Acute Pulmonary Embolism (PE)

Epidemiology

  • Incidence: increasing since advent of CT pulmonary angiogram (see Computed Tomography Pulmonary Angiogram, [[Computed Tomography Pulmonary Angiogram]])
    • Increasing Incidence of Acute PE (2011) [MEDLINE]
      • 1993-1998: 62 cases per 100k
      • 1998-2005: 112 cases per 100k
    • Autopsy Incidence of Acute PE: evidence of old PE is found in 25-30% of all autopsies
  • Co-Incidence of DVT and Malignancy: 20% of patients with DVT have a known active malignancy

Risk Factors for Venous Thromboembolism

General Comments

  • Same Risk Factors as for Deep Venous Thrombosis (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])
    • Risk Factor Can Be Identified in >80% of Patients with Venous Thrombosis: more than one factor may often be present
      • 50% of thrombotic events in patients with inherited hypercoagulable states are associated with an additional risk factor (pregnancy, surgery, prolonged immobilization, oral contraceptives)

Inherited Risk Factors (see Hypercoagulable States, [[Hypercoagulable States]])

  • General Comments
    • Factor V Leiden gene mutation and prothrombin gene mutation account 50-60% of inherited (primary) hypercoagulable states
  • Antithrombin Deficiency (see Antithrombin Deficiency, [[Antithrombin Deficiency]])
  • Dysfibrinogenemia (see Dysfibrinogenemia, [[Dysfibrinogenemia]]): rare
  • Factor V Leiden (see Factor V Leiden, [[Factor V Leiden]])
  • Factor XII Deficiency (see Factor XII Deficiency, [[Factor XII Deficiency]])
  • Family History of Venous Thromboembolism: strong risk factor
  • Heparin Cofactor II Deficiency: unclear risk factor
  • Plasminogen Deficiency: unclear risk factor
  • Protein C Deficiency (see Protein C Deficiency, [[Protein C Deficiency]])
  • Protein S Deficiency (see Protein S Deficiency, [[Protein S Deficiency]])
  • Prothrombin Gene Mutation (see Prothrombin Gene Mutation, [[Prothrombin Gene Mutation]])

Acquired Risk Factors (see Hypercoagulable States, [[Hypercoagulable States]])

  • Active Tuberculosis (see Tuberculosis, [[Tuberculosis]])
  • Age: hazard ratio of 1.7 (95 percent confidence interval: 1.5 to 2.0) for every decade of life after age 55 (ARIC and CHS studies)
  • Anti-Phospholipid Antibody Syndrome (see Anti-Phospholipid Antibody Syndrome, [[Anti-Phospholipid Antibody Syndrome]])
  • Asthma (see Asthma, [[Asthma]])
  • Bevacizumab (Avastin) (see Bevacizumab, [[Bevacizumab]])
    • Clinical: increased risk of venous and arterial events
  • Central Venous Catheters
  • Chronic Kidney Disease (CKD), Especially with Hemodialysis (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
  • Chronic Myeloproliferative Diseases (see Chronic Myeloproliferative Diseases, [[Chronic Myeloproliferative Diseases]])
    • Essential Thrombocythemia (see Essential Thrombocythemia, [[Essential Thrombocythemia]])
    • Polycythemia Vera (see Polycythemia Vera, [[Polycythemia Vera]])
      • Physiology: hyperviscosity and qualitative platelet defects
  • Chronic Psoriasis (see Psoriasis, [[Psoriasis]])
  • Congenital Venous Malformation of the Inferior Vena Cava
  • Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
  • Diabetes Mellitus (DM) (see Diabetes Mellitus, [[Diabetes Mellitus]])
  • Erythropoiesis-Stimulating Agents
  • Glucocorticoids (see Corticosteroids, [[Corticosteroids]]): data come from a Dutch population-based case-control study of 38,765 Danish adults who developed venous thromboembolism in a 7-year period, compared with 387,650 controls [MEDLINE]
    • Systemic vs Non-Systemic Steroids: risk of venous thromboembolism was highest with use of systemic glucocorticoids, as compared to a relatively lower risk with inhaled or gastrointestinal glucocorticoids
    • Time of Onset-Related Effect: risk of venous thromboembolism was highest with new use of glucocorticoids (incidence ratio 3.06), as compared to continuing or past use
    • Dose-Effect: risk of venous thromboembolism increased with increasing cumulative doses of the glucocorticoids
    • Possible Study Flaws: study may not have been able to fully account for all of the confounding risks of venous thrombombolism related to the underlying disease itself (for which the steroids were prescribed): the underlying disease may have increased the risk of venous thromboembolism or the increased risk of immobility (which could indirectly increase the risk of venous thromboembolism)
  • Heparin-Induced Thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia, [[Heparin-Induced Thrombocytopenia]])
  • Hormone Replacement Therapy (see Estrogen, [[Estrogen]])
  • Hyperhomocysteinemia (see Hyperhomocysteinemia, [[Hyperhomocysteinemia]])
  • Hypertension (see Hypertension, [[Hypertension]])
  • Hyperviscosity States (see Hyperviscosity, [[Hyperviscosity]])
    • Hyperfibrinogenemia
    • Waldenstrom’s Macroglobulinemia: due to hypergammaglobulinemia
    • Multiple Myeloma: due to hypergammaglobulinemia
    • Leukostasis (see Leukostasis, [[Leukostasis]])
    • Sickle Cell Disease (see Sickle Cell Disease, [[Sickle Cell Disease]])
  • Immobilization
    • Bedrest
    • Extended Travel
    • Lower Extremity Fracture/Injury
  • Inflammatory Bowel Disease (see Inflammatory Bowel Disease, [[Inflammatory Bowel Disease]])
  • Intravenous Drug Abuse (IVDA) (see Intravenous Drug Abuse, [[Intravenous Drug Abuse]]): due to femoral injection of drugs
  • Lenalidomide (Revlimid) (see Lenalidomide, [[Lenalidomide]])
  • Liver Disease (see End-Stage Liver Disease, [[End-Stage Liver Disease]])
    • Epidemiology: there is a high (6.3%) risk of venous thromboembolism in hospitalized liver disease patients, despite abnormal coagulation parameters [MEDLINE]
  • Lower Extremity Venous Insufficiency
  • Malignancy: clinical venous thromboembolism occurs in 5% of patients with cancer
    • Co-Incidence of DVT and Malignancy: 20% of patients with DVT have a known active malignancy
    • Risk of Venous Thrombembolism in Course of Cancer: highest risk during initial hospitalization, at the onset of chemotherapy, and at the time of disease progression
    • Presence of a Central Venous Catheter: futher compounds the risk of malignancy-associated venous thromboembolism
    • Common Sites of Malignancies at Time of Venous Thromboembolism Diagnosis: most cancers (78%) are diagnosed before the diagnosis of the DVT
      • Lung Cancer: 17%
      • Pancreatic Cancer: 10%
      • Colorectal cancer: 8%
      • Renal Cancer: 8%
      • Prostate Cancer: 7%
  • May-Thurner Syndrome
    • Physiology: compression of the left common iliac vein between the overlying right common iliac artery and underlying vertebral body
  • Nephrotic Syndrome (see Nephrotic Syndrome, [[Nephrotic Syndrome]])
  • Non-Steroidal Anti-Inflammatory Drugs (NSAID’s) (see Non-Steroidal Anti-Inflammatory Drug, [[Non-Steroidal Anti-Inflammatory Drug]])
    • Epidemiology
      • Systematic Review and Meta-analysis (Rheumatology, 2015) [MEDLINE]: NSAID’s increase risk of venous thromboembolism with RR of 1.80 (95% CI: 1.28-2.52)
  • Obesity with BMI ≥29 kg/m2 (see Obesity, [[Obesity]])
  • Obstructive Sleep Apnea (OSA) (see Obstructive Sleep Apnea, [[Obstructive Sleep Apnea]])
  • Oral Contraceptives (OCP) (see Oral Contraceptives, [[Oral Contraceptives]])
  • Ovarian Hyperstimulation Syndrome (see Ovarian Hyperstimulation Syndrome, [[Ovarian Hyperstimulation Syndrome]])
  • Paget-Schroetter Syndrome (see Paget-Schroetter Syndrome, [[Paget-Schroetter Syndrome]])
    • Physiology: underlying venous compression at the thoracic outlet
  • Paroxysmal Nocturnal Hemoglobinuria (PNH) (see Paroxysmal Nocturnal Hemoglobinuria, [[Paroxysmal Nocturnal Hemoglobinuria]])
  • Pregnancy (see Pregnancy, [[Pregnancy]])
    • Incidence of DVT is equal throughout pregnancy (first trimester: 22%/second trimester: 41%/third trimester: 37%)
    • Incidence of PE during pregnancy: 34% occur pre-partum, 66% occur post-partum (82% of these follow C-section)
    • Increased risk of DVT in left leg during pregnancy (possibly due to left common iliac vein compression by overlying right iliac artery)
    • ASA does not affect risk of DVT in pregnancy (even in presence of anti-phospholipid Ab syndrome)
  • Polycystic Ovary Syndrome (see Polycystic Ovary Syndrome, [[Polycystic Ovary Syndrome]])
  • Prior Thrombotic Event: major risk factor
  • Prothrombin Complex Concentrate-3 Factor (Profilnine SD) (see Prothrombin Complex Concentrate-3 Factor, [[Prothrombin Complex Concentrate-3 Factor]])
  • Prothrombin Complex Concentrate-4 Factor (Kcentra, Beriplex, Confidex) (see Prothrombin Complex Concentrate-4 Factor, [[Prothrombin Complex Concentrate-4 Factor]])
  • Recent Arterial Cardiovascular Event (Within 3 Months): short-term increase in venous thromboembolism risk
  • Recent Major Surgery
    • Cancer Surgery
    • Major Vascular Surgery
    • Neurosurgery
    • Orthopedic Surgery
      • Total Hip Replacement: 30-day risk of symptomatic non-fatal venous thromboembolism is 2.5% [MEDLINE][MEDLINE]
      • Total Knee Replacement: 30-day risk of symptomatic non-fatal venous thromboembolism is 1.4% [MEDLINE][MEDLINE]
  • Renal Transplant (see Renal Transplant, [[Renal Transplant]])
  • Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis, [[Rheumatoid Arthritis]])
  • Sepsis (see Sepsis, [[Sepsis]])
  • Superficial Thrombophlebitis/Superficial Venous Thrombosis (SVT) (see Superficial Venous Thrombosis, [[Superficial Venous Thrombosis]])
    • Epidemiology: SVT may occur in patients with inherited/acquired hypercoagulable states
    • Clinical
      • Occult DVT: occult DVT is present in 7-32% of superficial thrombophlebitis cases (suggests that screening of these patients with LE dopplers may be warranted)
      • Recurrence of SVT: 24% of cases have recurrent SVT [MEDLINE]
      • Later Development of DVT: 32% of SVT cases develop DVT at median interval of 4 years [MEDLINE]
  • Tamoxifen (see Tamoxifen, [[Tamoxifen]])
  • Testosterone (see Testosterone, [[Testosterone]])
  • Thalidomide (see Thalidomide, [[Thalidomide]])
  • Tobacco Abuse (see Tobacco, [[Tobacco]]): cigarette smoking >25 cigarettes per day increases risk
  • Trauma of Any Etiology
    • Physiology: decreased lower extremity venous blood flow, decreased fibrinolysis, and immobilization

Physiology

Virchow’s Triad: Contributors to the Development of Venous Thromboembolism

  • Alteration in Blood Flow: stasis
  • Vascular Endothelial Injury
  • Alteration in Constituents of Blood: inherited or acquired hypercoagulable state

Lower Extremity Venous Anatomy

Superficial Veins

  • Greater Saphenous Vein Above or Below the Knee
  • Non-Saphenous Veins
  • Small Saphenous Vein
  • Telangiectasias/Reticular Veins

Deep Veins

  • Inferior Vena Cava (IVC)
  • Iliac Veins
    • Common Iliac Vein
    • External Iliac Vein
    • Internal Iliac Vein
  • Pelvic Veins
    • Broad Ligament Vein
    • Gonadal Vein
    • Other Pelvic Veins
  • Femoral Veins
    • Common Femoral Vein
    • Deep Femoral Vein
  • Popliteal Vein
  • Crural Calf Veins
    • Anterior Tibial Vein: less common site of distal DVT
    • Posterior Tibial Vein: more common site of distal DVT
    • Peroneal Vein: more common site of distal DVT
  • Muscular Calf Veins: less common site of distal DVT
    • Gastrocnemius Vein
    • Soleal Vein
    • Other Muscular Calf Veins

Perforator Veins

  • Thigh Perforator Vein
  • Calf Perforator Vein

Upper Extremity Venous Anatomy

Superficial Veins

  • Basilic Vein
    • Common site of PICC placement
  • Cephalic Vein
  • Median Antebrachial Vein
  • Median Antecubital Vein
  • Accessory Cephalic Vein

Deep Veins

  • Radial Vein
  • Ulnar Vein
  • Interosseous Vein: in the forearm
  • Brachial Vein
    • Common site for PICC-related DVT
  • Axillary Vein
    • Common site for PICC-related DVT
  • Subclavian Vein
    • Common site for PICC-related DVT
  • Internal Jugular Vein
    • Most common site for CVC-related deep venous thrombosis

Lower Extremity Deep Venous Thrombosis

  • Calf Vein (Distal) DVT
    • Progression: left untreated, distal DVT will progress to proximal DVT in approximately 33% of cases
      • Usually progresses within the first 2 wks after diagnosis: if extension does not occur in the first 2 wks, it is unlikely to occur
      • Limited muscular calf vein distal DVT has a low risk of extension without treatment (risk of extension: 3%), as compared to extensive thrombosis of multiple calf veins (risk of extension: 15%)
    • Risk of Pulmonary Embolism with Distal DVT: risk of distal DVT embolization is approximately 50% the risk of proximal DVT embolization [MEDLINE]
  • Proximal DVT: thrombi in lower extremities develop within minutes, then organize, and fibrinolyse (stabilizing within 7-10 days)
    • Risk of Pulmonary Embolism with Proximal DVT: the risk of (symptomatic or asymptomatic) PE is approximately 50%
    • Highest Risk Period for Embolization of Proximal DVT: within first few days after DVT formation

Upper Extremity Deep Venous Thrombosis

Source of Pulmonary Embolism

  • In Situ Pulmonary Artery Thrombosis: rare
  • Lower Extremity Deep Venous Thrombosis (DVT): accounts for >95% of pulmonary embolism cases
    • Larger lower extremity veins (iliac, femoral, popliteal) are the source of most clinically significant pulmonary emboli
  • Pelvic Vein Deep Venous Thrombosis (DVT)
  • Arteriovenous Hemodialysis Fistula (see Arteriovenous Hemodialysis Fistula, [[Arteriovenous Hemodialysis Fistula]]): thrombectomy (including cases with paradoxical arterial embolism) may lead to pulmonary embolism
  • Upper Extremity Deep Venous Thrombosis (DVT): usually near venous valves

Clinical Consequences of Acute Pulmonary Embolism

  • Pulmonary Infarction: occurs in 10% of cases (since bronchial artery collateral vessels usually supply blood)
    • Physiology: inflammatory response in the lung and adjacent visceral/parietal pleura -> results in pleuritic chest pain and hemoptysis
  • Abnormal Gas Exchange
    • Mechanical Obstruction of Pulmonary Vascular Bed, Resulting in Alteration of V/Q Ratio: hypoxemia
    • Surfactant Dysfunction and Atelectasis, Resulting in Functional Intrapulmonary Shunting: hypoxemia
    • Inflammation Resulting in Respiratory Drive Stimulation: hypocapnia with respiratory alkalosis
  • Increased Pulmonary Vascular Resistance Due to Mechanical Obstruction of Pulmonary Vascular Bed and Hypoxic Pulmonary Vasoconstriction: obstruction of only 33% of pulmonary vasculature produces pulmonary hypertension, due to pulmonary arterial vasoconstriction (in addition, when obstruction of the pulmonary vascular bed approaches 75 percent, the right ventricle must generate a systolic pressure >50 mmHg to preserve adequate pulmonary artery flow)
    • *Right Ventricular Dilation/Flattening of the Interventricular Septum
    • Decreased Flow from the Right Ventricle and Right Ventricular Dilation Decrease Left Ventricular Preload
    • Decreased Left Ventricular Stroke Volume and Decreased Cardiac Output: hypotension
  • Increased Alveolar Dead Space Fraction: due to occluded vasculature with remaining ventilation
    • Most Patients with Acute PE Have Alveolar Dead Space Fraction >20% and Positive D-Dimer
    • Most Patients with Normal Alveolar Dead Space (<20%) and Negative D-Dimer Do No Have Acute PE

Resolution of Acute Pulmonary Embolism

  • Embolus in the Pulmonary Vasculature Lyses over Hours-Days

Diagnosis

Electrocardiogram (EKG) (see Electrocardiogram, [[Electrocardiogram]])

  • Normal: present in many cases
  • Sinus Tachycardia with Non-Specific ST-Segment and T-Wave Changes (see Sinus Tachycardia, [[Sinus Tachycardia]]): most common finding (present in 70% of cases)
  • Atrial Arrhythmias
    • Atrial Fibrillation (see Atrial Fibrillation, [[Atrial Fibrillation]]): associated with poor prognosis in acute PE
  • Sinus Bradycardia (see Sinus Bradycardia, [[Sinus Bradycardia]]): associated with poor prognosis in acute PE
  • S1Q3T3 Pattern: infrequent (<10% of cases), associated with poor prognosis in acute PE
  • New Right Bundle Branch Block (see Right Bundle Branch Block, [[Right Bundle Branch Block]]): associated with poor prognosis in acute PE
  • Inferior Q-Waves (II/III/AVF): associated with poor prognosis in acute PE
  • Anterior ST-Segment Changes and T-Wave Inversion: associated with poor prognosis in acute PE
  • Right Ventricular Strain Pattern: infrequent (<10% of cases)
    • ST-Segment Depression and T-Wave Inversion in the Leads Corresponding to the Right Ventricle
      • Right Precordial Leads: V1-V3 (and often V4)
      • Inferior Leads: II/III/AVF (most pronounced in III, as this is the most rightward-facing lead
  • P-Pulmonale

Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]])

  • Hypocapnia with Respiratory Alkalosis: due to hyperventilation due to pulmonary hypertension
  • Hypoxemia with Elevated A-a Gradient: due to V/Q mismatch/intrapulmonary shunt/decreased CO with low SvO2
    • However, 18% of cases have pO2 between 85-100 mmHg
    • Up to 6% of cases have a normal A-a gradient
    • Presence of SaO2 <95% at Time of Diagnosis: increased risk of in-hospital complications (respiratory failure, cardiogenic shock, and death)

Pleural Fluid (see Thoracentesis, [[Thoracentesis]])

  • Pattern
  • Appearance
    • Hemorrhagic: in some cases
      • this is not a considered a contraindication to anticoagulants or thrombolytics
  • Pleural Fluid Eosinophilia (see Pleural Effusion-Cell Count Patterns, [[Pleural Effusion-Cell Count Patterns]]): may be seen in cases where effusion is bloody

Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]])

  • DLCO: decreased (due to loss of capillary blood volume)
    • May be the only PFT abnormality

CXR/Chest CT Patterns (see Chest X-Ray, [[Chest X-Ray]] and Chest Computed Tomography, [[Chest Computed Tomography]])

  • Features
    • Atelectasis (see Atelectasis, [[Atelectasis]])
    • Alveolar Infiltrate (see Pneumonia, [[Pneumonia]]): may cavitate in some cases
    • Cardiomegaly: seen in 50% of cases
    • Enlarged PA and Enlarged RV: seen with large PE only
    • “Hampton’s Hump”: wedge-shaped infiltrate in area of PE (appears 12-36 hours later)
      • May cavitate
    • “Westermark Sign”: wedge-shaped area of vascular clearing in area of PE
    • Pleural Effusion: seen in 47% of cases
      • Usually unilateral and small: 86% are only blunted CPA
      • May precede infiltrates (50% of acute PE’s with effusion have associated parenchymal infiltrates)
      • Usually reach maximum size in first 3 days (enlargement after that suggests recurrent PE or other complication)
    • Normal CXR: most common pattern

Ventilation/Perfusion (V/Q) Scan (see Ventilation-Perfusion Scan, [[Ventilation-Perfusion Scan]])

  • Overall diagnostic accuracy of V/Q is poor (ranges from 15-86%) in 72% of all patients, insufficient to diagnose PE or exclude the diagnosis of PE
  • Normal scan: virtually excludes diagnosis of PE
  • Low probability scan: low clinical prob + low prob V/Q = 4% probability of PE
    -Note: if clinical prob is high, low prob V/Q has 40% probability of PE
  • Intermediate probability scan: ranges from 15-66% probability of PE (depending on clinical prob)
  • High probability scan: high clinical prob + high prob V/Q = 95% probability of PE (these patients can be treated with heparin, thrombolytics without pulmonary angio)
    • Note: if clinical prob is low, high prob V/Q has 56% probability of PE

Pulmonary Artery Angiogram (see Pulmonary Artery Angiogram, [[Pulmonary Artery Angiogram]])

  • Indications
    • Gold Standard Diagnostic Test: negative pulmonary angiogram excludes clinically relevant PE
  • Adverse Effects: generally safe in patients without acute, severe pulmonary hypertension
    • Procedure-Related Mortality: <2%
    • Procedure-Related Morbidity: 5% (due mainly to catheter insertion-related complications, contrast reactions, arrhythmias, respiratory failure)
    • Radiation Exposure: greater than that from CT pulmonary angiogram
  • Angiographic Patterns
    • “Rat Tail Configuration”: vessel tapers to a point
    • “Filling Defects”: may be seen in most cases
    • “Abrupt Cut-Off”: may be seen in complete occlusion

Computed Tomography Pulmonary Angiogram (CTPA) (see Computed Tomography Pulmonary Angiogram, [[Computed Tomography Pulmonary Angiogram]])

  • Sensitivity: 86% in large (main/lobar/segmental) vessels (75% in all vessels)
  • Specificity: 91% in large (main/lobar/segmental) vessels (89% in all vessels)
  • CT Pulmonary Angiogram Has Traditionally Been Considered Most Accurate for Large/Main/Lobar/Segmental PE’s and Less Accurate for Smaller/Peripheral Subsegmental PE’s: however, there is improved detection of PE by multi-detector CT pulmonary angiogram (9.4%) vs single-detector CT pulmonary angiogram (4.7%)
  • Low Risk of PE Following a Negative CT Pulmonary Angiogram: <2% risk of PE in 3-month F/U in patients with negative CT angio + low-intermediate clinical probability + negative LE dopplers
    • This risk increases to 5% if clinical probability is high

Gadolinium-Enhanced Magnetic Resonance Venogram and Pulmonary Angiogram (MRA) (see Magnetic Resonance Imaging, [[Magnetic Resonance Imaging]])

Advantages

  • No Exposure to Iodinated Radiographic Contrast
  • No Radiation Exposure

Disadvantages

  • Magnetic Resonance Venogram and Pulmonary Angiogram Have High Rates of Technically Inadequate Studies [MEDLINE]: technically inadequate studies were found in 25% (range: 11-52%) of studies performed in the PIOPED III Study (2010), depending on the center
    • Due to the large number of technically inadequate studies in PIOPED III, magnetic resonance venography and pulmonary angiogram only identified 57% of patients with pulmonary embolism
    • Vascular opacification and motion artifact are the principal factors which influence interpretability of MRA [MEDLINE]: some centers appear to obtain better images (for unclear reasons)
  • Technically Adequate Magnetic Resonance Pulmonary Angiogram
    • Sensitivity: 78%
    • Specificity: 99%
  • Technically Adequate Magnetic Resonance Pulmonary Angiogram + Magnetic Resonance Venogram: combination has significantly higher sensitivity than magnetic resonance pulmonary angiogram alone (however, only 52% of patients had technically inadequate results)
    • Sensitivity: 92%
    • Specificity: 96%

Recommendations

  • Magnetic Resonance Pulmonary Angiogram and Venogram Studies Should Only be Performed in Centers with Local Expertise

Lower Extremity Venogram (see Lower Extremity Venogram, [[Lower Extremity Venogram]])

  • Indications: gold standard for diagnosis of lower extremity DVT

Lower Extremity Venous Doppler Ultrasound (see Lower Extremity Venous Doppler Ultrasound, [[Lower Extremity Venous Doppler Ultrasound]])

  • May detect DVT
  • 3% false-positive rate
  • Only 29% of patients with PE (diagnosed by V/Q or angiogram) have DVT by U/S
  • Incidence of symptomatic DVT-PE is <1% in those with negative whole leg LE U/S during a 3 months of F/U period
  • Serial Ambulatory U/S Studies: 2-week monitoring (to assess for extension), without anticoagulation, may be indicated for patients with isolated calf vein DVT + adequate cardiopulmonary reserve + non-high prob V/Q scan [Hull; Arch Int Med, 1989] -> <3% of patients had PE during F/U period
  • Results cannot be generalized to patients with limited cardiopulmonary reserve or patients with a documented PE

Lower Extremity Impedance Plethysmography (IPG)

  • Indications: sensitive for above the knee DVT

Lower Extremity Radiofibrinogen Study

  • Indications: sensitive for calf/lower thigh DVT

Brain Natriuretic Peptide (BNP) (see Brain Natriuretic Peptide, [[Brain Natriuretic Peptide]])

  • May Be Elevated
    • Magnitude of increase in BNP correlates with risk of subsequent complications and prolonged hospitalization
    • BNP >90 pg/ml (within 4 hrs of presentation): associated with adverse outcomes (death, cardioplumonary resuscitation, mechanical ventilation, pressor therapy, thrombolysis, and embolectomy)
    • BNP <50 pg/ml (within 4 hrs of presentation): benign clinical course in 95% of cases
  • Sensitivity: 60%
  • Specificity: 62%

Troponin (see Troponin, [[Troponin]])

  • May Be Elevated: due to acute right heart overload
    • Not useful for diagnosis, but offers prognostic information (elevated troponin is associated with increased incidence of prolonged hypotension + increased 30-day mortality)
    • Troponin I: elevated in 30% of moderate-large PE
    • Troponin T: elevated in 50% of moderate-large PE

Elevated NT-proBNP level + Elevated Troponin (see Brain Natriuretic Peptide, [[Brain Natriuretic Peptide]])

  • Provide prognostic information
  • Troponin-T >0.07 µg/L + NT-proBNP >600 ng/L is associated with 33% 40-day mortality (as compared to 0% mortality with NT-proBNP level <600 ng/L)

D-Dimer (see D-Dimer, [[D-Dimer]])

  • Physiology: D-dimer is the degradation product of cross-linked fibrin
  • Assay
    • ELISA Method is More Sensitive: patient with normal D-dimer by ELISA has 95% likelihood of not having a PE (D-dimer by ELISA is effective to exclude PE, unless pretest probability is high)
    • Latex Agglutination Method is More Rapid: patient with normal D-dimer by latex agglutination has 85-98% likelihood of not having a PE (D-dimer by latex agglutination is less effective to exclude PE, unless pretest probability is low): normal D-dimer + low prob V/Q = 99% likelihood of not having a PE
  • Normal D-Dimer Level: D-dimer <1.3 (<500 ng/ml by ELISA)
  • Sensitivity/Specificity: good sensitivity and negative predictive value, but poor specificity (especially in hospitalized patients, those with malignancy or recent surgery) -> therefore, useful only to rule out PE
    • A normal D-dimer (<500 ng/mL) effectively excludes PE (including in patients who have had a prior PE, those with a delayed presentation, and women who are pregnant)
    • D-dimer specificity may decrease further with increasing age
    • D-dimer is elevated in 95% of acute PE, but only in 50% of subsegmental PE (although subsegmental PE’s rarely cause severe clinical symptoms, they predict future emboli)
    • D-dimer is normal in 25% of patients without PE

Echocardiogram (see Echocardiogram, [[Echocardiogram]])

  • General Comments
    • Only 30-40% of Acute PE’s Have Positive Echocardiographic Evidence of PE: percentage is higher in cases of massive PE
  • Features
    • Features of RV Strain/Overload: present in 30-40% of patients with acute PE (higher percentage in patients with massive PE)
      • Decreased RV Ejection Fraction
      • RV Enlargement
      • Tricuspid Regurgitation: Doppler of TR jet allows estimation of PA pressure
    • Pulmonic Regurgitation
    • RV Thrombus: >35% patients with RV thrombus develop PE, but only 4% of PE patients have an RV thrombus
    • McConnell’s Sign (77% sensitivity for diagnosis of acute PE): regional wall motion abnormalities that spare the RV apex
    • Normal LV Ejection Fraction: usually seen

Swan-Ganz Catheter (see Swan-Ganz Catheter, [[Swan-Ganz Catheter]])

  • RA: normal (at rest)
  • RV-SYS: moderately elevated (with normal RV-EDP)
  • PA-SYS and PA-DIA: moderately elevated (severe elevations suggest CTEPH, since vascular remodeling is required to raise pressures this high/acute severe elevations will also produce rapid RV failure)
  • PA-SaO2: lack of “step-up” excludes intracardiac shunt
  • PCWP: normal (reflects normal LA and LV-EDP)
  • CO: normal-decreased (at rest)
  • PVR: may be elevated

Clinical-Wells Criteria/Modified Wells Criteria [MEDLINE]

  • Criteria
    • Clinical Symptoms of DVT (Leg Swelling, Pain with Palpation): 3.0 pts
    • Other Diagnosis Less Likely than Pulmonary Embolism: 3.0 pts
    • Heart Rate >100: 1.5 pts
    • History of DVT/PE: 1.5 pts
    • Immobilization (≥3 Days) or Surgery in Previous 4 Weeks: 1.5 pts
    • Hemoptysis: 1.0 pts
    • Malignancy: 1.0 pts
  • Wells Criteria
    • High: >6 pts
    • Moderate: 2-6 pts
    • Low: <2 pts
  • Modified Wells Criteria
    • PE Likely: >4 pts
    • PE Unlikely: ≤4 pts

Diagnostic Algorithms for Acute Pulmonary Embolism [MEDLINE]

  • Christopher Study (2006): effective strategy to diagnose PE
    • Initial Modified Wells Criteria Scoring
    • Subsequent ELISA D-Dimer Testing
    • Subsequent CT Pulmonary Angiogram: for those with elevated D-dimer

Clinical Grading/Risk Stratification of Pulmonary Embolism Severity

  • Grading of CT Signs of Right Ventricular Dysfunction in Acute PE (2010) [MEDLINE]
    • Volumetric Determination of the Right Ventricular Volume/Left Ventricular Volume Ratio: most reproducible/least user-dependent of the CT measurements (as compared to septal bowing or IVC reflux) -> ratio >1.2 is suggestive of RV strain
  • Grading of Factors Associated with 30-Day Frequency of Adverse Events in Prep Study (2010) [MEDLINE]
    • Altered Mental Status: OR 6.8 (95% CI: 2.0-23.3)
    • Shock on Admission: OR 2.8 (95% CI: 1.1-7.5)
    • Cancer: OR 2.9 (95% CI: 1.2-6.9)
    • Elevated BNP: OR 1.3 for an increase of 250 ng/L (95% CI: 1.1-1.6)
    • Right Ventricular Volume/Left Ventricular Volume Ratio: OR 1.2 for an increase of 0.1 (95% CI: 1.1-1.4)
  • Grading of Low-Risk Pulmonary Embolism with Simplified Pulmonary Embolism Severity Index (sPESI) (2010) [MEDLINE]
    • Simplified Pulmonary Embolism Severity Index (sPESI): has similar prognostic accuracy and clinical utility and greater ease of use, as compared with the original PESI
  • Grading of Pulmonary Embolism Using Right Ventricular Dysfunction and Troponin Levels (2013) [MEDLINE]
    • Right Ventricular Dysfunction and Elevated Troponin Level: these criteria have an incremental prognostic value for risk stratification in hemodynamically-stable patients with acute pulmonary embolism
  • Grading of Intermediate-Risk Pulmonary Embolism Patients (2014) [MEDLINE]
    • SBP 90-100 mm Hg: 2 pts
    • Elevated Troponin: 2 pts
    • RV Dysfunction (by Echocardiogram or CT): 2 pts
    • HR ≥100 BPM: 1 pt
    • Scoring: range 0-7
      • Stage I (0-2 points)
        • 3.6% risk for in-hospital PE-related complications
        • 4.2% risk for 30-day PE-related complications
        • 1.7% 30-day PE-related mortality
      • Stage II (3-4 points)
        • 9.7% risk for in-hospital PE-related complications
        • 10.8% risk for 30-day PE-related complications
        • 5.0% 30-day PE-related mortality
      • Stage III (>4 points)
        • 28.0% risk for in-hospital PE-related complications
        • 29.2% risk for 30-day PE-related complications
        • 15.5% 30-day PE-related mortality

Clinical Manifestations

Cardiovascular Manifestations

  • Accentuated P2: occurs in 23% of cases
  • Atrial Fibrillation (AF) (see Atrial Fibrillation, [[Atrial Fibrillation]])
  • Hypotension/Cardiogenic Shock (see Hypotension, [[Hypotension]] and Cardiogenic Shock, [[Cardiogenic Shock]])): hypotension occurs in 8% of cases
  • Sinus Tachycardia (see Sinus Tachycardia, [[Sinus Tachycardia]]): occurs in 30% of cases
  • Supraventricular Tachycardia (SVT) (see Supraventricular Tachycardia, [[Supraventricular Tachycardia]])
  • S4: occurs in 24% of cases

Pulmonary Manifestations

  • Cough (see Cough, [[Cough]]): occurs in 37% of cases
  • Dyspnea (see Dyspnea, [[Dyspnea]]): occurs in 73% of cases
  • Hemoptysis (see Hemoptysis, [[Hemoptysis]]): occurs in 13% of cases
    • Physiology: due to pulmonary infarction
  • Hypocapnia with Respiratory Alkalosis (see Respiratory Alkalosis, [[Respiratory Alkalosis]])
  • Hypoxemia (see Hypoxemia, [[Hypoxemia]])
  • Pleural Rub
    • Physiology: due to pulmonary infarction
  • Pleuritic Chest Pain (see Chest Pain, [[Chest Pain]]): occurs in 66% of cases
  • Pulmonary Hypertension/Acute Cor Pulmonale (see Pulmonary Hypertension, [[Pulmonary Hypertension]])
    • Physiology: due to acute pulmonary hypertension with resulting right ventricular failure
  • Rales: occur in 51% of cases
  • Systolic/Continuous Murmur Over Lung: due to due to shunt of blood around pulmonary embolism
  • Tachypnea (see Tachypnea, [[Tachypnea]]): occurs in 70% of cases
  • Wheezing (see Obstructive Lung Disease, [[Obstructive Lung Disease]])
    • Physiology: due to platelet release of serotonin

Other Manifestations

  • Fever (see Fever, [[Fever]]): in association with pulmonary infarction

Treatment

General Goals of Anticoagulation

  • Prevention of Early Complications of Venous Thromboembolism: the benefits of anticoagulation are greatest during the initial period of anticoagulation
    • Acute Pulmonary Embolism (PE) (see Acute Pulmonary Embolism, [[Acute Pulmonary Embolism]])
    • Clot Extension: anticoagulation inhibits clot extension
    • Death: anticoagulation decreases risk of DVT recurrence and mortality rate [MEDLINE]
  • Prevention of Late Complications of Venous Thromboembolism
    • Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (see Chronic Thromboembolic Pulmonary Hypertension, [[Chronic Thromboembolic Pulmonary Hypertension]])
    • Recurrent Deep Venous Thrombosis (DVT) (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]])
      • Anticoagulation decreases risk of DVT recurrence and mortality rate [MEDLINE]
      • Anticoagulation decreases the risk of recurrence venous thromboembolism to 3.4% and risk of fatal venous thromboembolism to 0.4% [MEDLINE]
    • Post-Thrombotic (Post-Phlebitic) Syndrome (see Post-Thrombotic Syndrome, [[Post-Thrombotic Syndrome]])

Initial Treatment of Venous Thrombembolism (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

Requirements for Parenteral Anticoagulation with Specific Long-Term Anticoagulants

  • Parenteral Anticoagulation is Indicated Prior to Coumadin
    • Conversion from Parenteral Anticoagulation to Coumadin
      • Coumadin Should Be Started Concurrently with Parenteral Anticoagulation, Rather Than Waiting (Grade 2C recommendation) [MEDLINE]: start coumadin 5 mg qday (with a lower dose used in elderly or those with a high risk of bleeding, malnutrition, debility, congestive heart failure, or liver disease)
      • Coumadin Should Be Overlapped with Parenteral Anticoagulation for at Least 4-5 Days
      • Parenteral Anticoagulation Can Be Discontinued When INR Remains >2 for at Least 2 Consecutive Days
  • Parenteral Anticoagulation is Indicated Prior to Dabigatran (Pradaxa)
    • Conversion from Unfractionated Heparin Drip/Argatroban Drip to Dabigatran (Pradaxa) (see Dabigatran, [[Dabigatran]]): start dabigatran as soon as drip is stopped
    • Conversion from Low Molecular Weight Heparin (Enoxaparin, Dalteparin, Tinzaparin) or Fondaparinux to Dabigatran (Dabigatran) (see Dabigatran, [[Dabigatran]]): start dabigatran approximately 2 hrs prior to next scheduled dose of subcutaneous agent
  • Parenteral Anticoagulation is Indicated Prior to Edoxaban (Savaysa, Lixiana)
    • Conversion from Unfractionated Heparin/Argatroban Drip to Edoxaban (Savaysa, Lixiana) (see Edoxaban, [[Edoxaban]]): discontinue heparin/argatroban drip and initiate edoxaban 4 hrs later
    • Conversion from Low Molecular Weight Heparin (Enoxaparin, Dalteparin, Tinzaparin) to Edoxaban (Savaysa, Lixiana) (see Edoxaban, [[Edoxaban]]): discontinue low molecular weight heparin and initiate edoxaban at the time of the next scheduled administration of low molecular weight heparin
  • Parenteral Anticoagulation is Not Indicated Prior to Apixaban (Eliquis)/Rivaroxaban (Xarelto) (see Apixaban, [[Apixaban]] and Rivaroxaban, [[Rivaroxaban]])

Parenteral Anticoagulants

  • Argatroban (Acova) (see Argatroban, [[Argatroban]])
  • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]]): Grade 2C recommendation
  • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]])
  • Fondaparinux (Arixtra) (see Fondaparinux, [[Fondaparinux]])
  • Unfractionated Heparin (see Heparin, [[Heparin]])
  • Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]])

Risk Stratification for Anticoagulation-Associated Hemorrhage

  • Risk Factors for Anticoagulation-Associated Hemorrhage
  • Absolute Risk of Major Hemorrhage
    • Anticoagulation Duration: 0-3 mo
      • Low Risk (0 Risk Factors)
        • Baseline Risk of Hemorrhage = 0.6%
        • Increased Risk of Hemorrhage = 1.0%
        • Total Risk of Hemorrhage = 1.6%
      • Moderate Risk (1 Risk Factors)
        • Baseline Risk of Hemorrhage = 1.2%
        • Increased Risk of Hemorrhage = 2.0%
        • Total Risk of Hemorrhage = 3.2%
      • High Risk (At Least 2 Risk Factors)
        • Baseline Risk of Hemorrhage = 4.8%
        • Increased Risk of Hemorrhage = 8.0%
        • Total Risk of Hemorrhage = 12.8%
    • Anticoagulation Duration: After First 3 mo
      • Low Risk (0 Risk Factors)
        • Baseline Risk of Hemorrhage = 0.3%/year
        • Increased Risk of Hemorrhage = 0.5%/year
        • Total Risk of Hemorrhage = 0.8%/year
      • Moderate Risk (1 Risk Factors)
        • Baseline Risk of Hemorrhage = 0.6%/year
        • Increased Risk of Hemorrhage = 1.0%/year
        • Total Risk of Hemorrhage = 1.6%/year
      • High Risk (At Least 2 Risk Factors)
        • Baseline Risk of Hemorrhage = at least 2.5%/year
        • Increased Risk of Hemorrhage = at least 4.0%/year
        • Total Risk of Hemorrhage = at least 6.5%/year

Long-Term Treatment of Venous Thromboembolism without Cancer (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • First-Line Agents
    • Apixaban (Eliquis) (see Apixaban, [[Apixaban]]): Grade 2B recommendation
    • Dabigatran (Pradaxa) (see Dabigatran, [[Dabigatran]]): Grade 2B recommendation
    • Edoxaban (Savaysa, Lixiana) (see Edoxaban, [[Edoxaban]]): Grade 2B recommendation
    • Rivaroxaban (Xarelto) (see Rivaroxaban, [[Rivaroxaban]]): Grade 2B recommendation
  • Second-Line Agents
    • Coumadin (see Coumadin, [[Coumadin]]): Grade 2C recommendation
      • Recommended INR Range: 2-3 (Grade 1B recommendation) [MEDLINE]
  • Third-Line Agents: Low Molecular Weight Heparins
    • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]]): Grade 2C recommendation
    • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]]): Grade 2C recommendation
    • Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]]): Grade 2C recommendation

Long-Term Treatment of Venous Thromboembolism with Cancer (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • First-Line Agents: Low Molecular Weight Heparins
    • Dalteparin (Fragmin) (see Dalteparin, [[Dalteparin]]): Grade 2C recommendation
    • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]]): Grade 2C recommendation
    • Tinzaparin (Innohep) (see Tinzaparin, [[Tinzaparin]]): Grade 2C recommendation
  • Second-Line Agents
    • Coumadin (see Coumadin, [[Coumadin]]): Grade 2C recommendation
      • Recommended INR Range: 2-3 (Grade 1B recommendation) [MEDLINE]
    • Apixaban (Eliquis) (see Apixaban, [[Apixaban]]): Grade 2C recommendation
    • Dabigatran (Pradaxa) (see Dabigatran, [[Dabigatran]]): Grade 2C recommendation
    • Edoxaban (Savaysa, Lixiana) (see Edoxaban, [[Edoxaban]]): Grade 2C recommendation
    • Rivaroxaban (Xarelto) (see Rivaroxaban, [[Rivaroxaban]])): Grade 2C recommendation

Specific Duration of Anticoagulation (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Proximal DVT/Acute PE, Provoked by Surgery: 3 months (Grade 1B recommendation)
  • Proximal DVT/Acute PE, Provoked by Non-Surgical Transient Risk Factor: 3 months (Grade 1B recommendation)
  • Distal DVT, Unprovoked: 3 months (Grade 1B recommendation), assuming that anticoagulation is desired by the patient
  • Distal DVT, Provoked by Surgery or by a Non-Surgical Transient Risk Factor: 3 months (Grade 2C recommendation), assuming that anticoagulation is desired by the patient
  • First Unprovoked Proximal DVT/Acute PE
    • Low/Moderate Bleeding Risk (See Risk Factors for Hemorrhage Above): indefinite anticoagulation (Grade 2B recommendation)
    • High Bleeding Risk (See Risk Factors Above): 3 months (Grade 1B recommendation)
  • Second Unprovoked Proximal DVT/Acute PE
    • Low Bleeding Risk: indefinite anticoagulation (Grade 1B recommendation)
    • Moderate Bleeding Risk: indefinite anticoagulation (Grade 2B recommendation)
    • High Bleeding Risk: 3 months (Grade 2B recommendation)
  • Proximal DVT/Acute PE with Cancer
    • Low/Moderate Bleeding Risk: indefinite anticoagulation (Grade 1B recommendation)
    • High Bleeding Risk: indefinite anticoagulation (Grade 2B recommendation)

Specific Clinical Features Which May Influence the Choice of Specific Initial/Long-Term Anticoagulants (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Cancer: preferred anticoagulant(s) -> low molecular weight heparin
  • Parenteral Therapy is to Be Avoided: preferred anticoagulant(s) -> apixaban, rivaroxaban
    • Coumadin, dabigatran, and edoxaban require initial parenteral anticoagulant therapy
  • Once Daily PO Therapy is Preferred: preferred anticoagulant(s) -> edoxaban, rivaroxaban, coumadin
  • Liver Disease/Coagulopathy: preferred anticoagulant(s) -> low molecular weight heparin
    • Novel oral anticoagulants are contraindicated if INR is elevated due to liver disease
    • Coumadin is difficult to control and INR may not reflect anti-thrombotic effect in liver disease
  • Chronic Kidney Disease (CrCl <30 mL/min): preferred anticoagulant(s) -> coumadin
    • Novel oral anticoagulants and low molecular weight heparins are contraindicated with severe renal insufficiency
    • Dosing of novel oral anticoagulants are variable, dependent on the agent
    • Systematic Review/Meta-Analysis Comparing Rates of Hemorrhage of Novel Oral Anticoagulants vs Coumadin When Used in the Setting of Renal Insufficiency (2016) [MEDLINE]
      • CrCl 50-80 mL/min: novel oral anticoagulants had a significantly decreased risk of major bleeding, as compared to coumadin
      • CrCl <50 mL/min: novel oral anticoagulants had a non-significantly decreased risk of major bleeding, as compared to coumadin
      • Apixaban had the lowest rate of major bleeding in this subgroup (see Apixaban, [[Apixaban]])
  • Coronary Artery Disease (CAD): preferred anticoagulant(s) -> coumadin, apixaban, edoxaban, rivaroxaban
    • Coronary artery events occur more frequently with dabigatran than with coumadin: this is not seen with other novel oral anticoagulants
    • If possible, antiplatelet therapy (for coronary artery disease) should be avoided in patients on anticoagulants because of increased bleeding
  • Dyspepsia/Gastrointestinal Hemorrhage: preferred anticoagulant(s) -> coumadin, apixaban
    • Dabigatran increases dyspepsia
    • Dabigatran, rivaroxaban, and edoxaban may be associated with more gastrointestinal hemorrhage than coumadin
  • Poor Compliance: preferred anticoagulant(s) -> coumadin
    • INR monitoring can help to detect compliance problems
  • Thrombolytic Therapy Use: preferred anticoagulant(s) -> unfractionated heparin drip
    • There is a greater level of experience with unfractionated heparin use in patients treated with thrombolytic therapy
  • Reversal Agent Required: preferred anticoagulant(s) -> coumadin, unfractionated heparin drip, dabigatran
  • Pregnancy: preferred anticoagulant(s) -> low molecular weight heparin
    • There is a Potential for Other Agents to Cross the Placenta in Pregnancy
      • Coumadin is known to be teratogenic
  • Cost/Coverage Issues: preferred anticoagulant(s) -> variable
    • Cost-Effectiveness of Rivaroxaban Compared to Enoxaparin/Coumadin in Treatment of Venous Thrombembolism (2014): rivaroxaban cost $2,448 per-patient less and was associated with 0.0058 more QALY’s compared with enoxaparin + coumadin
    • Cost-Effectiveness of Novel Oral Anticoagulants, Compared to Coumadin, in Non-Valvular Atrial Fibrillation and Venous Thromboembolism (2015) [MEDLINE]: medical costs are reduced when novel oral anticoagulants are used instead of coumadin for the treatment of non-valvular atrial fibrillation/venous thromboembolism, with apixaban being associated with the greatest reduction in medical costs
    • UK Study of Cost-Effectiveness of Rivaroxaban Compared to Enoxaparin/Coumadin in Treatment of Venous Thrombembolism (2015) [MEDLINE]: rivaroxaban was a cost-effective choice for acute treatment of venous thromboembolism and secondary prevention of venous thromboembolism, compared with low molecular weight heparin/coumadin treatment, regardless of treatment duration

ANTICOAG PREF

Specific Treatment of Acute Pulmonary Embolism with Hypotension (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Rationale
    • Systemic Thrombolytic Therapy Accelerates Resolution of Pulmonary Embolism (with More Rapid Lowering of Pulmonary Artery Pressure, Improved Hypoxemia, and Resolution of Perfusion Scan Defects): however, systemic thrombolytic therapy also increases the risk of hemorrhage
    • Catheter-Directed Thrombolysis Uses Approximately 33% of the Dose of Thrombolytic That Systemic Thrombolysis Uses: effectively lowering bleeding risk
      • Catheter-Directed Thrombolysis Achieves Higher Local Concentrations of Thrombolytics at the Site of the PE and Also Facilitates Thrombus Fragmentation and Permeability Via the Catheter
  • Agents
    • Alteplase (Activase) (see Alteplase, [[Alteplase]])
  • Major Contraindications to Systemic Thrombolytic Therapy
    • Active Bleeding
    • Bleeding Diathesis
    • Diabetic Retinopathy
    • History of Intracranial Hemorrhage
    • History of Ischemic CVA <3 mo Ago
    • Recent Brain/Spinal Surgery
    • Recent Head Trauma with Fracture/Traumatic Brain Injury
    • Structural Intracranial Disease
  • Relative Contraindications to Systemic Thrombolytic Therapy
    • Age >75 y/o
    • Anticoagulation: coumadin, etc
    • Black Race
    • Diastolic BP >110
    • Female Sex
    • History of Ischemic CVA >3 mo Ago
    • Low Body Weight
    • Pericarditis/Pericardial Effusion
    • Pregnancy
    • Recent Invasive Procedure
    • Recent Non-Intracranial Hemorrhage
    • Recent Surgery
    • Systolic BP >180
    • Traumatic Cardiopulmonary Resuscitation
  • Clinical Efficacy
    • Meta-Analysis of Thrombolyis in Acute PE (2014) [MEDLINE]: meta-analysis (16 trials, n = 2115)
      • Thrombolysis decreased mortality rate (2.17%), as compared to anticoagulation alone (3.89%)
        • No mortality benefit was observed in patients >65 y/o, a population in whom the risk of hemorrhage was greatest
      • Thrombolysis decreased the risk of recurrent PE (1.17%) as compared to anticoagulation alone (3.04%)
      • Thrombolysis increased the risk of major hemorrhage (9.2%), as compared to anticoagulation alone (3.4%)
        • No significant difference in major hemorrhage in patients 65 y/o and younger
      • Thrombolysis increased the risk of intracranial hemorrhage (1.5%), as compared to anticoagulation alone (0.2%)
    • PEITHO Trial (2014) [MEDLINE]: RCT of tenecteplase (n = 1006), intention-to-treat analysis in normotensive, intermediate-risk PE patients
      • Thrombolysis decreased hemodynamic decompensation (2.6%), as compared to placebo group (5.6%)
      • No difference in 30-day mortality rate
      • Thrombolysis increased risk of major hemorrhage and stroke
  • Recommendations
    • Systemic Thrombolytics are Indicated for Acute PE with Hypotension (Grade 2B recommendation)
    • Systemic Thrombolytic Therapy is Recommended Over Catheter-Directed Thrombolysis for Acute PE with Hypotension (Grade 2C recommendation): however, the bleeding risk may indicate catheter-directed thrombolysis in centers where local expertise is present
    • Systemic Thrombolytic Therapy Can Also Be Considered in Patient Who Deteriorates After Starting Anticoagulation (Significant Hypoxemia, Poor Tissue Perfusion, etc), But Who Has Not Developed Hypotension Yet

Specific Treatment of Acute Subsegmental Pulmonary Embolism (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

Rationale/Background

  • Improvements in CT Angiography Have Led Increased Diagnosis of Subsegmental PE’s: subsegmental PE’s have increased from approximately 5% to more than 10% of all detected PE’s
  • Due to Small Size of Subsegmental PE’s, They are More Likely to Be a False-Positive Finding than a PE in the Segmental/More Proximal Pulmonary Arteries
    • Subsgmental PE is more likely to be a real finding if the CT pulmonary angiogram is of high quality with good opacification of the distal pulmonary arteries, there are multiple intraluminal defects, defects involve more proximal (larger) subsegmental arteries, defects are seen on more than one image, defects are surrounded by contrast rather than adherent to pulmonary artery walls, defects are seen on more than one projection, patient is symptomatic (as opposed to PE being an incidental finding), there is a high clinical pretest probability for PE, and/or D-dimer level is elevated without other explanation
  • Since a True Subsegmental PE is Likely to Have Arisen From a Small DVT, the Risk of Progressive or Recurrent VTE Without Anticoagulation is Expected to Be Lower Than in Patients with a Larger PE

Recommendations

  • Subsegmental Acute Pulmonary Embolism + No Proximal DVT + Low Risk of Recurrent Venous Thrombembolism: clinical surveillance (with serial LE Dopplers, etc) is recommended over anticoagulation (Grade 2C recommendation)
    • Factors Associated with Low Risk of Recurrent Venous Thromboembolism
      • Absence of Active Cancer
      • Normal Mobility
      • Outpatient Status
      • Presence of Reversible Risk Factor for Venous Thromboembolism (Recent Surgery, etc)
    • Presence of High Risk of Bleeding May Favor Clinical Surveillance Strategy Over Anticoagulation
  • Subsegmental Acute Pulmonary Embolism + No Proximal DVT + High Risk of Recurrent Venous Thrombembolism: anticoagulation is recommended over clinical surveillance (Grade 2C recommendation)
    • Factors Associated with High Risk of Recurrent Venous Thromboembolism
      • Active Cancer (Especially if Metastatic or on Chemotherapy)
      • Decreased Mobility
      • Hospitalization
      • Absence of Reversible Risk Factor for Venous Thromboembolism (Recent Surgery, etc)
    • Presence of Low Cardiopulmonary Reserve May Favor Anticoagulation Over Surveillance Strategy

Specific Treatment of Low-Risk Acute Pulmonary Embolism (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Criteria for Outpatient Treatment of Acute PE (or Early Discharge to Home)
    • Clinically Stable with Good Cardiopulmonary Reserve
    • No Specific Contraindications, Such as Recent Bleeding, Severe Renal Disease, Severe Liver Disease, or Severe Thrombocytopenia (Platelets <70k)
    • Patient is Expected to be Compliant with Treatment
    • Patient Feels Well Enough to be Treated at Home
  • Other Criteria-Pulmonary Embolism Severity Index (PESI): score <85
  • Other Criteria-Simplified Pulmonary Embolism Severity Index (Simplified PESI): score 0
  • Other Factors Which Might Merit Inpatient Treatment Instead of Outpatient Treatment
    • Increased Cardiac Biomarker Levels
    • Presence of Right Ventricular Dysfunction
  • Recommendations
    • Low Risk PE Patients May Be Treated at Home or Discharged Early (Such as After the First 5 Days of Treatment)

Specific Treatment of Recurrent Venous Thromboembolism While on Anticoagulation (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Rationale
    • Risk of Recurrent Venous Thromboembolism Decreases Rapidly After Starting Anticoagulation: based on this, a recurrence soon after therapy can generally be managed by increasing the intensity of anticoagulation
  • Risk Factors for Recurrent Venous Thromboembolism
  • Recommendations
    • Treatment of Recurrent Venous Thromboembolism on a Non-Low Molecular Weight Heparin (Coumadin or Oral Agent): switch to low molecular weight heparin is recommended, at least temporarily (Grade 2C recommendation)
    • Treatment of Recurrent Venous Thromboembolism on a Low Molecular Weight Heparin: higher dose of low molecular weight heparin (by 25-33%) is recommended (Grade 2C recommendation)

Specific Use of Aspirin for Extended Treatment of Venous Thromboembolism (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Unprovoked Proximal DVT/Acute PE: when anticoagulation is stopped, aspirin is recommended (if there is no contraindication) to decrease recurrence risk of venous thromboembolism
    • Note: aspirin is far less effective than anticoagulation and is therefore, not a substitute for anticoagulation

Inferior Vena Cava (IVC) Filter Placement (see Inferior Vena Cava Filter, [[Inferior Vena Cava Filter]])

  • Historical Perspective: IVC filter use in the management of venous thromboembolism has increased over the last few decades [MEDLINE] [MEDLINE]
  • Indications for Inferior Vena Cava Filter
    • Absolute Contraindication to Anticoagulation
      • Active Hemorrhage
      • Fall Risk: particularly in older patient
      • History of Intracranial Hemorrhage
      • Major Trauma
      • Recent or Planned Emergency Surgery/Procedure
      • Severe Coagulopathy (see Coagulopathy, [[Coagulopathy]])
      • Severe or Uncontrolled Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])
      • Severe Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]]): platelet count <50k
      • Unstable Aortic Dissection (see Aortic Dissection, [[Aortic Dissection]])
    • Relative Contraindication to Anticoagulation
      • Intracranial/Spinal Tumor
      • Large Abdominal Aortic Aneurysm with Severe Hypertension (see Abdominal Aortic Aneurysm, [[Abdominal Aortic Aneurysm]])
      • Mild or Controlled Gastrointestinal Hemorrhage (see Gastrointestinal Hemorrhage, [[Gastrointestinal Hemorrhage]])
      • Mild-Moderate Thrombocytopenia (see Thrombocytopenia, [[Thrombocytopenia]]): platelet count <150k
      • Stable Aortic Dissection (see Aortic Dissection, [[Aortic Dissection]])
    • Complication of Anticoagulation
      • Anticoagulation Failure: objectively documented extension of existing DVT (or new DVT) or PE while therapeutically anticoagulated
      • Coumadin Skin Necrosis (see Coumadin, [[Coumadin]])
      • Drug Reaction
      • Hemorrhage (Major or Minor)
      • Heparin-Induced Thrombocytopenia (HIT) (see Heparin-Induced Thrombocytopenia, [[Heparin-Induced Thrombocytopenia]])
      • Poor Compliance with Anticoagulation Regimen
    • Failure of Previous Device to Prevent Pulmonary Embolism: central extension of thrombus through an existing filter or recurrent PE
    • In Association with Thrombectomy, Embolectomy, or Lytic Therapy
    • Prophylaxis with No Thromboembolic Disease
    • Prophylaxis with Thromboembolism in Addition to Anticoagulation
  • Technique
    • Filter Positioning: IVC filters are typically placed infrarenally, since suprarenal filters may lead to renal vein compromise, if they become clotted
    • Retrievable Inferior Vena Cava Filters: may remain in place for approximately 2 mo
    • There is No Data to Support One IVC Filter Brand Over Another
  • Clinical Efficacy
    • Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group (PREPIC) Trial (NEJM, 1998) [MEDLINE]
      • At 2 years, IVC filter had no impact on the rate of symptomatic PE or mortality rate
      • However, IVC filter placement increased the rate of recurrent DVT
    • Randomized, Open-Label PREPIC2 Trial of IVC Filter Added to Anticoagulation in Severe Acute PE Requiring Hospitalization (JAMA, 2015) [MEDLINE]: retrievable IVC filter had no clinical benefit over anticoagulation alone (in terms of decreasing the risk of recurrent PE at 3/6 months or 3-month/6-month mortality rate)
      • Based on these data, IVC filter is not indicated in anticoagulated acute PE patients on the basis of poor cardiopulmonary reserve, large clot burden, or suspected risk of recurrence
    • Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines [MEDLINE]: for patients with venous thromboembolism treated with anticoagulation, IVC filter placement is not recommended

Specific Treatment of Lower Extremity Deep Venous Thrombosis

Ambulation

  • Ambulation is Indicated as Soon as Possible (Despite the Theoretical Risk for Embolization): usually a gradual increase in ambulation is advisable
    • Ambulation has not been shown to increase the risk of fatal pulmonary embolism

Graduated Compression Stockings (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Rationale: may provide symtomatic relief and facilitate ambulation
    • Theoretical goal of therapy is the prevention of post-phlebitic syndrome (although data are conflicting as to their efficacy in this regard)
  • Contraindications
    • Allergy to the Stocking Material
    • Inability to Apply Stockings
    • Severe Arterial Insufficiency
    • Skin Ulceration
  • Recommendations
    • Graduated Compression Stockings are Not Recommended in Acute DVT to Prevent Post-Thrombotic Syndrome (Grade 2B recommendation): however they may be used for patients with acute/chronic DVT symptoms

Catheter-Directed Thrombolysis of Acute Lower Extremity Deep Venous Thrombosis (see Deep Venous Thrombosis, [[Deep Venous Thrombosis]]) (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Rationale
    • Retrospective Analysis of Catheter-Directed Thrombolysis for Lower Extremity DVT (JAMA Int Med, 2014) [MEDLINE]
      • Catheter-Directed Thrombolysis of Lower Extremity DVT is Associated with 2x-Increased Risk of Transfusion, 3x-Increased Risk of Intracranial Hemorrhage, 1.5x-Increased Risk of Acute PE, and 2x-Increased Risk of IVC Filter Insertion: long-term outcomes were not reported
  • Indications (Patients Most Likely to Benefit from Catheter-Directed Thrombolysis of Lower Extremity DVT)
    • Failure of Anticoagulation
    • Good Functional Status
    • Iliofemoral DVT/Phlegmasia Cerulea Dolens
    • Life Expectancy of At Least 1 Year
    • Low Risk of Hemorrhage
    • Symptoms for <14 Days
  • Recommendations
    • Anticoagulation is Recommended Over Catheter-Directed Thrombolysis for Lower Extremity DVT (Grade 2C recommendation)
      • Patients who put a high value on the prevention of post-thrombotic (post-phlebitic) syndrome and lower value on initial complexity, cost, and risk of bleeding may choose catheter-directed thrombolysis (see Post-Thrombotic Syndrome, [[Post-Thrombotic Syndrome]])

Treatment of Isolated Distal (Calf) Deep Venous Thrombosis (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Rationale: approximately 15% of untreated distal DVT’s will ultimately extend proximally into the popliteal vein and may cause acute PE [MEDLINE]
  • Isolated Distal DVT without Severe Symptoms or Risk Factors for Extension: serial LE Dopplers x 2 wks are recommended (Grade 2C recommendation)
    • During Surveillance
      • Thrombus Extends within the Distal Veins -> Anticoagulation is Suggested (Grade 2C recommendation)
      • Thrombus Extends into the Proximal Veins -> Anticoagulation is Recommended (Grade 1B recommendation)
  • Isolated Distal DVT with Severe Symptoms or Risk Factors for Extension: anticoagulation is recommended (Grade 2C recommendation)
    • Risk Factors for Extension of Distal DVT
      • Active Cancer
      • Extensive Thrombosis: >5 cm in length, involving multiple veins, >7 mm in maximum diameter
      • History of Venous Thromboembolism
      • Inpatient Status
      • No Reversible Provoking Factor for DVT
      • Positive D-Dimer: particularly when markedly elevated without an alternative reason
      • Thrombosis Close to Proximal Veins: thrombosis confined to the muscular veins of the calf (soleus, gastrocnemius) has a lower risk of extension than thrombosis that involves the axial (true deep: peroneal, tibial) veins

Specific Treatment of Upper Extremity Deep Venous Thrombosis

General Treatment

  • Recommendations Chest Antithrombotic Therapy and Prevention of Thrombosis 2012 Guidelines) [MEDLINE]
    • Anticoagulation is Recommended for Upper Extremity Deep Venous Thrombosis Involving the Axillary or More Proximal Veins
    • xxxx

Catheter-Directed Thrombolysis of Upper Extremity Deep Venous Thrombosis Which Involves Axillary or More Proximal Veins (Chest Antithrombotic Therapy for VTE Disease 2016 Guidelines) [MEDLINE]

  • Indications (Patients Most Likely to Benefit from Catheter-Directed Thrombolysis of Upper Extremity DVT)
    • Good Functional Status
    • Life Expectancy of at Least 1 Year
    • Low Risk of Hemorrhage
    • Severe Symptoms
    • Symptoms for <14 Days
    • Thrombus Involving Most of the Axillary and Subclavian Vein
  • Recommendations
    • Anticoagulation is Recommended Over Catheter-Directed Thrombolysis in Upper Extremity Deep Venous Thrombosis (Grade 2C recommendation)
    • In Patients Who Undergo Catheter-Directed Thrombolysis of Upper Extremity Deep Venous Thrombosis, the Same Intensity/Duration of Anticoagulation is Recommended as in Those Who Do Not Undergo Thrombolysis (Grade 1B recommendation)

Prognosis

  • Mortality Rate: <10% of all PE’s result in death
    • 90% of deaths due to PE occur within the first 1-2 hrs
  • Contribution of Pulmonary Embolism to US Death Rate [MEDLINE]: PE’s account for 100k deaths per year in the US
    • Deaths from Acute PE are Declining [MEDLINE]

References

General

  • Anticoagulant drugs in the treatment of pulmonary embolism. A controlled trial. Lancet. 1960 Jun 18;1(7138):1309-12 [MEDLINE]
  • Source of non-lethal pulmonary emboli. Lancet. 1974 Feb 16;1(7851):258-9 [MEDLINE]
  • Deep vein thrombosis and pulmonary embolism. An autopsy study with multiple regression analysis of possible risk factors. Acta Chir Scand Suppl. 1977;478:1-120 [MEDLINE]
  • Genetic risk factors for superficial vein thrombosis. Thromb Haemost. 1999;82(4):1215 [MEDLINE]
  • A prospective study of venous thromboembolism after major trauma. N Engl J Med 1994; 331:1601–1606 [MEDLINE]
  • A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7):409 [MEDLINE]
  • Vena caval filters: a comprehensive review. Blood. 2000;95(12):3669 [MEDLINE]
  • Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty. N Engl J Med. 2000;343(24):1758 [MEDLINE]
  • Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet. 2001;358(9275):9 [MEDLINE]
  • Deep vein thrombosis and its prevention in critically ill adults. Arch Intern Med 2001;161:1268–1279 [MEDLINE]
  • Pulmonary embolism mortality in the United States, 1979-1998: an analysis using multiple-cause mortality data. Arch Intern Med. 2003;163(14):1711 [MEDLINE]
  • Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005; 172:1041-1046 [MEDLINE]
  • Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med. 2005 Jul;33(7):1565-71 [MEDLINE]
  • Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006;295(2):172 [MEDLINE]
  • Comparative study on risk factors and early outcome of symptomatic distal versus proximal deep vein thrombosis: results from the OPTIMEV study. Thromb Haemost. 2009 Sep;102(3):493-500. doi: 10.1160/TH09-01-0053 [MEDLINE]
  • RIETE Investigators. Simplification of the pulmonary embolism severity index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med 2010; 170: 1383–1389 [MEDLINE]
  • Coagulopathy does not protect against venous thromboembolism in hospitalized patients with chronic liver disease. Chest. 2010;137(5):1145 [MEDLINE]
  • Gadolinium-enhanced magnetic resonance angiography for pulmonary embolism. A multicenter prospective study (PIOPED III). Ann Intern Med 2010;152:434-443 [MEDLINE]
  • Reproducibility of CT signs of right ventricular dysfunction in acute pulmonary embolism. AJR Am J Roentgenol 2010; 194:1500-1506 [MEDLINE]
  • Prognostic factors for pulmonary embolism: the PREP study, a prospective multicenter cohort study. Am J Respir Crit Care Med 2010; 181:168-173 [MEDLINE]
  • Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med. 2010 May 4;152(9):578-89. doi: 10.7326/0003-4819-152-9-201005040-00008 [MEDLINE]
  • Deep vein thrombosis: a clinical review. J Blood Med. 2011; 2: 59–69 [MEDLINE]
  • Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med. 2011;171(9):831 [MEDLINE]
  • Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants’ data from seven trials. BMJ. 2011 May 24;342:d3036. doi: 10.1136/bmj.d3036 [MEDLINE]
  • Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):7S-47S. doi: 10.1378/chest.1412S3 [MEDLINE]
  • Impact of vena cava filters on in-hospital case fatality rate from pulmonary embolism. Am J Med. 2012 May;125(5):478-84. Epub 2012 Feb 4 [MEDLINE]
  • Factors in the technical quality of gadolinium enhanced magnetic resonance angiography for pulmonary embolism in PIOPED III. Int J Cardiovasc Imaging. 2012 Feb;28(2):303-12. doi: 10.1007/s10554-011-9820-7. Epub 2011 Feb 24 [MEDLINE]
  • A meta-analysis of anticoagulation for calf deep venous thrombosis. J Vasc Surg. 2012 Jul;56(1):228-37.e1; discussion 236-7. doi: 10.1016/j.jvs.2011.09.087. Epub 2011 Dec 29 [MEDLINE]
  • Use of Glucocorticoids and Risk of Venous Thromboembolism: A Nationwide Population-Based Case-Control Study. JAMA Intern Med. 2013 Apr 1:1-1 [MEDLINE]
  • Acute pulmonary embolism: external validation of an integrated risk stratification model. Chest 2013 Jun 13. doi: 10.1378/chest.12-2938 [MEDLINE]
  • Identification of intermediate-risk patients with acute symptomatic pulmonary embolism. Eur Respir J. 2014 Sep;44(3):694-703. doi: 10.1183/09031936.00006114. Epub 2014 Apr 2 [MEDLINE]
  • Vena cava filters in unstable elderly patients with acute pulmonary embolism. Am J Med. 2014 Mar;127(3):222-5. Epub 2013 Nov 23 [MEDLINE]
  • Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism: a systematic review and meta-analysis. Rheumatology (Oxford). 2015 Apr;54(4):736-42. doi: 10.1093/rheumatology/keu408. Epub 2014 Sep 24 [MEDLINE]
  • Diagnostic prediction models for suspected pulmonary embolism: systematic review and independent external validation in primary care. BMJ. 2015;351:h4438 [MEDLINE]
  • Trends in incidence versus case fatality rates of pulmonary embolism: Good news or bad news? Thromb Haemost. 2016 Jan;115(2):233-5. Epub 2015 Dec 03 [MEDLINE]

DVT Prophylaxis

  • Cost-effectiveness of ultrasound in preventing femoral venous catheter-associated pulmonary embolism. Am J Respir Crit Care Med 2003;168:1481–1487 [MEDLINE]
  • Efficacy of deep venous thrombosis prophylaxis in the medical intensive care unit. J Intensive Care Med. 2006 Nov-Dec;21(6):352-8 [MEDLINE]
  • Intermittent pneumatic compression or graduated compression stockings for deep vein thrombosis prophylaxis? A systematic review of direct clinical comparisons. Ann Surg. 2010 Mar;251(3):393-6. doi: 10.1097/SLA.0b013e3181b5d61c [MEDLINE]
  • PROTECT Trial: Dalteparin versus unfractionated heparin in critically ill patients. N Engl J Med. 2011 Apr 7;364(14):1305-14. doi: 10.1056/NEJMoa1014475 [MEDLINE]
  • Screening and prevention of venous thromboembolism in critically ill patients: a decision analysis and economic evaluation. Am J Respir Crit Care Med. 2011 Dec 1;184(11):1289-98. doi: 10.1164/rccm.201106-1059OC [MEDLINE]
  • LIFENOX: Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med. 2011 Dec 29;365(26):2463-72. doi: 10.1056/NEJMoa1111288 [MEDLINE]
  • Unfractionated heparin versus low molecular weight heparin for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Rev. 2012 Sep 12;9:CD007557. doi: 10.1002/14651858.CD007557.pub2 [MEDLINE]
  • DVT Surveillance Program in the ICU: Analysis of Cost-Effectiveness. PLoS One. 2014 Sep 30;9(9):e106793. doi: 10.1371/journal.pone.0106793. eCollection 2014 [MEDLINE]
  • Cost-effectiveness of Dalteparin vs Unfractionated Heparin for the Prevention of Venous Thromboembolism in Critically Ill Patients. JAMA. 2014 Nov 1. doi: 10.1001/jama.2014.15101 [MEDLINE]

Upper Extremity DVT

  • The long term clinical course of acute deep vein thrombosis of the arm: prospective cohort study. BMJ. 2004;329:484-5 [MEDLINE]
  • Upper extremity DVT in oncological patients: analysis of risk factors. Data from the RIETE registry. Exp Oncol. 2006;28:245-7
  • Upper extremity deep venous thrombosis. Semin Thromb Hemost. 2006;32:729-36 [MEDLINE]
  • Current perspective of venous thrombosis in the upper extremity. J Thromb Haemost. 2008;6:1262-6 [MEDLINE]
  • Accuracy of diagnostic tests for clinically suspected upper extremity deep vein thrombosis: a systematic review. J Thromb Haemost. 2010;8:684-92 [MEDLINE]
  • Safety and feasibility of a diagnostic algorithm combining clinical probability, d-dimer testing, and ultrasonography for suspected upper extremity deep venous thrombosis: a prospective management study. Ann Intern Med. 2014 Apr 1;160(7):451-7. doi: 10.7326/M13-2056 [MEDLINE]

Treatment

General Treatment

  • Use of Glucocorticoids and Risk of Venous Thromboembolism: A Nationwide Population-Based Case-Control Study. JAMA Intern Med. 2013 Apr 1:1-1 [MEDLINE]
  • Cost-effectiveness of rivaroxaban compared with enoxaparin plus a vitamin K antagonist for the treatment of venous thromboembolism. J Med Econ. 2014 Jan;17(1):52-64. doi: 10.3111/13696998.2013.858634. Epub 2013 Nov 14 [MEDLINE]
  • Comparison of differences in medical costs when new oral anticoagulants are used for the treatment of patients with non-valvular atrial fibrillation and venous thromboembolism vs warfarin or placebo in the US. J Med Econ. 2015 Jun;18(6):399-409. doi: 10.3111/13696998.2015.1007210. Epub 2015 Feb 9 [MEDLINE]
  • Cost-effectiveness analysis of treatment of venous thromboembolism with rivaroxaban compared with combined low molecular weight heparin/vitamin K antagonist. Thromb J. 2015 Jun 11;13:20. doi: 10.1186/s12959-015-0051-3. eCollection 2015 [MEDLINE]
  • Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-52. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7 [MEDLINE]
  • Major Bleeding and Hemorrhagic Stroke with Direct Oral Anticoagulants in Patients with Renal Failure: Systematic Review and Meta-Analysis of Randomized Trials. Chest. 2016,(): doi:10.1016/j.chest.2015.12.029 [MEDLINE]

Inferior Vena Cava Filter

  • A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep vein thrombosis: Prévention du Risque d’Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med. 1998;338(7):409-415 [MEDLINE]
  • PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation. 2005;112(3):416-422 [MEDLINE]
  • A population-based study of inferior vena cava filters in patients with acute venous thromboembolism. Arch Intern Med. 2010;170(16): 1456-1462 [MEDLINE]
  • Increasing use of vena cava filters for prevention of pulmonary embolism. Am J Med. 2011;124(7):655-661 [MEDLINE]
  • PREPIC2 Trial. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015 Apr 28;313(16):1627-35. doi: 10.1001/jama.2015.3780 [MEDLINE]

Embolectomy

  • Pulmonary embolectomy: a 20-year experience at one center. Ann Thorac Surg 1991; 51:232-236
  • Medical compared with surgical treatment for massive pulmonary embolism. Lancet 1994; 343:565-577

Thrombolytics

  • Urokinase pulmonary embolism trial. A national cooperative study. Circulation 1973; 47,48 (suppl 2):1-108
  • Alteplase versus heparin in acute pulmonary embolism: randomized trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993; 34:507-511
  • Thrombolytic therapy for pulmonary embolism. Cochrane Database System Rev. 2009;(3): CD004437 [MEDLINE]
  • Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014 Jun 18;311(23):2414-21. doi: 10.1001/jama.2014.5990 [MEDLINE]
  • PEITHO Trial: Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097 [MEDLINE]
  • Systematic review and meta-analysis for thrombolysis treatment in patients with acute submassive pulmonary embolism. Patient Prefer Adherence. 2014;8:275-282 [MEDLINE]
  • Comparative outcomes of catheter-directed thrombolysis plus anticoagulation vs anticoagulation alone to treat lower-extremity proximal deep vein thrombosis. JAMA Intern Med. 2014;174(9):1494-1501 [MEDLINE]
  • Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2015 Sep 30;9:CD004437. doi: 10.1002/14651858.CD004437.pub4 [MEDLINE]
  • Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016 Feb;149(2):315-52. doi: 10.1016/j.chest.2015.11.026. Epub 2016 Jan 7 [MEDLINE]