfunction (50).


Cangrelor

Cangrelor is an intravenous, rapid onset, potent, and direct-acting platelet ADP P2Y12 inhibitor that has rapidly reversible effects. When a bolus of cangrelor is administered, the antiplatelet effect is immediate, and the effect can be maintained with a continuous infusion. The plasma half-life of cangrelor is approximately 3 to 5 minutes, and platelet function is restored within 1 hour after cessation of the infusion (53).


In the CHAMPION PHOENIX trial, 11,145 patients undergoing either urgent or elective percutaneous coronary intervention (PCI) were enrolled in a double-blind, placebo controlled manner to evaluate the impact of clopidogrel and cangrelor on outcome; patients received guideline-recommended therapy of a bolus and infusion of cangrelor or a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; p = 0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; p = 0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; p = 0.01). The rates of adverse events related to the study treatment were low in both groups; the primary safety end point was severe bleeding at 48 hours (54). At the time of this writing the U.S. Food and Drug Administration (FDA) is continuing to evaluate cangrelor for approval.


Vorapaxar

In 2014, the FDA approved a new class of antiplatelet medication, to reduce the risk of MI or peripheral artery disease (PAD). This class of medication, considered a protease–activated-receptor 1 antagonist (PAR-1), is intended as part of a therapeutic regimen inclusive of aspirin and clopidogrel.


Approval of this medication was based on the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 P TIMI-50) trial. Results of the trial (n = 26,499 patients) demonstrated cardiovascular death, MI, stroke, or urgent coronary revascularization was decreased by 13% in patients taking vorapaxar. When coronary revascularization was excluded, the secondary endpoint of cardiovascular death, MI, or stroke was also significantly reduced (55). Because of vorapaxar’s antiplatelet effects, moderate or severe bleeding occurred in 3.4% of patients compared with 2.1% in the placebo-treated patients. Intracranial hemorrhage occurred in 0.6% of those taking vorapaxar compared with 0.4% taking placebo (55).


Glycoprotein IIb/IIIa Antagonists

Abciximab

This, the most successful GPIIb/IIIa antagonist, is a human-murine Fab chimeric monoclonal antibody fragment to the GPIIb/IIIa binding site; it is a large protein with a rapid and prolonged response, causing the bleeding time to remain elevated for 12 hours after injection. Abciximab is used in combination with aspirin and heparin in patients with unresponsive unstable angina or undergoing PCI. It has been demonstrated to deliver a 60% relative risk reduction in triple end points: MI, emergent revascularization, or cardiovascular deaths (56,57). The major complications of this agent include intracranial bleeding or a decrease in hemoglobin of more than 15%, reported as frequently as 10.5% (58). There is a high incidence of thrombocytopenia, which can be spurious (4%) due to platelet clumping, but true and severe thrombocytopenia may also develop, resulting in profound bleeding (59). In the event of profuse bleeding, platelet transfusions are required to normalize the platelet count. Desmopressin has been shown to normalize the bleeding time (60).


Eptifibatide

This disintegrin, derived from the southeastern pygmy rattlesnake, is rapidly bound and rapidly reversed, with a normalization of the bleeding time within 1 to 4 hours. This drug has been shown to be more effective in milder forms of ACSs (61).


Tirofiban

This is a small nonpeptide compound derived from tyrosine, which interacts with the arginine-glycine-aspartic acid fibrinogen receptor. Tirofiban has been used in unstable angina with mixed results (62).


Dipyridamole

Dipyridamole is a phosphodiesterase inhibitor, reversibly inhibiting platelet aggregation. As it increases c-AMP and c-GMP levels, through its inhibition of phosphodiesterases, it potentiates the effect of nitric oxide. It has been used adjunctively with aspirin to reduce stroke events in patients younger than 70 years (63).


ANTITHROMBOTIC THERAPY


Unfractionated Heparin

Unfractionated heparin (UH) is a naturally occurring acidic glycosaminoglycan. Its pentasaccharide sequence binds to antithrombin, causing a conformational change at the arginine reactive site that potentiates the effect of antithrombin, causing it to have an enhanced effect on inhibition of the coagulation enzymes, in particular thrombin (factor IIa) and factor Xa. Heparin also acts to inhibit activation of factors V and VIII by thrombin (Fig. 145.5) (64,65). The increase in inhibition of these enzymes in the presence of UH may be up to 2,000 times faster than in its absence. The molecular weight of UH is 3,000 to 35,000 daltons (d) on average, with a mean molecular weight of 15,000 d, composed of approximately 45 monosaccharide chains. Due to the variable size and structure of heparin, only about one-third of any given dose of heparin will demonstrate therapeutic anticoagulant activity. The different-sized molecules are cleared at different rates by the kidney, with the larger ones being cleared more rapidly. Thus, the combination of these factors leads to great variability in the anticoagulant effects on individuals, necessitating the need for monitoring with activated partial thromboplastin time (aPTT). Heparin is obtained from either bovine lung or porcine intestine and is available as a sodium or calcium salt.



FIGURE 145.5 The immune-mediated platelet activation involves the binding of heparin–platelet factor 4–IgG complex to the platelets and brings about conformational changes, exposing GPIIb/IIIa to fibrinogen. This complex leads to further platelet activation, cross-linking them into platelet aggregates. Thrombin plays a major role in the conversion of fibrinogen to fibrin, forming tight platelet aggregates. PF 4, platelet factor 4; IgG, immunoglobulin G; GPIIb/IIIa, glycoprotein IIb/IIIa.


The unit of heparin is measured in animals in a biologic assay, with the unit measurement being variable by as much as 50% on a weight basis. Therefore, UH is prescribed for patients on a unit basis/kg, not the weight of medication (66).


Uses of Unfractionated Heparin

Heparin is indicated for prophylaxis of venous thromboembolism. It is used in the treatment of DVT and pulmonary embolus, as well as for early treatment of patients suffering from ACSs.


Prevention of Thromboembolism. To prevent thromboembolism, UH at a fixed low dose of 5,000 units, subcutaneously every 8 to 12 hours, results in a 60% to 70% relative risk reduction for DVT and fatal pulmonary embolus (PE) (40,67). In high-risk surgical and acutely ill medical patients, the use of low–molecular-weight heparin (LMWH) is becoming the standard for prevention of thrombosis (68,69).


In the patient who is unable to tolerate any type of anticoagulation, the use of intermittent pneumatic compression is useful as a mechanical means for preventing DVT by intermittently squeezing the patient’s calves, leading to increased blood flow through the venous system. Intermittent pneumatic compression may also stimulate fibrinolysis by stimulating the vascular endothelium (70).


Venous Thromboembolism and Pulmonary Embolus. Therapy for treating proximal or symptomatic distal venous thromboembolism and PE is aimed at preventing extension of the clot with further embolization and recurrence; anticoagulation has long been an effective strategy for the treatment of both conditions (71). Multiple studies have demonstrated the efficacy of heparin in reducing mortality in patients with venous thromboembolism (72,73), as well as the high mortality in patients with PE who are not anticoagulated (74). More recent clinical studies further demonstrated the benefit of treating DVT with continuous intravenous heparin and, in some cases, LMWH (75–77). Additionally, data show the effectiveness of using subcutaneous heparin as the initial treatment for DVT, as long as adequate doses are used and the aPTT is prolonged into the therapeutic range (78–80). Recently, Kearon et al. (81) demonstrated that administration of a fixed dose, weight-adjusted, UH was as effective and safe as the administration of LMWH in patients with acute DVT and may also be suitable for treatment in the outpatient setting.


Perhaps the most efficient method for initiating intravenous heparin therapy is using weight-adjusted nomograms. The important consideration is to maintain a therapeutic range when heparin anticoagulation therapy is initiated, best achieved with frequent monitoring of plasma aPTT. Subtherapeutic dosing within the first 24 hours of a documented DVT resulted in a significantly greater frequency of venous thromboembolus recurrence when compared to those patients who reached a supratherapeutic threshold within 24 hours (82).


The weight-based method was developed by Raschke et al. (83) who found that a weight-based titration of UH resulted in a significant decrease in the time required to reach therapeutic levels as compared to a standard dosing scheme of heparin. These clinicians found that 97% of patients dosed using the weight-based nomogram achieve therapeutic levels within 24 hours of initiation as opposed to 77% in the standard dosing group (Tables 145.2 and 145.3).


Typically, the Raschke method of anticoagulation in the acute phase of venous thromboembolism is initiated with an intravenous loading dose of 80 units/kg, followed by 18 units/kg/hr. Subsequent doses should be adjusted using a standard nomogram to rapidly reach and maintain an aPTT that corresponds to therapeutic heparin levels of 1.5 to 2.5 times the baseline (83–88). Alternatively, therapeutic heparin anticoagulation is determined by achieving a plasma anti–factor Xa level of 0.35 to 0.7 units/mL (89,90). This therapeutic range is recommended based on animal studies (91), prospective studies and analysis of patients with established DVT (90), studies on the prevention of mural thrombus formation following MI (91) and prevention of recurrent ischemia following coronary thrombolysis (93). Heparin anticoagulation should be continued for up to 5 days so that adequate anticoagulation is achieved. During this time, the aPTT should be monitored every 6 hours until the therapeutic range is achieved, and once daily thereafter. Preferably on day 1, the patient may be transitioned to long-term warfarin (5 mg), a vitamin K–antagonist agent that may be administered orally if the patient can tolerate enteral intake. The anticoagulation effect of warfarin is monitored by the international normalized ratio (INR) to achieve a therapeutic range of two to three times the normal level for a first thrombotic episode. Warfarin is considered to be at therapeutic level if the INR of 2 to 3 is maintained for 2 consecutive days. If the patient is unstable and unable to tolerate oral anticoagulation, intravenous heparin may need to be continued. It is important to keep in mind that warfarin interacts with many commonly used drugs in the ICU, and its metabolism may be affected by hepatic and renal impairment. This may lead to erratic variation in the anticoagulant effect of warfarin, exposing the patient to increased risks of bleeding and thrombotic complications (7). The minimum recommended duration of warfarin therapy is 3 months (66,94) based upon the clinical scenario and patient risk factors, with follow-up evaluation to determine if longer therapy is necessary. Further studies have demonstrated that longer treatment may be beneficial (95–97) in higher-risk patients. In accordance with the American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy, it is now recommended that warfarin therapy be continued following a first unprovoked proximal or second unprovoked DVT or those with active cancer. For those with recurrent events or who have permanent or long-term risk factors, the panel recommends indefinite therapy (94).








TABLE 145.2 Weight-Based Heparin Dosing Nomogram







TABLE 145.3 Guidelines for Anticoagulation Using Unfractionated Heparin

Acute Coronary Syndromes. The ACC/AHA updated guidelines for the management of patients with acute myocardial infarction (AMI) (98) evaluated multiple trials comparing the use of LMWH with UH in non–ST elevation ACS (99–101). The studies cited demonstrate, as a whole, a benefit of LMWH over UH when it came to a lower event rate and relative risk reduction (102). These guidelines suggest considering LMWH, as opposed to UH due to its greater inhibition of factor Xa, the ability to administer the drug subcutaneously, and its high bioavailability. In those patients with impaired renal function (CrCl <30 mL/min) it may be necessary to consider a reduction in dose to one-half recommended and/or frequency of administration to only once daily. It should be noted that a sub study of the Enoxaparin and Thrombolysis Reperfusion for AMI-TIMI 25 trial demonstrated that for every 30 mL/min decrease in CrCl, the risk of major and minor bleeding increased by 50% (103,104). Until conclusive results are available regarding optimal dosing, it may be safer to use UFH in patients with impaired renal function presenting with ACS. However, other benefits of the drug are cited as well, such as the potential to prevent thrombin generation and inhibit thrombin, the lack of need to monitor coagulation, and the lower incidence of heparin-associated thrombocytopenia (105).


Monitoring UH

The most widely used test for evaluating the adequacy of heparin anticoagulation is the aPTT, a global coagulation test that is not always a reliable indicator of plasma heparin levels and/or the antithrombotic activity of heparin. The aPTT can be impacted by various acute phase reactant plasma proteins, including factor VIII. Additionally, the aPTT can be influenced by the coagulation timer and reagents used to perform the test (103). If a hospital is unable to measure plasma heparin levels directly, it is recommended that each laboratory standardize the therapeutic range of the aPTT to correspond to plasma levels of 0.3 to 0.7 IU/mL anti–factor Xa activity by an amidolytic assay.


Complications of Anticoagulation Therapy

Heparin Resistance

Patients are considered heparin resistant if their daily requirement of heparin exceeds 35,000 units/24 hr; unfortunately, multiple studies demonstrate that at least 25% of patients with venous thromboemboli are heparin resistant. Heparin resistance may be associated with antithrombin deficiency, increased heparin clearance, increases in heparin-binding proteins, and increases in factor VIII, fibrinogen, and platelet factor 4. Aprotinin and nitroglycerin have been reported to cause drug-induced resistance, but the association with nitroglycerin remains controversial (106). Factor VIII and fibrinogen are elevated in response to acute illness or pregnancy. Elevation of factor VIII alters the response of the aPTT to heparin without decreasing the antithrombotic effect, as the anticoagulant effect measured by the plasma aPTT and the antithrombotic effect is measured by anti–factor Xa activity become dissociated.


For those patients considered heparin resistant, the dose of heparin should be adjusted to maintain the anti–factor Xa heparin levels between 0.35 and 0.7 mIU/mL. In a randomized, controlled study by Levine and Hirsch (107), evaluating 131 patients with venous thromboembolism and manifesting heparin resistance, monitoring the aPTT was compared to anti–factor Xa activity; while there were no difference in clinical outcomes, it was found that the patient group monitored with anti–factor Xa heparin levels required significantly less heparin with no differences in bleeding.


Hemorrhagic Complications

The incidence of major hemorrhagic complications—defined as intracranial or retroperitoneal hemorrhage, hemorrhage requiring a transfusion, or hemorrhage directly related to death—from therapeutic anticoagulation is less than 5% (105). The risk increases with age, total dose of heparin/24 hr. patient premorbid condition, concomitant use of aspirin, GPIIb/IIIa antagonists, or thrombolytic therapy. Intravenous (IV) heparin infusion appears to produce less marked bleeding complications than when the agent is administered (107) subcutaneously. This may be due to a lower total dose of heparin via the IV, as compared to the subcutaneous, route (106).


The anticoagulant effect of UH can be neutralized rapidly by intravenous protamine. Protamine is a cationic protein derived from fish sperm that strongly binds to the anionic heparin compound in a ratio of approximately 100 units of UH/mg of protamine. When heparin has been infused, only the heparin given over the prior 2 hours should be included in the calculation. If the heparin infusion was discontinued for more than 30 minutes but less than 2 hours, use one-half of the calculated protamine dose. If the infusion was discontinued for longer than 2 hours, use one-quarter of the calculated protamine dose. One should avoid giving 50 mg of protamine at one time and, if given by infusion, it should not exceed 5 mg per minute to reduce the incidence of adverse reactions. Heparin neutralization can be confirmed by a fall in the aPTT.


The risks of severe adverse reactions to protamine, such as hypotension and bradycardia, are reduced with a slow administration of the drug over more than 3 minutes. Some clinicians will begin the protamine infusion following a 3- to 5-mg test dose administered over 1 minute (107,108). Allergic reactions including anaphylaxis are associated with a previous exposure to protamine-containing insulin—for example, NPH-insulin (108)—fish hypersensitivity (109), and vasectomy. Patients at risk for developing antiprotamine antibodies can be pretreated with corticosteroid and antihistamine medications.


Heparin-Associated (Induced) Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse reaction to the administration of heparin and/or LMWH and may lead to both arterial and venous thrombosis. The diagnosis is made both on clinical and serologic findings. HIT antibody formation, accompanied by an otherwise unexplained fall in platelet count by more than 50% from baseline and/or skin lesions at injection sites are the manifestations of HIT (110).


The incidence of HIT is less than 1% when heparin is given for less than 7 days; thereafter, when given to patients with an extended need for anticoagulation (such as ICU patients), the incidence may rise as high as 10% to 20% for the mild form (type 1) of HIT and to more than 5% for type 2, the more severe manifestation. A precipitous fall in platelet count from baseline is usually seen with the type 1 syndrome, and 50% to 75% of these patients may go on to develop the more ominous type 2 syndrome, which manifests with either the development of arterial, or more commonly, venous thrombotic complications.


Patients who develop HIT generate large amounts of thrombin. In vivo, platelet activation results from binding of the heparin PF4-IgG immune complexes to platelet factor IIa receptors. These increased levels of thrombin are demonstrated by elevated levels of thrombin–antithrombin complexes, which serve as an in vivo marker of thrombin generation, much higher than that seen in control patients with DVT (111). The diagnosis can be confirmed with platelet function testing or the identification in the blood of the antibody to heparin-platelet factor 4 complex using an enzyme-linked immunosorbent assay (ELISA) (111) (see Fig. 145.5).


Once the determination of HIT is made, it is not adequate simply to stop anticoagulation therapy with heparin or LMWH. Multiple studies document that patients continue to be at risk of thrombosis if no anticoagulation is given (112,113). Currently, alternative antithrombotic agents are being used and have been approved in many countries for the treatment of HIT. Three of the agents are direct thrombin inhibitors: argatroban, hirudin (lepirudin), and bivalirudin, and the other agent is a heparinoid, danaparoid (Table 145.4).


Argatroban is a small (MW 526) synthetic molecule derived from L-arginine that reversibly binds to thrombin. It is approved for prophylaxis and treatment of patients with HIT in both the United States and Canada. It reportedly has been associated with a lower thrombotic event rate in one prospective study. The half-life is less than 1 hour, and the drug is excreted normally, even in those with moderate renal failure. In the event of hepatic dysfunction, the dose of argatroban must be reduced. The anticoagulant effect is monitored by the aPTT.








TABLE 145.4 Alternatives to Heparin for the Treatment of Heparin-Induced Thrombocytopenia

Lepirudin is a recombinant polypeptide originally derived from the medicinal leech (see below). It inhibits thrombin directly and is approved only for the treatment of HIT. The anticoagulant effect of lepirudin is monitored by the aPTT. It is renally excreted, and the risk for accumulation and bleeding is high in patients with renal failure; the half-life of lepirudin is 1.3 hours.


Danaparoid is a mixture of heparan sulfate, dermatan sulfate, and chondroitin sulfate; the drug reduces thrombin generation in vivo by the inhibition of factor Xa. Although no longer available in the United States, it is used for the treatment of HIT elsewhere. It is important to consider that cross-reactivity between heparin and danaparoid may occur in up to 30% of cases; in this case, a direct thrombin inhibitor should be used for treatment.


A third direct thrombin inhibitor, bivalirudin, is not approved for the treatment of HIT but has been successfully used and reported off-label for this use (113). An early transition from intravenous heparin or LMWH anticoagulation to warfarin (or an equivalent anticoagulant) has been standard therapy for most patients with acute venous and arterial thromboembolism. This approach may also help prevent HIT by limiting a patient’s total dose-time exposure to heparin medications. One complication to be considered is that early transition has been associated with further thrombotic complications of venous limb gangrene and warfarin-induced skin necrosis (112,113).


Warfarin and other equivalent vitamin K antagonists counter thrombin generation by slowly decreasing the plasma levels of the vitamin K factors (II, VII, IX, X) while concurrently decreasing the natural anticoagulant factors C and S. During the transition to oral vitamin K antagonist therapy in patients with HIT, thrombin is still being generated (warfarin having failed to control this). Due to their shorter half-lives, factors VII and protein C are reduced faster than the prothrombotic factors II, IX, and X (Table 145.5). This results in a supratherapeutic INR secondary to factor VII depletion and a transient hypercoagulable state due to the decrease in protein C without a concurrent decrease in the prothrombotic levels of factors II and X. Throughout this process, there is still increased thrombin generation due to the HIT, and venous limb gangrene and/or warfarin-induced skin necrosis may develop as a result (110,113).


In these patients, it has been recommended to use the direct thrombin inhibitors available—argatroban, lepirudin, and bivalirudin or danaparoid—once HIT has been established and discontinue the use of heparin or LMWH. Anticoagulation needs to be ensured, and with use of these alternatives, there should be no interruption in anticoagulation therapy. Oral therapy with warfarin or an equivalent vitamin K–antagonist agent should be avoided until the patient’s platelet count has recovered to near-normal levels (>150,000 platelets/μL). Thereafter, one may begin administering warfarin at modest doses (2.5 to 5.0 mg orally [PO]), titrating to and maintaining the target INR; warfarin should not be used as the initial treatment for HIT (112,113,116).








TABLE 145.5 Half-Lives of the Vitamin K–Dependent Procoagulant and Natural Anticoagulant Factors

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Feb 26, 2020 | Posted by in CRITICAL CARE | Comments Off on Antithrombotic and Thrombolytic Therapy
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