Roger D. Yusen and Brian F. Gage
GENERAL PRINCIPLES
Definitions
· Venous thromboembolism (VTE) consists of the spectrum of disease defined by the presence of deep vein thrombosis (DVT) or pulmonary embolism (PE).
· PE arises from DVT or intracardiac clots that embolize to the pulmonary arterial system.
· Massive PE often refers to PE associated with systemic hypotension despite resuscitative measures (e.g., hydration, vasopressors), while submassive PE may refer to nonmassive PE that has associated significant cardiac dysfunction (e.g., right heart strain on echo). Alternatively, some definitions of massive and submassive PE depend on clot burden, while others depend on prognosis.
Anatomy
· The anatomic location of DVT and PE may affect prognosis and treatment recommendations.
· DVTs can be classified as deep or superficial and as proximal or distal.
o To emphasize its deep vein location, the term femoral vein replaced the term superficial femoral vein.
o Lower extremity proximal DVTs occur in or superior to the popliteal vein (or the confluence of tibial and peroneal veins), whereas distal lower extremity DVTs occur inferior to the popliteal vein.
o Upper extremity proximal DVTs occur in the axillary vein or more centrally, whereas distal upper extremity DVTs occur in the brachial vein or more peripherally.
· Location in the pulmonary arterial system characterizes PEs as central (main pulmonary artery, lobar, or segmental) or distal (subsegmental or smaller pulmonary artery branches).
Etiology/Pathophysiology
· Blood vessel damage or other events may produce a series of reactions that involve proteins, called clotting factors (identified by Roman numerals), and cause thromboses.
· Solidification of normally fluid blood into a dense aggregation of blood cells that is entangled within long fibrinous chains of molecules (fibrin) leads to a thrombosis.
· Acquired or genetic coagulation abnormalities can lead to thrombosis formation.
· Symptomatic DVTs most commonly develop in the lower limbs.
· Untreated DVTs may propagate proximally. Without treatment, half of patients with proximal lower extremity DVT develop PE.
· DVTs in the proximal lower extremities and pelvis produce most PEs.
· DVTs that occur in upper extremities, often secondary to an indwelling catheter, may also cause PE.
· DVT may occur concomitantly with superficial thrombophlebitis, which is seen in association with varicose veins, trauma, infection, and hypercoagulable disorders.
Risk Factors/Associated Conditions
· VTE has an increased incidence with conditions of blood stasis, hypercoagulability, and venous endothelial injury. Acute illnesses that lead to prolonged immobilization (trauma, surgery, and other major medical illnesses) also predispose to development of VTE.
· Hypercoagulable states may have an inherited or acquired etiology.
o Acquired hypercoagulable states may arise secondary to malignancy, nephrotic syndrome, obesity, pregnancy, and certain medications (e.g., estrogen, thalidomide, erythropoietin). Both heparin-induced thrombocytopenia (see Heparin-Induced Thrombocytopenia in Chapter 12) and the antiphospholipid antibody (APA) syndrome (see Chapter 33) can cause arterial or venous thrombi.
o Inherited thrombophilic disorders have a higher likelihood of occurring in the setting of a history of spontaneous VTE at a young age (<50 years), recurrent VTE, VTE in first-degree relatives, thrombosis in unusual anatomic locations, and recurrent fetal loss.1
o Inherited risk factors for VTE include genetic polymorphisms/mutations; deficiencies of the natural anticoagulants protein C, protein S, and antithrombin; dysfibrinogenemia; and hyperhomocysteinemia.
§ Common mutations that increase the risk of thrombosis affect the factor V gene (e.g., R506Q mutation) or the prothrombin (factor II) gene (e.g., G20210A mutation). For example, the factor V Leiden mutation can lead to resistance to the degrading properties of activated protein C, and this activated protein C resistance allows factor V to remain active longer.
§ Homocystinuria can cause arterial and venous thromboembolic events that often begin in childhood. Deficiency of cystathionine-β-synthase causes homocystinuria, though milder homocysteine elevations more commonly arise from an interaction between genetic mutations that affect enzymes involved in homocysteine metabolism and acquired factors such as inadequate folate consumption.1 The diagnostic criterion for homocystinuria consists of an elevated fasting plasma homocysteine level.
· Unusual spontaneous venous thromboses, such as cavernous sinus thrombosis, mesenteric vein thrombosis, or portal vein thrombosis, may be the initial presentation of paroxysmal nocturnal hemoglobinuria (PNH) or myeloproliferative disorders.
· Spontaneous (idiopathic) thrombosis, despite the absence of an inherited thrombophilia and detectable autoantibodies, predisposes patients to future thromboses.1
· Antiphospholipid antibody (APA) syndrome may cause thrombosis, and the diagnosis requires the presence of at least one clinical and one laboratory criteria.2
o Clinical criteria consist of (a) the occurrence of arterial or venous thrombosis in any tissue or organ and (b) pregnancy morbidities (unexplained late fetal death; premature birth complicated by eclampsia, preeclampsia, or placental insufficiency; and at least three unexplained consecutive spontaneous abortions).
o Laboratory criteria consist of persistent (at least 12 weeks apart) detection of autoantibodies (lupus anticoagulant [LA], anticardiolipin antibody, and β2-glycoprotein-1 antibodies) that react with negatively charged phospholipids.
o The APA syndrome may include other features, such as thrombocytopenia, valvular heart disease, livedo reticularis, neurologic manifestations, and nephropathy.
Prevention
VTE prevention, by identifying patients at high risk and instituting prophylactic measures, remains the ideal strategy for reducing its morbidity and mortality.
DIAGNOSIS
Clinical Presentation
· DVT may produce pain and edema in an affected extremity.
· DVT has neither sensitive nor specific symptoms and signs. However, pretest assessment of the probability of a DVT provides useful information when combined with the results of compression ultrasound or a D-dimer test, or both, in determining whether to exclude or accept the diagnosis of DVT or perform additional imaging studies.3
· Superficial thrombophlebitis presents as a tender, warm, erythematous, and often palpable thrombosed vein. Accompanying DVT may produce additional symptoms and signs.
· PE has neither sensitive nor specific symptoms and signs.
o PE may produce shortness of breath, pleuritic chest pain, shoulder or back pain, hemoptysis, presyncope, syncope, tachycardia, pleural rub, hypoxemia, hypotension, and right-sided heart failure.4
o Validated clinical risk factors for a PE in outpatients who present to an emergency department include signs and symptoms of DVT, high suspicion of PE by the clinician, tachycardia, immobility in the past 4 weeks, history of VTE, active cancer, and hemoptysis.5
o Clinical suspicion of DVT or PE should lead to objective testing.
Differential Diagnosis
· The differential diagnosis for unilateral lower extremity symptoms and signs of DVT, such as swelling and pain, includes Baker cyst, hematoma, venous insufficiency, postphlebitic syndrome, lymphedema, sarcoma, arterial aneurysm, myositis, cellulitis, rupture of the medial head of the gastrocnemius, and abscess.
· Symmetric bilateral lower extremity edema often suggests the presence of heart, renal, or liver failure or a low albumin level.
· Additional diseases to consider in association with lower extremity pain include musculoskeletal and arteriovascular disorders.
· The differential diagnosis of symptoms and signs of PE includes dissecting aortic aneurysm, myocardial ischemia, heart failure, pneumonia, acute bronchitis, bronchocarcinoma, pericardial or pleural disease, and costochondritis. Other causes of pulmonary arterial occlusion, including in situ thrombi (e.g., sickle cell disease), marrow fat embolism, amniotic fluid embolism, pulmonary artery sarcoma, and fibrosing mediastinitis, mimic signs and symptoms of PE.
Diagnostic Testing
Laboratories
D-Dimer
· D-dimers, cross-linked fibrin degradation products, may increase with VTE, though other acute conditions (e.g., surgery) also elevate levels.
· Assays used to measure D-dimers differ in accuracy and thresholds for a positive test.
· D-dimer testing for DVT or PE has a low positive predictive value and specificity; patients with an elevated D-dimer require further evaluation.
· A sensitive quantitative D-dimer assay has a negative predictive value high enough to exclude a DVT in conjunction with a low (objectively defined) clinical probability and/or a negative noninvasive test.6,7
· A negative D-dimer in combination with a low pretest probability based on an objective scoring tool can exclude almost all PEs.8
· In the setting of a moderate-to-high clinical pretest probability (e.g., patients with cancer), a negative D-dimer does not have sufficient negative predictive value for excluding the presence of DVT or PE.9
Hypercoagulability Testing
· Most patients with VTE do not need hypercoagulability testing; selected individuals who have an idiopathic VTE and a high likelihood of having an inherited thrombophilic disorder (See Risk Factors section) typically undergo testing.
· Signs and symptoms of the APA syndrome should lead to laboratory evaluation.
o Serologic tests (e.g., IgG and IgM β2-glycoprotein-1 antibodies and IgG and IgM cardiolipin antibodies) or clotting assays (e.g., LA) detect APAs; performing both serologic and clotting assays improves sensitivity.
o LAs may prolong the aPTT or PT/INR, but do not predispose to bleeding.
· To assess for PNH in the setting of unusual spontaneous venous thromboses, perform flow cytometry to detect missing antigens on red cells or leukocytes.
Imaging
DVT-Specific Testing
· Initial diagnostic testing for symptomatic acute DVT should consist of a noninvasive test, typically venous compression ultrasound (US; called duplex examination when performed with Doppler testing).10
o Compression US has low sensitivity for detecting calf DVT and also may fail to visualize parts of the deep femoral vein, the pelvic veins, and the more central upper extremity venous system.
o The presence of an old DVT on compression US may make new DVT harder to detect.
o Noninvasive testing has a low sensitivity in asymptomatic patients.
o Simplified compression US limited to only the common femoral vein in the groin and the popliteal vein (down to the trifurcation of the calf veins) has lower sensitivity than does a complete proximal lower extremity venous examination.
o Serial US testing can improve the diagnostic yield. If a patient with a clinically suspected lower extremity DVT has a negative US of good quality, one can withhold anticoagulant therapy and repeat testing 3 to 14 days later.
o Lower extremity venous compression US provides useful information in a patient with a suspected PE who has a nondiagnostic ventilation/perfusion (V/Q) or chest CT scan or when the clinician has a high suspicion of PE in the setting of a normal or low probability V/Q or a negative chest CT result. Detection of a proximal DVT may serve as a surrogate marker for PE, and this scenario often does not require further imaging.
· Venography, the gold standard technique for diagnosing DVT, has mostly been replaced by venous compression US because venography requires placement of an IV catheter, administration of iodinated contrast, and exposure to radiation. Contraindications to venography include renal dysfunction and dye allergy.
· MRI has good sensitivity for acute, symptomatic proximal DVT, but US is typically a much more practical test.
· CT venography testing for DVT may be done in conjunction with a contrast-enhanced PE protocol chest CT.11 CT venography allows for visualization of the veins in the abdomen, pelvis, and proximal lower extremities, though the additional radiation burden raises concern, and lower extremity US is preferred.
PE-Specific Testing
· Nondefinitive tests such as ECG (e.g., sinus tachycardia; right-sided strain pattern, with characteristic S wave in lead I, Q wave in lead III, and T wave inversion in lead III; right bundle branch block), troponin and brain natriuretic peptide (BNP) levels, arterial blood gas, and chest radiography (CXR) help determine the pretest probability, focus the differential diagnosis, and assess cardiopulmonary reserve, but they do not diagnose or exclude PE.
· A negative D-dimer test adequately rules out PE in patients with a low clinical suspicion of PE, but patients with a moderate or high clinical suspicion should undergo imaging.
· Contrast-enhanced spiral (helical) chest CT
o PE protocol chest CT requires IV administration of iodinated contrast and exposure to radiation.
o Contraindications to PE protocol CT may include renal dysfunction and dye allergy.
o Multidetector CT has better sensitivity than single-detector CT for evaluating patients with suspected PE.
o Used according to standardized protocols in conjunction with expert interpretation, spiral CT has good accuracy for detection of large (proximal) PEs, but it has lower sensitivity for detecting small (distal) emboli.12
o The strategy combining D-dimer and chest CT is as safe as the strategy using D-dimer followed by venous compression ultrasonography of the lower extremity and chest CT for the exclusion of PE.13
o Clinical suspicion discordant with the objective test finding (e.g., high clinical suspicion with a negative CT scan or low clinical suspicion with a positive CT scan) should lead to further testing.
o Advantages of CT scan over V/Q scan include more diagnostic results (positive or negative), with fewer indeterminate or inadequate studies, and the detection of alternative diagnoses, such as dissecting aortic aneurysm, pneumonia, and malignancy.11
· V/Q scanning
o V/Q scanning requires administration of radioactive material (via both inhaled and IV routes).
o V/Q scans may be classified as normal, nondiagnostic (i.e., very low probability, low probability, intermediate probability), or high probability for PE.
o V/Q scanning often produces a nondiagnostic result in the setting of an abnormal CXR.
o Use of clinical suspicion improves the accuracy of V/Q scanning; in patients with normal- or high-probability V/Q scans and matching pretest clinical suspicion, V/Q testing has a negative and positive predictive value of 96%.14
o A low probability V/Q scan result combined with a low clinical suspicion of PE excludes most PE.14
· MR angiography
o MR angiography requires IV administration of a nonionic contrast agent (e.g., gadolinium).
o MR angiography is suboptimal for the evaluation of suspected acute PE; spiral chest CT is the preferred imaging.15
· Pulmonary angiography
o Angiography is rarely performed for the evaluation of suspected PE because it requires placement of a pulmonary artery catheter, infusion of IV contrast, and exposure to radiation.
o Similar to venography and PE protocol CT scanning, contraindications to angiography may include renal dysfunction and dye allergy.
o Echocardiography can assess cardiopulmonary reserve, evaluate for cardiac dysfunction, assess for intracardiac thrombus or clot in transit, and look for other diagnoses.
Prognostic Testing
· Several clinical factors are associated with worse prognosis of acute PE: hypoxemia, hypotension, tachycardia, acute RV strain, advanced age, cancer, chronic cardiopulmonary disease, and increased clot burden.16
· Laboratory tests such as BNP and troponin have prognostic value, though they do not rule in or rule out PE.17
· Combinations of risk scores (e.g., PE severity index [PESI], simplified PESI [sPESI], and Geneva) and diagnostic tests (e.g., troponin, BNP, echocardiography, and lower extremity venous compression US) assist with prognostication of patients with PE.18,19
Additional Testing
The search for an associated occult malignancy in patients with VTE should include a thorough history and physical, routine blood work, standard screening tests done according to recommended schedules (e.g., colonoscopy, mammography, Pap smear), and specific cancer screening tests indicated for distinct populations (e.g., low-dose chest CT to search for lung cancer in older patients with a significant smoking history).
TREATMENT
· VTE therapy should aim to prevent recurrence and extension of VTE, consequences of VTE (e.g., postphlebitic syndrome [pain, edema, and ulceration], pulmonary arterial hypertension [PAH], and death), and complications of therapy (e.g., bleeding and heparin-induced thrombocytopenia).
· Clinicians should perform standard baseline laboratory tests (i.e., complete blood cell count, metabolic profile, PT/INR, and aPTT) before starting anticoagulants.
· Clinicians should review each patient’s medication list for drugs that could cause bleeding, clotting, or anticoagulant drug interactions.
Medications
· Unless a contraindication exists, the initial treatment of VTE should consist of anticoagulation, with unfractionated heparin (UFH), low molecular weight heparin (LMWH), pentasaccharide (fondaparinux), or a new oral anticoagulant (Table 14-1).
· IV UFH is usually reserved for inpatient treatment of VTE.
· SC LMWH, fondaparinux, or UFH and oral anticoagulants facilitate outpatient therapy, though SC drugs require the necessary training and resources for successful injection.
· Warfarin or other coumarins should not be used without initially overlapping with a more rapid acting anticoagulant.
· In general, the oral factor Xa and factor IIa inhibitors have similar efficacy and mortality risks when compared to traditional VTE therapy. However, the studies excluded patients that used drugs that may affect factor Xa and IIa inhibitor metabolism or elimination. Though rarely needed, the inability to reverse oral factor Xa and factor IIa inhibitors in the event of major or life-threatening bleeding raises additional concerns. Warfarin and other coumarins have a lower price and longer half-lives than the oral factor Xa and factor IIa inhibitors.
TABLE 14-1 Initial Treatment of Venous Thromboembolism
aNot an FDA-approved indication.
IU, anti-Xa units; for enoxaparin, 1 mg = 100 anti-Xa units.
Caution with the use of fondaparinux, tinzaparin, dalteparin, or enoxaparin for pregnancy, morbid obesity, or end-stage renal disease (CrCl <30 mL/minute); anti-Xa level monitoring is recommended in these settings.
Unfractionated Heparin
· UFH comes from porcine intestinal mucosa, and it mainly works indirectly by catalyzing the inactivation of thrombin and factor Xa by antithrombin.
· At usual doses, UFH prolongs the thrombin time and aPTT and has a small effect on the PT/INR.
· Because the anticoagulant effects of UFH normalize within hours of discontinuation and protamine sulfate reverses it even faster, UFH is the anticoagulant of choice for patients with increased risk of bleeding.
· Abnormal renal function does not typically affect UFH dosing.
· For therapeutic anticoagulation, UFH is usually administered IV with a bolus followed by continuous infusion, but this is almost exclusively done in the inpatient setting.
· Treatment doses of UFH may be administered SC, initial dose of 333 U/kg SC, followed by a fixed unmonitored dose of 250 U/kg every 12 hours.20 However, this regimen requires large-dose injections and is used infrequently.
· Monitored and adjusted SC UFH may be used to treat VTE, but this is not commonly done since many easier and potentially better alternatives exist. In addition, the therapeutic range (approximately 60 to 90 seconds) for aPTT is not standardized.
Low Molecular Weight Heparin
· LMWHs are produced by chemical or enzymatic cleavage of UFH, and they have a similar mechanism of action as UFH.
· Since LMWHs inactivate factor Xa to a greater extent than they do to thrombin (factor IIa), LWMHs minimally prolong the aPTT.
· Extensive clinical trials have confirmed the efficacy and safety of weight-based SC LMWH for the treatment of VTE.
· Factor Xa monitoring is not recommended, except in special circumstances where dose adjustments may be necessary, such as renal dysfunction, morbid obesity, cachexia, and pregnancy. Peak factor Xa levels, measured 4 hours after an SC dose, should be 0.6 to 1 IU/mL for q12-hour dosing and 1 to 2 IU/mL for q24-hour dosing.21
· Different LMWH preparations have different dosing recommendations (Table 14-1).
· Given the renal clearance of LMWHs, they are generally avoided in patients undergoing dialysis.
· Patients with a CrCl of 15 to 30 mL/minute require dose adjustments (e.g., enoxaparin 1 mg/kg once daily instead of twice daily).
· Patients with cancer may have reduced recurrent VTE when treated long-term with LMWH rather than warfarin (or other coumarins). For example, subcutaneous dalteparin at dose of 200 IU/kg daily for 1 month, followed by a daily dose of 150 IU/kg, has been used successfully in patients with VTE and cancer.22
· Protamine only partially reverses LMWH.
Fondaparinux
· Fondaparinux, a synthetic pentasaccharide that is structurally similar to a region of the heparin molecule, binds antithrombin and functions as a selective indirect inhibitor of factor Xa.
· Because fondaparinux inhibits factor Xa and does not inhibit thrombin, it does not significantly prolong the aPTT.
· Large clinical trials have confirmed the efficacy and safety of weight-based subcutaneously dosed fondaparinux for the treatment of VTE.23,24
· Similar to the LMWHs, fondaparinux does not require factor Xa monitoring, except for patients with significant renal dysfunction.
· The recommended dose for VTE therapy ranges from 5 to 10 mg SC daily, depending on weight (Table 14-1).23,24
Oral Direct Xa Inhibitors
· As compared to warfarin, the oral direct (i.e., do not require antithrombin) factor Xa inhibitors rivaroxaban and apixaban have a faster onset, shorter half-life, wider therapeutic window, and more predictable pharmacokinetics.
· In general, the features of the oral direct factor Xa inhibitors allow for fixed dosing without INR monitoring, though they may increase the INR and aPTT in a nonlinear fashion.
· Since both rivaroxaban and apixaban are substrates of cytochrome P450 (CYP) 3A4, strong inhibitors (e.g., clarithromycin) and inducers (e.g., St. John’s wort) alter plasma concentrations.
Rivaroxaban
· The dose of oral rivaroxaban for acute VTE is 15 mg twice daily × 3 weeks, then 20 mg daily. Therapy can be started at the time of diagnosis, without concomitant use of UFH or LMWH. Therapy can also begin after transition from initial treatment with a parenteral agent (e.g., IV UFH).
· Rivaroxaban has similar efficacy and safety compared to therapy with subcutaneous enoxaparin and an oral vitamin K antagonist.25,26
· After 6 to 12 months of standard VTE treatment, continued treatment with rivaroxaban 20 mg PO daily compared to placebo for 6 to 12 additional months decreased the annual risk of symptomatic VTE recurrence by 82%, with a modest increase in hemorrhage.25
· Rivaroxaban’s predominant renal elimination led to exclusion of patients with estimated CrCl <30 mL/minute from VTE treatment trials.
· Rivaroxaban is a substrate of the efflux transporter P-glycoprotein (Pgp), so concurrent use with drugs that interact with Pgp may lead to greater (e.g., amiodarone) or lesser (e.g., St. John’s wort) rivaroxaban exposure.
Apixaban
· Apixaban has recently been approved by the FDA for VTE treatment (10 mg PO bid × 7 days, then 5 mg PO bid).
· Apixaban has similar efficacy to standard enoxaparin/warfarin therapy, but causes less bleeding.27
· After 6 to 12 months of standard VTE treatment, extended-duration treatment (12-month duration) with apixaban at a dose of either 5 mg or 2.5 mg twice daily decreased the annual risk of symptomatic VTE recurrence by about 80%, with a minimal increase in hemorrhage.28
· Apixaban has limited renal elimination but treatment trials excluded patients with an estimated CrCl <25 mL/minute.
Oral Direct Thrombin Inhibitors
Dabigatran
· Compared with warfarin, dabigatran has a more rapid onset, shorter half-life, wider therapeutic window, and more predictable pharmacokinetics.
· In general, dabigatran’s features allow for oral anticoagulant therapy with fixed dosing without INR monitoring, though dabigatran may increase the INR, aPTT, and thrombin time in a nonlinear fashion.
· Compared with warfarin, studies suggest that dabigatran has a lower risk of intracranial (but not gastrointestinal) hemorrhage but a higher risk of myocardial infarction.29–31
· Dabigatran does not have FDA approval for VTE treatment in the United States, though it has approval in other countries (150 mg PO bid after LMWH or UFH for 5 to 11 days).
· After 6 to 18 months of standard VTE treatment, continued treatment with dabigatran (150 mg PO bid) compared to placebo for 6 additional months decreased the risk of VTE recurrence by 92%, with a modest increase in hemorrhage.30
· Dabigatran’s highly predominant renal elimination led to exclusion of patients with estimated CrCl <30 mL/minute from dabigatran trials.
· Dabigatran is not a substrate, inhibitor, or inducer of CYP3A4. However, dabigatran is a substrate of the efflux transporter Pgp, and concurrent use with drugs that interact with Pgp leads to greater (e.g., dronedarone or amiodarone) or lesser (e.g., St. John’s wort) dabigatran exposure.
Warfarin
· The oral anticoagulant warfarin inhibits reduction of vitamin K to its active form and leads to depletion of the vitamin K–dependent clotting factors II, VII, IX, and X and proteins C, S, and Z (see Fig. 12-1).
· Although warfarin has good oral absorption, it requires 4 to 5 days to achieve full anticoagulant effect.
o The initial INR rise primarily reflects warfarin-related depletion of factor VII; the depletion of factor II takes several days due to its relatively long half-life.
o Because of the warfarin-related rapid depletion of the anticoagulant protein C and a slower onset of its anticoagulant effect, patients may develop increased hypercoagulability during the first few days of warfarin therapy if warfarin is not combined with a parenteral anticoagulant.32
· The starting dose of warfarin depends upon factors such as age, size, concomitant drug use, and polymorphisms.33 The starting dose ranges from approximately 3 mg in older or petite patients to 10 mg in young, robust outpatients. Patients with polymorphisms in genes for CYP2C9 or vitamin K epoxide reductase (VKORC1) may benefit from cautious low-dose warfarin initiation.34
· For most indications, such as VTE, warfarin has a target INR of 2.5 and a therapeutic range of 2 to 3, though patients with mitral mechanical heart valves should receive a higher level of anticoagulation (e.g., INR target range, 2.5 to 3.5). See Table 14-2.
· Treatment of DVT/PE with warfarin requires overlap therapy with a faster acting anticoagulant (UFH, LMWH, pentasaccharide, or rivaroxaban) for at least 4.5 days and until patients achieve an INR of at least 2.0 for 2 days.35,36
· Warfarin nomogram dosing has more success than does nonstandardized dosing.
· INR monitoring should occur frequently during the first month of therapy (e.g., twice weekly for 1 to 2 weeks, then weekly for 2 weeks, and then less frequently). Typical dose adjustments after the first few weeks of therapy change the weekly dose by 10% to 25%. Subsequent dose adjustments should be smaller, with no dose adjustments needed for INRs that are in the therapeutic range (2 to 3).
o Patients receiving a stable warfarin dose often have INR monitoring monthly. However, patients with labile INRs should have more frequent monitoring (e.g., weekly). Selected, stable patients can have INRs monitored every 6 to 12 weeks.37
o The addition or discontinuation of medications that affect warfarin, especially antifungal agents or sulfa antibiotics, should trigger more frequent INR monitoring and may require dose adjustments of >25%.
o In eligible patients, home monitoring on point-of-care devices can decrease adverse events.38
o Compliant patients who have unacceptable INR lability, or those with LA and an elevated baseline INR, may benefit from long-term anticoagulation with an agent other than warfarin.
TABLE 14-2 Anticoagulation with Artificial Heart Valves
aAdd ASA for any caged valve, known or suspected coronary artery disease, h/o prior stroke, or mitral valve repair.
ASA, acetylsalicylic acid; INR, international normalized ratio.
Other Treatments
· Select patients may benefit from thrombolytic therapy, catheter embolectomy, and emergency surgical thrombectomy, but these are inpatient issues.35,36
· Inferior vena cava (IVC) filters are used for acute VTE when there are absolute contraindications to anticoagulation (e.g., active bleeding, severe thrombocytopenia, or urgent surgery) or recurrent PE despite therapeutic anticoagulation.
o Although prophylactic IVC filters in anticoagulated patients with acute DVT/PE reduce the risk of recurrent PE, a reduction in overall mortality has not been demonstrated, and they increase DVT recurrence.39,40
o Relative indications for IVC filters include primary or metastatic CNS cancer or limited cardiopulmonary reserve after a PE.
o Patients who had an IVC filter placed because of a temporary contraindication to anticoagulation should receive standard-duration anticoagulation when safe (to reduce the risk of filter-related thromboses and recurrent VTE).35,36
o Several types of removable IVC filters exist and can provide a temporary barrier against emboli from the lower extremities, but filter removal requires a second procedure.
· Leg elevation reduces edema associated with DVT.
· Ambulation is encouraged for patients with DVT, especially after improvement of pain and edema, though strenuous lower extremity activity should initially be avoided.
· Fitted graduated compression stockings help to reduce the high incidence of postphlebitic syndrome in patients with lower extremity DVT.
· Superficial vein thrombosis (SVT)
o Oral NSAIDs and warm compresses can relieve discomfort.
o For infusion thrombophlebitis (superficial thrombophlebitis associated with a peripheral IV), anticoagulant therapy generally is not used.35
o For patients with spontaneous SVT, treatment with low-dose LMWH (e.g., enoxaparin 40 mg SQ qd) for 8 to 12 days or fondaparinux 2.5 mg PO qd for 45 days may lower the short-term incidence of additional thrombosis.36,41
o Extensive SVT can be treated with a prophylactic dose of fondaparinux for about 6 weeks.35,36
o Recurrent SVT may be treated with anticoagulation.
o Surgical therapy (with ligation of the saphenofemoral junction or stripping of thrombosed superficial veins) of SVT appears to be associated with higher rates of VTE than treatment with anticoagulants.35,36
· Catheter-associated upper extremity DVT does not necessarily require catheter removal if it is functional.35
Duration of Anticoagulation
· Duration of anticoagulation depends on patient preferences and values and the risk of recurrent VTE off anticoagulant therapy versus the added risk of bleeding complications from continued anticoagulation.35,36
· Patients with a first episode of VTE provoked by surgical or nonsurgical transient risk factors have a low risk of recurrence (<6%/year) after completing 3 months of anticoagulation.35,36
· Three months of anticoagulant therapy is also sufficient for patients with a first episode of idiopathic VTE associated with other transient risk factors, such as prolonged travel, minor injury, or oral contraceptive pills/hormone replacement therapy that has been stopped.35,36
· For patients with unprovoked proximal lower extremity DVT or PE, at least 3 months of anticoagulation should be prescribed.35,36 Longer (extended) duration of anticoagulant therapy with warfarin (target INR of 2 to 3 or 1.5 to 2), apixaban (either 5 or 2.5 mg, twice daily), rivaroxaban (20 mg PO q day), or dabigatran (150 mg PO bid) reduces the relative risk of recurrent VTE, but it increases the risk of bleeding.28,30
· Patients with cancer and VTE should receive anticoagulation for more than 3 months and possibly until cancer resolution or development of a contraindication.35,36
· For patients with a first VTE and one inherited hypercoagulable risk factor, duration of anticoagulation depends on the type of thrombophilia.36
o Heterozygous factor V Leiden and heterozygous prothrombin 20210A do not necessitate long-term therapy because they increase the odds of VTE recurrence modestly (approximately 1.5-fold).42
o Deficiency of protein S, protein C, or antithrombin carries a high risk of recurrence, which necessitates long-term anticoagulation.42
· Patients with a first VTE and antiphospholipid antibodies or two inherited risk factors should receive a longer course of anticoagulation (e.g., 12 months), and indefinite therapy should be considered.
· Patients with isolated calf DVT or upper extremity DVT should typically receive standard-duration (e.g., 3 months) anticoagulation.35,36
· Patients with recurrent idiopathic VTE should receive extended-duration (more than 3 months) anticoagulation, possibly indefinitely, unless a contraindication develops, or patient preferences dictate otherwise.35,36
· Patients with a history of VTE, especially those with ongoing risk factors, should possibly receive temporary prophylactic anticoagulation during periods of increased VTE risk (e.g., prolonged air travel).36
· After completing the course of anticoagulant therapy, aspirin (e.g., 81 mg) use should be strongly considered to decrease the risk of recurrent VTE and acute coronary syndrome.43
SPECIAL CONSIDERATIONS
· Outpatient VTE therapy
o Patients selected for outpatient DVT therapy should have no other indications for hospitalization (i.e., other problems or complications of VTE), adequate cardiopulmonary reserve, adequate instruction and understanding of the signs of bleeding and VTE recurrence, access to a telephone, ability to receive the anticoagulant, and adequate outpatient follow-up.44
o Patients selected for outpatient PE therapy should have a low-risk classification and should meet eligibility criteria similar to those used for outpatient DVT therapy.45
o Pregnant women with VTE (and without artificial heart valves) may undergo long-term anticoagulation with SC LMWH, fondaparinux, or UFH, and those who receive LMWH or fondaparinux should undergo factor Xa level monitoring.46
o Pregnant women with VTE should avoid warfarin and the oral thrombin and factor Xa inhibitors. Warfarin is contraindicated in the first trimester of pregnancy because of its teratogenicity, and it is often avoided later in pregnancy because of the risk of fetal bleeding, but it is safe for infants of nursing mothers.
· For failure of oral warfarin or other vitamin K antagonists, with confirmed new VTE despite consistently therapeutic INRs, consider prescribing a different anticoagulant.
COMPLICATIONS/RISK MANAGEMENT
Bleeding
· Major bleeding occurs in 2% to 3% of patients who receive short-term anticoagulant therapy for VTE. The risk of intracranial hemorrhage is probably lower with oral thrombin and factor Xa inhibitors than with vitamin K antagonists. Antiplatelet agents used concomitantly with any anticoagulant nearly double the risk of bleeding.
· Major bleeding in a patient with an acute VTE should lead to the discontinuation of anticoagulation.35,36
· Asymptomatic INR elevation on warfarin
o Asymptomatic minor INR elevations of >3.4 and <5 should be managed by holding or reducing warfarin dose until the INR falls to a safe level and then resuming warfarin at a lower dose.
o Moderate (INR ≥5 but <9) elevation of the INR in asymptomatic patients should be treated by holding one or more warfarin doses. Treatment with oral vitamin K1 1 to 5 mg probably does not reduce the risk of hemorrhage in this setting (as compared with warfarin cessation alone) but lowers the INR (Table 14-3).47
o Severe (INR >9) elevation of the INR should be treated with vitamin K (e.g., oral vitamin K1 2 to 10 mg) unless the INR is likely to be spurious (Table 14-3).48
· General approach to bleeding with anticoagulants
o Stop the anticoagulant and other drugs (e.g., antiplatelet agents) that may exacerbate bleeding.
o Provide supportive interventions (e.g., IV fluid, compression of bleeding site, surgery).
o Check coagulation tests to see effect of the drug on board, follow CBC, and check CMP.
o Red blood cell transfusion for anemia and platelet transfusion for patients on antiplatelet agents as needed.
· Anticoagulant-specific approaches may also be necessary.
· Bleeding with warfarin (Table 14-3)49:
o Prothrombin complex concentrate (PCC), or fresh frozen plasma (FFP) if PCC not available, should be given to treat major bleeding associated with warfarin therapy.50,51
o Vitamin K (e.g., 10 mg) by slow IV infusion should be given for serious hemorrhages caused by a high INR. Because of the long half-life of warfarin (approximately 36 hours, depending on CYP2C9 genotype), vitamin K should be repeated every 8 to 12 hours to prevent INR rebound.
· Bleeding with UFH
o Stopping UFH usually restores hemostasis within a few hours.
o With moderate-to-severe bleeding, give FFP.
o For patients receiving UFH who develop major bleeding or have an UFH overdose, UFH can be completely reversed by infusion of protamine sulfate in situations where the potential benefits outweigh the risks (e.g., intracranial bleed, epidural hematoma, and retinal bleed).
o After IV administration, UFH serum concentrations decline rapidly because of a short half-life, so only the UFH administered in the last 2 to 3 hours needs to be reversed with protamine sulfate.
o Approximately 1-mg protamine sulfate IV neutralizes 100 U of UFH, up to a maximum dose of 250 mg.
· Bleeding with LMWH
o With moderate-to-severe bleeding, give FFP.
o For major bleeding associated with LWMH, protamine sulfate has less efficacy compared with its effect on UFH since it neutralizes only approximately 60% of LMWH.52
· Bleeding with fondaparinux
o With moderate-to-severe bleeding, give FFP.
o For patients with very serious bleeding receiving fondaparinux, give concentrated factor VIIa (up to 90 mcg/kg) and tranexamic acid (1-mg IV), but these agents can cause serious thrombosis.53
· Bleeding with oral direct thrombin inhibitor (dabigatran)54
o An increase in the thrombin time (and INR and aPTT) may indicate dabigatran ingestion, but the coagulation tests do not indicate the degree of anticoagulation.
o Determine amount consumed and timing of the last dose. Consider activated charcoal within 2 hours of last dose.
o Consider dialysis for severe bleeding or overdose (especially with renal failure).
o Consider using PCC for severe bleeding (limited data).
· Bleeding with oral factor Xa antagonists54
· An increase in the INR or aPTT may indicate a factor Xa antagonist ingestion, though the coagulation tests do not indicate the degree of anticoagulation.
· Consider using PCC for severe bleeding (limited data).
TABLE 14-3 Treatment of Elevated INR >5
FFP, fresh frozen plasma; INR, international normalized ratio; PCC, prothrombin complex concentrate; PLT, platelets; PRBC, packed red blood cells.
Other Complications
· Occult gastrointestinal or genitourinary bleeding is a relative and not absolute contraindication to anticoagulation, though its presence warrants investigation.
· Warfarin-induced skin necrosis, associated with rapid depletion of protein C, may occur during initiation of warfarin therapy.32 Necrosis occurs most often in areas with a high percentage of adipose tissue, such as breast tissue, and it can be life threatening. Therapeutic anticoagulation with an immediate-acting anticoagulant (UFH, LMWH, etc.) and/or avoidance of loading doses of warfarin may prevent warfarin-induced skin necrosis.
· If possible, anticoagulants should be avoided in patients about to undergo neuraxial procedures (lumbar puncture, epidural/spinal anesthesia, and epidural catheter removal) because of the risk of development of epidural hematomas and subsequent spinal cord compression and paralysis.55
· Osteoporosis may occur with long-term heparin or warfarin use.56
Perioperative Management of Anticoagulants
· Minor elective procedures (including uncomplicated dental extractions, skin biopsies, placement of pacemakers, and cataract extraction) can be done without cessation of anticoagulant therapy.57
· Perioperative management of anticoagulation requires coordination with the surgeon (see Chapter 2).
· Invasive procedures typically benefit from discontinuation of anticoagulant therapy.
o Warfarin
§ Cessation for 5 days results in an INR ≤1.4 in most patients. However, patients taking >3 mg/day may require 6 days until the INR declines ≤1.4. If an INR of around 1.7 is acceptable for the procedure, the warfarin dose can be halved for 4 days preoperatively.58
§ To minimize time without therapeutic anticoagulation, UFH or LMWH or fondaparinux SC bridging preprocedure therapy can be initiated when the INR becomes subtherapeutic (e.g., 3 days after the last warfarin dose). In pregnant women with a mechanical heart valve, IV UFH appears safer than LMWH or fondaparinux.
§ After the procedure, resume warfarin (with or without UFH and LMW heparin, depending on the risks of bleeding and thrombosis).
o UFH, LMWH, and fondaparinux. Depending on the half-life of the anticoagulant, renal function (for LMWH and fondaparinux), and dosing frequency, stopping UFH for 6 hours, LMWH for 12 to 24 hours, and fondaparinux for 12 to 48 hours before an invasive procedure is usually adequate.
o Oral direct thrombin inhibitor (dabigatran)
§ Cessation of the oral direct thrombin inhibitor dabigatran for 24 to 48 hours should allow for invasive procedures in patients with normal bleeding risk whose Cr clearance is >50 mL/minute. With high bleeding risk or lower Cr clearance, 2 to 5 days of cessation may be necessary.59
§ Temporary interruption of dabigatran can cause stroke in patients who have atrial fibrillation.
o Oral direct factor Xa inhibitors (rivaroxaban or apixaban)
§ Cessation for 24 hours should allow for invasive procedures in patients whose Cr clearance >30 mL/minute.
§ With lower Cr clearance, rivaroxaban’s half-life is prolonged and 2-day cessation is necessary.59
FOLLOW-UP
· In the case of a suspicious clinical presentation, testing for intrinsic hypercoagulable risk factors of the coagulation cascade ideally should wait until the patient is in stable health.1 Hypercoagulable testing is not recommended for most patients with VTE.
o LA testing can be done in the acute setting. A positive LA test result should be rechecked for persistent positivity at a later date.
o Genetic testing for the prothrombin gene mutation and factor V Leiden can be done at any time.
o Testing for protein C, protein S, and antithrombin deficiency or low activity can occur before initiating anticoagulation, but an acute thrombosis can depress their levels. Some anticoagulants may also affect these protein levels. Because proteins C and S are vitamin K dependent, levels should not be assessed during warfarin therapy.
· For patients with suspected lower extremity DVT, an initial negative compression ultrasound, and no satisfactory alternative explanation, serial compression ultrasonography in 3 to 14 days improves the diagnostic yield.
· If patient preferences or contraindications lead to the withholding of anticoagulant therapy for calf DVT, we recommend further evaluation with a repeat compression ultrasonography to assess for proximal extension, which would mandate therapy.
· Testing for PE in patients with DVT and testing for DVT in patients with PE will produce many positive findings, but such test results rarely affect therapy. However, baseline results may provide comparison data for patients who return with symptoms of VTE, though studies have not determined the cost-effectiveness of this practice.
· Prolongation of anticoagulation in patients with residual thrombosis on compression ultrasonography at the end of standard duration anticoagulation for proximal DVT reduces VTE recurrence but can cause hemorrhage.60
· Repeated elevation of D-dimer at the end of standard duration anticoagulation for a first episode of unprovoked VTE is associated with an increased risk of recurrence, though limited data exist regarding extension of anticoagulation duration based on D-dimer test results.61
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