Anticoagulation and Thrombolytic Therapy in the Emergency Department: Part II

Authors: Richard V. Aghababian, MD, Professor and Chair, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester; Robert L. Levine, MD, Associate Professor of Neurosurgery and Emergency Medicine, Chief, Division of Neurointensive Care, The University of Texas School of Medicine at Houston; and Marcie J. Hursting, PhD, DABCC, Director, Clinical Science Consulting, Austin, TX.

Peer Reviewers: Frank LoVecchio, DO, MPH, FACEP, Medical Director, Banner Good Samaritan Regional Poison Center, Research Director, Maricopa Medical Center, Department of Emergency Medicine, Associate Professor, Arizona College of Osteopathic Medicine, Phoenix, AZ; and Brian Tiffany, MD, PhD, Chairman, Department of Emergency Medicine, Chandler Regional Hospital, Chandler, AZ; Chairman, Department of Emergency Medicine, Mercy Gilbert Medical Center, Gilbert, AZ.

Part II of this series discusses the use of anticoagulants in the emergency department (ED) and some of the complications seen with their use. As our society ages, more and more patients are on chronic anticoagulants. This leads to a new set of problems for our patients such as increased risk of bleeding and medication interaction. In addition, the emergency physician must be on the lookout for complications such as heparin-induced thrombocytopenia and warfarin-related skin necrosis.

Patients who are on chronic anticoagulation should, in general, have their clotting studies checked when they are seen in the ED if blood is being drawn for other reasons or if they are acutely ill. This is because so many factors change the patient's INR. Changes in medication or diet may lead to changes in the INR. Finding this early can prevent serious issues later on.

One of the difficult situations that an emergency physician faces is the patient on anticoagulation who is bleeding. It can be a delicate decision of whether the bleeding or the need for anticoagulation takes precedence. With more patients than ever on some form of anticoagulation, this decision will be increasingly faced by all physicians.

Finally, the paper discusses the role of pathways in our practice. Many physicians rebel against pathways because they believe they represent "cookbook medicine." However, pathways, used intelligently by physicians, have been shown to reduce variation in care, decrease errors, and provide more efficient, effective care. Pathways together with sophisticated medical decision-making will benefit all our patients.

—Sandra M. Schneider, MD, FACEP, Editor

Managing Patients with Acute Vascular Occlusion

Treatment Options. Care of patients with acute vascular occlusion has been significantly improved through the use of treatment pathways. Pathways and guidelines have been developed by many specialty-driven societies and recently have become "evidence-based," limited only by the amount and quality of evidence available. This is true for acute coronary syndrome (ACS) including unstable angina and acute myocardial infarction (AMI), acute venous thromboembolism (VTE), and for acute ischemic stroke. At the institutional levels, local protocols have been developed that have supplemented or replaced published guidelines that have undergone peer review. These local protocols may work well in the institution that created them, but need to be carefully implemented. In addition, they may not extrapolate to other institutions dealing with different patient populations or different formularies. A note of caution is also warranted in that many institutions have implemented "therapeutic-equivalence" policies, allowing substitution of a less expensive agent, usually from the same class of drugs, for the agent in question. For anticoagulants, each drug, even within classes, must stand on its own evidence due to the fact that they have not been shown to be equivalent, and there are no established equivalency dosing schemes to translate treatment of ACS or VTE with the various low molecular weight heparin (LMWH) drugs currently available.

Classes of Pharmacologic Agents. Anticoagulants. Anticoagulants inhibit clot formation by reducing the generation or activity of coagulation proteins. These agents vary in their onset of action (slow or rapid) and mechanism of action (indirect or direct). Warfarin and other vitamin K antagonists have a slow onset of action, exerting their anticoagulant effects by inhibiting formation of the vitamin K-dependent coagulation factors II (prothrombin), VII, IX, and X and proteins C and S. Stable, therapeutic levels of warfarin anticoagulation are achieved only after approximately 5 days. Common indications for warfarin include prophylaxis or treatment of venous thromboembolism, prophylaxis or treatment of thromboembolic complications associated with atrial fibrillation, and reduction of thrombotic risk after myocardial infarction. It is also indicated for the prevention of thromboses related to implantation of mechanical heart valves. Although patients may present to the ED who are on warfarin or who ultimately are bridged to warfarin, acute anticoagulation in the ED typically is provided when needed using a rapidly acting drug.

When a patient presents to the ED on chronic anticoagulant therapy, usually warfarin, the PT/INR almost always should be checked. This is especially true for patients presenting with any type of bleeding, no matter how minor (epistaxis, gingival bleeding) or potentially life-threatening complaints (headache on warfarin, or any type of anticoagulant or antiplatelet). The therapeutic range of warfarin is an INR of 2-3 for most conditions. The baseline PT/INR helps establish the next step. The ED physician may be confronted with three situations requiring a change in the patient's warfarin: subtherapeutic INR in a patient with no contraindication to continued anticoagulation; supratherapeutic INR in a patient with no active bleeding; and a therapeutic range or supratherapeutic INR in a patient actively bleeding. The subtherapeutic patient not taking the warfarin should just be restarted on 5 mg/day without a loading dose. If the patient is taking the medication, the dose can be increased by 5-20% based on the patient's cumulative weekly dose, with more frequent monitoring indicated.1 Daily, follow-up PT/INR should be arranged until the patient's INR stabilizes, at which time the dose can be fine-tuned to achieve the desired INR. Patients with life-threatening bleeding, with an INR in the therapeutic range, or a supratherapeutic INR should be reversed with the administration of 10-25 mg vitamin K daily for 3 days. In addition, these patients should be administered 6 units of fresh frozen plasma (FFP) as soon as possible to reverse warfarin's effects. Factor VII or prothrombin concentrates can be given to immediately reverse warfarin. Finally, the supratherapeutic INR in an asymptomatic patient can be treated with small doses of oral vitamin K (5-10 mg) using established algorithms.1 The goal is to lower the INR to the therapeutic range without fully reversing warfarin's effects. This can be achieved with small doses of PO or IV vitamin K. In emergent situations, rFVIIa and prothrombin concentrates have been administered for immediate reversal of anticoagulant effect.2 For example, recombinant factor VIIa is indicated for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage in patients with Glasgow Coma Score > 8 (non-comatose).3 In addition, recombinant factor VIIa and Prothrombin Complex Concentrates may be used in other life-threatening hemorrhages, although the optimal dose to correct a hemorrhage diathesis in these situations is less well defined.4 For excellent discussions of this topic, the reader is referred to the articles cited by Ansell and Schulman in Chest and Transfusion Medicine Reviews, respectively.

The rapidly acting anticoagulants include antithrombin-dependent agents and direct thrombin inhibitors (DTIs). Their indications are summarized in Table 1, and safety concerns in Table 2. The antithrombin-dependent anticoagulants include unfractionated heparin (UFH), which usually is derived from animal sources, e.g., porcine intestine or bovine lung, and low-molecular-weight heparins (LMWHs), which are prepared from UFH by enzymatic or chemical processes. These drugs act indirectly via interaction with the cofactor antithrombin, which in turn predominantly inactivates factors IIa (thrombin) and Xa, but also factors IXa, XIa, and XIIa. (See Figure 1.) Compared with UFH, LMWHs have a greater antifactor Xa-to-antifactor IIa activity ratio and superior dose-response relationships. LMWHs available in the United States as of November 2006 are enoxaparin, dalteparin, and tinzaparin. Another antithrombin-dependent anticoagulant is fondaparinux, a synthetic pentasaccharide modeled after the antithrombin-binding region of heparin. Via its interaction with antithrombin, fondaparinux selectively inhibits factor Xa. Unlike heparins or fondaparinux, DTIs bind the thrombin active site and exert their anticoagulant effects without need of a cofactor. There are three DTIs currently available in the United States: lepirudin, a recombinant hirudin protein; argatroban, a small molecule derived from L-arginine; and bivalirudin, a polypeptide with sequence homology to hirudin. Rapid-onset anticoagulants currently in advanced development include the factor Xa inhibitors rivaroxaban (oral) and idraparinux (parenteral), and the oral DTI dabigatran.

Antiplatelet Agents. Antiplatelet drugs decrease platelet aggregation and thereby inhibit thrombus formation. Table 3 summarizes their indications and safety concerns. These agents include aspirin (and other cyclooxygenase inhibitors), dipyridamole, thienopyridines, and glycoprotein (GP) IIb/IIIa receptor antagonists. Aspirin blocks thromboxane A2-mediated platelet aggregation and vasoconstriction. Dipyridamole (Persantine) inhibits phosphodiesterase and adenosine uptake in platelets, leading to increased intraplatelet levels of cyclic adenosine monophosphate, a platelet inhibitor. The thienopyridines, ticlopidine (Ticlid) and clopidogrel (Plavix) inhibit adenosine diphosphate (ADP)-mediated platelet aggregation. (Another ADP receptor antagonist, prasugrel, is currently in advanced development.) Administered intravenously, the GPIIb/IIIa receptor antagonists include abciximab (ReoPro, a monoclonal antibody), eptifibatide (Integrilin, a synthetic peptide), and tirofiban (Aggrastat, a nonpeptide derivative of tyrosine). Each blocks the binding of fibrinogen, von Willebrand factor, and other adhesive molecules to GPIIb/IIIa, hence inhibiting platelet-platelet interactions and aggregation.

Thrombolytic Agents. Thrombolytic drugs(also known as fibrinolytic drugs) activate plasminogen to plasmin, which in turn cleaves fibrin (and fibrinogen) and hence dissolves thromboses. Thrombolytics available in the United States include streptokinase (Streptase), urokinase (Abbokinase), anistreplase (Eminase), alteplase (Activase), reteplase (Retavase), and tenecteplase (TNKase). Urokinase and streptokinase, enzymes isolated from human kidney cells and streptococcus respectively, activate plasminogen systemically throughout the entire circulating blood volume. Anistreplase is a complex of streptokinase and plasminogen in which the catalytic region is temporarily blocked by a chemical moiety that is removed hydrolytically in the blood. When unblocked, the complex activates both circulating and clot-bound plasminogen. Alteplase, a recombinant tissue plasminogen activator, primarily activates clot-bound plasminogen with limited systemic proteolysis. Reteplase and tenecteplase are modified, recombinant tissue plasminogen activators. Their indications and complications are summarized in Table 3.

Contraindications and Dosing Issues. Decision-making concerning the choice of an antithrombotic agent should include factors such as its efficacy and safety profile, including contraindications and warnings, in the intended use; availability, if needed, of methods for monitoring; and the patient's status including age, weight, and renal and hepatic function. Pharmacologic agents are contraindicated in patients with hypersensitivity to the drug or components of the drug product. Additional contraindications, safety concerns, and dosing issues are subsequently discussed separately for the anticoagulant (see Table 2), antiplatelet, and thrombolytic agents. (See Table 3.)

The potential for drug interactions (pharmacodynamic or pharmacokinetic) should be recognized when making pharmacologic decisions. The combination use of any drugs affecting hemostasis, i.e., anticoagulants, antiplatelets, or thrombolytics, potentiates the risk of bleeding, and this risk should be weighed carefully against the benefit of the treatment. Certain combination therapies are routinely used however, such as GPIIb/IIIa receptor inhibition with concurrent aspirin and heparin in patients undergoing PCI, and recombinant TPA agents with concurrent aspirin and heparin in patients with AMI. Warfarin and the DTIs exert a combined effect on the PT/INR. Previously established relationships between INR and bleeding risk are altered during combination therapy with warfarin and argatroban. INRs greater than 5 without bleeding are common during argatroban-warfarin cotherapy and argatroban monotherapy.8 Pharmacokinetic interactions occur between warfarin and a variety of medications, botanicals, and foods, with effects mainly attributed to liver enzyme induction or inhibition or altered plasma protein binding; careful monitoring is important. The thienopyridines are metabolized extensively in the liver, and the dose of other hepatically metabolized drugs may require adjustments when starting or stopping ticlopidine or clopidogrel. (See Table 4.)

Table 4. Warfarin Therapy: Monitoring and Potential Effectors of Activity

Anticoagulants. The rapidly acting anticoagulants are administered intravenously (UFH, DTIs) or subcutaneously (UFH, LMWHs, fondaparinux) and are not to be given intramuscularly. UFH, LMWHs, and fondaparinux should not be used interchangeably (unit for unit) with one another. The rapidly acting anticoagulants are contraindicated in patients with active major bleeding and should be used with extreme caution in patients at increased risk of hemorrhage, e.g., bacterial endocarditis; congenital or acquired bleeding disorders such as hemophilia; active ulcerative and angiodysplastic gastrointestinal disease; hemorrhagic stroke and intracranial neoplasms; severe uncontrolled hypertension; immediately following lumbar puncture; spinal anesthesia; major surgery, especially involving the brain, spine, or eye; or in patients treated concomitantly with platelet inhibitors. Because of bleeding risk, tinzaparin is contraindicated in patients undergoing regional anesthesia who have unstable angina or myocardial infarction. The antithrombin-dependent anticoagulants have labeled contraindications or warnings against use in patients with current or previous heparin-induced thrombocytopenia (LMWHs), severe thrombocytopenia (UFH), or thrombocytopenia associated with a positive in vitro test for antiplatelet antibodies in the presence of drug (enoxaparin, dalteparin, fondaparinux).

UFH should be monitored routinely using the aPTT (or ACT for higher doses), with doses adjusted as needed to achieve target levels of anticoagulation. Bleeding risk with UFH appears to increase with the heparin dosage and patient age older than 70 years.9 The American College of Chest Physicians (ACCP) recommends UFH over LMWH for full therapeutic anticoagulation in patients with severe renal failure (creatinine clearance less than 30 mL/min).9 When enoxaparin is used for thromboprophylaxis (or treatment), a dose reduction is required in severe renal failure. Antifactor Xa monitoring is considered prudent for monitoring weight-based doses of LMWH in patients weighing more than 150 kg9 and can be used whenever deemed important, such as if severe renal impairment or bleeding develops.

Fondaparinux is contraindicated in severe renal impairment (creatinine clearance less than 30 mL/min) and should be used with caution in moderate renal impairment (creatinine clearance 30-50 mL/min). Renal function should be checked periodically. Fondaparinux also is contraindicated for thromboprophylaxis (but not VTE therapy) in patients weighing less than 50 kg.

DTIs should be monitored, with doses adjusted as needed, using the aPTT or for higher levels of anticoagulation, the ACT. Bivalirudin requires reduced doses in severe renal impairment. Relative overdose can also occur with standard dosing of lepirudin in renal impairment. Depending on the degree of renal dysfunction, lepirudin dosing should be reduced (creatinine clearance 15-60 mL/min) or avoided (creatinine clearance less than 15 mL/min). Argatroban, which is predominantly hepatically metabolized, requires dose reduction in hepatic impairment assessed as a Child-Pugh score greater than 6 or serum total bilirubin greater than 1.5 mg/dL.10

Antiplatelets. Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug products and in patients with the syndrome of asthma, rhinitis, and nasal polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm, and should not be used in children or teenagers for viral infection because of the risk of Reye's syndrome. Aspirin should be avoided during the third trimester of pregnancy and in patients with severe renal failure (glomerular filtration rate < 10 mL/min), severe hepatic dysfunction, or active peptic ulcer disease. Patients with a history of alcohol abuse or with inherited or acquired bleeding disorders have an increased risk of bleeding while taking aspirin. Aspirin-induced gastrointestinal toxicity appears to be dose-dependent.11

Dipyridamole should be used with caution in patients with severe coronary artery disease or hypotension.

The thienopyridines are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. Ticlopidine, but not clopidogrel, is also contraindicated in patients with hematopoietic disorders such as neutropenia, thrombocytopenia, or history of thrombotic thrombocytopenia purpura or aplastic anemia; severe liver impairment; or a hemostatic disorder. Reduced doses of ticlopidine may be needed in patients with renal impairment. Clopidogrel should be used with caution in patients at increased risk of bleeding from trauma, surgery, or other conditions and in patients with severe hepatic disease or severe renal impairment.

Because of an increased risk of bleeding, GPIIb/IIIa receptor inhibitors are contraindicated in patients with active internal bleeding or a recent history of bleeding diathesis; recent stroke or history of hemorrhagic stroke; recent major surgery or trauma; and severe, uncontrolled hypertension. Other labeled contraindications include history of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm (tirofiban, abciximab); concomitant use of another parenteral GPIIb/IIIa inhibitor (tirofiban, eptifibatide) or dextran (abciximab); history of thrombocytopenia following prior exposure to the drug (tirofiban); history, symptoms, or findings suggestive of aortic dissection (tirofiban); acute pericarditis (tirofiban); vasculitis (abciximab); recent, clinically significant gastrointestinal or genitourinary bleeding (abciximab); and oral anticoagulant use with 7 days, unless the prothrombin time is less than or equal to 1.2 times control (abciximab). GPIIb/IIIa inhibitors are either contraindicated (abciximab) or should be used with caution (tirofiban, eptifibatide) in patients with a platelet count less than 100-150 x 109/L, and each should be used with caution in conjunction with other drugs that affect hemostasis. Patients should be monitored for potential bleeding.

Eptifibatide is contraindicated in patients dependent on renal dialysis, and its dose should be reduced in patients with creatinine clearance less than 50 mL/min. Tirofiban should be used with caution in patients on chronic hemodialysis, and its dose should be reduced in severe renal insufficiency (creatinine clearance less than 30 mL/min). Redosing abciximab should be done with caution due to its long half life.

Thrombolytics. Because the use of thrombolytic drugs increases the risk of bleeding, their contraindications include active internal bleeding; recent cerebrovascular accident; recent intracranial or intraspinal injury or trauma; intracranial neoplasm, arteriovenous malformation, or aneurysm; known bleeding diatheses; and severe, uncontrolled hypertension.

Alteplase is further contraindicated for treating acute ischemic stroke if the patient has evidence of intracranial hemorrhage on pretreatment evaluation; suspicion of subarachnoid hemorrhage on pretreatment evaluation; recent intracranial or intraspinal surgery, serious head trauma, or previous stroke; history of intracranial hemorrhage; uncontrolled hypertension at the time of treatment; or seizure at the onset of stroke. Treatment is not recommended if stroke symptom onset was greater than 3 hours earlier or if the patient has minor neurologic deficit or rapidly improving symptoms.12

The increased risk of bleeding associated with thrombolysis should be weighed carefully against the potential benefits in patients with recent major surgery, obstetrical delivery, organ biopsy, previous puncture of noncompressible vessels; recent trauma; recent serious gastrointestinal or genitourinary bleeding; high likelihood of left heart thrombus; subacute bacterial endocarditis; acute pericarditis; hemostatic defects including those secondary to severe hepatic or renal disease; pregnancy; cerebrovascular disease; diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions; severe hepatic disease; septic thrombophlebitis or occluded arteriovenous cannula at a seriously infected site; advanced age; concurrent use of warfarin; recent GPIIb/IIIa inhibitor administration; and any other condition in which bleeding constitutes a significant hazard or would be particularly difficult to manage because of its location. Careful monitoring for bleeding is recommended in any treated patient.

Complications Associated with Antithrombotic Therapies in the ED

Bleeding. The primary complication of antithrombotic therapies is bleeding, with major, life-threatening events such as intracranial hemorrhage possible.9 Bleeding can occur from any site and should be considered if an unexpected fall in hemoglobin or blood pressure or other unexplained symptoms occur. To minimize bleeding during thrombolytic therapy, intramuscular injections should be avoided, and venipunctures should be performed carefully and as infrequently as possible. If arterial puncture is required, compressible vessels of the upper extremity are preferable, with at least 30 minutes of pressure after the puncture and careful monitoring.

When administration of an anticoagulant, antiplatelet, or thrombolytic agent is complicated by severe or life-threatening hemorrhage, the agent should be immediately discontinued, and the patient should be provided symptomatic and supportive therapy. In addition, the agent should be acutely reversed through general and specific means, when possible. Protamine sulfate can be administered to help reverse bleeding associated with UFH and LMWHs, if needed, although protamine does not fully neutralize antifactor Xa activity and carries a risk of anaphylactoid reactions. The DTIs and fondaparinux lack antidotes. Because the DTIs are eliminated relatively rapidly (half-life of 1.7 h for lepirudin, 39-51 minutes for argatroban, and 36 minutes for bivalirudin), their anticoagulant effects usually are reversed completely, returning to baseline within a few hours of discontinuing infusion. However, elimination may take much longer if renal impairment (lepirudin, bivalirudin) or hepatic impairment (argatroban) is present.13 Recombinant factor VIIa has been used clinically to reverse the effects of warfarin, and may be useful for the immediate reversal of rapid-onset anticoagulant effects. Recombinant factor VIIa has been shown to reverse the effects of fondaparinux in healthy volunteers.14 In patients receiving abciximab who experience serious bleeding, platelet function may be restored in part with platelet transfusions. If needed, tirofiban can be removed by hemodialysis. If spontaneous bleeding uncontrolled by pressure occurs in a patient receiving thrombolysis, the thrombolytic agent and any concomitant anticoagulant should be stopped immediately, and reversal of the bleeding tendency can be managed by administering whole blood, packed red cells, and cryoprecipitate or fresh frozen plasma.

Evidence-based, comparative information regarding hemorrhagic complications of anticoagulant treatment is available from the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.9 In treatment of acute VTE, the bleeding risk with intravenous UFH is less than 3%, there is less major bleeding with LMWH than UFH, and the bleeding risk is similar with fondaparinux vs. LMWH or heparin. There is an increased risk of major bleeding and intracranial bleeding with short-term, therapeutic-dose LMWH or UFH in ischemic stroke. In ischemic coronary syndromes, UFH and LMWH are not associated with increased major bleeding, although extended treatment with LMWH is associated with increased bleeding. A more recent study5 in acute coronary syndromes found that major bleeding is reduced with fondaparinux versus the LMWH enoxaparin. Table 5 summarizes various strategies that have been used for reversing the effects of anticoagulants, antiplatelets, and thrombolytic agents.

Neuraxial Hematoma and Spinal Puncture. Epidural or spinal hematoma is a rare, devastating complication of neuraxial anesthesia that may cause neurologic injury resulting in long-term or permanent paralysis and that often is associated with anticoagulation. The estimated incidence of spinal hematoma is less than 1 in 150,000 epidurals and less than 1 in 220,000 spinal anesthetics.15 Reports of 43 cases of neuraxial hematoma associated with enoxaparin use between 1993 and 1998 resulted in a class-effect, "black box" warning for LMWHs and danaparoid (a heparinoid no longer available in the United States).16 In addition, dalteparin is contraindicated due to increased bleeding risk in patients undergoing regional anesthesia who have unstable angina or myocardial infarction. Risk factors for neuraxial hematoma with heparins include the use of indwelling epidural catheters; concomitant use of additional drugs affecting hemostasis such as nonsteroidal anti-inflammatory drugs, platelet inhibitors, or other anticoagulants; traumatic or repeated epidural or spinal puncture; immediate preoperative (or intraoperative) or early postoperative LMWH administration; female gender; and increased age.15,16 In the only published report of neuraxial hematoma associated with fondaparinux, which has a similar black box warning, the event occurred after multiple unsuccessful attempts to place an epidural catheter in a patient receiving a supratherapeutic dose.17 There have been no reports of neuraxial hematoma in patients administered a DTI.

In patients anticoagulated or scheduled to be anticoagulated for thromboprophylaxis, physicians should consider the benefits vs. risks before neuraxial anesthesia or spinal puncture. Guidelines from the American Society of Regional Anesthesia and Pain Medicine for minimizing risk associated with neuraxial anesthesia are published.15 Patients should be monitored for neurologic impairment, with prompt intervention critical if neurologic compromise is noted.

Heparin-Induced Thrombocytopenia (HIT). During anticoagulation, thrombocytopenia of any degree should be monitored closely. HIT is an immune-mediated prothrombotic disorder associated with an unexplained 50% drop in the platelet count, often to less than 150 x 109/L, that occurs in approximately 1-5% of patients administered UFH and less than 1% administered LMWH for at least 5 days. Approximately 38-76% of affected patients will develop thrombosis, approximately 10% with thrombosis will require a limb amputation, and approximately 20-30% will die within a month.13 For prompt recognition of HIT, the American College of Chest Physicians18 recommends routine platelet count monitoring in most heparin-treated patients, including a pretreatment assessment particularly if there is recent (within 100 days) or uncertain history of heparin exposure. HIT also should be considered if a currently or recently heparin-treated patient or a recently hospitalized (and presumably recently heparin-treated) patient presents with thrombosis—an estimated 1 in 8 UFH-treated patients with new or recurrent venous thromboembolism has HIT.19

When HIT is strongly suspected, heparins should be stopped and rapid-onset, nonheparin anticoagulation should be initiated.20,21 Heparins should continue to be avoided, if possible, at least while HIT antibodies persist (a minimum of 90 days), and the British Committee for Standards in Haematology21 recommends using a heparin alternative for most patients with previous HIT who require anticoagulation. DTIs do not cause thrombocytopenia, do not induce or cross-react with HIT antibodies, and are indicated for use in patients with HIT (argatroban) or HIT with thrombosis (argatroban, lepirudin), and in patients with or at risk of HIT undergoing percutaneous coronary intervention (argatroban, bivalirudin). It has been suggested that fondaparinux, which exhibits negligible crossreactivity with HIT antibodies, may be useful for managing VTE in the context of recent heparin exposure and suspected, but not yet confirmed, HIT.20

Other Complications and Safety Concerns. Anticoagulation. The use of enoxaparin for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied, and frequent monitoring of antifactor Xa activity, with dose adjustment, may be needed. There is an increased risk of thrombosis, sometimes fatal, when bivalirudin is used with gamma brachytherapy. Lepirudin frequently induces formation of antihirudin antibodies that may increase plasma lepirudin concentrations, requiring careful monitoring and dose adjustments to avoid bleeding, and approximately 0.2% of patients reexposed to lepirudin experience anaphylactoid reactions, including possible death.13

Antiplatelets. Ticlopidine may induce serious, life-threatening hematologic disorders, including thrombotic thrombocytopenia purpura and aplastic anemia, requiring prompt treatment. Severe neutropenia has been reported in 1-3% of ticlopidine-treated patients. Clopidogrel, which has a better safety profile than ticlopidine regarding bone marrow toxicity, has wide patient variability in inhibition of platelet function, with "nonresponders" and "clopidogrel resistance" described.11 Thrombocytopenia, sometimes severe, may occur during abciximab treatment, usually within the first day. Readministration of abciximab, particularly within a month, is associated with an increased incidence and severity of thrombocytopenia and therefore should be undertaken only with caution. Affected patients should have abciximab stopped immediately.

Thrombolytics. Cholesterol embolization, sometimes fatal, rarely occurs in patients treated with thrombolytics. Coronary thrombolysis may result in arrhythmias associated with reperfusion. Anistreplase should not be used in a patient with a previous severe allergic reaction to streptokinase. Hypotension, sometimes severe and not secondary to bleeding or anaphylaxis, occurs in approximately 1-10% of patients treated with streptokinase. Anaphylaxis and other infusion reactions may occur within an hour of initiation of urokinase. Patients affected by allergic or anaphylactic conditions should be monitored closely and administered appropriate therapy.

Today, emergency physicians must be aware of the use and contraindications for a wide variety of anticoagulation medications. Clearly, the ideal anticoagulant for all patients has not been found. Not all anticoagulants are the same, and physicians must remember that each has a different profile of use, safety, and warnings.

References

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