Venous Thromboembolism

Clinical Snapshot

Venous thromboembolism (VTE) is a single disease process that manifests as deep vein thrombosis (DVT), pulmonary embolism (PE), or both — a thrombus forming in the deep veins (most often the legs) can embolize through the venous system and lodge in the pulmonary arteries, so DVT and PE are managed as one continuum rather than two separate conditions.^[1] The clinical spectrum ranges from an asymptomatic calf-vein clot to a hemodynamically unstable, life-threatening pulmonary embolism, and the core management questions are the same in every case: how likely is this VTE before committing to imaging (pretest probability), how should anticoagulation be started (which agent, and whether a parenteral lead-in is needed), and how long should it continue (a decision driven by whether the event was provoked by a transient risk factor or occurred without one).

Recognize the Condition

The two clinical faces of VTE

Deep vein thrombosis (DVT)

Unilateral leg swelling, pain, warmth, and erythema, with tenderness along the deep venous system. Calf circumference is often measurably larger than the unaffected leg, and collateral (non-varicose) superficial veins may become visible. A massively swollen, painful, cyanotic limb with threatened arterial supply (phlegmasia cerulea dolens) is a limb-threatening emergency, not a routine DVT presentation.

Pulmonary embolism (PE)

Sudden dyspnea, pleuritic chest pain, tachypnea, and tachycardia are the most common findings. Hemoptysis and syncope occur less often but both raise concern for a larger clot burden. Hypotension or overt signs of right ventricular strain indicate a hemodynamically significant PE requiring immediate escalation, not routine outpatient management.

Both DVT and PE can also be entirely asymptomatic, discovered incidentally on imaging obtained for another reason — an incidental finding still requires the same treatment-duration decision-making as a symptomatic one once it is confirmed as a true, clinically relevant clot.

Risk Factors

Recent major surgery (especially orthopedic, abdominal, or pelvic) or major trauma.
Immobilization — hospitalization, long-haul travel over 8 hours, paralysis, or a lower-limb cast.
Active cancer, including ongoing chemotherapy or a cancer diagnosis within the past 6 months.
Personal history of a prior VTE.
Pregnancy and the postpartum period.
Estrogen-containing contraception or hormone therapy.
Inherited thrombophilia — factor V Leiden, prothrombin gene mutation, protein C or protein S deficiency, antithrombin deficiency.
Antiphospholipid syndrome.
Obesity.
A central venous catheter or transvenous pacemaker/defibrillator lead.
Inflammatory bowel disease, nephrotic syndrome, and myeloproliferative disorders.
Age over 65, and a family history of VTE in a first-degree relative.

Red Flags & Refer

Escalate immediately — do not manage any of the following as routine outpatient VTE:

Hemodynamic instability suggesting massive (high-risk) PE — systolic blood pressure under 90 mmHg, a drop of 40 mmHg or more from baseline, or the need for vasopressor support.
Cardiac arrest, syncope, or new signs of right ventricular strain in a patient with suspected or confirmed PE.
Severe hypoxemia or respiratory failure.
Signs of phlegmasia cerulea dolens — a massively swollen, painful, cyanotic limb with threatened arterial supply — a limb-threatening surgical emergency.
Active major bleeding in a patient on anticoagulation, or any intracranial, retroperitoneal, or gastrointestinal bleeding.
Suspected heparin-induced thrombocytopenia — a falling platelet count with new or worsening thrombosis during heparin or LMWH exposure.
New or worsening VTE symptoms in a patient already on adequate anticoagulation — this is a treatment-failure presentation, not something to manage by simply continuing the current regimen.

Assessment & Diagnosis

Differentiating DVT from its common mimics

Feature	DVT	Cellulitis	Ruptured Baker (popliteal) cyst	Superficial thrombophlebitis
Distribution	Usually unilateral, whole-leg or calf swelling	Unilateral, follows the area of skin infection	Unilateral, calf swelling with a posterior-knee onset	Follows a superficial vein, often a visibly cord-like tender area
Skin changes	Warmth, mild erythema, no sharply demarcated border	Warmth, erythema with a well-demarcated, spreading border; fever may be present	Mild erythema possible	Erythema and tenderness directly over the palpable vein
Tenderness pattern	Deep, along the venous system	Diffuse over the infected skin	Posterior knee/calf, often sudden onset	Localized to the palpable superficial cord
Key distinguishing step	Compression ultrasound	Clinical diagnosis; ultrasound if DVT cannot be excluded clinically	Ultrasound identifies the cyst and excludes DVT (both can coexist)	Ultrasound confirms the superficial location and excludes extension into the deep system

Pretest probability first

Apply a validated clinical pretest-probability score before ordering any test — Wells' Criteria for DVT or Wells' Criteria for PE, depending on presentation (see the scoring tables below).^[2]^[3] The result determines the next step: a low/unlikely pretest probability combined with a negative D-dimer excludes VTE without imaging, while a higher pretest probability, or a positive D-dimer at any pretest probability, requires imaging.

D-dimer

D-dimer is highly sensitive but not specific — use it only to rule out VTE in patients with a low or "unlikely" pretest probability, never to rule in VTE or as the sole basis for a high-probability patient to skip imaging. Age-adjusted D-dimer thresholds (age × 10 mcg/L, for patients over 50) increase the proportion of older patients who can safely avoid imaging without missing clinically important VTE.

Imaging

Compression ultrasound of the proximal deep veins is the standard test for DVT. CT pulmonary angiography (CTPA) is the standard test for PE; a ventilation-perfusion (V/Q) lung scan is the preferred alternative when CT contrast is contraindicated — significant renal impairment, contrast allergy, or pregnancy (to reduce breast-tissue radiation exposure, although both tests deliver a low fetal dose).

Isolated distal (calf) DVT

A thrombus confined to the calf veins, with mild symptoms and no extension risk factors, does not automatically require anticoagulation — serial compression ultrasound at 1 week, and again at 2 weeks if still not extending, is a reasonable alternative to treatment; anticoagulate if the clot extends on repeat imaging.

Once PE is confirmed: severity stratification

Every confirmed PE needs a severity assessment that is separate from the diagnostic pretest-probability score — it determines admission, monitoring intensity, and thrombolysis candidacy. Hemodynamic instability defines massive (high-risk) PE outright.^[4] In hemodynamically stable patients, the simplified Pulmonary Embolism Severity Index (sPESI) identifies patients with a low risk of short-term mortality who are potential candidates for outpatient management; troponin/BNP elevation together with right ventricular dysfunction on imaging identifies an intermediate-risk (submassive) group that needs closer inpatient monitoring even without hemodynamic instability.^[5]

Thrombophilia testing

Reserve thrombophilia testing for patients under 40 years of age with recurrent VTE or a strong family history — testing does not change management in most other patients and should never be ordered reflexively after a first unprovoked VTE in an older patient. Time testing carefully: warfarin lowers protein C and protein S, and heparin lowers antithrombin, so results obtained during active anticoagulation can be falsely low.

Wells' Criteria for DVT

Clinical criterion	Points
Active cancer (treatment ongoing, within 6 months, or palliative)	+1
Paralysis, paresis, or recent plaster immobilization of the lower extremity	+1
Recently bedridden ≥3 days, or major surgery within 12 weeks requiring general/regional anesthesia	+1
Localized tenderness along the deep venous system	+1
Entire leg swollen	+1
Calf swelling ≥3 cm larger than the asymptomatic leg (measured 10 cm below the tibial tuberosity)	+1
Pitting edema confined to the symptomatic leg	+1
Collateral superficial (non-varicose) veins	+1
Previously documented DVT	+1
An alternative diagnosis is at least as likely as DVT	−2

Score interpretation: 3-tier — 0 points or fewer is low probability, 1–2 points is moderate probability, 3 or more is high probability. The 2-tier "DVT unlikely" (≤1 point) versus "DVT likely" (≥2 points) dichotomization is the version most widely validated for pairing with D-dimer in clinical practice.^[6]

Wells' Criteria for PE

Clinical criterion	Points
Clinical signs and symptoms of DVT (leg swelling and pain with palpation of the deep veins)	+3
An alternative diagnosis is less likely than PE	+3
Heart rate over 100 bpm	+1.5
Immobilization for ≥3 days, or surgery in the previous 4 weeks	+1.5
Previous objectively diagnosed DVT or PE	+1.5
Hemoptysis	+1
Malignancy (treatment ongoing, within 6 months, or palliative)	+1

Score interpretation: 3-tier — under 2 points is low probability, 2–6 points is moderate probability, over 6 points is high probability. The 2-tier "PE unlikely" (≤4 points) versus "PE likely" (>4 points) dichotomization is the version most widely used in clinical practice for pairing with D-dimer.^[3]

Treatment Targets

Deep vein thrombosis

Prevent pulmonary embolism.
Prevent thrombus extension.
Prevent post-thrombotic syndrome.
Reduce morbidity from the acute event.

Pulmonary embolism

Prevent death.
Prevent recurrent thromboembolism.
Prevent chronic thromboembolic pulmonary hypertension.

Choose Initial Treatment

Direct treatment rule

Hemodynamic triage

Massive/high-risk PE hemodynamic instability changes everything: admit, and proceed directly to the thrombolysis decision rather than routine outpatient anticoagulant selection.

Everyone else most hemodynamically stable patients with DVT or a low/intermediate-risk PE, without severe symptoms, high bleeding risk, or a barrier to reliable follow-up, can be treated entirely as outpatients from diagnosis.

First-line anticoagulant

Apixaban or rivaroxaban both can be started alone, with no parenteral lead-in required, and are the preferred first-line agents for most adults with normal renal function.^[1]

Dabigatran or edoxaban use after 5–10 days of a parenteral anticoagulant (LMWH preferred); reserve for when apixaban/rivaroxaban are not suitable or not preferred.

LMWH or warfarin use instead of a DOAC for significant renal impairment, antiphospholipid syndrome (especially triple-positive), pregnancy, or when an unavoidable DOAC drug interaction is present; if warfarin is chosen, overlap with a parenteral anticoagulant for a minimum of 5 days and until the INR is 2 or higher for 24–48 hours.^[7]

Duration of anticoagulation

Provoked by a major transient risk factor (surgery) treat for 3 months and stop.

Provoked by a minor transient or a persistent minor risk factor (immobilization, travel, estrogen therapy, inflammatory bowel disease, obesity) 3 months is the minimum; extending beyond 3–6 months is reasonable and should be discussed individually.

Unprovoked, or provoked by a persistent/irreversible major risk factor (active cancer, antiphospholipid syndrome) indefinite anticoagulation should be considered, balanced against bleeding risk and reassessed at least annually.^[1]

Cancer-associated thrombosis

Apixaban, edoxaban, or rivaroxaban preferred over LMWH for most patients with cancer-associated VTE.^[8]

LMWH preferred over a DOAC specifically for luminal gastrointestinal or genitourinary cancers (higher DOAC-associated GI bleeding risk in this group), a significant drug interaction, or malabsorption.^[9]

Continue anticoagulation for as long as the cancer remains active, reassessing periodically rather than stopping at a fixed timepoint.

Non-Pharmacologic Treatment

Deep vein thrombosis

Early ambulation is preferred over bed rest — it is at least as effective for symptom resolution and does not increase embolization risk.
Elevate the affected limb while resting to reduce swelling.
Graduated compression stockings can relieve acute swelling and pain and help symptoms of established post-thrombotic syndrome, but randomized trial evidence does not support their use to prevent post-thrombotic syndrome from developing in the first place. Avoid in patients with peripheral arterial disease.

Pulmonary embolism

Supplemental oxygen for documented hypoxemia.
IV fluids for hypotension or volume depletion — use cautiously, since aggressive fluid resuscitation can worsen right ventricular strain.
Vasopressor support for shock.
Temporary mechanical cardiopulmonary support (veno-arterial ECMO) can bridge selected patients with refractory shock or cardiac arrest.

Analgesia

Acetaminophen first, for pain from the acute event.
Avoid NSAIDs in a patient on anticoagulation — they add gastric and bleeding risk on top of the anticoagulant.
Opioids can be used short-term if acetaminophen is insufficient.

Procedural and mechanical options

IVC filter reserve for acute proximal DVT or PE when anticoagulation has failed (recurrent VTE on adequate therapy) or is absolutely contraindicated (active major bleeding). A retrievable filter is preferred over a permanent one, and it should be removed once anticoagulation can be safely resumed.
Catheter-directed or pharmacomechanical thrombolysis reserve for limb-threatening DVT (phlegmasia cerulea dolens) in a patient with an acceptably low bleeding risk; randomized trial evidence has not shown a reduction in post-thrombotic syndrome for routine iliofemoral DVT, and bleeding complications are higher than with anticoagulation alone, so this is not a routine escalation for ordinary proximal DVT.

Pharmacologic Treatment Options

Drug / intervention	Role	Dose / use	Important adverse effects	Teaching points
Apixaban Preferred	1st-line DOAC, DVT/PE monotherapy	10 mg PO BID x7 days, then 5 mg PO BID	Bleeding	No parenteral lead-in needed. Not recommended if ClCr under 15 mL/min; use caution at ClCr 15-29 mL/min.
Rivaroxaban Preferred	1st-line DOAC, DVT/PE monotherapy	15 mg PO BID x21 days, then 20 mg PO daily with the largest meal of the day	Bleeding	No parenteral lead-in needed; food is required for adequate absorption. Not recommended if ClCr under 30 mL/min.
Dabigatran Alternative	DOAC after a parenteral lead-in	150 mg PO BID (110 mg PO BID if age >=80 or high bleeding risk) after 5-10 days of a parenteral anticoagulant	Bleeding, dyspepsia	Contraindicated if ClCr under 30 mL/min.
Edoxaban Alternative	DOAC after a parenteral lead-in	60 mg PO daily (30 mg PO daily if ClCr 30-50 mL/min, weight <=60 kg, or with a P-glycoprotein inhibitor) after 5-10 days of a parenteral anticoagulant	Bleeding	Not recommended if ClCr under 30 mL/min.
Enoxaparin Special situation	Preferred parenteral agent when a DOAC is not appropriate	1 mg/kg SC Q12H, or 1.5 mg/kg SC once daily	Bleeding, injection-site bruising, rare HIT	Preferred parenteral bridge/monotherapy agent for renal impairment (with dose adjustment), pregnancy, and most cancer-associated VTE.
Warfarin Special situation	Vitamin K antagonist when a DOAC is not appropriate	Individualized dose to target INR 2-3, overlapped with a parenteral anticoagulant for a minimum of 5 days and until INR >=2 for 24-48h	Bleeding, skin necrosis (rare)	Preferred over a DOAC for antiphospholipid syndrome (especially triple-positive) and mechanical heart valves.
Fondaparinux Alternative	Parenteral alternative, especially with a HIT history	Weight-based once-daily SC dose (5 mg under 50kg, 7.5 mg 50-100kg, 10 mg >100kg)	Bleeding	Avoid if ClCr under 30 mL/min.
Alteplase or tenecteplase Special situation	Massive/high-risk PE with an acceptable bleeding risk	Weight-based, single IV bolus (tenecteplase) or 2-hour infusion (alteplase) per institutional protocol	Bleeding, intracranial hemorrhage	Reserve for hemodynamically unstable PE; greatest benefit within 14 days of symptom onset.

Special Populations

Pregnancy

LMWH is the anticoagulant of choice throughout pregnancy — it does not cross the placenta. Continue a full weight-adjusted treatment dose for the duration of pregnancy. Treat for a minimum of 3 months in total, including at least 6 weeks postpartum. Avoid warfarin — it crosses the placenta and is teratogenic. Avoid DOACs — they are not adequately studied in pregnancy and cross the placenta. Use fondaparinux only if no other agent can be used. Plan delivery around LMWH dosing together with the obstetric team; if delivery must occur within the first month of treatment for acute VTE, discuss a retrievable IVC filter for the period while anticoagulation is held.

Breastfeeding

Warfarin, UFH, and LMWH are all compatible with breastfeeding. DOACs are not recommended during breastfeeding — safety data are insufficient.

Renal impairment

Apixaban and rivaroxaban are not recommended below a ClCr of 15 and 30 mL/min respectively; dabigatran and edoxaban are contraindicated/not recommended below a ClCr of 30 mL/min. LMWH requires dose reduction and anti-Xa monitoring as renal function falls, and unfractionated heparin — with no renal clearance dependence — is preferred once impairment is severe.

Hepatic impairment

Avoid DOACs in significant hepatic impairment or any coagulopathy from liver disease. Warfarin is difficult to titrate reliably in advanced liver disease given baseline coagulopathy; LMWH or UFH under close monitoring is often more practical.

Older adults

Bleeding risk rises with age across every anticoagulant class. Reduce the dabigatran dose to 110 mg PO BID at age 80 or older, or in a younger patient with additional bleeding risk factors. Choose the anticoagulant and dose based on current renal function, not an assumed baseline.

Antiphospholipid syndrome

Avoid DOACs, particularly in triple-positive antiphospholipid syndrome — trial evidence shows a higher rate of thrombotic events with a DOAC than with warfarin in this group. Warfarin (INR 2-3) remains the preferred long-term agent.

Heparin-induced thrombocytopenia (HIT)

Stop all heparin products immediately — including LMWH and heparin flushes — the moment HIT is confirmed or strongly suspected, and start a non-heparin anticoagulant (argatroban, danaparoid, fondaparinux, or bivalirudin) while confirmatory testing is pending; do not wait for laboratory confirmation before acting. Do not start warfarin until the platelet count has substantially recovered (generally to at least 150 x10⁹/L) — starting warfarin during acute HIT can precipitate venous limb gangrene.^[10]

Pediatrics

VTE in children is uncommon, and dosing is weight- and age-based with specialist guidance — refer to pediatric hematology rather than extrapolating adult dosing directly.

Monitoring & Follow-Up

Warfarin: check INR daily or every other day during the first week, then every 3 days for a week, then once or twice weekly, then every 2-4 weeks once stable; intervals up to 12 weeks apart are appropriate once results have been consistently stable for an extended period. DOACs: no routine coagulation monitoring is needed, but check renal function at baseline and periodically thereafter — more frequently in older adults, in reduced renal function, or when an interacting drug is added. Heparin/LMWH: monitor platelet count for HIT surveillance, particularly around days 4-14 of exposure in a patient with recent heparin exposure. Every patient: reassess the anticoagulation-duration decision at 3 months, and at least annually thereafter if extended therapy was chosen, weighing updated recurrence risk against bleeding risk (the HERDOO2 rule can help identify women with a first unprovoked VTE who have a low enough recurrence risk to safely stop^[11]); ask about symptoms of post-thrombotic syndrome (chronic limb swelling, pain, skin changes) and, after PE, persistent or worsening dyspnea that could indicate chronic thromboembolic pulmonary hypertension; and reinforce adherence at every dispensing, since VTE recurrence after early, unplanned anticoagulant discontinuation is a preventable failure.

Treatment Failure / Next Step

Recurrent VTE while on anticoagulation: before assuming true treatment failure, confirm adherence, confirm the dose is correct for current weight/renal function, and screen for an interacting drug.
Confirmed adherent on a DOAC or warfarin with genuine recurrence: switch to therapeutic-dose LMWH, and investigate for an unrecognized malignancy or thrombophilia if this has not already been done.
Recurrence while already on LMWH: increase the dose by approximately 20-25% and check anti-Xa levels to guide further adjustment.
Extending or limb-threatening DVT (phlegmasia): urgent evaluation for thrombolysis or thrombectomy.
Major bleeding on anticoagulation: hold the agent, apply local hemostatic measures, use the appropriate reversal strategy (see Drug Tables), and reassess the net risk-benefit of resuming therapy once the patient is stable.
Suspected HIT during heparin or LMWH therapy: stop all heparin products immediately and start a non-heparin anticoagulant — act on clinical suspicion rather than waiting for laboratory confirmation.

Common Errors to Avoid

Starting dabigatran or edoxaban without a 5-10 day parenteral lead-in — unlike apixaban and rivaroxaban, which can be started alone.
Forgetting that rivaroxaban needs to be taken with the largest meal of the day for adequate absorption, especially during the 15 mg BID loading phase.
Using a DOAC in a patient with triple-positive antiphospholipid syndrome — warfarin is preferred based on trial evidence of higher DOAC failure in this group.
Continuing a heparin product after HIT is confirmed or strongly suspected, or starting warfarin before the platelet count has substantially recovered.
Assuming compression stockings prevent post-thrombotic syndrome — trial evidence does not support this; they help acute symptoms, not PTS prevention.
Treating every isolated distal (calf) DVT identically to a proximal DVT, rather than considering serial ultrasound surveillance as an alternative to anticoagulation for a non-extensive clot.
Ordering thrombophilia testing at the wrong time — while on warfarin (which lowers protein C/S) or heparin (which lowers antithrombin) — or in a patient who doesn't meet the age/recurrence/family-history criteria that would actually change management.
Stopping extended anticoagulation at an arbitrary point without reassessing bleeding risk and recurrence risk together.
Prescribing an NSAID for VTE-related pain in a patient on anticoagulation instead of acetaminophen.
Checking vital signs once rather than trending them — hemodynamic instability in PE can evolve over hours.

Clinical Decision Algorithm

Diagnostic approach: suspected DVT or PE

Suspected DVT or PE

Apply Wells' Criteria (DVT or PE version) to estimate pretest probability

Low/unlikely pretest probability

Obtain D-dimer

D-dimer negative

VTE excluded - no imaging required

D-dimer positive

Proceed to imaging: compression ultrasound (DVT) or CTPA/V-Q scan (PE)

Moderate/high or likely pretest probability

Proceed directly to imaging without D-dimer: compression ultrasound (DVT) or CTPA/V-Q scan (PE)

Isolated distal (calf) DVT

Thrombus confined to the calf veins, mild symptoms, no extension risk factors

Not anticoagulated initially

Serial compression ultrasound at 1 week, then 2 weeks if unchanged

Extension seen

Start anticoagulation

No extension

No anticoagulation needed

Severe symptoms or extension risk factors present

Anticoagulate as for proximal DVT

Initial anticoagulant selection for confirmed VTE

VTE confirmed (DVT and/or PE)

Hemodynamically unstable PE

Massive/high-risk PE - admit and proceed to the PE severity/thrombolysis pathway

Standard patient, normal renal function

Apixaban 10 mg PO BID x7 days then 5 mg PO BID, or rivaroxaban 15 mg PO BID x21 days then 20 mg PO daily with food - no parenteral lead-in needed

Alternative: LMWH lead-in 5-10 days, then dabigatran 150 mg PO BID or edoxaban 60 mg PO daily

Renal impairment, antiphospholipid syndrome, pregnancy, or DOAC-inappropriate cancer

LMWH (enoxaparin preferred), or warfarin overlapped with a parenteral anticoagulant to INR >=2 for 24-48h, minimum 5 days

Classify as provoked (transient risk factor) vs unprovoked/persistent risk factor to determine duration

PE severity triage and thrombolysis decision

PE confirmed

Hemodynamically unstable (massive/high-risk)

Systemic thrombolysis (alteplase or tenecteplase) if bleeding risk is acceptable and not contraindicated

Thrombolysis failed or contraindicated: surgical or catheter-directed embolectomy/thrombolysis

Stable, but RV dysfunction plus positive troponin/BNP

Intermediate-risk (submassive) PE - admit, monitor closely; reserve thrombolysis for clinical deterioration rather than giving it routinely

Stable, sPESI 0, no RV dysfunction

Low-risk PE - outpatient anticoagulation appropriate for most patients with adequate support at home

Duration-of-anticoagulation decision at 3 months

Initial 3-month anticoagulation course completed

Provoked by a major transient risk factor (surgery)

Stop anticoagulation at 3 months

Provoked by a minor transient or persistent minor risk factor

Extend beyond 3-6 months; reassess bleeding vs recurrence risk with the patient

Unprovoked, or persistent/irreversible major risk factor (active cancer, antiphospholipid syndrome)

Consider indefinite anticoagulation; reassess at least annually - HERDOO2 can help identify women with a first unprovoked VTE at low enough recurrence risk to stop

Drug Tables

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

Treatment of VTE

Direct Factor Xa Inhibitors (DOACs)

Preferred first-line oral anticoagulants for most adults with normal renal function; no routine coagulation monitoring required.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Apixaban	VTE treatment: 10 mg PO BID x7 days, then 5 mg PO BID Extended VTE-recurrence prevention (after 6 months of treatment): 2.5 mg PO BID	Bleeding	Contraindicated with combined strong dual inhibitors of CYP3A4 and P-glycoprotein (e.g., itraconazole, ritonavir)	No parenteral lead-in needed. Not recommended if ClCr under 15 mL/min; use caution at ClCr 15-29 mL/min.
Rivaroxaban	VTE treatment, loading phase: 15 mg PO BID x21 days VTE treatment, maintenance: 20 mg PO daily Extended VTE-recurrence prevention (after 6 months of treatment): 10 mg PO daily (20 mg daily if higher recurrence risk)	Bleeding	Contraindicated with combined strong dual inhibitors of CYP3A4 and P-glycoprotein (e.g., itraconazole, ritonavir)	No parenteral lead-in needed. Take with the largest meal of the day, especially during the loading phase, for adequate absorption. Not recommended if ClCr under 30 mL/min.
Edoxaban	VTE treatment: 60 mg PO daily after 5-10 days of a parenteral anticoagulant (30 mg PO daily if ClCr 30-50 mL/min, weight <=60 kg, or with a P-glycoprotein inhibitor)	Bleeding	Avoid combined strong inducers of both CYP3A4 and P-glycoprotein (e.g., rifampin); reduce dose with P-glycoprotein inhibitors (e.g., ketoconazole)	Requires a parenteral lead-in, unlike apixaban/rivaroxaban. Not recommended if ClCr under 30 mL/min.

Direct Thrombin Inhibitor (DOAC)

Drug	Dosage	Adverse effects	Drug interactions	Comments
Dabigatran	VTE treatment: 150 mg PO BID after 5-10 days of a parenteral anticoagulant (110 mg PO BID if age >=80 years)	Bleeding, dyspepsia	Contraindicated if ClCr under 30 mL/min or with strong P-glycoprotein inhibitors (e.g., quinidine); use caution with other P-glycoprotein-active drugs	Requires a parenteral lead-in. Consider 110 mg BID over age 75 with additional bleeding risk factors (e.g., recent GI bleed, active ulcerative GI disease).

Low Molecular Weight Heparins

Preferred parenteral anticoagulant when a parenteral agent is needed; dose individualized by body weight, with caution in renal impairment.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Enoxaparin	VTE treatment: 1 mg/kg SC Q12H, or 1.5 mg/kg SC once daily (maximum 180 mg/day)	Bleeding; HIT and osteoporosis are both less common than with UFH	Additive bleeding risk with ASA, other antiplatelet agents, and oral anticoagulants	1 mg = 100 units. Contraindicated with a history of HIT; use with caution in renal dysfunction.
Dalteparin	VTE treatment: 200 units/kg SC once daily (maximum 18,000 units/day), or 100 units/kg SC Q12H if increased bleeding risk Extended cancer-associated VTE treatment: 200 units/kg SC once daily for month 1, then approximately 150 units/kg SC once daily for months 2-6	Bleeding; HIT and osteoporosis are both less common than with UFH	Additive bleeding risk with ASA, other antiplatelet agents, and oral anticoagulants	Contraindicated with a history of HIT; use with caution in renal dysfunction.
Tinzaparin	VTE treatment: 175 units/kg SC once daily	Bleeding; HIT and osteoporosis are both less common than with UFH	Additive bleeding risk with ASA, other antiplatelet agents, and oral anticoagulants	Contraindicated with a history of HIT; use with caution in renal dysfunction.

Indirect Factor Xa Inhibitor

Drug	Dosage	Adverse effects	Drug interactions	Comments
Fondaparinux	VTE treatment, under 50 kg: 5 mg SC once daily VTE treatment, 50-100 kg: 7.5 mg SC once daily VTE treatment, >100 kg: 10 mg SC once daily	Bleeding, thrombocytopenia; allergic reactions are rare	Additive bleeding risk with ASA and oral anticoagulants	Use with caution in renal dysfunction. A reasonable non-heparin option with a history of HIT.

Unfractionated Heparin

Drug	Dosage	Adverse effects	Drug interactions	Comments
Heparin (UFH)	IV treatment: 80 units/kg bolus, then 18 units/kg/h infusion adjusted to a therapeutic aPTT IV treatment, alternative fixed dosing: 5,000-10,000 unit bolus, then 15,000-20,000 units Q12H adjusted to a therapeutic aPTT SC treatment, fixed weight-based dosing: 333 units/kg SC initial dose, then 250 units/kg SC Q12H	Bleeding, HIT, osteoporosis	Additive bleeding risk with ASA and oral anticoagulants	Preferred over LMWH in severe renal impairment (no renal clearance dependence) and when rapid reversibility is needed. Monitor platelets closely; contraindicated with a history of HIT.

Vitamin K Antagonist

Drug	Dosage	Adverse effects	Drug interactions	Comments
Warfarin	Usual dose: 0.5-10 mg PO daily, individualized to a target INR of 2-3	Bleeding; hair loss and blue/purple toes are uncommon; skin necrosis is rare	Numerous clinically significant interactions - consult a current drug interaction reference before combining any new drug	Overlap with a parenteral anticoagulant for a minimum of 5 days and until the INR is >=2 for 24-48 hours. Monitor INR frequently at initiation, spacing out to every 2-4 weeks once stable.

Thrombolytics (massive/high-risk PE only)

Reserve for hemodynamically unstable PE with an acceptable bleeding risk; weigh benefit against intracranial hemorrhage risk in every patient.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Alteplase	PE: 100 mg IV over 2 hours	Bleeding, including intracranial hemorrhage	Additive bleeding risk with any concurrent anticoagulant	Not a Health Canada-approved indication for PE; dosing reflects specialty guideline recommendations. Greatest benefit within 14 days of symptom onset.
Tenecteplase	PE: Single weight-based IV bolus per institutional protocol	Bleeding, including intracranial hemorrhage	Additive bleeding risk with any concurrent anticoagulant	An alternative thrombolytic to alteplase for massive/high-risk PE.

Non-heparin anticoagulants for heparin-induced thrombocytopenia

Start immediately on clinical suspicion of HIT - do not wait for laboratory confirmation. Fondaparinux (above) is also a reasonable choice.

Drug	Dosage	Adverse effects	Drug interactions	Comments
Argatroban	HIT, treatment: IV infusion per institutional protocol, adjusted to a therapeutic aPTT	Bleeding	Additive bleeding risk with other anticoagulants/antiplatelet agents	Hepatically cleared - reduce the dose in hepatic impairment. Does not require renal dose adjustment.
Danaparoid	HIT, treatment: IV bolus and infusion per institutional protocol, adjusted to anti-Xa levels	Bleeding	Additive bleeding risk with other anticoagulants/antiplatelet agents	Renally cleared - use with caution in renal impairment. Minimal cross-reactivity with heparin antibodies.
Bivalirudin	HIT, treatment: IV infusion per institutional protocol, adjusted to a therapeutic aPTT	Bleeding	Additive bleeding risk with other anticoagulants/antiplatelet agents	Short half-life; renally cleared, so reduce the dose in renal impairment.

Reversal agents

Drug	Dosage	Adverse effects	Drug interactions	Comments
Idarucizumab	Dabigatran reversal: 5 g IV (two 2.5 g/50 mL boluses given no more than 15 minutes apart)	Headache; hypersensitivity reactions are uncommon	None significant	Reverses dabigatran's anticoagulant effect within minutes.
Andexanet alfa	Apixaban or rivaroxaban reversal: Low- or high-dose IV bolus followed by a 120-minute infusion; the specific regimen depends on which factor Xa inhibitor, its dose, and the time since the last dose	Thrombotic events, infusion reactions	Can reduce the anticoagulant effect of any concurrently administered heparin/LMWH product	Consult the product monograph's dosing table to select the correct regimen.
Protamine sulfate	UFH reversal: 1 mg IV per 100 units of UFH given in the preceding 2-3 hours (maximum 50 mg per dose, given slowly) Enoxaparin reversal (partial): 1 mg IV per 1 mg enoxaparin if within 8 hours of the last dose (0.5 mg per 1 mg if given later)	Hypotension, bradycardia, rare anaphylactoid reactions (increased risk with fish allergy or prior protamine/NPH insulin exposure)	None significant	Only partially reverses LMWH anti-Xa activity.
Vitamin K1 (phytonadione)	Warfarin reversal, major bleeding: 5-10 mg IV, combined with prothrombin complex concentrate per institutional major-bleeding protocol Warfarin reversal, elevated INR without bleeding: Hold warfarin, +/- low-dose oral vitamin K1, per current INR-management guidance	Rare anaphylactoid reaction with IV administration - give slowly	Antagonizes warfarin's anticoagulant effect	Reduces INR more slowly than prothrombin complex concentrate; combine the two for major bleeding requiring immediate reversal.

Reversal evidence note: full-cohort dabigatran-reversal and factor Xa inhibitor-reversal trial data for idarucizumab and andexanet alfa above.^[12]^[13]

VTE Prophylaxis (Surgical and Medical Patients)

DOACs for post-orthopedic-surgery prophylaxis

Drug	Dosage	Adverse effects	Drug interactions	Comments
Apixaban	Hip replacement: 2.5 mg PO BID starting 12-24h after surgery, for 32-38 days Knee replacement: 2.5 mg PO BID starting 12-24h after surgery, for 14 days	Bleeding	Contraindicated with combined strong dual inhibitors of CYP3A4 and P-glycoprotein (e.g., itraconazole, ritonavir)
Rivaroxaban	Hip replacement: 10 mg PO daily starting 6-10h after surgery, for 35 days Knee replacement: 10 mg PO daily starting 6-10h after surgery, for 14 days	Bleeding	Contraindicated with combined strong dual inhibitors of CYP3A4 and P-glycoprotein (e.g., itraconazole, ritonavir)	Not recommended in severe renal impairment.
Dabigatran	Hip replacement: 110 mg PO 1-4h after surgery, then 220 mg PO daily, for 28-35 days Knee replacement: 110 mg PO 1-4h after surgery, then 220 mg PO daily, for 10 days	Bleeding, dyspepsia	Contraindicated if ClCr under 30 mL/min or with strong P-glycoprotein inhibitors (e.g., quinidine)	Contraindicated if ClCr under 30 mL/min. Consider 150 mg daily over age 75.

LMWH prophylaxis

Drug	Dosage	Adverse effects	Drug interactions	Comments
Enoxaparin	General surgery: 40 mg SC once daily Orthopedic surgery: 30 mg SC Q12H	Bleeding, HIT (rare), osteoporosis with long-term use	Additive bleeding risk with ASA and oral anticoagulants	1 mg = 100 units. Contraindicated with a history of HIT.
Dalteparin	General surgery: 2,500 units SC once daily Orthopedic surgery: 5,000 units SC once daily	Bleeding, HIT (rare), osteoporosis with long-term use	Additive bleeding risk with ASA and oral anticoagulants	Contraindicated with a history of HIT.
Tinzaparin	General surgery: 3,500 units SC once daily Orthopedic surgery: 50-75 units/kg SC once daily	Bleeding, HIT (rare), osteoporosis with long-term use	Additive bleeding risk with ASA and oral anticoagulants	Contraindicated with a history of HIT.

Other prophylaxis agents

Drug	Dosage	Adverse effects	Drug interactions	Comments
Fondaparinux	High-risk orthopedic surgery, >=50 kg: 2.5 mg SC once daily	Bleeding, allergic reactions (rare)	Additive bleeding risk with ASA and oral anticoagulants	Not recommended below 50 kg or with renal dysfunction.
Heparin (UFH)	General surgery, moderate risk: 5,000 units SC Q8-12H	Bleeding, HIT, osteoporosis	Additive bleeding risk with ASA and oral anticoagulants	Monitor platelets closely during the first week of therapy.
ASA	Extended prophylaxis after hip replacement: 81 mg PO daily for 28 days, started after an initial 5-10 day course of LMWH or a DOAC Extended prophylaxis after knee replacement: 81 mg PO daily for 9 days, started after an initial 5-day course of a DOAC	Bleeding, usually minor (epistaxis); GI intolerance	Additive bleeding risk with other antiplatelet agents and anticoagulants	A step-down option after an initial LMWH/DOAC course, not a stand-alone first-line prophylaxis agent.

References

Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report — Chest, American College of Chest Physicians (Stevens SM, Woller SC, Kreuziger LB, et al.). Chest 2021;160(6):e545-e608
Value of assessment of pretest probability of deep-vein thrombosis in clinical management — The Lancet (Wells PS, Anderson DR, Bormanis J, et al.). Lancet 1997;350(9094):1795-1798
Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer — Annals of Internal Medicine (Wells PS, Anderson DR, Rodger M, et al.). Ann Intern Med 2001;135(2):98-107
2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS) — European Heart Journal, European Society of Cardiology (Konstantinides SV, Meyer G, Becattini C, et al.). Eur Heart J 2020;41(4):543-603
Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism — Archives of Internal Medicine (Jimenez D, Aujesky D, Moores L, et al.). Arch Intern Med 2010;170(15):1383-1389
Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis — New England Journal of Medicine (Wells PS, Anderson DR, Rodger M, et al.). N Engl J Med 2003;349(13):1227-1235
American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism — Blood Advances, American Society of Hematology (Ortel TL, Neumann I, Ageno W, et al.). Blood Adv 2020;4(19):4693-4738
American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer — Blood Advances, American Society of Hematology (Lyman GH, Carrier M, Ay C, et al.). Blood Adv 2021;5(4):927-974
Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH — Journal of Thrombosis and Haemostasis (Khorana AA, Noble S, Lee AYY, et al.). J Thromb Haemost 2018;16(9):1891-1894
American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia — Blood Advances, American Society of Hematology (Cuker A, Arepally GM, Chong BH, et al.). Blood Adv 2018;2(22):3360-3392
Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study — BMJ (Rodger MA, Le Gal G, Anderson DR, et al.). BMJ 2017;356:j1065
Idarucizumab for Dabigatran Reversal - Full Cohort Analysis — New England Journal of Medicine (Pollack CV Jr, Reilly PA, van Ryn J, et al.). N Engl J Med 2017;377(5):431-441
Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors — New England Journal of Medicine (Connolly SJ, Crowther M, Eikelboom JW, et al.). N Engl J Med 2019;380(14):1326-1335

Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.