Venous thromboembolism

Introduction

• VTE in 1/500 persons per year
• 1/300 adult ED patients diagnosed with VTE
• 1/100 per year for adults >80yo
• PE is second-leading cause of sudden, unexpected, non-traumatic death
• Case fatality rates for PE
  • 58% if haemodynamically unstable vs. 15% if haemodynamically stable (deAlwis)
  • 45% if in shock (only seen in 4-5% of PE patients) (Tintinalli)
  • 1% if under 50, not in shock and no other comorbidities
  • Overall <8% if correct diagnosis and Rx (Dunn)
  • >90% of deaths occur in unrecognised PE
  • Chronic pulmonary HTN in 2-4% of patients with PE
• Post-thrombotic syndrome seen in 20% of proximal DVT patients

Pathophysiology

• Provoked VTE
  • Recent surgery, trauma, immobility, active cancer, pregnancy/post-partum, impaired venous flow, infection, chronic disease, oestrogen use, age >50 (each year over 50 increases risk)
  • Have higher 1-year mortality rate (likely due to underlying cause)
• Most VTE’s diagnosed in the ED are unprovoked (50% of all VTE are unprovoked)
• Unprovoked PE
  • 15% chance of recurrence in the next years vs. 5% for provoked PE
  • 10% risk of cancer in next 12 months
  • Important for thorough hx/examination but routine CT does not provide benefit in diagnosing cancer early
• 1/3 of patients with DVT have concomitant PE (even if asymptomatic)
• 80% of hospitalised patients with PE have image-confirmed DVT vs. 40% of ambulatory patients with PE
• If no comorbidities, usually 20% of lung vasculature has to be involved before symptoms arise
  • Dual pulmonary circulation means lung infarction is rare

Risk of recurrence

Pathophysiology

• Principle mechanisms of death from PE
  • Sudden near-total pulmonary artery occlusion leading to PEA
  • Asystole from ischaemic effect on His-purkinje system
• 1/3 of survivors of large PE’s go on to have right heart failure
• 5% of patients with PE experience chronic vascular obstruction, leading to progressive lung vessel damage, pulmonary hypertension and right heart failure termed chronic thromboembolic pulmonary hypertension
• The risk of recurrent VTE in those with a known thrombophilia is the same the risk for those who have had a prior unprovoked VTE absent that condition

Risk factors

• Most important risk factors in ED (OR >2)
  • Previous VTE
  • Surgery in last 4 weeks
  • Unilateral leg swelling
  • Oestrogen therapy
  • SpO2 <95% on RA
  • Non-cancer-related thrombophilia
• Trauma
  • 25% of PE’s occur within 4 days
  • 50% within one week

Risk factors

• Surgical (recent major surgery)
• Non-surgical
  • Transient
    • Acute medical illness with immobilization for >=3 days
    • Oestrogen therapy
    • Pregnancy/post-partum
    • Leg injury with reduced mobility for at least 3 days
    • Long-haul travel
  • Persistent
    • Active cancer
    • IBD/chronic inflammatory states
    • Antiphospholipid syndrome
• VTE within 2 months of a transient provoking factor has half the risk of recurrence as an unprovoked VTE

Pathophysiology

• Limb immobility
  • Risk increases depending on joint: Hip > knee >ankle >shoulder >elbow
• Travel
  • Risk NOT increased by travel, even if >8 hours
• Surgery
  • Average time from surgery to VTE diagnosis is >10 days and >50% diagnosed after discharge
  • Risk increases with age, longer surgery, open surgery and no thromboprophylaxis
  • Highest risk is abdominal surgery to remove cancer, joint replacement surgery and surgery on brain or spinal cord in the setting of neurological deficits
• Cancer
  • Higher the tumour burden and the more undifferentiated = higher risk
  • Pancreatic, stomach, ovarian and renal cell cancers carry the highest risk
  • Adenocarcinoma, glioblastoma, metastatic melanoma, lymphoma and multiple myeloma are particularly high also
  • Minimal risk with localised breast cancer, cervica, prostate and SCC/BCC
  • VTE risk is high though in initial phase of chemotherapy for breast cancer
• Smoking is not an independent risk factor
• Obesity
  • Increased risk once BMI >35
• Thrombophilias
  • Non-O blood type, lupus anticoagulant, shortened APTT, Factor V Leiden, Protein C/S/antithrombin deficiency
• Bed rest becomes a risk factor at 72 hours
• CCF
  • Risk factor depending on severity
• Stroke
  • Greatest risk in first month
• All oestrogen-containing preparations increase VTE risk
• IBD/SLE/nephrotic syndrome all increase risk proportional to severity of underlying disease

Clinical features of PE

• Hallmark is dyspnoea unexplained
• Chest pain with pleuritic features is the second most common symptom
  • Although 50% of diagnoses have no chest pain
• Basilar PE can refer pain to shoulder or mimic biliary/ureteric colic
• Proximal PE without infarction can cause pleuritic chest pain without focal pain
• History
  • 3-4% have syncope
  • 1-2% present with new-onset seizure or confusion
  • Paradoxical embolism syndrome (20% of population has patent foramen ovale)
    • May be localised findings, staring spells, transient altered LOC, atypical myelopathy symptoms

Clinical features

• History (Dunn)
  • Dyspnoea – 85%
  • Pleuritic chest pain – 75%
  • Apprehension – 60%
  • Cough – 50%
  • Haemoptysis – 30%
  • Sweating – 25%
  • Syncope – 15%
  • Non-pleuritic chest pain – 15%

Clinical features

• Three main syndromes
  • Isolated dyspnoea
  • Pulmonary infarction – Pleurisy and haemoptysis
  • Circulatory collapse – Transient, shock or arrest
• May simply present as sinus tachycardia/SVT or exacerbation of CCF/COAD

Clinical features of PE

• Examination
  • Tachycardia, tachypnoea, low SpO2 and sometimes mild fever
  • 50% have HR <100 and 1/3 have abnormal early vital signs that normalise in the ED
  • Clot burden DOES NOT predict vital sign derangement
  • 10% of patients have temp >38, but only 2% temp >39.2
  • Rales may be heard over infarcted lung

Clinical features

• Examination
  • RR >16 – 90%
  • HR >100 – 45%
  • Fever – 45%
  • RR <20 – 35%
  • Clinical evidence of DVT – 33%
  • Hypotension – 25%

Factors that affect presentation of PE

• Previously healthy and young
  • Less severe symptoms and signs with 50% having normal vital signs
• Prior cardiopulmonary disease
  • Can amplify or obscure findings
  • Describe dyspnoea as worse than usual
• Cognitive dysfunction
  • 20% of missed PE’s have baseline dementia
• Clot size and location
  • Proximal clots cause V-Q mismatch and dyspnoea vs. distal clots causing infarction with pain
• Gradual loading of PE over time
  • Gradual onset of fatigue and dyspnoea 
  • Remember, <50% of patients describe sudden onset symptomatology
  • Overlaps with CCF

Clinical features of DVT

• Swelling >2cm 10cm distal to tibial tubercle = 2x risk of DVT
• ¼ have tenderness and erythema in affected extremity, resembling cellulitis
• Calf vein thrombosis may cause Homan’s sign (no predictive value whatsoever)
• Proximal DVT
  • Increased compartment pressures
    • Swollen/painful/pale limb (phlegmasia alba dolens)
    • Dusky/blue limb (phlegmasia cerulea dolens)
  • Poses threat of limb loss and can require thrombolysis/thrombectomy

Diagnosis of VTE

• CXR
  • Most patients have at least one of basilar atelectasis, pleural effusion, cardiomegaly or infiltrate
  • Abnormal in 70-85%
  • NO change is diagnostic
  • <5% will have positive Westermark sign or peripheral dome-shaped dense opacification (Hampton hump) but very specific
    • Normal vessels should be visible within 2cm of chest wall
  • Presence of dyspnoea/hypoxaemia clear lungs suggests PE

Hampton’s hump

Westermark sign

ECG

• ECG
  • ECG changes in 85% of cases
  • TWI in V1 (40% of all PE and 70% of large PE)
    • The more T waves inverted from V1-4, the greater the risk of haemodynamically significant PE
    • T wave inversion in >= 7 leads correlates with RV dysfunction
  • ST elevation in aVR (35%)
  • Sinus tachycardia (40% and 70% of those with haemodynamic compromise)
  • Rightward axis (11%)
  • If RV systolic pressure >40, ECG can show TWI V1-4, RBBB and classic but uncommon S1Q3T3 (25% due to acute RV dilatation)
  • S1Q3T3 in 4% overall (Large S wave in I, Q wave in III and TWI in III)
  • Atrial arrhythmias in 15%
  • RBBB seen in 12% (incomplete or complete)
  • Can use scoring method to assess severity

ABG

• Marked increase in A-a gradient with normal CXR should raise suspicion
• A-a gradient >20 is 95% sensitive but not good enough to rule out PE

Diagnosis of VTE

• Low gestalt pre-test probability + PERC is reliable to rule out PE
  • 1-3% false negative rate
  • Reduces need for further testing in 10-20% of cases
• Post-test probability <1.5-2.0% is considered acceptable to exclude PE
• Modified Well’s score is most robust scoring system
  • High pre-test = PE in >60% of patients
  • Low pre-test probability = PE in 1.3-4%
• Gestalt has been shown to be as good as Wells’ or Geneva scores and did not show a decrease in sensitivity based on training level
  • Low suspicion = <15% likelihood of VTE

Diagnosis of VTE

• D-dimer testing
  • Qualitatitive testing has lower sensitivity but higher specificity
  • Quantitative testing has higher sensitivity but lower specificity
    • Sensitivity 94-98%; Specificity 50-60%
  • Has half-life of 8 hours and can be elevated for at least 3 days after symptomatic VTE
  • Age-adjusted (10x age in nanograms/mL) has been validated to give a very low false negative rate (0.3%)
  • Low pre-test with negative ELISA D-dimer = <0.4% risk of VTE in next 3 months

Diagnosis of VTE

• False positive D-dimer
  • Age >70
  • Pregnancy
  • Active malignancy
  • Surgical procedure in previous week
  • Liver disease
  • Rheumatoid arthritis
  • Infections
  • Trauma

• False negative D-dimer
  • Warfarin treatment
  • Symptoms >5 days
  • Presence of small clots
  • Isolated small PE
  • Isolated calf vein thrombosis
  • Lipaemia

Diagnosis of PE

• YEARS study (Van Der Hulle et al. 2017 Lancet)

Diagnosis of PE

• YEARS
  • Outpatients or inpatients with suspected acute or recurrent PE
  • Included pregnant patients
  • 3465 patients enrolled
  • 13% absolute reduction in CTPA compared to Wells/D-dimer
  • 8% absolute reduction in CTPA compared to Wells/Age-adj. D-dimer
  • 0.61% risk of PE in rule out group over next 3 months

Diagnosis of PE

• Pregnancy-adjusted YEARS algorithm (van der Pol et al. 2019 NEJM)
  • Same with addition of lower limb 2-point compression USS as first-step
  • 510 consecutive pregnant women
  • 46% third trimester
  • 16 patients had a PE on VQ (1) or CTPA (15) + 4 with proximal DVT
  • Of ruled out patients
    • No patient had PE in the 3 month follow-up
    • 1 popliteal DVT on USS at day 90
    • 0.42% if all patients lost to follow-up had VTE in worst-case scenario
  • Acts as an external validation of the original YEARS also

• Specifically patients had new or worsening chest pain or dyspnoea +- haemoptysis or tachycardia
• CTPA could be avoided in 39% of patients (32% in third trimester and 65% in first trimester reflecting rise in D-dimer with pregnancy duration)
• 2-point compression USS may have missed some lower limb DVT
• Not all patients underwent CTPA BUT lack of symptoms or Ix over 90 day follow-up makes the presence of any missed PE likely clinically irrelevant

Diagnosis of VTE

• PEGeD (Kearon et al. 2019)
  • Prospective study with 3 month follow-up
  • Validated cut-off D-dimer of <1000ng/mL for low-risk pre-test probability (Wells 0-4)
  • 0 patients had missed VTE
  • Chest imaging utilised in 34.3% of patients vs. 51.9% if cut-off of <500ng/mL utilised

Diagnosis of VTE

• CTPA
  • CTPA >90% sensitivity and specificity
  • 3-5mSv
  • 8-22% of cases will have diagnosis of alternative pathology on CTPA e.g. pneumonia
  • 15-25% of CTPA in Australian ED’s show PE while 70% of scans provide information about other diagnoses
  • Interobserver agreement for subsegmental clots is poor
  • 10% are inadequate due to secondary motion artifact or poor pulmonary artery opacification (obese or tachypnoeic patients)
  • 1/1000 suffer acute anaphylaxis or pulmonary oedema
  • 15% of patients suffer contrast-induced nephropathy (defined as creatinine >25% rise within 2-7 days)
    • Hydration with crystalloid is the only proven preventative measure
  • Contrast extravasation is also a risk with subsequent thrombophlebitis/compartment syndrome

Diagnosis of VTE

• CTPA
  • Lifetime attributable risk for breast Ca
    • 1/1200 for women age 20
    • 1/2000 if age 30
    • 1/3500 if age 40
  • PIOPED II study showed sensitivity 83% and specificity 96%
  • LR+ 24, LR – 0.1
  • If high clinical probability but negative CTPA – 1.5% incidence of VTE in 3 weeks (approximately the threshold for further testing)
    • 0.5% if patient also has negative D-dimer so can do this
    • US only positive in 1% of these patients and is probably largely a waste of time

Diagnosis of VTE

• VQ scan
  • 100% sensitivity to rule out PE if homogenous scintillation perfusion pattern
  • 2 or more apex central wedge-shaped defects in perfusion phase with normal ventilation = >80% probability of PE
  • Any other findings are non-diagnostic
  • 27-55% of scans are non-diagnostic
  • Preferred in pregnancy as most scans in this group are diagnostic. Can make shared decision making with mother if preferred
• Pulmonary angiography
  • Can demonstrate smaller filling defects in vessels <3mm, can measure pulmonary artery pressures and can treat with intrapulmonary modalitities or deploy an IVC filter
  • Disadvantages include availability, radiation exposure, cardiac dysrhythmias and rarely cardiac or pulmonary artery perforation

VQ scan

• Results
  • Normal scan
    • High NPV (96%). LR – 0.2
    • Excludes PE in low pre-test probability
    • May require further testing if high pre-test probability (post-test risk 3-5%) – other sources state 100% sensitive in this group
  • Low probability
    • LR 0.37
    • No further testing if low pre-test (post-test risk 1%)
    • Further testing if intermediate pre-test (post-test 5-10%)
    • Further testing if high pre-test probability (post-test risk 30-40%)

VQ scan

• Results
  • Intermediate probability
    • LR 0.93
    • Excludes PE if low pre-test probability (post-test risk 2-3%)
    • Further testing required if intermediate or high pre-test probability
  • High probability
    • LR 14-18
    • PPV 96% when combined with high pre-test probability
    • PPV only 56% if low pre-test probability
    • Consider further investigation if low or moderate pre-test probability

VQ scan

• Disadvantages
  • Does not provide info on other diagnoses
  • Need normal CXR
  • High rate of non-diagnostic scans that then require a follow-up CTPA anyway
  • Reduced breast irradiation but increased fetal irradiation
  • Not as easily obtainable or rapid as CTPA
  • Not suitable for unstable patients
  • Interpretation closely linked to pre-test probability

Diagnosis of VTE

• Venous US
  • 90-93% sensitivity and 95% specificity
  • Sensitivity of 40% as surrogate method to diagnose PE
  • Sensitivity of trained ED physician scans is 96.1% and specificity 96.8% compared to experienced ultrasonographer
  • Colour flow doppler may indicate recanalisation, suggesting a chronic clot, and may not then need anticoagulation
  • Presence of proximal DVT warrants anticoagulation with no further testing and in the setting of haemodynamic compromise can warrant thrombolysis
  • Useful as adjunct in pregnant patient to alleviate need for CTPA if positive
• CT venogram
  • Low rate of clinical utility, increased gonadal radiation, poor technical resolution and low interobserver reliability for below-knee DVT points away from routine use
  • May be helpful in intra-abdominal/pelvic venous clot studies

Diagnosis of VTE

• What if high pre-test probability but CTPA negative?
  • Likely need to go on to D-dimer, CT venogram, duplex uSS lower limbs or VQ scan or conventional pulmonary angiogram
• What if high pre-test probability and VQ scan negative?
  • Probably do not need any further testing
• What if CTPA is indeterminate for PE?
  • Venous USS
    • Positive – Treat as for DVT/PE
    • Negative
      • D-dimer 8x ULN – Treat as for DVT/PE
      • D-dimer normal or <150% ULN – VQ scan
        • VQ scan – Low-probability – Do not treat and repeat US in 2-7 days to help exclude PE
        • VQ scan – Indeterminate – Weigh up bleeding risk and consider treatment. Repeat US 2-7 days

Diagnosis of VTE

• What if high risk for DVT on Well’s, USS negative?
  • D-dimer negative – Ruled out
  • D-dimer positive – Repeat US in 1 week

Suspected PE if previous thromboembolism?

• This is incorporated into PERC and Well’s
• Just follow the algorithm

Prognostic factors associated with poor short-term outcomes in normotensive PE

• Syncope or seizure with respiratory distress at presentation
• Age >70
• Presence of CCF
• COAD
• Prior PE
• >50% pulmonary vascular occlusion
• ECG: TWI in V1-4, atrial arrhythmias, bradycardia <50, tachycardia >100, new RBBB, inferior Q waves, anterior ST segment changes and TWI, S1Q3T3
• HR : SBP >1.0
• SpO2 <94% on room air
• Increased troponin levels
• RV dysfunction on echo or CT
• Cancer
• Immobilisation due to neurological disease

Right heart strain pattern

• TWI in V1-V4 +- II, III, aVR
• Other findings (not seen below)
  • ST depression V1-V4
  • Right axis deviation
  • Dominant R wave in V1
  • Dominant S wave in V5/6

Troponin

• Raised in 20-40% of PE
• Correlates with TTE findings of RV dysfunction
• Correlates with CTPA findings and more segmental defects on VQ
• 18% mortality vs. 2.3% if normal (including haemodynamically stable pts)
• NPV is 93% for mortality
• PPV is too low to guide treatment in isolation

Treatment of VTE

• LMWH preferred over UFH re: bleeding/death/cost risk
  • UFH if CrCl< 30 or morbidly obese
• Rivaroxaban is also an option
• If uncertain about PE presence, benefit of empiric anticoagulation for 24 hours exceeds the risks (bleeding, HITTS) if pretest probability of PE >20%
• Delay in anticoagulation of patients with PE increases risk of death (no study has shown benefit of pre-CTPA dosing however)
• If severe renal insufficiency, UFH is preferred over LMWH
• Treat upper extremity DVT the same as lower limb
• Heparin interferes with thrombophilia screening but DO NOT DELAY UFH for any added thrombophilia screening when VTE is clearly present
  • Evaluation can be postponed to the future
  • There is no clinical benefit in thrombophilia screening to guide intensity or duration of anticoagulation
• DOACs and warfarin not in pregnancy. Warfarin in breastfeeding. LMWH preferred

Treatment of VTE

• Fluid loading
  • Beneficial to optimally fill RV but if overfilled, can raise RV pressures and impair LV filling with subsequent deleterious effect on CO
• Vasopressors
  • Must increase MAP and reduce RV pressure to improve right coronary artery perfusion
  • Noradrenaline is the most appropriate; Adrenaline may be helpful also
  • Risk with systemic vasodilators of reducing MAP and impairing RV coronary flow
• IABP and ECMO may be considered as last ditch attempts
• Ideally, get CVL prior to thrombolysis to allow ongoing vasopressor delivery

Treatment of VTE

• Phlegmasia cerulea dolens
  • Requires rapid action to reduce venous pressure
  • Anticoagulation, place limb at neutral level, removal constrictive materials and arrange catheter-directed thrombolysis
  • Consider systemic fibrinolytics if catheter-directed thrombolysis not available and no contraindications
    • E.g. 50-100mg alteplase IV over 4 hours

Treatment of VTE

• Superficial thrombophlebitis
  • Previously thought to be benign but concomitant DVT seen in 25% and PE in 5%
  • Extent is often under-estimated clinically
  • Oral NSAID or topical diclofenac if <5cm and >3cm from sapheno-pop or saphenofemoral junction
  • Risk factors for extension (and therefore anticoagulation)
    • >5cm long
    • Within 3cm of SFJ and SPJ
    • Male
    • Non-varicose vein
    • Severe symptoms
    • Above knee
    • Previous VTE
    • Active cancer
    • Recent surgery
  • Compression stockings are not helpful
  • 45 days prophylactic LMWH recommended if anticoagulating

Treatment of VTE

• Isolated calf vein thrombosis
  • Soleal, gastrocnemius and saphenous veins
  • Options
    • 3 months of oral anticoagulation
    • No treatment with repeat US in 1 week to check for progression of clot
    • Outpatient LMWH
  • Who should get treated (UpToDate)
    • Symptomatic
    • Near popliteal vein
    • Unprovoked
    • D-dimer >500
    • >5cm; >7mm diameter
    • Multiple veins
    • Persistent/irreversible risk factor e.g. Cancer
    • Prior VTE
  • If history of VTE or risk factors for VTE, should receive 3 months of full-dose anticoagulation unless contraindicated

Treatment of VTE

• Outpatient PE management
  • Safe in highly selected group (Hestia or simplied PE severity index score)
  • If deemed low risk and no high-risk features (troponin, BNP, RV strain ECG or bleeding risks can treat as outpatient after ED stay up to 23 hours
  • This is more achievable with Rivaroxaban due to difficulties in setting up monitoring for warfarin, injection education for LMWH

Treatment of VTE

• Simplified PE Severity Index Score
  • 0 = Low risk; 1 = High risk
  • Age >80
  • History of cancer
  • History of heart failure or chronic lung disease
  • HR >110
  • SBP <100
  • SpO2 <90%

Treatment of VTE

• Hestia criteria
  • SBP >100
  • No thrombolysis required
  • No active bleeding
  • No O2 required >24 hours to maintain SpO2 >90%
  • Not already anticoagulated
  • Absence of severe pain requiring narcotics >24 hours
  • Absence of other medial/social reasons to admit
  • CrCl >30
  • Not pregnant, liver disease or HIT

Echo

• Signs of right heart strain on Echo
  • Seen in 30-40% of patients with PE and extent of dysfunction directly correlates with degree of perfusion deficit on CTPA
  • Increased RV size
  • Decreased RV function (TAPSE <2cm)
    • Insensitive (53%) and non-specific (61%)
  • Tricuspid regurgitation
  • Abnormal septal wall motion
  • McConnell’s sign
    • Normokinesia/hyperkinesia of apical segment of free wall despite hypokinesia/akinesia of remaining parts of AV free wall (apical sparing)
    • 77% sensitive but highly specific (can help differentiate pulmonary HTN [global dysfunction] vs. PE)
  • Lack of IVC collapse in inspiration
• Other signs
  • RV thrombus – 35% have PE
  • Pulmonary artery thrombus – Definitively diagnoses PE

Echo

• Roles
  • In shocked patient, bedside echo can guide treatment
  • Absence of RV strain on echo rules out PE as cause of haemodynamic distress
  • Can rule out or diagnose other differentials e.g. tamponade
  • In non-high-risk patients, can prognosticate low-risk vs. intermediate-risk patients and can be considered for patients with elevated troponin or BNP

CT

• CT risk stratification
  • RV enlargement on CT indicates fivefold increase of death in next 30 days
  • 40% of patients deteriorate if this is seen on TTE vs. 10% if seen on CT
• Signs of right heart strain on CT
  • Flattening of IV septum
  • Paradoxical IV septum bowing (towards LV in systole)
  • RV enlargement > LV
  • Pulmonary trunk enlargement (> aorta)
  • Signs of RV failure
    • IVC contrast reflux
    • Dilated azygous venous system
    • Dilated hepatic veins +- contrast reflux

Treatment of VTE

• Severity and fibrinolysis
  • Massive PE/High-risk
    • SBP <90 for >15 minutes (50% mortality rate)
    • SBP <100 with hx of hypertension or
    • >40% reduction in baseline systolic blood pressure
    • +- markers of RV dysfunction or myocardial injury (not mandatory)
    • Short-term mortality 15%

Treatment of VTE

• Submassive PE
  • Not hypotensive (as above) but other evidence of cardiopulmonary stress
    • Any positive HESTIA or simplified PE severity index criteria
    • Shock index >1.0
    • SpO2 <95%
    • Echo: RV hypokinesis, RV dilatation, RSVP >40 or CT findings of right heart strain
    • Elevated Tn, BNP (>90), D-dimer
  • May benefit from fibrinolysis (improved survival and QoL but increased bleeding risk – PEITHO)
  • No difference in long-term pulmonary hypertension outcomes (long-term PEITHO)
  • Overall short-term mortality 3-15%
• Less severe PE
  • All the others
  • Short-term mortality 3%
    Normotensive without signs of RV dysfunction

Treatment of VTE

• Systemic fibrinolysis
  • Consider if no contraindications and any of:
    • Cardiac arrest
    • Hypotension (SBP <90 for >15 min)
  • Major contraindications
    • Intracranial disease
    • Uncontrolled HTN at presentation
    • Recent major surgery or trauma (<3 weeks)
    • Metastatic cancer
  • Alteplase 10mg bolus the 90mg over 2 hours (total 100mg) + heparin 80IU/kg bolus then 18U/kg/hr infusion after thrombolysis given
    • Some authors advise tenecteplase as for weight-based STEMI dosing
  • In cardiac arrest, can give 50mg IV bolus then repeat in 15 minutes if necessary
  • If high haemorrhage risk, can stop as soon as haemodynamic stability achieved
  • It is not clear whether anticoagulant (UFH) should be stopped while thrombolysis is delivered (US stop and Europe do not)
  • 10% risk of major haemorrhage, 0.5% risk of ICH and benefit up to 14 days post-onset (Oh’s)

Complications of systemic thrombolysis

• ICH 1.8%
• Major bleeding 9-13%
• Minor bleeding 23%
• Bleeding rates lower when non-invasive imaging techniques used to confirm PE

Treatment of VTE

• Catheter-directed thrombolysis
  • Better outcomes than heparin alone but no better than systemic tPA
  • May confer lower bleeding risk due to lower alteplase dosing
  • May be an option for:
    • Age >65 where intracranial bleeding risk is highest
  • Half-dose alteplase is also an option with safety advantages in patients at increased bleeding risk
  • Mortality still around 20-30%
• Surgical embolectomy
  • Option in young patients with large, proximal PE accompanied by hypotension with contraindications to thrombolysis or where lysis has failed or PFO with intracardiac thrombus
  • Contraindicated if no ROSC after cardiac arrest
  • Mortality rate of 30% (often delayed) – more recent data showed 8-14% perioperative mortality
  • Removal of large clot burden may improve later cardiopulmonary complications
  • Little evidence to compare to systemic thrombolysis

Treatment of VTE

• Low-dose thrombolysis in submassive PE
  • MOPETT trial
  • Moderate-risk PE (CT or angiography findings of >70% involvement of embolism in >=2 lobar arteries or main pulmonary arteries or by high probability VQ in >= 2 lobes
  • tPA dose was <= 50% of usual
  • Lower rates of pulmonary HTN (by echo), lower pulmonary artery systolic pressures, faster resolution of pulmonary HTN and similar rates of bleeding
  • Prevalence of RV dysfunction was low in this group
  • Echo not the optimal tool for assessing right heart pressures
  • Not enough to recommend this therapy

Treatment of VTE

• Special populations
  • Pregnancy
    • CTPA still warranted if suspected and positive D-dimer
    • Pregnancy-corrected D-dimer may become commonplace but not validated at this stage
  • Isolated subsegmental PE
    • Filling defect in one small pulmonary artery; usually <3mm diameter and in the absence of DVT
    • Found in 1-5% of CTPA done for ?PE
    • Radiologists often disagree on this
    • May be a radiographic artefact vs. true disease
    • No strong data to support withholding treatment in anyone else
    • Most still receive standard anticoagulation for minimum 3 months
    • Treatment especially important for higher risk patients (poor cardiorespiratory reserve, active cancer, pulmonary HTN, concomitant DVT and RV dilatation)

Treatment of VTE

• Indications for admission for DVT
  • Extensive iliofemoral DVT with circulatory compromise
  • Increased bleeding risk requiring close monitoring
  • Limited cardiorespiratory reserve warranting monitoring
  • Poor compliance risk
  • CI to LMWH and inability to use oral agent necessitating IV heparin
  • Known or suspected PE with any one of simplified PE severity index score or HESTIA
  • High suspicion of HIT with or without thrombosis
  • Renal insufficiency requiring anti-Xa level monitoring or use of UFH

Therapeutic Anticoagulation

• LMWH, fondaparinux, IV/SC UFH, rivaroxaban/apixaban or warfarin
• Only rivaroxaban and apixaban are licensed for ’dry start’ anticoagulation
• Rivaroxaban 15mg BD for 30 days then 20mg daily
• UFH
  • Preferred if massive PE where subcut absorption may be impaired or considering thrombolysis
  • Also preferred in severe renal impairment and those at high bleeding risk (as can reverse rapidly)
  • 80IU/kg bolus then infusion 18U/kg/hr and target APTT
• LMWH
  • Probably preferable to UFH in most other situations
  • First-line if active malignancy, pregnant
  • Enoxaparin 1mg/kg total body weight BD (no max dose in obesity)
  • Risk of recurrent VTE less with BD vs. 1.5mg/kg/day dosing
  • Consider anti-Xa monitoring if Creatinine 30-60, BMI >35 or <20

Greenfield filters

• Indications
  • Recurrent PE despite anticoagulation
  • Life-threatening ilio-femoral or proximal DVT in patient with limited cardiorespiratory reserve
  • Anticoagulation contraindicated
  • High-risk trauma patients: Severe TBI, spinal injury, pelvic/lower limb long bone fractures
• Removed once risk of PE is sufficiently low
• If acute DVT or PE is present, should be removed after at least 3 weeks of anticoagulation
• USS prior to removal if purely prophylactic
• Evidence
  • PREPIC study prevented symptomatic PE (15% vs. 6%) but no reduction in mortality or post-phlebitic syndrome

PIOPED II

• CTPA overall 83% sensitivity and 96% specificity
• PPV of PE with positive CTPA
  • High pre-test probability = 96%
  • Intermediate 92%
  • Low 58%
• NPV of PE with negative CTPA
  • Low pre-test probability = 96%
  • Intermediate 89%
  • High 60%
• Overall CTPA over-diagnoses possibly insignificant peripheral PE in low-risk patients and underdiagnoses PE in high-risk patients

Long-term PEITHO outcomes

• No long-term improvement with systemic thrombolysis for submassive PE
• Therefore, goal is purely avoidance of short-term mortality by preventing arrest
• Half-dose thrombolysis could play a role, especially in patients >65 or other risk factors for ICH

Prognosis

• Recurrence rate of VTE 1% per year while on therapy
• Recurrence rate 2-10% per year once therapy ceased

Cardiac arrest due to PE

• Mortality rate 66-95%
• Thrombolysis shows clear benefit
• No absolute CI to thrombolysis in this setting
• Can deliver thrombolysis more rapidly
  • 50mg then another 50mg in 15 min if no ROSC
  • If given thrombolysis should continue CPR for 2 hours
  • Improves ROSC, may improve survival to discharge
  • Concern regarding bleeding risk post-prolonged CPR has been dispelled

Duration of anticoagulation

• Most patients should receive minimum 3-6 months
• Extending beyond this is unusual if provoked VTE unless
  • Significant risk factors persist, idiopathic PE or documented past VTE, phlegmasia cerulea dolens
• Persistently raised D-dimer is associated with increased risk of recurrence
• If cancer:
  • LMWH specifically for 3-6 months recommended
  • Extended with LMWH or warfarin if active cancer and if recurrent despite anticoagulation
• Indefinite if:
  • Unprovoked proximal DVT, symptomatic PE or with active cancer and low risk of bleeding in whom stable anticoagulation can be achieved
  • Recurrent unprovoked VTE

VQ scan interpretation

• Modified PIOPED criteria
  • High-risk
    • Two or more large mismatched segmental defects or equivalent moderate/large defects wth a normal CXR 
    • Any perfusion defect substantially greater than the radiographic abnormality
  • Intermediate probability
    • Multiple perfusion defects with associated radiographic opacities
    • >25% of a segment and <2 mismatched segmental perfusion defects with:
      • Normal radiograph
      • One moderate segment
      • One large or two moderate segmental
      • One large and one moderate segment
      • Three moderate segmental
    • Triple match: solitary moderate-large matching segmental defect with matching radiograph

VQ scan interpretation

• Low probability
  • Non-segmental defects: Small effusion, blunted costophrenic angle, cardiomegaly, elevated diaphragm, ectatic aorta
  • Any perfusion defect with a substantially larger radiographic abnormality
  • Match VQ defects with a normal CXR
  • Small subsegmental perfusion defects
• Normal scan

Inherited thrombophilia

• Currently identified inherited thrombophilias present in 15% of general Caucasian population but 50% of those with first episode of VTE
• All patients with VTE have proven themselves to have a prothrombotic tendency and as such there is no justification to treat patients who test negative differently to those that test positive
• Positive results do NOT change duration of therapy either except:
  • Helps work out balance of bleeding vs. recurrent VTE risk
  • If moderate or high levels of antiphospholipid antibodies
    • Probably warrant lifelong anticoagulation, even if initial VTE provoked by surgery or trauma
    • 40% higher risk of recurrence in unprovoked VTE than those without lupus anticoagulant
  • If multiple thrombophilias, increases benefits of anticoagulation
  • Even strongest prothrombotic abnormalities (Antithrombin, Protein C and Protein S deficiencies) increase risk of recurrence by 50% at most
• Clinical benefit lies in obtaining at least a partial explanation of cause for VTE and avoidance of COCP/HRT + antepartum/postpartum anticoagulation

Inherited thrombophilia

• It is not necessary to ascertain thrombophilia status at the time of VTE diagnosis
• Many tests ordered at this point in time can have falsely low results due to active thrombosis
• The presence of anticoagulants can cause false positives (esp. antiphospholipid antibodies)
• Anyone with a previous VTE warrants prophylaxis at times of increased risk irrespective of thrombophilia screening results
• Patients with provoked VTE have a low risk of recurrence irrespective of thrombophilia status

Inherited thrombophilias

• Testing recommended for people with confirmed VTE (UpToDate):
  • FHx of VTE in first-degree relative
  • No FHx and:
    • <45yo
    • Recurrent thrombosis
    • Multiple venous sites or unusual venous beds
    • Warfarin-induced skin necrosis
    • Arterial thrombosis at risk of antiphospholipid syndrome
• Major benefit is risk management in future high-risk periods e.g. surgery/pregnancy, avoiding hormonal contraception/HRT
• Not recommended outside of above after first unprovoked VTE
• Not recommended for upper limb DVT

Occult malignancy

• Other than age-appropriate cancer screening, routine evaluation for occult malignancy is not recommended in unselected patients
• Testing leads to increased identification of cancer but no survival advantage
• Incidence of cancer after confirmed VTE is 2-25% (mean 10%)
  • Most commonly haematological malignancy and occult cancers of pancreas, ovary, liver, kidney and lung
• More aggressive/extensive approach suitable for:
  • Symptoms/signs of underlying malignancy
  • Recurrent VTE
  • Hepatic/portal vein thrombosis
  • Arterial thromboembolism suggestive of nonbacterial thrombotic endocarditis
  • Splanchnic vein thrombosis or cerebral vein thrombosis 

Upper limb DVT

• 80% due to secondary causes
  • E.g. catheter, cancer, surgery, trauma
• Less likely to be due to thrombophilia (??) – UpToDate states higher risk of thrombophilia than lower limb DVT and that screening is warranted
• Always consider strenuous exercise of arm in young males (so-called effort thrombosis)
  • Can cause thoracic outlet syndrome
• Risk factors
  • Younger age, athletic muscular male, strenuous upper arm activity, cervical rib, thrombophilia
• D-dimer testing is unreliable
• Less risk of post-thrombotic syndrome and recurrence
• PE rate 6% (vs. 15-32% for lower limb DVT)
• Treatment – At least 3 months anticoagulation
• If <2 weeks duration and moderate-severe symptoms, may warrant catheter-directed thrombolysis
• Thoracic outlet decompression may be required if anatomical predisposition exists

Age-adjusted D-dimer

• Can safely reduce the rate of subsequent imaging by 10-25%
• Age x 10 microg/L for patients >50
• Has been derived and validated for DVT and PE
• Increases specificity without reducing sensitivity
• Systematic review also showed benefit without loss of safety

Risk factors for recurrence

• Strong
  • Unprovoked
  • Previous VTE
  • Antiphospholipid, protein C or S deficiency
  • Persistent risk factor e.g. active cancer
  • PE or proximal DVT
• Moderate
  • VTE provoked by non-surgical transient risk factor
  • Male sex
  • Elevated D-dimer after cessation of anticoagulation
• Little or no effect
  • Factor V Leiden or prothrombin gene heterozygosity
  • Residual thrombus on imaging

Non-thrombotic emboli

• Needle embolism
  • Seen in IVDU
  • Can be left alone and observed with removal if complication

Fat embolism

• Mostly following long bone trauma
• 1% incidence for multiple femoral fractures
• Usually 12-36 hours after trauma
• Lipid release from marrow leads to complement activation within vasculature with combination of respiratory distress, haematological, neurological and cutaneous features
• May have fulminant RV failure, CVS collapse and ARDS
• More often gradual relative hypoxia, confusion/ALOC, petechial rash (upper thorax, conjunctiva, arms), thrombocytopaenia (45%) and unexplained anaemia (65%)
• CXR shows ARDS-type
• Supportive management and overall low mortality risk
• ORIF of femoral fractures within 24 hours reduces risk

Amniotic fluid embolism

• 1/8000 to 1/80 000 pregnancies
• 80% maternal mortality and 40% fetal mortality
• Seen in difficult/prolonged labour, fetal death in utero and C/S
• Small tears in uterine veins during labour lead to amniotic fluid pressurised delivery into circulation
• Sudden obstruction of pulmonary vasculature leading to acute RV failure, collapse, ARDS and DIC response

Recurrent VTE despite anticoagulation

• Subtherapeutic anticoagulation is most common cause
  • Malabsorption
  • Discontinuance for procedure
  • Poor compliance
  • Altered pharmacokinetics e.g. dietary vitamin K, weight change
  • Incorrect dosing
• Ongoing prothrombotic stimuli e.g. malignancy, Protein C/S/Antithrombin deficiency and antiphospholipid syndrome

Last Updated on August 28, 2023 by Andrew Crofton