Deep venous thrombosis (DVT) is a frequently encountered condition that is often diagnosed and treated in the outpatient setting. Risk stratification is helpful and recommended in the evaluation of DVT. An evidence-based diagnostic approach is discussed here. Once diagnosed, the mainstay of DVT treatment is anticoagulation. The specific type and duration of anticoagulation depend upon the suspected etiology of the venous thromboembolism, as well as risks of bleeding and other patient comorbidities. Both specific details and a standardized approach to this vast treatment landscape are presented.
Deep venous thrombosis (DVT) is part of the venous thromboembolic spectrum and is a relatively common condition.
Evaluation and diagnosis are performed by risk stratification utilizing the Wells score, d-dimer testing, and duplex ultrasound.
Treatment depends on individual conditions, but usually consists of anticoagulation for a finite or infinite period of time, depending on the suspected etiology of the thrombosis.
Adjunctive therapies such as caval filters, thrombolysis, and clot extraction play specific and limited roles.
Risks and benefits of anticoagulation or other modalities should be discussed with and individualized for patients.
An adjunctive search for causes of venous thromboembolism (VTE) should be investigated, beginning by looking for causes of provoked DVT, considering malignancy in the appropriate population, and finally assessing personal and family history in consideration of risks for thrombophilia.
Upper Extremity DVT is a rare condition that is usually associated with catheters, implantable devices, malignancy, or thrombophilia and is primarily treated with anticoagulation.
Deep venous thrombosis (DVT) is part of a spectrum of venous thromboembolic disorders that includes superficial thrombophlebitis and pulmonary embolism. DVT may be defined as “the formation of a blood clot within a deep vein. ” Although DVT most commonly occurs in the deep veins of the lower leg and thigh, it may also occur within the upper limb deep veins, visceral veins, and even the vena cava.
Deep venous thrombosis (DVT) is part of a spectrum of venous thromboembolic disorders that includes superficial thrombophlebitis and pulmonary embolism. DVT may be defined as “the formation of a blood clot within a deep vein. ” Although DVT most commonly occurs in the deep veins of the lower leg and thigh, it may also occur within the upper limb deep veins, visceral veins, and even the vena cava.
The true incidence of DVT is unknown. The estimated risk for first time venous thromboembolism (VTE) is 100 cases per 100,000 persons per year, yielding an annual incidence of 0.1% and generating an annual US incidence of over 1 million patients per year. The incidence of DVT appears to be equal between the sexes, although women present 1.6 times more often for evaluation of suspected DVT. DVT occurs more commonly as people age, with the rate in persons aged 60 years and older rising to nearly 1%. VTE remains a disease with high morbidity and mortality. The case fatality rate for VTE has been reported to be 10.6% at 30 days and 23% at 1 year. With prompt diagnosis and treatment, mortality declines dramatically. The 10-year recurrence rate after diagnosis of first-time DVT is approximately 25%. This peaks at 6 months and gradually declines to 2% per patient per year after 3 years, but is dependent on the etiology of the thrombosis. The estimated overall mortality from VTE in the United States ranges from 60,000 to 100,000 deaths per year. A subset of DVT is upper extremity DVT (UEDVT), which is far less common than lower extremity DVT (LEDVT). The prevalence of UEDVT is 0.15%, which constitutes about 1% to 4% of all DVTs. Survival rates of patients with UEDVT are also lower than those with LEDVT.
Virchow’s triad of alterations in blood flow, endothelial vascular injury, and derangements in the constitution of blood remain relevant over 150 years after they were first described. Stasis, whether caused by obstruction or immobilization, is thought to prevent the clearance and dilution of activated clotting factors. Injury to the vascular endothelium prevents the inhibition of coagulation and activates the clotting cascade. A propensity toward clotting secondary to hypercoagulability may be inherited or acquired.
DVT commonly begins in the calf, and, less commonly, the proximal veins of the lower extremity. Obstruction of venous outflow leads to swelling and pain with the subsequent activation of the inflammatory cascade. Many DVTs isolated within the calf veins will spontaneously resolve and are unlikely to embolize and cause pulmonary embolism (PE). Twenty-five percent of isolated calf vein DVTs will subsequently extend into more proximal deep veins. It is estimated that 50% of these may embolize, resulting in PE. DVT occasionally compromises vascular flow within the extremity, resulting in phlegmasia cerulea dolens, a painful and limb-threatening vascular disorder.
There are many risk factors for the development of DVT ( Table 1 ). Pregnancy increases the risk secondary to mechanical obstruction of the inferior vena cava, relative immobility, and hormonal influence. The increase in risk is approximately 0.13% and begins in the first trimester. Oral contraceptive (OCP) use roughly doubles the risk of VTE in patients, but the overall risk remains low because of the use of OCPs in generally healthy and young patients. Malignancies may double the risk of developing a DVT, although this risk is highly dependent upon the type of cancer, the use of chemotherapy or surgical treatment options, and immobility. Table 1 shows estimated relative risks for multiple conditions.
|Condition||Approximate Relative Risk|
|Protein C or S deficiency||10|
|Factor V Leiden mutation||Heterozygous: 5; homozygous: 50|
|Prothrombin gene mutation||2.5|
|Major surgery or trauma||5–200|
|History of VTE||50|
|Medical illness with hospitalization||5|
|Estrogen||OCPs: 5; hormone replacement: 2|
|Estrogen chemotherapy||Tamoxifen: 5; raloxifene: 3|
|Elevated factors VIII, IX or X (>90th percentile)||2.2–3|
In hospitalized surgical patients of all types, older data suggest that up to 25% of postoperative patients suffer VTE when not given prophylaxis, with higher rates (40%–60%) noted in postoperative orthopedic patients. Newer data suggest that with appropriate prophylaxis, this rate worldwide has dropped to 1%, and is perhaps 2% to 3% in the United States. Medical patients admitted to the hospital also have about a 25% risk of VTE without DVT prophylaxis. Among these patients, stroke patients carry the highest risk, up to 50%. Acute coronary syndrome patients have VTE rates of about 20% without prophylactic measures. Obesity is associated with increased risk of VTE. A body mass index (BMI) over 30 is estimated to roughly double the risk of VTE through a mechanism of venous stasis related to decreased lower extremity muscle contraction and venous pump. Individuals with a personal history of VTE are at increased risk for subsequent VTE 5 times above the normal population. Although often suspected by patients and some clinicians, there is no evidence to suggest uncomplicated varicose veins increase risk of VTE.
Long-haul flights are often assumed to be an independent risk for VTE, although the medical literature fails to adequately describe the associated risk. The proposed pathogenesis of VTE during air travel is related to relative hypoxia in airplane cabins, venous stasis from prolonged sitting, and dehydration. The rate of VTE (PE or DVT) on long-haul flights has been estimated to lie between 1.1 case per million person-days (roughly the rate of VTE in the healthy population) to 2000 times that (3%–12% of travelers). One analysis postulates flights of 8 hours or more may pose an increased risk of VTE if additional risk factors are present. In a separate outcome study in which 545 patients (6.9%) had VTE, risks of VTE were substantially increased by the presence of limb, whole-body, or neurologic immobility, but not by travel greater than 8 hours. There is general consensus in the literature that many underlying prothrombotic conditions (age >40, obesity, OCP use, genetic thrombophilia) enhance the risk of developing VTE during long travel, whether by airplane, train, or car.
Superficial thrombophlebitis (ST) is a distinct disease entity from DVT but has similar causal mechanisms, with an associated risk of DVT of 6.8% to 40%. The high range of associated DVT is thought to be caused by variation in study design; therefore ST is not thought to be an independent risk for DVT. However, it is considered prudent to perform a duplex ultrasound of the affected limb to evaluate for ST and concomitant DVT. Complete assessment and treatment of ST are beyond the scope of this article, but when DVT is diagnosed in the setting of nonsuppurative ST, the treatment of DVT is unchanged.
Underlying thrombophilia is an independent risk for VTE, above and beyond the aforementioned risks. Approximately 50% of individuals with VTE are found to have inherited thrombophilia disorders. Thrombophilic testing identifies an etiology in about one-third of patients but has not been shown to alter outcome or duration of therapy in the past. Table 2 demonstrates the quantified risks of recurrent VTE from specific thrombophilic disorders.
|Risk Factor||Estimated Relative Risk of Recurrent Venous Thromboembolism|
|Protein C or S deficiency||1.5–3|
|Factor V Leiden mutation||1–4|
|Prothrombin gene mutation||1–5|
|Elevated factor VIII or IX levels||1–7|
Thrombophilia is broadly classified into loss-of-function (protein C, protein S, antithrombin III) or gain-of-function (factor V Leiden and prothrombin 20210A gene mutation) protein disorders that fail to provide homeostasis between clot formation and dissolution. Factor V Leiden is present in about 5% of the population, with heterozygotes at 3 times increased risk of VTE compared with the normal population, and homozygotes 50 to 80 times the normal population. Prothrombin 20210A is a noncoding gene mutation that leads to elevated plasma prothrombin levels. Hyperhomocysteinemia and elevated levels of coagulation factors VIII, IX, and XI are suggested to have an additive, but not independent, effect in generating VTE.
In cases of UEDVT, the subclavian (74%) and axillary (38%) veins are most commonly affected. Risk factors for UEDVT are cancer, central venous catheters, and thrombophilia. Central venous catheters (CVCs) are the largest independent risk for the development of UEDVT, but only 3% of those with these devices develop a clot. Cancer appears to be an important risk factor in UEDVT in those DVTs that are not related to CVCs. Implantable pacemakers have a rate of UEDVT of about 5%. UEDVT is thought to be less common than LEDVT because of higher rates of flow, increased mobility, and use of the upper extremity compared with the lower extremities and less stasis from gravity.
The presentation of DVT can range from completely asymptomatic to pain, heaviness, or a cramping sensation in the affected extremity. Local swelling or discoloration of the affected limb may accompany these complaints. Multiple eponymous signs and tests (Michaelli sign, Mahler sign, Homan test, Loewenberg test) attempt to quantify or qualify the history and examination findings. Despite the focus on calf tenderness, the signs and tests have failed to consistently or adequately diagnose DVT and have diagnostic accuracies around 50%. Thus, these subjective and objective findings lack the sensitivity and specificity to diagnose DVT.
The differential diagnosis for LEDVT is broad. In one study, DVT was found in 21% of patients, while alternative diagnoses were found 8% of the time or less and included Baker cyst (3%), general edema (8%), calf hematoma (4%), superficial vein thrombosis (5%), muscle vein thrombosis (4%), cellulitis and erysipelas (4%), and varicose veins (3%). Also included in the differential are Achilles tendonitis, trauma, abscess, torn gastrocnemius muscle, acute arterial ischemia, venous or lymphatic obstruction, femur fracture, hemarthrosis of the knee, torn meniscus, congestive heart failure, nephrotic syndrome, liver failure, soft tissue tumor, and others.
UEDVT is most commonly found after a patient develops swelling of the upper extremity. Few are associated with erythema (6% in one study), although pain (40%) was the most common associated complaint. CVC-related UEDVT is less commonly associated with pain or symptoms because of slower clot growth. These CVC-associated clots are often more subtle and suggested by transient hand edema after dialysis, high dialysis pressures, or difficulty drawing blood from the catheter.
Diagnosing deep venous thrombosis
As already indicated, physical examination and elements of a patient’s history are poor independent predictors of VTE and are therefore not sufficient for the diagnosis of DVT. Comprehensive evaluation for VTE should always begin with risk stratification, followed by adjunctive testing based upon an identified level of risk. Adjunctive testing for DVT usually includes d-dimer or duplex ultrasound testing, and in very limited cases may include venography.
To improve upon the poor sensitivity and specificity of clinical examination findings, several scoring systems have been developed. Despite these objective analysis tools, 1 meta-analysis demonstrated that nonformal physician judgment was comparable to the validated scoring systems.
The Wells Scoring System
Developed in 1995, the Wells score ( Table 3 ) is the most widely used clinical decision instrument (CDI) for the diagnosis of DVT. The CDI risk stratifies patients into low, intermediate, or high risk for DVT based upon a point system that identifies risk factors and has been further developed to dichotomize patients into high and low probability categories. The interobserver reliability of the Wells score is excellent (kappa 0.85), with the most variability seen in the element of the score that considers the likelihood of an alternative diagnosis. Currently, the Wells score is recommended for use in practice in order to dichotomize or trichotomize patients into risk categories, and both methods have been independently validated.
|Findings on History and Examination||Point Value|
|Active cancer |
Treatment or palliation within 6 mo
|Bedridden recently ≥3 d or major surgery within 12 wk||1|
|Calf swelling >3 cm compared with the other leg |
Measured 10 cm below tibial tuberosity
|Collateral (nonvaricose) superficial veins present||1|
|Entire leg swollen||1|
|Localized tenderness along the deep venous system||1|
|Pitting edema, confined to symptomatic leg||1|
|Paralysis, paresis, or recent plaster immobilization of the lower extremity||1|
|Previously documented DVT||1|
|Alternative diagnosis to DVT at least as likely||−2|
In the original, 3-part risk stratification assessment, a Wells score (see Table 3 ) indicates levels of risk and includes low (Wells score 0 or less), moderate (Wells score 1–2), and high pretest probability (Wells score 3 or more) categories.
A 2-level risk assessment is also valid and combines the moderate- and higher-risk patients into one category. Low-risk (<2 points) and combined intermediate/high-risk (2 or more points) categories are thus created.
Both the 2-level and 3-level risk stratification techniques are used in clinical practice with adjunctive d-dimer and duplex ultrasound scanning to evaluate for DVT. A 2003 clinical policy recommendation from the American College of Emergency Physicians supports the use of DVT risk stratification using the Wells criteria along with d-dimer testing to safely exclude DVT (Level B recommendation).
D-dimer is a molecular marker that results from the dissolution of cross-linked fibrin. It is often elevated in thrombotic conditions; however, it may also be elevated in nonthrombotic conditions including pregnancy, malignancy, trauma, infection, and inflammatory conditions and is therefore not a specific marker for DVT. Multiple assays are available, with the enzyme linked immunosorbent assay (ELISA) possessing the highest sensitivity (94%). The current recommended testing strategy for first-time DVT includes assessment of pretest probability combined with high sensitivity d-dimer testing and compression ultrasound assessment.
In the dichotomized risk stratification approach, patients in the low category can safely undergo d-dimer testing, and if negative, the diagnosis of DVT can be reasonably excluded. If the d-dimer level is elevated, or if the pretest probability of DVT is intermediate or high based on the CDI, a duplex of the lower extremity should be performed.
In the trichotomized version, low-probability patients (Wells score 0 or less), should be offered the use of d-dimer, or proximal vein ultrasound. In moderate-probability patients (Wells score 1–2), highly sensitive d-dimer, proximal-vein ultrasound, or whole-leg ultrasound is favored over other modalities. In low- and moderate-risk patients, if d-dimer is negative, no further testing is warranted, while a positive d-dimer testing prompts compression ultrasound, but does not necessitate treatment. In high pretest probability patients, d-dimer testing should not be utilized, and one should proceed with duplex ultrasound of the extremity to evaluate for DVT. In addition, in a patient with a moderate or high pretest probability, if compression ultrasound is utilized and is initially negative, repeat testing with compression ultrasound or a moderate or high sensitivity d-dimer is recommended at 1 week follow-up. In cases where a patient has high pretest probability and there is no immediate access to utrasound, a single dose of low molecular weight heparin and a return visit within 12 hours for planned ultrasound are reasonable.
Testing for recurrent DVT is controversial, but recommendations favor the same modalities as for primary DVT assessment. Repeat duplex testing is warranted if d-dimer is positive but initial duplex is negative.
Increased age has the propensity to increase d-dimer values and may therefore decrease the diagnostic accuracy and specificity of the d-dimer. A 2014 systematic review found that age-adjusted (age × 10 μg per liter as the upper limit of normal) d-dimer values in older, nonhigh-risk patients increased the specificity and did not significantly decrease the sensitivity of the study. It is important to note that this was a derivation study, not a validation study, and to date the results have not undergone validation. Although not specifically evaluating the age-adjusted D-dimer on DVT, the ADJUST-PE trial did validate age-adjusted D-dimer for use in the evaluation of acute PE.
Pregnancy Adjusted D-dimer
Data have shown a consistent elevation in d-dimer levels as pregnancy progresses. This would serve to reduce the specificity of the d-dimer test, prompting unnecessary further evaluation. In 1 small study of asymptomatic women, none of the women had a d-dimer value less than the traditional cutoff value of 0.50 mg/L in the third trimester. The authors advocate for a prospective validation of cutoff values at 0.750, 1.0, and 1.5 mg/L for the first, second, and third trimesters, respectively. A small trial prospectively validated 3 d-dimer cutoff values at 286, 457, and 644 ng/mL in the first, second, and third trimesters, respectively and found 100% sensitivity for the adjusted values. The authors note their trial should be viewed as a pilot study and advocate for additional, larger studies.
Duplex ultrasound imaging, which includes B-mode imaging of veins as well as pulsed Doppler flow assessment, can evaluate for DVT in the proximal veins with specificity of 94% and sensitivity of 90%. A meta-analysis pooled 7 studies and demonstrated a 0.57% 3-month rate of VTE after single negative LE compression ultrasound. Duplex imaging modalities may include proximal-vein-only methods or whole leg scanning. Positive compression ultrasound of the lower extremity is sufficient to warrant treatment, and venography is not recommended for confirmation. Although venography remains an option, it may be associated with decreased availability, increased discomfort, and more complications, but it has a lower false-positive rate. A 2003 clinical policy recommendation from ACEP supports (level B evidence) the use of venous ultrasonography to safely exclude all proximal and symptomatic distal DVT. Serial ultrasounds are recommended for high-probability cases with negative initial imaging.
A 2014 study identified 362 individuals with DVT on compression ultrasound, of whom 6.3% had findings of isolated thrombi in proximal veins. The study authors used the data to support the recommendation of the addition of femoral and deep femoral vein evaluation to standard compression ultrasound of the common femoral and popliteal veins. In agreement with this are the 2015 guidelines from the American Institute of Ultrasound in Medicine (AIUM), which recommend :
“The fullest visualized extent of the common femoral, femoral, and popliteal veins must be imaged using an optimal gray scale compression technique. The popliteal vein is examined distally to the tibioperoneal trunk. The proximal deep femoral and proximal great saphenous veins should also be examined. Venous compression is applied every 2 cm or less in the transverse (short axis) plane with adequate pressure on the skin to completely obliterate the normal vein lumen.”
In addition, focal symptoms require individualized assessment.
For a normal examination, the minimum assessment and imaging documentation should include gray scale images with and without compression of the
Common femoral vein
Junction of the common femoral vein with the great saphenous vein
Proximal deep femoral vein separately or along with the proximal femoral vein
Proximal femoral vein
Distal femoral vein
In addition, color spectral Doppler waveforms from the long axis should be recorded at these levels :
Right common femoral or external iliac vein
Left common femoral or external iliac vein
Popliteal vein on symptomatic side or on both sides if the examination is bilateral
Abnormal examination findings require documentation and imaging of the abnormal finding.
For upper extremity assessment, the 2015 AIUM guidelines recommend that gray scale images or cine loops should be recorded without and with compression at each of the following levels :
Internal jugular vein
Peripheral subclavian vein
Brachial vein in the upper arm
Cephalic vein in the upper arm
Basilic vein in the upper arm
Focal symptomatic areas, if present
Color and spectral Doppler images are recorded at each of the following levels using the appropriate color technique to show filling of the normal venous lumen:
Internal jugular vein
If seen, the innominate vein should be recorded with color Doppler imaging.
At a minimum, both the right and left subclavian venous spectral Doppler waveforms should be recorded to evaluate for asymmetry or loss of cardiovascular pulsatility and respiratory phasicity.
Emergency Department Physician-Performed Imaging
A 2013 meta-analysis of 16 studies that assessed the diagnostic accuracy of emergency department physician lower extremity ultrasound for DVT demonstrated a kappa value of 0.83 between investigators, with a mean sensitivity of 96.5%. In the studies analyzed, there was high variability in training among emergency department physicians and variable study type (whole leg, 2 point, 3 point). Additional studies regarding emergency department physician DVT diagnoses have been conducted and have demonstrated highly variable results (sensitivity from 66% to 100%) but were subject to poor study methods. Overall, the studies seem to demonstrate that bedside performance of ultrasound for the evaluation of LEDVT by emergency department physicians is reasonable, but perhaps dependent upon experience and level of training.
Upper Extremity Deep Venous Thrombosis
Only about 50% of clinical investigations identify DVT in patients with suspected UEDVT. Contrast venography is the gold standard but invasive and requires contrast use. Ultrasound is 82% to 97% sensitive and 82% to 96% specific, and benefits from portability and lack of radiation use. Recommendations for the evaluation of UEDVT begin with risk stratification of patients into high or low probability. Both groups should begin their evaluation with color flow duplex ultrasonography. If UEDVT is found on ultrasound, treatment should be initiated. In low-risk patients in whom ultrasound is negative, serial ultrasound can be considered, or the evaluation can be stopped. In high-risk patients, contrast venography is recommended for further evaluation.
The approach to evaluation for LEDVT is summarized in Fig. 1 .
The management of DVT depends upon individual patient factors including the underlying etiology of the DVT, risks for bleeding, symptom severity, and patient preference. Given the multitude of combinations and possibilities, The American College of Chest Physicians has published guidelines for evaluation and management of VTE. These consensus guidelines are evidence based and updated every few years, referred to as the CHEST guidelines.
Isolated Distal Calf Deep Venous Thrombosis
Isolated distal calf VTE is special, as these cases may not progress to proximal DVT or PE. Authors suggest that all proximal LEDVT be treated and that calf vein DVT should either be treated empirically or followed with serial ultrasound to devaluate for proximal progression. Some authors recommend acute isolated DVT without severe symptoms or risks for progression be followed with serial ultrasound rather than anticoagulation, while those patients with severe symptoms or high risk for progression be treated with anticoagulation. Shared decision-making plays a large role in the decision to treat or perform serial imaging in isolated distal DVT, as patient preference may affect adherence to the treatment plan.
The remaining discussion of therapies reflects the treatment of proximal LEDVT.
Graded compression elastic stockings utilized for 2 years have demonstrated no decreased risk of recurrence of DVT, but did reduce the risk of post-thrombotic syndrome (PTS) at 5 years. In patients with acute DVT of the leg, the CHEST guidelines suggest not using compression stockings routinely to prevent PTS. This recommendation focuses on prevention of the chronic complication of PTS and not on the treatment of symptoms. For patients with acute or chronic symptoms, a trial of graduated compression stockings is often justified. No specific compression value is mentioned by the authors, and reference is only made to graded compression stockings.
Inferior Vena Cava Filters
In patients with acute DVT or PE who are treated with anticoagulants, the routine use of inferior vena cava (IVC) filters is not recommended. Although early embolism was reduced by filter placement in one study, the effect was transient, and data at 2 years indicated no significant reduction in mortality or recurrent symptomatic PE. In fact, another study showed increased risk of subsequent DVT at 2-year follow-up after IVC filter placement. IVC filters might be considered in patients who have acute DVT and suffer complications necessitating cessation of anticoagulation, and in those who have failed multiple forms of anticoagulation, including vitamin K antagonists (VKAs) at both the traditional international normalized ratio (INR) of 2.0 to 3.0, as well as an elevated INR of 3.0 to 4.0, and other therapies including low molecular weight heparin (LMWH) or novel oral anticoagulants (NOACs).
Aspirin therapy is not considered an adequate alternative to anticoagulation for treatment of DVT or PE. However, after completion of traditional therapy, aspirin may be an effective measure to prevent recurrence. The WARFASA and ASPIRE studies both evaluated ASA versus placebo in patients with unprovoked (noncancer- and nonimmobility-related VTE) after completion of traditional treatment for VTE. Both studies demonstrated reduced rates of VTE in the aspirin groups. Multiple studies of varying design, including 2 meta-analyses, have demonstrated reductions in VTE among patients on ASA or placebo for cardiovascular risk control (primary prevention). Pitfalls of studies related to the primary prevention of VTE with aspirin are largely related to VTE prevention being a secondary outcome or the result of post-hoc analysis. In none of these studies was prevention of PE by ASA a primary end point. Other large, population-based observational studies have failed to demonstrate an effect on VTE prevention by ASA.
Given the previously mentioned data, the risks and benefits of aspirin for prevention of recurrent DVT should be considered upon cessation of traditional anticoagulation. Although the data are not conclusive, aspirin therapy for secondary prevention of DVT seems a reasonable and probably effective measure, and should be considered and weighed against the risk of bleeding in the appropriate patient. In those patients with unprovoked DVT and low risk of bleeding, and in whom cessation of therapy is planned, the CHEST guidelines recommend aspirin therapy, as long as there is no contraindication to such therapy. Additionally, the use of aspirin for other primary or secondary prevention purposes (eg, stroke) should be assessed.
Aspirin has also been studied for primary prevention of VTE after orthopedic surgery, with conflicting results. The American Academy of Orthopedic Surgeons, in a 2009 statement, recommended primary prevention of VTE with ASA, based on the Pulmonary Embolism Prevention Study. CHEST recommendations now recommend ASA therapy as an alternative therapy to heparin or LMWH. A study published in 2013 was halted prematurely because of poor patient recruitment, but has been cited as evidence of aspirin noninferiority compared with dalteparin treatment.
A seminal work by Barritt and Jordan was a small and technically poor study that seemingly demonstrated the efficacy of anticoagulation for the prevention of progression of VTE following initial diagnosis. Although their methods were flawed, several more rigorous subsequent studies have proven the benefit of anticoagulation on morbidity and mortality.
Current options for anticoagulation in VTE include
Anticoagulation with heparin or a LMWH, with transition to a VKA until the INR is greater than 2 on 2 consecutive days
Oral dabigatran or edoxaban after 5 days of heparin or LMWH
Oral apixaban or rivaroxaban only, with loading doses
LMWH treatment only for those patients with active cancer
Treatment options regarding anticoagulation are categorized by the mechanism or class of drug when studied or described in the literature.
Unfractionated heparin (UFH) is an anticoagulant that complexes with antithrombin III (ATIII), producing a conformational change and converting the ATIII molecule into a potent inhibitor of thrombin. ATIII exerts its anticoagulant effect through inhibition of thrombin and factor Xa.
UFH is delivered intravenously and requires partial thromboplastin time (PTT) monitoring. The range of PTT depends on reagent and desired coagulation parameters. A fixed ratio of 1.5 to 2.5 times the control value is suggested but often results in variable and subtherapeutic degrees of anticoagulation. More ideal is the correlation of PTT values with ex vivo values of antifactor Xa between 0.3 and 0.7 u/mL. Weight-based nomograms are often used to estimate the amount of heparin required for anticoagulation. Adverse effects include hemorrhage in up to 7% of patients and osteoporosis in patients with prolonged (longer than one month) use. The risk of hemorrhage is affected by age and concomitant use of thrombolytic or antiplatelet agents. Heparin-induced thrombocytopenia (HIT) is an immune-mediated phenomenon defined by the presence of heparin-dependent immunoglobulin G (IgG) antibodies, which appear to activate platelets in a complex of heparin, platelet, and platelet factor 4, occurring in up to 2.7% of patients receiving heparin. The thrombocytopenia can be complicated by thrombotic events, likely through platelet activation, and usually occurs on or after day 5 of heparin therapy. Patients with a history of HIT should receive heparin alternatives to anticoagulation.
Low Molecular Weight Heparins
LMWHs differ from unfractionated heparins in their pharmacokinetic and biologic properties, namely decreased plasma protein binding and increased serum bioavailability when delivered via a subcutaneous route. LMWH drugs can thus be administered subcutaneously, do not require frequent laboratory monitoring, and exhibit fewer biologic phenomena than unfractionated heparin.
A 1999 meta-analysis found the use of LMWH decreased mortality in the treatment of DVT when compared with UFH. In addition, the LMWH products demonstrated similar safety profiles with respect to bleeding and were as effective as UFH in preventing recurrent DVT. Most patients can be treated safely and effectively with LMWH, with appropriate infrastructure in place. Outpatient treatment with LMWH is reasonable in many patients, provided a high risk of bleeding (very advanced age, recent surgery, history of renal of liver disease), serious coexisting illness, and massive thrombosis are absent. Direct comparisons of LMWH and UFH have shown lower VTE recurrence rates, less major bleeding, and lower mortality rates with treatment using LMWH.
In patients who have recurrent VTE on long-term LMWH (and are believed to be compliant), increasing the dose of LMWH by one-quarter to one-third is recommended. Recurrent VTE while on therapeutic-dose anticoagulant therapy is unusual and should prompt evaluation for underlying malignancy, antiphospholipid syndrome, evaluation of compliance with anticoagulation, and whether the perceived recurrent VTE is an acute finding or a chronic VTE.
In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or NOACs and are believed to be compliant, the CHEST guidelines recommend switching to treatment with LMWH, at least temporarily.
Specific adverse events associated with LMWH include the HIT phenomena, as well as bleeding. LMWH can cross-react with the antibodies that cause HIT and should thus be avoided in patients with a history of HIT. Use of LMHW (dalteparin) in women during pregnancy demonstrated less decline in bone mineral density compared with UFH during and no significant difference in osteoporosis 3 years after delivery, compared with healthy women who did not require anticoagulation.
Warfarin and Vitamin K Antagonists
VKAs include warfarin, acenocoumarol, phenprocoumon, and others, which inhibit gamma carboxylation of factors II, VII, IX, X, C, and S. Drug absorption is rapid and complete, but therapeutic levels take 4 to 5 days to obtain, owing to the mechanism of action of the drugs.
VKA therapy is traditionally started on the same days as parenteral anticoagulation with heparin or LMWH and titrated to an INR of 2 to 3. A small randomized controlled trial demonstrated a significant reduction (20% vs 6.7%) in VTE recurrence in those patients treated with intravenous unfractionated heparin and transitioned to a vitamin K antagonist versus a vitamin K antagonist alone, respectively. Utilized at an INR of 2.0 to 3.0, VKAs have been shown to reduce the risk of recurrent thromboembolism. INRs higher than 3 have demonstrated increased risks of bleeding without benefit of reduced recurrence of DVT. Although INRs higher than 3 were recommended for the management of DVT in patients with antiphospholipid syndrome, 2 trials failed to demonstrate superiority compared with standard (INR 2–3) recommendations.
In trials comparing VKA therapy to novel (or direct) oral anticoagulant therapy, VTE recurrence rates for LMWH/VKA therapy were 2.2% to 3.5% in patients treated for 3 to 12 months, with a risk of major bleeding 8.5% to 10.3%. A large VTE registry found VTE recurrence rates of 2.5%, similar to recent trials, but increased risk of major bleeding, about 2.5% beyond that seen in the same trials.
In addition to bleeding risks, adverse effects of warfarin therapy include vascular purpura and consequent skin necrosis in the first few weeks of therapy, which has been associated with protein C deficiency and malignancy. Coumarin derivatives are known teratogens and should be avoided in pregnancy. The rate of recurrent DVT while on well-coordinated VKA is about 2%. The risk of bleeding at 90 days is about 2.2%. Long-term therapy with VKAs has demonstrated decreased risks of recurrent VTE compared with short-term (3 months) therapy (relative risk 0.20), but was associated with increased risks of bleeding (relative risk 3.44) and no significant difference in mortality.
Novel (Direct) Oral Anticoagulant Therapy
The direct or novel oral anticoagulant therapies differ from VKAs in mechanism, from UFH and LMWH at their sites of action, and from argatroban, in that these novel medications are orally bioavailable. Dabigatran, like argatroban, is a univalent direct thrombin inhibitor, inhibiting thrombin (factor IIa) at its active site. Rivaroxaban, apixaban, and edoxaban are factor Xa inhibitors. Collectively, the NOAC drugs exhibit relatively rapid onsets of action, with peak levels being achieved 1 to 4 hours after oral dosing. The half-lives approximate 12 hours. Advantages of these therapies include ease of dosing, lack of need for monitoring, and improved management for anticoagulation for procedures that might cause bleeding. In support of this is the fact that antifactor IIa and antifactor Xa activities are directly proportional to drug levels. Renal function plays a large role in the elimination of these drugs, and compromised renal function may lead to accumulation, supratherapeutic drug levels, and consequential bleeding. Apixaban and Rivaroxaban have the advantages of not requiring heparin bridging to attain therapeutic levels. In addition, the NOACs have far fewer drug-drug interactions when compared with warfarin, allowing for more stable levels and drug effects. It is important to note that potent inhibitors or inducers of CYP3A4 or p-glycoproteins can affect NOAC drug levels.
All of the trials for the NOACs were designed as noninferiority trials when compared with LMWH or VKAs, although different criteria for noninferiority were utilized across studies. The details of individual trials are discussed, but in general, consistent findings of noninferiority of the NOACs were present throughout. Recurrence rates for VTE in these trials was about 2% for DOACs compared with 2.2% for VKAs; however, study parameters for duration of treatment differed among the trials. Recent meta-analyses showed similar rates of recurrent DVTs between the NOACs and traditional therapies but reduced rates of major and fatal bleeding, as well as all-cause mortality with the NOACs. A significant reduction in bleeding among the NOACs was noted, with a number needed to treat (with NOAC as opposed to VKAs) between 19 and 167. There are limited real-world data to determine the outcomes for patients outside of the selected study groups for the phase III trials for these drugs.
Direct Thrombin Inhibitors
RE-COVER and RE-COVER II were double-blinded trials that compared the treatment of VTE with warfarin. Both demonstrated noninferiority for recurrent VTE or VTE-related death and reduction in bleeding. The RE-MEDY study was a randomized study that demonstrated the noninferiority of dabigatran to warfarin for extended therapy for VTE, with a nonstatistically significant reduction in bleeding. RE-SONATE was a placebo-controlled, double-blinded study with dabigatran versus placebo for extended therapy after initial completion of VTE treatment for first VTE. Dabigatran significantly reduced recurrent VTE in the study population.
When dabigatran was compared with VKAs for long-term treatment of VTE, the data showed an anticipated absolute risk difference of 5 fewer (per 1000) episodes (95% confidence interval [CI]: 2–10) of major bleeding. Specifically, in the RE-LY trial, major gastrointestinal (GI) bleeding compared with warfarin was significantly increased in the twice-daily 150 mg dose, but comparable at the 110 mg twice-daily dose. Bleeding in the 75 mg twice-daily dose was not assessed. Dabigatran at both the 150 mg and 110 mg dosing was associated with significantly less intracranial hemorrhage compared with warfarin. The RE-COVER trial showed lower rates of intracranial hemorrhage in the dabigatran group as well.
Factor Xa Inhibitors
The EINSTEIN study assessed rivaroxaban against placebo for extended VTE prevention after initial traditional anticoagulation for first VTE and demonstrated superior efficacy compared with placebo. EINSTEIN-DVT and EINSTEIN-PE were open-label trials that demonstrated noninferiority of rivaroxaban compared with warfarin in the treatment of DVT and PE, respectively. Similar bleeding rates were noted between rivaroxaban and vitamin K antagonists.
When rivaroxaban was compared with LMWH and VKAs in 2 studies that assessed the acute and the long-term treatment of VTE, the anticipated absolute risk difference in major bleeding was 8 fewer (per 1000) episodes (95% CI: 3–11). In the ROCKET-AF trial, rivaroxaban 20 mg daily demonstrated an increased risk of major GI bleeding when compared with warfarin (hazard ratio 1.61). A post hoc analysis of data showed similar rates of life-threatening bleeding (4 or more units of packed red blood cells transfused) between the 2 groups and fewer (1 vs 5) fatal events with rivaroxaban. The ROCKET-AF trial also demonstrated rivaroxaban to have significantly less acute intracranial hemorrhage when compared with warfarin, with lower rates of both intracerebral hemorrhage and subdural hemorrhage. In the EINSTEIN-DVT trial, intracranial hemorrhage rates were not reported separately, but bleeding in a critical location was similar between the rivaroxaban and warfarin groups. In EINSTEIN-PE, lower rates of intracranial hemorrhage were observed in the rivaroxaban group.
The AMPLIFY study evaluated patients treated for first VTE and randomized patients to 3 groups: 2.5 mg apixaban, 5 mg apixaban, or placebo for 12 months. Both doses of apixaban demonstrated superior efficacy at preventing death compared with placebo and equivalent rates of bleeding.
In a comparison of apixaban to LMWH and VKAs for the acute and long-term treatment of VTE, the absolute anticipated risk of major bleeding was 13 fewer episodes (per 1000) (95% CI: 2 more to 10 fewer). The ARISTOTLE trial showed no significant differences in major GI bleeding between apixaban and warfarin and demonstrated lower rates of intracranial hemorrhage in favor of apixaban.
A randomized, double-blinded, 12-month noninferiority trial demonstrated that in VTE treated first with LMWH or heparin, edoxaban showed no significant difference in recurrent VTE (3.2% vs 3.5% respectively), compared with warfarin. Additionally, a significantly lower rate of major or clinically relevant nonmajor bleeding (8.5% vs 10.3% respectively) was observed. Another randomized, double-blind trial (ENGAGE AF-TIMI 48) evaluated over 21,000 patients with atrial fibrillation and increased risk of stroke. Significant reductions in rates of major bleeding (2.75% vs 3.43%), intracranial bleeding (0.39% vs 0.85%), and cardiovascular death (2.74%vs 3.17%) were observed with edoxaban. Edoxaban compared with VKA for long-term treatment of VTE showed an anticipated absolute risk difference of 2 fewer episodes (per 1000) (95% CI: 3 more to 6 fewer) for major bleeding.
Direct comparisons of GI bleeding, intracranial bleeding, or other types of bleeding among the NOACs are not yet available but should be performed in the future to more thoroughly assess the associated risks with each agent.
The safety of NOACs in pregnancy and children has not yet been sufficiently evaluated, and therefore specific recommendations cannot be made for the NOACs in the treatment of DVTs in these populations. Studies in pregnancy have not yet been conducted, and studies in children are underway currently.
Thrombolysis for deep venous thrombosis
Because of the risk of bleeding, thrombolysis of DVT is usually reserved for patients with a low risk of bleeding and limb-threatening thrombosis. A Cochrane database review of 17 studies suggested that any type of thrombolysis improved clot resolution and reduced the risk of post-thrombotic syndrome, with an expected increase in bleeding complications. UK guidelines recommend considering thrombolysis in specific patients with low risk of bleeding, good functional status, and iliofemoral DVT.
In patients with acute proximal DVT of the leg, anticoagulant therapy alone over catheter-directed thrombolysis (CDT) is recommended. A retrospective observational study of over 90,000 patients with lower extremity proximal DVT demonstrated no difference in mortality between CDT plus anticoagulation versus anticoagulation only, but did find an increased incidence of adverse events in the thrombolysis group. However, a subset of patients with acute (within 14 days) iliofemoral DVT, good functional status, and a life expectancy of at least a year with a low risk of bleeding might be the most optimal candidates for the therapy, in cases where it is offered.
Recommendations by type of anticoagulant therapy
Choosing the type anticoagulant can be daunting. One can begin to narrow the options by basing the decision on the patient’s presumed underlying DVT etiology, individual risks, and clinical condition. Heparin is a reasonable choice for those individuals with extensive or massive DVT or PE or high risk of bleeding, so that levels may be monitored and doses properly titrated. This requires hospitalization. NOACs may not be appropriate for these patients, as they have not been evaluated in these respects. In cases of DVT in pregnancy or in the setting of active malignancy, LMWH appears to be the best option. NOACs play a specific role at this time and require that a particular set of conditions be met. In cases in which NOACs are available; consistent oral dosing is obtainable; patient preference is for no need for monitoring; and in patients with normal renal function (Cr clearance >30 mL/min), the NOACs rivaroxaban, apixaban, and edoxaban seem to be the best option. Anticoagulation parameters are not required on a regular basis. However, in cases in which NOACs are prohibited by cost, or the previously mentioned conditions are not met, LMWH with transition to warfarin is the best option. In more specific cases, patients with dyspepsia or recent acute coronary syndrome should avoid dabigatran. Patients with recent upper GI bleeding had less recurrent bleeds while on apixaban (compared with other NOACs) and should be offered this therapy as a first choice.
Upper extremity deep venous thrombosis management
Treatment options for UEDVT are as varied as those for LEDVT. Treatment of UEDVT is related to risks of developing PE (which is lower in UEDVT than LEDVT), symptom management, the development of recurrent DVT or PE, and management of patient symptoms. Anticoagulation is the preferred management of UEDVT, and recommendations largely mimic those for the treatment of LEDVT. Initial treatment recommendations are for 3 months. The decision concerning removing a CVC related to UEDVT is an individualized decision that is influenced by the symptoms of the DVT as well as the necessity of the device. Although anticoagulation is routinely preferred over thrombolysis, individualized treatment plans for thrombolysis can be made in specific situations to help manage severe or refractory symptoms.