Pulmonary embolism resident survival guide
For pulmonary embolism prevention resident survival guide click here.
Editor(s)-In-Chief: The APEX Trial Investigators, C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Rim Halaby, M.D. [2]; Pratik Bahekar, MBBS [3]; Chetan Lokhande, M.B.B.S [4]
Pulmonary embolism Resident Survival Guide Microchapters |
---|
Overview |
Causes |
FIRE |
Diagnosis |
Long term treatment |
Do's |
Overview
Pulmonary embolism (PE) is the acute obstruction of the pulmonary artery or one of its branches by a thrombus, air, tumor, or fat. Most often, PE is due to a venous thrombus which has been dislodged from its site of formation in the deep veins of the lower extremities, a process referred to as venous thromboembolism. PE is a potentially lethal condition. The patient can present with a range of signs and symptoms; however, the typical presentation is characterized by dyspnea (78-81% of the cases), pleuritic chest pain (39-56% of the cases), and/or syncope (22-26% of the cases).[1] The diagnostic approach of PE depends on whether the patient is a high-risk patient due to the presence of hypotension and/or shock or a non-high risk patient, as well as on the pre-test probability of this disease. While fibrinolytic therapy is the treatment of choice for patients with massive PE, patients with non-massive PE are treated with anticoagulation therapy.[2]
Causes
Life Threatening Causes
Pulmonary embolism is a life-threatening condition and must be treated as such irrespective of the underlying cause.
Common Causes
- Blood clot (most common cause)
- Air bubble
- Fragment of a tumor
- Fragment of fat (secondary to bone fracture)
- Amniotic fluid
Classification
Massive Pulmonary Embolism
Massive pulmonary embolism falls under the category "high risk patients" in the European guidelines. High risk PE patients have a risk of PE-related early mortality of > 15%.[3]
Massive PE is characterized by the presence of:
- Sustained hypotension (systolic blood pressure <90 mm Hg) not due to arrhythmia, hypovolemia, sepsis, or left ventricular dysfunction, that is either lasting for at least 15 minutes or necessitating the administration of inotropes
OR
OR
- Persistent profound bradycardia (heart rate < 40 bpm) plus findings of shock[4]
Submassive Pulmonary Embolism
Submassive pulmonary embolism falls under the category "intermediate risk patients" in the European guidelines. Intermediate risk PE patients have a risk of PE-related early mortality ranging between 3 and 15%.[3]
Submassive PE is characterized by:
AND
- Absence of systemic hypotension (systolic blood pressure >90 mm Hg)[4][5]
Right Ventricular Dysfunction
Right ventricular (RV) dysfunction is characterized by the presence of AT LEAST ONE of the following:[4][5]
- Echocardiography findings:
- RV dilation (ratio of apical 4-chamber RV diameter to left ventricle (LV) diameter > 0.9)
- RV systolic dysfunction
- CT findings: RV dilation (ratio of 4-chamber RV diameter to LV diameter > 0.9)
- BNP > 90 pg/mL
- N-terminal pro-BNP >500 pg/mL
- EKG findings:
- New complete or incomplete right bundle-branch block
- Anteroseptal ST elevation or ST depression
- Anteroseptal T-wave inversion
Myocardial Necrosis
Myocardial necrosisis defined as the presence of:[4][5]
- Elevation of troponin I (>0.4 ng/mL)
OR
- Elevation of troponin T (>0.1 ng/mL)
Low-Risk Pulmonary Embolism
Low risk PE patients have a risk of PE-related early mortality of <1%.[3] Low risk PE is characterized by the absence of hypotension, shock, RV dysfunction, and myocardial necrosis.[4]
FIRE: Focused Initial Rapid Evaluation
A Focused Initial Rapid Evaluation (FIRE) should be performed to identify patients in need of immediate intervention.[3][4][2]
Abbreviations: CT: Computed tomography; IV: Intravenous; IVC: Inferior vena cava; PE: Pulmonary embolism; PERC: PE Rule-Out Criteria; RV: Right ventricle; SC: Subcutaneous; VKA: Vitamin K antagonist
Step 1: Confirm PE
Identify cardinal findings that increase the pretest probability of PE ❑ Dyspnea ❑ Pleuritic chest pain ❑ Syncope ❑ Tachycardia ❑ Tachypnea | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Does the patient who is suspected to have PE have hypotension or shock? | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Yes | No | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Suspected high-risk PE | Suspected non-high risk PE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
❑ Administer parenteral anticoagulation (in case there are no contraindications) during the diagnostic workup | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Is a CT available immediately? | What is the pretest probability of PE? | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No | Yes | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
❑ Order Echocardiography | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Does the patient have RV overload? | Low pretest probability | Intermediate pretest probability | High pretest probability OR PE is likely | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
❑ Administer parenteral anticoagulation (in case there are no contraindications) during the diagnostic workup | ❑ Administer anticoagulation (in case there are no contraindications) during the diagnostic workup | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No | Yes | ❑ Order CT | ❑ Order D-dimer | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Positive | Negative | Positive | Negative | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Is the patient unstable OR no other tests are available? | Is the patient stabilized AND CT is now available? | ❑ Order CT | PE is excluded | ❑ Order CT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Positive | Negative | Positive | Negative | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
PE is excluded | ❑ Consider thrombolytic therapy OR ❑ Embolectomy | ❑ Order CT | PE is confirmed | PE is excluded | PE is confirmed | PE is excluded | PE is confirmed | PE is excluded | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Positive for PE | Negative for PE | Click here for the initial treatment | Click here for the initial treatment | Click here for the initial treatment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
PE is confirmed | PE is excluded | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Click here for the initial treatment | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment of the Pretest Probability of PE
The assessment of the pretest probability of PE can be achieved through scoring systems. The most commonly used score is the Wells score. Other scores, such as Geneva score and PERC can also be used.
Wells Score
The Wells score is a simple, commonly used clinical risk prediction tool to evaluate the need for further testing in patients suspected to have pulmonary embolism.[6][7][8][9]
Calculation of Wells Score
Pulmonary embolism Wells Score Calculator
Variable | Wells Score[8] |
Clinically suspected DVT (leg swelling, pain with palpation) | 3.0 |
Alternative diagnosis is less likely than PE | 3.0 |
Immobilization/surgery in previous four weeks | 1.5 |
Previous history of DVT or PE | 1.5 |
Tachycardia (heart rate more than 100 bpm) | 1.5 |
Malignancy (treatment for within 6 months, palliative) | 1.0 |
Hemoptysis | 1.0 |
Interpretation of Wells Score
Wells Criteria
Shown below is the pretest probability of PE according to Wells criteria.[8][9][10]
- Score >6.0: High probability (Rate of PE: ~66.7%)
- Score 2.0 to 6.0: Moderate probability (Rate of PE: ~20.5%)
- Score <2.0: Low probability (Rate of PE: ~3.6%)
Modified Wells Criteria
Shown below is the pretest probability of PE according to the modified Wells Criteria.[8][9][10][11]
- Score > 4: PE likely (Rate of PE: ~40.7%)
- Score 4 or less: PE unlikely (Rate of PE: ~7.8%)
Step 2: Initial Treatment
Assess the severity of pulmonary embolism | |||||||||||||||||||||||||||||||||||||||||||||||||
Massive PE (also known as high-risk PE) Cardiogenic shock OR Persistent hypotension (≤90mmHg) OR Drop of the blood pressure by ≥ 40mmHg for > 15 min[12] OR Pulselessness OR Profound bradycardia (<40 bpm) with findings of shock[4] | Submassive PE (also know as intermediate-risk PE) Right ventricular dysfunction AND/OR Myocardial injury (Troponin +) | Low-risk PE No cardiogenic shock AND No hypotension AND No right ventricular dysfunction AND No myocardial injury (Troponin -) | |||||||||||||||||||||||||||||||||||||||||||||||
Provide hemodynamic and respiratory support ❑ Begin high dose unfractionated heparin[12]
❑ Administer rapidly 500-1000 mL of normal saline (caution with fluid overload)[12] | |||||||||||||||||||||||||||||||||||||||||||||||||
Is there any contraindication to fibrinolytic therapy? | Is there any contraindication for anticoagulation therapy? | Is there any contraindication for anticoagulation therapy? | |||||||||||||||||||||||||||||||||||||||||||||||
NO | YES | NO | YES | NO | YES | ||||||||||||||||||||||||||||||||||||||||||||
❑ Discontinue unfractionated heparin AND ❑ Begin fibrinolytic therapy | ❑ Surgical pulmonary embolectomy OR ❑ Percutaneous catheter embolectomy | ❑ Anticoagulation therapy AND ❑ Hospital admission | ❑ IVC filter AND ❑ Hospital admission | ❑ Anticoagulation therapy AND ❑ Early discharge/home treatment | ❑ IVC filter AND ❑ Early discharge/home treatment | ||||||||||||||||||||||||||||||||||||||||||||
Does the patient fail to improve OR Develop cardiogenic shock OR Develop hypotension? | Does the patient fail to improve OR Develop cardiogenic shock OR Develop hypotension (<90 mmHg) OR Develop respiratory distress (SaO2<95% with Borg score>8 or altered mental status) OR Have moderate to severe RV dysfunction (RV hypokinesis or estimated RVSP>40 mmHg) OR Have elevated biomarkers (troponin> upper limit of normal, BNP>100 pg/mL, or pro-BNP>900 pg/mL)?[4] | ||||||||||||||||||||||||||||||||||||||||||||||||
YES | NO | YES | NO | ||||||||||||||||||||||||||||||||||||||||||||||
❑ Surgical pulmonary embolectomy OR ❑ Percutaneous catheter embolectomy | ❑ Continue with the same treatment | Is there any contraindication for fibrinolytic therapy? | ❑ Continue with the same treatment | ||||||||||||||||||||||||||||||||||||||||||||||
NO | YES | ||||||||||||||||||||||||||||||||||||||||||||||||
❑ Hold anticoagulation and give thrombolytics | ❑ Surgical pulmonary embolectomy OR ❑ Percutaneous catheter embolectomy | ||||||||||||||||||||||||||||||||||||||||||||||||
Does the patient fail to improve? | |||||||||||||||||||||||||||||||||||||||||||||||||
YES | NO | ||||||||||||||||||||||||||||||||||||||||||||||||
❑ Surgical pulmonary embolectomy OR ❑ Percutaneous catheter embolectomy | ❑ Continue with the same treatment | ||||||||||||||||||||||||||||||||||||||||||||||||
Dosage of Fibrinolytic Therapy
Shown below is the dosage schedule for the thrombolytic agents:[4]
- Streptokinase (FDA-approved)
- Loading dose: 250 000 IU over 30 min
- Maintenance dose: 100 000 IU/h over 12–24 hr
- Accelerated regimen: 1.5 million IU over 2 hr
- Urokinase (FDA-approved)
- Loading dose: 4400 IU/kg over 10 min
- Maintenance dose: 4400 IU/kg/h over 12–24 hr
- Accelerated regimen: 3 million IU over 2 hr
- Recombinant tissue plasminogen activator (rtPA)[13]
- Alteplase (FDA-approved): 10-mg IV bolus followed by 90 mg IV infusion over 2 hours
- Reteplase: 10-U IV bolus followed in 30 mins by another 10-U IV bolus
- Tenecteplase: 0.5-mg/kg IV bolus (max 50mg)
Contraindications to Fibrinolytic Therapy
Shown below is a table summarizing the absolute and relative contraindications to fibrinolytic therapy among pulmonary embolism patients.[3]
Absolute contraindications | Relative contraindications |
❑ Previous hemorrhagic stroke or stroke of unknown origin ❑ Ischemic stroke within the last 6 months |
❑ Transient ischemic attack within the last 6 months ❑ Oral anticoagulant therapy intake |
Choice of Initial Anticoagulation Therapy
Begin initial anticoagulation therapy in: ❑ Confirmed PE OR ❑ High or intermediate probability of PE while awaiting the diagnostic tests | |||||||||||||||||||||||
Is the patient high risk or non-high risk? | |||||||||||||||||||||||
High risk | Non-high risk | ||||||||||||||||||||||
❑ Administer IV unfractionated heparin
| |||||||||||||||||||||||
Yes | No | ||||||||||||||||||||||
❑ Administer unfractionated heparin:[3]
| ❑ Administer ONE of the following:
| ||||||||||||||||||||||
Adjustment of Heparin Dosage According to aPTT
aPTT | Variation in the dosage[3] |
< 1.2 x control (<35 s) | Bolus: 80 U/kg Infusion rate: increase by 4 U/kg/h |
1.2-1.5 x control (35-45 s) | Bolus: 40 U/kg Infusion rate: increase by 2 U/kg/h |
1.5-2.3 x control (46-70 s) | Continue the same dosage |
2.3-3.0 x control (71-90 s) | Infusion rate: decrease by 2 U/kg/h |
> 3.0 x control (>90s) | Stop infusion for a period of 1 hour, then Infusion rate: decrease by 3 U/kg/h |
Contraindications to Anticoagulation
- Disorders predisposing to bleeding
- Gastrointestinal bleeding
- Genitourinary tract bleeding
- Prior history of peptic ulcer disease
- Severe thrombocytopenia
- Surgery within the prior 14 days
- Thrombotic stroke within the prior 14 days[15]
Complete Diagnostic Approach
A complete diagnostic approach should be carried out after a focused initial rapid evaluation is conducted and following initiation of any urgent intervention.
Abbreviations: DVT: Deep venous thrombosis; JVD: Jugular venous distention; P2: Second heart sound; RV: right ventricle; S3: Third heart sound ; S4: Fourth heart sound
Characterize the symptoms: ❑ Dyspnea (78–81%)[16]
❑ Symptoms suggestive of shock (in case of massive PE) | |||||||||
Elicit a detailed history:
❑ Previous episode of VTE
❑ Past medical history of diseases associated with hyperviscosity
❑ History of thrombophilia
❑ Abortion
❑ Drugs that may increase the risk of VTE ❑ Family history (suggestive of inherited thrombophilia)
❑ Social history
| |||||||||
Examine the patient: Vital signs
❑ Tachycardia (26%)[3] Skin Heart
❑ Accentuated P2 Lungs | |||||||||
Order tests:
❑ CBC ❑ EKG
| |||||||||
Long Term Treatment
The long term treatment of PE depends on whether the episode is the first one or not, whether it is provoked or unprovoked, and on the risk of bleeding of the patient. Among non cancer patients, the first line therapy for long term management of PE is vitamin K antagonists (VKA); whereas the first line treatment among cancer patients is low molecular weight heparin. If long term treatment with VKA is decided, VKA should be started at the same day with heparin allowing for at least 5 days of overlap until the INR is ≥2 for at least 24 hours. Among patients on extended anticoagulation therapy, the risk vs benefits of the anticoagulation therapy should be assessed regularly (for example annually).[2]
Is this the first episode of PE? | |||||||||||||||||||||||||||||||||||||||
YES | NO | ||||||||||||||||||||||||||||||||||||||
Is PE provoked? | What is the risk of bleeding? | ||||||||||||||||||||||||||||||||||||||
Yes, transient reversible risk factor | Yes, cancer | No (unprovoked) | Low or moderate | High | |||||||||||||||||||||||||||||||||||
Therapy for 3 months | Extended therapy or until cancer is cured | Therapy for ≥ 3 months | Extended therapy | Therapy for 3 months | |||||||||||||||||||||||||||||||||||
Re-assess the risk of bleeding | |||||||||||||||||||||||||||||||||||||||
Low or moderate | High | ||||||||||||||||||||||||||||||||||||||
Extended therapy | Do not extend the therapy beyond the initial 3 months | ||||||||||||||||||||||||||||||||||||||
Note that edoxaban[19] has been evaluated for the treatment of VTE and is currently seeking approval for this indication.
Vitamin K Antagonist
- Begin with 5 mg warfarin for 2 days followed by dosing based on the INR.
- Start at the 1st or 2nd day of the initial parenteral therapy.
- Target INR is 2-3.
- Monitor INR monthly.
- If the INR is stable but there is one value 0.5 below or above the target range, continue the same dose and repeat INR within 1-2 weeks.
- Avoid NSAIDs, COX2 selective NSAIDs and some antibiotics[14]
Assessment of Risk of Bleeding
The risk factors of bleeding with anticoagulation therapy are:[2]
- Age > 75 years
- Alcohol abuse
- Anemia
- Antiplatelet therapy
- Cancer
- Comorbidity and reduced functional capacity
- Diabetes
- Frequent falls
- Liver failure
- Metastatic cancer
- Poor anticoagulant control
- Previous bleeding
- Prior stroke
- Recent surgery
- Renal failure
- Thrombocytopenia
Shown below is a table summarizing the risk of bleed based on the number of risk factors. Note that, although the presence of one risk factor signify moderate risk of bleeding, if the single risk factor is severe (such as severe thrombocytopenia or recent major surgery) then the patient is at high risk of bleeding despite the presence of a single risk factor.
Risk of bleeding | Number of risk factors[2] |
Low Risk | 0 |
Moderate Risk | 1 |
High Risk | ≥2 |
Do's
- When indicated, administer fibrinolytic therapy for a short infusion time (for 2 hours) rather than over prolonged perfusion (for 24 hours).[2]
- When indicated, administer fibrinolytic therapy via a peripheral vein rather than pulmonary artery catheter. [2]
- Begin anticoagulation therapy among high-risk patients suspected to have pulmonary embolism and those with high or intermediate pre-test probability of pulmonary embolism during the diagnostic workup while awaiting confirmatory tests.[2]
- If long term anticoagulation is extended for a longer period beyond 3 months, the same drug initially started should be continued.[2]
- Among patients started on heparin, if the risk of heparin induced thrombocytopenia is more than 1%, monitor platelet count every 2 to 3 days from the 4th until the 14th day of treatment or until the discontinuation of heparin.[2]
- Screen for thrombophilia if this is a first episode of VTE in a patient less than 50 years of age.[2]
References
- ↑ Miniati M, Cenci C, Monti S, Poli D (2012). "Clinical presentation of acute pulmonary embolism: survey of 800 cases". PLoS One. 7 (2): e30891. doi:10.1371/journal.pone.0030891. PMC 3288010. PMID 22383978.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ; et al. (2012). "Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e419S–94S. doi:10.1378/chest.11-2301. PMC 3278049. PMID 22315268.
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galiè N, Pruszczyk P; et al. (2008). "Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)". Eur Heart J. 29 (18): 2276–315. doi:10.1093/eurheartj/ehn310. PMID 18757870.
- ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ; et al. (2011). "Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association". Circulation. 123 (16): 1788–830. doi:10.1161/CIR.0b013e318214914f. PMID 21422387.
- ↑ 5.0 5.1 5.2 Cannon CP, Goldhaber SZ (1996). "Cardiovascular risk stratification of pulmonary embolism". Am. J. Cardiol. 78 (10): 1149–51. PMID 8914880. Retrieved 2011-12-21. Unknown parameter
|month=
ignored (help) - ↑ Wells PS, Hirsh J, Anderson DR, Lensing AW, Foster G, Kearon C, Weitz J, D'Ovidio R, Cogo A, Prandoni P (1995). "Accuracy of clinical assessment of deep-vein thrombosis". Lancet. 345 (8961): 1326–30. PMID 7752753. Unknown parameter
|month=
ignored (help);|access-date=
requires|url=
(help) - ↑ Wells PS, Ginsberg JS, Anderson DR, Kearon C, Gent M, Turpie AG, Bormanis J, Weitz J, Chamberlain M, Bowie D, Barnes D, Hirsh J (1998). "Use of a clinical model for safe management of patients with suspected pulmonary embolism". Ann Intern Med. 129 (12): 997–1005. PMID 9867786.
- ↑ 8.0 8.1 8.2 8.3 Wells P, Anderson D, Rodger M, Ginsberg J, Kearon C, Gent M, Turpie A, Bormanis J, Weitz J, Chamberlain M, Bowie D, Barnes D, Hirsh J (2000). "Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer". Thromb Haemost. 83 (3): 416–20. PMID 10744147.
- ↑ 9.0 9.1 9.2 Wells PS, Anderson DR, Rodger M, Stiell I, Dreyer JF, Barnes D, Forgie M, Kovacs G, Ward J, Kovacs MJ (2001). "Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer". Ann Intern Med. 135 (2): 98–107. PMID 11453709.
- ↑ 10.0 10.1 Stein PD, Woodard PK, Weg JG, Wakefield TW, Tapson VF, Sostman HD, Sos TA, Quinn DA, Leeper KV, Hull RD, Hales CA, Gottschalk A, Goodman LR, Fowler SE, Buckley JD (2007). "Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II Investigators". Radiology. 242 (1): 15–21. doi:10.1148/radiol.2421060971. PMID 17185658.
- ↑ van Belle A, Büller HR, Huisman MV, Huisman PM, Kaasjager K, Kamphuisen PW; et al. (2006). "Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography". JAMA. 295 (2): 172–9. doi:10.1001/jama.295.2.172. PMID 16403929.
- ↑ 12.0 12.1 12.2 12.3 12.4 Kucher N, Goldhaber SZ (2005). "Management of massive pulmonary embolism". Circulation. 112 (2): e28–32. doi:10.1161/CIRCULATIONAHA.105.551374. PMID 16009801.
- ↑ Fengler BT, Brady WJ (2009). "Fibrinolytic therapy in pulmonary embolism: an evidence-based treatment algorithm". Am J Emerg Med. 27 (1): 84–95. doi:10.1016/j.ajem.2007.10.021. PMID 19041539.
- ↑ 14.0 14.1 14.2 14.3 14.4 14.5 Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ; et al. (2012). "Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines". Chest. 141 (2 Suppl): e152S–84S. doi:10.1378/chest.11-2295. PMC 3278055. PMID 22315259.
- ↑ Stein PD, Hull RD, Raskob GE (2000). "Withholding treatment in patients with acute pulmonary embolism who have a high risk of bleeding and negative serial noninvasive leg tests". Am J Med. 109 (4): 301–6. PMID 10996581.
- ↑ 16.0 16.1 16.2 16.3 16.4 Cohen AT, Dobromirski M, Gurwith MM (2014). "Managing pulmonary embolism from presentation to extended treatment". Thromb Res. 133 (2): 139–48. doi:10.1016/j.thromres.2013.09.040. PMID 24182642.
- ↑ 17.0 17.1 Anderson FA, Spencer FA (2003). "Risk factors for venous thromboembolism". Circulation. 107 (23 Suppl 1): I9–16. doi:10.1161/01.CIR.0000078469.07362.E6. PMID 12814980.
- ↑ Worsley DF, Alavi A, Aronchick JM, Chen JT, Greenspan RH, Ravin CE (1993). "Chest radiographic findings in patients with acute pulmonary embolism: observations from the PIOPED Study". Radiology. 189 (1): 133–6. doi:10.1148/radiology.189.1.8372182. PMID 8372182.
- ↑ Hokusai-VTE Investigators. Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S; et al. (2013). "Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism". N Engl J Med. 369 (15): 1406–15. doi:10.1056/NEJMoa1306638. PMID 23991658. Review in: Ann Intern Med. 2014 Jan 21;160(2):JC4 Review in: Ann Intern Med. 2014 Mar 18;160(6):JC4