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Pulmonary Hypertension Summit Proceedings Online Monograph

Session I – Acute and Chronic Pulmonary Embolism

Gustavo A. Heresi, MD; John R. Bartholomew, MD; Irene Marthe Lang, MD; William R. Auger, MD

Acute Pulmonary Embolism: Current Concepts

Pulmonary embolism (PE) is the third leading cause of cardiovascular death. The mortality rate for acute PE exceeds 15% in the first 3 months after diagnosis. The mortality rate is higher than for myocardial infarction, because myocardial infarction is much easier to detect and treat. Each year, 60,000 to 300,000 Americans die from PE. About 25% of these mortalities are considered sudden cardiac death. It is the most common cause of preventable death in hospitalized patients. Mortality can be reduced by prompt recognition, diagnosis, and treatment.

Pulmonary embolism leads to right ventricular pressure overload, right ventricular hypokinesis, and dilatation. Consequently, it can lead to decreased left ventricular preload, systemic arterial hypotension, and decreased coronary perfusion, which then progresses to right ventricular ischemia and infarction.

Risk factors for PE have been identified:

  • Acute illnesses, heart failure, infectious disease, rheumatic disease, or gastrointestinal disease;
  • Age older than 60;
  • Previous thrombosis or cancer;
  • Use of lupus anticoagulants or existence of anticardiolipin antibodies;
  • Recent surgery, trauma, or injury;
  • Extreme limitations in mobility;
  • Use of estrogen therapy;
  • Pregnancy;
  • Obesity.

Genetic risk factors identified include antithrombin deficiency, protein C and S deficiencies, and factor V Leiden gene and prothrombin gene mutations, but they are only considered mild thrombophilias.

The clinical presentation features dyspnea in almost 80% of cases and tachypnea in about 60%. Approximately half of patients have pleuritic pain, leg edema, erythema, and tenderness or palpable cord. Hemoptysis occurs less often. Syncope or near syncope can be another presentation.

For diagnosis, start with the validated clinical decision rules Wells Rule and the Geneva Score to arrive at a pretest diagnostic probability (low, intermediate, or high). A negative D dimer is highly sensitive, excluding PE in more than 95% of cases if the clinical pretest probability is low or intermediate. However, a negative D dimer does not reliably exclude PE if the clinical probability is high.

Patients with a high pretest probability from Geneva Score or Wells Rule scores require CAT scan imaging, which is now the imaging modality of choice. Ventilation perfusion scan can be used when CAT scan imaging is not feasible. A confirmed deep venous thrombosis (DVT) via leg duplex ultrasound is enough to start anticoagulation. Echocardiography and CAT scan imaging can also provide prognostic information of right ventricular strain.

Anticoagulation options include low molecular-weight heparin, antithrombin factor Xa inhibitor (fondaparinux), and IV unfractionated heparin; monotherapy with rivaroxaban or apixaban; and transition therapy with dabigatran or edoxaban, remembering that the latter two must be initiated after 5 days of a parenteral anticoagulant. Advanced therapies include thrombolytic therapy, catheter therapies, or pharmacomechanical thrombolysis, inferior vena cava filters, and surgical embolectomy.

In the 2016 CHEST guidelines, non-vitamin K oral antagonists are recommended over warfarin for the initial and long-term treatment of DVT and PE in patients without cancer. For subsegmental PE with no proximal DVT and low risk of recurrence, clinical surveillance over anticoagulation is suggested.

Every patient with a PE should be risk stratified. There are several PE severity indices, both full and simplified. Risk evaluation includes the clinical examination, vital signs, measuring biomarkers including troponin and B-type natriuretic peptide (BNP) and N-terminal proBNP, echocardiogram to determine the right ventricle and pulmonary pressures, and CAT scan to assess the right ventricle and the size of the PE.

Patients with normal blood pressure and no elevated biomarkers have a low risk for mortality, and they can be treated with standard anticoagulation. However, if the patient has normal blood pressure but elevated biomarkers or right ventricle dilatation on echocardiogram, there is some controversy regarding whether to treat them with advanced therapies or standard anticoagulation. In this setting, hospital mortality can be as high as 10%. In patients who experience shock, thrombolytic therapy or surgical embolectomy, with or without a filter, are indicated because the mortality of these cases can be 30% or higher.

In the PEITHO trial, fibrinolysis for patients with intermediate-risk PE showed that thrombolysis prevented hemodynamic deterioration but increased the risk for intracranial hemorrhage. Half-dose fibrinolysis is an option to reduce bleeding complications, but support from high-quality clinical trial data is lacking. A recent meta-analysis of 16 randomized trials comparing thrombolysis to standard anticoagulation in over 2000 patients found that 71% of them had intermediate-risk PE. All-cause mortality and recurrent PE were lower, but rates of major bleeds and intracranial bleeds were higher.

Catheter-directed low-dose fibrinolysis could decrease the risk of major bleeding associated with systemic fibrinolysis. The ULTIMA trial in patients with acute main or lower PE had no major bleeds among the fibrinolysis recipients, but there was one mortality in the heparin group and no recurrent venous thromboembolic disease. Also, there was a reduction in the right ventricular/left ventricular ratio in individuals who received thrombolytic therapy.

Guidelines recommend use of surgical embolectomy in patients with an absolute contraindication to thrombolytic therapy or in whom thrombolysis has failed. If surgical embolectomy is not available, then catheter embolectomy or thrombus fragmentation is recommended.

Treatment strategies vary considerably by services (medical vs surgical service) and patient location. There is not necessarily a standard algorithm or consistency in decision making, no single team approach, and no centralized locations for care or centers of excellence. To address these systematic challenges, many institutions have assembled multidisciplinary PE response teams (called PERTs).

From Acute to Chronic PE: Pathobiology

Risk factors for recurrent venous thromboembolism (VTE) include proximal deep vein thrombosis (DVT) and PE (as opposed to distal DVT), idiopathic or unprovoked VTE, more than one VTE episode, cancer, ongoing hormonal replacement therapy, and elevated D-dimer during or after warfarin therapy. Data from trials using oral anticoagulants suggest that extended anticoagulation greatly decreases the risk of recurrence.

The frequency of residual pulmonary obstruction after an episode of acute PE varies considerably, ranging from 15% to 50% after 6 months. Residual pulmonary obstruction is a risk factor for chronic thromboembolic pulmonary hypertension (CTEPH) in patients who survive acute PE. Compared with pulmonary arterial hypertension, risk factors for CTEPH include previous VTE, recurrent VTE, antiphospholipid antibodies, malignancy, splenectomy, ventriculo-atrial shunt, infected pacemaker, and thyroid hormone replacement therapy.

The incidence rate of CTEPH after acute PE also varies considerably, from 0.5% to 9%. One reason for this wide range is that CTEPH can be mistaken for acute PE with right ventricular strain. The ongoing German FOCUS study is expected to provide additional data in this area.

Several factors influence this rate. Evidence shows that CTEPH has a proximal and a small arterial disease component, which is not present in acute PE. Venule involvement also has been described, apparently due to systemic flow from bronchial collateral circulation. There is no evidence that BMPR2 gene mutation plays a role. Fibrinogen mutations are more common in CTEPH. The ABO blood type group loci achieved significance in a recent genome wide association study in CTEPH. Previous studies have shown that non-O blood type subjects, particularly group A1, are more common in CTEPH. These subjects have higher plasma levels of coagulation factor VIII, which have been documented in CTEPH. Coagulation/fibrinolysis was assumed to play a role in thrombotic disorders, but inherited thrombotic factors are not more prevalent in CTEPH. The only more prevalent thrombophilia is antiphospholipid antibody syndrome. A healthy pulmonary artery has high fibrinolytic activity. In contrast, CTEPH fibrinogen is resistant to lysis. There is local derangement of fibrinolytic proteins, with increased plasminogen activator inhibitor type 1 in thrombus endothelial cells. Plasma levels of the thrombin-activated fibrinolysis inhibitor are elevated in CTEPH. Of note, thrombolytic therapy for acute PE does not prevent the onset of CTEPH. Inflammation plays a role in CTEPH. Elevated C-reactive protein portends a worse prognosis. Platelet endothelial cell adhesion molecule (PECAM-1) is high in plasma but low in the thrombus. P-selectin is also very high in CTEPH.

In summary, the conventional thought is that PE is the starting point for CTEPH. Modifiers include infection, inflammation, impaired fibrinolysis, blood type, and impaired angiogenesis.

Epidemiology and Diagnosis of Chronic Thromboembolic Disease

As noted, CTEPH starts with acute PE. For reasons that are not entirely clear, a PE clot incompletely resolves with a subsequent loss of pulmonary vascular bed. If left untreated, it can lead to a rise in pulmonary vascular resistance, development of right ventricular hypertrophy, right heart failure, and death. The thromboembolic material within the pulmonary vascular bed becomes scar-like tissue, narrowing or obstructing the proximate pulmonary vascular bed with subsequent attenuation of the more distal vascular bed. Over time, small vessel changes develop, primarily in areas distal to unobstructed arteries, which ultimately lead to a gradual rise in pulmonary vascular resistance. It is probable that many patients develop chronic thromboembolic disease in the absence of pulmonary hypertension.

Risk factors for the development of CTEPH include prior or recurrent venous thromboembolism and unprovoked PE. Several factors increase the likelihood of developing CTEPH in patients with PE: right heart dysfunction, large thrombus, symptoms for a period of time greater than 2 weeks, older age, and persistent pulmonary hypertension after antithrombotic treatment. Other risk factors are prior splenectomy, chronic inflammatory states, presence of VA shunts, infected intravascular devices such as pacemaker wires, malignancy, thyroid replacement therapy, and having a non-O blood type.

The reported incidence of CTEPH after acute PE varies. The Pengo study found a 3.8% incidence rate within 2 years. A meta-analysis showed a 0.5% rate for all studies, raising to around 3% if only using survivors of the acute event. Some of the incidence rate variability may be explained by the fact that many patients present with CTEPH for the first time as an acute event. Another challenge is to account for the variable timeline from the acute PE event to the onset of CTEPH, which can be several years.

Who should be evaluated for CTEPH? There are probably three relevant patient groups to consider for this diagnosis. First, patients who experience persistent cardiopulmonary symptoms after a course of anticoagulant therapy need to be assessed. Second, all patients with pulmonary hypertension need to be screened for chronic thromboembolic disease. Finally, patients with unexplained exertional dyspnea, regardless of history of previous VTE, should be evaluated for pulmonary hypertension and chronic thromboembolic disease.

Recommendations are to screen these patient groups for pulmonary hypertension with echocardiography and to screen for occlusive pulmonary vascular disease with lung perfusion scintigraphy. If scintigraphy is normal, chronic thromboembolic disease is excluded. If the scan is not normal, then further diagnostic imaging is needed because lung scintigraphy is not specific for CTEPH. For example, abnormal ventilation perfusion scans can be seen in patients with extensive small vessel disease such as pulmonary arterial hypertension, pulmonary arteritis, and pulmonary artery sarcoma.

Typically, CT angiography is the most accurate study to image the pulmonary vascular bed. Abnormalities consistent with chronic thromboembolic disease-lining clot, eccentric clot, partially recanalized clot, web-like defect, and vessel attenuation. Other CT findings include hypertrophied collateral bronchial arteries and parenchymal mosaic perfusion pattern. It is very important to distinguish between acute pulmonary embolic disease and chronic thromboembolic disease on the CT scan.

Use of CT has limitations in the more distal vascular bed. It can sometimes underestimate the chronic thrombotic burden at the segmental and subsegmental level. In these areas, a conventional digital distraction pulmonary arteriogram can effectively map out the disease burden. Both CT scans and magnetic resonance imaging are probably superior to angiography in the more proximal pulmonary vascular bed, but conventional pulmonary angiography is better at the segmental and subsegmental level.

In conclusion, the true incident rate of CTEPH following acute pulmonary embolic disease is not known. Our overall impression is that CTEPH is an under-recognized disease. A significant percentage of patients first present already with CTEPH as if they have had their first pulmonary embolism. Clinicians and radiologists need to assess for evidence of chronic thromboembolic disease on the initial studies. Symptomatic chronic thromboembolic disease is likely a much larger problem. The V/Q scan is recommended to screen for CTEPH; however, advanced diagnostic testing is still required for disease confirmation and to begin with the operability assessment.

Key Points

  • Pulmonary embolism is the third leading cause of cardiovascular death.
  • Anticoagulation options for PE include low molecular-weight heparin, antithrombin factor Xa inhibitor (fondaparinux), and IV unfractionated heparin followed by warfarin; monotherapy with rivaroxaban or apixaban; and transition therapy with dabigatran or edoxaban.
  • Advanced therapies for PE include thrombolytic therapy, catheter therapies, or pharmacomechanical thrombolysis, inferior vena cava filters, and surgical embolectomy.
  • Patients with PE and normal blood pressure and no elevated biomarkers have a low risk for mortality; they can be treated with standard anticoagulants.
  • Risk factors for the development of CTEPH include prior or recurrent venous thromboembolism and unprovoked PE, antiphospholipid antibodies, malignancy, splenectomy, ventriculo-atrial shunt, infected pacemaker, and thyroid hormone replacement therapy.
  • The ventilation perfusion scan is the screening test of choice for CTEPH, but additional imaging with CT tomography, conventional pulmonary angiography, and/or magnetic resonance imaging is needed to confirm the diagnosis. A right heart catheterization is mandatory to assess hemodynamics.

Session I – Acute and Chronic Pulmonary Embolism References

Acute Pulmonary Embolism: Current Concepts Related References

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From Acute to Chronic PE: Pathobiology Related References

  1. Bonderman D, Wilkens H, Wakounig S, et al. Risk factors for chronic thromboembolic pulmonary hypertension. Eur Respir J. 2009;33(2):325-31.
  2. Boutitie F, Pinede L, Schulman S, et al. 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;342:d3036.
  3. Feng YX, Liu D, Sun ML, et al. BMPR2 germline mutation in chronic thromboembolic pulmonary hypertension. Lung. 2014;192(4):625-7.
  4. Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119.
  5. Heit JA, Lahr BD, Petterson TM, et al. Heparin and warfarin anticoagulation intensity as predictors of recurrence after deep vein thrombosis or pulmonary embolism: a population-based cohort study. Blood. 2011;118(18):4992-9.
  6. Heit JA. Predicting the risk of venous thromboembolism recurrence. Am J Hematol. 2012;87(Suppl 1):S63-7.
  7. Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170(19):1710-6.
  8. Konstantinides SV, Torbicki A, Agnelli G, et al; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2014;35(43):3033-69.
  9. Prandoni P1, Noventa F, Ghirarduzzi A, et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica. 2007;92(2):199-205.
  10. Zhu T, Martinez I, Emmerich J. Venous thromboembolism: risk factors for recurrence. Arterioscler Thromb Vasc Biol. 2009;29(3):298-310.

Epidemiology and Diagnosis of Chronic Thromboembolic Disease Related References

  1. Guérin L, Couturaud F, Parent F, et al. Prevalence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism. Prevalence of CTEPH after pulmonary embolism. Thromb Haemost. 2014;112(3):598-605.
  2. Hoeper MM, Barberà JA, Channick RN, et al. Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S85-96.
  3. Pengo V, Lensing AW, Prins MH, et al; Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350(22):2257-64.