DEEP VEIN THROMBOSIS

• ACRONYMS AND DEFINITIONS

• ACCP - American College of Chest Physicians
• AHA - American Heart Association
• ASA - Acetylsalicylic acid (aspirin)
• ASH - American Society of Hematology
• aPTT - activated Partial Thromboplastin Time
• DOAC - Direct-acting oral anticoagulant (factor Xa inhibitors, dabigatran)
• DVT - Deep vein thrombosis
• HIT - Heparin-induced thrombocytopenia
• HRT - Hormone replacement therapy
• INR - International Normalized Ratio
• LMWH - Low molecular weight heparin
• OCPs - Oral contraceptive pills
• PCI - Percutaneous coronary intervention (heart cath and associated procedures - stents, angioplasty, etc.)
• PE - Pulmonary embolism
• RCT - Randomized controlled trial
• SVT - Superficial vein thrombosis
• THA - Total hip arthroplasty
• TKA - Total knee arthroplasty
• VTE - Venous thromboembolism (deep vein thrombosis and pulmonary embolism)

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• EPIDEMIOLOGY

• In the U.S., an estimated 900,000 people (0.1 - 0.3% of the adult population) develop a DVT or PE each year. Sudden death is the presenting symptom in up to 25% of PE cases. An individual's risk for DVT depends on a number of risk factors that are often identifiable. [33]

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• PHYSIOLOGY

• Overview
• A deep vein thrombosis (DVT) is a blood clot that forms in the deep veins of the leg. DVTs can cause pain and swelling in the affected extremity, but more importantly, pieces of the clot can break off and travel to the lungs, where it becomes a pulmonary embolism (PE). DVTs are treated with anticoagulation to prevent their extension and hasten their dissolution.

• DVT location
• Proximal DVT - DVT located in the veins of the thigh (femoral vein, deep femoral vein, common femoral vein, iliac veins, popliteal vein)
• Distal DVT - DVT located in the veins of the calf (anterior tibial vein, posterior tibial vein, peroneal vein)
• Illustration of deep veins of the leg


• In a study of 189 patients with a symptomatic DVT, 88% had a proximal DVT, and 12% had an isolated distal DVT. Of the patients with a proximal DVT, 99% had an associated distal DVT. As for the natural course of untreated isolated distal DVTs, 15 - 25% will extend into the proximal veins, typically within 2 weeks. [6,7,10]
• The table below shows the location of proximal DVTs diagnosed with venography in 166 consecutive patients with suspected VTE

• Reference [7]

DVT location in 166 patients with a proximal DVT diagnosed by venography
Location of DVT	% of patients
Popliteal	10%
Popliteal and femoral	42%
Popliteal, femoral, and common femoral	5%
All proximal veins	35%
Common femoral +/- femoral or iliac	8%

• Pulmonary embolism risk
• The risk of developing a PE from an untreated DVT is unknown, as most DVT patients are anticoagulated, and withholding treatment would be considered unethical. In one study, the 3-year incidence of a PE after isolated DVT was 5.1%; however, the study did not distinguish between patients who received long-term anticoagulation and those who did not. PEs can also be asymptomatic and go undetected. In one study, 40% of DVT patients without PE symptoms had evidence of PE on ventilation-perfusion lung scanning. [1]

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• RISK FACTORS FOR DVT

• Previous pulmonary embolism or DVT
• Age (1 in 10,000 annually before 40, rising to 6 in 1000 annually by age 80) [34]
• Cancer (see cancer risk and DVT below)
• Cigarette smoking [3]
• First-degree relative with history of unprovoked VTE - the younger the age of the relative when the VTE occurred, the higher the risk [17]
• Human immune globulin products (ex. IVIG, Gamimune®, Sandoglobulin®, Polygam®) [15]
• Hypercoagulable disorders
• Immobilization for an extended period (ex. travel, surgery, hospitalization)
• Estrogen-containing medications (e.g. oral contraceptives, hormone replacement, SERMs) - see also hormone therapy after VTE [3]
• Obesity
• Peripherally inserted central catheters (PICC lines) [21]
• Ponatinib (Iclusig®) [16]
• Pregnancy
• Superficial vein thrombosis (SVT) - in one study, 2.5% of patients with an SVT developed a DVT within 3 months of SVT diagnosis; the incidence of PE was 0.9% during the same period. At 5 years, the risk of VTE was 5-fold higher in SVT patients compared to unaffected patients. [18]

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• PROVOKED VS UNPROVOKED DVT

• Overview
• Recommendations for providing extended anticoagulation after a DVT are based on whether the DVT is considered provoked or unprovoked. In general, these terms have the following meanings:
• Provoked DVT - DVT with a preceding identifiable risk factor
• Unprovoked DVT - DVT with no preceding identifiable risk factor


• Significant provoking risk factors are not consistently defined across the medical literature. For example, in some studies, oral contraceptive use is considered a significant provoking factor, while in others, it is not. The same goes for pregnancy and a list of other conditions. [11]
• The 2021 ACCP VTE recommendations define two categories of provoking risk factors that are used to make extended anticoagulation recommendations. Those categories are described in the table below, along with major risk factors used in the Wells score.

• References [4,31]

ACCP 2021 DVT Risk Factor Categories
DVT provoked by a major transient risk factor Surgery with general anesthesia for greater than 30 minutes Confinement to bed in hospital (only bathroom privileges) for at least 3 days with an acute illness Cesarean section
DVT provoked by a minor transient risk factor Surgery with general anesthesia for less than 30 minutes Admission to hospital for less than 3 days with an acute illness Confinement to bed out of hospital for at least 3 days with an acute illness Leg injury associated with reduced mobility for at least 3 days Estrogen therapy (OCPs or HRT) Pregnancy and the six weeks after delivery
Major risk factors in the Wells score Active cancer Paralysis or recent immobilization of the lower extremity (this could include prolonged travel) Recently bedridden for ≥ 3 days, or major surgery within previous 12 weeks

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• DIAGNOSIS

• Symptoms
• Common symptoms of DVT are listed below. It's important to note that DVTs may also be asymptomatic and discovered incidentally on imaging for other indications.
• Symptoms of DVT include:
• Pain in the affected leg
• Swelling in the affected leg
• Dilated superficial veins (nonvaricose) in the affected leg

• Physical exam findings
• Localized tenderness along distribution of deep vein system
• Swelling of affected leg
• Dilated superficial veins (nonvaricose) in the affected leg
• Calf swelling ≥ 3 cm larger than that of the unaffected leg (measured 10 cm below the tibial tuberosity)

• Ultrasound
• Lower extremity ultrasound (US) is the preferred method for diagnosing DVT. When venography is used as the reference standard, US has a sensitivity of 97% for proximal DVT and 71% for distal DVT. Specificity is greater than 90%. [32]

• D-dimer
• D-dimer, a degradation product of fibrin cross-linking whose levels rise during clot formation (see coagulation cascade illustration), can be helpful in diagnosing a DVT. An elevated D-dimer is sensitive for a DVT, but not specific, as a number of other conditions can cause elevations (e.g. advanced age, cancer, pregnancy, recent surgery). Therefore, a normal D-dimer essentially rules out a DVT in many patients, while a high level is nonspecific and requires further testing.

• Age-adjusted D-dimer
• D-dimer levels rise naturally with age, so older patients have higher levels. In most laboratories, the upper limit of normal for a D-dimer is 500 mcg/L (0.500 mg/L). Studies have found that using age-adjusted cutoff levels in patients 50 and older increases the specificity of the test without sacrificing sensitivity, and some experts argue that age-adjusted levels should be the standard. [PMID 26320520, PMID 23645857, PMID 24643601].
• The formula for calculating an age-adjusted level is as follows:
• Age-adjusted D-dimer cutoff = patient's age (if 50 or older) X 10 mcg/L [Online calculator]

• DVT Diagnostic Algorithm
• STEP 1 - Use Wells score to determine patient's risk of DVT

• If both legs are symptomatic, use more symptomatic leg
• Reference [4]

Wells score
Finding / History	Points
Active cancer (treatment ongoing, administered within previous 6 months or palliative)	+1
Paralysis or recent immobilization of the lower extremity	+1
Recently bedridden for ≥ 3 days, or major surgery within previous 12 weeks	+1
Localized tenderness along distribution of deep vein system	+1
Swelling of entire leg	+1
Calf swelling ≥ 3 cm larger than that of the unaffected leg (measured 10 cm below the tibial tuberosity)	+1
Pitting edema confined to affected leg	+1
Dilated superficial veins on affected leg (nonvaricose)	+1
Previously documented DVT	+1
Alternative diagnosis at least as probable as DVT	-2

• STEP 2 - Determine probability of DVT

• Reference [4]

Wells Score	DVT probability
≤ 0	Low probability
1 - 2	Intermediate probability
≥ 3	High probability

• STEP 3 - Based on the patient's probability, do the following:

• Reference [3,4]

Probability	Testing
High probability	Perform ultrasound
Intermediate or low probability	Order D-dimer If D-dimer is elevated, order ultrasound If D-dimer is normal, DVT unlikely [3,4]

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• TREATMENT | Anticoagulation

• DVT treatment is divided into three phases:
• Initiation phase (5 - 10 days) - period where the patient is quickly anticoagulated to prevent clot expansion
• Treatment phase (3 months) - continued anticoagulation to prevent clot expansion and promote dissolution
• Extended phase (beyond 3 months) - extended anticoagulation to prevent reoccurrence in appropriate patients

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• TREATMENT | Initiation phase (5 - 10 days)

• Initiation phase (5 - 10 days)
• In the initiation phase, patients are quickly anticoagulated to stop the clot from spreading. For many years, warfarin, which takes 3 - 5 days to become therapeutic and requires coverage with quick-acting injectable therapy during that time, was the only oral anticoagulant available. Rivaroxaban and apixaban, two newer DOACs, have a rapid onset of action and do not require injections during the first days of use. Two other DOACs, dabigatran and edoxaban, are FDA-approved for treatment after 5 - 10 days of parenteral therapy.

• Early ambulation
• In the past, patients were often prescribed bed rest in the acute phase of a DVT because it was theorized that activity could disrupt the clot and cause pieces to break off. Studies have found this to be untrue, and patients should be encouraged to ambulate early and often if tolerated. [9]

• ACCP 2021 recommendations
• Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) or dabigatran are preferred over warfarin. Parenteral therapy is not required with apixaban and rivaroxaban, whereas 5 to 10 days are recommended with dabigatran and edoxaban.
• Patients with distal DVT - see distal (calf) DVT
• Patients with antiphospholipid syndrome - warfarin (target INR 2.5) is preferred with initial parenteral therapy
• Patients with cancer - Factor Xa inhibitors (apixaban, edoxaban, rivaroxaban) are preferred over LMWH. Edoxaban and rivaroxaban appear to be associated with a higher risk of GI major bleeding than LMWH in patients with cancer-associated thrombosis and a luminal GI malignancy, while apixaban does not. Apixaban or LMWH may be the preferred option in patients with luminal GI malignancies (see Factor Xa inhibitors for cancer-associated VTE treatment) [31]

• ASH 2021 recommendations for patients with active cancer
• Apixaban, rivaroxaban, or LMWH is recommended for treatment during the first week [30]
• Studies
• Factor Xa inhibitors for cancer-associated VTE treatment
• A study published in 2015 comparing tinzaparin, a LMWH, to warfarin in cancer patients with acute VTE found no significant difference between the therapies for recurrent VTE or major bleeding at 6 months. [PMID 26284719]

• Heparins
• Unfractionated heparin - typically referred to as "heparin" for short. Heparin works by activating antithrombin, which in turn, inhibits Factor IIa (thrombin) and Factor Xa (coagulation inhibition illustration). Heparin can be administered intravenously or subcutaneously and requires aPTT monitoring. It causes HIT in 1 - 5% of patients. [8]

• Low molecular weight heparin (LMWH) - LMWHs, also called "fractionated heparin," include enoxaparin (Lovenox®), dalteparin (Fragmin®), and tinzaparin (Innohep®). LMWHs are similar to heparin except that they consist of smaller molecules (hence "low molecular weight") because they have been fractionated (divided into parts). Like heparin, LMWHs work by stimulating antithrombin activity (see coagulation inhibition illustration). LMWHs are given by subcutaneous injection, and they do not require lab monitoring. Enoxaparin (Lovenox®), the most widely used LMWH, is dosed 1 mg/kg every 12 hours for VTE treatment and 40 mg once daily for VTE prevention. The risk of HIT with LMWH is 0.1 - 1.0%. [8]

• Fondaparinux (Arixtra®) - fondaparinux is a synthetic heparin derivative that activates antithrombin, but unlike heparins where Factor Xa and IIa are inhibited, only Factor Xa is inhibited when antithrombin is stimulated by fondaparinux (see coagulation inhibition illustration). Fondaparinux carries a negligible risk of HIT, and some experts recommend its use in HIT patients; however, it is not FDA-approved for this indication. Fondaparinux is administered once daily by subcutaneous injection and does not require lab monitoring. [8]

• Heparin-induced thrombocytopenia (HIT)
• Heparins can cause a syndrome called heparin-induced thrombocytopenia (HIT) that is marked by the development of antibodies to complexes of platelet factor 4 (PF4) and heparin. Anti-PF4 antibodies can activate platelets, causing thrombosis and platelet depletion. During HIT, platelet counts typically fall by 50% between 5 and 14 days after heparin initiation; patients with previous heparin exposure may see counts drop within 24 hours. If HIT is suspected, testing for anti-PF4 antibodies can be performed; however, a positive test has low specificity, as antibodies are present in up to 20% of heparin-exposed patients, but only a small fraction of these patients will develop HIT. To help make a diagnosis, a calculator has been developed that estimates the probability of HIT based on 4 findings (see 4Ts Score Calculator for HIT). HIT, which has a mortality of 5 - 10%, is treated by stopping heparin and switching to a non-heparin anticoagulant. [8,24]

• Non-heparins
• Argatroban - argatroban is a direct thrombin inhibitor FDA-approved for VTE treatment in patients with HIT syndrome. It is administered via continuous IV infusion and requires aPTT monitoring.
• Bivalirudin (Angiomax®) - bivalirudin is a direct thrombin inhibitor FDA-approved for use during PCI in patients with HIT syndrome. It is administered via continuous IV infusion and requires aPTT monitoring.

• Parenteral therapy treatment recommendations
• Patients with no history of HIT:
• LMWH or fondaparinux are preferred. Intravenous or subcutaneous unfractionated heparin may also be used.
• Therapy should last at least 5 days. See initiating warfarin for recommendations on dosing warfarin.
• Patients with ongoing HIT
• Direct thrombin inhibitor (argatroban)
• If cardiac surgery or PCI is needed, then use bivalirudin
• Patients with a history of HIT
• Fondaparinux [10]

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• TREATMENT | Treatment phase (3 months)

• Treatment phase (3 months)
• During the treatment phase, acute-phase anticoagulation is extended for a total of 3 months to facilitate clot reabsorption. Patients who received parenteral therapy during the acute phase are typically switched to oral therapy.

• ACCP 2021 recommendations
• All patients should be treated for 3 months with the anticoagulant they received in the initiation phase [31]
• Patients with distal DVT - see distal (calf) DVT

• ASH 2021 recommendations for patients with active cancer
• First-line: apixaban, edoxaban, or rivaroxaban
• Second-line: LMWH
• Third-line: vitamin K antagonist [30]
• Studies
• Factor Xa inhibitors for cancer-associated VTE treatment
• A study published in 2015 comparing tinzaparin, a LMWH, to warfarin in cancer patients with acute VTE found no significant difference between the therapies for recurrent VTE or major bleeding at 6 months. [PMID 26284719]

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• TREATMENT | Extended phase (beyond 3 months)

• Extended phase (beyond 3 months)
• After 3 months of treatment, extended anticoagulation is used to prevent VTE recurrence, which can be as high as 8% in the first year after an unprovoked VTE. The 2021 ACCP recommendations for extended anticoagulation divide VTEs into the following three categories:
• VTE provoked by a major transient risk factor (see major and minor risk factor definitions)
• VTE provoked by a minor transient risk factor
• Unprovoked VTE or persistent risk factor (e.g. thrombophilia)

• ACCP 2021 recommendations
• NOTE: see ACCP categories for definitions of major and minor transient risk factors
• Patients with a major transient risk factor should not receive extended coagulation
• Patients with a minor transient risk factor should not receive extended coagulation
• Patients with an unprovoked DVT or persistent risk factor (e.g. thrombophilia) should receive extended coagulation with a DOAC. If a DOAC cannot be used, a vitamin K antagonist should be offered. Patients with antiphospholipid syndrome should receive warfarin.
• Extended-phase apixaban dosing should be 2.5 mg twice daily, and extended-phase rivaroxaban dosing should be 10 mg once daily.
• In patients with an unprovoked proximal DVT or PE who stop anticoagulant therapy, taking low-dose daily aspirin may help to prevent VTE recurrence [31]

• ASH 2021 recommendations for patients with active cancer
• Extended anticoagulation is recommended in all cancer patients with VTE
• Apixaban, edoxaban, rivaroxaban, or LMWH may be used [30]

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• TREATMENT

• Distal (calf) DVT
• Distal DVTs (see location above) do not pose a significant risk for pulmonary embolism. They also have a lower risk of recurrence (see distal DVT recurrence risk below).
• If left untreated, approximately 15 - 25% of distal DVTs will extend into the proximal veins, typically within 2 weeks [6, 10]
• The ACCP recommends that patients with an isolated distal DVT without severe symptoms or risk factors for extension (see below) be monitored with ultrasound once a week for 2 weeks. If the DVT has any extension on serial ultrasound (even if it remains in the distal veins), it should then be treated like a proximal DVT.
• A study published in 2016 compared treatment with LMWH to placebo in patients (n=152) with isolated calf DVT. The composite primary outcome of extension of calf DVT to proximal veins, contralateral proximal DVT, or symptomatic pulmonary embolism at day 42 occurred in 3% of the LMWH group and 5% of the placebo group (p=0.54). Bleeding risk was significantly higher in the LMWH group. [PMID 27836513]
• Risk factors for extension are defined as:
• Elevated D-dimer
• Blood clot that is extensive (> 5cm in length, involves multiple veins, > 7mm in diameter) or close to the proximal veins
• Unprovoked DVT
• Active cancer
• History of previous DVT
• Inpatient status
• COVID-19
• Highly symptomatic
• Patient prefers to avoid repeat imaging
• Factors that may favor serial ultrasound as opposed to anticoagulation
• Thrombosis is confined to the muscular veins of the calf (e.g. soleus, gastrocnemius)
• There is a high or moderate risk for bleeding
• Patient wishes to avoid anticoagulation [10,31]

• Recurrent DVT while taking anticoagulants
• In rare cases, patients may experience a recurrent DVT while they are receiving anticoagulant therapy
• If an on-treatment DVT has been confirmed, then an underlying malignancy should be considered
• The ACCP gives the following treatment recommendations for on-treatment DVTs
• ACCP recommendations for treating recurrent DVTs while on anticoagulants:
• In patients receiving warfarin, dabigatran, rivaroxaban, apixaban or edoxaban, switch to LMWH temporarily (defined as at least 1 month)
• In patients receiving LMWH, increase the dose of LMWH by about one-quarter to one-third [22]

• Anticoagulant + antiplatelet therapy
• Patients with a DVT who have coronary artery disease have indications for both anticoagulation and antiplatelet therapy. Recommendations for antithrombotic therapy in these patients are provided at the links below.
• Triple therapy recommendations (patients who are < 12 months since ACS, PCI, or CABG)
• Stable coronary artery disease (patients who are > 12 months since ACS, PCI, or CABG)

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• OTHER TREATMENTS

• Inferior Vena Cava (IVC) filters
• IVC filters are devices placed in the inferior vena cava that "filter" blood clots from the venous blood headed to the lungs.
• 2021 ACCP recommendations
• In patients with acute proximal DVT of the leg and a contraindication to anticoagulation, IVC filters are recommended
• IVC filters should not be added to anticoagulation [31]

• Thrombolysis
• Thrombolytics can be administered systemically through an IV or directly into a blood clot using catheter-directed thrombolysis (CDT)
• Small studies have suggested that thrombolysis may decrease the risk of post-thrombotic syndrome. However, a study published in 2017 found that CDT did not reduce the risk of post-thrombotic syndrome, but it did increase the risk of major bleeding. [PMID 29211671]
• 2021 ACCP recommendations
• The ACCP does not recommend interventional (thrombolytic, mechanical, or pharmacomechanical) therapy for leg DVTs [31]

• Thrombectomy
• Blood clots can be removed from the vein through open surgery or with catheter-based devices that mechanically aspirate the clot
• 2021 ACCP recommendations
• The ACCP does not recommend interventional (thrombolytic, mechanical, or pharmacomechanical) therapy for leg DVTs [31]

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• RISK OF RECURRENT DVT

• Overall risk
• The risk of recurrent VTE depends on a number of factors including VTE type (provoked vs unprovoked), sex, VTE site, and other patient-specifc comorbidities
• A number of studies have looked at the risk of recurrent VTE. The first table is from a meta-analysis that looked at recurrence risk during the first year after an event based on VTE type. The second table is from a meta-analysis that followed recurrence rates for up to 10 years in patients who discontinued anticoagulation after a first unprovoked VTE.

• Reference [11]

Recurrence rate in first year after treatment of initial VTE with no extended anticoagulation
Type of VTE	Recurrence
Provoked by surgery	1.0%
Provoked by nonsurgical risk factor	5.8%
Unprovoked VTE	7.9%

• Reference [25]

Cumulative recurrent VTE risk for patients who discontinued anticoagulation after a first unprovoked VTE
Time	VTE (Men)	VTE (Women)
2 years	18.3%	13.6%
5 years	28.6%	21.2%
10 years	41.2%	28.8%

• Recurrent VTE after stopping estrogen-containing OCPs
• A systemic review and meta-analysis published in 2022 examined the risk of recurrent VTE in women with a history of estrogen-provoked VTE. The review included 14 studies where women with a VTE thought to be provoked by estrogen-containing OCPs received acute treatment for at least 3 months and were then followed after they discontinued anticoagulation. The overall annual rate of recurrent VTE after stopping anticoagulation was 1.57%. In studies where all patients definitely stopped hormonal use after the first VTE or were strongly encouraged to do so (N=8), the annual rate was 1.31%. The annual rate among studies that included patients with high-risk thrombophilia (N=4) was 1.95%, compared to 1.40% among studies that excluded these women. [PMID 35108438]
• Summary
• This observational study provides some meaningful information on the risk of VTE recurrence in females who experience a VTE while taking estrogen-containing OCPs. OCP use is considered a minor transient risk factor by the most recent ACCP guidelines, and chronic anticoagulation is not recommended. Given that the overall annual risk of recurrence in these women was 1.57%, this analysis supports their recommendation.

• Distal DVT
• Isolated distal DVTs (see location above) have a lower risk of VTE recurrence
• The recurrence rate for VTE in patients with isolated unprovoked first distal DVT who were not anticoagulated was followed for 20 years in one study. Results from that study are presented in the table below.

• Reference [27]

Cumulative recurrent VTE risk by initial VTE site for patients with first unprovoked VTE who were not anticoagulated
Time	Distal DVT	Proximal DVT	PE
10 years	17%	37%	34%
20 years	30%	47%	44%

• Recurrent VTE after negative D-dimer
• The D-dimer test (see D-dimer above) is used in the diagnosis of DVT. D-dimer is a degradation product of clot formation.
• Some studies have shown that patients with a VTE who have an elevated D-dimer after stopping therapy have a higher risk of recurrence. The study detailed below was performed to test the utility of D-dimer testing in predicting VTE recurrence.

• STUDY
  D-dimer testing to predict recurrent VTE in patients with first unprovoked proximal DVT, Ann of IM (2015) [PubMed abstract]
• The study enrolled 410 adults with first unprovoked proximal DVT who had completed 3 - 7 months of anticoagulation
• Patients had a D-dimer test during treatment, and if that test was negative, anticoagulation was stopped. A second D-dimer test was then performed 1 month after stopping treatment.
• Patients who had two negative tests (N=321) stopped anticoagulation indefinitely. The risk of recurrent VTE in these patients is detailed in the table below. Women were subdivided into whether their first DVT occurred during estrogen therapy (OCPs or HRT) or not.

• Estrogen women were taking estrogen-containing OCPs or hormone replacement therapy when their first DVT occurred
• ^✝Five-year results were reported in a separate study [PMID 31033194]
• References [26,28]

Risk of recurrent VTE after negative D-dimer testing
Follow-up	Men	Non-estrogen Women	Estrogen Women
Average of 2.2 years	18.3%	11%	0%
Median of 5 years✝	29.7%	17%	2.3%

• Summary
• The results of this study show that D-dimer testing is not useful in predicting future VTE risk
• Men with negative D-dimer tests had a 5-year cumulative risk of 29.7% which is about the same as that seen in general cohorts of men with VTE (28.6%). The same is true for non-estrogen women (17% vs 21%)
• Women who had a VTE while taking estrogen had a low risk of recurrent VTE in this study which indicates that estrogen therapy is a significant provoking factor in many women

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• BLEEDING RISK

• Overview
• Bleeding risk categories used in the ACCP guidelines are based on the risk factors presented below. It's important to note that estimating bleeding risk is an imperfect science, and criteria from different organizations often vary.
• Once the bleeding risk category is determined, it can be used in the risk-benefit estimation below


• Categories of major bleeding risk:
• Low-risk: 0 risk factors
• Moderate-risk: 1 risk factor
• High-risk: ≥ 2 risk factors


• Risk factors for bleeding:
• Age > 65 years
• Age > 75 years (NOTE: An 80 year old would have 2 risk factors by age (> 65 and 75) and a 70 year old would have one risk factor by age)
• Previous bleeding
• Cancer
• Metastatic cancer (NOTE: A person with localized cancer would have one risk factor by cancer and a person with metastatic cancer would have 2 risk factors by cancer)
• Kidney failure
• Liver failure
• Low platelets (thrombocytopenia)
• Previous stroke
• Diabetes
• Anemia
• Antiplatelet therapy
• Poor anticoagulant control
• Comorbidity and reduced functional capacity
• Recent surgery
• Frequent falls
• Alcohol abuse [10]

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• RISK-BENEFIT ESTIMATION

• ACCP risk-benefit estimation
• The ACCP published a table in their 2012 guidelines that estimates the risk and benefits of extended anticoagulation. The table has not been validated in a prospective study, but it does offer a quantitative estimate of bleeding risk and recurrent VTE in different patient populations.

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• THROMBOPHILIA TESTING / HYPERCOAGULABLE WORKUP

• See thrombophilia testing for a review of recommendations on testing patients with VTE for hypercoagulable disorders

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• UNPROVOKED DVT AND CANCER RISK

• Overview
• Up to 10% of patients with an unprovoked venous thromboembolism (VTE) are diagnosed with cancer within a year following their event
• This observation causes some providers to order extensive cancer workups in patients with unprovoked venous thromboembolism. Whether this practice is prudent is a matter of debate. [19,20]
• A study published in 2015 in the NEJM compared the effectiveness of two cancer screening approaches in patients with unprovoked venous thromboembolism

• Summary
• The SOME study found no benefit of adding an abdominal and pelvic CT to standard screening in patients with unprovoked VTE
• It's unclear if an unprovoked VTE is a marker of increased cancer risk. In order to evaluate this, a group of patients with unprovoked VTE would have to be compared with a matched control group that underwent all of the same testing. No such study has been performed. The high incidence of cancer in patients diagnosed with VTE may be a product of surveillance bias as opposed to an association of VTE with cancer risk. Some studies have found that the risk of cancer following VTE returns to normal after 6 months. This finding tends to argue against VTE being a marker of increased cancer risk. [20]

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• POST-THROMBOTIC SYNDROME

• Overview
• Post-thrombotic syndrome is a condition marked by leg pain, swelling, leg heaviness, skin changes (brownish pigmentation), and in some cases, venous insufficiency with ulcers. It occurs in up to a third of patients after their first DVT, typically within 2 years.
• Symptoms are typically mild (small amount of leg swelling), and severe symptoms are rare (intense pain and leg ulcers). In one study, the cumulative incidence of severe symptoms after 5 years of follow-up was 8%. [3, 12]
• Compression stockings have been proposed as a means to prevent post-thrombotic syndrome. A study that compared compression stockings to placebo stockings is presented below.

• 2021 ACCP recommendations
• In patients with acute DVT of the leg, compression stockings are not recommended to prevent post-thrombotic syndrome [31]

• Summary
• The SOX trial found no benefit of compression stockings in preventing post-thrombotic syndrome. Compression stockings can be uncomfortable and hot to wear, and only about 56% of participants in the trial complied with the treatment.
• Catheter-directed thrombolysis (CDT) of the DVT has also been hypothesized to decrease the risk of post-thrombotic syndrome. A study published in 2017 found that CDT did not reduce the risk of post-thrombotic syndrome, but it did increase the risk of major bleeding. [PMID 29211671]

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• SUPERFICIAL VEIN THROMBOSIS

• Overview
• Superficial vein thrombosis occurs when a blood clot forms in the veins underneath the skin. Varicose veins in the legs are the most common site for an SVT, with the saphenous vein involved in about two-thirds of cases.
• In the past, SVT was considered a somewhat benign process and was either not treated or treated with aspirin. However, this thinking has changed as several studies have found that patients with SVT are at significant risk of VTE. In one study, patients with an SVT ≥ 5 cm in length also had an accompanying proximal DVT in 10% of cases and a distal DVT in 13% of cases. [4] Another study found that patients with an SVT had a DVT incidence of 2.5% in the first 3 months following SVT diagnosis. PE incidence was 0.9% in the same 3 months, and at 5 years after SVT diagnosis, the risk of VTE was 5-fold higher when compared to patients without a history of SVT. [12]
• A study published in 2010 found that patients with an SVT (≥ 5 cm in length) who were treated with the heparin derivative fondaparinux (2.5 mg once daily for 45 days) had a significantly lower incidence of subsequent deep vein thrombosis and pulmonary embolism (absolute risk reduction 5%). [PMID 20860504]


• 2021 ACCP SVT treatment recommendations
• In patients with SVT of the lower limb at increased risk for clot progression to VTE (see below), anticoagulation for 45 days is recommended
• Fondaparinux 2.5 mg once daily for 45 days is preferred over other anticoagulant regimens such as (prophylactic or therapeutic dose) LMWH
• In patients who refuse or are unable to use parenteral anticoagulation, rivaroxaban 10 mg daily is a reasonable alternative
• Risk factors for progression to VTE
• Extensive SVT (≥ 5 cm)
• Involvement above the knee, particularly if close to the saphenofemoral junction
• Severe symptoms
• Involvement of the greater saphenous vein
• History of VTE or SVT
• Active cancer
• Recent surgery [31]

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• ASPIRIN FOR VTE PREVENTION | Secondary prevention

• Overview
• Daily aspirin has been evaluated in the secondary prevention of VTE in several studies
• The WARFASA and ASPIRE studies compared aspirin to placebo in patients with a first episode of unprovoked VTE
• The EINSTEIN CHOICE study compared aspirin to two different doses of rivaroxaban in patients with provoked and unprovoked VTE
• All three studies are presented below. Results from a meta-analysis that combined the WARFASA and ASPIRE studies are also presented.

• STUDY
  Meta-analysis of WARFASA and ASPIRE Trials, NEJM (2012) [PubMed abstract]
• The authors of the ASPIRE study and the WARFASA study performed a pre-specified meta-analysis that combined the two studies
• Results of the meta-analysis showed the following:
• Aspirin reduced the relative risk of recurrent venous thromboembolism by 32% (HR 0.68, 95%CI [CI 0.51 - 0.90], p=0.007)
• There was no significant difference between the two groups in clinically relevant bleeding. Aspirin - 2.92%, Placebo - 1.97% (HR 1.47, 95%CI [0.70 - 3.08], p=0.31) [14]

• Summary
• The ASPIRE study did not show a statistically significant effect of aspirin in preventing recurrent VTE, although there was a trend towards significance with a p-value of 0.09. The study had poor enrollment and was underpowered.
• The WARFASA study, a much smaller study, found a significant effect with aspirin after two years of follow-up
• The meta-analysis that combined the two studies found that aspirin reduced the relative risk of VTE by 32%
• Not surprisingly, the EINSTEIN-CHOICE trial found rivaroxaban to be superior to aspirin for preventing VTE. Also of note, the 10 mg dose of rivaroxaban was as effective as the 20 mg dose.
• Across all 3 studies, the risk of recurrent VTE with daily aspirin was between 4.4 - 6.6% per year. The risk for patients in the EINSTEIN CHOICE trial with a provoked VTE as the index event was slightly lower at 3.6%. In the placebo arms of WARFASA and ASPIRE, the risk of recurrent VTE was 11.2% and 6.5%, respectively.
• Collectively, these three trials help quantify the risk of recurrent VTE for patients who choose to take aspirin over anticoagulation

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• ASPIRIN FOR VTE PREVENTION | Primary prevention after TKA / THA

• Overview
• Patients who undergo total hip or knee replacement surgery are at high risk for VTE in the immediate postoperative period. Anticoagulants, including low-molecular-weight heparins and factor Xa inhibitors, are often prescribed for 15 (knee) to 35 (hip) days after surgery to prevent VTE.
• The study below compared a full course of rivaroxaban to 5 days of rivaroxaban followed by aspirin in patients who received primary or revision hip or knee arthroplasty

• Summary
• In the study above, five days of rivaroxaban followed by aspirin was noninferior to a full course of rivaroxaban for preventing VTE after hip and knee replacement surgery. Another study that compared aspirin to dalteparin in hip replacement surgery came to a similar conclusion. [PMID 23732713]

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• ASPIRIN FOR VTE PREVENTION | Primary prevention after fracture

• Overview
• Traumatic fractures increase the risk of VTE, particularly during the immediate post-fracture/operative phase. Professional guidelines recommend anticoagulation during this high-risk period, and low-molecular-weight heparins (LMWH) are typically used. Recent studies have suggested that aspirin may be equally effective and is preferred by patients due to its low cost and oral administration. The METRC study detailed below compared aspirin to enoxaparin for VTE prevention after traumatic fracture.

• Summary
• In the METRC study, aspirin was noninferior to enoxaparin for mortality and PE prevention in patients hospitalized with significant fractures. DVT incidence was significantly higher in the aspirin group, but only by 0.80%. Bleeding complications and other adverse events were similar between groups.

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