Disclosures: Gregory YH Lip, MD, FRCPE, FESC, FACC Speaker's Bureau: Bayer [Atrial fibrillation and thrombosis (rivaroxaban)]; BMS/Pfizer [Atrial fibrillation and thrombosis (apixaban)]; Boehringer Ingelheim [Atrial fibrillation and thrombosis (dabigatran)]; Daiichi-Sankyo [Atrial fibrillation and thrombosis (edoxaban)]; Medtronic [Atrial fibrillation and thrombosis]; Sanofi Aventis [Atrial fibrillation and thrombosis]. Consultant/Advisory Boards: Bayer/Janssen [Atrial fibrillation and thrombosis (rivaroxaban)]; BMS/Pfizer [Atrial fibrillation and thrombosis (apixaban)]; Boehringer Ingelheim [Atrial fibrillation and thrombosis (dabigatran)]; Daiichi-Sankyo [Atrial fibrillation and thrombosis (edoxaban)]; Merck [Atrial fibrillation and thrombosis]; Sanofi [Atrial fibrillation and thrombosis]; Biotronik [Atrial fibrillation and thrombosis]; Medtronic [Atrial fibrillation and thrombosis]; Portola [Atrial fibrillation and thrombosis]. Russell D Hull, MBBS, MSc Grant/Research/Clinical Trial Support: LEO Pharma [VTE (Tinzaparin)]; Sanofi [VTE (Enoxaparin)]; Portola [VTE (Betrixaban)]; Bayer [VTE (Rivaroxaban)]. Lawrence LK Leung, MD Nothing to disclose. Jess Mandel, MD Nothing to disclose. Geraldine Finlay, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Deep vein thrombosis (DVT) and acute pulmonary embolism (PE) are two manifestations of venous thromboembolism (VTE). VTE contributes to significant morbidity and mortality both in the community and in hospital. The mainstay of therapy for DVT is anticoagulation, provided there is no contraindication. Following initial anticoagulation, patients with DVT are anticoagulated further to prevent future recurrences, embolism, and thrombosis-related death.
An overview of the treatment of lower extremity DVT (distal and proximal), including indications for anticoagulation, alternate therapies, and treatment of special populations of patients with DVT, are discussed in this topic. Initial, long-term, and extended (indefinite) anticoagulation for DVT, as well as the treatment of PE, upper extremity DVT, and the diagnosis and prevention of DVT are discussed in detail, separately. (See "Lower extremity deep venous thrombosis: Initiation of anticoagulation (first 10 days)" and "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)" and "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism" and "Anticoagulation in acute pulmonary embolism" and "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults" and "Diagnosis of suspected deep vein thrombosis of the lower extremity" and "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults" and "Prevention of venous thromboembolic disease in surgical patients".)
NOMENCLATURE — For the purposes of discussion in this topic, the following terms apply:
●The term unprovoked deep venous thrombosis (DVT) implies that no identifiable cause or provoking event for DVT is evident. In contrast, a provoked DVT is one that is usually caused by a known event (eg, surgery, hospital admission). Provoking events and risk factors associated with the development of DVT can be transient (ie, reversible; eg, estrogen therapy) or persistent. Persistent risk factors include reversible conditions (eg, prolonged immobility following surgery, pregnancy, or curable malignancy) and irreversible conditions such as inheritable thrombophilias, chronic heart failure, and metastatic end-stage malignancy. (See "Overview of the causes of venous thrombosis".)
●Proximal DVT is one that is located in the popliteal, femoral, or iliac veins. Isolated distal DVT has no proximal component, is located below the knee, and is confined to the calf veins (peroneal, posterior, anterior tibial, and muscular veins) (table 1).
●Symptomatic DVT refers to the presence of symptoms that usually leads to the radiologic confirmation of DVT, whereas asymptomatic DVT refers to the incidental finding of DVT on imaging in a patient without symptoms (eg, computed tomography). (See "Approach to the diagnosis and therapy of lower extremity deep vein thrombosis", section on 'Initial approach' and "Diagnosis of suspected deep vein thrombosis of the lower extremity".)
●Initial anticoagulation is administered in the first 5 to 10 days following a diagnosis of DVT. Long-term anticoagulant therapy is typically administered for a finite time beyond the initial period, usually three to six months, and occasionally up to 12 months. Extended anticoagulation refers to therapy that is administered indefinitely. (See "Lower extremity deep venous thrombosis: Initiation of anticoagulation (first 10 days)" and "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)" and "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism".)
●Factor Xa and direct thrombin inhibitors have been referred to using a variety of names including newer/novel oral anticoagulants, non-vitamin K antagonist oral anticoagulants (NOAs, NOACs), direct oral anticoagulants (DOACs), and target-specific oral anticoagulants (TOACs, TSOACs) [1,2]. Throughout this topic, we refer to these agents by their pharmacologic class, factor Xa and direct thrombin inhibitors. (See "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors".)
INDICATIONS — Anticoagulation is the mainstay of therapy for patients with deep venous thrombosis (DVT). Anticoagulation is indicated for all patients with proximal deep venous thrombosis (DVT) and select cases of distal DVT. The decision to anticoagulate must weigh the benefits of anticoagulation against the risk of bleeding for an individual. The primary objective of anticoagulation is the prevention of further thrombosis and of early and late complications. Major early complications of DVT include further clot extension, acute pulmonary embolus (PE), major bleeding (from anticoagulation), and death. Late complications include recurrent clot, post-thrombotic (post phlebitic) syndrome and chronic thromboembolic pulmonary hypertension. (See "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults" and "Post-thrombotic (postphlebitic) syndrome" and "Clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension".)
The indication to anticoagulate is stronger for patients with proximal DVT (popliteal, femoral, iliac vein) than with distal DVT (calf vein) because the risk of complications is higher, especially embolization and death. As an example, older studies reported that over 90 percent of acute PE arise from the proximal veins [3,4]. Another prospective analysis of 1643 patients anticoagulated for acute DVT (OPTIMEV) reported that the mortality rate of proximal DVT is higher than that of distal DVT (8 versus 4 percent) .
The indications to anticoagulate are based upon a definitive diagnosis of DVT, usually made on compressive ultrasound (CUS) of the lower extremities. In patients with asymptomatic proximal or distal DVT found incidentally by another imaging modality usually computed tomography (CT), the diagnosis should be sought using CUS before anticoagulation, due to the poorer sensitivity and specificity of CT. (See "Diagnosis of suspected deep vein thrombosis of the lower extremity".)
Proximal DVT — Proximal lower extremity DVT is one that is located in the popliteal, femoral, or iliac veins (table 1). Anticoagulant therapy is indicated for all patients with proximal DVT, regardless of the presence of symptoms and provided there is no contraindication to anticoagulation (algorithm 1). This approach is supported by a seminal randomized trial that demonstrated a survival benefit with anticoagulation as well as randomized trials and meta-analyses of patients treated with variable durations of anticoagulant therapy.
Accurate estimates of recurrent thrombosis and death in patients with proximal DVT who are not treated with anticoagulant therapy are unknown. In the seminal trial, performed in 1960, that compared anticoagulation with observation in patients with acute DVT, anticoagulation resulted in a dramatic reduction in recurrence, which translated into a mortality benefit . Since then, most other trials have compared various doses and durations of anticoagulant therapy for DVT to provide an estimate of the risk of recurrence . Nonetheless, these data all support low rates of recurrent venous thromboembolism (VTE) and death in patients treated with anticoagulant therapy for proximal DVT, with the greatest benefit occurring within the first few days or weeks of the initial event. As an example, one 2010 meta-analysis of 13 prospective cohort studies and 56 randomized clinical trials reported rates of recurrent VTE and fatal VTE during the first three months of anticoagulant therapy as 3.4 and 0.4 percent, respectively .
For patients with proximal DVT, the absence of symptoms (ie, incidental DVT) does not alter the indication for anticoagulation. Although the safety and efficacy of anticoagulant therapy in patients with asymptomatic proximal vein DVT compared with symptomatic DVT is unknown, we and others prefer that this population of patients be managed in the same manner as symptomatic patients . This preference is based upon indirect evidence that is extrapolated from patients with symptomatic proximal DVT.
Distal DVT — Isolated distal DVT encompasses thromboses located below the knee in the calf veins (ie, the popliteal vein is not involved). Most calf vein DVTs are located in the posterior tibial and peroneal veins while anterior tibial and muscular vein DVTs are uncommon (table 1). While in the past whole leg ultrasound frequently identified asymptomatic patients with isolated distal DVT, a shift towards presentation with symptomatic DVT has occurred. The treatment of isolated distal DVT varies among centers and clinicians and represents a major challenge therapeutically. In general, the following applies:
●Symptomatic – In general, most clinicians agree that anticoagulation is indicated in most patients with symptomatic isolated distal DVT, provided the risk of bleeding is low [8-10]. However, some experts choose not to treat select patients who are considered a very low risk of embolization and are suitable candidates for surveillance; such patients include those with minor thrombosis in the muscular veins, those with a negative D-dimer level, those with non diagnostic ultrasonography results, and those at high risk of bleeding.
●Asymptomatic – Additional indications for anticoagulation in asymptomatic patients or in patients with symptomatic DVT who opt for surveillance include:
•Patients with documented DVT extension into or toward the proximal veins during surveillance
•Patients considered by their clinician to be at risk of extension to the proximal veins. This includes patients with:
-D-dimer >500 mg/mL
-Extensive thrombosis involving multiple veins (eg, >5 cm in length, >7 mm in diameter)
-Thrombosis close to the proximal veins
-Persistent/irreversible risk factors such as active cancer
-Prior DVT or pulmonary embolism (PE)
Support for this approach is based upon the risk of extension into the proximal veins (ie the popliteal vein or higher) where the indication to anticoagulate is stronger due to the higher risk of embolization and the proven efficacy in this population of anticoagulation in reducing clot extension . As examples:
●Natural history studies suggest that when left untreated, approximately one-third of patients with symptomatic isolated distal DVT will develop extension into the proximal veins, most often within the first two weeks after diagnosis [11-20].
●One meta-analysis that included two randomized and six nonrandomized cohort studies of patients with isolated distal DVT reported that, compared with those who were followed with serial ultrasound, proximal thrombus propagation was less likely to occur in those receiving anticoagulation (odds ratio 0.29, 95% CI 0.14-0.62) . However, the methodologic quality of most studies was poor and the number of outcome events that occurred (ie, deaths, PE, proximal DVT extension, bleeding) was small, which limited the analysis.
When the decision is made to anticoagulate patients with isolated distal DVT, full therapeutic anticoagulation should be administered similar to those with proximal DVT, assuming the bleeding risk is low.
Surveillance with serial ultrasound — Select patients with distal DVT (eg, those at high risk of bleeding) may be subjected to surveillance with serial ultrasound to look for extension of lower extremity clot into the proximal veins. Candidates that may be suitable for this approach are discussed above (see 'Distal DVT' above). Serial ultrasound is not recommended in patients with proximal DVT. (See 'Proximal DVT' above.)
Support for this approach is derived from studies that suggest that the risk of embolization in patients with isolated distal DVT is low and approximately half that of proximal DVT . As an example, several retrospective and prospective observational studies reported that limited thrombosis confined to the muscular veins, compared with extensive thrombosis of multiple calf veins, appears to have a low risk of extension without therapy (about 3 versus 15 percent) [8,10-13,15,18,19]. In addition, if extension does not occur within two weeks, it is unlikely to occur.
The optimal frequency, duration, and method of surveillance are unknown. We generally survey patients every week for two weeks with proximal compressive ultrasound (CUS) for clot extension or resolution. If thrombus resolves, no anticoagulation is required. If, however, clot extension is observed into the proximal veins, patients should be anticoagulated or treated with an inferior vena cava filter if a contraindication to anticoagulation exists. For those in whom clot extends toward the proximal veins but remains confined to the calf, anticoagulation should be considered or the patient should be subjected to further observation with CUS. Patients in whom clot does not resolve but remains stable, as well as patients with multiple risk factors, may require longer periods of surveillance.
For surveillance, we prefer proximal rather than whole leg CUS because it is sufficient for the detection of proximal DVT, where the indication for anticoagulation is strong.
ASSESSING BLEEDING RISK — All patients should be assessed before and during anticoagulant therapy for bleeding risk (table 2). Patients, especially those on factor Xa and direct thrombin inhibitors and those >75 years, should also be assessed for the signs and symptoms of conditions that may prolong the half-life of the administered anticoagulant (eg, renal failure, weight loss). In all patients, the decision to anticoagulate should be individualized and the benefits of venous thromboembolism (VTE) prevention carefully weighed against the risk of bleeding. Absolute and relative contraindications to anticoagulation are discussed separately. (See 'Patients with contraindications to anticoagulation' below.)
The administration of anticoagulation is always associated with an increased risk of bleeding, which is in turn dependent upon the degree of anticoagulation and the presence of pre-existing factors for bleeding. Tools are available for estimating the risk of bleeding in anticoagulated individuals (eg, HAS-BLED score) (calculator 1). However, none of these tools has been validated in patients anticoagulated for VTE and no one index can reliably predict bleeding risk in a particular patient such that for practical purposes, many clinicians use a gestalt estimate for assessing bleeding risk. Details regarding the use of scoring systems that estimate the risk of bleeding are discussed separately. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Assessing the risk of bleeding' and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Bleeding risk'.)
Most clinicians agree that patients with a three-month bleeding risk of less than 2 percent (low risk) should be anticoagulated. In addition, most clinicians agree that patients with a three-month bleeding risk of more than 13 percent (high risk) should not be anticoagulated . For patients with an estimated bleeding risk between these values, there is no agreement regarding the preferred approach such that the decision to anticoagulate in this population must be individualized according to the values and preferences of the patient as well as the risk-benefit ratio, which may change over time. As an example, the benefits of anticoagulation are greater during the initial period of anticoagulation than at the end of a finite period of three months. Patients who wish to avoid the risk of bleeding on anticoagulation should be considered for an inferior vena cava filter. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Our approach' and "Placement of vena cava filters and their complications" and 'Inferior vena cava filter' below.)
INITIAL ANTICOAGULATION (FIRST 10 DAYS)
Selection of agent — Initial anticoagulation refers to systemic anticoagulation administered for the first 5 to 10 days following a diagnosis of deep venous thrombosis (DVT [8,23]). In most patients, anticoagulation should be started immediately as a delay in therapy may increase the risk of potentially life threatening embolization [24,25].
For most patients, particularly patients with active cancer and pregnant women, we prefer low molecular weight (LMW) heparin rather than other agents (unfractionated heparin [UFH], factor Xa and direct thrombin inhibitors). Heparin agents and fondaparinux are typically preferred over factor Xa and direct thrombin inhibitors because of the longer clinical experience with them as initial anticoagulants, as well as their reversibility with available antidotes. Intravenous (IV) UFH is our preferred agent for patients with severe renal failure (eg, creatinine clearance <30 mL/minute) and for patients in whom we anticipate a need for acute reversal of anticoagulation. (See "Lower extremity deep venous thrombosis: Initiation of anticoagulation (first 10 days)", section on 'Selection of agent'.)
Oral factor Xa and direct thrombin inhibitors may be an acceptable alternative for patients with normal renal function who prefer an oral anticoagulant and wish to avoid the burden of daily injections, and are also willing to accept the risk of bleeding on an irreversible agent. The factor Xa inhibitors, rivaroxaban and apixaban, have been studied and approved by regulatory agencies as monotherapy (ie, the only initial anticoagulant) for the treatment of patients with DVT. The factor Xa inhibitor, edoxaban and the direct thrombin inhibitor, dabigatran, have unproven efficacy as monotherapy and as such should only be administered following the typical five day course of parenteral or subcutaneous heparin (ie, dual therapy). (See "Lower extremity deep venous thrombosis: Initiation of anticoagulation (first 10 days)", section on 'Selection of agent'.)
Warfarin cannot be administered alone as an initial anticoagulant for DVT. Heparin or fondaparinux are typically administered for at least five days together with warfarin at a starting dose of 10 mg per day; the warfarin dose is adjusted until the international normalized ratio (INR) is therapeutic at 2 to 3 (target 2.5) for a minimum of two consecutive days, at which point heparin can be discontinued. When an oral factor Xa or direct thrombin inhibitor is chosen for initial anticoagulation, we prefer that they be initiated at doses that are in accordance with study criteria that demonstrated their efficacy. (See "Lower extremity deep venous thrombosis: Initiation of anticoagulation (first 10 days)", section on 'Timing, duration, and dosing'.)
Selecting an agent and initial dosing for parenteral and oral anticoagulation, and empiric therapy, as well as initial anticoagulation of patients with malignancy and pregnancy, are discussed in detail, separately. (See "Lower extremity deep venous thrombosis: Initiation of anticoagulation (first 10 days)" and "Treatment of venous thromboembolism in patients with malignancy" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment".)
Outpatient therapy — Not all patients who have acute DVT need to be admitted to the hospital for systemic anticoagulation. The decision to treat DVT in the outpatient setting should be made in the context of the patient's understanding of the risk-benefit ratio, preferences, and clinical condition. Factors determining who may be considered for outpatient therapy are not well defined. However, several randomized trials and meta-analyses that have compared outpatient therapy with low molecular weight (LMW) heparin to inpatient therapy with IV unfractionated heparin (UFH) suggest that treatment at home with LMW heparin is safe and effective in select patients [8,26-38]. Anticoagulant therapy should not be delayed while the decision is being made to treat the patient at home.
When considering outpatient administration of LMW heparin, patient selection is critical:
●Outpatient therapy can be considered when patients have all of the following features (table 3):
•A low risk of bleeding
•No renal insufficiency
•A practical system in place at home for the administration and surveillance of anticoagulant therapy (eg, good living conditions, caregiver support, phone access, understanding and ability to return to the hospital should deterioration occur)
●Outpatient therapy is not appropriate in patients with :
•Massive DVT (eg, iliofemoral DVT, phlegmasia cerulea dolens)
•Concurrent symptomatic pulmonary embolism
•High risk of bleeding on anticoagulant therapy
•Comorbid conditions or other factors that warrant in-hospital care
Evidence to support this approach is derived from randomized trials and meta-analyses that have compared LMW heparin delivered at home following immediate discharge from the emergency or outpatient department or following a brief inpatient stay (eg, one day). However, these trials have been intrinsically flawed because of differences in the LMW heparin used, follow-up therapy (warfarin and LMW heparin), and differences in randomization to home therapy, which was not explicitly performed in many studies.
●One 2012 meta-analysis of six randomized trials totaling 1708 patients with acute DVT compared outpatient use of LMW heparin with inpatient IV UFH . Outpatient therapy with LMW heparin was associated with reductions in the rate of recurrent venous thromboembolism (VTE) (risk reduction [RR]; 0.61, 95% CI 0.42-0.9), major bleeding (RR 0.67, 95% CI 0.33-1.36), and mortality (RR 0.72, 95% CI 0.45-1.15). Another 2007 meta-analysis of six older studies reported similar results .
●A 2003 meta-analysis of eight trials that also included patients with brief inpatient stays (24 hours or less) for acute DVT reported that compared with inpatients treated with heparin, those treated as an outpatient had similar rates of recurrent DVT (4 versus 6 percent) and major bleeding (0.5 versus 1 percent) .
Cost savings due to the avoidance of an inpatient stay is a frequently cited advantage of outpatient anticoagulation, and is estimated to range from $500 to $2500 per patient [33,40-46]. Randomized trials and meta-analyses of nonrandomized trials have suggested that the cost of outpatient therapy with LMW heparin is similar to, or lower than, the cost of strategies that utilize unfractionated heparin, regardless of the treatment setting (eg, inpatient versus outpatient) [40,41,47-49]. These data should be interpreted with caution as many studies were biased and were limited in their sensitivity analysis.
For patients in whom outpatient therapy is selected, we suggest the use of LMW heparin overlapped with warfarin rather than the use of factor Xa or direct thrombin inhibitors. This preference is based upon our clinical experience and data described above that was derived specifically from the outpatient population. Trials that reported efficacy for dabigatran (direct thrombin inhibitor) and edoxaban (factor Xa inhibitor) used a minimum of five days of anticoagulation with LMW heparin or UFH prior to their administration for long-term oral therapy (ie, dual therapy) [50,51]. Consequently, we suggest that dabigatran and edoxaban not be routinely used as a monotherapy for initial anticoagulation in outpatients but can be used in this setting provided they overlap with heparin, similar to the original study protocols that proved their efficacy. In contrast, trials of rivaroxaban and apixaban reported efficacy of both agents as the sole initial anticoagulant (monotherapy). Although short periods (<48 hours) of heparin were allowed prior to randomization, our experience with these agents is in keeping with the data that suggest monotherapy with these agents is safe and effective when administered to the outpatient population (ie, without heparin overlap) [52,53]. Subcutaneous UFH has not been adequately studied in this population and as such cannot be routinely recommended. (See "Therapeutic use of unfractionated heparin and low molecular weight heparin" and "Anticoagulation with direct thrombin inhibitors and direct factor Xa inhibitors" and "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)".)
The outpatient treatment of pulmonary embolism is discussed separately. (See "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Outpatient anticoagulation'.)
LONG-TERM ANTICOAGULATION (10 DAYS TO THREE MONTHS) — Long-term anticoagulant therapy is administered beyond the initial 5 to 10 days of anticoagulation for a finite period of typically three to six months, and up to 12 months in some cases (eg, phlegmasia cerulea dolens, a persisting but reversible risk factor). Full anticoagulation should be ensured during the transition from initial to long-term therapy. Interruptions should be minimized during the first three months of long-term anticoagulation because this is the period that has the highest risk of recurrent thrombosis. (See "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)".)
Selection of agent — For most patients, we prefer warfarin adjusted to an international normalized ratio (INR) range (2 to 3; target 2.5) rather than other agents with the exception of patients with malignancy and pregnant women where low molecular weight (LMW) heparin is the agent of choice. The preference for warfarin is largely based upon the longer clinical experience with this agent and the availability of reversible agents for warfarin-related bleeding. LMW heparin and fondaparinux are acceptable alternatives for patients who wish to avoid the burden of INR monitoring and are willing to accept daily injections. Similarly, factor Xa and direct thrombin inhibitors can be considered in patients who also wish to avoid the burden of INR monitoring and daily injections. Because individual patients perceive burdens differently, patient's values and preferences are critical in selecting a long-term agent for anticoagulation in acute DVT. (See "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)", section on 'Selection of agent'.)
Duration of therapy — A decision regarding the optimal duration of anticoagulation must take into account the presence or absence of provoking events, risk factors for recurrence and bleeding, as well as to the individual patient's preferences and values. Although there is agreement on the minimum length of time a patient with a first episode of DVT should be treated (ie, three months), the optimal length of time is not known. For most patients with a first episode of DVT (provoked and unprovoked, proximal and distal), anticoagulants should be administered for three months rather than for shorter periods (eg, four or six weeks) (algorithm 1). Most experts agree that extending anticoagulation beyond three months is considered in select populations, particularly in patients with provoked DVT with persistent but reversible risk factors (extended finite periods; eg, 6 to 12 months or until risk factor is resolved) and unprovoked DVT (indefinite anticoagulation). In contrast, anticoagulation beyond three months is NOT typically performed in patients with an episode of DVT provoked by a transient risk factor (eg, surgery) or in those at high risk of bleeding. (See "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)", section on 'Duration of treatment' and "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Our approach'.)
Agent selection for long-term anticoagulation and transitioning agents during therapy are discussed in detail, separately. (See "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)" and "Perioperative management of patients receiving anticoagulants".)
INDEFINITE ANTICOAGULATION — The decision to anticoagulate patients with deep venous thrombosis (DVT) indefinitely should be based upon an estimate of the risk of recurrence and bleeding in the context of the clinical nature of the episode of the DVT (eg, provoked or unprovoked DVT, reversible or irreversible risk factors) as well as the patient's values and preferences (eg, occupation, life expectancy, burden of therapy).
While there is consensus regarding the need to anticoagulate select patients with acute DVT indefinitely, there is no agreed-upon best approach [8,54,55]. Most experts agree that patients with a first and in particular, recurrent, unprovoked episode of DVT, especially proximal DVT, should be strongly considered for indefinite anticoagulation. Weaker indications include recurrent provoked DVT and provoked DVT with multiple persistent irreversible risk factors (eg, active malignancy, antiphospholipid syndrome). In contrast, anticoagulation should not be routinely considered in patients with a provoked episode of DVT with a transient risk factor or those in whom the risk of bleeding is considered to be high.
Patients in whom indefinite anticoagulation should be considered are discussed separately. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism" and "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)", section on 'Duration of treatment'.)
SPECIAL POPULATIONS — Special populations of patients with acute DVT require specific consideration including those listed below.
Patients with contraindications to anticoagulation — For patients with acute proximal DVT in whom anticoagulation is contraindicated or in whom the risk of bleeding is estimated by the clinician to outweigh the risk of VTE, an inferior vena cava (IVC) filter should be placed promptly. Patients with acute distal DVT in whom anticoagulation is contraindicated may be managed with surveillance ultrasonography. The indications and details of IVC filter placement are discussed separately. (See 'Inferior vena cava filter' below.)
Absolute contraindications to anticoagulation include:
●Severe bleeding diathesis
●Platelet count <50,000/microL
●Recent, planned, or emergent surgery/procedure
●History of intracranial hemorrhage
●History of heparin-induced thrombocytopenia
Relative contraindications to anticoagulation include:
●Recurrent bleeding from multiple gastrointestinal telangiectasias
●Intracranial or spinal tumors
●Platelet count <150,000/microL
●Large abdominal aortic aneurysm with concurrent severe hypertension
●Stable aortic dissection
Special consideration should also be given to avoiding anticoagulation, when feasible, in older patients (eg, >65 years) with a history of multiple falls, and the presence of more than one factor that elevates the bleeding risk. Such patients are at high risk of bleeding or have a high risk of a catastrophic result should a bleed occur. Consequently, the decision to anticoagulate in these populations should be even more cautious to allow the benefits of VTE prevention to be carefully weighed against the risk of bleeding.
Patients with a recent episode of minor bleeding such as epistaxis or heavy menstrual bleeding are not generally considered high risk for bleeding and anticoagulation can usually be administered safely in this population.
Assessing the risk of bleeding is discussed separately. (See 'Assessing bleeding risk' above.)
Patients with malignancy — In patients with cancer, treatment of DVT is associated with higher morbidity, due to higher than usual rates of both recurrent thrombosis and anticoagulant-associated bleeding. For patients with malignancy and DVT who have a reasonable life expectancy and who do not have renal insufficiency (creatinine clearance <30 mL/minute), or a contraindication to anticoagulation, low molecular weight (LMW) heparin is preferred for both initial and long-term anticoagulation rather than other agents. For long-term anticoagulation, warfarin may be preferred by those with a preference for oral medication who are injection averse. There is insufficient evidence to support the use of factor Xa and direct thrombin inhibitors in patients with malignancy at this time. The decision to anticoagulate for extended periods (finite or indefinite) should be similar to that in the general population and be balanced against the risk of bleeding, while also taking into consideration the presence of active or progressive cancer, quality of life, life expectancy, and patient preference. The treatment of venous thromboembolism in patients with malignancy is discussed in detail, separately. (See "Treatment of venous thromboembolism in patients with malignancy".)
Pregnancy — Pregnancy is a risk factor for the development of DVT. Adjusted-dose subcutaneous LMW heparin is the preferred agent for initial and long-term anticoagulation in pregnant women with acute DVT. This agent is preferred, because it has a more favorable safety profile, especially when compared with warfarin. Warfarin freely crosses the placental barrier and can produce an embryopathy when given between the sixth and ninth weeks of pregnancy. Intravenous and subcutaneous forms of unfractionated heparin are alternatives to LMW heparin. Fondaparinux and oral factor Xa and direct thrombin inhibitors have not been adequately tested in pregnant women with acute DVT and as such should not be administered.
The optimal duration of anticoagulation in pregnancy is unknown and should be individualized on a case-by-case basis. In general, the total duration of anticoagulant therapy (pregnancy plus the postpartum period) should be at least three to six months for women whose only risk factors for DVT were transient (eg, pregnancy, cesarean section). Anticoagulant therapy generally continues for at least six weeks postpartum. Patients with persistent risk factors for DVT may require a longer duration of therapy.
The treatment of DVT and use of anticoagulants in pregnancy are discussed in detail separately. (See "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment" and "Use of anticoagulants during pregnancy and postpartum".)
Phlegmasia cerulea dolens — Although uncommon, it is important to identify patients with phlegmasia cerulea dolens (PCD) because they should be considered for more aggressive management, usually thrombolysis and/or thrombectomy.
PCD is part of a clinical spectrum that ranges from phlegmasia alba dolens to venous gangrene [56-59]. PCD results from acute massive venous thrombosis that causes an obstruction of the venous drainage of an extremity (upper or lower) and is associated with a high degree of morbidity. Patients usually present with sudden severe pain, swelling, cyanosis, edema, venous gangrene, and compartment syndrome that together impair arterial supply, such that circulatory collapse and shock frequently ensue. Delay in treatment may result in death or loss of the patient's limb.
PCD occurs at any age but is more common during the fifth and sixth decades [56,57,60]. The incidence is higher in females than in males. Malignancy is the most common triggering factor and is present in approximately 20 to 40 percent of patients. Other associated risk factors include the typical risk factors for thrombosis (eg, inherited thrombophilias, surgery, trauma, vena caval filter insertion, pregnancy). Approximately 10 percent of patients have idiopathic PCD.
In the lower extremities, left-sided involvement is three to four times more common than right-sided involvement . Upper extremity PCD is unusual and occurs in less than 5 percent of patients.
Manifestations may be gradual or fulminant. Most cases are preceded by phlegmasia alba dolens, with symptoms of edema, pain, and blanching (alba) without cyanosis. As it progresses, massive fluid sequestration may lead to bleb and bullae formation and eventually cyanosis (cerulea) and venous gangrene ensue. The pain is constant, severe, and usually starts at the femoral triangle and progresses to the entire extremity. Cyanosis is the pathognomonic finding of PCD, progressing from distal to proximal areas.
PCD is the only accepted indication for thrombolysis and/or thrombectomy in patients with DVT, especially in those with signs of ischemia or gangrene. Accordingly, catheter-directed thrombolysis or rapid removal of the occluding thrombus using manual techniques (eg, surgical or catheter-directed thrombectomy) should be seriously considered in this population of patients [61-67]. Thus, it is prudent to obtain an interventional radiology and/or vascular surgery consultation for patients with PCD, especially those with impending gangrene. The selected intervention(s) will depend upon available expertise. Delayed implementation of these procedures should not prohibit the administration of systemic anticoagulation. Thrombolytic therapy and thrombectomy are discussed separately. (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Lower extremity deep vein thrombosis' and 'Thrombolytic therapy and thrombectomy' below.)
Heparin-induced thrombocytopenia — For patients with a DVT and a diagnosis of heparin-induced thrombocytopenia (HIT), all forms of heparin should be discontinued. This includes unfractionated heparin, LMW heparin, heparin flushes, heparin-bonded catheters, and heparin-containing medications. Immediate anticoagulation with a nonheparin anticoagulant (eg, argatroban, danaparoid, fondaparinux) is indicated, unless there is a strong contraindication to anticoagulation. The diagnosis and management of patients with HIT are discussed in detail, separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Management of heparin-induced thrombocytopenia".)
ADDITIONAL THERAPIES — Additional considerations for patients diagnosed with acute DVT include ambulation and graduated compression stockings for the prevention of post-thrombotic syndrome (PTS) as well as thrombolytic therapy and inferior vena cava filter placement, which are discussed in the sections below.
Ambulation — Despite prior concerns regarding the potential for embolization, early ambulation is safe in patients with acute deep venous thrombosis (DVT) and should be encouraged as soon as is feasible.
Several small randomized studies and meta-analyses have shown that early ambulation does not increase the risk of recurrent or fatal pulmonary embolism (PE) [26,27,68-76]. The risk of PE during more aggressive forms of exercise, physical therapy, or rehabilitation is unknown. However, in this setting we typically gradually increase exercise training as tolerated by the patient. Symptoms such as pain or leg edema may limit ambulation. Compression stockings may be useful for symptomatic relief and the promotion of ambulation.
Compression stockings for the prevention of PTS — Clinicians vary in their use of elastic graduated compression stockings (GCS) that provide 30 to 40 mmHg of ankle pressure for the prevention of post-thrombotic (postphlebitic) syndrome (PTS). While studies evaluating GCS have had mixed results regarding their efficacy, it is clear that they are not associated with harm. When the decision is made to use compression stockings, they should be started after anticoagulant therapy, within two weeks of the diagnosis, and continued for two years.
Evidence supporting the use of elastic GCS for the prevention of PTS is conflicting [8,47,77-84]. Most trials are hampered by methodologic flaws including imprecise estimation of recurrence and differing criteria for the assessment of PTS (Ginsberg or Villalta criteria). In addition, many trials were not blinded and had variable initial randomization periods (zero to two weeks) and control groups (no stockings, stockings with 5 mmHg pressure at the ankles, GCS one to two sizes too big). Small randomized trials of patients with acute DVT (first or recurrent) that used the Villalta criteria for PTS, suggested that GCS that apply an ankle pressure of 30 to 40 mmHg started within two weeks and continued for two years to reduce the occurrence of PTS by 50 percent without increasing the frequency of recurrent VTE [78,79]. Patients most likely to benefit included those with a proximal DVT, prior DVT, and those with symptoms. In contrast, a randomized placebo-controlled trial of 806 patients with first proximal DVT reported no difference in the rate of PTS with GCS as measured by the less stringent Ginsberg criteria (leg pain and swelling one month or more; 14 versus 13 percent) . A similar lack of benefit was reported when the more rigorous Villalta criteria were applied.
Although GCS are not harmful, many patients decline their use because they are uncomfortable, costly, inconvenient, and often require a healthcare giver for their application. However, a subset of patients with recurrent DVT or moderate to severe symptoms may consider the potential benefits of GCS to outweigh these inconveniences. When the decision is made to wear compression stockings, they should be started after anticoagulant therapy. This is to avoid the theoretical risk of promoting embolism to the lung from fresh clot in the lower extremity. GCS should be continued for two years, replaced every six months, and may require refitting once local swelling is reduced. Alternative approaches of compressive bandages, application of GCS for limited periods (eg, for the duration of anticoagulation) or following thrombolytic therapy have not been adequately evaluated.
Contraindications to GCS include skin ulceration, severe arterial insufficiency, allergy to the stocking material, and inability to apply stockings.
The use of compression stockings as a therapy for PTS is discussed separately. (See "Post-thrombotic (postphlebitic) syndrome".)
Thrombolytic therapy and thrombectomy — For most patients with acute lower extremity DVT, anticoagulant therapy alone is sufficient such that the routine use of thrombolytic therapy (systemic and catheter-directed) and/or thrombectomy (surgical or catheter-directed) is not indicated. Thrombolysis and/or thrombectomy are usually reserved for patients with phlegmasia cerulea dolens or massive iliofemoral DVT or for patients who fail therapeutic anticoagulation. Additionally, suitable candidates for thrombolysis should have symptoms for <14 days (ie, fresh clot; organized clot will not undergo lysis), good functional status, and low bleeding risk .
Thrombolytic therapy is not routinely administered for most patients with DVT. When compared with parenteral anticoagulation, although thrombolysis is associated with more rapid and complete lysis, reduced rates of PTS, and higher rates of preserved venous valve function, rates of recurrent venous thromboembolism and mortality are unchanged. In addition, the risk of major bleeding associated with systemic thrombolysis is considered by most experts to be unacceptably high when weighed against the benefits of decreased PTS.
Thrombolytic agents can be administered systemically or via a catheter inserted into the affected lower extremity vein (catheter-directed thrombolysis). It is generally considered that compared with systemic thrombolysis, catheter-directed thrombolysis can achieve clot lysis more rapidly and with lower doses, thereby reducing the risk of bleeding. One theoretical advantage of thrombolysis is a more complete removal of clot from smaller venules that cannot be removed surgically, a feature that may be important for patients with PCD who have severe venous gangrene [86,87]. (See 'Phlegmasia cerulea dolens' above.)
Mechanical thrombectomy (using catheter extraction or fragmentation) or surgical thrombectomy may also be considered as an alternative or adjunctive therapy to thrombolysis. It is thought that combined catheter-directed procedures (eg, thrombolysis plus fragmentation) may further minimize the risk of bleeding .
Despite insufficient data, we and others prefer that following thrombolytic therapy and/or thrombectomy, routine anticoagulation be administered for a minimum of three months in this population .
Thrombolytic therapy and the regimens used for acute pulmonary embolism and DVT are discussed in detail, separately. (See "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Lower extremity deep vein thrombosis' and "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Embolectomy'.)
Inferior vena cava filter — Inferior vena cava (IVC) filters are not routinely inserted in patients with acute DVT. Typically, IVC filters (table 4) are used in patients with acute proximal DVT and pulmonary embolism (PE) who have an absolute contraindication to anticoagulant therapy (eg, recent surgery, hemorrhagic stroke, active bleeding). Although not considered absolute indications, placement of an IVC filter is also often considered as an adjunctive therapy in patients with recurrent embolism despite adequate anticoagulation, as well as in patients in whom an additional embolic event would be poorly tolerated (eg, those with poor cardiopulmonary reserve from massive PE or underlying cardiopulmonary disease, hemodynamically unstable patients). The efficacy of IVC filter placement in patients with isolated distal DVT is unknown. Filters are typically placed in the infrarenal portion of the IVC; as such, their major purpose is the prevention of embolization of lower extremity clot to the lung. In general, we prefer retrievable filters but the compliance with retrieval tends to be low. (See "Placement of vena cava filters and their complications".)
For patients in whom an IVC filter is placed, we and others agree that once the risk of bleeding is assessed as low that a conventional course of anticoagulation therapy should be administered and the filter removed, when feasible . (See 'Initial anticoagulation (first 10 days)' above.)
The many types of filters that are available, some of which are approved by regulatory agencies, are listed in the table (table 4). However, there are no data to suggest that one type of filter is superior to another.
In patients with acute DVT who have a contraindication to anticoagulation, retrospective and observational case series report that rates of recurrent PE following filter insertion are low (2 to 4 percent in most series) [88-90]. Although some cohort studies of patients with contraindications to anticoagulation report lower fatality rates from PE in patients with IVC filters, there is no evidence that IVC filters prevent PE-related death [91,92].
When IVC filters are used as an adjunctive therapy to anticoagulation, reports are conflicting on their efficacy. As examples:
●In one of the largest trials to date (PREPIC1) that examined the effectiveness of IVC filters, 400 patients with proximal DVT were randomly assigned to either standard anticoagulation alone or anticoagulation plus insertion of an IVC filter . During the first 12 days after randomization, significantly fewer patients in the IVC filter group developed a PE (1 versus 5 percent). However, after a two-year follow-up period, there were no significant differences in survival or symptomatic PE between the two groups, and a significantly higher rate of DVT was observed among patients who had received an IVC filter (21 versus 12 percent). An eight-year follow-up of the same population of patients confirmed these findings that filter placement was associated with a successful reduction in the rate of PE (15 versus 6 percent) but an increase in the rate of DVT (35 versus 28 percent) . No difference in mortality was reported.
●A similarly designed randomized trial (PREPIC2) reported outcomes in 399 patients with severe PE (eg, older patients >75 years, active cancer, signs of right ventricle dysfunction, chronic respiratory insufficiency) who received either standard anticoagulation alone or anticoagulation plus an IVC filter that was retrieved at three months . The addition of an IVC filter to anticoagulation did not alter the rate of PE recurrence (1.5 versus 3 percent), DVT recurrence (0.5 percent), or mortality (7.5 versus 6 percent) at three months. The lack of benefit associated with IVC filter placement persisted by six months. The rate of filter complications (eg, thrombosis) was low (<2 percent).
●Data derived from the National Inpatient Sample reported that compared with thrombolytic therapy alone, the insertion of a vena cava filter was associated with a lower in-hospital case fatality rate among unstable patients who received thrombolytic therapy (8 versus 18 percent) as well as unstable patients who did not receive thrombolytic therapy (33 versus 51 percent) [92,96]. Filters did not improve in-hospital case fatality rate if DVT was diagnosed in hemodynamically stable patients. Additionally, in a Japanese database, analysis of over 13,000 patients with pulmonary embolism who were treated with either thrombolytic or anticoagulant therapy, a reduction in hospital mortality was reported in those who were adjunctively treated with an IVC filter compared with those who did not receive a filter (3 versus 5 percent) .
Several studies report higher rates of DVT with IVC filter insertion, particularly in those in whom anticoagulation is contraindicated and those with known DVT [88,95,98-100]. As examples:
●A comprehensive review of retrospective case series reported that venous thrombosis at the site of insertion occurs in 10 percent of patients when an IVC filter was placed when anticoagulation was contraindicated .
●An additional prospective observational study of patients in whom permanent filters were placed reported that filter thrombosis occurred in 30 percent, DVT in 20 percent, and PE in 5 percent .
●A systematic review of 11 studies in patients in whom a permanent filter was placed for primary or secondary prevention reported high rates of the signs and symptoms of PTS (50 and 20 percent, respectively) [98,99].
●In PREPIC1, which was comprised of patients with DVT who were fully anticoagulated, the rate of DVT associated with adjunctive IVC filter insertion was 21 and 35 percent, at two and eight years, respectively. In contrast, in PREPIC2, which was comprised of patients with PE who were fully anticoagulated, rates of DVT in association with a retrievable filter were less than 1 percent .
Although retrievable filters have the theoretical potential to eliminate the risk of DVT, there is no direct evidence to support this hypothesis and data from observational case series suggest low compliance with their insertion as well as low retrieval rates in practice [101-104].
Several practical factors that may influence the decision to place a filter should be considered in every patient:
●The site of origin of the embolic event must be such that the filter will provide a beneficial effect. For example, infrarenal caval filter placement will not be of prophylactic value if the emboli originated in the renal veins, a cardiac chamber, or the upper extremity veins.
●IVC filter placement is associated with its own set of complications (eg, guidewire entrapment, local hemorrhage, fracture, embolization) and mortality (0.12 to 0.3 percent) such that weighing these risks against those of recurrence is prudent. (See "Placement of vena cava filters and their complications", section on 'Complications' and "Placement of vena cava filters and their complications", section on 'Mortality'.)
For patients with PE who do not have proven clot in the lower extremities who also have a contraindication to anticoagulation, vena cava filters are often placed. This is because clot can quickly reform in the leg veins after embolization and may also remain undetected in the pelvis or calf veins with the potential to embolize. (See "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in adults", section on 'Inferior vena cava filters'.)
The placement and complications of inferior vena cava filters are discussed separately. (See "Placement of vena cava filters and their complications".)
MONITORING AND FOLLOW-UP — Patients should be monitored for the complications of DVT as well as those of anticoagulation. These include further clot extension, recurrence, embolization, post-thrombotic (postphlebitic) syndrome, chronic thromboembolic pulmonary hypertension, bleeding, and thrombosis-related or bleeding-related death. During anticoagulation patients should also be monitored for the development of conditions that affect the half-life of the anticoagulant used (eg, renal failure, pregnancy, weight gain/loss). The most common laboratory test used to monitor warfarin is the prothrombin time (PT) ratio usually expressed as the international normalized ratio (INR). The goal INR is 2 to 3 (target 2.5). Low molecular weight heparin, fondaparinux, and the factor Xa and direct thrombin inhibitors do not require routine laboratory monitoring. Monitoring patients for therapeutic efficacy and bleeding is discussed separately. (See "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)", section on 'Monitoring' and "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism", section on 'Making the decision to indefinitely anticoagulate'.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
●Basics topics (see "Patient information: Deep vein thrombosis (blood clots in the legs) (The Basics)")
●Beyond the Basics topics (see "Patient information: Deep vein thrombosis (DVT) (Beyond the Basics)" and "Patient information: Warfarin (Coumadin) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Anticoagulation is the mainstay of therapy for patients with acute deep venous thrombosis (DVT). Initial anticoagulation is administered over the first 5 to 10 days to provide protection from recurrent thrombosis in this period of highest risk. Long term (finite) anticoagulation is administered for a minimum of three months and extended for 6 to 12 months in some cases. A small population of patients will require indefinite anticoagulation. (See 'Nomenclature' above.)
●For most patients with acute symptomatic proximal DVT, we recommend anticoagulation rather than no anticoagulation (Grade 1B), provided the risk of bleeding is low. In patients with asymptomatic lower extremity DVT, we suggest anticoagulation identical to that for patients with symptomatic DVT. For most patients with symptomatic isolated distal DVT we suggest anticoagulation rather than observation (Grade 2C). For select patients with isolated distal DVT (eg, those at high risk of bleeding, asymptomatic distal DVT, and extensive thrombosis), we suggest surveillance with serial ultrasound over a two-week period rather than anticoagulation (Grade 2C). (See 'Indications' above.)
●In most patients, anticoagulation should be started immediately (initial anticoagulation) as a delay in therapy increases the risk of potentially life-threatening embolization (see "Lower extremity deep venous thrombosis: Initiation of anticoagulation (first 10 days)"):
•For most patients, we suggest low molecular weight (LMW) heparin, fondaparinux, or intravenous unfractionated heparin (UFH) rather than factor Xa or direct thrombin inhibitors as initial therapy for DVT (Grade 2B). Of these, we prefer LMW heparin or fondaparinux rather than UFH for most patients; a decision between these two agents is usually made based on clinician experience and availability. In contrast, we prefer UFH in patients with severe renal failure (eg, creatinine clearance <30 mL/minute) and in those more likely to require rapid reversal of anticoagulation. LMW heparin is the agent of choice in pregnancy and in patients with malignancy.
•Oral anticoagulation with a factor Xa inhibitor (eg, rivaroxaban, apixaban, edoxaban) or direct thrombin inhibitor (dabigatran) may be an acceptable alternative for patients who wish to avoid the burden of daily injections. Only rivaroxaban and apixaban (factor Xa inhibitors) have proven efficacy as monotherapy, while edoxaban (factor Xa inhibitor) and dabigatran (direct thrombin inhibitor) require a short course of systemic heparin prior to their administration (ie dual therapy).
●Therapeutic anticoagulation should be ensured during the transition from initial to long-term (maintenance) therapy. Interruptions should be minimized during the first three months of anticoagulation due to the high risk of recurrent thrombosis (see "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)"):
•Options for patients who wish to avoid the burden of INR monitoring include LMW heparin, fondaparinux, factor Xa inhibitors, and direct thrombin inhibitors. For such patients, we suggest LMW heparin or fondaparinux rather than factor Xa or direct thrombin inhibitors (Grade 2C). LMW heparin is the agent of choice in pregnancy and patients with malignancy.
●For patients with acute DVT, the duration of anticoagulation should be individualized according to the presence or absence of provoking events, risk factors for recurrence and bleeding, as well as to the individual patient's preferences and values (algorithm 1).
•For most patients with a first episode of proximal DVT (provoked or unprovoked), we recommend anticoagulation for a minimum of three months rather than for shorter periods (eg, four or six weeks) (Grade 1B). For patients with provoked DVT who have persistent but reversible risk factors (eg, continued estrogen use, prolonged immobility following trauma), we suggest extending anticoagulation for a finite period until the risk factor is resolved rather than stopping anticoagulation at three months (Grade 2C). (See "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)", section on 'Duration of treatment'.)
•For most patients with a first episode of isolated distal DVT (provoked or unprovoked) in whom anticoagulation is indicated, we suggest anticoagulation for three months rather than shorter (eg, four or six weeks) periods (Grade 2C). (See "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)", section on 'Duration of treatment'.)
•Patients most likely to benefit from indefinite anticoagulation are those with a first or recurrent episode of unprovoked DVT, in particular those with proximal DVT. Indefinite anticoagulation should NOT be routinely administered to patients with an episode of VTE provoked by major transient risk factors (eg, surgery) or those in whom the risk of bleeding is considered to be high. (See "Rationale and indications for indefinite anticoagulation in patients with venous thromboembolism".)
●Special populations of patients with acute DVT require specific consideration:
•For patients in whom anticoagulation is contraindicated or in whom the risk of bleeding is estimated to outweigh the risk of recurrent thromboembolism, we suggest the insertion of an IVC filter rather than no therapy (Grade 2C). We also suggest that an IVC filter be placed for patients with acute proximal DVT who have recurrent embolism despite adequate anticoagulation and for patients who have poor cardiopulmonary reserve who may not tolerate additional embolism. We prefer retrievable filters for the avoidance long term complications of filter placement. Additionally, we prefer that patients with DVT receive a conventional course of anticoagulation once the contraindication resolves. (See 'Patients with contraindications to anticoagulation' above and 'Inferior vena cava filter' above.)
•For patients with malignancy and pregnant women, we suggest that LMW heparin be selected as the initial and long-term anticoagulant of choice rather than other agents (Grade 2C). Factor Xa and direct thrombin inhibitors have not been adequately tested in patients with malignancy or in pregnant women with acute DVT and as such should not be administered. (See 'Special populations' above and "Treatment of venous thromboembolism in patients with malignancy" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment".)
•For patients with massive iliofemoral DVT or phlegmasia cerulea dolens with symptoms for <14 days and good functional status, we suggest systemic or catheter-directed thrombolytic therapy, and/or clot removal (eg, catheter extraction, catheter fragmentation, surgical thrombectomy) rather than anticoagulation alone (Grade 2C). The most appropriate intervention depends upon the institution's expertise. (See 'Phlegmasia cerulea dolens' above and "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein thrombosis", section on 'Lower extremity deep vein thrombosis'.)
•For patients with a DVT and a diagnosis of heparin-induced thrombocytopenia (HIT), all forms of heparin should be discontinued and immediate anticoagulation with a nonheparin anticoagulant started. (See "Management of heparin-induced thrombocytopenia".)
●For patients with acute DVT who are fully anticoagulated, hemodynamically stable, and whose symptoms (eg, pain, swelling) are under control, we suggest early ambulation in preference to bed rest (Grade 2C). For patients in whom the prevention of post thrombotic syndrome is a consideration, we suggest elastic graduated compression stockings (GCS) with a pressure of 30 to 40 mmHg at the ankle rather than no compression stockings (Grade 2C). GCS may be applied within two weeks and continued for two years. (See 'Ambulation' above and 'Compression stockings for the prevention of PTS' above.)
●Patients should be monitored for the complications of DVT as well as those of anticoagulation. These include further clot extension, recurrence, embolization, post-thrombotic (postphlebitic) syndrome, chronic thromboembolic pulmonary hypertension, bleeding, and thrombosis-related or bleeding-related death. (See 'Monitoring and follow-up' above.)
- Husted S, de Caterina R, Andreotti F, et al. Non-vitamin K antagonist oral anticoagulants (NOACs): No longer new or novel. Thromb Haemost 2014; 111:781.
- Barnes GD, Ageno W, Ansell J, et al. Recommendation on the nomenclature for oral anticoagulants: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13:1154.
- Browse NL, Thomas ML. Source of non-lethal pulmonary emboli. Lancet 1974; 1:258.
- Havig O. Deep vein thrombosis and pulmonary embolism. An autopsy study with multiple regression analysis of possible risk factors. Acta Chir Scand Suppl 1977; 478:1.
- Galanaud JP, Sevestre-Pietri MA, Bosson JL, et al. Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study. Thromb Haemost 2009; 102:493.
- BARRITT DW, JORDAN SC. Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet 1960; 1:1309.
- Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010; 152:578.
- Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e419S.
- Palareti G, Cosmi B, Legnani C, et al. D-dimer to guide the duration of anticoagulation in patients with venous thromboembolism: a management study. Blood 2014; 124:196.
- Horner D, Hogg K, Body R, et al. The anticoagulation of calf thrombosis (ACT) project: results from the randomized controlled external pilot trial. Chest 2014; 146:1468.
- Kearon C. Natural history of venous thromboembolism. Circulation 2003; 107:I22.
- Masuda EM, Kistner RL. The case for managing calf vein thrombi with duplex surveillance and selective anticoagulation. Dis Mon 2010; 56:601.
- Righini M, Paris S, Le Gal G, et al. Clinical relevance of distal deep vein thrombosis. Review of literature data. Thromb Haemost 2006; 95:56.
- Schwarz T, Schmidt B, Beyer J, Schellong SM. Therapy of isolated calf muscle vein thrombosis with low-molecular-weight heparin. Blood Coagul Fibrinolysis 2001; 12:597.
- Macdonald PS, Kahn SR, Miller N, Obrand D. Short-term natural history of isolated gastrocnemius and soleal vein thrombosis. J Vasc Surg 2003; 37:523.
- Gillet JL, Perrin MR, Allaert FA. Short-term and mid-term outcome of isolated symptomatic muscular calf vein thrombosis. J Vasc Surg 2007; 46:513.
- Lautz TB, Abbas F, Walsh SJ, et al. Isolated gastrocnemius and soleal vein thrombosis: should these patients receive therapeutic anticoagulation? Ann Surg 2010; 251:735.
- Schwarz T, Buschmann L, Beyer J, et al. Therapy of isolated calf muscle vein thrombosis: a randomized, controlled study. J Vasc Surg 2010; 52:1246.
- Sales CM, Haq F, Bustami R, Sun F. Management of isolated soleal and gastrocnemius vein thrombosis. J Vasc Surg 2010; 52:1251.
- Palareti G, Cosmi B, Lessiani G, et al. Evolution of untreated calf deep-vein thrombosis in high risk symptomatic outpatients: the blind, prospective CALTHRO study. Thromb Haemost 2010; 104:1063.
- De Martino RR, Wallaert JB, Rossi AP, et al. A meta-analysis of anticoagulation for calf deep venous thrombosis. J Vasc Surg 2012; 56:228.
- Boutitie F, Pinede L, Schulman S, et al. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials. BMJ 2011; 342:d3036.
- 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:e152S.
- den Exter PL, van Es J, Erkens PM, et al. Impact of delay in clinical presentation on the diagnostic management and prognosis of patients with suspected pulmonary embolism. Am J Respir Crit Care Med 2013; 187:1369.
- Smith SB, Geske JB, Maguire JM, et al. Early anticoagulation is associated with reduced mortality for acute pulmonary embolism. Chest 2010; 137:1382.
- Koopman MM, Prandoni P, Piovella F, et al. Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group. N Engl J Med 1996; 334:682.
- Levine M, Gent M, Hirsh J, et al. A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med 1996; 334:677.
- Boccalon H, Elias A, Chalé JJ, et al. Clinical outcome and cost of hospital vs home treatment of proximal deep vein thrombosis with a low-molecular-weight heparin: the Vascular Midi-Pyrenees study. Arch Intern Med 2000; 160:1769.
- O'Shaughnessy D, Miles J, Wimperis J. UK patients with deep-vein thrombosis can be safely treated as out-patients. QJM 2000; 93:663.
- Grau E, Tenias JM, Real E, et al. Home treatment of deep venous thrombosis with low molecular weight heparin: Long-term incidence of recurrent venous thromboembolism. Am J Hematol 2001; 67:10.
- Dunn A, Bioh D, Beran M, et al. Effect of intravenous heparin administration on duration of hospitalization. Mayo Clin Proc 2004; 79:159.
- Dunn AS, Schechter C, Gotlin A, et al. Outpatient treatment of deep venous thrombosis in diverse inner-city patients. Am J Med 2001; 110:458.
- Segal JB, Bolger DT, Jenckes MW, et al. Outpatient therapy with low molecular weight heparin for the treatment of venous thromboembolism: a review of efficacy, safety, and costs. Am J Med 2003; 115:298.
- Chong BH, Brighton TA, Baker RI, et al. Once-daily enoxaparin in the outpatient setting versus unfractionated heparin in hospital for the treatment of symptomatic deep-vein thrombosis. J Thromb Thrombolysis 2005; 19:173.
- Daskalopoulos ME, Daskalopoulou SS, Tzortzis E, et al. Long-term treatment of deep venous thrombosis with a low molecular weight heparin (tinzaparin): a prospective randomized trial. Eur J Vasc Endovasc Surg 2005; 29:638.
- Ramacciotti E, Araújo GR, Lastoria S, et al. An open-label, comparative study of the efficacy and safety of once-daily dose of enoxaparin versus unfractionated heparin in the treatment of proximal lower limb deep-vein thrombosis. Thromb Res 2004; 114:149.
- Othieno R, Abu Affan M, Okpo E. Home versus in-patient treatment for deep vein thrombosis. Cochrane Database Syst Rev 2007; :CD003076.
- Trujillo-Santos J, Lozano F, Lorente MA, et al. A prognostic score to identify low-risk outpatients with acute deep vein thrombosis in the lower limbs. Am J Med 2015; 128:90.e9.
- Douketis JD. Treatment of deep vein thrombosis: what factors determine appropriate treatment? Can Fam Physician 2005; 51:217.
- Rodger M, Bredeson C, Wells PS, et al. Cost-effectiveness of low-molecular-weight heparin and unfractionated heparin in treatment of deep vein thrombosis. CMAJ 1998; 159:931.
- O'Brien B, Levine M, Willan A, et al. Economic evaluation of outpatient treatment with low-molecular-weight heparin for proximal vein thrombosis. Arch Intern Med 1999; 159:2298.
- Bäckman K, Carlsson P, Kentson M, et al. Deep venous thrombosis: a new task for primary health care. A randomised economic study of outpatient and inpatient treatment. Scand J Prim Health Care 2004; 22:44.
- Huse DM, Cummins G, Taylor DC, Russell MW. Outpatient treatment of venous thromboembolism with low-molecular-weight heparin: an economic evaluation. Am J Manag Care 2002; 8:S10.
- Spyropoulos AC, Hurley JS, Ciesla GN, de Lissovoy G. Management of acute proximal deep vein thrombosis: pharmacoeconomic evaluation of outpatient treatment with enoxaparin vs inpatient treatment with unfractionated heparin. Chest 2002; 122:108.
- Tillman DJ, Charland SL, Witt DM. Effectiveness and economic impact associated with a program for outpatient management of acute deep vein thrombosis in a group model health maintenance organization. Arch Intern Med 2000; 160:2926.
- van den Belt AG, Bossuyt PM, Prins MH, et al. Replacing inpatient care by outpatient care in the treatment of deep venous thrombosis--an economic evaluation. TASMAN Study Group. Thromb Haemost 1998; 79:259.
- Segal JB, Streiff MB, Hofmann LV, et al. Management of venous thromboembolism: a systematic review for a practice guideline. Ann Intern Med 2007; 146:211.
- Gould MK, Dembitzer AD, Sanders GD, Garber AM. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A cost-effectiveness analysis. Ann Intern Med 1999; 130:789.
- de Lissovoy G, Yusen RD, Spiro TE, et al. Cost for inpatient care of venous thrombosis: a trial of enoxaparin vs standard heparin. Arch Intern Med 2000; 160:3160.
- Hokusai-VTE Investigators, Büller HR, Décousus H, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369:1406.
- Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361:2342.
- EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499.
- Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369:799.
- Wells PS, Forgie MA, Rodger MA. Treatment of venous thromboembolism. JAMA 2014; 311:717.
- Kearon C, Akl EA. Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism. Blood 2014; 123:1794.
- Sarwar S, Narra S, Munir A. Phlegmasia cerulea dolens. Tex Heart Inst J 2009; 36:76.
- Haimovici H. The ischemic forms of venous thrombosis. 1. Phlegmasia cerulea dolens. 2. Venous gangrene. J Cardiovasc Surg (Torino) 1965; 5:Suppl:164.
- Langeron P, Gillot C. [Phlegmasia caerulea dolens . Acute venous stasis and ischemic phlebothrombosis]. J Mal Vasc 1992; 17:116.
- Perkins JM, Magee TR, Galland RB. Phlegmasia caerulea dolens and venous gangrene. Br J Surg 1996; 83:19.
- Brockman SK, Vasko JS. Phlegmasia cerulea dolens. Surg Gynecol Obstet 1965; 121:1347.
- Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:454S.
- Meissner MH, Gloviczki P, Comerota AJ, et al. Early thrombus removal strategies for acute deep venous thrombosis: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg 2012; 55:1449.
- Tung CS, Soliman PT, Wallace MJ, et al. Successful catheter-directed venous thrombolysis in phlegmasia cerulea dolens. Gynecol Oncol 2007; 107:140.
- Oguzkurt L, Tercan F, Ozkan U. Manual aspiration thrombectomy with stent placement: rapid and effective treatment for phlegmasia cerulea dolens with impending venous gangrene. Cardiovasc Intervent Radiol 2008; 31:205.
- Vedantham S. Interventional approaches to acute venous thromboembolism. Semin Respir Crit Care Med 2008; 29:56.
- Casey ET, Murad MH, Zumaeta-Garcia M, et al. Treatment of acute iliofemoral deep vein thrombosis. J Vasc Surg 2012; 55:1463.
- Bashir R, Zack CJ, Zhao H, et al. Comparative outcomes of catheter-directed thrombolysis plus anticoagulation vs anticoagulation alone to treat lower-extremity proximal deep vein thrombosis. JAMA Intern Med 2014; 174:1494.
- Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133:454S.
- Schellong SM, Schwarz T, Kropp J, et al. Bed rest in deep vein thrombosis and the incidence of scintigraphic pulmonary embolism. Thromb Haemost 1999; 82 Suppl 1:127.
- Partsch H, Blättler W. Compression and walking versus bed rest in the treatment of proximal deep venous thrombosis with low molecular weight heparin. J Vasc Surg 2000; 32:861.
- Aschwanden M, Labs KH, Engel H, et al. Acute deep vein thrombosis: early mobilization does not increase the frequency of pulmonary embolism. Thromb Haemost 2001; 85:42.
- Partsch H. Therapy of deep vein thrombosis with low molecular weight heparin, leg compression and immediate ambulation. Vasa 2001; 30:195.
- Aldrich D, Hunt DP. When can the patient with deep venous thrombosis begin to ambulate? Phys Ther 2004; 84:268.
- Anderson CM, Overend TJ, Godwin J, et al. Ambulation after deep vein thrombosis: a systematic review. Physiother Can 2009; 61:133.
- Aissaoui N, Martins E, Mouly S, et al. A meta-analysis of bed rest versus early ambulation in the management of pulmonary embolism, deep vein thrombosis, or both. Int J Cardiol 2009; 137:37.
- Kahn SR, Shrier I, Kearon C. Physical activity in patients with deep venous thrombosis: a systematic review. Thromb Res 2008; 122:763.
- Snow V, Qaseem A, Barry P, et al. Management of venous thromboembolism: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 2007; 146:204.
- Prandoni P, Lensing AW, Prins MH, et al. Below-knee elastic compression stockings to prevent the post-thrombotic syndrome: a randomized, controlled trial. Ann Intern Med 2004; 141:249.
- Brandjes DP, Büller HR, Heijboer H, et al. Randomised trial of effect of compression stockings in patients with symptomatic proximal-vein thrombosis. Lancet 1997; 349:759.
- Kahn SR, Ginsberg JS. The post-thrombotic syndrome: current knowledge, controversies, and directions for future research. Blood Rev 2002; 16:155.
- Ginsberg JS, Hirsh J, Julian J, et al. Prevention and treatment of postphlebitic syndrome: results of a 3-part study. Arch Intern Med 2001; 161:2105.
- Partsch H, Kaulich M, Mayer W. Immediate mobilisation in acute vein thrombosis reduces post-thrombotic syndrome. Int Angiol 2004; 23:206.
- Aschwanden M, Jeanneret C, Koller MT, et al. Effect of prolonged treatment with compression stockings to prevent post-thrombotic sequelae: a randomized controlled trial. J Vasc Surg 2008; 47:1015.
- Kahn SR, Comerota AJ, Cushman M, et al. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation 2014; 130:1636.
- Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet 2014; 383:880.
- Mousa A, Henderson P, Dayal R, et al. Endoluminal recanalization in a patient with phlegmasia cerulea dolens using a multimodality approach. Vascular 2005; 13:313.
- Lin SC, Mousa A, Bernheim J, et al. Endoluminal recanalization in a patient with phlegmasia cerulea dolens using a multimodality approach-a case report. Vasc Endovascular Surg 2005; 39:273.
- Streiff MB. Vena caval filters: a comprehensive review. Blood 2000; 95:3669.
- Becker DM, Philbrick JT, Selby JB. Inferior vena cava filters. Indications, safety, effectiveness. Arch Intern Med 1992; 152:1985.
- Girard P, Stern JB, Parent F. Medical literature and vena cava filters: so far so weak. Chest 2002; 122:963.
- Muriel A, Jiménez D, Aujesky D, et al. Survival effects of inferior vena cava filter in patients with acute symptomatic venous thromboembolism and a significant bleeding risk. J Am Coll Cardiol 2014; 63:1675.
- Stein PD, Matta F. Vena cava filters in unstable elderly patients with acute pulmonary embolism. Am J Med 2014; 127:222.
- Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med 1998; 338:409.
- PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d'Embolie Pulmonaire par Interruption Cave) randomized study. Circulation 2005; 112:416.
- Mismetti P, Laporte S, Pellerin O, et al. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA 2015; 313:1627.
- Stein PD, Matta F, Keyes DC, Willyerd GL. Impact of vena cava filters on in-hospital case fatality rate from pulmonary embolism. Am J Med 2012; 125:478.
- Isogai T, Yasunaga H, Matsui H, et al. Effectiveness of inferior vena cava filters on mortality as an adjuvant to antithrombotic therapy. Am J Med 2015; 128:312.e23.
- Hajduk B, Tomkowski WZ, Malek G, Davidson BL. Vena cava filter occlusion and venous thromboembolism risk in persistently anticoagulated patients: a prospective, observational cohort study. Chest 2010; 137:877.
- Fox MA, Kahn SR. Postthrombotic syndrome in relation to vena cava filter placement: a systematic review. J Vasc Interv Radiol 2008; 19:981.
- Hemmila MR, Osborne NH, Henke PK, et al. Prophylactic Inferior Vena Cava Filter Placement Does Not Result in a Survival Benefit for Trauma Patients. Ann Surg 2015; 262:577.
- Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123:1788.
- Mismetti P, Rivron-Guillot K, Quenet S, et al. A prospective long-term study of 220 patients with a retrievable vena cava filter for secondary prevention of venous thromboembolism. Chest 2007; 131:223.
- Nicholson W, Nicholson WJ, Tolerico P, et al. Prevalence of fracture and fragment embolization of Bard retrievable vena cava filters and clinical implications including cardiac perforation and tamponade. Arch Intern Med 2010; 170:1827.
- Dabbagh O, Nagam N, Chitima-Matsiga R, et al. Retrievable inferior vena cava filters are not getting retrieved: where is the gap? Thromb Res 2010; 126:493.