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3. Deep Venous Thrombosis
INTRODUCTION: Constipation is a common gastrointestinal symptom which is experienced by most persons at some point during their lifetimes. However, chronic constipation can be a debilitating problem affecting quality of life and the ability to function. It is also a problem that has a large economic impact, both on direct costs with large expenditures on, health care utilization, laxatives, and indirect costs with work or school absenteeism.
Constipation is a symptom-based disorder and therefore, the diagnosis relies on subjective criteria. Constipation can be defined by bowel infrequency, defecatory symptoms and/or stool consistency. Although practitioners have tended to focus on frequency to define constipation, patients often focus on other symptoms, such as difficulty defecating, a sensation of incomplete evacuation, hard stools, and excessive straining. Diagnosis includes differentiating chronic constipation as either primary (arising from the GI tract) or secondary (due to a non- gastrointestinal cause). It is important to distinguish chronic constipation from irritable bowel syndrome with constipation in which abdominal pain is a central feature; however, there is great overlap between these entities in clinical practice. It is also important to differentiate chronic functional constipation from disorders which may require specific therapy (e.g. colon cancer, ovarian cancer, neurologic diseases, etc.). Risk factors which may contribute to constipation include comorbid medical problems, medications, and lifestyle factors. Management is focused on a rational approach to testing, and to judicious use of prescription and nonprescription treatments.

4. VTE refers to Venous ThromboEmbolism
DVT versus VTE
DVT refers to Deep Venous Thrombosis, which is the focus of this material
VTE refers to Venous ThromboEmbolism
VTE includes DVT plus the embolic consequences of DVT
Which hospitalized surgical patients should receive prophylaxis and what modalities should clinicians use?
Clinicians should first consider the patient's risk for DVT related to both the type of surgery and the patient-related risk factors. The Caprini Risk Assessment Model is the most widely used tool to assess levels of thromboembolic risk (Table 2) (17). The American College of Chest Physicians (ACCP) makes the following recommendations for general and abdominal-pelvic surgery: for patients at very low risk (Caprini score 0), no prophylaxis other than early ambulation; for patients at low risk (Caprini score 1-2), intermittent pneumatic compression; for patients at moderate risk (Caprini score 3-4), LMWH, low-dose UFH, or intermittent pneumatic compression; for patients at high risk (Caprini score ≥ 5), LMWH or low-dose UFH (18). For patients at in- creased risk for bleeding or at risk for severe consequences of bleeding should it occur (including patients undergoing spinal surgery and craniotomy), the ACCP recommends intermittent pneumatic compression. For patients having craniotomy or spinal surgery at very high risk for VTE, pharmacologic prophylaxis, such as LMWH or UFH, can be added once adequate hemostasis is achieved and the risk for bleeding decreases.
For patients undergoing total hip or knee arthroplasty, LMWH, fondaparinux, rivaroxaban, apixaban, or warfarin are recommended for 10 –14 days. Addi- tional benefit may arise from extending the treatment for up to 35 days from the day of surgery (19 –20). Aspirin 81 mg daily, started after 10 –14 days of LMWH and continued for 28 days, may be an alternative for the extended prophylaxis regimen in hip replacement patients (21).

5. Should clinicians screen specific types of patients for DVT?
No evidence supports using ultrasound in:
Hospitalized medical patients
Orthopedic surgery patients
Limited evidence supports using ultrasound in:
Asymptomatic nonambulatory neurosurgery patients
Ultrasound screening for VTE in hospitalized medical patients has not been systematically studied, and there is no evidence to support its use in this population (10). Data on use in hospitalized orthopedic surgery patients are also lacking. There is, however, limited evidence for screening ultrasonography in asymptomatic nonambulatory neurosurgery patients who were given unspecified mechanical prophylaxis (11).
Should clinicians screen specific types of patients for DVT?

6. Which hospitalized medical patients should receive prophylaxis and what should be used?
Assess VTE risk with Padua Prediction Score
Assess bleeding risk with IMPROVE model
Independent bleeding risk factor: Gastroduoduodenal ulcer bleeding w/in 3 mo admission
Independent bleeding risk factor: Platelets <50,000/µl
High VTE risk + low bleeding risk: pharmacologic prophylaxis
UFH, LMWH, or fondaparinux
High VTE risk + high bleeding risk: mechanical prophylaxis
Intermittent pneumatic compression or graduated compression stockings
Which hospitalized medical patients should receive prophylaxis, and what should be used?
Clinicians should consider both whether the patient is at high risk for VTE and at risk for bleeding. For hospitalized medical patients, the Padua Prediction Score provides a risk estimate for VTE (12) (Table 1). Gastroduoduodenal ulcer bleeding within 3 months of admission and a platelet count below per microliter are two major independent risk factors for bleeding (13). One risk model for assessing bleeding risk, the IMPROVE model, includes those risks as well as any prior bleeding within 3 months, hepatic failure, renal failure, cardiovascular catheterization, intensive care unit or critical care unit stay, rheumatic disease, current cancer, age, and sex (13).
Unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and fondaparinux all reduce the risk for VTE. Use of any of these agents is recommended for patients at increased risk for DVT but not at high risk for bleeding (10). Although twice-daily UFH dosing causes fewer major bleeding episodes, thrice-daily dosing offers somewhat better efficacy in preventing clinically relevant thrombotic events (14).
In a recent meta-analysis, LMWH was favored over UFH, with a reduced risk for both VTE and bleeding (15). Although there is limited evidence that mechanical prophylaxis is effective in medical inpatients, for patients who are at increased risk for VTE and bleeding, expert guidelines recommend mechanical prophylaxis with graduated compression stockings or intermittent pneumatic compression (10). A recent study showed that intermittent pneumatic compression reduced the risk for DVT among patients who have had stroke (16). For patients at low risk for DVT, no prophylaxis is indicated.

7. Risk Factor Guide for VTE in Hospitalized Medical Patients
Points
Active Cancer 3
Previous VTE with exclusion of superficial vein thrombosis
Reduced Mobility
Already known thrombophilic condition of antithrombin, protein C or S, factor V Leiden, antiphospholipid syndrome
Recent (< 1 month) trauma and/or surgery 2
Elderly age (> 70 y) 1
Heart and/or Respiratory failure
Acute myocardial Infarction or ischemic stroke
Acute Infection or rheumatologic disorder
Obesity (BMI > 30)
Ongoing hormonal treatment
High risk is defined by a cumulative score ≥4 and low risk <4
Table 1. Padua Prediction Score: Risk Factor Guide for VTE in Hospitalized Medical Patients*
(High risk for VTE is defined by a cumulative score equal or greater than 4 and low risk less than 4)
BMI = body mass index; VTE = venous thromboembolism. * From reference 12. High risk for VTE is defined by a cumulative score ≥4 and low risk < 4.

8. Which pregnant patients should receive prophylaxis, and what methods should be used?
Consider screening for thrombophilia when:
Patient had VTE unrelated to a known risk factor
First-degree relative has high-risk thrombophilia
Base pharmacologic VTE prevention on:
Personal and family (first-degree relative) Hx of VTE
Whether patient has a known thrombophilia
LMWH preferred over UFH in pregnancy
Oral thrombin and Xa inhibitors not recommended prenatally or during breastfeeding
VTE prevention methods vary by pregnancy subgroups
Which pregnant patients should receive prophylaxis, and what methods should be used?
The ACCP and the American College of Obstetrics and Gynecology have made recommendations regarding VTE prevention in pregnant patients who have had prior VTE or who may be at increased risk for VTE.
In general, women with previous idiopathic VTE, VTE related to pregnancy, estrogen therapy or thrombophilia are at higher risk than those with previous VTE related to a temporary risk factor. Screening for thrombophilia may be considered when a patient had VTE unrelated to a known risk factor or when a first-degree relative has a known high-risk thrombophilia (22–23).
Pharmacologic VTE prevention is suggested in certain patients based on personal and family (first-degree relative) history of VTE and whether the patient has a known thrombophilia (Table 3) (22, 24). A recent report concluded that any recommendations concerning VTE prophylaxis in pregnancy were made from trials that were not of high methodological quality (25).
When anticoagulation regimens are used in pregnancy, LMWH is preferred over UFH. Oral thrombin and Xa inhibitors are not recommended prenatally or during breastfeeding (24).

9. Suggested VTE Prevention Methods in Subgroups of Pregnant Patients
Risk factors
Antepartum
Postpartum LMWH
Personal history of VTE related to temporary risk factors (not pregnancy or estrogen related), no thrombophilia
Vi​gilance
LMWH x 6 weeks
Personal history of idiopathic VTE or VTE related to pregnancy or estrogen
LMWH
No personal or family history of VTE and patient has low risk thrombophiliaa
Vigilance
No personal history of VTE but has family history of VTE and patient has low risk thrombophilia
No personal or family history VTE and patient has high risk thrombophilia
No personal history of VTE but has family history of VTE and patient has high risk thrombophilia
Table 3. Suggested VTE Prevention Methods in Subgroups of Pregnant Patients*
LMWH = low-molecular-weight heparin; VTE = venous thromboembolism. * From references 22 and 24. Low risk for thrombophilia includes patients heterozygous for factor V Leiden and the prothrombin G20210A mutation and protein C or S deficiency. High risk includes patients homozygous for factor V Leiden and the prothrom- bin G20210A mutation; double heterozygous for factor V Leiden and the prothrombin G20210A mutation; and having antithrom- bin deficiency.

10. Which patients with thrombophilic disorders should receive prophylaxis, and what methods should be used?
Inherited thrombophilias
Factor V Leiden, prothrombin G20210A, protein C and S deficiency
Acquired thrombophilias
Estrogen use, cancer, the antiphospholipid antibody syndrome, sepsis
Prophylaxis is not recommended to prevent thrombosis in patients with thrombophilia who do not have a Hx of VTE
Which patients with thrombophilic disorders should receive prophylaxis, and what methods should be used?
Thrombophilias are inherited (such as factor V Leiden, prothrombin G20210A, protein C and S deficiency) or acquired (such as estrogen use, cancer, the antiphospholipid antibody syndrome, and sepsis) (4).
Patients with thrombophilia without a history of VTE are not recommended to use any form of prophylactic treatment for primary prevention of thrombosis (10). Because the incidence of VTE in the general population is low, even if some thrombophilias are associated with a substantial relative risk for VTE, the absolute risk is small. Inherited thrombophilic disorders are usually identified as a result of screening after an apparently idiopathic VTE (26). The effect of thrombophilia on the duration of anticoagulation therapy after VTE is discussed below.

11. How should physicians counsel patients about prevention during prolonged immobility associated with travel?
Patients at high risk for travel-associated VTE
Prior VTE, recent surgery, pregnancy, active cancer
Known thrombophilic disorder, morbid obesity
Prevention for patients at high risk
Graduated compression stockings
Frequent ambulation
Maintaining hydration
Sitting in an aisle seat
Consider pharmacologic prophylaxis on individual basis
How should physicians counsel patients about prevention during prolonged immobility associated with travel?
A meta-analysis of 14 studies examining the relationship of travel and VTE found that there was an 18% higher risk for each 2-hour increase in duration of travel by any mode and a 26% higher risk for each 2-hour increase in air travel (27). Patients at high risk for travel-associated VTE include patients with prior VTE, recent surgery, pregnancy, active cancer, a known thrombophilic disorder, or morbid obesity (10, 28). Although data are limited, expert guidelines suggest that patients at high risk may benefit from graduated compression stockings (below knee, 15–30 mm Hg pressure), frequent ambulation, maintaining hydration, and sitting in an aisle seat (10). Pharmacologic prophylaxis may also be considered on an individual basis for patients at very high risk (10).

12. CLINICAL BOTTOM LINE: Prevention...
Risk factor assessment models determine individual risk
Screening for DVT in most settings is not advised
LMWH preferred to UFH for prevention in medical patients
Intermittent pneumatic compression preferred to heparin when bleeding risk is elevated in medical or non-orthopedic surgical patients
Several different agents can be used for prevention in patients undergoing total hip or knee replacement
For heparin use in pregnancy, LMWH is preferred
Clinical Bottom Line: Prevention…DVT has many risk factors, and clinicians should consider using risk factor assessment models when determining a surgical or medical patient's individual risk. Screening for DVT in most settings is not advised. To prevent DVT in medical patients, a recent meta-analysis suggests that LMWH is preferable over UFH. Intermittent pneumatic compression is preferable over either form of heparin when the risk for bleeding is elevated in medical or nonorthopedic surgical patients. Several different agents can be used in patients having total hip or knee replacement, and the benefit may continue when these agents are used for up to 35 days from the day of surgery. Data are limited on the decision to use DVT prophylaxis in pregnant women, patients with thrombophilia, and per- sons traveling by air for an extended period. When heparin is used during pregnancy, LMWH is preferred.

13. What signs and symptoms should lead clinicians to suspect DVT?
Always use a formal prediction rule if VTE is suspected
Wells score
Primary Care Rule
Combine the results from the prediction rule with the results from D-dimer testing to determine next steps
What signs and symptoms should lead clinicians to suspect VTE? Individual clinical features, such as warmth and erythema, have limited diagnostic value; therefore, a formalized clinical score should be used in all patients suspected of having DVT.
The Wells score has been the most extensively evaluated (29) (Table 4). This rule may not accurately predict distal DVT and has not been validated in intravenous drug abusers or pregnant patients. Data regarding the efficacy of this score in the primary care setting conflict (30). Its performance may also be suboptimal in the elderly population as well as in those with a history of DVT or active cancer.
An alternative prediction score, termed the Primary Care Rule, was derived and validated in primary care patients presenting with symptoms of DVT (31) (Table 4). This rule has also been shown to be effective regardless of patient age, sex, and history of VTE. No matter which is used, a clinical prediction score should not be the sole criteria for diagnosing DVT and must be calculated in conjunction with D-dimer testing to determine whether additional studies are necessary.

14. Modified Wells Clinical Score DVT unlikely (score ≤1) or DVT likely (score ≥2)
Active cancer (treatment ongoing, within 6 mo, or palliative) = 1
Paralysis, paresis, or recent plaster immobilization of lower extremities = 1
Recently bedridden >3 d or major surgery ≤12 wk requiring general or regional anesthesia = 1
Localized tenderness on distribution of deep venous system = 1
Entire leg swollen = 1
Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below tibial tuberosity) = 1
Pitting edema confined to the symptomatic leg = 1
Collateral superficial veins (nonvaricose) = 1
Previously documented DVT = 1
Alternative diagnosis at least as likely as DVT = –2
Table4. Modified Wells Clinical Score and Primary Care Rule Modified Wells Score* Score
Active cancer (treatment ongoing, within 6 mo, or palliative) 1
Paralysis, paresis, or recent plaster immobilization of the lower extremities 1
Recently bedridden >3 d or major surgery within 12 wk requiring general or regional anesthesia 1
Localized tenderness along the distribution of the deep venous system 1
Entire leg swollen 1
Calf swelling 3 cm larger than asymptomatic side (measured 10 cm below the tibial tuberosity) 1
Pitting edema confined to the symptomatic leg 1
Collateral superficial veins (nonvaricose) 1
Previously documented DVT 1
Alternative diagnosis at least as likely as DVT –2
DVT unlikely (score ≤1) or DVT likely (score ≥2)
Primary Care Rule†
Male 1
Use of hormonal contraceptives 1
Active cancer in past 6 mo 1
Surgery in previous month 1
Absence of leg trauma 1
Distention of collateral leg veins 1
Difference in calf circumference ≥3 cm 2
Abnormal D-dimer assay result 6
Very low risk (score ≤3) or increased risk (score ≥4)
DVT = deep venous thrombosis. * From Wells PS, Anderson DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003;349: † From Toll DB, Oudega R, Vergouwe Y, Moons KG, Hoes AW. A new diagnostic rule for deep vein thrombosis: safety and efficiency in clinically relevant subgroups. Fam Pract. 2008;25:3-8.

15. Primary Care Rule Very low risk (score ≤3) or increased risk (score ≥4)
Male = 1
Use of hormonal contraceptives = 1
Active cancer in past 6 mo = 1
Surgery in previous month = 1
Absence of leg trauma = 1
Distention of collateral leg veins = 1
Difference in calf circumference ≥3 cm = 2
Abnormal D-dimer assay result = 6
Table 4. Primary Care Rule†
Male 1
Use of hormonal contraceptives 1
Active cancer in past 6 mo 1
Surgery in previous month 1
Absence of leg trauma 1
Distention of collateral leg veins 1
Difference in calf circumference ≥3 cm 2
Abnormal D-dimer assay result 6
Very low risk (score ≤3) or increased risk (score ≥4)
DVT = deep venous thrombosis. * From Wells PS, Anderson DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003;349: † From Toll DB, Oudega R, Vergouwe Y, Moons KG, Hoes AW. A new diagnostic rule for deep vein thrombosis: safety and efficiency in clinically relevant subgroups. Fam Pract. 2008;25:3-8.

16. What is the role of D-dimer testing?
Combine D-dimer testing with assessment of pre-test probability to safely exclude DVT
Testing can r/o VTE in ED, outpatient practice
Enzyme-linked immunoassays:  sensitivity,  specificity
Whole-blood agglutination assays:  sensitivity,  specificity
Sensitivity and specificity suboptimal in:
Pregnant women
Patients receiving anticoagulation therapy
Prolonged clinical symptoms of DVT, prior DVT, or cancer
D-dimer levels normally increase with age
What is the role of D-dimer testing? A meta-analysis showed that the 3-month incidence of VTE was 0.4% among patients with a low or intermediate clinical probability of VTE and a normal highly sensitive D-dimer assay concentration (32).
Enzyme-linked immunoassay D-dimer tests have higher sensitivity and lower specificity, whereas whole-blood agglutination assays have lower sensitivity and higher specificity (33). Point-of-care testing is also available and can be used to rule out VTE in the emergency department or in outpatient practice.
A diagnostic meta-analysis of point-of-care D-dimer assays showed that quantitative assays had better sensitivity than qualitative assays. In this analysis, the most sensitive test had a sensitivity of 0.96 and a posttest probability of VTE of 0.9% in low-risk patients (34).
The sensitivity and specificity of D-dimer assays are suboptimal in pregnant women; patients receiving anticoagulation therapy; and those with prolonged clinical symptoms of DVT, prior DVT, or cancer. D-dimer levels also normally increase with age; however, the combination of a negative D-dimer assay along with a low pretest clinical probability has been shown to be associated with an acceptable negative predictive value in the elderly. D-dimer testing must be combined with an assessment of pre-test probability to safely exclude DVT.

17. What is the role of venous ultrasonography?
Proximal ultrasonography
Examines only the common and popliteal veins
Whole-leg ultrasonography
Examines entire deep vein system, including calf veins
Avoids repeated testing
But may identify more patients with isolated, calf vein DVT
Both methods associated with acceptable 3-month incidence of VTE after negative results
What is the role of venous ultrasonography?
Figure 1 outlines the role of ultrasonography in the diagnosis of DVT.
A meta-analysis of 100 cohort studies showed that venous ultrasonography has 94% sensitivity for detecting proximal venous thrombosis, 63% sensitivity for distal DVT, and 94% specificity for both (35).
Whereas one ultrasound method involves interrogation of only the common and popliteal veins (proximal ultrasonography), the other examines the entire deep vein system, including the calf veins (whole-leg ultrasonography). These methods have been investigated in prospective cohort and randomized studies and have been shown to be associated with an acceptable 3-month incidence of VTE after negative results.
A meta-analysis of randomized and prospective cohort studies investigating the risk for VTE after a single negative, whole-leg ultrasound showed that this technique was associated with a low 3-month incidence of VTE (pooled incidence, 0.57%) (36).
The potential advantage of whole-leg ultrasonography is to avoid repeated testing. However, it may identify more patients with isolated, calf vein DVT, which has an uncertain clinical significance. In the meta-analysis, 52.1% of all DVTs diagnosed on the initial study were isolated calf vein thrombi (36).

18. What is the role of other types of testing?
CT venography and MRI
Uncertain role in diagnosis
Not recommended as first-line diagnostic tests
Except in cases when ultrasonography cannot be performed (lower-extremity casting; severe edema)
What is the role of other types of testing?
The role of other testing, such as computed tomography (CT) venography and magnetic resonance imaging (MRI), in diagnosing DVT is uncertain.
Two separate meta-analyses of CT and MRI for the diagnosis of DVT showed high pooled sensitivity and specificity compared with a reference standard, which was most often ultrasonography for the CT studies and venography for the MRI investigations. However, the individual studies in both analyses had significant heterogeneity (37–38).
There are no management studies that have shown an acceptably low 3-month rate of VTE after negative results on CT or MRI, as has been shown with ultrasonography. Consequently, these methods are not recommended as first-line diagnostic tests, except in cases when ultrasonography cannot be performed (i.e., lower-extremity casting or severe edema precluding the ability to adequately visualize and compress vessels) (39).

19. How should a pregnant patient be evaluated for suspected DVT?
Compression ultrasound should be the initial test
Follow-up ultrasonography is recommended for patients with a normal result on initial testing
Thrombosis in the iliac veins
Suggestive symptoms include whole-leg edema or discomfort in the flank, back, or buttock
Evaluate pelvic vessels with ultrasonography and/or MRI
D-dimer assays have decreased specificity during pregnancy, but results become reliable by 3rd trimester in most women
How should a pregnant patient be evaluated for suspected DVT?
Clinical prediction rules have not been formally validated in pregnant patients. Furthermore, D-dimer assays are associated with poor specificity, as most pregnant women have positive results on D-dimer testing by the third trimester. Compression ultrasonography is thus recommended as the initial test in this patient population, and follow-up ultrasonography is suggested in patients with an initial normal ultrasonogram. Patients with symptoms suggestive of iliac venous thrombosis (whole-leg edema or discomfort in the flank, back, or buttock) should have the pelvic vessels evaluated with ultrasonography and/or MRI (24).

20. What other diagnoses should clinicians consider?
Venous insufficiency (venous reflux)
Superficial thrombophlebitis
Muscle strain, tear or trauma
Leg swelling in a paralyzed limb
Baker’s cyst
Cellulitis
Lymphedema
What other diagnoses should clinicians consider? The differential diagnosis of suspected VTE is extensive. Table 5 outlines the main alternative considerations. Such conditions as tendinitis, calf hematoma, PTS, advanced venous insufficiency, and arthritis should also be considered.

21. When should clinicians consider consulting a specialist?
Imaging is nondiagnostic
Recurrent DVT is suspected
Post-thrombotic syndrome occurs in 20%-50% of patients with symptomatic DVT, and differentiating post-thrombotic syndrome from recurrent DVT can be challenging
Criteria for diagnosing recurrent DVT are lacking, especially in venous segments with residual abnormalities
Suspicion for DVT should be high despite negative testing
When should clinicians consider consulting with a specialist?
PTS occurs in 20%–50% of patients diagnosed with symptomatic VTE (40). Differentiating this condition from recurrent VTE can be challenging. Few well-designed studies have investigated diagnostic strategies to diagnose recurrent VTE. Furthermore, guidelines differ on which strategy should be used in suspected recurrent cases. Residual abnormalities on ultrasonography are common. Specific, well- defined criteria for diagnosing recurrent VTE, especially in venous segments with residual abnormalities, are lacking. For patients with recurrent VTE (particularly if the recurrence is questionable), a clinician should thus consider consulting a specialist. A referral should also be considered if imaging is nondiagnostic or if suspicion for VTE remains high despite negative testing.

22. What other underlying conditions and clinical manifestations should clinicians look for?
Cancer
3.5%-10% diagnosed with cancer within 12 months of VTE
Benefit of an extensive screening protocol has not been established
Tailor cancer screening to age, symptoms, risk factors
Recurrent VTE
There is no consensus on which, if any, patients should be tested for thrombophilia
What other underlying conditions and clinical manifestations should clinicians look for? Within 12 months of a VTE diagnosis, 3.5%–10% of patients will be diagnosed with cancer (41), and this risk seems to be higher in patients with an unprovoked thrombosis. Although a systematic review showed that an extensive screening strategy significantly increased the proportion of patients diagnosed with cancer, there are no randomized, controlled trials that have shown a mortality benefit of an extensive screening protocol. Other factors, such as patient anxiety, radiation exposure, and risks of additional diagnostic procedures have not been formally investigated. Cancer screening that is tailored according to the patient's age, symptoms, and risk factors is thus suggested in patients who are diagnosed with VTE.
The role of thrombophilia testing is also uncertain. There are no randomized, controlled clinical trials that have investigated the role of such testing to assess the risk for recurrent VTE (42). Consequently, there is no consensus among the guidelines regarding which, if any, patients should be tested. Some societies advocate testing young patients with a family history of VTE, whereas others do not.

23. CLINICAL BOTTOM LINE: Diagnosis...
To stratify a patient’s risk for thrombosis
Use a clinical prediction rule
Combine the results with a sensitive D-dimer assay
Whole-leg ultrasound may limit the need for repeat testing but will identify more patients with isolated calf vein thrombi
In patients diagnosed with DVT
Extensive cancer screening strategy and thrombophilia testing is controversial
Consult a specialist when
Recurrent VTE is possible
Imaging studies are nondiagnostic or negative, particularly if the suspicion for thrombosis is high
Clinical Bottom Line: Diagnosis... Individual clinical features have little predictive value in diagnosing VTE. Clinicians should consider using a clinical prediction rule which incorporates a sensitive D-dimer assay to stratify a patient’s risk for a thrombosis. Various clinical scores exist, of which the Wells score appears to be the most studied. An alternative to this score is the Primary Care Rule which has also been shown to be effective in ruling out VTE in the primary care setting. The use of a whole-leg ultrasound may limit the need for repeat testing but will identify more patients with isolated calf vein thrombi. The use of an extensive cancer screening strategy and thrombophilia testing is controversial in patients who are diagnosed with VTE. Clinicians should consider consulting a specialist for patients with possible recurrent VTE or in situations where the imaging studies are non-diagnostic or negative, particularly if there is a high suspicion for a thrombosis.

24. How should clinicians decide whether to treat patients on an oupatient or inpatient basis?
Most people with VTE can be safely treated as outpatients
With LMWH treatment
Outcome is better at home than in hospital
Consider admitting patients who have difficulty managing outpatient treatment
INTRODUCTION TO TREATMENT SECTION: As shown in Figure 2, VTE treatment is divided into several phases. Some of the novel oral anticoagulants (NOACs), such as rivaroxaban and apixaban, can be used immediately during the initial phase of treatment, whereas others, such as dabigatran etexilate and edoxaban, should not be used until the patient has been treated with a parenteral anticoagulant, such as UFH or LMWH, for at least 5 days. Table 6 summarizes the dosing regimens, mechanisms of action, and side effects of the available anticoagulants; as the table shows, a reduced dose of apixaban (2.5 mg twice daily) has also been approved for VTE treatment during the extended phase of therapy.
How should clinicians decide whether to treat patients on an outpatient or inpatient basis?
Most patients with VTE can be safely treated with LMWH as outpatients.
Several systematic reviews comparing patients with VTE treated with LMWH administered at home with those treated in the hospital found no difference in outcomes (43). Furthermore, outpatient treatment of patients with PE at low risk for adverse events (as measured by a clinical prediction rule) has been shown to be safe and effective in several randomized, controlled trials and a systematic review (44).
A recent registry of more than patients found that home treatment was associated with a better outcome than hospital treatment (45). However, clinicians should consider admitting patients who have difficulty managing their outpatient treatment.

25. What local measures should clinicians recommend?
Compression therapy
Conflicting data on efficacy for reducing risk for post- thrombotic syndrome
Early ambulation
Not associated with increased risk for PE in patients with acute DVT
May lead to more rapid resolution of limb pain
Has the potential to decrease the frequency and severity of post-thrombosis syndrome
What local measures should clinicians recommend?
Data regarding the efficacy of compression therapy in reducing the risk for PTS conflict. For example, elastic compression stockings did not prevent PTS in a recent randomized, placebo- controlled trial (46). However, the clinician should consider early ambulation because it has not been shown to be associated with increased risk for PE in patients with acute DVT, and it may lead to more rapid resolution of limb pain (47). Early ambulation also has the potential to decrease PTS (39).
There is conflicting data regarding the efficacy of compression therapy in reducing the risk of post-thrombotic syndrome (PTS). For example, elastic compression stockings did not prevent PTS in the most recent randomized, placebo-controlled trial.45 However, the clinician should consider early ambulation because it has not been shown to be associated with an increased risk of PE in patients with an acute DVT, and it may lead to a more rapid resolution of limb pain.46 Also, early ambulation has the potential to decrease PTS.38
When should clinicians start anticoagulants to treat deep venous thrombophlebitis?
There are no randomized studies investigating the timing of anticoagulation initiation in patients with a suspected DVT. In patients who have a high pretest probability of a DVT and a low risk of bleeding, it is reasonable to initiate a short-acting anticoagulant while awaiting the results of the diagnostic work-up, particularly if there is a delay in testing. In patients who are diagnosed with an acute proximal DVT, the clinician should initiate anticoagulation with either a parental anticoagulant or apixaban or rivaroxaban immediately unless contra-indicated. If a vitamin k antagonist (VKA) is chosen for the long-term phase of therapy, it should be started on the same day as the parental anticoagulant is initiated. There is a lack of robust evidence for the treatment of an isolated, calf vein thrombosis. Immediate initiation of anticoagulation is preferred in patients whose symptoms (particularly if severe) are likely related to the calf vein thrombosis or if the patient has a high risk for thrombus propagation (i.e. active malignancy, large thrombus burden, location of thrombus close to the popliteal junction or history of DVT), particularly if the bleeding risk is low.38 Two weeks of surveillance ultrasound is preferred in other patients.3

26. When should clinicians start anticoagulants?
If there is a high probability of VTE before testing plus a low risk for bleeding
Initiate short-acting anticoagulant while awaiting results of diagnostic work-up
If the diagnosis is acute proximal DVT
Initiate parental anticoagulant, apixaban, or rivaroxaban immediately unless these drugs are contraindicated
If vitamin k antagonist is chosen for long-term therapy, start it on same day as parental anticoagulant
If the diagnosis is isolated calf vein thrombosis
Initiate anticoagulation immediately, especially if the risk for proximal propagation is high and the risk for bleeding is low
When should clinicians start anticoagulants? There are no randomized studies investigating the timing of anticoagulation therapy initiation in patients with suspected VTE. In patients with a high pretest probability of VTE and a low risk for bleeding, it is reasonable to initiate a short-acting anticoagulant while awaiting the results of the diagnostic work-up, particularly if there is a delay in testing. In patients who are diagnosed with an acute proximal DVT, the clinician should initiate anticoagulation with either a parental anti-coagulant or apixaban or rivaroxaban immediately unless contraindicated. If a vitamin k antagonist (VKA) is chosen for the long-term phase of therapy, it should be started on the same day as the parental anticoagu- lant. Robust evidence on the treatment of an isolated calf vein thrombosis is lacking. Immediate initiation of anticoagulation is preferred in patients whose symptoms (particularly if severe) are probably related to calf vein thrombosis or if the patient has a high risk for thrombus propagation (i.e., active cancer, large thrombus burden, location of thrombus close to the popliteal junction, or history of DVT), particularly if the bleeding risk is low (39). Two weeks of surveillance ultrasonography is preferred in other patients (3).

27. Which anticoagulants should clinicians use?
LMWH, dalteparin, enoxaparin, or tinzaparin
IV or SC UFH
Coumarin derivatives
Apixaban
Rivaroxaban
IV direct thrombin inhibitors (lepirudin, bivalirudin, argatroban)
Oral direct thrombin inhibitor (dabigatran etexilate)
Which anticoagulants should clinicians use? Figure 2 summarizes the treatment options for each phase of anticoagulation therapy. Several of the NOACs have been studied for the treatment of VTE and have been shown to be effective and safe (48). Table 6 outlines the anticoagulant regimens that can be used for DVT. Subcutaneous heparin (either with activated partial thromboplastin time [aPTT]) is an alternative to intravenous heparin in patients with renal insufficiency, those with poor intravenous access, or pregnant patients beyond 36 weeks of gestation.
A meta-analysis comparing the efficacy and safety of various anticoagulation options showed that the combination of UFH and VKAs was associated with a higher risk for recurrent VTE than the combination of low-molecular- weight heparin (LMWH) and VKAs. All of the NOACs were found to be as effective as standard therapy. Rivaroxaban and apixaban were associated with a lower risk for major bleeding than either the UFH- or the LMWH-VKA combination in this analysis (49). In a separate meta-analysis, the NOACs were found to be as effective as the VKAs and were associated with a lower risk for bleeding complications (50).
All of the NOACs as well as the LMWHs undergo renal excretion. UFH and VKAs thus remain the anticoagulants of choice in patients with renal insufficiency. The elderly and patients with active cancer or underlying thrombophilia were underrepresented in the NOAC clinical trials. In a pooled analysis, clinically relevant bleeding occurred more often in patients older than 85 years who were treated with dabigatran for VTE than in those who received warfarin. However, sex, creatinine clearance, ethnicity, and body mass index did not influence bleeding outcomes. In this analysis, there was no difference in efficacy between dabigatran and standard therapy in patients with cancer or those who presented with a symptomatic PE (51). In a pooled analysis of the rivaroxaban trials, fragility (age >75 years, creatinine clearance <50 mL/min, and body weight <50 kg) and cancer did not influence efficacy. However, there was a statistically significant difference in favor of rivaroxaban for major bleeding in the fragile patient population (52). LMWH is the anticoagulant of choice in patients with cancer for the first 3 months of treatment.
Use of the potent inhibitors or inducers of the cytochrome p-450 and p-glycoprotein systems, such as protease inhibitors, ketoconazole, rifampin, carbamazepine, and phenytoin, with oral Xa inhibitors is contraindicated. Treatment of VTE with dabigatran should be avoided in patients receiving a p-glycoprotein inducer (e.g., rifampin) and in those with renal insufficiency (creatinine clearance <50 mL/min) receiving p-glycoprotein inhibitors (e.g., ketoconazole, amiodarone, clarithromycin, dronedarone, quinidine, and verapamil).
Direct thrombin inhibitors (lepirudin, bivalirudin, and argatroban) are generally only used to treat VTE in patients with known heparin hypersensitivity or heparin- induced thrombocytopenia. The use of dabigatran for heparin-induced thrombocytopenia has not been systematically investigated and should be avoided for this condition.

28. Some novel oral anticoagulants can be used immediately
Others should not be used until patient is treated with a parenteral anticoagulant ≥5 days
Anticoagulants for use during initial phase
Rivaroxaban, apixaban
Fondaparinux, IV or SC heparin, LMWH
Anticoagulants for long-term and extended use
Dabigatran, edoxaban
Vitamin K antagonist
LMWH
From Figure 2.
Figure 2 summarizes the treatment options for each phase of anticoagulation therapy.

29. How should clinicians monitor anticoagulation?
Heparin
Use aPTT to adjust the dose of UFH but not LMWH
Vitamin K antagonists
Evidence lacking on specific dosing-algorithms
Consider lower initial doses for the elderly
Monitor with INR every 4 weeks once the level of anticoagulation stable
Home monitoring is safe and effective in motivated patients who demonstrate competency
How should clinicians monitor anticoagulation? Clinicians should use aPTT to adjust the dose of UFH, but it is not necessary to do so in patients treated with LMWH. The NOACs were specifically designed to be used without monitoring. Currently, there are no validated assays to assess the anticoagulant effects of these medications.
Evidence to recommend specific dosing-algorithms for VKAs in defined patient populations is insufficient; however, lower initial doses should be considered for the elderly. VKAs should be monitored with the international normalized ratio every 4 weeks for the duration of therapy once the level of anticoagulation is stable, aiming for a ratio between 2 and 3. Several meta-analyses have shown that home monitoring of VKAs is a safe and effective method of treatment in motivated patients who demonstrate competency for self-testing (53).
A recent meta-analysis revealed that a genotype-guided dosing strategy compared with standard dosing protocols did not increase time in the therapeutic range or reduce bleeding or thromboembolic complications (54).

30. When should clinicians stop anticoagulation?
Reversible risk factor
Pregnancy, hormonal therapy, surgery, temporary immobilization
Treat for 3 months
Unprovoked or recurrent VTE or active cancer
Extended anticoagulation with no prespecified stopping point (if bleeding risk is low)
Reevaluate risks and benefits annually
Recurrence risk may be higher when D-dimer levels are elevated 1 mo after anticoagulation discontinued
When should clinicians stop anticoagulation?
Patients with a reversible risk factor for VTE (such as pregnancy, hormonal therapy, surgery, temporary immobilization) should be treated for 3 months. Extended anticoagulation with no prespecified stopping point should be considered when the patient has a low risk for bleeding and an unprovoked VTE, active cancer, or recurrent VTE (39). Patients receiving extended therapy should have risks and benefits reevaluated annually (39).
Patients with unprovoked VTE and elevated D-dimer levels may be at higher risk for recurrence when D-dimer levels are checked 1 month after discontinuation of anticoagulation (55). The presence of residual vein obstruction, when checked on compression ultrasonography at the end of intended treatment, does not predict risk for recurrent VTE among patients with unprovoked VTE, although it may predict risk among patients with provoked VTE (56).

31. What options are available for patients who cannot use anticoagulants?
Anticoagulant contraindications
Active bleeding
Recent surgery or recent hemorrhagic stroke
Inferior vena cava filters
May be used in acute VTE when anticoagulation is absolutely contraindicated
May increase risk for recurrent DVT
Use usually requires an absolute contraindication to anticoagulation
What options are available for patients who cannot use anticoagulants?
Inferior vena cava filters may be used in patients with acute VTE when anticoagulation is absolutely contraindicated (such as active bleeding, recent surgery, or recent hemorrhagic stroke) (57). However, these filters may increase risk for recurrent DVT, and use in settings other than an absolute contraindication to anti- coagulation is questionable (58).

32. When should clinicians use thrombolysis?
Anticoagulant therapy alone is usually recommended instead of thrombolysis
Thrombolysis increases the risk for bleeding
Consider thrombolytic therapy for patients who
Have iliofemoral DVT or impending venous gangrene and a low risk for bleeding
Are more concerned about preventing post- thrombosis syndrome and less concerned about bleeding
When should clinicians use thrombolysis?
Thrombolytic therapy may result in more complete lysis of the blood clot and reduces risk for PTS compared with anticoagulation alone. However, there is no mortality benefit to thrombolytic therapy and it increases risk for bleeding (59). No randomized trials have compared catheter- directed thrombolytic therapy with systemic thrombolytic therapy. For VTE, the ACCP has recommended anticoagulant therapy alone over thrombolytic therapy (39). Thrombolytic therapy may be considered for patients who have a low risk for bleeding and iliofemoral DVT or impending venous gangrene. It may also be considered for patients who are especially concerned about preventing PTS but less so about the risk for thrombolytic therapy–associated bleeding (39).

33. What treatment modifications are needed in pregnancy and in other hypercoagulable states?
Novel oral anticoagulants are contraindicated
LMWH therapy preferred over warfarin and UFH
When VTE develops in pregnancy, continue treatment for 3 mo or until 6 wk after delivery, whichever is longer
Warfarin may be used postpartum and during lactation
Initial management of acute VTE same in patients with thrombophilia as in those without
Consider extended course for patients with first episode of VTE and thrombophilia who have other persistent risk factors or who have had a life-threatening thrombosis
What treatment modifications are needed in pregnancy and in other hypercoagulable states?
Information on the efficacy and safety of anticoagulant drugs in pregnancy is extremely limited. NOACs are presently contraindicated. LMWH therapy is preferred over warfarin and UFH (60). When LMWH is used, routine monitoring of anti-Xa levels is not recommended (24). When pregnant patients develop VTE, treatment should continue for 3 months, or until 6 weeks after delivery, whichever is longer. Warfarin may be used safely in the postpartum period and during lactation.
Initial management of acute VTE is the same in patients with thrombophilia as in those without (one exception may be the rare deficiency of antithrombin, which requires higher doses of heparin). The overall rate of recurrent VTE while receiving warfarin was not increased among patients with a single or multiple thrombophilic defects compared with patients with no thrombophilic defects (61).
In general, patients with thrombophilia and a first episode of VTE should be managed in the standard fashion and not receive a longer course of anticoagulation because of thrombophilia (4, 39). Clinicians may consider an extended course for patients with a first episode of VTE and thrombophilia who have other persistent risk factors (e.g., leg paresis) or who have had a life-threatening thrombosis, such as near-fatal pulmonary embolism.

34. How should clinicians treat the post-thrombotic syndrome?
It occurs in 20%-50% of patients following DVT and is characterized by recurrent pain and swelling with ulceration and signs of stasis skin changes
Consider the possibility of recurrent DVT
Advise patients to elevate their feet whenever possible
Use graduated compression stockings (20-40mm Hg)
Contraindications include severe peripheral arterial disease and open wounds
Out-patient pneumatic compression is reserved for patients who don’t respond to foot elevation and stockings
How should clinicians treat the post thrombotic syndrome?
PTS occurs in 20%–50% of patients following DVT and is characterized by symptoms of recurrent pain and swelling and signs of stasis skin changes and ulceration (62). Clinicians should advise patients with the syndrome to elevate their feet whenever possible and should prescribe graduated compression stockings with pressures ranging from 20 – 40 mm Hg, depending on severity of edema. Patients should be instructed to replace their stockings after 6 months of repeated use because they lose the elasticity needed to maintain adequate pressure. Contraindications to compression stockings include severe peripheral arterial disease and open wounds. Out- patient pneumatic compression is usually reserved for patients who do not respond to foot elevation and stockings. Recurrent DVT should also be considered in patients developing symptoms and signs of PTS.

35. When should clinicians consider consulting a specialist?
Recurrent idiopathic VTE
Recurrent VTE while on anticoagulation
Complications necessitating alternatives to anticoagulation
Management of DVT in pregnant patients
When should clinicians consider consulting a specialist?
Clinicians should consider consulting a specialist with expertise in vascular medicine and coagulation disorders for patients with: (1) recurrent idiopathic VTE; (2) recurrent VTE while on anticoagulation; (3) complications necessitating alternatives to anticoagulation; or (4) management of DVT in pregnant patients.

36. CLINICAL BOTTOM LINE: Treatment...
Most DVT can be treated with LMWH outside the hospital
LMWH + VKA results in less recurrence than UFH + VKA
NOACs are as effective as LMWH+VKA, and the bleeding risk is lower
Data conflict on elastic compression stockings to prevent PTS
Treat patients with reversible risk factor for 3 months
Treat longer if the bleeding risk is low and VTE is unprovoked, recurrent, or accompanied by active malignancy
Only use IVC filters when anticoagulation is contraindicated
Consider thrombolytic therapy when there is a low risk of bleeding and either massive iliofemoral DVT or impending venous gangrene
Manage most patients with thrombophilia like those without it
Clinical Bottom Line: Treatment… Most patients with VTE can be safely treated as outpatients with LMWH. The combination of LMWH and VKA is associated with a lower risk of recurrent VTE compared to UFH and VKA. The NOACs were found to be as effective as the LMWH-VKA combination and were associated with a lower risk for bleeding. There is conflicting data whether elastic compression stockings prevent PTS. Patients with a reversible risk factor for VTE should be treated for three months. Longer treatment should be considered when the patient has a low risk for bleeding and an unprovoked VTE, an active malignancy or recurrent VTE. IVC filters should only be used in patients when anticoagulation is absolutely contraindicated. Thrombolytic therapy may be considered for patients who have a massive iliofemoral DVT, impending venous gangrene and a low risk of bleeding. Most patients with thrombophilia should be managed similarly to patients without a known thrombophilia.