Thrombolysis is a systemic treatment with a specific capacity to dissolve thrombi: thrombus located in pulmonary arteries or even in the deep venous system circulation also thrombus in-transit [10]. This therapeutic approach is accessible to the majority of the centers; it can be started bed-side with a rapid effect. Although FDA approved drugs for PE treatment, a specific position related with in-transit thrombus is not mentioned (Table 8.3).

Treatment benefit among PE patients has been proved, but major bleeding is the main limiting risk. Konstantinides et al. [17] reported a major bleeding risk of 11.1 % among 169 patients: 21.9 % in thrombolytic treated versus 7.8 % in heparin treated, although intracranial bleeding was scarce, only 2 patients in each group: 1.2 % and 0.4 %, respectively. A review of the literature from 1966 to 1998, in which different drugs and doses were evaluated, showed that benefit is higher and faster with thrombolytic treatment; but also the bleeding risk, compared with heparin monotherapy; these results are even more important when a small but significant risk of intracranial bleeding was observed [18].

A more recent report [19], that included new thrombolytic drugs showed a 9.24 % major bleeding risk with thrombolysis compared with 3.42 % when only anticoagulation was used, intracranial bleeding occurred in 1.46 % versus 0.19 %, respectively. Those evidences forced experts to insist about relative and absolute contraindications when thrombolytic treatment is proposed.

Talking about in-transit thrombus there are some crucial questions: what happens with the thrombus after thrombolytic treatment is started, and how long does this lesion last and when does it disappear? Small studies address this question, like the published by Ferrari et al. [20]. They reported 343 patients admitted with PE, 18 of them (5.3 %) diagnosed with in-transit thrombus, 16 patients were treated with thrombolysis (recombinant human plasminogen activator (rt-PA) 10 mg in bolus and 90 mg in continuous infusion for 2 h) and follow-up with echocardiogram showing 50 % thrombus resolution in <2 h after infusion, 50 % showed resolution at 12 h and the other half by 24 h, all patients were alive at 24 h and also at 30 days.

Greco et al. [21] analyzed thrombus behavior by echocardiogram during rt-PA infusion in seven patients with in-transit thrombus; they noted clot lysis between 45 and 60 min after the start of treatment. Lysis occurred with a progressive fragmentation in small particles that migrate from the heart cavities to pulmonary circulation to finally disappear. After 2 h of infusion all echocardiographic parameters showed significant improvement. During treatment and hospitalization no adverse events were noted, there was no PE recurrence, major bleeding, or death.

This is an event caused by a thrombus that remains trapped through patent foramen ovale, adding the risk of paradoxical embolism [22]. In 1930 the first case of “paradoxical embolism” was diagnosed and the risk of systemic or cerebral embolism was considered [23]. Diagnosis criteria for paradoxical embolism are: history of venous thrombosis or PE, abnormal right to left heart communication, clinical, angiographic, or pathological evidence of systemic embolism, and favorable pressure gradient to promote right to left heart communication [22, 24].

Two studies, published by Meacham et al. [24] in 1998, and Myers et al. [22] in 2014, with 30 and 174 cases, respectively, describe 24-h mortality of 11.5 % and 30-day mortality of 18.4 %, respectively. Most patients were treated immediately but 55 % had systemic embolism. Surgical treatment was performed in 103 patients (62.4 %), thrombolysis in 19 (11.5 %), and anticoagulation in only 46 (26.1 %). Twenty-four hour mortality was 10.6 %, 26.3 %, and 25.6 %, respectively. Despite these reports, therapeutic debate remains, since in these severely ill, complex, and heterogeneous patients, individualized treatment is always needed. Hospital resources and also clinical experience are mandatory to choose the best options [22].

Evidence-based guides are difficult to implement since this is a rare condition and even the largest reports like Myers et al. [22], tend to be slanted and show heterogeneous patients without standardized treatments (Table 8.4). Previous evidence reported that although patent foramen ovale prevalence was high (26 %) [25], paradoxical embolism was rare. However, current evidence suggest higher patent foramen ovale and paradoxical embolism incidence [26]. In acute PE associated to patent foramen ovale the ischemic stroke prevalence, and the “gold standard” diagnosis method, remain unknown.

A prospective monocentric study in 41 consecutive PE intermediate-risk patients was conducted to evaluate patent foramen ovale and ischemic stroke prevalence, and to identify, which transesophageal- or transthoracic-echocardiography is the best diagnostic method in this context. Brain magnetic resonance imaging was used to confirm clinically obvious strokes or to diagnose subclinical ones [26].

Contrast transesophageal echocardiography revealed patent foramen ovale in 56.1 %, whereas contrast transthoracic echocardiography showed so in only 19.5 % (P < 0.001). Of note, all patent foramen ovale observed with transthoracic echocardiography were also diagnosed by transesophageal echocardiography. Ischemic stroke occurred in 17.1 % and was always associated with patent foramen ovale and large shunt. Transesophageal echocardiography revealed that patent foramen ovale was associated with atrial septal aneurysm in 71 % in patients with recent ischemic stroke and 32.4 % in nonrecent ischemic stroke [26].

Recent ischemic stroke patients (seven) had new neurologic signs at admission (28.6 %), electrocardiogram with right ventricular strain (100 %), troponin 0.39 (0.07–0.59), and brain natriuretic peptide type-B expression 500 (223–708) pg/dL compared with nonrecent ischemic stroke patients (34) new neurologic signs at admission (0), electrocardiogram with right ventricular strain (82.4 %), troponin 0.16 (0.06–0.56), and brain natriuretic peptide type-B expression 434 (250–662) pg/dL [26].

In this study the patients with intermediate-risk PE presented a high incidence of paradoxical embolism. This study could be the first to show such a high incidence (17.7 %) of paradoxical embolism in submassive PE. Because patent foramen ovale and related ischemic strokes was frequent in intermediate-risk PE, transesophageal echocardiography is much more efficient than transthoracic echocardiography for patent foramen ovale diagnosis. Considering the high risk of intracranial bleeding with thrombolysis in PE, which may be partly due to hemorrhagic transformation of subclinical strokes, the screening patent foramen ovale with transesophageal echocardiography TEE should be considered in intermediate-risk PE when thrombolytic treatment is discussed [26].

Considering venous thromboembolism endothelial dysfunction, complex thrombus mechanisms, the broad thrombus distribution (venous system, pulmonary arteries and in-transit), high incidence of patent foramen ovale, with paradoxical cerebral embolism and possible also systemic, as well as right and left ventricular myocarditis [2], PE could be considered as complex and systemic disease.

Although surgical and percutaneous procedures are out of the scope of this book, for in-transit thrombus complexity both therapeutic approaches will be analyzed.

Has been recommended in PE patients with absolute thrombolysis contraindication, as well as in those suffering in-transit thrombus and paradoxical embolism [15, 16]. Leacche et al. [27] reported surgical success in 47 PE with right ventricular with thrombolysis contraindications and medical treatment failure.

Early mortality was reported on only 6 %, and a high experienced surgical team helped with a preoperative transesophageal echocardiogram-performed surgery. Preoperative transesophageal echocardiogram, allowed a more defined intracardiac image, foramen ovale patency, or septal defects. In some cases, an epicardial echocardiogram helped surgeons to establish exact thrombus location to guide cannulation. Surgery was performed on normothermia without cardioplegia with longitudinal or transverse main pulmonary arteriotomy, although a right pulmonary artery arteriotomy between ascendant aorta and superior vena cava was occasionally performed. Thrombi were removed under direct visualization using a gallbladder stone forceps. No Fogarty catheter was used to avoid pulmonary artery lesions. Inferior vena cava filters were also implanted.

Multidisciplinary approach resulted in favorable outcomes along with a 24/7 availability team, a fast and precise diagnosis, and an always-ready operating room. Obviously, few centers have enough resources to perform these cardiothoracic surgeries to allow imitate this methodology [27]. Moreover, since shock raises mortality 3–7 times and most of fatalities occurred in the first hour (“golden hour”) [28, 29]. Other potential complications are related to anesthesia, and also a prolonged surgery related to the increased difficulty to remove thrombi when they reach sites beyond central arteries.

It is another potential therapeutic approach that can be performed during pulmonary angiography. Potential complications are related to the tendency of catheters to fragment thrombus instead of removing it. Particles produced can compromise pulmonary circulation even more, resulting in a dangerous and acute pulmonary hypertension [30].

Previous evidence shows fast and suitable diagnostic and therapeutic strategies are needed in this uncommon but severe disease. Treatment including heparin, thrombolysis, and/or surgical embolectomy should search for less complications and improving survival. Current guides are mainly based on expert recommendations and case reports with limited scientific evidence. Future trials should be oriented in comparing different treatments to establish the best options for individualized patients.

Thrombolysis advantages include availability, fast and systemic effect, but this approach has the intrinsic risk of bleeding. Careful patient selection and strict surveillance can decrease this complication. This recommendation is particularly important in the case of in-transit thrombus, where the additional risk of embolism is present, particularly for thrombus trapped inside a foramen ovale that can complicate with systemic embolism. Those risks should be taken into account during treatment selection [31].

Multidisciplinary team formation is essential to get the best results regarding mortality and complications. Team experience can only be reached by treating patients in large centers, and reporting results obtained. Joining forces of different centers should enable improve our knowledge of this interesting and challenging disease.