High Yield Teaching & Journal Club:

Venous Thromboembolism

Connor Harrigan

August 10, 2026

Background: Venous Thromboembolism

• Venous thromboembolism (VTE):
• Deep vein thrombosis (DVT)
• Pulmonary embolus (PE)

Background: Venous Thromboembolism

• VTE is diagnosed in 1-2 per 1000 persons per year
• PE is the third leading cause of overall cardiovascular death and sudden death in hospitalized patients
• The estimated total cost for VTE and complications in Canada is at least $600 million per year.

Etiology

Risk Factors of VTE

Virchow’s triad

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Risk Factors of VTE

Virchow’s triad

1. Hypercoagulability
1. Inherited thrombophilia
2. Malignancy
3. Hyper-estrogen states
4. Prior VTE

Risk Factors of VTE

Virchow’s triad

• Hypercoagulability
• Inherited thrombophilia
• Malignancy
• Hyper-estrogen states
• Prior VTE
• Endothelial injury
• Trauma/surgery
• Lines (ex: CVCs)

Risk Factors of VTE

Virchow’s triad

• Hypercoagulability
• Inherited thrombophilia
• Malignancy
• Hyper-estrogen states
• Prior VTE
• Endothelial injury
• Trauma/surgery
• Lines (ex: CVCs)
• Venous stasis
• Trauma/surgery
• Hospitalization
• Immobility

Etiology of VTE: DVT

• Most commonly in the leg, though not exclusive
• Others: UE DVT, abdominal DVT, CNS DVT
• Deep veins of the lower leg are:
• Proximal (proximal to the popliteal trifurcation):
• Inferior vena cava
• Common iliac
• External iliac
• Common femoral vein
• Superficial femoral vein
• Popliteal vein
• Distal:
• Anterior & posterior tibial vein
• Peroneal vein

Etiology of VTE: PE

• Majority of PEs originate in proximal deep veins of the leg
• Ex: iliac, femoral and popliteal veins
• ~¾ of patients with PE have evidence of DVT in their legs
• If untreated, ~50% of proximal DVTs embolize to form PEs

Superficial Vein Thrombosis

Superficial vein thrombosis (SVT)

• = superficial vein thrombophlebitis
• Thrombus formation in superficial vein with associated inflammation of vessel wall
• 6-fold more common than DVT or PE
• Most commonly in the extremities
• Greater saphenous vein is most common
• N.B. SVT is different from a thrombus in the superficial femoral vein → = DVT!
• Risk factors → Virchow’s triad
• LEs: often occurs in presence of varicose veins
• UE: often associated with intravenous catheters
• Diagnosis: can be made clinically (erythema, warmth and tenderness along a palpable cord, esp. at IV site), but U/S is often suggested to R/O DVT and to delineate the length of thrombus + proximity to junction with deep venous system

Thrombosis Canada

SVT Treatment

CALISTO Trial (2010): Fondaparinux

SURPRISE Trial (2016): Rivaroxaban

SVT Treatment: Shift Towards Apixaban?

VTE Presentation

Signs and Symptoms of DVT

• Unilateral leg pain, swelling, erythema, warmth
• DDx:
• Vascular: SVT, post-thrombotic syndrome
• Infectious/Inflammatory: cellulitis, necrotizing fasciitis, gout
• MSK: ruptured popliteal (Baker’s) cyst, compartment syndrome
• Chronic/Systemic: unilateral lymphedema, chronic venous insufficiency

Signs and Symptoms of PE

Symptoms:

• Pleuritic chest pain, SOB, hemoptysis, syncope

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Signs:

• Tachycardia, hypoxia, tachypnea, fever, signs of DVT
• Signs of RV dysfunction (ex: distended jugular veins)

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ECG Findings in PE

Most sensitive?

• Sinus tachycardia

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ECG Findings in PE

Most sensitive?

• Sinus tachycardia

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Others:

• S1Q3T3

ECG Findings in PE

Most sensitive?

• Sinus tachycardia

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Others:

• S1Q3T3
• T-wave inversion
• New onset AF
• Evidence of increased pulmonary pressures
• Right axis deviation
• Right ventricular hypertrophy
• Right atrial enlargement
• Right bundle branch block

PE Diagnosis

PE Diagnosis: PERC Rule

• ONLY for patients under the age of 50

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• If negative, no further testing is required

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PE Diagnosis: Well’s Criteria for PE

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D-Dimer

• Positive D-dimer = there is a possibility that VTE is present

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• NON-SPECIFIC
• Infection, cancer, trauma, inflammatory states

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• If high suspicion → order imaging instead

PE Diagnosis: Imaging

• Bedside PoCUS: look for evidence of right heart strain → D-sign

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Normal

D-sign

PE Diagnosis: Imaging

• CT pulmonary angiography (CTPA): Detects filling defects in pulmonary vasculature

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PE Diagnosis: Imaging

• Ventilation-perfusion (VQ) scan

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• Nuclear medicine test evaluating pulmonary vasculature perfusion and segmental bronchoalveolar tree ventilation

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• Use in patients with renal failure, contrast allergy, pregnant patients

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Classification

PE Classification

• Hemodynamics:
• Massive: hemodynamically unstable
• Submissive: hemodynamically stable but evidence of strain (troponin elevation, RV strain on imaging, etc.)
• Low-risk

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PE Classification

• Hemodynamics:
• Massive: hemodynamically unstable
• Submissive: hemodynamically stable but evidence of strain (troponin elevation, RV strain on imaging, etc.)
• Low-risk
• Temporal pattern:
• Acute
• Subacute
• Chronic

PE Classification

• Hemodynamics:
• Massive: hemodynamically unstable
• Submissive: hemodynamically stable but evidence of strain (troponin elevation, RV strain on imaging, etc.)
• Low-risk
• Temporal pattern:
• Acute
• Subacute
• Chronic
• Vessel:
• Saddle
• Lobar
• Segmental
• Subsegmental

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New Classification?

Classification: Provoked

Unprovoked VTE

Unprovoked PE

Possible causes:

1. Unknown malignancy
• Work-up?
• Age-appropriate cancer screening

Age-Appropriate Cancer Screening

Age-Appropriate Cancer Screening: Lung

Age-Appropriate Cancer Screening: Colorectal

Age-Appropriate Cancer Screening: Cervical

Age-Appropriate Cancer Screening: Ovarian

Age-Appropriate Cancer Screening: Breast

Age-Appropriate Cancer Screening: Prostate

Unprovoked PE

Possible causes:

• Unknown malignancy
1. Work-up?
1. Age-appropriate cancer screening
2. Pan-CT?

SOME Trial

SOME Trial

• Multicenter, open-label, RCT in Canada
• Randomly assigned to undergo limited occult-cancer screening (basic blood testing, CXR, and screening for breast, cervical, and prostate cancer) or limited occult-cancer screening in combination with CT
• Primary outcome: confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period
• Overall: 3.9% had new diagnosis of occult cancer between randomization and 1-year follow-up:
• 3.2% in limited-screening group
• 4.5% in limited-screening-plus-CT group (P=0.28).
• 29% of occult cancers were missed by the limited screening strategy, whereas 26% were missed by the strategy of limited screening plus CT (P=1.0).
• Conclusions:
• The prevalence of occult cancer was low among patients with a first unprovoked venous thromboembolism

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• **Routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit**

2. Antiphospholipid Syndrome (APS)

• Multisystem autoimmune disorder
• Autoantibodies targeting phospholipid-binding proteins
• Thrombotic events (arterial or venous) and/or pregnancy morbidity in the setting of persistently positive antiphospholipid antibodies (APLAs)
• Thrombotic: DVT, stroke, etc
• Obstetric: unexplained fetal death ≥ 10 weeks, recurrent early miscarriage (<10 weeks, ≥3 consecutive), premature birth <34 weeks due to preeclampsia/placental insufficiency
• Catastrophic APS: thrombosis in ≥ 3 organs within 1 week with microvascular involvement
• Treatment:
• Thrombotic: warfarin (NOT DOACs)
• Obstetric: low dose ASA + prophylactic dose LMWH

2023 ACR/EULAR classification criteria

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3. Myeloproliferative Neoplasms

• Clonal hematopoietic stem cell disorders characterized by overproduction of mature blood cells

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• Activation of JAK-STAT signaling pathway through driver mutations (JAK2, CALR, MPL)

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• Types:

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1. Polycythemia vera
2. Essential thrombocytosis
3. Primary myelofibrosis

4. Paroxysmal Nocturnal Hemoglobinuria

• Rare, acquired clonal hematopoietic stem cell disorder characterized by complement-mediated intravascular hemolysis, thrombosis, and bone marrow failure
• Clinical manifestations:
• Thrombosis: occurs in ~20% of patients, often at unusual sites (hepatic veins (Budd-Chiari), portal, mesenteric, and cerebral veins)
• Hemolytic anemia: fatigue, pallor, dark urine (classically morning), elevated LDH, low haptoglobin, reticulocytosis
• Smooth muscle dystonia: abdominal pain, dysphagia, erectile dysfunction
• Bone marrow failure: cytopenias; PNH has a well-established association with aplastic anemia
• Progression to leukemia in ~5% of cases
• Diagnosis: High-sensitivity flow cytometry

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5. Heparin-Induced Thrombocytopenia (HIT)

• Immune-mediated adverse reaction to heparin caused by IgG antibodies directed against complexes of platelet factor 4 (PF4) and heparin

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• Clinical features and diagnosis: 4T score

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4-T Score

5. Heparin-Induced Thrombocytopenia (HIT)

• Immune-mediated adverse reaction to heparin caused by IgG antibodies directed against complexes of platelet factor 4 (PF4) and heparin

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• Clinical features and diagnosis: 4T score

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• Lab tests:
• Immunologic: anti-PF4 ELISA
• Functional: serotonin release assay

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• Treatment:
• Non-heparin agents: argatroban or bivalirudin
• Indirect/synthetic inhibitors: fondaparinux
• DOACs

Thrombosis Canada

6. Nephrotic Syndrome

• Clinical syndrome characterized by heavy proteinuria, hypoalbuminemia, peripheral edema, and hyperlipidemia
• Results from increased glomerular permeability to plasma proteins
• Primary: membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD)
• Secondary: DM, SLE, infections (hepatitis, HIV), medications, amyloidosis, malignancy
• PALE-T
• Proteinuria (>3.5 g/day)
• Albumin (low)
• Lipids (hyperlipidemia)
• Edema
• Thrombosis → losing “natural anticoagulants” (antithrombin III, protein C&S)

Summary of Possible Causes of Unprovoked VTE

1. Malignancy

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• Antiphospholipid syndrome

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• Myeloproliferative neoplasms

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• Paroxysmal nocturnal hemoglobinuria

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• Heparin-induced thrombocytopenia

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• Nephrotic syndrome

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* N.B. this is not an exhaustive list

Treatment of VTE

PE Treatment: Medical Options

Anticoagulation

• Subcutaneous LMWH: enoxaparin, dalteparin, tinzaparin
• IV UFH
• DOACs: apixaban, rivaroxaban, dabigatran, edoxaban

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Thrombolytics

• IV tPA

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PEITHO Trial (2014)

• Normotensive patients with intermediate risk PE (RV dysfunction on imaging) + myocardial injury (troponin elevation)
• Tenecteplase + heparin versus placebo + heparin
• Primary outcome: death or hemodynamic decompensation within 7 days
• Safety outcome: major extracranial bleed or ischemic/hemorrhagic stroke within 7d
• Findings: fibrinolytic therapy prevented hemodynamic decompensation (OR = 0.44, P = 0.02) but increased the risk of major hemorrhage and stroke
• In practice: systemic thrombolysis is NOT supported in intermediate-risk PE

PE Treatment: Procedural Options

Catheter-directed treatment

IVC filter

HI-PEITHO Trial (2026)

• Intermediate risk PE (RV/LV ratio >1)
• US-facilitated, catheter-directed fibrinolysis with alteplase + A/C versus A/C alone
• Primary outcome: PE-related death, cardiorespiratory decompensation or symptomatic recurrence of PE within 7 days
• Safety outcome: major bleeding
• Findings: intervention led to a lower risk of the primary outcome (4.0% versus 10.3%, RR 0.39, P = 0.005)
• No significant difference in major bleeding

PE Treatment: Duration

• Provoked: 3 months after the provoking factor is gone
• Unprovoked: indefinite

Anticoagulation for VTE: Evidence

VTE Treatment: EINSTEIN Trial

• Randomized, open-label, non-inferiority trial

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• Compared rivaroxaban to enoxaparin followed by warfarin in patients with acute PE with or without DVT

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• Primary efficacy outcome was symptomatic recurrent VTE

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• Findings: rivaroxaban (2.1%) was non-inferior to standard therapy (1.8%); HR 1.12, 95% CI 0.75 - 1.68

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• Principal safety outcome (major or clinically relevant nonmajor bleeding): 10.3% in rivaroxaban vs 11.4% in warfarin (P=0.23)

VTE Treatment: AMPLIFY Trial

• Randomized, double-blinded, non-inferiority trial

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• Compared apixaban to enoxaparin followed by warfarin in patients with acute VTE

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• Primary efficacy outcome was recurrent symptomatic VTE or death related to VTE

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• Findings: apixaban (2.3%) was non-inferior to standard therapy (2.7%); RR 0.84, 95% CI 0.60 - 1.18

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• Principal safety outcome was major bleeding and clinically relevant nonmajor bleeding: 4.3% in apixaban vs 9.7% in warfarin (RR 0.44, P<0.001)

Critical Appraisal of an RCT

Section A: Is the basic study design valid?

• Clearly focused research question?
• Randomized assignment of participants?
• All participants accounted for?

Section B: Was the study methodologically sound?

• Blinding
• Baseline characteristics
• Were patients in both groups treated equally apart from experimental intervention?

Critical Appraisal of an RCT

Section C: What are the results?

• Were effects of intervention reported comprehensively?
• Do the benefits of the experimental intervention outweigh harms and costs?

Section D: Will the results help locally?

• Can the results be applied to your local population/in your context?
• Would the intervention provide greater value to the people in your care than any of the existing interventions?

Did the study address a clearly focused research question?

PICO

Inclusion Criteria

• Adults
• Symptomatic acute VTE
• Acute proximal lower-limb DVT or segmental or more proximal PE

Exclusion Criteria

• Received therapeutic anticoagulation therapy for more than 72 hours immediately before the enrollment visit
• Renal insufficiency with a creatinine clearance < 30 mL/min
• Any contraindication to rivaroxaban or apixaban
• Active cancer
• Weight of more than 120 kg
• Known liver disease (Child–Pugh B or C)
• Use of contraindicated interacting medications
• Current pregnancy or breast-feeding
• Another indication for long-term A/C therapy (ex: AF)

Was the assignment of participants to interventions randomized?

Randomization

• Randomly assigned in a 1:1 ratio to receive 3 months of treatment with rivaroxaban or apixaban
• Randomization was conducted by means of a centralized Web-based system and a permuted block design with varying block sizes (4 and 6), with stratification according to:
• Renal insufficiency (creatinine clearance, <50 ml per minute vs. ≥50 ml per minute)
• Planned continued use of antiplatelet therapy during the trial period (yes vs. no)
• Participating center.

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Were all participants who entered the study accounted for at its conclusion?

December 2017 to January 2025

Was there appropriate blinding?

Blinding

• Open-label
• Treating clinicians and patients were aware of the treatment assignments

How did the trial mitigate its conflicts?

• NOT an industry-sponsored study

Were the study groups similar at the start of the randomized control trial?

Apart from the experimental intervention, did each study group receive the same treatment?

Apart from the experimental intervention, did each study group receive the same treatment?

Were the effects of intervention reported comprehensively?

Primary outcome

Clinically relevant bleeding:

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• 3.3% apixaban group

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• 7.1% rivaroxaban group

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• RR 0.46; 95% CI 0.33-0.65, P < 0.001)

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• Findings appeared to be consistent across prespecified subgroups

Major bleeding:

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• Apix: 5 pts (0.4%)

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• Riva: 32 pts (2.4%)

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• RR 0.16; 95% CI, 0.06 to 0.40

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Clinically relevant nonmajor bleeding:

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• Apix: 39 pts (2.9%)
• Riva: 67 pts (4.9%)
• RR 0.59; 95% CI, 0.40 to 0.86

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Secondary outcomes: recurrent symptomatic VTE

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• Apix: 15 pts (1.1%)

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• Riva: 14 pts (1.0%)

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• RR 1.08; 95% CI, 0.52 to 2.23

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Secondary outcomes

Medication Adherence

Do the benefits of the experimental intervention outweigh the harms and costs?

Can the results be applied in your local population?

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Would the experimental intervention provide greater value to the people in your care than any of the existing interventions?

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Generalizability

• Large sample size, international, multicentre

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• Several sites in Canada

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• Though mostly white men

Limitations

• Open-label design

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• Collected data only during the first 3 months of A/C therapy
• Whether the differences in bleeding risk persist beyond this time period is unknown

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• Exclusion of certain populations:

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• Patients with cancer-associated thrombosis (LMWH was standard care at the time of the trial design)

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• Patients with a body weight of more than 120 kg

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Conclusions

“The trial showed that apixaban (at a dose of 10 mg twice daily for 7 days followed by 5 mg twice daily) was superior to rivaroxaban (at a dose of 15 mg twice daily for 21 days followed by 20 mg daily) regarding the primary outcome of clinically relevant bleeding, a composite of major bleeding or clinically relevant nonmajor bleeding, during the 3-month trial period. There was no apparent difference in the risk of the secondary outcome of recurrent venous thromboembolism between the two groups.”

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Why?

• Longer period of higher intensity dosing (21 days vs 7 days)?
• Twice daily dosing of apixaban → steady state??
• Adherence?
• Inherent drug differences in pharmacokinetics and pharmacodynamics?

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Is this practice changing?

• Yes and no

Further Similar Trials

• Direct head-to-head comparisons of apixaban versus rivaroxaban to assess bleeding rates and superiority in patients with new-onset non-valvular atrial fibrillation

Additional Information

DOACs

PE Treatment: DOACs

Points to consider

• Cost
• Adherence
• Renal disease
• Liver disease
• Drug interactions

PE Treatment: DOACs

Points to consider

• Renal disease
• Liver disease
• Drug interactions
• Cost
• Adherence
• Bleeding risk
• So… what DOAC should we use?

Extended Low-Dose Apixaban for Secondary Prevention of VTE: API-CAT & HI-PRO Trials

VTE Treatment: RE-COVER Trial

VTE Treatment: HOKUSAI Trial

HI-PRO Trial

CXR Findings in PE

• Unilateral bibasilar atelectasis

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• Hampton’s hump
• Pleural based infarct of lung
• Dome-shaped, pleural-based opacification in the lung

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CXR Findings in PE

• Unilateral bibasilar atelectasis

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• Hampton’s hump
• Pleural based infarct of lung
• Dome-shaped, pleural-based opacification in the lung

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• Westermark sign
• Calcified area distal to a large vessel that is occluded by a pulmonary embolus

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Unusual Sites of Thrombosis

• Cerebral venous sinus thrombosis (CVST)
• Blood clot in the dural venous sinuses, cerebral veins, or both
• Younger patients
• S&S of increased ICP (headaches, seizure, papilledema, neurological deficits, vision loss)
• Splanchnic
• A) portal vein, mesenteric
• Risk factors: cirrhosis, malignancy (ex: MPN), APLS, IBD
• Mostly silent
• C) Hepatic vein
• Acute liver failure
• Risk factors: MPN, APLS
• B) Splenic vein
• Risk factors: embolic, malignancy
• Abdo pain