Michael Ganetsky
The antithrombotics have multiple life-saving indications and life-threatening complications. In acute coronary syndromes (ACS), venous thromboembolism, and acute ischemic stroke both treatment and prevention, the antithrombotics save lives. Patients may present to the ED with life-threatening complications related to outpatient use or develop iatrogenic complications while receiving antithrombotic therapy as part of ED care. Emergency physicians must understand the basic mechanisms, indications, and complications of antithrombotic therapy. This chapter provides a practical review of the complications of common antithrombotic therapy including the antiplatelet, anticoagulant, and fibrinolytic agents.
ANTIPLATELET AGENTS
Aspirin
Originally discovered by Hoffman in the late 1800s, aspirin remains the most effective, safest, and least expensive of all antithrombotic drugs. At doses as low as 75 mg, aspirin irreversibly blocks platelet synthesis of thromboxane A2, a potent inducer of platelet aggregation and vasoconstriction (1). Aspirin is commonly prescribed for the prevention and management of cerebrovascular and coronary artery disease and for the prevention of stroke in low-risk patients with atrial fibrillation or with contraindications to anticoagulant therapy. Other indications include the treatment of pain, rheumatic fever, pre-eclampsia, and Kawasaki disease. Nonenteric-coated aspirin is rapidly absorbed in the stomach and inhibits platelet function within 1 hour versus 3 to 4 hours for enteric-coated. Antithrombotic effects last the 10-day life span of the individual platelet with 50% replacement of the platelet pool within 5 days (1). Given the significant benefit in ACS, occult gastrointestinal (GI) bleeding requires close monitoring but is not an absolute contraindication to aspirin therapy.
ADP Inhibitors
The thienopyridines, ticlopidine, clopidogrel, ticagrelor, and prasugrel selectively inhibit adenosine diphosphate (ADP)-induced platelet aggregation. Delayed onsets and significant side effects, such as thrombotic thrombocytopenic purpura and neutropenia, have limited the use of ticlopidine. FDA indications for clopidogrel include unstable angina, non-ST segment elevation myocardial infarction (NSTEMI), ACS with aspirin intolerance, and reduction of secondary atherosclerotic events in patients with recent MI, recent stroke, or peripheral vascular disease. Clopidogrel is commonly prescribed after stent placement with aspirin in the prevention of atherosclerotic disease (2). Prasugrel was approved by the FDA in 2009 and ticagrelor approved in 2011 as alternatives to clopidogrel for patients undergoing percutaneous coronary intervention (PCI) for ACS.
Glycoprotein IIb/IIIa Receptor Inhibitors
Studies of a rare bleeding disorder, Glanzmann thromboasthenia, led to the discovery of the glycoprotein IIb/IIIa receptor. Fibrinogen binding to the IIb/IIIa receptor is the “final common pathway” of platelet activation and aggregation. Several glycoprotein IIb/IIIa receptor inhibitors (GPI) have been developed within three broad categories; abciximab (ReoPro) is a monoclonal antibody, eptifibatide (Integrilin) is a synthetic peptide, and tirofiban (Aggrastat) is a nonsynthetic peptide. GPIs have been extensively studied and proven to be beneficial in patients with unstable angina or NSTEMI undergoing PCI (3). Use in low-risk patients with unstable angina who are not undergoing PCI is not recommended. However, in high-risk patients in whom PCI is not possible, GPIs, specifically eptifibatide or tirofiban, may be considered in consultation with the admitting cardiologist.
ANTICOAGULANTS
Heparin
Heparin, derived from the Latin “hepar,” meaning liver, was first discovered by McLean in 1916 from a liver extract. By inducing a conformational change in antithrombin III (ATIII), heparin produces a very rapid inhibition of thrombin (4). This complex inactivates several enzymes of the coagulation cascade’s intrinsic system including IXa, XIa, and XIIa and highly sensitive enzymes of the common pathway Xa and IIa (thrombin). In addition, heparin inhibits platelet function and binds to endothelial cells. In contrast to fibrinolytics, heparin has no effect on clot already present but prevents new clot formation and existing clot propagation. Intravenous heparin is indicated in the ED for acute deep venous thrombosis (DVT), pulmonary embolism (PE), atrial fibrillation, and ACS. In hospitalized patients, intravenous heparin is used for those undergoing cardiac bypass, vascular surgery, or coronary angioplasty and for select patients with disseminated intravascular coagulopathy (DIC) (4). In contrast to warfarin, both heparin and low-molecular-weight heparin (LMWH) are safe to use in pregnancy as neither crosses the placenta.
Low–Molecular-Weight Heparins and Pentasaccharides
In the 1970s, work to improve heparin’s anticoagulant effect while minimizing hemorrhagic side effects led to the depolymerization of heparin into fragments approximately one-third the size producing the LMWHs. Most unfractionated heparin molecules have the required long saccharide units needed to form a tertiary complex with ATIII and thrombin compared to only 25% of LMWH molecules (4). In addition, LMWH has less of an effect on platelet function and vascular permeability, theoretically further reducing hemorrhagic complications. Clinical effects of these differences are summarized in Table 198.1.
TABLE 198.1
Clinically Significant Differences of Heparin and LMWH
Multiple studies have compared LMWH to heparin in the management of ACS, DVT, and PE and have found it to be safe and effective (4). Outpatient enoxaparin has been shown to be safe, efficacious, and cost-effective when compared with inpatient heparin in the management of DVT (5). Enoxaparin is renally cleared and studies have shown that patients with a creatinine clearance less than 30 mL/min treated with standard dosing (1 mg/kg bid) have an increased risk of major bleeding; empirical dose reduction of 50% (1 mg/kg qd) reduces this risk (4).
The FDA has approved several LMWHs, each with unique pharmacokinetic profiles resulting from different depolymerization techniques that prevent easy interchangeable use. Current FDA indications include acute management of DVT with or without PE with enoxaparin, outpatient DVT with enoxaparin, postsurgical DVT prophylaxis with enoxaparin or dalteparin, and unstable angina and NSTEMI with enoxaparin or dalteparin.
The minimum heparin fragment necessary for ATIII binding has been demonstrated to be a pentasaccharide; this led to the development of fondaparinux, a synthetic analog of the heparin ATIII-binding pentasaccharide. Similar to enoxaparin, it is administered subcutaneously and can be used for treatment of DVT, PE, and ACS (4).
Warfarin
In 1941, Link isolated dicumarol from moldy sweet clover that was later developed and marketed as a rat poison by the Wisconsin Alumni Research Foundation. Coumadin, the brand name of sodium warfarin, is the most commonly prescribed oral anticoagulant. Warfarin inhibits regeneration of the vitamin K cofactor required for hepatic carboxylation of factors II, VII, IX, and X and the anticoagulant proteins C and S. The coagulation cascade’s extrinsic system and common pathway are thereby blocked. The relatively short half-life of the anticoagulant Protein C (6 to 8 hours) compared to the four coagulation factors (6 to 60 hours) results in an iatrogenic hypercoagulable state for 24 to 36 hours, necessitating anticoagulation with heparin or LMWH as a bridge while beginning therapy with warfarin (6). In addition to this hypercoagulable state, physicians must be aware of the dissociation of laboratory response and the clinical response to warfarin. Reduction in factor VII (half-life 6 hours) results in an increased international normalized ratio (INR) within 24 to 36 hours. However, a reduction in thrombin levels (half-life 60 hours) and hence a reduction in significant clot formation does not occur until the fifth day of warfarin therapy, necessitating continued effective anticoagulation with IV heparin or LMWH therapy during the initial 5 days of management of acute thrombosis (6).
Warfarin is most commonly indicated for the management of venous thromboembolism and prevention of embolism with prosthetic heart valves or atrial fibrillation. Warfarin is completely absorbed from the GI tract, achieving peak levels within 4 hours with a mean effective half-life of 40 hours. Adjustments in warfarin dosing are made based on the INR, a standardized measurement of prothrombin time (PT) that corrects for differing laboratory reagents. The typical therapeutic range is 2 to 3 for most indications with the exception of mechanical valves requiring a higher INR of 2.5 to 3.5. Frequent monitoring is necessary to determine the ideal dose in each patient as many factors such as age, use of other medications, diet, comorbidities, and even race may affect patient response. Table 198.2 provides a brief listing of factors that may increase or decrease the response to warfarin. Warfarin crosses the placenta and may cause multiple birth defects and spontaneous abortions, so it is categorized as class X in pregnancy.
TABLE 198.2
Factors that may Increase or Decrease INR/PT Response to WARFARIN
Direct Thrombin Inhibitors
Leeches were first used in the middle ages to rid the body of “black humors.” Derived from a salivary extract of the leech Hirudo medicinalis, hirudin tightly binds to and inactivates thrombin. Currently used direct thrombin inhibitors (DTIs) include bivalirudin, argatroban, and dabigatran. DTIs inhibit both free and clot-bound thrombin and reduce platelet aggregating effects of thrombin. Dabigatran, an orally administered DTI, was approved by the FDA in 2010 for stroke prevention in patients with nonvalvular atrial fibrillation. Dabigatran has several advantages over warfarin: It has very few drug–drug and drug–food interactions and has a stable hematologic response thus not requiring frequent laboratory monitoring. Dabigatran has a fairly short duration of action (elimination half-life of 12 to 17 hours), is predominately renally cleared, and a large portion can be removed via hemodialysis. In trials comparing dabigatran to warfarin, rates of major bleeding episodes tend to be similar, while dabigatran tends to cause less intracranial hemorrhages (ICHs) (7). Argatroban and bivalirudin are intravenous DTIs used in patients with ACS undergoing PCI or who have thrombotic complications and are at risk for or have confirmed heparin-induced thrombocytopenia (HIT) syndrome.
Factor Xa Inhibitors
Two orally administered direct factor Xa inhibitors have received recent FDA approval: rivaroxban in 2011 for stroke prophylaxis in patients with nonvalvular atrial fibrillation and in 2012 for treatment of DVT and PE; apixaban in 2012 for stroke prophylaxis in patients with nonvalvular atrial fibrillation. These factor Xa inhibitors are reversible and highly selective; they inhibit free and clot-bound factor Xa and prothrombinase activity without direct effect on platelet aggregation. Rivaroxaban has a short elimination half-life of 7 to 13 hours but factor Xa activity does not normalize for 24 hours after a dose. It is largely hepatically metabolized while one-third is renally excreted unchanged. Rivaroxaban has a predictable, dose-dependent anticoagulation effect; so routine monitoring of anticoagulation markers is not recommended. In clinical trials, bleeding rates are similar between rivaroxaban and enoxaparin (7).
Fibrinolytics
Streptokinase (SK) was the first fibrinolytic agent to be discovered by Tillett and Garner in 1932. The first use of fibrinolytics for reperfusion in acute MI was not reported until 1958 (8). Today’s many different agents have one common mechanism: the conversion of plasminogen to plasmin, which then degrades fibrin and hence thrombus. First-generation, less fibrin-specific agents include SK, anistreplase, and urokinase. Second-generation, more fibrin-specific agents include recombinant tissue plasminogen activator (TPA; alteplase) and several mutants of TPA including reteplase and tenecteplase (TNK-TPA).
SK is a purified preparation of a bacterial protein of group C β-hemolytic streptococci. SK binds to plasminogen, forming an activator complex that activates both fibrin-bound plasminogen and free circulating plasminogen producing localized thrombus breakdown and a generalized “systemic lytic state.” Anistreplase is a modified SK molecule with a longer half-life (100 minutes) allowing for single-bolus dosing. IV or SQ heparin therapy is typically delayed 4 hours after SK and anistreplase to reduce bleeding complications.
Vascular endothelial cells produce TPA. Alteplase is a commercially produced recombinant TPA molecule. Alteplase has several advantages compared to SK, including increased fibrin specificity, resulting in less systemic fibrinolysis; a lower rate of allergic reactions; and an ability to lyse more highly linked fibrin clots, theoretically resulting in increased effectiveness in patients with prolonged symptoms. Reteplase is a deletion mutation of TPA with less fibrin specificity but a longer serum half-life of 18 minutes (vs. 5 minutes for recombinant TPA) allowing for bolus administration. No antigenicity has been reported with reteplase. Tenecteplase (TNK) is a triple substitution variant mutant of TPA with improved fibrin specificity and a longer half-life, again allowing bolus administration. Mortality benefits have not been demonstrated, but a significant reduction in bleeding with TNK compared to TPA was demonstrated in one study (8). Current indications for thrombolytic therapy includes ST-elevation MI (STEMI), acute ischemic stroke, and PE with signs of hemodynamic instability.
CLINICAL PRESENTATION
Patients with complications related to antithrombotic therapy may present to the ED in many different ways. Presentations may be occult, or dramatic, reported by the patient, or detected only during a meticulous history, physical examination, and workup. Regardless of the presentation, a high index of suspicion is necessary to rule out life threats in the patient on antithrombotic therapy.
GI bleeding is the major complication of aspirin therapy. Patients taking antiplatelet agents such as aspirin or clopidogrel may present with occult or massive GI bleeds. Although risk of bleeding is dose-dependent, bleeding may occur even with low-dose therapy.
Warfarin has been a main-stay of oral anticoagulant therapy for decades. Up to 15% of patients will suffer bleeding complications each year, 4.9% major bleeding complications, and up to 0.8% fatal, most commonly ICH (9). The risk of bleeding is directly related to the INR, increasing above 4, and is inversely related to the amount of time spent in the therapeutic range. Risk factors for bleeding include age greater than 75, past GI bleeding, hypertension, cerebrovascular disease, severe heart disease, renal insufficiency, alcoholism, known malignancy, and occult GI and genitourinary malignancies (10). Recent changes in drug doses, diet, and addition or discontinuation of other drugs may interact with warfarin, as described in Table 198.2.
Several types of skin lesions may result from anticoagulation therapy. The classic lesions of warfarin skin necrosis begin on the third to eighth day of therapy, resulting from capillary thrombosis in subcutaneous fat. Commonly associated with protein C deficiency, skin necrosis may also occur with protein S deficiency and in patients with normal levels. Unique skin lesions may occur with heparin and less commonly LMWH. An urticarial rash secondary to local histamine release is becoming less common owing to improved heparin purification techniques. Well-circumscribed plaques may occur at injection sites up to 20 days later, typically in obese or pregnant women. Heparin skin necrosis may occur within 1 day but typically at 1 week after starting therapy, often in patients without prior heparin exposure. The lesions start as an erythematous plaque before becoming hemorrhagic, necrotic, and often pruritic and painful. Biopsy often reveals antibodies, and thrombocytopenia may occur as part of the HIT syndrome (11). Skin necrosis with LMWH typically occurs in patients with prior heparin exposure, often without thrombocytopenia, and with fewer thrombotic complications.
In the ED, patients treated with antithrombotic medications require frequent re-evaluation. Minor bleeding, such as bleeding from puncture sites, or life-threatening GI or ICH must be detected and treated early to minimize further harm. For IV heparin, the risk of bleeding is <6% (10). Bleeding risk with heparin is directly related to dose and patient response as indirectly measured by the activated partial thromboplastin time (APTT). Dose adjustments based on every-6-hour APTT have been the traditional method of reducing hemorrhagic complications, but bleeding can occur even within the therapeutic range. Risk factors for bleeding complications include recent surgery or trauma, renal failure, aspirin use, GPIs, fibrinolytics, and age older than 70 years. LMWH has been associated with more bleeding complications after subcutaneous administration when compared with subcutaneous heparin and unusual bleeding episodes such as intrahepatic and psoas hematoma (11).
ED patients started on GPI or DTI may develop bleeding from vascular puncture sites, GI bleeding, or ICH, especially when treated with fibrinolytic therapy. Lower adjunctive heparin dose reduces the risk of bleeding with GPIs and fibrinolytics. Rates of life-threatening bleeding and intracranial bleeding for GPIs and DTIs are low as compared to fibrinolytics in ACS. Risk factors for bleeding from dabigatran include older age, baseline renal insufficiency, and acute kidney injury (7).
Patients started on fibrinolytic therapy in the ED may develop transient hypotension, mild-to-severe allergic reactions, and mild-to-life-threatening bleeding complications. In the absence of contraindications, risk factors for fibrinolytic-associated bleeding include older age, female gender, lower body weight, and hypertension.
ED EVALUATION
Many chief complaints are complicated by anticoagulation. The emergency physician should question the patient and family about the reason for anticoagulation, compliance with recent INR testing, other prescriptions, any potential recent medication adjustments, and over-the-counter and alternative medicines. Discussions with primary care physicians and medical record reviews often help fill in historical blanks. The ED physician should also question the family about subtle changes in mental status, recent “minor falls,” or bleeding. Changes in vital signs may be evidence of early hemorrhagic shock or ICH. Hypertension may be secondary to Cushing response in ICH. Examine carefully for pallor, contusions, abrasions, ecchymosis, and other skin lesions. Perform a rectal examination with any suspicion of bleeding and in any patient beginning anticoagulation in the ED.
In patients with complaints related to antithrombotic therapy, check hemoglobin, platelets, PTT, INR, and other tests as indicated. Patients with bleeding related to aspirin therapy may have normal platelet levels but functional platelet deficits. Medication noncompliance, medication changes, diet factors, and concurrent illness may affect the adequacy of anticoagulation, necessitating laboratory screening in the ED.
GPI therapy may have mild or dramatic effects on platelet levels. Mild thrombocytopenia occurs in 5% of patients that are treated. Severe thrombocytopenia (<50,000) occurs in 2% of patients receiving abciximab versus 1% of eptifibatide and tirofiban. Acute profound thrombocytopenia (<20,000) occurs within 24 hours of administration of abciximab in 0.7% of patients but is rarer with eptifibatide and tirofiban. Platelet counts must be checked daily in patients receiving GPI to detect this rare but life-threatening complication (12).
Similarly, heparin and LMWH may have mild or dramatic effects on platelets. An early nonimmune-mediated transient thrombocytopenia occurs in 25% of patients, resolving in the majority within 3 days despite ongoing treatment. HIT syndrome develops in up to 3% of patients, typically presenting 5 days after initial heparin exposure but earlier in patients with prior exposure. The clinicopathologic syndrome is characterized by HIT antibody formation accompanied by a fall in the platelet count of >50% or skin lesions at injection sites. A hypercoagulable state may result in producing both venous and arterial thrombosis and DIC. The HIT antigen is platelet factor IV conformationally modified by interaction with medium-chain heparin molecules accounting for the reduced incidence of HIT with low-molecular-weight shorter-chained heparins (11).
The DTIs and factor Xa inhibitors have various effects on coagulation parameters that impact on assessing degree of anticoagulation. Ecarin clotting time has a linear dose–response correlation with dabigatran; however it is not readily available. Thrombin clotting time is overly sensitive and the aPTT has a nonlinear response to dabigatran concentrations. Therefore, a normal thrombin clotting time or aPTT can be used to qualitatively exclude dabigatran-induced anticoagulation; however, when elevated, are not useful to determine degree of anticoagulation (7). The PT and HepTest are sensitive markers of the degree of anticoagulation with apixaban. For rivaroxaban, conventional PT/INR assays are not useful; anti-Factor Xa chromogenic assays or specialized PT assays with rivaroxaban calibrators are recommended and have recently become commercially available (13).
A low threshold for imaging of patients on antithrombotic therapy is required to detect occult but life-threatening bleeding. Even with minor mechanisms of blunt head trauma without loss of consciousness or blunt abdominal trauma without significant tenderness, head and abdominal computed tomography (CT) scans are recommended to diagnose occult life-threatening bleeding in patients on daily warfarin therapy (14,15).
For patients started on fibrinolytic therapy in the ED, repeat physical examinations are essential for the detection of bleeding. The majority of bleeding will occur at vascular puncture sites. Check laboratory values every 6 hours for 24 hours after therapy to detect occult blood loss. A fall in hemoglobin without an obvious source of blood loss necessitates a more diligent search. Repeat rectal examinations and a CT scan of the abdomen and pelvis may be necessary. Any change in mental status requires discontinuing therapy and an immediate head CT.
KEY TESTING
• CBC, serum chemistries (to assess for renal function)
• Type and screen/cross if transfusion of blood products is expected
• Routine coagulation studies (PT/PTT/INR)
• Focused coagulation studies and drug concentrations (i.e., thrombin time, bleeding time, ecarin clotting time, clotting factor concentrations, HepTest) are typically not routinely available nor are currently recommended to guide ED management
• Focused assessment of bleeding site (i.e., CT head, CT abdomen, GI consultation for endoscopy/colonoscopy)
ED MANAGEMENT
In the anticoagulated patient with bleeding, several factors must be considered. What is the severity of this bleeding episode? Is the bleeding into a closed space? Why is the patient on anticoagulation, and what is the risk of reversal? What other modalities such as endoscopy and proton pump inhibitors may be efficacious? If the risk of reversal is high (i.e., mechanical valve), can the patient be managed with just transfusions?
Patients with GI bleeding related to outpatient antiplatelet agents such as aspirin and clopidogrel require standard treatment including large-bore IV access, volume replacement and packed red blood cell replacement as indicated, proton pump inhibitor therapy, and specialty consultation for endoscopy. Despite normal levels, a functional platelet deficiency exists, requiring platelet transfusion of 5 to 10 U of random donor platelets to raise functional platelet levels by 50,000. Use of DDAVP (desmopressin), in addition to platelet transfusion, has been advocated for reversal of aspirin and clopidogrel. The standard dose is 0.3 to 0.4 μg/kg in 100 mL saline over 30 minutes (16). A summary of the management of bleeding complications from antithrombotic therapy is presented in Table 198.3.
TABLE 198.3
Management of Bleeding Complications Related to Antithrombotic Therapy
Rapid reversal of GPI blockade may be necessary in patients who need emergent coronary artery bypass grafting or develop significant bleeding. Abciximab is a long-acting receptor blocker with 50% receptor blockade and platelet inhibition at 24 hours. Fortunately, the plasma half-life of the drug is only 15 to 30 minutes. Discontinuation of infusion and platelet transfusion are effective in reversing abciximab. Eptifibatide and tirofiban are competitive dose-dependent receptor blockers with return of normal hemostasis after only 4 hours. Reversal of these two agents requires discontinuation of the drug and time for clearance. With renal failure, hemodialysis may be necessary. Platelet transfusion is of little use, as the high number of drug molecules will easily saturate new glycoprotein receptors on transfused platelets. Treatment of GPI thrombocytopenia includes discontinuation of the GPI and heparin and platelet transfusion (12).
Careful consideration must be given to the appropriate management of the anticoagulated patient even without bleeding. A subtherapeutic INR may require anticoagulation with heparin or LMWH while the warfarin dose is increased depending on the indication for warfarin. For the 50-year old with a mechanical valve who “ran out of warfarin a week ago” and now has an INR of 1, simply restarting warfarin may result in an iatrogenic hypercoagulable state and breakthrough thromboembolism. A supra-therapeutic INR may require little more than holding the next dose. Specific management depends on the degree of elevation, presence of bleeding, and the reason for anticoagulation. Methods to lower the INR include withholding or lowering the next dose, vitamin K (Phytonadione), and replacement products such as fresh-frozen plasma (FFP), prothrombin concentrate complex (PCC), or recombinant Factor VIIa (rFVIIa). The American College of Chest Physicians’ evidence-based guidelines for the asymptomatic patients with an elevated INR are included in Table 198.3 (17). Major bleeding has not been clearly defined in the literature but for practical purposes may be considered to be any life-threatening bleeding, bleeding into a closed space, or bleeding requiring transfusion or surgical intervention.
Vitamin K is not without risk. A classic concern is anaphylaxis, which may occur at any dose when given IV and IM; however, anaphylaxis is very rare with modern preparations of Vitamin K (16). Subcutaneous absorption is unpredictable. Intramuscular administration may result in hematoma formation. Complete correction of the INR may result in breakthrough thromboembolism. High-dose vitamin K risks prolonged warfarin resistance and may precipitate thromboembolism for up to 1 week. Of the three routes, oral administration is considered the safest and most predictable, with effects beginning in 6 to 10 hours. Oral vitamin K (1 mg) lowers an elevated INR between 4 and 10 in an asymptomatic patient more rapidly than 1 mg subcutaneously without an increased risk of thromboembolism (18). However, a randomized controlled trial did not find a difference in bleeding rates in nonbleeding patients with an INR between 4.5 and 10 treated with Vitamin K or placebo (19). Slow IV infusion over 10 minutes to prevent anaphylaxis is recommended only for life-threatening active bleeding with effects beginning in 1 to 2 hours. However, up to 24 hours may be needed for the full effects of Vitamin K, so doses typically need to be repeated and either FFP or PCC should be administered if immediate effects are desired. Vitamin K is not effective in advanced liver failure when coagulation factors are no longer synthesized.
The treatment of life-threatening bleeding related to warfarin requires administering vitamin K (10 mg) by slow IV infusion, along with factor replacement with FFP, PCC, or recombinant factor VIIa (rVIIa). Traditionally, 2 to 4 U of FFP are given for immediate control of bleeding; however, this may lead to volume overload, allergic reactions, and there is often a delay in thawing and delivering the blood products (13).
PCC provides a more rapid reversal of warfarin-associated coagulopathy than FFP and are recommended by many national guidelines (13). First used to treat hemophilia B, PCC is a fractionation product of FFP containing various amounts of factors II, VII, IX, and X. Long shelf-life and easy reconstitution into a highly concentrated volume (500 to 1,000 U/20 mL vs. 1 L of FFP per dose) allow for rapid and quick reversal without volume overload or infectious risk. Available PCCs include Bebulin VH, Profilnine, Octaplex, and Beriplex. However, until 2013 only 3-factor PCCs were available in the United States, which are less effective in reversing INR than the 4-factor concentrates. In 2013, the FDA approved Kcentra, a 4-factor concentrate marketed as Beriplex internationally for use in the United States. PCCs carry risk of thrombotic complications and DIC and are very expensive; therefore use should be limited to life-threatening bleeding (13). Also, outcome studies of PCC for ICH do not have control groups, so strength of evidence is mostly based on consensus. Emergency physicians should become familiar with their hospital’s availability of PCCs and guidelines for reversal of warfarin-associated bleeding as there is significant variability amongst institutions. rVIIA has also been shown to reverse INR value but not restore normal hemostasis in patients with warfarin-associated coagulopathy; therefore, PCCs or FFP are preferred agents (13).
Management of heparin-associated bleeding begins with stopping heparin therapy (half-life of 30 to 150 minutes for doses of 25 to 400 U/kg). With life-threatening bleeding, protamine may be used to reverse heparin anticoagulation in a dose of 1 mg/100 U of heparin administered in the previous 2 to 3 hours. As with vitamin K, there are risks associated with protamine administration. Hypotension, bradycardia, flushing, and fatal anaphylactic reactions have been reported. Dose is limited to 50 mg and must be given slowly over 10 minutes. As the duration from last treatment with heparin increases, heparin activity decreases, requiring less protamine for reversal. Although reversal is rapid, the half-life of protamine is shorter than heparin, necessitating repeat dosing if rebound bleeding occurs. In contrast to heparin, LMWHs cannot simply be turned off after subcutaneous administration. The long half-life must be weighed against the benefits when deciding on LMWHs versus heparin. The dose of protamine is compound-specific: 1 mg/1 mg of enoxaparin, 1 mg/100 U dalteparin, or 1 mg/100 U ardeparin. Repeat dosing is often needed at 0.5 mg/1 mg of enoxaparin, 1 mg/100 U of dalteparin, or 1 mg/100 U ardeparin. To date, only a few case reports of neutralization of LMWH have been published with relatively poor efficacy in comparison to heparin neutralization (11).
Management of HIT syndrome and warfarin skin necrosis includes discontinuing all heparin or warfarin products and administration of a rapid-acting anticoagulant such as danaparoid, a mixture of anticoagulant glycosaminoglycans with predominant antifactor Xa activity, or a DTI such as bivalirudin or argatroban.
Bleeding rates with the pentasaccharide fondaparinux are similar to enoxaparin. Use of rVIIa in healthy volunteers given fondaparinux will normalize prolonged coagulation parameters and there is anecdotal evidence of rVIIa controlling fondaparinux-induced bleeding. The recommended dose of rVIIa is 90 μg/kg intravenously; however routine use is still considered experimental and further clinical experience is necessary before these can be recommended as standard of care (16).
Optimal reversal of the DTI dabigatran is still controversial and no effective reversal agent has been established. Given dabigatran’s relatively short half-life, most bleeding episodes can be managed expectantly with supportive care and transfusion of red blood cells. However, closed-space bleeding (i.e., ICH) will likely not respond to this approach. Transfusion of FFP is controversial and is often recommended for repletion of any possible concomitant factor deficiency. Animal studies suggest rVIIa can decrease bleeding times from dabigatran. However, anecdotal experience with bleeding from the DTIs melagatran and lepirudin showed mixed results with rVIIa. In animals given dabigatran, PCCs have improved clotting time and bleeding, but in healthy volunteers given dabigatran, PCC did not reverse coagulation parameters (20). Given the thrombogenic risks of PCCs, routine use for reversal of dabigatran is not recommended. Dialysis can rapidly increase serum dabigatran elimination and thus, theoretically reverse the anticoagulated state. Dialysis may be an effective therapy for dabigatran-induced closed-space bleeding if it can be initiated quickly, but has not be studied clinically as of yet (13,16,21).
Factor Xa inhibitors such as rivaroxaban and apixaban are fairly novel and there is not much experience as of yet with reversal. In animal models, PCC has been shown to reverse anticoagulation induced by rivaroxaban (13) In healthy human volunteers given rivaroxaban, a single dose of PCC completely reversed prolonged coagulation markers (20). Therefore, PCCs seem the most promising reversal agent for Factor Xa inhibitors, but further clinical experience is necessary before these can be recommended as standard of care.
The best way to reduce complications from fibrinolytic therapy is to carefully review indications and contraindications before administration. Each institution should create protocols for STEMI, acute ischemic stroke, and massive PE with easy-to-follow pathway of indications, contraindications, patient consents, consultants to notify, adjunctive medications, and treatment of complications. Avoid unnecessary procedures and blood draws. Nasal intubation and nasogastric tubes may precipitate massive epistaxis. Arterial lines are rarely essential for ED management. If central access is absolutely required, femoral vein cannulation is preferred as manual pressure of a missed jugular or a subclavian site and a chest tube for an iatrogenic pneumothorax are unnecessarily challenging.
The bulk of fibrinolytic bleeding will occur from puncture sites requiring only direct point pressure to the wound without discontinuing fibrinolytic therapy. Management of life-threatening GI bleeding requires aggressive volume replacement with crystalloid and packed red blood cells as indicated, reversal of fibrinolytic therapy, and adjunctive measures including proton pump inhibitors and endoscopy. Management of ICH requires cryoprecipitate, FFP, platelets, an antifibrinolytic agent, and neurosurgic evaluation. Most life-threatening hemorrhage related to fibrinolytic therapy responds to the administration of 10 U of cryoprecipitate and 2 U of FFP (22). With persistent bleeding or ICH, administer 5 to 10 U of platelets and an antifibrinolytic agent such as aminocaproic acid with a loading dose of 4 to 5 g or 0.1 g/kg over 30 to 60 minutes followed by continuous infusion of 0.5 to 1 g/hr until bleeding is controlled. Be careful to avoid antifibrinolytics in the patient with DIC.
With either SK or anistreplase, allergic reactions may occur typically with mild symptoms of chills, fever, and rigors but in severe forms may include anaphylaxis. Treat with standard therapy including antihistamines, epinephrine, steroids, and airway management. Although controversial, repeat dosing or readministration within 1 year is not recommended (8). Hypotensive episodes secondary to bradykinin generation respond well to decreasing rate of infusion, vasopressors, and IV fluids.
CRITICAL INTERVENTIONS
• Inquire about recent changes in drug doses, diet, and addition or discontinuation of other drugs that may interact with warfarin.
• Maintain a low threshold for imaging the head or abdomen in patients with minor trauma on antithrombotic therapy to detect occult, but life-threatening, bleeding.
• Administer reversal agents for major bleeding complications associated with antithrombotic therapy (Table 198.3).
DISPOSITION
Most patients who present with or develop complications related to antithrombotic therapy will require hospitalization, especially if they have signs of active bleeding. They will typically need monitoring of hematocrit, coagulation factors, and extent of their bleeding. They may need endoscopic or surgical intervention dependent on the site of bleeding. They may also need replacement of significant blood loss or reversal of anticoagulation dependent on which agent they are taking.
The sub-therapeutic patient on warfarin often requires adequate anticoagulation with heparin or LMWH to prevent a paradoxical hypercoagulable state and breakthrough thromboembolism. Outpatient enoxaparin therapy followed by increased warfarin with close follow-up prevents unnecessary hospitalization.
The asymptomatic patient with a supra-therapeutic INR need not be an automatic admission for “coagulopathy.” Although the rate of serious bleeding increases with an INR >4, the overall rate remains low. The indication for anticoagulation, reason for supra-therapeutic level, underlying comorbidities, overall risk of bleeding, fall risk, social situation, reliability, and availability of follow-up must all be considered. Holding warfarin doses, discharge to home, and repeating an INR in the next 24 to 48 hours are typically sufficient for patients with good follow-up who are not at increased risk of falling. HIT syndrome and skin lesions require admission for anticoagulation with alternative agents in consultation with a hematologist.
Anticoagulated patients with bleeding may have an underlying disorder that has been unmasked by the anticoagulant. GI or GU bleeding after starting anticoagulation requires aggressive evaluation for malignancy. Up to 25% of these patients will have an otherwise occult malignancy detected during evaluation for anticoagulant-related bleeding.
For the asymptomatic anticoagulated patient with minor trauma, therapeutic INR, stable hemoglobin, normal imaging studies, and reliable caretakers, discharge with close follow-up is appropriate. The symptomatic anticoagulated trauma patient with evidence of active bleeding requires aggressive management including reversal of anticoagulation, blood replacement, early surgical consultation for operative intervention, and hospitalization. These patients often require transport to a level-one trauma center after initial stabilization for definitive care.
Patients treated with fibrinolytic therapy require admission to an intensive care unit for treatment of the primary disease; close observation and treatment of complications; and cardiology, neurology, and/or neurosurgery consultation.
Common Pitfalls
• Failing to ask about anticoagulation; indication for, changes in dose, timing, and result of last INR, compliance, bleeding or skin lesions, comorbidities, new medicines, changes in diet, and changes in mental status or back pain.
• Failure to realize a patient’s medication is actually an anticoagulant or specifically ask about novel anticoagulants. There has been a significant number of oral anticoagulants and antiplatelet agents recently approved by the FDA (i.e., dabigatran, rivaroxaban, apixaban, prasugrel, ticagrelor) and clinicians must add these to their mental list of medications that increase bleeding risk when evaluating a patient with trauma or bleeding.
• Inappropriate use of vitamin K, protamine, or PCCs. These have serious potential complications. High-dose vitamin K may result in prolonged warfarin resistance for up to 1 week. PCCs carry risk of thrombotic complications and DIC and are very expensive.
• Clinicians should become familiar with their institution’s guidelines on reversal of anticoagulation. Many institutions are adopting use of PCCs for warfarin-induced life-threatening bleeding and the clinician should learn ahead of time which product is available and the recommended dose.
• The safest place for an asymptomatic supra-therapeutic patient may be at home “resting on their couch.” Decide on admission versus close follow-up on a case-by-case basis in consultation with the patient’s primary physician.
• The patient with a mechanical valve who ran out of warfarin a week ago with an INR of 1 cannot simply be sent home with a “little extra” warfarin. Adequate anticoagulation with heparin or enoxaparin is necessary in conjunction with restarting warfarin.
REFERENCES
1. Patrono C, Coller B, FitzGerald GA, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):234S–264S.
2. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16):1706–1717.
3. Pollack CV Jr, Roe MT, Peterson ED. 2002 update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: implications for emergency department practice. Ann Emerg Med. 2003;41(3):355–369.
4. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest. 2012; 141(2 suppl):e24S–43S.
5. Yusen RD, Gage BF. Outpatient treatment of acute venous thromboembolic disease. Clin Chest Med. 2003;24(1):49–61.
6. Hyers TM, Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic disease. Chest. 2001;119(1 suppl):176S–193S.
7. Ageno W, Gallus AS, Wittkowsky A, et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest.2012;141(suppl 2):e44S–88S.
8. Ohman EM, Harrington RA, Cannon CP, et al. Intravenous thrombolysis in acute myocardial infarction. Chest. 2001;119(1 suppl):253S–277S.
9. Makris M, Watson HG. The management of coumarin-induced over-anticoagulation annotation. Br J Haematol. 2001;114(2):271–280.
10. Levine MN, Raskob G, Landefeld S, et al. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119(1 suppl):108S–121S.
11. Kleinschmidt K, Charles R. Pharmacology of low molecular weight heparins. Emerg Med Clin North Am. 2001;19(4):1025–1049.
12. Tcheng JE. Clinical challenges of platelet glycoprotein IIb/IIIa receptor inhibitor therapy: Bleeding, reversal, thrombocytopenia, and retreatment. Am Heart J. 2000;139(2–2):S38–S45.
13. Bauer K. Reversal of antithrombotic agents. Am J Hematol. 2012;87(suppl 1):S119–S126.
14. Mina AA, Bair HA, Howells GA, et al. Complications of preinjury warfarin use in the trauma patient. J Trauma. 2003;54(5):842–847.
15. Ferrera PC, Bartfield JM. Outcomes of anticoagulated trauma patients. Am J Emerg Med. 1999;17(2):154–156.
16. Levi M, Eerenberg E, Kamphuisen PW. Bleeding risk and reversal strategies for old and new anticoagulants and antiplatelet agents. J Thromb Haemost. 2011;9:1705–1712.
17. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(suppl 2):e152S–184S
18. Crowther MA, Douketis JD, Schnurr T, et al. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy. A randomized, controlled trial. Ann Intern Med. 2002;137(4):251–254.
19. Crowther MA, Ageno W, Garcia D, et al. Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: A randomized trial. Ann Intern Med. 2009;150:293–300.
20. Eerenberg ES, Kamphuisen PW, Sijpkens MK, et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: A randomized, placebo-controlled, crossover study in healthy subjects. Circulation.2011;124(14):1573–1579.
21. Ganetsky M, Babu KM, Salhanick SD, et al. Dabigatran: Review of pharmacology and management of bleeding complications of this novel oral anticoagulant. J Med Toxicol. 2011;7(4):281–287
22. Sane DC, Califf RM, Topol EJ, et al. Bleeding during thrombolytic therapy for acute myocardial infarction: Mechanisms and management. Ann Intern Med. 1989;111(12):1010–1022.