Management of Pulmonary Thromboembolism

*G. Ravi Kiran*

## **Abstract**

Pulmonary thrombo-embolism (PTE) is a major cause of cardiovascular morbidity and mortality. Incidence of PTE and its associated mortality is affected by the Prescence of associated risk factors, comorbid conditions and advancement in the treatment options. Clinical probability, D-Dimer, echocardiography and CT pulmonary angiography are used in the diagnosis. Management starts with stratification, with high-risk category being benefited from the thrombolytic therapy. Catheter directed therapy may be used in ineligible or failed cases with surgical embolectomy being used as final salvage therapy. Patients with persistent hemodynamic stability can be started on anticoagulation alone. Supportive therapy with fluid expansion and inhalational Nitric oxide may provide benefit in few. Patients with PTE should receive secondary preventive anticoagulation to prevent recurrences. High risk patients with sub-segmental PTE may benefit from anticoagulation. For early detection of long-term complications of PTE a patient cantered follow-up is needed. Chronic thrombo-embolic pulmonary hypertension (CTEPH) is a dreaded complication with pulmonary end-arterectomy being a gold standard management option in eligible patients with non-surgical therapy (balloon pulmonary angioplasty and pulmonary vasodilators) also being used in many cases.

**Keywords:** Pulmonary thrombo-embolism, Thrombolysis, Anti-coagulation, CTEPH, Sub-segmental PTE, Covid-19

## **1. Introduction**

Pulmonary thrombo-embolism (PTE) is a most dangerous form of venous thrombo-embolism (VTE), and undiagnosed or untreated can be fatal. Furthermore individuals who survive PTE can develop post-PTE syndrome that is characterized by chronic thrombotic remains in pulmonary arteries, causing persistent right ventricular dysfunction, decreased quality of life and/or chronic functional limitations.

Clinical probability, assessed by validated prediction rule and age adjusted D-dimer testing is the basis for all diagnostic strategies. Computer tomographic pulmonary angiography (CTPA) is the definitive diagnostic investigation.

Acute PTE presents with varying degrees of clinical stability & thus a careful clinical assessment is needed. Patients should be evaluated in the context of various available treatment options including medical, catheter-based, and surgical interventions. Several improvements are made in therapeutic management of acute PTE in recent years.

A crisp review of the best available literature on which, multiple societal guidelines on PTE management where based, is made. Also, an evidence-based suggestions on the debatable and poorly studied PTE management topics like follow-up, sub-segmental PTE, catheter directed thrombolysis, CTEPH and covidassociated PTE were made. Areas where further need for clinical research were also highlighted.

## **2. Management of acute pulmonary thromboembolism**

## **2.1 Supportive therapy**

The initial approach to patients with PTE should focus on the supportive measures. It includes oxygen therapy, mechanical ventilatory support, volume expansion therapy and antibiotics (e.g., in lung infarction).

## *2.1.1 Volume expansion therapy*


So, in patients with no (or probably mild) RV dysfunction & when central venous pressure (CVP) is not high (< 12-15 mm Hg), then fluid therapy may be considered in hypotensive patients. However, in any case, monitoring of the RV function on a regular basis during volume expansion is recommended [1, 2].

## *2.1.2 Oxygen and ventilatory support*


## *2.1.3 Circulatory support*

a.The ideal pharmacological agent should enhance RV function through positive inotropic effects and increase mean arterial pressure (MAP) through peripheral vasoconstriction without significantly increasing pulmonary vascular resistance (PVR).

#### *Management of Pulmonary Thromboembolism DOI: http://dx.doi.org/10.5772/intechopen.100040*


Though epoprostenol causes pulmonary vasodilatation, a major concern about its use is the possible risk of worsening V/P mismatch or increasing PCWP in patients with concurrent LV dysfunction. On contrary, iNO appears to improve the V/P mismatch by increasing perfusion only to areas that are well-ventilated.

f. Based on minimal clinical data it may be suggested that if CO remains low despite vasopressors and inotropes, a pulmonary vasodilator trial with iNO may be beneficial when pulmonary hypertension is present [5–8].

Whenever possible, vasopressors and inotropic agents be used with caution, only if absolutely necessary, at the lowest possible doses.

g.Mechanical circulatory support (VA-ECMO) is sometimes may be used to provide temporary cardiopulmonary support to patients with acute cardiopulmonary failure. In the latest ESC recommendations, ECMO was classified as "may be considered".

The Impella RP®™ (axial flow pump) and TandemHeart Protek®™ (Centrifugal pump) are RV assist devices to augment the antegrade flow; There are limited single centre reports describing the use of these devices in high-risk PTE cases [9].

To summarize the issue of supportive therapy, it can be concluded that, while used empirically based on clinical and theoretical data, there are no robust guidance emerging from the evidence-based medicine and hence needs further studies.

## **2.2 Medical therapy**

The medical management [10–22] of acute PTE consists of anticoagulation and systemic thrombolysis.

## *2.2.1 Anticoagulation*

a.When acute PTE is considered likely, anticoagulation should be begun while pursuing the diagnostic workup. In a hemodynamically unstable patient, it is reasonable to start anticoagulation immediately and preferably with short-acting, intravenously administered unfractionated heparin (UFH).

The rapid reversibility of IV UFH is important for these patients who may require thrombolysis or surgical embolectomy. Short-acting, intravenously administered UFH should be initiated with a bolus of 80 U/kg followed by a continuous infusion of 18 U/kg per hour.

For stable patients with PTE, low-molecular-weight heparin (LMWH) or fondaparinux are preferred to UFH due to lesser incidence of inducing major bleeding, thrombocytopenia and are associated with equal or probably superior efficacy. These agents should be continued for at least 5 days and until the INR is >2.0 for at least 24 h followed by long-term coagulation with vitamin K antagonist, VKA (the dose of warfarin should be adjusted to maintain an INR of: 2.0-3.0) or DOACs, Dabigatran and edoxaban (preferred over VKA) administered after an initial treatment of 5-10 days with LMWH.

	- 1.Optimal duration of anticoagulation remains uncertain and has to be considered on a case-to-case basis. In patients with provoked (identifiable risk factor) PTE, a minimum of 3 months is usually recommended, but a 6-month therapy may be considered if the patient with minor transient risk factor has low bleeding risk. Clinical data suggests against thrombophilia testing to decide the duration of anticoagulation.
	- 2.Indefinite anticoagulation is probably appropriate for majority of the patients with unprovoked PTE (except in patients with high bleeding risk where 6 months therapy is recommended).

In certain circumstances, such as when balance between risks and benefits is uncertain, use of prognostic scores (HERDOO2, Vienna, DASH), D-dimer testing (6 month after the start of initial anticoagulation), or ultrasound assessment for residual thrombosis (after completing 6 months of anticoagulation) from an initial DVT episode may aid in reaching a final decision.


For patients with breakthrough PTE during therapeutic VKA treatment, LMWH is preferred over DOAC therapy. For patients with concomitant stable CVD who initiate anticoagulation and were previously taking aspirin for cardiovascular risk modification, suspending aspirin over continuing it for the duration of anticoagulation therapy is recommended (not apply to patients with a recent acute coronary event or intervention).

## *2.2.2 Thrombolytic therapy*


In has to be noted that even, intrinsic thrombolysis is also potent and several studies suggest that 1 week after anticoagulant therapy, the degree of vascular obstruction and right ventricular dysfunction are similar between thrombolysis-treated and anticoagulation-treated patients.

c.In clinical practice, the net benefit of thrombolysis for PTE likely exists on a continuum, highly dependent on the severity of the clinical presentation, patient's comorbidities and bleeding risk, as well as the availability of alternative therapies.

Different societal guidelines and consensus statements convey differing approaches to risk stratification, largely based on echocardiographic features and cardiac biomarkers (troponin and BNP). Systematic review data suggest that of the 17 different pulmonary embolism risk prediction scores Pulmonary Embolism Severity Index (PESI) and the simplified-PESI (sPESI) had the most robust evidence and validation for clinical risk assessment of patients with PTE.

d.Data from randomized trials and systematic literature reviews suggest that:


In light of this evidence, full-dose systemic TT is routinely recommended for intermediate-high risk PTE and should be only be reserved as rescue therapy for those presenting with clinical deterioration after initial anticoagulation.

Because the bleeding risk associated with TT is dose dependent, lower doses of thrombolytic drugs may provide a more favorable safety profile with comparable efficacy. In fact, in a systematic review, low-dose tPA was associated with lower risk of major bleeding than full-dose tPA, with no difference in recurrent PTE.

Thus, in low bleeding risk patients (ex. young, < 65 kg) with intermediate high-risk PTE, low-dose systemic thrombolysis (with tPA) at presentation may result in the net favorable outcomes & should be considered (PEITHO-III [NCT04430569] is an ongoing placebo-controlled RCT evaluating the mortality benefit of this approach).


Alteplase is the most commonly administered thrombolytic agent. Although the FDA-approved dose of 100 mg of alteplase over 2 hours is most commonly used, European and Canadian guidance supports the option of alteplase 0.6 mg/kg administered over 15 minutes.

Though not approved many studies had shown the efficiency of reteplase (2 bolus doses of 10 U each, 30 min apart) and tenecteplase (single bolus dose of 0.5 mg/Kg) in treating pulmonary embolism.

Only few comparison trials of available thrombolytic agents have been conducted. Available data suggest a clinical superiority of tenecteplase over streptokinase, alteplase over urokinase and streptokinase. Further studies are needed to truly identify the choice of thrombolytic agent and regimen in PTE.

## **2.3 Catheter directed therapies**

a.Catheter-directed therapy provides an alternative reperfusion approach that allows localized drug delivery and can be combined with mechanical thrombus removal that may result in better clinical outcomes.

Catheter-based therapies include MT, mechanical thrombectomy (thrombus fragmentation, aspiration, rheolytic thrombectomy), Pharmacologic catheter directed thrombolysis (CDT, via thrombolytic infusion catheter or ultrasoundfacilitated CDT), or a combination of both.

	- 1.Thrombus maceration (Using a pigtail catheter or guidewire). However, distal embolization may be an inadvertent risk.
	- 2.Rheolytic thrombectomy using AngioJet®™ device uses rapid-speed saline that facilitate thrombus fragmentation. The catheter can also be used to deliver low-dose thrombolytic agent into the thrombus to aid clot removal.
	- 3.Aspiration thrombectomy using FlowTriever®™ device is the first MT procedure approved by FDA. The Indigo Thrombectomy CAT 8 system®™ and AngioVac®™ catheter are other systems used for this purpose.
	- 1.To improve the efficacy and speed of clot clearance, fibrinolysis can be combined with low-intensity ultrasound waves (EkoSonic Endovascular System®™) in an approach called ultrasound-assisted thrombolysis [25]. However, there is no clear evidence demonstrating the benefit of ultrasoundenhanced thrombolysis over standard CDT. On the contrary, the procedure times are significantly longer than for standard CDT [26–28].
	- 2.The major advantage of CDT over systemic thrombolysis is lower bleeding risk [25]. In fact, in a meta-analysis of outcomes of CDT, the rates of major bleeding were significantly lower were compared to systemic thrombolysis in patients with high- and intermediate-risk patients. However, current evidence supporting the use of CDT in acute PTE is limited to a small RCTs or single-arm studies focusing on short-term surrogate outcomes rather than long-term clinical outcomes.
	- 3.Due to lack of strong RCT evidence regarding the short- and long-term clinical benefits, based on the critical review of meta-analytic and clinical studies it may be suggested that [26–32]:

In patients with high-risk PTE, CDT is recommended when systemic thrombolysis is contraindicated or has failed or as alternative in high bleeding risk patients (e.g., coagulopathy).

Though in Intermediate-risk PTE, CDT is associated with lower mortality with equivalent rates of major bleeding compared to systemic anti-coagulation alone, quality of evidence is not robust. CDT may thus be reserved for these patients who develop signs of hemodynamic instability despite adequate anticoagulation as an alternative to systemic thrombolysis in case-to-case basis.

Additional studies with larger sample sizes are required to elucidate the optimal use of CDT in sub-massive PTE.

## **2.4 Surgical pulmonary embolectomy**


## **2.5 Follow-up**

	- 1.Though the gold standard technique for assessing the pulmonary arterial hypertension (PAH) is right heart catheterization (RHC). TTE (transthoracic echocardiography) should always be performed at discharge to evaluate PAH. TTE at follow-up (at 3 months) should be considered only for those patients with RV–RA gradient >45mmHg or in the presence of both dyspnoea and a RV–RA gradient ranging between 32 and 45mmHg at discharge.
	- 2.Lung perfusion scan must be performed 3months after the acute event in those patients with persisting symptoms and/or in the presence of right ventricular dysfunction or pulmonary artery hypertension.
	- 3.Computed tomography of pulmonary vasculature and pulmonary vascular MRI are not useful to define therapeutic strategies during the follow-up and are thus not recommended.

suggest against testing in provoked PTE, where as in unprovoked PTE there is only limited data to suggest the benefit of testing and is usually not recommended except in those patients with a positive familiar history of VTE or recurrent thrombosis or suspecting APLA syndrome.

Though ESC guidelines recommend against the use of DOAC in APLA syndrome, recent systematic review suggests that rate of VTE recurrence and bleeding events were both low and comparable in patients with various thrombophilia receiving VKA or DOAC suggesting that DOAC are appropriate treatment option even in this population.

d.Extensive screening for occult cancer in every patient with unprovoked VTE is not recommended, however guidelines suggest a limited screening strategy though clinically significant benefit of this approach is unknown.

"Limited screening strategy" includes medical history, physical examination and laboratory analyses with blood cell count, renal and liver function parameters and calcium levels as well as a simple chest x-ray. In addition, according to national recommendations, specific screening based on sex and age (colon, breast, cervical and prostate) should be performed [35–41].

However, some patients with high-risk features (RIETE score of >3 may benefit from extensive cancer screening with CT imaging. Prospective validation of this approach is still being tested (SOME RIETE, NCT03937583 & MVTEP2-SOME2, NCT04304651 trails).

## **3. Prophylaxis**

## **3.1 Medical prophylaxis**

a.Many meta-analysis that includes both observational and intervention studies suggest a beneficial effect of statin use for prevention (primary and secondary) of VTE. In intervention studies, therapy with rosuvastatin significantly reduced VTE (including PTE) compared with other statins.

But scientific committees feel it is still too early to make any guideline recommendations based on the current evidence [42, 43].


For assessing VTE risk is patients undergoing non-orthopedic surgery, modified Caprini risk assessment score is used. Based on this assessment score, patients with moderate to high-risk should receive pharmacological prophylaxis (+/− mechanical methods).

d.Although data comparing pharmacologic prophylaxis to placebo is of low quality, major clinical practice guidelines still recommend pharmacologic VTE prophylaxis for almost all acute medical critically illness.

Commonly used pharmacological agents for prophylaxis are: UFH, LMWH & Fondaparinux (later two are usually preferred over UFH) [45].

Duration of DVT prophylaxis is typically until the patients can ambulate or discharge from the hospital. In patients undergoing abdominal or pelvic surgery for cancer and with a low risk of bleeding, pharmacological prophylaxis is extended to a total duration of 4 weeks [45].

## **3.2 IVC filters**


In-fact, meta-analytic data suggest that the IVC filters were associated with reduction of recurrent PE but causes increased risk of DVT, and albeit no significant effect on PTE-related or overall mortality [47, 48].

c.In should be noted that majority of the evidence for the use of IVC filters in people with VTE was of very low quality, which is majorly insufficient to make any strong recommendations.

Expert consensus based on all the available evidence recommend not to offer IVC filters to people with DVT or PTE unless it is part of a clinical trial or was covered by their other recommendations for people in whom anticoagulation is contraindicated or who have PTE taking appropriate anticoagulation treatment.

Systematic review [49] suggests that IVC filters with cylindrical or umbrella elements have highest reported risk of IVC thrombosis compared to conical filters, clinical relevance of this is yet to be studied.

## **4. Hot topics in PTE**

## **4.1 Isolated sub-segmental pulmonary embolism**

ISSPE is defined as a contrast defect in a sub-segmental artery, that is, the 1st arterial branch of any segmental artery independent of artery diameter.


uncontrolled outcome studies shows no increase in VTE recurrence for patients who were not anticoagulated compared to patients who received anticoagulation.

c.However, some patients may be at higher risk of recurrent events. A clinical expert panel favors anticoagulation treatment in case of prior VTE, APLAS antiphospholipid syndrome, active cancer and proximal DVT [50–54].

## **4.2 Covid associated PTE**

	- 1.The frequency of PTE in patients with COVID-19 is highest in the ICU (25-50%), followed by general wards (15-25%). PTE in COVID-19 is more commonly located in peripheral than in central pulmonary arteries, which suggests local thrombosis to play a major role. Increasing age & body mass index was associated with an increasing prevalence of PTE.
	- 2.Patients with PTE had significantly higher D-dimer levels and a D-dimer assessment may help to select patients with COVID-19 for CTPA, using D-dimer cut-off levels of at least 1000 μg/L (cut-off levels which have been used to identify patients with PE varied between 1000 and 4800 μg/L in different studies). The odds of mortality are significantly higher among patients who developed PTE compared to those who did not.

Though Anticoagulation dosing varied throughout the studies and may be classified as standard VTE prophylaxis, intermediate dosing, or full dose AC. Limited data also suggests that therapeutic doses might be associated with better survival compared to prophylactic doses.

However, at present, no randomized data is available to support one approach over another. Based on the available clinical evidence it may be suggested that


Though little data suggested D-dimer driven escalated thrombo-prophylaxis i.e. Using therapeutic anticoagulation in patients with very high D-Dimer levels (ex. > 3.0 μg/ml) or significantly rising D-dimer levels (ex. > 0.5 μg/ml per day) even after prophylactic dosing; may improve clinical outcomes, large scale studies are needed and presently daily monitoring of d-dimer for the purpose of guiding anticoagulant therapy is not recommended (but, worsening clinical

status in conjunction with rising D-dimer, may necessitate the escalation of anticoagulation therapy). In should be noted that a French guidance document recommends full-therapeutic dose anticoagulation for patient with increase in fibrinogen to >8 g/l or D-dimer of >3.0 μg/ml.


COVID-19 patients who are at low bleeding risk (VTE-Bleed score < 2 or Orbit score < 3) and were admitted to the ICU, intubated, sedated, and possibly paralyzed for multiple days may get benefited from out-of-hospital prophylaxis.

	- 1.Coagulopathy associated with covid changes from supressed-fibrinolytic (elevated D-dimer, normal fibrinogen) to enhanced-fibrinolytic type (elevated D-dimer, decreased fibrinogen) during the disease progression and thrombolytic therapy (TT) may be dangerous in the later type.
	- 2.Due to critically ill nature of disease, cause for hemodynamic instability cannot ascertained to PTE with certainty in all.
	- 3.Associated comorbid condition (GI and kidney dysfunction) may increase attendant bleeding risk with TT.

*Management of Pulmonary Thromboembolism DOI: http://dx.doi.org/10.5772/intechopen.100040*

Though there is a scare data on the efficiency of inhalation therapy with fibrinolytic substances in PTE in general, they should be used only in clinical trial settings and in all other situations TT (systemic thrombolysis using a peripheral vein over CDT) should be considered in high-risk PTE patients when other causes of instability are reasonably excluded [55–65].

## **5. Management of CTEPH**

CTEPH is major cause of chronic pulmonary hypertension leading to right heart failure and death. Lung ventilation/perfusion scintigraphy is the screening test of choice; a normal scan rules out CTEPH. In the case of an abnormal perfusion scan, a high-quality pulmonary angiogram is necessary to confirm and define the pulmonary vascular involvement and prior to making a treatment decision. Its management principles are [66–73]:


Systematic review data suggest that only 60% of CTEPH cases are operable and in 25% of operated patients, pulmonary hypertension persists; for whom nonsurgical alternative therapies (BPA and Pulmonary vasodilator therapy) must be considered, because they were shown to improve pulmonary hemodynamics and 6-minute walk distance (6MWD). However, their impact on mortality is yet to be proven.


Though, preliminary encouraging data suggests that BPA might have higher survival rate with fewer complication rate compared with PEA [74], at this point of time CTEPH still remains the standard therapy for operable CTEPH cases and guidelines state that BPA may be considered for patients who are technically inoperable or who carry an unfavorable risk/benefit ratio for PEA.

e.Anticoagulation: Lifelong anticoagulation is routinely recommended and used in CTEPH to prevent recurrent venous thromboembolism. The ideal choice of anticoagulation agent has not been established.

Multi-centre data suggested that the use of DOAC therapy resulted in a higher incidence of PTE recurrence compared with VKA without any survival difference. Although, there are an emerging positive data regarding the efficacy of DOAC therapy in this setting, standard practice is to use VKA (target INR of 2-3).

## **6. Important relevant latest guidelines**

See references [75–82].

## **7. Conclusion**

a.Management of acute PTE starts with risk stratification based on (s)PESI scoring and the patients with hemodynamic instability should receive systemic thrombolysis (ST). Patients with intermediate-high risk PTE may be thrombolysed if they deteriorate after initial anticoagulation or upfront low dose ST may be considered particularly if the patient has no high bleeding risk.

However, choice of thrombolytic agent and evidence-based indications to stop ST in indicated patients is largely unknown.

b.Both catheter-based therapies (CBT) and surgical pulmonary embolectomy (SPE) are well accepted second line therapies in patients who have failed ST. However, comparative effectiveness of these approaches is difficult to study with systematic review data suggesting significantly higher absolute mortality with SPE compared to CBT.

Based on the available evidence catheter directed thrombolysis (CDT) may be considered as 2nd line therapy in appropriate patients, if ST fails. Use of CDT in sub-massive PE need further evidence to define its appropriate role.


Further studies are in need of the hour to identify the significance of subsegmental PE and appropriate candidates for systemic anticoagulation.


Use of IVC filters is based on low quality evidence and at present may be inserted in only a subset of PE patients (ex. contra-indication for anticoagulation) as secondary prophylaxis.

g.Covid associated PTE is related to thrombo-inflammation and routine prophylaxis with standard dose of LMWH is recommended in all hospitalized patients and role of therapeutic dose of LWWH as prophylaxis in yet to be properly defined. Extended VTE prophylaxis in patients with no documented in-hospital VTE episode should be considered on case-to-case basis.

Ongoing clinical trials will shed more light on the role of aspirin for VTE prophylaxis, dose and duration of AC for VTE prophylaxis in hospitalized and non-hospitalized patients.

## **Conflict of interest**

None to declare.

## **Author details**

G. Ravi Kiran Department of Cardiology, Government General Hospital, Kurnool, Andhra Pradesh, India

\*Address all correspondence to: drrxrk@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 8**

## Advances of Thrombectomy in Venous Thromboembolism

*Jia-Ling Lin, Po-Sheng Chen, Po-Kai Yang and Chih-Hsin Hsu*

## **Abstract**

Venous thromboembolism (VTE) presenting as deep vein thrombosis and pulmonary embolism clinically is a potentially fatal cardiovascular diseases with short-term and long-term sequelae. Furthermore, there is high recurrent rate in VTE patients during follow-up. Anticoagulation with traditional anticoagulants or new generation of oral anticoagulants is the gold standard treatment in patients with VTE. On the other hand, there is remarkable progression in device-based or surgical thrombectomy in managements of VTE in recent years. Current evidence also demonstrates the efficacy and safety of these invasive procedures in selective VTE patients. The present article will illustrate recent advances of device-based or surgical thrombectomy in VTE treatment.

**Keywords:** deep vein thrombosis, pulmonary embolism, catheter-directed thrombolysis, (mechanical thrombectomy), rheolytic embolectomy, aspiration thrombectomy, rotational thrombectomy

## **1. Introduction**

Venous thromboembolism (VTE) is a set of diseases in which blood clot forms and occludes venous circulation and regard as the third frequent acute cardiovascular disease [1]. Clinically, VTE presents as deep vein thrombosis (DVT) and pulmonary embolism (PE) which account for two-third and one-third of VTE, respectively [2]. The estimated annual rate of incidence of VTE is 80 to 260 per 100000 population [3]. In general, the incidence of VTE increases with age. One epidemiologic study in United States showed that the incidence of VTE was 143 per 100000 in papulation at age 45–49 years and 1134 per 100000 in those at age > 80 years [4]. There is difference of incidence between ethnicities and black and white have higher incidence than other races [2]. Although patients with VTE might be asymptomatic, VTE is a potentially fatal disease. One study reported that the estimated annual VTE-related death was around 300000 in U.S [5] and nearly 30% of VTE patients died within 30 days after diagnosis. Compared to DVT, PE accounts for majority of early-stage mortality of VTE [6, 7]. In addition to VTErelated mortality and cardiovascular sequelae, such as post-thrombotic syndrome, chronic venous insufficiency and chronic thromboembolic pulmonary hypertension, etc., patients with VTE have high risk of other atherosclerotic diseases and acute cardiovascular events, such as acute myocardial infarction and ischemic stroke, in the short-term and long-term follow-up [8–10]. With a brief review of pathogenesis and risk factors of VTE, the following of this chapter focuses on percutaneous interventions for VTE.

## **2. Pathogenesis and risk factors of venous thromboembolism**

Virchow's triad composed of stasis, vascular damage and hypercoagulable status describes the essential components contributing to the thrombus formation [11]. In most cases of VTE, stasis plays a major role triggering the formation of venous thrombosis [12]. However, the exact pathogenesis of VTE seems to be more complex and is not fully understood [2, 13]. Only one existing contributing factor is hard to result in the development of clot formation [14]. Nonetheless, the interaction between multiple concurrent contributing factors increases the risk of formation of venous thrombosis which progresses to significant VTE clinically thereafter.

In clinical aspect, many diseases and circumstances regarded as risk factors are identified to predispose to the development of VTE. In general, these risk factors are classified into genetic and acquired risk [15–18]. Genetic risk factors including protein C and S deficiency, antithrombin deficiency, the factor V Leiden gene mutation, antiphospholipid syndrome, etc. Acquired risk factors are further divided into concurrent diseases (elderly, chronic diseases, active cancer, obesity) and transient states (surgery, trauma, hospitalization, immobility, central venous catheter or device indwelling, oral contraceptives, etc.) [2]. Of note, hospitalization is an important period that multiple risk factors encounter concurrently and increase the risk of VTE greatly [2, 19]. Although predisposing factors are identified in most cases of VTE, there are still almost 20% of case having no obvious etiology. The result suggests the significance of unknown genetic or acquired risk factors to the development of VTE [2, 3].

## **3. Thrombectomy in management of VTE**

To date, anticoagulation is still the principal treatment in VTE. In addition to traditional anticoagulation, including heparin, low molecular weight heparin and vitamin K antagonists, as well as direct thrombin inhibitors, non-vitamin K oral anticoagulants (NOACs), known as direct oral-anticoagulant (DOACs) change the strategy in medical treatment of VTE. The update of principles and strategies of medical treatment of VTM will be illustrated in another chapter. On the other hand, endovascular or surgical thrombectomy and embolectomy have role in treatment of VTE. Historically, Läwen conducted the first thrombectomy for venous thrombosis of upper extremity in 1938 [20]. After evolution in nearly 90 years, there are great advances in techniques and modalities in performing thrombectomy and embolectomy. However, thrombectomy or embolectomy is still indicated in limited population in modern treatment of VTE, especially in patients with massive or submassive thrombus burden accompanied by unstable hemodynamic status or critical complications [21–23]. Theoretically, endovascular or surgical thrombectomy removes majority of thrombus load more completely and recanalization of occluded vessels earlier [24, 25]. Moreover, some previous studies even reported that thrombectomy may have potential benefits comparing to anticoagulation alone in long-term complications and quality of life in certain VTE patients [22, 26]. The aim of this chapter will focus on the advances of modalities of endovascular and surgical thrombectomy.

#### **4. Catheter-based therapy**

Percutaneous management, also known as catheter-based therapy (CBT), for VTE can be divided into two mechanisms: thrombolysis-based and mechanical

thrombectomy. There are also devices combining these two mechanisms. For certain conditions, percutaneous approaches also include balloon angioplasty and stenting. We describe different types of CBT in the following sections.

## **4.1 Catheter-directed thrombolysis**

Compared to systemic thrombolysis, catheter-based thrombolysis is, by concept, more likely a local therapy. The advantage of this approach is a reduceddose thrombolysis. Therefore, there is less risk of bleeding [27, 28]. Although with lower dosage needed, absolute contraindications for catheter-directed thrombolysis are the same as for systemic thrombolysis, including history of any intracranial hemorrhage, ischemic stroke within three months, structural intracranial lesion, active bleeding, recent head, eye or spinal surgery, and recent head trauma [29, 30].

This approach is done by placing an infusion catheter with multiple side holes and a tip occluding wire or a dedicated catheter specifically for a certain device, preferentially into the thrombus. It may sometimes require two catheters to be placed in each of the main pulmonary arteries. If there is no specialized catheter, a standard pig-tail or pulmonary artery catheter may also serve to deliver thrombolytic agent locally. When performing intervention for pulmonary embolism (PE), power injection may be necessary to take clear angiography to localizes the emboli. For each main pulmonary artery, perform contrast injection at 15–20 m/s for a total volume of 30 ml [28]. For intervention of deep venous thrombosis (DVT), careful hand injection with low-volume contrast is preferred to avoid disruption of thrombi with progression to PE [30].

Thrombolytic agent is administered via the carefully placed catheter. There is no standard for the agent and dosage used. It varies according to accompanied device, patients' bleeding tendency, and physicians' preferences. A commonly used regimen is tissue plasminogen activator (tPA) 0.5–1.0 mg/hr for 6–24 hours, with total dosage usually between 12 and 24 mg. Fibrinogen should be monitored during infusion of fibrinolytic agent. Dose reduction or discontinuation should be considered if level of fibrinogen falls below 150 mg/dL. During t-PA infusion, a low-dose heparin infusion is usually kept, with a partial thromboplastin time (PTT) just around the lower limit of therapeutic range, usually PTT 40–50 seconds [28, 30].

Catheter-directed thrombolysis applies for both DVT and PE. A key factor to success of lytic-based approach is that whether the thrombolytic agent is delivered into the thrombus with good penetration. A resolution to this problem is combining other method to enhance efficacy of drug delivery, such as the EkoSonic system.

EkoSonic™ Endovascular System (EKOS) is a device for ultrasound-assisted catheter-directed thrombolysis. It includes a control unit and a uniquely designed catheter to achieve better penetration of thrombolytics by so-called acoustic pulse thrombolysis. The catheter is composed of an ultrasonic core in central lumen, central coolant lumen, and drug delivery lumen. The ultrasonic core generates an acoustic field to enhance drug delivery into the clot and to unwind the fibrin for better exposure to thrombolytic agents. This system is indicated for both DVT and PE [31].

There were also devices designed for a true localized therapy. Trellis™ Peripheral Infusion System is a specialized device for isolated thrombolysis. It consists of two occlusive balloons to isolate the treatment area, an infusion zone to deliver thrombolytic agents, an oscillation drive unit to better disperse the drug to thrombi, and an aspiration window to remove the dissolved clot. Although with a unique design to ensure localized thrombolysis and thrombi removal, the devices were recalled due to incorrectly labelling of proximal and distal balloons [32].

Of note, catheter-directed thrombolysis alone may not be sufficient to clear all blood clots, although it is true that the goal of catheter-directed thrombolysis for PE is not to remove emboli completely, but to reduce the risk from high to intermediate [29]. Further intervention to remove emboli and thrombi may be needed and there are devices combining local thrombolysis and sequential blood clot removal, which would be described later.

#### **4.2 Mechanical thrombectomy**

Mechanical thrombectomy is achieved by physical disruption of thrombus via different methods, with various devices designed for this purpose. These devices have different benefits, adverse effects, and special concerns while manipulation. Overall, they are less invasive compared with traditional surgical thrombectomy. Some devices achieve thrombus removal in a single session, sparing the use of thrombolytic agents. The following section describes devices with approval. Devices still under development are not covered.

#### *4.2.1 Thrombus fragmentation*

Mechanical thrombectomy without a device has long been described in both treatment for DVT and PE. It is usually done by a pigtail with manual rotation or by balloon angioplasty [28]. An important issue of fragmentation is that it might create distal emboli, causing worse distal obstruction; and fragmentation alone may not be enough to resolve obstruction. It may be followed by systemic thrombolysis, catheter-directed thrombolysis, or thrombi removal by manual aspiration. Due to lack of clinical evidence, there is no recommendation for how to combine other strategy after manual thrombus fragmentation.

#### *4.2.2 Aspiration thrombectomy*

Besides manual thrombus aspiration with a regular guide catheter or specialized catheters with greater power of suction, there are devices designed to remove thrombus by suction via negative pressure. The advantages are the ability to remove large thrombi or even chronic thrombi, avoidance of thrombolytic agents, and possible less risk of bleeding.

The AngioVac® system works in an extracorporeal circuit and needs two large venous access sites for AngioVac inflow cannula (22Fr) and reinfusion outflow cannula (16–20 Fr). The third generation uses funnel-shaped and different-angled tip (20 degree or 180 degree) to facilitate navigation. Besides the need of two largebore accesses, another disadvantage of this device is that perfusionist is required. It is indicated for removal of fresh, soft thrombi or emboli in right atrium, right ventricle, superior vena cava, inferior vena cava, and iliofemoral veins during extracorporeal bypass. It is not indicated in pulmonary vasculature although there are case series [33].

The FlowTriever® system includes an Triever Aspiration Catheter, a FlowTriever catheter, and a retraction aspiration device. Thrombus removal is done by manual aspiration with a syringe via the large-lumen aspiration catheter. There are nitinol mesh disks on the tip of FlowTriever catheter to disrupt and drag residual clots into the aspiration catheter for extraction. This system is indicated for PE [34]. A similar system dedicated for DVT is the ClotTriever® system. It includes a ClotTriever sheath and a ClotTriever catheter. The procedure steps are somewhat different. The ClotTriever catheter is position beyond the thrombus. A mesh collection bag on the tip of ClotTriever catheter retracts thrombi into the ClotTriever

sheath with a self-expanding funnel tip, providing embolic protection. Manual aspiration is applied if there are residual thrombi in the sheath. Since treatment is completed in a single session and there is no need for thrombolysis, care in intensive care unit (ICU) after procedure may not be necessary. However, a large-bore vascular access (20 Fr) is needed [35].

Penumbra's Indigo® Aspiration System operates in a more "automatic" way, with less need of manual control. The main components of the system are a catheter, a Penumbra ENGINE to generate vacuum for aspiration, and a tubing system. When the catheter is in position, the system performs automatic aspiration. With different catheters, there are corresponding Separator wires to remove clot in the lumen of aspiration catheters. Compared to AngioVac® and FlowTriever®, the Indigo® system does not require large-bore vascular access but may therefore unable to remove larger thrombi. It is indicated for removal of fresh, soft thrombi or emboli in both peripheral arterial and venous system and for treatment of PE [36].

Syringed-based thrombectomy offers limited force and aspirated volume, and operators could not further manipulate. Pump systems with specific devices provide increased force and volume but usually with increased complexity of the procedure and increased cost. Control Mechanical Thrombectomy™ system (Aspire) works in a different way. The system includes a thrombectomy catheter and a control mechanical aspirator which is like a handle. Through the handle, the operator can adjust strength of the aspirated force, and switch between continuous and pulsed force. It is indicated for removal of fresh, soft thrombi in peripheral vasculature, but not PE [37].

#### *4.2.3 Rotational thrombectomy*

The concept of rotational thrombectomy is thrombus disruption by a catheter with rotating head. Most devices also have the ability to remove thrombus via active suction.

Aspirex® mechanical thrombectomy device consists of a catheter with a handle and a drive system. At the tip of the catheter, there is aspiration port to suck in thrombi; and inside the catheter, there is rotational coil to break down thrombi. The fragmented thrombi are then aspirated out. The device is indicated for both arterial and venous thrombi. With limited case studies, it is not approved for treatment of PE [38].

CLEANER™ Rotational Thrombectomy System is a one-piece device. Rotating action of its sinusoidal wire breaks down thrombi. The sinusoidal shape provides atraumatic action on thrombi adhered to vessel wall. The device also enables infusion of thrombolytic agents via a distal side hole. It is indicated for removal of thrombus in peripheral vasculature, but not for PE [39].

## *4.2.4 Rheolytic thrombectomy*

Rheolytic thrombectomy is based on Bernoulli effect. A high-velocity saline jet creates a low-pressure, drawing thrombi into the catheter. To eliminate thrombi better, it may be accompanied with thrombolysis or other mechanical method such as aspiration.

Among this category, the mostly studied device is AngioJet™ Rheolytic Thrombectomy System, consisting of a console and a thrombectomy catheter. The system works in both pharmacological and mechanical ways. Operators can deliver thrombolytic agents directly into the clot to facilitate removal of thrombus. The console generates pressurized saline to draw thrombi into the catheter via an inflow window near the tip of the catheter, and then evacuates the thrombi.

Notable adverse events include pain, cardiac arrythmia (mainly bradyarrhythmia), hypotension, transient hemolysis, bleeding, and acute kidney injury. Hydration before, during, and after the procedure may be considered. AngioJet™ system is indicated in removal of thrombi in peripheral vasculature. When used in PE, there were severe adverse events, including death; so, there is a "black box" warning for AngioJet™ in treating PE [40].

### **4.3 Combined thrombolytic and mechanical approaches**

The concept of combination works in at least two modes. One is to combine multiple mechanisms at the same time, usually by devices, like EKOS or AngioJet™. The other way is to use different methods sequentially. For instance, physicians may perform balloon angioplasty first to disrupt the thrombi; and then leave an infusion catheter for thrombolysis. This concept also works in a reverse way. Physicians may place an infusion catheter for thrombolysis first, usually for 24 hours; and then break the loosen thrombi with balloon angioplasty. Theoretically, combing thrombolysis and mechanical thrombectomy improves efficacy of thrombus removal, but there is no standard for how to combine multiple strategies due to limited studies. This so-called pharmacomechanical approach is therefore, largely based on clinicians' experience.

#### **4.4 Angioplasty and stenting**

Besides thrombolysis and mechanical thrombectomy, some adjuvant procedures may be needed, mainly for DVT. Balloon angioplasty plays a role in chronic thromboembolic pulmonary hypertension, but not for acute PE. For DVT, placement of inferior vena cava filter before procedure may be considered to prevent PE, especially for patients with poor cardiopulmonary function and deemed unable to tolerate PE [30]. The results of studies regarding stenting for DVT were inconsistent, although some showed reduced severity in post-thrombotic syndrome and improved quality of life in some aspects [41–43]. This approach is therefore largely based on clinicians' experience.

Stenting is considered if there is residual thrombi or residual venous outflow obstruction. It may also be considered when there is non-thrombotic cause of stenosis, such as in May-Thurner syndrome. Therefore, careful assessment of the lesion is important. It is helpful to combine other image modality such as computed tomography or intravascular ultrasound. Besides anatomical nature, clinicians should put patients' life expectancy, bleeding risk, and likelihood of symptom improvement into consideration. When a stent is placed, there is always risk of in-stent restenosis or occlusion. Risk factors include poor inflow, external compression, inappropriate stent design, stent misplacement or migration, stent fracture, and bleeding. Patients should be notified about the possibility of reintervention [44].

#### **4.5 Summary of catheter-based therapy**

The purpose of CBT is to relieve obstruction quicker, compared with traditional medical therapy. However, there is no strong evidence that CBT is better than traditional systemic thrombolysis since randomized trial assessing hard outcomes, such as mortality, is lacking. Also, among CBT, there is no trial comparing catheter-directed thrombolysis and mechanical thrombectomy or comparing different devices. It is also important to remember that published studies for CBT with devices are of small patient numbers. There are many trials still going on. Hopefully, these trials will provide evidences for more specific guidance.

*Advances of Thrombectomy in Venous Thromboembolism DOI: http://dx.doi.org/10.5772/intechopen.100044*

For any intervention, there are always complications. Possible complications of CBT include access site bleeding, vascular injury, major bleeding (including intracranial hemorrhage), distal emboli (especially of concern with PE when performing intervention for DVT), cardiac tamponade (intervention for PE), hemodynamic deterioration, and deterioration in renal function. Some studies did not demonstrate the presumed benefit of less major bleedings (including intracranial hemorrhage) in percutaneous methods, compared with systemic thrombolysis [28, 29]. The balance between risk and benefit of these interventions should be personalized.

Generally speaking, CBT may be considered in patients with iliofemoral DVT who have severe symptoms and a low risk of bleeding [45]. For PE, CBT is an alternative to systemic thrombolysis and surgical embolectomy, considered when these approaches are contraindicated or fail [46]. For now, the choice of CBT largely remains on physicians' experience and local availability.

## **5. Surgical embolectomy**

Surgical intervention is an old skill compared with percutaneous intervention. Surgical embolectomy of PE requires cardiopulmonary bypass. After thoracotomy, emboli are removed manually with forceps. Balloon catheter and suction may be used for residual emboli. Although surgical embolectomy is a class I indication for massive pulmonary embolism, it is usually reserved as a salvage therapy when other therapies fail or are contraindicated, due to its invasive nature. If there is thrombus in right heart or thrombus across patent foramen ovale, surgical embolectomy would be considered the first-line therapy [27].

On the other hand, surgical thrombectomy for DVT is usually done with a special balloon catheter to pull out thrombi in the direction of venous flow, called Fogarty maneuvers [47]. Unlike for PE, surgical thrombectomy for DVT is not recommended by clinical guidelines. Although there are studies showing good patency rates after surgery, it is usually considered only in certain conditions when rapid reduction of venous obstruction is needed, such as in patients with phlegmasia cerulea dolens [48].

## **6. Conclusions**

Although rapid evolution of modalities and relatively high successful rate in experienced center, routine use of endovascular or surgical thrombectomy and thrombolysis in patient with VTE is not recommended. To date, large-scale clinical trial assessing the efficacy and safety of invasive thrombolysis or thrombectomy is still lack. The application of endovascular or surgical strategies should be considered in selective VTE patients with unstable hemodynamic status or critical VTE-associated complications or having contraindications or high risk of bleeding while receiving systemic thrombolysis. In addition, future studies focusing on cost-effectiveness are needed to integrate these invasive procedures with medical strategies in the protocol of VTE treatment.

## **Author details**

Jia-Ling Lin1,2, Po-Sheng Chen1,3, Po-Kai Yang2 and Chih-Hsin Hsu1,3\*

1 Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan

2 Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, Dou-Liou Branch, College of Medicine, National Cheng Kung University, Yunlin, Taiwan

3 Division of Critical Care, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

\*Address all correspondence to: chihhsinhsu@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Advances of Thrombectomy in Venous Thromboembolism DOI: http://dx.doi.org/10.5772/intechopen.100044*

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## **Chapter 9**
