1 Introduction

Harika Dabbara and Julie C. Bulman

Venous thromboembolism (VTE), constituted of deep vein thrombosis (DVT) and pulmonary embolism (PE), is a clinically morbid and highly prevalent chronic illness. Although precise numbers of individuals affected by VTE is not tracked, epidemiological analyses estimate an incidence between 1 and 2 individuals per 1,000 every year or 300,000 to 600,000 individuals are affected annually in the United States ( ? Fig. 1.1). ? [1], ? [2], ? [3] However, this incidence rate varies based on age, race, and gender. ? [1], ? [4] In individuals older than 80 years, the incidence rises to 1 in 100 individuals ( ? Fig. 1.2). Men have a slightly higher incidence than women, aside from women in reproductive years, and the overall incidence is higher in black and white individuals than in other races. ? [1], ? [4] Although most events are unprovoked, cancer and perioperative patients are at an increased risk. VTE can also often be fatal, with an estimated 25% of PE cases presenting with sudden death and all VTE carrying a 10 to 30% mortality rate within 30 days. ? [1] Given this high incidence, VTE imposes a considerable economic burden, costing $7,594 to $16,644 per patient and an annual cost of $2 to $10 billion. ? [1], ? [5] Furthermore, it is the leading preventable cause of in-hospital mortality in the United States. ? [6]

Fig. 1.1  Trend in venous thromboembolism (VTE) incidence over time in the Worcester VTE study from 1985 to 2009. Reproduced with permission from: Huang W, Goldberg RJ, Anderson FA, Kiefe CI, Spencer FA. Secular trends in occurrence of acute venous thromboembolism: the Worcester VTE study (1985-2009). Am J Med 2014;127(9):829-839.

Fig. 1.2  Incidence of venous thromboembolism (VTE) by age from 1966 to 1990 in Olmsted County, MN. Reproduced with permission from: Huang W, Goldberg RJ, Anderson FA, Kiefe CI, Spencer FA. Secular trends in occurrence of acute venous thromboembolism: the Worcester VTE study (1985-2009). Am J Med 2014;127(9):829-839.

Diagnosing VTE based on clinical symptoms is generally unreliable due to nonspecific signs. Clinical symptoms of DVT include unilateral calf or thigh pain, leg swelling, or redness, while symptoms of PE include dyspnea and pleuritic chest pain. ? [7] Definitive diagnosis of VTE requires radiological imaging, which includes compression ultrasonography (CUS), computed tomography (CT), and conventional venography for DVT and CT pulmonary angiography (CTPA), nuclear medicine lung scintigraphy, and conventional pulmonary angiography for PE. ? [7], ? [8], ? [9], ? [10]

Treatment of VTE has evolved significantly over time and seeks to prevent propagation of thrombus and long-term recurrent events and address any clinical symptoms in the short term. Early attempts to prevent VTE date back to the late 1800s, when K.G. Lennander, a Swedish surgeon, identified the benefit of hydration to encourage blood circulation as well as compression and elevation of the leg to prevent DVT. ? [11] In 1937, heparin became available to prevent thrombosis after heart surgery and in 1959, the first controlled trial on the prevention of VTE was published evaluating phenindione, a vitamin K antagonist (VKA), as an effective preventative agent of thrombosis. ? [11] Starting in the 1970s, clinical trials with low-dose heparin showed its efficacy at preventing DVT in surgical patients. ? [12] Low-molecular-weight heparin (LMWH) was later evaluated in 1982 due to its longer half-life, improved subcutaneous absorption, and decreased affinity for plasma proteins and platelets compared to unfractionated heparin allowing for longer injection intervals. ? [13] Once daily injection of LMWH followed by long-term VKA treatment using warfarin still remains a common modality for preventing VTE in many surgical and medical patients. ? [11], ? [14] In recent decades, direct oral anticoagulants (DOACs) have become available after extensive clinical trials for the prevention of VTE and are now recommended by the 2016 American College of Chest Physicians and the 2017 European Society of Cardiology guidelines. ? [15], ? [16] Compared to VKAs, DOACs have a rapid onset of action and more predictable pharmacokinetic profile, which make for simple drug administration without laboratory monitoring or adjustments. ? [17] DOACs were also identified to be noninferior to LMWH followed by long-term VKA treatment, and were associated with a lower risk of bleeding. ? [11], ? [15] However, DOACs are avoided in certain patients due to renal impairment, drug-drug interactions, and cost. ? [17]

Although anticoagulation is the main treatment of VTE, filter placement, thrombolytic therapy, and mechanical interventions to dissolve or remove VTE are also available and commonly used to treat submassive and massive PE. ? [15], ? [16], ? [18] The first inferior vena cava (IVC) filter was introduced in the late 1960s made to be implanted in the IVC to prevent thrombi from reaching pulmonary circulation. ? [19] Since their inception, many different types of filters have continued to be developed to reduce complications such as vena cava perforation, filter dislocation, migration, rupture, recurrent VTE, thrombophlebitis, and venous stasis disease. ? [19] In the late 1970s, streptokinase and urokinase were approved for thrombolytic therapy for acute PE. ? [20] Thrombolytic therapy involves the use of medication administered systemically or locally, sometimes using catheter-directed therapy (CDT) if systemic therapy is contraindicated due to high risk of bleeding. ? [17], ? [21] Tissue plasminogen activator (tPA), which was approved in 1987, is most commonly used today. ? [22] Historically, thrombolytic therapy was the first-line treatment for only high-risk PE but was then expanded to include treatment for some intermediate-risk PE due to improved outcomes compared to anticoagulant therapy. ? [15], ? [23] More recently, endovascular techniques have been used in conjunction with local administration of half-dose tPA using CDT to assist in dissolving the thrombus and have evolved over time. ? [21] Previously, mechanical techniques were only considered in patients who did not qualify for thrombolytic therapy; however, today these techniques are more commonly used as primary reperfusion strategies. ? [24] The simplest mechanical technique, referred to as fragmentation and published in 2000, involves using a pigtail catheter to fragment the thrombus through repetitive manual rotation of the catheter. ? [25] More advanced techniques are classified by their mechanism under rheolytic, aspiration, and rotational thrombectomy and will be described in greater detail in later chapters. ? [21]

Identifying the best therapeutic approach for a patient with VTE is important and often not clear to the practitioner despite extensive guidelines and many new therapeutic options. Understanding the patient's specific clinical circumstances and characteristics is important to identifying an appropriate treatment. For this reason, PE response teams (PERTs) have become more commonplace, bringing a multidisciplinary team together to identify the best management plan using available clinical data and local resources. ? [26] PERTs allow for the most up-to-date decision-making and have been shown to reduce in-hospital mortality and length of stay, making them an important tool in managing PE. ? [26] In this textbook, the evaluation and diagnosis of the VTE patient will be described in detail, including medical and interventional therapies currently available and those being developed.

1.1 References

[1] Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med. 2010; 38(4) Suppl: S495-S501 PubMed

[2] Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ III. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998; 158(6): 585-593 PubMed

[3] Spencer FA, Emery C, Lessard D, et al. The Worcester venous thromboembolism study: a population-based study of the clinical epidemiology of venous thromboembolism. J Gen Intern Med. 2006; 21(7): 722-727 PubMed

[4] White RH, Zhou H, Murin S, Harvey D. Effect of ethnicity and gender on the incidence of venous thromboembolism in a diverse population in California in 1996. Thromb Haemost. 2005; 93(2): 298-305 PubMed

[5] Spyropoulos AC, Lin J. Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations. J Manag Care Pharm. 2007; 13(6): 475-486 PubMed

[6]  Preventing Hospital-Associated Venous...