Keywords

Pathophysiology

Venous thromboembolism (VTE) encompasses deep vein thrombosis (DVT) and subsequent pulmonary embolism (PE). Historically, the first description of DVT was in the Ayurveda medical texts of ancient India (~600–900 BC) [1, 2]. It was not until the 1850s that Rudolf Virchow described his famous triad of thrombosis: hypercoagulability, vessel injury, and stasis [3].

The first documented case of DVT was in the Middle Ages. It described a 20-year-old Norman cobbler named Raoul suffering from right calf pain and swelling that progressed to the thigh and resulted in ulceration [4]. This was treated with intense prayer at the tomb of King Saint Louis. After several days, Raoul applied dust from the tomb directly onto the ulcer, which led to a miraculous cure. In the centuries that followed, treatment for DVT moved away from bloodletting toward therapies that are more recognizable by today’s standards [1, 4].

VTE is a disease that affects a considerable number of people annually in the USA. It is the third most common life-threatening cardiovascular disease in the USA, after myocardial infarction and stroke [5]. Approximately 900,000 cases of lower extremity DVT are reported annually. Pulmonary embolism, a serious consequence of DVT, occurs in up to 600,000 people annually, resulting in the mortality of 50,000 individuals. Furthermore, VTE can develop into a chronic disease for many patients. One-third of patients with VTE will have some form of recurrent disease within 10 years, and 50% of patients with DVT will experience long-term complications such as post-thrombotic syndrome or venous ulcers [5, 6].

The three components involved in thrombosis are venous stasis, hypercoagulability , and abnormalities of the venous endothelium . Venous stasis can occur as a consequence of external compression on a vein by enlarged lymph nodes or bulky tumors, a May-Thurner lesion or May-Thurner variant, or prior thrombosis leading to luminal narrowing. Trauma or foreign body within a vein (e.g., venous catheter, inferior vena cava (IVC) filter) can also cause abnormal venous blood flow. Lastly, venous stasis can occur with prolonged immobilization (e.g., patients who have undergone recent major surgery). Hypercoagulable states are associated with a myriad of hematologic disorders not limited to factor V Leiden deficiency, antithrombin III deficiency , or protein C or S deficiency. Hypercoagulability can also be a result of oral contraceptive use, pregnancy, postpartum state, or underlying malignancy. Finally, abnormalities of the venous endothelium can result from prior trauma secondary to venous catheters, prior DVT or injury from the infusion of deleterious agents such as chemotherapeutic drugs or total parenteral nutrition [6,7,8].

Key Point

The three factors leading to venous thromboembolism (Virchow’s triad):

  • Venous stasis

  • Hypercoagulability

  • Abnormalities of the venous endothelium

Clinical Indication

The presentation of VTE can be variable, but clinical hallmarks of the disease reflect its pathophysiology. DVT typically presents with pain, erythema, tenderness, and swelling of the affected limb, which is typically circumferentially larger than the contralateral side . Although thrombi can form in the upper extremities or spontaneously in the right ventricle, the majority of pulmonary emboli are believed to originate from DVT in the lower extremities. As thrombi in the calf veins extend to the deep veins of the thigh, they can break, dislodge, and travel to the right heart and pulmonary arteries. PE can present with the sudden onset of dyspnea, pleuritic chest pain, cough, wheezing, tachycardia, tachypnea, hemoptysis, or cardiovascular collapse and shock. These symptoms are non-specific such that further diagnostic testing is needed [8, 9].

Compression ultrasound is the noninvasive test of choice for diagnosis of DVT. It is highly sensitive for the detection of femoropopliteal DVT but less sensitive for calf and iliocaval thrombosis. The diagnosis of lower extremity DVT is made by evaluation of the common femoral to popliteal veins using a 5–10-MHz transducer. Upper extremity DVT is diagnosed by ultrasound of the upper arm, axilla, neck, and subclavian veins during quiet respiration using a 7.5-MHz imaging transducer coupled to a 5-MHz pulsed Doppler transducer . Criteria for a positive exam include (1) vessel non-compressibility, (2) absent Doppler signal, (3) absence of respiratory phasicity or augmentation, and/or (4) visible thrombus, typically a hypo-echoic or hyper-echoic intraluminal mass. Respiratory phasicity suggests patency between the imaged vein and the heart. Normal augmentation suggests patency between the imaged vein and the site of manual venous compression. In patients with suspected thrombosis and a negative compression ultrasound, the test should be repeated in 7 days [6, 8].

Key Point

Compression US is the noninvasive test of choice for diagnosis of DVT. Diagnostic criteria include:

  • Non-compressible vessel

  • Absent Doppler signal

  • Absence of respiratory phasicity or augmentation

  • Visible thrombus

CT (computed tomography) angiography is the most commonly used imaging test to evaluate for PE. It is more reliable than ventilation-perfusion (V/Q) scanning using technetium DTPA (ditriaminopentaric acid), historically, a more popular method for PE evaluation, and less invasive than pulmonary angiography, the previous gold standard [8, 9]. CT angiography has the added benefit of visualizing pulmonary arterial anatomy over V/Q scanning. Filling defects in the pulmonary arteries during the appropriate phase of contrast injection confirms the diagnosis (Fig. 10.1a). CT angiography has limited sensitivity for more peripheral emboli in smaller vessels [8, 9]. The use of fibrin D-dimer is also used to add to the diagnostic accuracy of noninvasive tests . In one study, the sensitivity of D-dimer concentrations over 500 μg for the presence of PE was 98% with a negative predictive value of 98% [8].

Fig. 10.1
figure 1

A 51-year-old female who presents with acute shortness of breath after prolonged car ride. CT pulmonary angiogram (CTPA) (a) demonstrates saddle embolus extending across the bifurcation of the main pulmonary artery , with a large clot within the right main pulmonary artery and (b) a markedly abnormal RV:LV ratio. Frontal radiograph (c) demonstrates lysis catheters extending into the bilateral lower lobe pulmonary arteries

Full size image

Key Point

PE is most commonly diagnosed with CTPA although V/Q scan and pulmonary angiography can also be used.

Findings of PE on chest radiograph (CXR) are neither sensitive nor specific. The Westermark sign (hyperlucency surrounding oligemia), Fleischner sign (prominent central artery), and Hampton hump (pleural opacification indicating pulmonary infarct) have all been described as radiographic signs of PE. The role of the CXR in the setting of suspected PE is to rule out other causes, such as pneumonia, as most CXRs in the setting of PE are normal. The same is often true of the electrocardiogram (ECG), although there are characteristic ECG findings of right heart strain in the setting of PE. ECG can also diagnose left bundle branch block (LBBB) , which is of significance if the patient undergoes pulmonary artery catheterization. The interventionist must be aware of preexisting LBBB because complete heart block can be induced during catheterization of the right heart [9].

Anticoagulation is the standard of care in the treatment of most patients with VTE; however, a small number of patients with DVT present with acute limb-threatening venous hypertension known as phlegmasia . In its early phase, the condition presents as phlegmasia alba dolens, characterized by a painful, swollen, and pale extremity. With subsequent progression and occlusion of venous collaterals, the condition progresses to phlegmasia cerulea dolens, characterized by blue discoloration of the extremity (Fig. 10.2a). This condition can rapidly progress to arterial compromise, venous gangrene, and limb loss. Most experts agree that in the absence of high bleeding risk, these patients will benefit from active thrombus removal techniques, including catheter-directed thrombolysis (CDT) [10]. In addition, some experts support the escalation of therapy and use of CDT in patients with progressive IVC thrombosis or progression of DVT symptoms despite adequate anticoagulation [11].

Fig. 10.2
figure 2

A 62-year-old female with history of ovarian cancer and right pelvic lymph node mass presents with severe right leg pain and swelling. Right leg photograph (a) demonstrates painful blue discoloration characteristic of phlegmasia cerulea dolens. Prone venogram (b) demonstrates significant filling defects (arrows) within the entirety of the right femoral vein and lack of patent collaterals. Follow-up prone venogram (c) after CDT demonstrates restored patency of the right femoral vein. Right leg photograph (d) 10 days after CDT demonstrates improvement in appearance of right leg. Courtesy of Brooke Spencer, MD

Full size image

Key Point

Anticoagulation for a minimum of 3 months is the standard of care for treatment of VTE. CDT may help in high-risk patients (i.e., massive PE).

Key Point

Acute limb-threatening venous hypertension due to DVT:

  • Phlegmasia alba dolens = painful, swollen, pale extremity

  • Phlegmasia cerulea dolens = blue discoloration of the extremity

Patients with PE are stratified into high-, intermediate-, and low-risk categories. Patients with high-risk (massive) PE present with hemodynamic instability (tachycardia, hypotension) and are at high risk of mortality. In addition to anticoagulation , these patients may require treatments such as thrombolytic therapy or embolectomy . Patients with intermediate-risk (sub-massive) PE present with hemodynamic stability but demonstrate signs of right ventricular dysfunction, which have been associated with early clinical deterioration and mortality . Presence of right heart dilation on echocardiography or CT pulmonary angiogram (right ventricle/left ventricle ratio > 0.9, Fig. 10.1b) and/or elevated serum troponin or brain natriuretic peptide (BNP) supports the diagnosis of intermediate-risk PE. Use of catheter-based therapies in addition to anticoagulation, remains controversial [12]. All other patients have low-risk PE and may potentially be managed as outpatients [5, 12].

Key Point

Signs of right heart strain:

  • RV:LV ratio > 0.9

  • Elevated troponin or BNP

Conventional Therapy

As mentioned, anticoagulants are the mainstay of therapy for VTE [12]. Anticoagulants, such as heparin, warfarin, low-molecular-weight heparins (enoxaparin, dalteparin), direct factor Xa inhibitors (apixaban, rivaroxaban, edoxaban), and direct thrombin inhibitors (dabigatran), mainly function to inhibit clot propagation [12]. In general, anticoagulation for a minimum of 3 months is the standard of care for the majority of patients with PE, with some patients requiring prolonged or indefinite anticoagulation [12, 13].

Systemic thrombolytics and surgical embolectomy are typically reserved for patients with massive PE. Thrombolytics , such as recombinant tissue plasminogen activator (rTPA) , actively lyse clot by interacting with plasminogen to form plasmin, a proteolytic enzyme that degrades fibrin strands. Absolute contraindications to the use of thrombolytics and anticoagulants include active bleeding or cerebrovascular accident within 2 months, intracranial neoplasm, or recent head trauma. Major bleeding is a known complication of thrombolytics and anticoagulation; the risks and benefits of therapy must be carefully weighed in each individual clinical scenario. Relative major and minor contraindications also exist. In the case of an absolute contraindication to anticoagulation, an IVC filter may be placed to provide a physical barrier to clot migration to the lungs, though their efficacy has not been well documented and their long-term deleterious consequences are well known (refer to Chap. 11 for more information) [5, 14].

Key Point

Absolute contraindications to thrombolytics and anticoagulation:

  • Active bleeding

  • Cerebrovascular accident within 2 months

  • Intracranial neoplasm

  • Recent head trauma

Similar to PE, anticoagulation for a minimum of 3 months is the standard of care for treating the vast majority of patients with DVT [12]. One of the main goals in medical therapy of DVT is to preserve function of the venous valves. When these valves become damaged, normal venous blood flow becomes compromised leading to venous hypertension and venous stasis , subsequently causing further problems [10, 15]. Most patients with DVT can be treated as outpatients, except in cases of significant comorbidity such as chronic kidney disease or limb-threatening venous hypertension. Furthermore, anticoagulation is not routinely recommended for distal calf vein thrombosis, unless the patient is symptomatic, has risk factors for proximal extension, or the thrombus shows extension at 2-week follow-up imaging [5].

Interventional Therapy

Many institutions use a pulmonary embolism response team (PERT) to standardize and expedite the treatment of patients with PE [16]. This multidisciplinary team includes medical, surgical, and interventional specialists interested in treating PE. Convening at the time of PE diagnosis in a virtual space, such as a phone or video conference, the PERT allows rapid evaluation and formulation of a treatment plan. In general, endovascular intervention is reserved for the most severe situations, specifically patients with high-risk (massive) and intermediate-risk (sub-massive) PE. The Pulmonary Embolism Severity Index (PESI) was developed to help identify patients at risk of complication from PE and guide initial treatment [17]. Using 11 patient characteristics, the PESI stratifies a patient with PE into 5 classes of increasing risk of mortality and adverse outcome.

Key Point

PESI score clinical criteria:

  • Age

  • Sex

  • History of cancer

  • History of heart failure

  • History of chronic lung disease

  • HR ≥110

  • SBP <100 mmHg

  • RR ≥30

  • Temp <36▫

  • Altered mental status

  • O2 saturation < 90%

In these high-risk patients, prompt improvement of right ventricular function may be necessary to avoid cardiogenic shock and death [18]. The effects of heparin on right ventricular function are minimal in the first 28–48 h [19]. Options for transcatheter therapy include fragmentation of the thrombus into smaller pieces that are less obstructive to flow or removing the thrombus using a thrombectomy device. Several devices exist which use rotation, aspiration, or rheolysis to mechanically break and remove the thrombus from the pulmonary circulation. These methods will quickly improve right ventricular function compared to CDT, which will slowly improve function over time as thrombolysis occurs. As such, CDT is more often appropriate for treating patients with intermediate-risk PE given their hemodynamic stability.

Prior to CDT, patients must be evaluated for contraindications to thrombolytic therapy. Absolute contraindications include active bleeding, recent stroke, intracranial lesion (mass or aneurysm), recent gastrointestinal bleeding, and spinal surgery. Relative contraindications include recent major abdominal surgery, pregnancy, or coagulopathy. In patients who cannot receive anticoagulation and thrombolytic medications, mechanical thrombectomy may be the favored treatment.

Key Point

Absolute contraindications for CDT:

  • Active bleeding

  • Recent stroke

  • Intracranial mass

  • Intracranial aneurysm

  • Recent GI bleeding

  • Spinal surgery

In most cases, lysis catheter placement is relatively painless for both DVT and PE treatment. However, patients may require moderate sedation for positioning and/or anxiety. Pre-procedure imaging includes CT pulmonary angiogram and echocardiography. BMP and troponin can also be useful tools for assessing organ function.

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