Lower Extremity Deep Venous Thrombosis_ Initiation of Anticoagulation (First 10 Days)

7/25/2019 Lower Extremity Deep Venous Thrombosis_ Initiation of Anticoagulation (First 10 Days)

1/28

3/6/2016 Lower extremity deep venous thrombosis: Initiation of anticoagulation (first 10 days)

http://www.uptodate.com/contents/lower-extremity- deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days?topicKey=PULM%2F95336&elapsedTi

Offi cial reprint from UpToDatewww.uptodate.com 2016 UpToDate

AuthorsGregory YH Lip, MD, FRCPE,FESC, FACCRussell D Hull, MBBS, MSc

Section EditorsLawrence LK Leung, MDJess Mandel, MD

Deputy EditorGeraldine Finlay, MD

Lower extremity deep venous thrombosis: Initiation of anticoagulation (first 10 days)

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2016. | This topic last updated: Nov 03, 2014.

INTRODUCTION Venous thromboembolism (VTE) is comprised of two entities, deep venous thrombosis

(DVT) and pulmonary embolus (PE). VTE has significant morbidity and mortality for both the inpatient and

outpatient population. The risk of recurrent thrombosis and embolization is highest in the first few days and weeks

following diagnosis. Initial anticoagulation during the first 5 to 10 days is critical in the prevention of recurrence and

VTE-related death.

The agents used, timing, duration, and dosing of initial anticoagulation for the treatment of DVT are discussed in

this topic. The indications and overview of DVT treatment, as well as long-term (3 to 12 m onths) and extended

(indefinite) anticoagulation for patients with VTE are discussed separately. (See "Overview of thetreatment oflower extremity deep vein thrombosis (DVT)", section on 'Patients with contraindications to anticoagulation' and

"Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)" and "Rationale

and indications for indefinite anticoagulation in patients with venous thromboembolism".)

NOMENCLATURE For the purposes of discussion in this topic, the following terms apply:

INDICATIONS Most patients with ultrasound-proven proximal DVT (popliteal, femoral, or iliac vein DVT) and

select cases of distal DVT (below the knee and in the calf veins peroneal, posterior, and anterior tibial DVT)

should be anticoagulated. The indication to anticoagulate is stronger for patients with proximal DVT than with

distal DVT because the risk of complications, particularly embolization, is higher. Although the efficacy ofanticoagulant therapy in patients with asymptomatic DVT (ie, incidental DVT) is unknown, we and others prefer

that this population of patients be managed or anticoagulated in the same manner as symptomatic patients [ 2]. For

each patient, the decision to anticoagulate must weigh the risk of morbidity and mortality without anticoagulation

against the risk of bleeding on anticoagulation. Details of the indications for anticoagulation are discussed

separately. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on

'Indications'.)

BLEEDING RISK In all patients, the decision to anticoagulate should be individualized and the benefits of

venous thromboembolism (VTE) prevention carefully weighed against the risk of bleeding (table 1). Most clinicians

agree that patients with a three-month bleeding risk less than 2 percent (low risk) should be anticoagulated and

Initial anticoagulation is administered over the first 5 to 10 days following a diagnosis of DVT. Long-term

anticoagulant therapy is typically administered for a finite period beyond the initial period, usually three to six

months and occasionally up to 12 months. Extended anticoagulation usually refers to therapy that is

administered indefinitely. (See "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days

to three months)" and "Rationale and indications for indefinite anticoagulation in patients with venous

thromboembolism".)

Factor Xa and direct thrombin inhibitors have a variety of names including newer/novel oral anticoagulants,

non-vitamin K antagonist oral anticoagulants (NOAs, NOACs), and target-specific oral anticoagulants

(TOACs, TSOACs) [1]. Throughout this topic we refer to these agents by their pharmacologic class, factor

Xa and direct thrombin inhibitors. (See "Anticoagulation with direct thrombin inhibitors and direct factor Xa

inhibitors".)
http://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt?source=see_link&sectionName=INDICATIONS&anchor=H3#H3http://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt?source=see_link&sectionName=INDICATIONS&anchor=H3#H3http://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt?source=see_link&sectionName=INDICATIONS&anchor=H3#H3http://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt?source=see_link&sectionName=INDICATIONS&anchor=H3#H3http://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt?source=see_link&sectionName=INDICATIONS&anchor=H3#H3http://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt?source=see_link&sectionName=INDICATIONS&anchor=H3#H3http://www.uptodate.com/contents/anticoagulation-with-direct-thrombin-inhibitors-and-direct-factor-xa-inhibitors?source=see_linkhttp://www.uptodate.com/contents/anticoagulation-with-direct-thrombin-inhibitors-and-direct-factor-xa-inhibitors?source=see_linkhttp://www.uptodate.com/contents/rationale-and-indications-for-indefinite-anticoagulation-in-patients-with-venous-thromboembolism?source=see_linkhttp://www.uptodate.com/contents/rationale-and-indications-for-indefinite-anticoagulation-in-patients-with-venous-thromboembolism?source=see_linkhttp://www.uptodate.com/contents/rationale-and-indications-for-indefinite-anticoagulation-in-patients-with-venous-thromboembolism?source=see_linkhttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-long-term-anticoagulation-10-days-to-three-months?source=see_linkhttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/rationale-and-indications-for-indefinite-anticoagulation-in-patients-with-venous-thromboembolism?source=see_linkhttp://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt?source=see_link&sectionName=Patients+with+contraindications+to+anticoagulation&anchor=H256309218#H256309218http://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt?source=see_link&sectionName=Patients+with+contraindications+to+anticoagulation&anchor=H256309218#H256309218http://www.uptodate.com/home/editorial-policyhttp://www.uptodate.com/contents/anticoagulation-with-direct-thrombin-inhibitors-and-direct-factor-xa-inhibitors?source=see_linkhttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/1http://www.uptodate.com/contents/rationale-and-indications-for-indefinite-anticoagulation-in-patients-with-venous-thromboembolism?source=see_linkhttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-long-term-anticoagulation-10-days-to-three-months?source=see_linkhttp://www.uptodate.com/contents/image?imageKey=PULM%2F97160&topicKey=PULM%2F95336&rank=8%7E150&source=see_linkhttp://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt?source=see_link&sectionName=INDICATIONS&anchor=H3#H3http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/2http://www.uptodate.com/contents/rationale-and-indications-for-indefinite-anticoagulation-in-patients-with-venous-thromboembolism?source=see_linkhttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-long-term-anticoagulation-10-days-to-three-months?source=see_linkhttp://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt?source=see_link&sectionName=Patients+with+contraindications+to+anticoagulation&anchor=H256309218#H256309218http://www.uptodate.com/home/editorial-policyhttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/contributorshttp://www.uptodate.com/


2/28


3/28


http://www.uptodate.com/contents/lower-extremity- deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days?topicKey=PULM%2F95336&elapsedTi 3

TIMING, DURATION, AND DOSING For patients with proximal DVT, the greatest risk of embolization is

during the first three months of anticoagulant therapy and, in particular, during the first few days following the

diagnosis. When the decision is made to anticoagulate patients with DVT, anticoagulant therapy should be started

immediatelyas a delay may potentially increase the risk of life-threatening embolization. Baseline coagulation

tests (prothrombin time, International Normalized Ratio [INR], activated partial thromboplastin time [aPTT]) should

be drawn prior to the initiation of anticoagulation to guide therapy. The timing, duration, and dose of initial

anticoagulation vary with the agent selected and are discussed in the sections below.

For most patients, warfarin and heparin are started on the first day, and heparin is continued for a minimum of four

to five days until the INR has been within therapeutic range for a minimum of 24 to 48 hours. There is no benefit to

prolonged courses of systemic heparin beyond the achievement of a therapeutic INR. (See 'Transitioning to

maintenance therapy' below.)

Low-molecular-weight heparin As described above, low-molecular-weight (LMW) heparin is our preferred

anticoagulant for most patients with newly diagnosed DVT, in particular for those with active cancer or pregnancy.

(See 'Selection of agent'above.)

Dosing The initial therapeutic dose of LMW heparin (eg, enoxaparin, dalteparin, tinzaparin) varies by

product. Dosing is typically weight based and renally adjusted, and all are administered subcutaneously (SC).

Typical starting doses are:

Dosing for obese patients and patients with renal insufficiency is listed in the tables ( table 2 and table 3). (See

"Therapeutic use of unfractionated heparin and low molecular weight heparin", section on 'LMW heparin'.)

Efficacy Evidence from several randomized trials and meta-analyses have reported that, compared with

intravenous (IV) and SC unfractionated heparin (UFH), SC LMW heparin has higher rates of thrombus regressionand lower rates of recurrent thrombosis, major bleeding, and mortality [6-19]. However, the data are fraught with

methodologic flaws, including publication bias in favor of LMW heparin. Thus, at minimum, LMW heparin appears

to be as safe and as effective as UFH (IV and SC).

cancer or pregnant women, their safety and efficacy is unproven, and, as such, they should not be routinely

used in these populations.

Enoxaparin 1 mg/kg twice daily (or 1.5 mg/kg once daily)

Dalteparin 200 units/kg once daily for the first 30 days followed by 150 units/kg for maintenance

Tinzaparin 175 units/kg once daily (not available in the United States)

In a 2010 meta-analysis of 23 studies that compared LMW heparin with IV or SC UFH in patients with acute

venous thromboembolism (VTE DVT and/or pulmonary embolus [PE]), LMW heparin was associated with

the following [15]:

Fewer thrombotic complications (eg, recurrence, extension, embolization) (3.6 versus 5.3 percent odds

ratio [OR] 0.70, 95% CI 0.57-0.85)

Improved thrombus regression (53 versus 45 percent of participants OR 0.69, 95% CI 0.59-0.81)

Reduced rates of major hemorrhage (1 versus 2 percent OR 0.58, 95% CI 0.40-0.83)

Reduced mortality (4 versus 6 percent OR 0.77, 95% CI 0.63-0.93)

An older meta-analysis of 13 studies of patients with acute VTE performed between 1980 and 1994 reported

that, compared with UFH, LMW heparin was associated with a lower rate of both recurrent VTE (2.7 versus

7 percent) and major bleeding (0.9 versus 3.2 percent) [9].

A 1999 meta-analysis of 11 trials of patients with acute DVT found a lower mortality rate at three to six

months among patients treated with LMW heparin, compared with those receiving UFH (OR 0.71, 95% CI
http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/9http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/15http://www.uptodate.com/contents/tinzaparin-drug-information?source=see_linkhttp://www.uptodate.com/contents/dalteparin-drug-information?source=see_linkhttp://www.uptodate.com/contents/enoxaparin-drug-information?source=see_linkhttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/6-19http://www.uptodate.com/contents/heparin-unfractionated-drug-information?source=see_linkhttp://www.uptodate.com/contents/therapeutic-use-of-unfractionated-heparin-and-low-molecular-weight-heparin?source=see_link&sectionName=LMW+HEPARIN&anchor=H29#H29http://www.uptodate.com/contents/image?imageKey=HEME%2F90258&topicKey=PULM%2F95336&rank=8%7E150&source=see_linkhttp://www.uptodate.com/contents/image?imageKey=HEME%2F65464&topicKey=PULM%2F95336&rank=8%7E150&source=see_linkhttp://www.uptodate.com/contents/tinzaparin-drug-information?source=see_linkhttp://www.uptodate.com/contents/dalteparin-drug-information?source=see_linkhttp://www.uptodate.com/contents/enoxaparin-drug-information?source=see_linkhttp://www.uptodate.com/contents/warfarin-drug-information?source=see_link


4/28



Once daily regimens of LMW heparin appear to be as effective as twice daily regimens. Meta-analyses of trials

directly comparing once versus twice daily administration found no differences in recurrent thrombosis, major

hemorrhage, or mortality [11,12,20-25]. The largest study of 900 patients with symptomatic DVT, a third of whom

also had PE, compared the LMW heparin, enoxaparin, administered as a standard twice daily regimen (1 mg/kg

twice daily), with a lower once daily regimen (1.5 mg/kg per day) [11]. Although rates of recurrence (3 versus 4

percent) and hemorrhage (1 versus 2 percent) were lower with the twice daily regimen, the difference was not

significant and may have been explained by the lower total daily dose administered in the once daily treatment

group. Except for enoxaparin, we prefer, when once daily dosing is being considered, that it be administered at the

same total daily dose as a twice daily schedule.

The LMW heparins have a number of advantages over unfractionated heparin [26,27]. (See "Therapeutic use of

unfractionated heparin and low molecular weight heparin", section on 'Advantages and limitations' .)

Disadvantages of LMW heparin compared with UFH include the higher cost, and, although protamine is an

antidote for hemorrhage, its effect is incomplete. In addition, efficacy is less certain in the obese population, in

patients with renal failure, and in older patients who are underweight (


5/28


6/28



discussed in detail separately. (See 'Selection of agent' above and 'Low-molecular-weight heparin'above.)

The efficacy of IV UFH depends upon achieving a critical therapeutic level as soon as possible, preferably within

the first 24 hours of treatment, usually via a continuous IV infusion [ 14,30,38-42]. The critical therapeutic level of

heparin, as measured by the aPTT, is a target aPTT ratio range of 1.5 to 2.5 times the control. This corresponds to

a heparin level of 0.3 to 0.7 units/mL, when measured by an anti-Xa assay [43,44]. Studies that support this target

range include the following:

Although there is a strong correlation between subtherapeutic aPTT values and recurrent thromboembolism, the

relationship between supratherapeutic aPTT (ie, an aPTT ratio 2.5 or more) and bleeding is less definite [ 31].

Nonetheless, aiming for a therapeutic range with the avoidance of periods of both subtherapeutic and

supratherapeutic levels is prudent.

The advantages of UFH compared with LMW heparin include its lower cost and its safe use in those with renal

insufficiency. An additional advantage of the IV formulation is its short half-life, particularly for patients in whom

there is a potential need for acute discontinuation (eg, surgery). Disadvantages include that infusions of UFH

require hospital admission, and both SC and IV UFH are associated with a higher potential for HIT. (See

"Therapeutic use of unfractionated heparin and low molecular weight heparin", section on 'Other complications' .)

Direct factor Xa and thrombin inhibitors

Dosing We advocate for the use of oral factor Xa (rivaroxaban, apixaban, edoxaban) or direct thrombin

inhibitors (dabigatran) in accordance with criteria in clinical trials that demonstrated their efficacy. These agents

are attractive candidates as initial anticoagulants in patients with acute DVT due to their quick onset of action

(peak efficacy one to four hours after ingestion). In trials that evaluated dabigatran and edoxaban, all patients were

treated with five days of heparin prior to their administration (ie, "dual therapy" initial anticoagulation) as such, we

prefer that a short course of heparin be administered before transitioning to either dabigatran or edoxaban. In

contrast, rivaroxaban and apixaban were evaluated as anticoagulants without prior administration of heparin (ie,

monotherapy) our clinical experience is in keeping with the data that support their use as the sole initial

anticoagulant. Importantly, anticoagulant therapy with heparin should not be delayed while the decision is being

made to treat with one of these newer oral agents. (See 'Selection of agent'above.)

Many of these agents are renally excreted, and patients with a creatinine clearance of 1.5,

patients who had an aPTT ratio


7/28



Maintenance doses for long-term anticoagulation are discussed separately. (See "Anticoagulation with direct

thrombin inhibitors and direct factor Xa inhibitors" and "Lower extremity deep venous thrombosis: Long-term

anticoagulation (10 days to three months)", section on 'Direct thrombin and factor Xa inhibitors'.)

In keeping with the clinical trials that demonstrated their efficacy, in patients who are receiving heparin as the

initial anticoagulant, we prefer that oral factor Xa or direct thrombin inhibitors be given within 6 to 12 hours

following the last dose of SC LMW heparin when administered as a twice daily regimen, or within 12 to 24 hours

for once daily regimens. Infusions of UFH can be immediately discontinued following the administration of these

oral agents. (See "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)",

section on 'Transitioning to long-term therapy'.)

The efficacy and safety of factor Xa and direct thrombin inhibitors as anticoagulants for extensive DVT (eg,

patients with phlegmasia cerulea dolens) or hemodynamically significant pulmonary embolus are unknown, and, as

such, they should NOTbe used in these patient populations where their use may interfere with the potential

administration of thrombolytic therapy. Similarly, because their safety and efficacy is unproven, we prefer that

these agents NOTbe administered in patients who are pregnant or in patients with active malignancy. (See

"Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on 'Phlegmasia cerulea

dolens' and "Fibrinolytic (thrombolytic) therapy in acute pulmonary embolism and lower extremity deep vein

thrombosis" and "Deep vein thrombosis and pulmonary embolism in pregnancy: Treatment" and "Treatment of

venous thromboembolism in patients with malignancy".)

Efficacy Randomized trials of these oral agents in patients with acute DVT examined efficacy and safety in

the context of long-term anticoagulation with the same oral agent for three months or more. When compared with

conventional courses of LMW heparin or IV UFH followed by long-term anticoagulation with warfarin, these agents

had similar rates of recurrent thrombosis and major hemorrhage [45-48]. However, trials that reported efficacy for

dabigatran (direct thrombin inhibitor) and edoxaban(factor Xa inhibitor) used a minimum of five days of

anticoagulation with LMW heparin or UFH prior to their administration for long-term oral therapy (ie, dual therapy)

[47,48]. In contrast, trials of rivaroxaban and apixaban reported efficacy of both agents as the sole initial

anticoagulant (monotherapy). Although short periods (


8/28



withhold when the suspicion is low, provided testing is not delayed for >24 hours [ 3]. Empiric anticoagulation may

be considered for those in whom the suspicion is assessed as intermediate, particularly when testing is expected

to be delayed for more than four hours. For empiric anticoagulation, we prefer therapeutic low-molecular-weight

(LMW) or unfractionated heparin(UFH) for as short a period as is feasible, provided there are no contraindications.

The diagnosis of DVT is discussed separately. (See "Diagnosis of suspected deep vein thrombosis of the lower

extremity".)

SPECIAL POPULATIONS When choosing an initial anticoagulant, patients with malignancy, pregnant women,

outpatients, and those with a history of heparin-induced thrombocytopenia (HIT) deserve special consideration.

Malignancy For most patients with malignancy and DVT who have a reasonable life expectancy and adequate

renal function (creatinine clearance 30 mL/min), low-molecular-weight (LMW) heparin is the preferred agent for

initial anticoagulation, rather than other agents. There is insufficient evidence to support the use of factor Xa and

direct thrombin inhibitors in patients with malignancy at this time. This is discussed in more detail separately. (See

"Treatment of venous thromboembolism in patients with malignancy".)

Pregnancy For pregnant women with acute DVT, adjusted-dose subcutaneous (SC) LMW heparin is the

preferred agent for initial anticoagulation because it has a more favorable safety profile, especially when compared

with warfarin. Warfarin freely crosses the placental barrier and can produce an embryopathy when given between

the sixth and ninth weeks of pregnancy. Intravenous (IV) and SC forms of unfractionated heparin (UFH) are

alternatives to LMW heparin. Factor Xa and direct thrombin inhibitors have not been adequately tested in pregnantwomen with acute DVT and should not be administered. (See "Deep vein thrombosis and pulmonary embolism in

pregnancy: Treatment" and "Use of anticoagulants during pregnancy and postpartum".)

Outpatients Not all patients who have acute DVT need to be admitted to the hospital for initial anticoagulation.

Several randomized trials and meta-analyses that have compared outpatient therapy with SC LMW heparin with

inpatient therapy with IV UFH suggest that, in select populations, treatment at home with LMW heparin is safe

and effective. Most clinicians agree that outpatient therapy with LMW heparin can be considered in

hemodynamically stable patients with a low bleeding risk, who have a practical system in place for the

administration and surveillance of anticoagulant therapy, who are also without renal insufficiency, massive DVT,

concurrent pulmonary embolism, or other comorbid conditions that require inpatient care (table 7). The decision to

anticoagulate as an outpatient should be made in the context of the patients understanding of the risk-benefit ratio,preferences, and clinical condition. The outpatient treatment of DVT and pulmonary embolism are discussed

separately. (See "Overview of the treatment of lower extremity deep vein thrombosis (DVT)", section on

'Outpatient therapy' and "Overview of the treatment, prognosis, and follow-up of acute pulmonary embolism in

adults", section on 'Outpatient anticoagulation'.)

Heparin-induced thrombocytopenia For patients with a DVT and a prior diagnosis of HIT, any form of heparin

is contraindicated. This includes systemic UFH, LMW heparin, heparin flushes, heparin-bonded catheters, and

heparin-containing medications. Immediate anticoagulation with a non-heparin anticoagulant (eg, argatroban,

danaparoid, fondaparinux, bivalirudin) is indicated (table 8). The diagnosis and management of patients with HIT

are discussed in detail separately. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia"

and "Management of heparin-induced thrombocytopenia".)

TRANSITIONING TO MAINTENANCE THERAPY Therapeutic anticoagulation should be ensured during the

transition from initial to long-term (maintenance) therapy. The optimal transition strategy varies with the long-term

anticoagulant chosen.

When warfarin is chosen as the agent for long-term anticoagulation, it is typically started on the same day with

low-molecular-weight (LMW) heparin, unfractionated heparin(UFH), or fondaparinuxand dose adjusted until the

International Normalized Ratio (INR) is within the therapeutic range (2 to 3 target 2.5) for a minimum of 24 to 48

hours [50]. Typical starting doses of warfarin are 5 mg/day for two days (range 2 mg to 10 mg/day) (table 9). Initial

doses at the lower range (2 to 5 mg/day) may be considered in those assessed at high bleeding risk (eg, older

adults), and doses in the higher range (5 to 10 mg/day) may be selected in healthy individuals who are without
http://www.uptodate.com/contents/image?imageKey=HEME%2F71791&topicKey=PULM%2F95336&rank=8%7E150&source=see_linkhttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/50http://www.uptodate.com/contents/fondaparinux-drug-information?source=see_linkhttp://www.uptodate.com/contents/heparin-unfractionated-drug-information?source=see_linkhttp://www.uptodate.com/contents/warfarin-drug-information?source=see_linkhttp://www.uptodate.com/contents/management-of-heparin-induced-thrombocytopenia?source=see_linkhttp://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-heparin-induced-thrombocytopenia?source=see_linkhttp://www.uptodate.com/contents/image?imageKey=HEME%2F73727&topicKey=PULM%2F95336&rank=8%7E150&source=see_linkhttp://www.uptodate.com/contents/bivalirudin-drug-information?source=see_linkhttp://www.uptodate.com/contents/fondaparinux-drug-information?source=see_linkhttp://www.uptodate.com/contents/danaparoid-drug-information?source=see_linkhttp://www.uptodate.com/contents/argatroban-drug-information?source=see_linkhttp://www.uptodate.com/contents/overview-of-the-treatment-prognosis-and-follow-up-of-acute-pulmonary-embolism-in-adults?source=see_link&sectionName=Outpatient+anticoagulation&anchor=H286668969#H286668969http://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt?source=see_link&sectionName=Outpatient+therapy&anchor=H726449277#H726449277http://www.uptodate.com/contents/image?imageKey=HEME%2F70140&topicKey=PULM%2F95336&rank=8%7E150&source=see_linkhttp://www.uptodate.com/contents/use-of-anticoagulants-during-pregnancy-and-postpartum?source=see_linkhttp://www.uptodate.com/contents/deep-vein-thrombosis-and-pulmonary-embolism-in-pregnancy-treatment?source=see_linkhttp://www.uptodate.com/contents/heparin-unfractionated-drug-information?source=see_linkhttp://www.uptodate.com/contents/warfarin-drug-information?source=see_linkhttp://www.uptodate.com/contents/treatment-of-venous-thromboembolism-in-patients-with-malignancy?source=see_linkhttp://www.uptodate.com/contents/diagnosis-of-suspected-deep-vein-thrombosis-of-the-lower-extremity?source=see_linkhttp://www.uptodate.com/contents/heparin-unfractionated-drug-information?source=see_linkhttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/3


9/28



obvious risk for bleeding. Subsequent dose adjustments are made to target an INR of 2 to 3. Initial dosing and

maintenance therapy for warfarin are discussed separately. (See "Therapeutic use of warfarin and other vitamin K

antagonists", section on 'Warfarin administration' and "Lower extremity deep venous thrombosis: Long-term

anticoagulation (10 days to three months)", section on 'Warfarin' .)

When subcutaneous LMW heparin and fondaparinux are chosen for long-term anticoagulation and they have not

been chosen as the initial anticoagulant, they can be administered subcutaneously (SC) and intravenous (IV) UFH

immediately discontinued. Oral factor Xa or direct thrombin inhibitors are generally given within 6 to 12 hours

following the last dose of a twice daily regimen of SC LMW heparin, within 12 to 24 hours for once daily regimens,

and upon the discontinuation of the IV UFH infusion. Transitioning from initial to maintenance therapy and

switching anticoagulants during therapy are discussed in detail separately. (See "Lower extremity deep venous

thrombosis: Long-term anticoagulation (10 days to three months)", section on 'Transitioning to long-term therapy'

and "Lower extremity deep venous thrombosis: Long-term anticoagulation (10 days to three months)", section on

'Transitioning during therapy'.)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and

Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade

reading level, and they answer the four or five key questions a patient might have about a given condition. These

articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond

the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written

at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable

with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these

topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on

patient info and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

Basics topics (See "Patient information: Deep vein thrombosis (DVT) (Beyond the Basics)".)

Beyond the Basics topics (see "Patient information: Deep vein thrombosis (DVT) (Beyond the Basics)" and

"Patient information: Warfarin (Coumadin) (Beyond the Basics)")

Initial anticoagulation refers to systemic anticoagulation administered for the first 5 to 10 days following a

diagnosis of deep venous thrombosis (DVT). Anticoagulation should be started immediately as a delay

increases the risk of embolization and death. The choice of initial anticoagulation is the same for patients

with proximal, distal, symptomatic, and asymptomatic DVT. (See 'Nomenclature'above.)

Every patient with acute DVT should be assessed for the risk of bleeding prior to anticoagulation. Most

clinicians agree that anticoagulation should be administered to patients with a low risk of bleeding and

avoided in those at high risk. For patients with a moderate risk of bleeding, the decision to anticoagulate

must be individualized according to the values and preferences of the patient as well as the risk-benefit ratio

as assessed by the clinician. (See 'Bleeding risk' above and "Overview of the treatment of lower extremity

deep vein thrombosis (DVT)", section on 'Assessing bleeding risk' and "Management of warfarin-associated

bleeding or supratherapeutic INR", section on 'Bleeding risk'.)

For patients with acute DVT, treatment options for initial anticoagulation include the following: low-molecular-

weight (LMW) heparin, fondaparinux, unfractionated heparin(UFH), and oral factor Xa and direct thrombin

inhibitors. In general:

For most patients, we suggest LMW heparin rather than other agents (fondaparinux, intravenous [IV]

UFH, factor Xa or direct thrombin inhibitors) (Grade 2B). Fondaparinux is an acceptable alternative for

nonpregnant patients. A decision between LMW heparin and fondaparinux is usually made based on

clinician experience and availability. Dosing is individualized for each product. (See 'Selection of agent'
http://www.uptodate.com/contents/grade/5?title=Grade%202B&topicKey=PULM/95336http://www.uptodate.com/contents/fondaparinux-drug-information?source=see_linkhttp://www.uptodate.com/contents/heparin-unfractionated-drug-information?source=see_linkhttp://www.uptodate.com/contents/fondaparinux-drug-information?source=see_linkhttp://www.uptodate.com/contents/management-of-warfarin-associated-bleeding-or-supratherapeutic-inr?source=see_link&sectionName=BLEEDING+RISK&anchor=H624013#H624013http://www.uptodate.com/contents/overview-of-the-treatment-of-lower-extremity-deep-vein-thrombosis-dvt?source=see_link&sectionName=ASSESSING+BLEEDING+RISK&anchor=H102101510#H102101510http://www.uptodate.com/contents/warfarin-coumadin-beyond-the-basics?source=see_linkhttp://www.uptodate.com/contents/deep-vein-thrombosis-dvt-beyond-the-basics?source=see_linkhttp://www.uptodate.com/contents/deep-vein-thrombosis-dvt-beyond-the-basics?source=see_linkhttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-long-term-anticoagulation-10-days-to-three-months?source=see_link&sectionName=TRANSITIONING+DURING+THERAPY&anchor=H105730846#H105730846http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-long-term-anticoagulation-10-days-to-three-months?source=see_link&sectionName=TRANSITIONING+TO+LONG-TERM+THERAPY&anchor=H28215420#H28215420http://www.uptodate.com/contents/fondaparinux-drug-information?source=see_linkhttp://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-long-term-anticoagulation-10-days-to-three-months?source=see_link&sectionName=Warfarin&anchor=H105731110#H105731110http://www.uptodate.com/contents/therapeutic-use-of-warfarin-and-other-vitamin-k-antagonists?source=see_link&sectionName=WARFARIN+ADMINISTRATION&anchor=H21#H21


10/28


http://www.uptodate.com/contents/lower-extremity- deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days?topicKey=PULM%2F95336&elapsed 10

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Husted S, de Caterina R, Andreotti F, et al. Non-vitamin K antagonist oral anticoagulants (NOACs): No

above and 'Low-molecular-weight heparin'above and 'Fondaparinux'above.)

For patients with severe renal failure (eg, creatinine clearance


11/28



longer new or novel. Thromb Haemost 2014 111:781.

2. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the initialtreatment of proximal venous thrombosis. N Engl J Med 1990 322:1260.

3. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy andPrevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical PracticeGuidelines. Chest 2012 141:e419S.

4. den Exter PL, van Es J, Erkens PM, et al. Impact of delay in clinical presentation on the diagnosticmanagement and prognosis of patients with suspected pulmonary embolism. Am J Respir Crit Care Med2013 187:1369.

5. Smith SB, Geske JB, Maguire JM, et al. Early anticoagulation is associated with reduced mortality for acutepulmonary embolism. Chest 2010 137:1382.

6. Segal JB, Streiff MB, Hofmann LV, et al. Management of venous thromboembolism: a systematic review fora practice guideline. Ann Intern Med 2007 146:211.

7. Kakkar VV, Hoppenstead DA, Fareed J, et al. Randomized trial of different regimens of heparins and in vivothrombin generation in acute deep vein thrombosis. Blood 2002 99:1965.

8. Lensing AW, Prins MH, Davidson BL, Hirsh J. Treatment of deep venous thrombosis with low-molecular-weight heparins. A meta-analysis. Arch Intern Med 1995 155:601.

9. Siragusa S, Cosmi B, Piovella F, et al. Low-molecular-weight heparins and unfractionated heparin in thetreatment of patients with acute venous thromboembolism: results of a meta-analysis. Am J Med 1996

100:269.10. Dolovich LR, Ginsberg JS, Douketis JD, et al. A meta-analysis comparing low-molecular-weight heparins

with unfractionated heparin in the treatment of venous thromboembolism: examining some unansweredquestions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000160:181.

11. Merli G, Spiro TE, Olsson CG, et al. Subcutaneous enoxaparin once or twice daily compared withintravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med 2001134:191.

12. Breddin HK, Hach-Wunderle V, Nakov R, et al. Effects of a low-molecular-weight heparin on thrombusregression and recurrent thromboembolism in patients with deep-vein thrombosis. N Engl J Med 2001344:626.

13. Gould MK, Dembitzer AD, Doyle RL, et al. Low-molecular-weight heparins compared with unfractionatedheparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials.Ann Intern Med 1999 130:800.

14. Prandoni P, Carnovali M, Marchiori A, Galilei Investigators. Subcutaneous adjusted-dose unfractionatedheparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism. ArchIntern Med 2004 164:1077.

15. Erkens PM, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted doseunfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev 2010 :CD001100.

16. Faivre R, Neuhart Y, Kieffer Y, et al. [A new treatment of deep venous thrombosis: low molecular weightheparin fractions. Randomized study]. Presse Med 1988 17:197.

17. Lopaciuk S, Meissner AJ, Filipecki S, et al. Subcutaneous low molecular weight heparin versussubcutaneous unfractionated heparin in the treatment of deep vein thrombosis: a Polish multicenter trial.Thromb Haemost 1992 68:14.

18. Kearon C, Ginsberg JS, Julian JA, et al. Comparison of fixed-dose weight-adjusted unfractionated heparinand low-molecular-weight heparin for acute treatment of venous thromboembolism. JAMA 2006 296:935.

19. Castellucci LA, Cameron C, Le Gal G, et al. Clinical and safety outcomes associated with treatment ofacute venous thromboembolism: a systematic review and meta-analysis. JAMA 2014 312:1122.

20. Couturaud F, Julian JA, Kearon C. Low molecular weight heparin administered once versus twice daily inpatients with venous thromboembolism: a meta-analysis. Thromb Haemost 2001 86:980.

21. Bhutia S, Wong PF. Once versus twice daily low molecular weight heparin for the initial treatment of venousthromboembolism. Cochrane Database Syst Rev 2013 7:CD003074.

22. van Dongen CJ, MacGillavry MR, Prins MH. Once versus twice daily LMWH for the initial treatment of
http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/22http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/21http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/20http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/19http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/18http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/17http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/16http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/15http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/14http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/13http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/12http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/11http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/10http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/9http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/8http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/7http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/6http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/5http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/4http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/3http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/2http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/1


12/28



venous thromboembolism. Cochrane Database Syst Rev 2005 :CD003074.

23. Charbonnier BA, Fiessinger JN, Banga JD, et al. Comparison of a once daily with a twice dailysubcutaneous low molecular weight heparin regimen in the treatment of deep vein thrombosis. FRAXODIgroup. Thromb Haemost 1998 79:897.

24. Holmostrm M, Berglund MC, Granquist S, et al. Fragmin once or twice daily subcutaneously in thetreatment of deep venous thrombosis of the leg. Thromb Res 1992 67:49.

25. Siegbahn A, Y-Hassan S, Boberg J, et al. Subcutaneous treatment of deep venous thrombosis with lowmolecular weight heparin. A dose finding study with LMWH-Novo. Thromb Res 1989 55:767.

26. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia:Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest PhysiciansEvidence-Based Clinical Practice Guidelines. Chest 2012 141:e495S.

27. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997 337:688.

28. Bller HR, Davidson BL, Decousus H, et al. Fondaparinux or enoxaparin for the initial treatment ofsymptomatic deep venous thrombosis: a randomized trial. Ann Intern Med 2004 140:867.

29. Leroyer C, Bressollette L, Oger E, et al. Early versus delayed introduction of oral vitamin K antagonists incombination with low-molecular-weight heparin in the treatment of deep vein thrombosis. a randomizedclinical trial. The ANTENOX Study Group. Haemostasis 1998 28:70.

30. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared with a"standard care" nomogram. A randomized controlled trial. Ann Intern Med 1993 119:874.

31. Hull RD, Raskob GE, Rosenbloom D, et al. Optimal therapeutic level of heparin therapy in patients withvenous thrombosis. Arch Intern Med 1992 152:1589.

32. Fennerty AG, Thomas P, Backhouse G, et al. Audit of control of heparin treatment. Br Med J (Clin Res Ed)1985 290:27.

33. Wheeler AP, Jaquiss RD, Newman JH. Physician practices in the treatment of pulmonary embolism anddeep venous thrombosis. Arch Intern Med 1988 148:1321.

34. Cruickshank MK, Levine MN, Hirsh J, et al. A standard heparin nomogram for the management of heparintherapy. Arch Intern Med 1991 151:333.

35. Hylek EM, Regan S, Henault LE, et al. Challenges to the effective use of unfractionated heparin in thehospitalized management of acute thrombosis. Arch Intern Med 2003 163:621.

36. Vardi M, Zittan E, Bitterman H. Subcutaneous unfractionated heparin for the initial treatment of venousthromboembolism. Cochrane Database Syst Rev 2009 :CD006771.

37. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy:Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest PhysiciansEvidence-Based Clinical Practice Guidelines. Chest 2012 141:e152S.

38. Basu D, Gallus A, Hirsh J, Cade J. A prospective study of the value of monitoring heparin treatment withthe activated partial thromboplastin time. N Engl J Med 1972 287:324.

39. Hull RD, Raskob GE, Hirsh J, et al. Continuous intravenous heparin compared with intermittentsubcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986 315:1109.

40. Brandjes DP, Heijboer H, Bller HR, et al. Acenocoumarol and heparin compared with acenocoumarol alonein the initial treatment of proximal-vein thrombosis. N Engl J Med 1992 327:1485.

41. Hull RD, Raskob GE, Brant RF, et al. The importance of initial heparin treatment on long-term clinicaloutcomes of antithrombotic therapy. The emerging theme of delayed recurrence. Arch Intern Med 1997157:2317.

42. Hull RD, Raskob GE, Brant RF, et al. Relation between the time to achieve the lower limit of the APTTtherapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis.

Arch Intern Med 1997 157:2562.

43. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: the Seventh ACCP Conference onAntithrombotic and Thrombolytic Therapy. Chest 2004 126:188S.

44. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic Therapy and Prevention ofThrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest 2012 141:e24S.
http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/44http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/43http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/42http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/41http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/40http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/39http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/38http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/37http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/36http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/35http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/34http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/33http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/32http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/31http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/30http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/29http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/28http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/27http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/26http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/25http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/24http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/23http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/22


13/28



45. EINSTEIN Investigators, Bauersachs R, Berkowitz SD, et al. Oral rivaroxaban for symptomatic venousthromboembolism. N Engl J Med 2010 363:2499.

46.Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. NEngl J Med 2013 369:799.

47. Hokusai-VTE Investigators, Bller HR, Dcousus H, et al. Edoxaban versus warfarin for the treatment ofsymptomatic venous thromboembolism. N Engl J Med 2013 369:1406.

48. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venousthromboembolism. N Engl J Med 2009 361:2342.

49. Gallus A, Jackaman J, Tillett J, et al. Safety and efficacy of warfarin started early after submassive venousthrombosis or pulmonary embolism. Lancet 1986 2:1293.

50.Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: AmericanCollege of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008133:160S.

Topic 95336 Version 7.0
http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/50http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/49http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/48http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/47http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/46http://www.uptodate.com/contents/lower-extremity-deep-venous-thrombosis-initiation-of-anticoagulation-first-10-days/abstract/45


14/28



GRAPHICS

Risk factors for bleeding with anticoagulant therapy and estimated

risk of major bleeding in low, moderate, and high risk categories

Risk factors*

Age >65 years

Age >75 years

Previous bleeding

Cancer

Metastatic cancer

Renal failure

Liver failure

Thrombocytopenia

Previous stroke

Diabetes

Anemia

Antiplatelet therapy

Poor anticoagulant control

Comorbidity and reduced functional capacity

Recent surgery

Frequent falls

Alcohol abuse

Estimated absolute risk of major bleeding (%)

Categorization of

risk of bleeding

Low risk (0 risk

factors)

Moderate risk (1

risk factor)

High risk (2 risk

factors)

Anticoagulation 0 to 3 months

Baseline risk

(%)

0.6 1.2 4.8

Increased risk

(%)

1 2 8

Total risk (%) 1.6 3.2 12.8

Anticoagulation after first 3 months

Baseline risk

(%/years)

0.3 0.6 2.5

Increased risk

(%/years)

0.5 1 4

Total risk

(%/years)

0.8** 1.6** 6.5


15/28



* The increase in bleeding associated with a risk factor will vary with (1) severity of the risk factor (eg,

location and extent of metastatic disease, platelet count), (2) temporal relationships (eg, interval from

surgery or a previous bleeding episode), and (3) how effectively a previous cause of bleeding was

corrected (eg, upper-GI bleeding).

Important for parenteral anticoagulation (eg, first 10 days), but less important for long-term or

extended anticoagulation.

Although there is evidence that risk of bleeding increases with the prevalence of risk factors, this

categorization scheme has not been validated. Furthermore, a single risk factor, when severe, will resultin a high risk of bleeding (eg, major surgery within the past two days, severe thrombocytopenia).

Compared with low risk patients, moderate risk patients are assumed to have a twofold risk and high

risk patients an eightfold risk of major bleeding.

The 1.6% corresponds to the average of major bleeding with initial UFH or LMWH therapy followed by

VKA therapy. We estimated baseline risk by assuming a 2.6 relative risk of major bleeding with

anticoagulation (refer to footnote ).

Consistent with frequency of major bleeding observed by Hull et al in high risk patients .

We estimate that anticoagulation is associated with a 2.6-fold increase in major bleeding based on

comparison of extended anticoagulation with no extended anticoagulation. The relative risk of major

bleeding during the first three months of therapy may be greater than during extended VKA therapy

because (1) the intensity of anticoagulation with initial parenteral therapy may be greater than with VKA

therapy (2) anticoagulant control will be less stable during the first three months and (3)

predispositions to anticoagulant-induced bleeding may be uncovered during the first three months of

therapy. However, studies of patients with acute coronary syndromes do not suggest a 2.6 relative risk

of major bleeding with parenteral anticoagulation (eg, UFH or LMWH) compared with control.

Our estimated baseline risk of major bleeding for low risk patients (and adjusted up for moderate and

high risk groups as per footnote ).

** Consistent with frequency of major bleeding during prospective studies of extended anticoagulation

for VTE.

Reference:

1. Hull RD, Raskob GE, Rosenbloom D, et al. Heparin for 5 days as compared with 10 days in the

initial treatment of proximal venous thrombosis. N Engl J Med 1990 322:1260.

Reproduced from: Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease:

Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians

Evidence-Based Clinical Practice Guidelines. Chest 2012 141:e419S. Table used with the permission of

Elsevier Inc. All rights reserved.

Graphic 97160 Version 2.0

[1]


16/28



Suggested doses of low molecular weight heparins in obese patients

VTE

treatment

Acute

coronary

syndromes

VTE

prophylaxis

Official

prescribing

information

on use in

obesepatients

Enoxaparin* Use standard

treatment dosing

(ie, 1 mg/kg every

12 hours based on

ABW).

In patients with a

BMI 40 kg/m , a

lower dose (ie,

0.74 mg/kg every

12 hours, based

on ABW), was

suggested in a

small case series

based on peak

anti-factor Xa

levels, but has not

been clinically

evaluated.

Once daily dosingregimens of

enoxaparin are

not

recommended.

Unstable angina

or non-STEMI:

Use standard

treatment dosing

(ie, 1 mg/kg every

12 hours based on

ABW) as

alternative to UFH

for patients not

undergoing an

early invasive

approach.

STEMI (for

patients not

managed with

PCI):

Age 50

kg/m : 60 mg

every 12 hours.

Marginal increase

observed in mean

anti-factor Xa

activity using

actual body weight

[ABW] and once

daily dosing in

healthy obese

persons (BMI 30to 48 kg/m )

compared with

non-obese

persons.

Dalteparin Approved by the Unstable angina BMI 30 to 39 Use ABW-based

2

[1]

[2,3]

[2,3]

2

2

2

[4,5]

2

[5]

2

[3]


17/28



US FDA only for

extended

treatment of

cancer-associated

VTE. Use standard

treatment dosing

(ie, 200 units/kg

once daily based

on ABW for thefirst month,

followed by 150

units/kg once daily

for subsequent

months).

Consider using

100 units/kg

every 12 hours

based on ABW for

patients weighing

>100 kg.

or non-STEMI:

Use standard

treatment dosing

(ie, 120 units/kg

every 12 hours

based on ABW).

kg/m : Use

standard

prophylaxis dosing

(ie, 2500 or 5000

units once daily).

BMI 40

kg/m :

Empirically

increase standard

prophylaxis dose

by 30 percent (ie,

increase to 3250

or 6500 units

once daily).

dosing for patients

weighing up to 90

kg (acute coronary

syndromes) or 99

kg (cancer-

associated VTE).

Use a maximum

dose of 10,000

units per dose forpatients weighing

>90 kg (acute

coronary

syndromes) or

18,000 units per

day for patients

weighing >99 kg

(cancer-associated

VTE).

Tinzaparin

(not

available in

the United

States)

Use standard

treatment dosing

(ie, 175 units/kg

once daily based

on ABW).

Not indicated. BMI 30 to 39

kg/m : For

orthopedic surgery

use standard

prophylaxis dosing

(ie, 50 or 75 anti-

factor Xa units/kg

based on ABW

once daily) for

general surgery

use standard fixed

dosing (ie, 3500

anti-factor Xa

units once daily).

BMI 40

kg/m : For

orthopedic surgery

use standard

prophylaxis dosing

(ie, 50 or 75 anti-

factor Xa units/kg

based on ABW

once daily) for

general surgery

empirically

increase fixed dose

by 30 percent (ie,

increase to 4500

anti-factor Xa

Safety and efficacy

in patients

weighing >120 kg

has not been fully

determined.

Individualized

clinical and

laboratory

monitoring is

recommended

(Canada product

monograph).

[4]

2

2

[2]

[7]

2

2

[8]


18/28



units once

daily).

All doses shown are for patients with normal renal function and are for subcutaneous

administration (except initial intravenous bolus of enoxaparin for treatment of STEMI in

patients


19/28



Suggested dose adjustments of low molecular weight heparins in

renal insufficiency for adults

VTE treatment VTE prophylaxis*

Dalteparin Cl 30 mL/min : No adjustment

Cl 20 to 29 mL/min: Due to

variable response, adjust dose based

upon anti-factor Xa levels

Cl 20 mL/min: No adjustment

En oxaparin Cl 30 mL/min : No adjustment

Cl 20 to 29 mL/min: Reduce to 1

mg/kg once daily


Cl 20 to 29 mL/min: Reduce to

30 mg once daily (medical or surgical

patients)

Nadroparin

(not available in

US)


Cl 30 to 50 mL/min: Reduce dose

by 25 to 33 percent (optional)

Cl


20/28



(Garcia et al. Chest 2012 141:e24S)

Dosing suggested in prescribing information other approaches including dose adjustment based on

anti-factor Xa activity are discussed in UpToDate topics on use of LMW heparin.

Data from:

1. Dalteparin sodium injection. US FDA approved prescribing information (revised January, 2015).

Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020287s062lbl.pdf

2. Enoxaparin sodium injection. US FDA approved prescribing information (revised October, 2013).

Available at: at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020164s102lbl.pdf

3. Nadroparin calcium injection. Canada product monograph (revised February, 2015). Available at

http://webprod5.hc-sc.gc.ca/dpd-bdpp/index-eng.jsp

4. Tinzaparin sodium injection. Canada product monograph (revised May, 2014). Available at

http://webprod5.hc-sc.gc.ca/dpd-bdpp/index-eng.jsp

http://webprod5.hc-sc.gc.ca/dpd-bdpp/index-eng.jsphttp://webprod5.hc-sc.gc.ca/dpd-bdpp/index-eng.jsphttp://www.accessdata.fda.gov/drugsatfda_docs/label/2013/020164s102lbl.pdfhttp://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020287s062lbl.pdf


21/28



Example of a weight-based nomogram for intravenous

unfractionated heparin infusion for treatment of venous

thromboembolism and/or pulmonary embolism

Initial dose 80 units/kg bolus, then 18 units/kg per hour*

aPTT result Action Next aPTT

aPTT 3.0 x control)

Hold infusion 1 hour, then

decrease infusion rate by 3

units/kg per hour

6 hours

aPTT: activated partial thromboplastin time.

This table is provided as an example of a locally developed and validated

unfractionated heparin weight-based dose adjustment nomogram. It reflects the

original aPTT ranges, bolus sizes, and suggested changes in infusion rate that were present at

the time the study was performed. The therapeutic ranges (ie, relationship between the

aPTT and anti-factor Xa activity), initial and subsequent bolus sizes, and sizes of the infusion

rate changes, as well as dosing differences depending on the disorder under treatment (eg,

venous thromboembolism, stroke, acute coronary syndrome) should be established separately

for each institution.

* Use of total body weight (TBW) is suggested for calculating the initial bolus dose and infusion rate for

most obese patients. For additional information refer to "Management of the critically ill obese patient",

section "Anticoagulants".

Therapeutic aPTT range of 46 to 70 seconds corresponded to anti-Xa activity of 0.3 to 0.7 units/mL.

The target aPTT range in a particular institution should reflect what is known about the local reagentsand equipment to perform the assay .

The first aPTT should be obtained 4 to 6 hours after the initial heparin bolus.

References:

1. Raschke RA, Reilly BM, Guidry JR, et al. The weight-based heparin dosing nomogram compared

with a "standard care" nomogram. A randomized controlled trial. Ann Intern Med 1993 119:874.

2. Garcia DA, Baglin TP, Weitz JI A, et al. Parenteral Anticoagulants: Antithrombotic therapy and

Prevention of Thrombosis, American College of Chest Physicians Evidence-Based Clinical Practice

Guidelines (9th Edition). Chest 2012 141:e24S-e43S.


[1]

[2]


22/28



Example of a non-weight-based intravenous heparin protocol: Part I

Initial intravenous heparin bolus: 5000 units.

Continuous intravenous heparin infusion: commence at 42 mL/hour of 20,000 units (1680

units/hour) in 500 mL of two-thirds dextrose and one-third saline (a 24-hour heparin dose of

40,320 units), except in the following patients, in whom heparin infusion will be commenced at a

rate of 31 mL/hour (1240 units/hour) (ie, a 24-hour dose of 29,760 units).

Patients who have undergone surgery within the previous two weeks.

Patients with a previous history of peptic ulcer disease, gastrointestinal or genitourinary bleeding.

Patients with (thrombotic) stroke within the previous two weeks.

Patients with a platelet count


23/28



Example of a non-weight-based intravenous heparin protocol: Part

II titration based upon the activated partial thromboplastin time

IV infusion

aPTT Rate change,

mL/hour*

Dose change,

units/24-hour Additional action

45 +6 +5760 Repeated aPTT in 4

to 6 hours

46 to 54 +3 +2880 Repeated aPTT in 4 to

6 hours

55 to 85 0 0 None

86 to 110 3 2880 Stop heparin sodium

treatment for 1 hour

repeated aPTT 4 to 6

hours after restarting

heparin treatment

>110 6 5760 Stop heparin

treatment for 1 hour

repeated aPTT 4 to 6

hours after restarting

heparin treatment

NOTE: This table reflects the original aPTT ranges, bolus sizes, and suggested changes in

infusion rate that were present at the time this study was performed. The therapeutic ranges

(ie, relationship between the aPTT and anti-factor Xa activity), initial and subsequent bolus

sizes, and sizes of the infusion rate changes, as well as dosing differences depending on thedisorder under treatment (eg, venous thromboembolism, stroke, acute coronary syndrome)

should be established separately for each institution.

aPTT: activated partial thromboplastin time IV: intravenous.

* Heparin sodium concentration, 20,000 units in 500 mL = 40 units/mL.

With the use of Actin-FS thromboplastin reagent (Dade, Mississauga, Ontario).

During the first 24 hours, repeated aPTT in 4 to 6 hours. Thereafter, the aPTT will be determined once

daily, unless subtherapeutic.

Redrawn from: Hull RD, Raskob GE, Rosenbloom D, et al. Optimal therapeutic level of heparin therapy in

patients with venous thrombosis. Arch Intern Med 1 992 152:1589.



24/28



Pretest probability of deep vein thrombosis (Wells score)

Clinical feature Score

Active cancer (treatment ongoing or within the previous six months or palliative) 1

Paralysis, paresis, or recent plaster immobilization of the lower extremities 1

Recently bedridden for more than three days or major surgery, within four weeks 1

Localized tenderness along the distribution of the deep venous system 1

Entire leg swollen 1

Calf swelling by more than 3 cm when compared to the asymptomatic leg (measured

below tibial tuberosity)

1

Pitting edema (greater in the symptomatic leg) 1

Collateral superficial veins (nonvaricose) 1

Alternative diagnosis as likely or more likely than that of deep venous thrombosis -2

Score

High probability 3 or

greater

Moderate probability 1 or 2

Low probability 0 or less

Modification:

This clinical model has been modified to take one other clinical feature into account: a previously

documented deep vein thrombosis (DVT) is given the score of 1. Using this modified scoring

system, DVT is either likely or unlikely, as follows:DVT likely 2 or

greater

DVT unlikely 1 or less

Adapted from:

1. Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein

thrombosis in clinical management. Lancet 1997 350:1795

2. 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 349:1227.



25/28



Minimal requirements for early hospital discharge or outpatient

therapy of venous thromboembolic disease

The responsible physician must ensure that all of the following

conditions apply:

The patient is ambulatory and in stable condition, with normal vital signs

There is a low a priori risk of bleeding in the patient

Severe renal insufficiency is not present

There is a practical system in place for the following:

Administration of LMW heparin and/or warfarin with appropriate monitoring, and

Surveillance and treatment of recurrent VTE and bleeding complications

VTE: venous thromboembolism LMW heparin: low molecular weight heparin.

Adapted from Hyers, TM, Agnelli, G, Hu ll, RD, et al. Antithrombotic therapy for venous thromboembolic

disease. Chest 2001 119:176S. (Sixth ACCP Consensus Conference on Antithrombotic Therapy).



26/28



2012 ACCP recommended treatment of heparin-induced

thrombocytopenia (HIT)

The following non-heparin agents are recommended for use in acute HIT whether or not

complicated by thrombosis: argatroban or danaparoid. Argatroban is suggested over danaparoid

in those with renal insufficiency. (Editor's note: Lepirudin is no longer available).

In pregnant patients with HIT, the use of danaparoid is suggested over other non-heparin

anticoagulants. The use of fondaparinux is suggested only if danaparoid is not available.

In patients with antibody-positive HIT who require urgent cardiac surgery, the use of bivalirudin is

suggested over other non-heparin anticoagulants. In patients with antibody-positive HIT who

require percutaneous coronary interventions, the use of bivalirudin or argatroban is suggested over

other non-heparin anticoagulants.

Warfarin alone should not be used to treat HIT because of the risk of causing venous limb

gangrene and/or skin necrosis.

Warfarin is safe to use when it is given to a patient adequately and stably anticoagulated with a

drug that reduces thrombin generation (eg, danaparoid, argatroban) it is prudent to delay use of

warfarin until the platelet count is >150,000/microL.

LMWH should not be given to patients with HIT, whether or not complicated by thrombosis.

Prophylactic platelet transfusions should not be administered for the treatment of patients with HIT

who do not have active bleeding.

ACCP: American College of Chest Physicians DVT: deep venous thrombosis LMWH: low molecular weight

heparin.

Adapted from Linkins LA, et al. Treatment and prevention of heparin-induced thrombocytopenia:

Antithrombotic therapy and prevention of thrombosis, 9th edition: American College of Chest Physicians

Evidence-based clinical practice guidelines. Chest 2012 141:e495S.



27/28


28/28

Documents

Lower Extremity Deep Venous Thrombosis_ Initiation of Anticoagulation (First 10 Days)